R a d io lo g y a n d O n c o lo g y I V o lu m e 5 5 I N u m b e r 1 I P a g e s 1 -1 2 0 I M a r c h 2 0 2 1 march 2021 vol.55 no.1 Pfizer Luxembourg SARL, GRAND DUCHY OF LUXEMBOURG, 51, Avenue J. F. Kennedy, L-1855 Pfizer, podružnica Ljubljana, Letališka cesta 29a, Ljubljana BISTVENI PODATKI IZ POVZETKA GLAVNIH ZNAČILNOSTI ZDRAVILA IBRANCE 75 mg, 100 mg, 125 mg trde kapsule(1) IBRANCE 75 mg, 100 mg, 125 mg filmsko obložene tablete(2) Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi varnosti. Zdravstvene delavce naprošamo, da poročajo o kateremkoli domnevnem neželenem učinku zdravila. Glejte poglavje 4.8 povzetka glavnih značilnosti zdravila, kako poročati o neželenih učinkih. Sestava in oblika zdravila: (1) Ena trda kapsula vsebuje 75 mg, 100 mg ali 125 mg palbocikliba in 56 mg, 74 mg ali 93 mg laktoze (v obliki monohidrata). (2) Ena filmsko obložena tableta vsebuje 75 mg, 100 mg ali 125 mg palbocikliba. Indikacije: Zdravljenje lokalno napredovalega ali metastatskega na hormonske receptorje (HR – Hormone Receptors) pozitivnega in na receptorje humanega epidermalnega rastnega faktorja 2 (HER2 – Human Epidermal growth factor Receptor 2) negativnega raka dojk: v kombinaciji z zaviralcem aromataze ali v kombinaciji s fulvestrantom pri ženskah, ki so prejele predhodno endokrino zdravljenje. Pri ženskah v pred- in perimenopavzi je treba endokrino zdravljenje kombinirati z agonistom gonadoliberina. Odmerjanje in način uporabe: Zdravljenje mora uvesti in nadzorovati zdravnik, ki ima izkušnje z uporabo zdravil za zdravljenje rakavih bolezni. Priporočeni odmerek je 125 mg enkrat na dan 21 zaporednih dni, sledi 7 dni brez zdravljenja (shema 3/1), celotni cikel traja 28 dni. Zdravljenje je treba nadaljevati, dokler ima bolnik od zdravljenja klinično korist ali dokler se ne pojavi nesprejemljiva toksičnost. Pri sočasnem dajanju s palbociklibom je treba zaviralec aromataze dajati v skladu s shemo odmerjanja, ki je navedena v Povzetku glavnih značilnosti zdravila (PGZZ). Pri sočasnem dajanju s palbociklibom je priporočeni odmerek fulvestranta 500 mg intramuskularno 1., 15. in 29. dan ter nato enkrat na mesec, glejte PGZZ za fulvestrant. Prilagajanja odmerkov: Za prilagajanja odmerkov zaradi hematološke toksičnosti glejte preglednico 2, zaradi nehematološke toksičnosti pa preglednico 3 v PGZZ-ju. Pri bolnikih s hudo intersticijsko boleznijo pljuč (ILD)/pnevmonitisom je treba zdravljenje trajno prekiniti. Posebne skupine bolnikov: Starejši: Prilagajanje odmerka ni potrebno. Okvara jeter ali ledvic: Pri bolnikih z blago ali zmerno okvaro jeter ali blago, zmerno ali hudo okvaro ledvic prilagajanje odmerka ni potrebno. Pri bolnikih s hudo okvaro jeter je priporočeni odmerek 75 mg enkrat na dan po shemi 3/1. Pediatrična populacija: Varnost in učinkovitost pri otrocih in mladostnikih, starih < 18 let, nista bili dokazani. Način uporabe: Peroralna uporaba. (1) Jemanje s hrano, priporočljivo z obrokom. (2) Tablete se lahko jemlje s hrano ali brez nje. (1, 2) Ne smemo jemati z grenivko ali grenivkinim sokom. Kapsule oz. tablete zdravila je treba pogoltniti cele. Kontraindikacije: Preobčutljivost na učinkovino ali katerokoli pomožno snov. Uporaba pripravkov s šentjanževko. Posebna opozorila in previdnostni ukrepi: Ženske v pred- in perimenopavzi: Kadar zdravilo uporabljamo v kombinaciji z zaviralcem aromataze je obvezna ovarijska ablacija ali supresija z agonistom gonadoliberina. Hematološke bolezni: Pri nevtropeniji stopnje 3 ali 4 je priporočljiva prekinitev odmerjanja, zmanjšanje odmerka ali odložitev začetka ciklov zdravljenja, bolnike pa je treba ustrezno spremljati. ILD/pnevmonitis: Pri bolnikih se lahko pojavita huda, življenjsko ogrožajoča ali smrtna ILD in/ali pnevmonitis, kadar zdravilo jemljejo v kombinaciji z endokrinim zdravljenjem. Bolnike je treba spremljati glede pljučnih simptomov, ki kažejo na ILD/pnevmonitis (npr. hipoksija, kašelj, dispneja), in pri pojavu novih ali poslabšanju respiratornih simptomov oz. sumu na ILD/pnevmonitis zdravljenje prekiniti. Okužbe: Zdravilo lahko poveča nagnjenost k okužbam, zato je bolnike treba spremljati glede znakov in simptomov okužbe ter jih ustrezno zdraviti. Okvara jeter ali ledvic: Pri bolnikih z zmerno ali hudo okvaro jeter ali ledvic je treba zdravilo uporabljati previdno in skrbno spremljati znake toksičnosti. (1) Laktoza: Vsebuje laktozo. Bolniki z redko dedno intoleranco za galaktozo, odsotnostjo encima laktaze ali malabsorpcijo glukoze-galaktoze ne smejo jemati tega zdravila. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Učinki drugih zdravil na farmakokinetiko palbocikliba: Zaviralci CYP3A: Sočasni uporabi močnih zaviralcev CYP3A, med drugim klaritromicina, indinavirja, itrakonazola, ketokonazola, lopinavirja/ritonavirja, nefazodona, nelfinavirja, posakonazola, sakvinavirja, telaprevirja, telitromicina, vorikonazola in grenivke ali grenivkinega soka, se je treba izogibati. Induktorji CYP3A: Sočasni uporabi močnih induktorjev CYP3A, med drugim karbamazepina, enzalutamida, fenitoina, rifampicina in šentjanževke, se je treba izogibati. Učinek zdravil za zmanjševanje kisline: (1) Če palbociklib zaužijemo s hrano, klinično pomembnega učinka na izpostavljenost palbociklibu ni pričakovati. (2) Klinično pomembnega učinka na izpostavljenost palbociklibu ni pričakovati. Učinki palbocikliba na farmakokinetiko drugih zdravil: Pri sočasni uporabi bo morda treba zmanjšati odmerek občutljivih substratov CYP3A z ozkim terapevtskim indeksom (npr. alfentanil, ciklosporin, dihidroergotamin, ergotamin, everolimus, fentanil, pimozid, kinidin, sirolimus in takrolimus), saj IBRANCE lahko poveča izpostavljenost tem zdravilom. Študije in vitro s prenašalci: Palbociklib lahko zavira prenos, posredovan s P-gp v prebavilih in beljakovino odpornosti pri raku dojk (BCRP). Uporaba palbocikliba z zdravili, ki so substrati P-gp (npr. digoksin, dabigatran, kolhicin) ali BCRP (npr. pravastatin, rosuvastatin, sulfasalazin) lahko poveča njihov terapevtski učinek in neželene učinke. Palbociklib lahko zavira privzemni prenašalec organskih kationov OCT1. Plodnost, nosečnost in dojenje: Med zdravljenjem in vsaj 3 tedne (ženske) oziroma 14 tednov (moški) po koncu zdravljenja je treba uporabljati ustrezne kontracepcijske metode. Zdravila ne uporabljajte pri nosečnicah in ženskah v rodni dobi, ki ne uporabljajo kontracepcije. Bolnice, ki prejemajo palbociklib, ne smejo dojiti. Zdravljenje s palbociklibom lahko ogrozi plodnost pri moških. Pred začetkom zdravljenja naj moški zato razmislijo o hrambi sperme. Vpliv na sposobnost vožnje in upravljanja s stroji: Ima blag vpliv na sposobnost vožnje in upravljanja strojev. Potrebna je previdnost. Neželeni učinki: Zelo pogosti: okužbe, nevtropenija, levkopenija, anemija, trombocitopenija, pomanjkanje teka, stomatitis, navzea, diareja, bruhanje, izpuščaj, alopecija, suha koža, utrujenost, astenija, pireksija, povečane vrednosti ALT/AST. Način in režim izdaje: Rp/Spec - Predpisovanje in izdaja zdravila je le na recept zdravnika specialista ustreznega področja medicine ali od njega pooblaščenega zdravnika. Imetnik dovoljenja za promet: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgija. Datum zadnje revizije besedila: 09.11.2020 Pred predpisovanjem se seznanite s celotnim povzetkom glavnih značilnosti zdravila. PP-IBR-EEP-0188 Datum priprave: januar 2021. Samo za strokovno javnost. HR+/HER2- = pozitiven na hormonske receptorje in negativen na receptorje humanega epidermalnega rastnega faktorja 2. Literatura: Povzetek glavnih značilnosti zdravila Ibrance, 9.11.2020. Za zdravljenje lokalno napredovalega ali metastatskega HR+/HER2- raka dojk: • v kombinaciji z zaviralcem aromataze, • v kombinaciji s fulvestrantom pri ženskah, ki so prejele predhodno endokrino zdravljenje. Pri ženskah v pred- in perimenopavzi je treba endokrino zdravljenje kombinirati z agonistom gonadoliberina (LHRH – Luteinizing Hormone–Releasing Hormone). ZAUPANJE, ZGRAJENO NA MOČI Radiol Oncol 2021; 55(1): A. March 2021 Vol. 55 No. 1 Pages 1-120 ISSN 1318-2099 UDC 616-006 CODEN: RONCEM Publisher Association of Radiology and Oncology Aims and Scope Radiology and Oncology is a multidisciplinary journal devoted to the publishing original and high quality scientific papers and review articles, pertinent to diagnostic and interventional radiology, computerized tomography, magnetic resonance, ultrasound, nuclear medicine, radiotherapy, clinical and experimental oncology, radiobiology, medical physics and radiation protection. Therefore, the scope of the journal is to cover beside radiology the diagnostic and therapeutic aspects in oncology, which distinguishes it from other journals in the field. Editor-in-Chief Gregor Serša, Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia (Subject Area: Experimental Oncology) Executive Editor Viljem Kovač, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana, Slovenia (Subject Areas: Clinical Oncology, Radiotherapy) Deputy Editors Andrej Cör, University of Primorska, Faculty of Health Science, Izola, Slovenia (Subject Areas: Clinical Oncology, Experimental Oncology) Božidar Casar, Institute of Oncology Ljubljana, Department for Dosimetry and Quality of Radiological Procedures, Ljubljana (Subject Area: Medical Physics) Maja Čemažar, Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia (Subject Area: Experimental Oncology) Igor Kocijančič, University Medical Center Ljubljana, Institute of Radiology, Ljubljana, Slovenia (Subject Areas: Radiology, Nuclear Medicine) Karmen Stanič, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana, Slovenia (Subject Areas: Radiotherapy; Clinical Oncology) Primož Strojan, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana, Slovenia (Subject Areas: Radiotherapy, Clinical Oncology) Editorial Board Subject Areas: Radiology and Nuclear Medicine Sotirios Bisdas, University College London, Department of Neuroradiology, London, UK Boris Brkljačić, University Hospital “Dubrava”, Department of Diagnostic and Interventional Radiology, Zagreb, Croatia Maria Gődény, National Institute of Oncology, Budapest, Hungary Gordana Ivanac, University Hospital Dubrava, Department of Diagnostic and Interventional Radiology, Zagreb, Croatia Luka Ležaić, University Medical Centre Ljubljana, Department for Nuclear Medicine, Ljubljana, Slovenia Katarina Šurlan Popovič, University Medical Center Ljubljana, Clinical Institute of Radiology, Ljubljana, Slovenia Jernej Vidmar, University Medical Center Ljubljana, Clinical Institute of Radiology, Ljubljana, Slovenia Subject Areas: Clinical Oncology and Radiotherapy Serena Bonin, University of Trieste, Department of Medical Sciences, Cattinara Hospital, Surgical Pathology Blg, Molecular Biology Lab, Trieste, Italy Luca Campana, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy Christian Dittrich, Kaiser Franz Josef - Spital, Vienna, Austria Blaž Grošelj, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana Luka Milas, UT M. D. Anderson Cancer Center, Houston, USA Miha Oražem, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana Gaber Plavc, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana Csaba Polgar, National Institute of Oncology, Budapest, Hungary Dirk Rades, University of Lubeck, Department of Radiation Oncology, Lubeck, Germany Luis Souhami, McGill University, Montreal, Canada Borut Štabuc, University Medical Center Ljubljana, Division of Internal Medicine, Department of Gastroenterology, Ljubljana, Slovenia Andrea Veronesi, Centro di Riferimento Oncologico- Aviano, Division of Medical Oncology, Aviano, Italy Branko Zakotnik, Institute of Oncology Ljubljana, Department of Medical Oncology, Ljubljana, Slovenia Subject Area: Experimental Oncology Metka Filipič, National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Ljubljana, Slovenia Janko Kos, University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia Tamara Lah Turnšek, National Institute of Biology, Ljubljana, Slovenia Damijan Miklavčič, University of Ljubljana, Faculty of Electrical Engineering, Ljubljana, Slovenia Ida Ira Skvortsova, EXTRO-lab, Dept. of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Tyrolean Cancer Research Institute, Innsbruck, Austria Gillian M. Tozer, University of Sheffield, Academic Unit of Surgical Oncology, Royal Hallamshire Hospital, Sheffield, UK Subject Area: Medical Physics Robert Jeraj, University of Wisconsin, Carbone Cancer Center, Madison, Wisconsin, USA Mirjana Josipovic, Rigshospitalet, Department of Oncology, Section of Radiotherapy, Copenhagen, Denmark Häkan Nyström, Skandionkliniken, Uppsala, Sweden Ervin B. Podgoršak, McGill University, Medical Physics Unit, Montreal, Canada Matthew Podgorsak, Roswell Park Cancer Institute, Departments of Biophysics and Radiation Medicine, Buffalo, NY ,USA Advisory Committee Tullio Giraldi, University of Trieste, Faculty of Medicine and Psyhology, Department of Life Sciences, Trieste, Italy Vassil Hadjidekov, Medical University, Department of Diagnostic Imaging, Sofia, Bulgaria Marko Hočevar, Institute of Oncology Ljubljana, Department of Surgical Oncology, Ljubljana, Slovenia Miklós Kásler, National Institute of Oncology, Budapest, Hungary Maja Osmak, Ruder Bošković Institute, Department of Molecular Biology, Zagreb, Croatia Radiol Oncol 2021; 55(1): B. Editorial office Radiology and Oncology Zaloška cesta 2 P. O. Box 2217 SI-1000 Ljubljana Slovenia Phone: +386 1 5879 369 Phone/Fax: +386 1 5879 434 E-mail: gsersa@onko-i.si Copyright © Radiology and Oncology. All rights reserved. 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Actual knowledge and possible biological mechanisms Mihaela Jurdana nuclear medicine 18 Clinical relevance of 18F-FDG PET/CT in the postoperative follow-up of patients with history of medullary thyroid cancer Jelena Saponjski, Djuro Macut, Dragana Sobic Saranovic, Branislava Radovic, Vera Artiko radiology 26 Radiological evaluation of ex novo high grade glioma: velocity of diametric expansion and acceleration time study Roberto Altieri, Francesco Certo, Giuseppe La Rocca, Antonio Melcarne, Diego Garbossa, Alberto Bianchi, Salvatore Crimi, Alessandro Pluchino, Simone Peschillo, Giuseppe M.V. Barbagallo 35 Tumoral volume measured preoperatively by magnetic resonance imaging is related to survival in endometrial cancer Pluvio J. Coronado, Javier de Santiago-López, Javier de Santiago-García, Ramiro Méndez, Maria Fasero, Miguel A. Herraiz clinical oncology 42 Trends in population-based cancer survival in Slovenia Vesna Zadnik, Tina Zagar, Katarina Lokar, Sonja Tomsic, Amela Duratovic Konjevic, Branko Zakotnik 50 Completely resected stage III melanoma controversy - 15 years of national tertiary centre experience Barbara Peric, Sara Milicevic, Andraz Perhavec, Marko Hocevar, Janez Zgajnar 57 Surgical resection of synchronous liver metastases in gastric cancer patients. A propensity score-matched study Tomaz Jagric, Matjaz Horvat contents contents Radiol Oncol 2021; 55(1): D. 66 Postoperative radiotherapy for patients with completely resected pathological stage IIIA-N2 non-small cell lung cancer: a preferential benefit for squamous cell carcinoma Cuimeng Tian, Guimei Liu, Yongxiang Xu, Guangrong Xia, Tongmei Zhang, Jiaqiang Huang, Hui Jiang, Ji Ming Wang, Baolan Li 77 Radiotherapy-associated angiosarcoma in the breast reconstructed by autologous free-flap and treated with electrochemotherapy Romi Cencelj-Arnez, Jerica Novak, Andreja Klevisar Ivancic, Masa Bosnjak, Maja Cemazar, Marko Snoj 82 Clinical and volumetric predictors of local control after robotic stereotactic radiosurgery for cerebral metastases: active systemic disease may affect local control in the brain Sławomir Blamek, Magdalena Stankiewicz, Bogusław Maciejewski 88 Prospective evaluation of probabilistic dose-escalated IMRT in prostate cancer Daniel Wegener, Bernhard Berger, Zhoulika Outtagarts, Daniel Zips, Frank Paulsen, Martin Bleif, Daniela Thorwarth, Markus Alber, Oliver Dohm, Arndt-Christian Müller 97 Effect of the oral intake of astaxanthin on semen parameters in patients with oligo-astheno-teratozoospermia: a randomized double-blind placebo- controlled trial Senka Imamovic Kumalic, Irma Virant Klun, Eda Vrtacnik Bokal, Bojana Pinter radiophysics 106 Semi-supervised planning method for breast electronic tissue compensation treatments based on breast radius and separation Alexander R. Podgorsak, Lalith K. Kumaraswamy 116 Efficacy of breast shielding during head computed tomography examination Nika Zalokar, Nejc Mekis I slovenian abstracts contents Radiol Oncol 2021; 55(1): 1-6. doi: 10.2478/raon-2020-0068 1 review Artificial intelligence in musculoskeletal oncological radiology Matjaz Vogrin1,2, Teodor Trojner1, Robi Kelc1,2 1 Department of Orthopaedic Surgery, University Medical Center Maribor, Slovenia 2 Faculty of Medicine, University of Maribor, Slovenia Radiol Oncol 2021; 55(1): 1-6. Received 1 June 2020 Accepted 29 September 2020 Correspondence to: Assist. Prof. Robi Kelc, M.D., Ph.D., Department of Orthopaedic Surgery, University Medical Centre Maribor, Ljubljanska ulica 5; SI-2000 Maribor. E-mail: robi.kelc @gmail.com Disclosure: No potential conflicts of interest were disclosed. Background. Due to the rarity of primary bone tumors, precise radiologic diagnosis often requires an experienced musculoskeletal radiologist. In order to make the diagnosis more precise and to prevent the overlooking of potentially dangerous conditions, artificial intelligence has been continuously incorporated into medical practice in recent dec- ades. This paper reviews some of the most promising systems developed, including those for diagnosis of primary and secondary bone tumors, breast, lung and colon neoplasms. Conclusions. Although there is still a shortage of long-term studies confirming its benefits, there is probably a consid- erable potential for further development of computer-based expert systems aiming at a more efficient diagnosis of bone and soft tissue tumors. Key words: artificial intelligence; deep learning; tumor recognition; cancer imaging; image segmentation Introduction Primary bone and soft tissue neoplasms present a minority among neoplastic lesions. Due to their rarity, precise radiologic diagnosis often requires an experienced radiologist with special interests in musculoskeletal oncology. To surmount the chal- lenge of making precise diagnoses, and more im- portantly, to prevent overlooking potentially fatal conditions, attempts to incorporate artificial intelli- gence and its related techniques into medical prac- tice have occurred in the last decades (Figure 1). Being first introduced by McCarthy in the 1950s, artificial intelligence (AI) is a general term that describes computer machines that imitate hu- man intelligence.1 Machine learning, a subset of AI, uses computational algorithms, which learn with experience and therefore improve the per- formance of tasks.2 The rapid progress of compu- tational power and big data availability allowed the emergence of an even more specialized sub- field of machine learning, called deep learning. It is a promising method capable of processing raw data to perform detection or classification tasks.3 Deep learning algorithms, implemented as arti- ficial neural networks, mimic biological nervous systems.4 The network is organized in layers com- posed of interconnected nodes imitating archi- tecture in a biologic brain.2,5 Nodes are weighted individually for the purpose of increasing data extraction. In order to classify data, weights are automatically and dynamically optimized during the training phase.5,6 Regarding the layers, three different kinds are present in each neural network. It begins with an input layer, which receives input data, followed by numerous hidden layers extract- ing the pattern within the data. It terminates with the output layer, which produces results or output data (Figure 2).5 Among the different types of artificial neural networks, convolutional neural networks, in par- ticular, gained attention in radiology due to their high performance in recognizing images.7 By cal- culating the intensity of each pixel or voxel, to- gether with evaluating complex patterns in each image, they provide reliable quantitative image Radiol Oncol 2021; 55(1): 1-6. Kelc R et al. / Artificial intelligence in musculoskeletal oncological radiology2 interpretations, eventually surpassing human per- formance.8 However, to build an intelligent machine a train- ing phase is required, which requires sufficient computational power and large datasets. The latter is obtained from radiological images, which is in the domain of radiomics. Radiomics is a process of quantitative extraction of a high number of seman- tic and agnostic features from diagnostic images.9 Its approaches, like feature extraction and feature engineering techniques, are essential in the forma- tion of AI applications.10 Artificial intelligence in cancer imaging (oncologic radiology) Until recently, radiologists’ decisions were based predominantly on his or her experience of recog- nizing patterns and appreciating various features of each tumor including size, location, intensity, and surface characteristics, all combined with pa- tients’ demographic data. However, after many consecutive image interpretations, they were con- sciously or subconsciously faced with fatigue11, which could lead to errors and potentially jeopard- ize patients’ health and own credibility.12 AI’s potentials are developing exponentially. Instead of qualitative and subjective image inter- pretations, it allows quantifiable and objective data extraction with the ability to reproduce the same results.13 Furthermore, by quantifying information otherwise not detectable to humans, AI may com- plement clinical decision-making.5,13 Computer-aided detection (CADe) and comput- er-aided diagnosis (CADx) algorithms have been used for the last two decades14 predominantly in mammography15, detection of lung16, and colon17 malignancies. In contrast to CAD algorithms, which only highlight the features they have been exactly trained for, actual AI systems continue to learn and improve in time. By focusing on the spe- cific diagnosis, systems learn to discover new typi- cal patterns that have not been linked with the dis- ease before.18 For example, Beck et al. developed a machine learning-based computer program named “Computational Pathologist (C-Path)” to automat- ically analyze breast cancer and predict its prog- nosis.19 Importantly, regardless of all well-known histological characteristics that were implemented into the program, C-Path recognized surrounding stroma as another important prognostic factor.19 Convolutional neural networks have also given optimistic results in automated detection.6 It has been used for automated detection of liver tumors on CT scans with high detection accuracy and pre- cision of 93% and 67%, respectively.20 Similarly, a deep learning-based CADe for detection of brain metastasis on magnetic resonance imaging (MRI) has been developed and achieved a sensitivity of 96% and reasonable specificity.21 In general, characterization is composed of segmentation, diagnosis, and staging of tumors.13 Image segmentation is the process used in cancer imaging to outline pathological area and distin- guish it from non-pathological adjacent tissue. It can range from planar measurements to advanced 3-dimensional assessment of tumor volume.13 Tumors have traditionally been manually labelled by radiologists, which is indeed time-consuming, as well as a subject of interobserver variability.13,22 Thus, implementation of AI into automated image segmentation could potentially take over, increase the quality and reproducibility of measurements, and also save time.5,13 For example, machine learn- ing has been used for breast density segmentation on mammography, which turns out to be as ac- curate as manual ones.23 Ye et al. successfully pro- posed and verified a fully automatic nasopharyn- geal carcinoma segmentation method based on dual-sequence MRI and convolutional neural net- work.24 The mean dice similarity coefficient (DSC) of the models with only T1 sequence, only T2 se- quence, and dual sequence were 0.620 ± 0.0642, FIGURE 1. Schematic illustration of the hierarchy of artificial intelligence and its machine learning and deep learning subfields. Radiol Oncol 2021; 55(1): 1-6. Kelc R et al. / Artificial intelligence in musculoskeletal oncological radiology 3 0.642 ± 0.118, and 0.721 ± 0.036, respectively. The combination of different features acquired from T1 and T2 sequences significantly improved the seg- mentation accuracy.24 Ability to quantitatively extract tumor features has great potential in the process of making diag- nosis. With machine learning, Liu et al. quantita- tively represented radiological traits characteris- tics of lung nodules and showed improved accu- racy of cancer diagnosis in pulmonary nodules.25 Convolutional neural network has also shown to be an effective and objective method that provides an accurate diagnosis of pancreatic cancer.26 Another important aspect of tumor characteri- zation includes staging. Mainly, TNM classifica- tion is used to assess the extent of primary tumor, lymph nodes, and metastases and therefore classi- fy the lesion in a specific stage. However, attempts to extend the TNM cancer staging system have been made. For instance, CAD has shown to be a promising method of evaluation of tumor extent and multifocality in invasive breast cancer patients and therefore expanding the staging algorithms.27 In tumor response monitoring, many AI ap- proaches have shown some potential. For example, AI and machine learning have been successfully implemented into the pre-procedural prediction of trans-arterial chemoembolization treatment outcomes in patients with hepatocellular carci- noma using clinical and imaging features.28 Ha et al. demonstrated promising results in the utiliza- tion of convolutional neural network to predict neoadjuvant chemotherapy response prior to the first cycle of therapy in breast carcinoma using baseline MRI tumor datasets.29 Positive response to chemotherapy led to decreased tumor metabolism, opening a potential opportunity to detect lower ac- cumulation rates of a radiotracer.30 Differentiating between responders and non-responders based on low-dose 18F-FDG PET/MRI scans might, therefore, be another opportunity of the implementation of convolutional neural networks.6 Complementary to radiologic diagnosis, ad- ditional advanced methods have been proposed, promising even further advances in cancer man- agement. Liquid biopsy based on circular tumor DNA (ctDNA) analysis may importantly improve early tumor detection, diagnosis, monitoring ther- apy, and progression in time.31 Contrary to stand- ard tissue biopsies, liquid biopsies taken from blood may provide us with detailed biochemical characteristics of the neoplastic lesion and detect potential metastasis.32 What is more, a combina- tion of liquid biopsies and radiomics, supervised by deep learning may significantly improve cancer management in the future. FIGURE 2. Schematic presentation of a neural network. Regions of interests (ROI) are defined, either by user or by an automated computer process. These present the input cells (in pink) a neural network. For each ROI the neural network extracts and compute features within the hidden layers (in grey) by using pre-trained data sets. Finally, the output cell offers the final results in different possible forms (yes/no, final diagnosis, probability of malignancy etc.). Radiol Oncol 2021; 55(1): 1-6. Kelc R et al. / Artificial intelligence in musculoskeletal oncological radiology4 Artificial intelligence in skeletal tumors The first attempts to introduce computational power into diagnostic procedures of primary bone tumors date back to the 1960s.33 Based on Bayes’ formula, a computer program accurately predicted a bone tumor diagnosis in 77.9% of cases. Later in 1980, the same author set a milestone by publish- ing an article about computed-based radiographic grading of bone tumor destruction.34 This was a cornerstone for further research and implementa- tion of neural networks into the diagnosis of focal bone lesions.35,36 A scarce number of articles regarding AI and primary bone tumors have been published so far, while considerably more has been done on the de- tection and segmentation of bone metastasis. For example, Burns et al. successfully identified and segmented sclerotic lesions in the thoracolumbar spine using CADe techniques. The sensitivity for lesions detection was 79%.37 What is more, Wang et al. developed a Siamese convolutional neural network to research the potential of automated spinal metastasis detection in MRI. The proposed approach accurately detected all spinal metastatic lesions with a false-positive rate of 0.4 per case.38 Another research proposed a machine learning- based whole-body automatic disease classification tool to distinguish benign processes and malignant bone lesions in 18F-NaF PET/CT images.39 Healthy and tumorous bone differs in numer- ous characteristics. Unlike healthy osseous tissue, which consists of cortical and trabecular part, pri- mary bone malignancies may penetrate cortex and spread into adjacent soft tissue, as well as cause swelling around the bone or even weaken the bone architecture and lead to pathological fracture.40 Radiologically, they differ in absorption rate, which can be quantitatively evaluated. For exam- ple, CADx has been used to detect and classify pri- mary bone tumors into benign and malignant le- sions using x-ray images. In their study, Ping et al. an overall greater intensity of pixels for malignant bone tumors compared to benign bone tumors.41 Another study by Bandyopadhyay et al. proposed a CADx method to automatically analyze bone x- ray images. By integrating several classifiers, the method achieved accurate decisions regarding a bone-destruction pattern, stage, and grade of can- cer in 85% of cases.42 When describing sarcomas, diagnosed on MRI, features like tumor size, shape, and enhancement pattern are estimated and taken into consideration along with patient’s demographic data.2 Machine learning and artificial neural network excel in quantifying and extracting supplementary fea- tures, which can correlate with clinical character- istics, diagnosis, and outcomes. Most of these are out of human visual perception and include inter- voxel relationships, image intensity analysis, and filtered images analysis.43 Deep learning-based algorithm has also been developed to predict sur- vival rates in patients with synovial sarcoma.44 Its prediction was more precise compared to the Cox proportional hazard model, which is a commonly used regression model in medical research. In primary bone tumors, bone tumor matrix, its density, and zone of transition represent suit- able characteristics than may be classified through deep learning techniques. In fact, recurrent con- volutional neural network outshined experienced musculoskeletal radiologists in bone tumor matrix classification with 86% vs. 72%, respectively.45 Li et al. proposed a super label guided convolutional neural network to classify CT images of bone tu- mors.46 In comparison, results exceeded the classic convolutional neural network. However, the classi- fication included only nine types of the most com- mon skeletal tumors. Limitations and future directions There are indeed some limitations of AI. First, it could potentially still be a subject of interobserv- er variability, due to different algorithms used in a neural networks of different AI systems or un- equal learning stages in which the systems pro- cess a specific task. Standardization is mandatory to establish a large database. Data also needs to be accessible in order to integrate them into large sets. Prior to that quality check, labelling, classifi- cation, and segmentation need to be done manu- ally by experts, making the process expensive and time-consuming.13 However, introducing deep learning-based techniques to the extensive quality ground-truth training datasets is essential for the development of accurate algorithms.47,48 Also, ethi- cal dilemmas should be taken into consideration. When dealing with systems that operate with enor- mous amounts of data, patients’ privacy as well as human dignity may be jeopardized, unless meticu- lous safety mechanisms are implemented. There are also no long-term follow-up studies available thus far. On the contrary, the appreciating results Radiol Oncol 2021; 55(1): 1-6. Kelc R et al. / Artificial intelligence in musculoskeletal oncological radiology 5 of the already published studies and the presenta- tion of a commercially available application is only a matter of time. Undoubtedly, all kinds of artificial intelligence are persistently being integrated into the com- plex management of musculoskeletal tumors and tumors of other sites. Deep learning-based tech- niques are expected to minimalize false positive rates as well as assure accurate decisions and di- agnoses.49 Further automatization of radiological tasks is expected to take place in the future. Among physicians, radiologists in particular are required to perform many time-consuming tasks, like im- age segmentation, delineation of regions of inter- est, and image annotation. AI techniques have an enormous potential to transform their workflow, which will allow them to focus on more meaning- ful tasks.11 On the other hand, “imaging is not an isolated measure of disease.”13 Neoplastic lesions are com- plex conditions, following DNA mutations that cause abnormal cellular proliferation.50 Despite many mutations being discovered and related to specific malignancies, intertumoural and in- tratumoural heterogeneity exist.51 Undoubtedly, molecular approaches, like genetic biomarkers and molecular imaging have already significantly contributed to a better understanding of cancer management. Finally, combining radiomics with other aspects of a broad family of “-omics”, includ- ing genomics, proteomics, and metabolomics, and therefore drastically expanding datasets available for advanced AI modalities, might move us closer to the precision medicine.52 References 1. Han X-G, Tian W. Artificial intelligence in orthopedic surgery: current state and future perspective. Chin Med J (Engl) 2019; 132: 2521-3. doi: 10.1097/ CM9.0000000000000479 2. Gyftopoulos S, Lin D, Knoll F, Doshi AM, Rodrigues TC, Recht MP. Artificial intelligence in musculoskeletal imaging: current status and future direc- tions. AJR Am J Roentgenol 2019; 213: 506-13. doi: 10.2214/AJR.19.21117 3. LeCun Y, Bengio Y, Hinton G. Deep learning. Nature 2015; 521: 436-44. doi: 10.1038/nature14539 4. King BF. Guest editorial: discovery and artificial intelligence. ARJ Am J Roentgenol 2017; 209: 1189-90. doi: 10.2214/AJR.17.19178 5. Pesapane F, Codari M, Sardanelli F. 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Predicting treatment response to intra-arterial therapies of hepatocel- lular carcinoma using supervised machine learning - an artificial intel- ligence concept. J Vasc Interv Radiol 2018; 29: 850-57.e1. doi: 10.1016/j. jvir.2018.01.769 29. Ha R, Chin C, Karcich J, Liu MZ, Chang P, Mutasa S, et al. Prior to initiation of chemotherapy, can we predict breast tumor response? Deep learning convolutional neural networks approach using a breast MRI tumor dataset. J Digit Imaging 2019; 32: 693-701. doi: 10.1007/s10278-018-0144-1 30. Kleis M, Daldrup-Link H, Matthay K, Goldsby R, Lu Y, Schuster T, et al. Diagnostic value of PET/CT for the staging and restaging of pediatric tumors. Eur J Nucl Med Mol Imaging 2009; 36: 23-36. doi: 10.1007/s00259-008- 0911-1 31. Cheng F, Su L, Qian C. Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer. Oncotarget 2016; 7: 48832-41. doi: 10.18632/ oncotarget.9453 32. Mader S, Pantel K. 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Berlin, Heidelberg: Springer; 2008. p. 544-7. doi: 10.1007/978-3-540-69139-6_136 42. Bandyopadhyay O, Biswas A, Bhattacharya BB. Bone-cancer assessment and destruction pattern analysis in long-bone x-ray image. J Digit Imaging 2019; 32: 300-13. doi: 10.1007/s10278-018-0145-0 43. McBee MP, Awan OA, Colucci AT, Ghobadi CW, Kadom N, Kansagra AP, et al. Deep learning in radiology. Acad Radiol 2018; 25: 1472-80. doi: 10.1016/j. acra.2018.02.018 44. Han I, Kim JH, Park H, Kim H-S, Seo SW. Deep learning approach for sur- vival prediction for patients with synovial sarcoma. Tumour Biol 2018; 40: 1010428318799264. doi: 10.1177/1010428318799264 45. Reicher JJ, Palo Alto VA, Do BH, Nguyen M, Beaulieu CF. Single-input bone tumor diagnosis based on convolutional neural network classification of bone tumor matrix. SIIM 2018 Annual Meeting, May 31-June 2, National Harbor, MD, 2018. 46. Li Y, Zhou W, Lv G, Luo G, Zhu Y, Liu J. Classification of bone tumor on CT im- ages using deep convolutional neural network. In: Kůrková V, Manolopoulos Y, Hammer B, Iliadis L, Maglogiannis I, editors. Lecture notes in computer science. Artificial neural networks and machine learning - ICANN 2018. Cham: Springer International Publishing; 2018. p. 127-36. doi: 10.1007/978- 3-030-01421-6_13 47. Choy G, Khalilzadeh O, Michalski M, Do S, Samir AE, Pianykh OS, et al. Current applications and future impact of machine learning in radiology. Radiology 2018; 288: 318-28. doi: 10.1148/radiol.2018171820 48. Gorelik N, Chong J, Lin DJ. Pattern recognition in musculoskeletal imaging using artificial intelligence. Semin Musculoskelet Radiol 2020; 24: 38-49. doi: 10.1055/s-0039-3400266 49. Burns JE, Yao J, Summers RM. Artificial intelligence in musculoskeletal imaging: a paradigm shift. J Bone Miner Res 2020; 35: 28-35. doi: 10.1002/ jbmr.3849 50. Jokar N, Velez E, Shooli H, Dadgar H, Sadathosseini S, Assadi M, et al. Advanced modalities of molecular imaging in precision medicine for mus- culoskeletal malignancies. World J Nucl Med 2019; 18: 345. doi: 10.4103/ wjnm.WJNM_119_18 51. Hinohara K, Polyak K. Intratumoral heterogeneity: more than just muta- tions. Trends Cell Biol 2019; 29: 569-79. doi: 10.1016/j.tcb.2019.03.003 52. Acharya UR, Hagiwara Y, Sudarshan VK, Chan WY, Ng KH. Towards precision medicine: from quantitative imaging to radiomics. J Zhejiang Univ Sci B 2018; 19: 6-24. doi: 10.1631/jzus.B1700260 Radiol Oncol 2021; 55(1): 7-17. doi: 10.2478/raon-2020-0063 7 review Physical activity and cancer risk. Actual knowledge and possible biological mechanisms Mihaela Jurdana Faculty of Health Sciences, University of Primorska, Izola, Slovenia Radiol Oncol 2021; 55(1): 7-17. Received 11 July 2020 Accepted 25 September 2020 Correspondence to: Mihaela Jurdana, Ph.D., Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenija. Phone: +386 5 662 64 69; Fax.: +386 5 662 64 80 Disclosure: No potential conflicts of interest were disclosed. Background. Scientific evidence has shown that an increase in regular physical activity is associated with a de- crease in the development of many types of cancer. Potential mechanisms that link physical activity to reduced cancer risk include a decrease in systemic inflammation, hyperinsulinemia, insulin-like growth factor (IGF-I), sex hor- mones, pro-inflammatory leptin and other obesity-related cytokines, and a significant increase in anti-inflammatory adiponectin levels. In addition, physical activity improves immune function and the composition and diversity of the gastrointestinal microbiota. Moderate physical activity is important for cancer protection, but the most significant changes in the inflammatory profile are conferred by physical activity performed at higher intensities. Thus, there is a need for further investigation into the type, intensity, and duration of physical activity for the prevention of some types of cancer and the development of effective recommendations. Conclusions. There is a strong evidence that physical activity of moderate to vigorous intensity protects against colon and breast cancer, and probably against cancer at all other sites. Key words: physical activity; cancer; pro-inflammatory and anti-inflammatory cytokines; biological mechanisms Introduction The International Agency for Research on Cancer (IARC) reports that 25% of all cancer cases world- wide are caused by obesity and sedentary life- style.1 The idea of physical activity as a means for preventing cancer was explored in the early 20th century when two studies were published, sug- gesting that cancer mortality rates among men with different occupations decreased with in- creased physical activity.2,3 To date, the evidence of “skeletal muscle contraction effect” has been growing rapidly and many epidemiological stud- ies on the role of physical activity in cancer pre- vention have been published. There is substantial evidence that greater physical activity levels lower the risk of some cancers.4 Recently gathered data has revealed that physical activity is associated with various site-specific cancers in many ways. In addition, preclinical studies have indicated that physical activity may similarly reduce cancer pro- gression, its recurrence and have an impact on bet- ter survival rates.5 Furthermore, physical activity could decrease breast and colon cancer incidence with a linear dose response relationship indicating that engaging in longer exercise sessions or exer- cising with higher intensity will result in a greater reduction in cancer risk.4,6 New evidence suggests that a comparable association might exist for other cancers, but for a complete evaluation, physical activity type, frequency and intensity need to be assessed.7 The World Cancer Research Fund’s first report indicated a strong positive impact of physi- cal activity in relation to colorectal and breast can- cer.8,9 Furthermore, cancer risk varies within popu- lation subgroups such as a gender, age, race, body mass index, and physical fitness level. The effects of physical activity on the cancer outcome are as- sociated with these parameters. 6 The recent data of a multi-ethnic cohort study confirm the association Radiol Oncol 2021; 55(1): 7-17. Jurdana M / Physical activity and cancer8 between physical activity and colon cancer risk, and suggest possible differences in the strength of the association according to race and ethnicity.10 Several acceptable biological mechanisms link physical activity with cancer, including changes in sex hormones and other metabolic hormones, de- crease in body fat mass and central adiposity, an increase in anti-inflammatory myokines exerting anti-inflammatory responses, and recently demon- strated changes in microbiota composition. This review provides data from epidemiological studies on physical activity and cancer, and biolog- ical mechanisms to explain the association between physical activity and cancer. Physical activity recommendations Significant decreases in cancer incidence have been demonstrated among those who take into ac- count the physical activity recommendations.11 The American Cancer Society (ACS), the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and the World Health Organization (WHO) have published recommen- dations considered to reduce the risk of various diseases including cancer.12 In summary, the rec- ommendations for adults of 150 minutes (2.5h) to 300 minutes (5h) of moderate physical activity, or at least 75 minutes (1.25 hours) to 150 minutes (2.5h) of vigorous physical activity per week, can reduce cancer risk. For additional health benefits, muscle-strengthening activities involving major muscle groups should be conducted on two or more days a week. 12,13 To express the intensity level of physical ac- tivity, the rate of energy expenditure expressed as metabolic equivalents (METs) are commonly used.13 One MET is the rate of energy expenditure while sitting at rest, which for most people ap- proximates an oxygen uptake of 3.5 millilitres per kilogram of body weight per minute. The energy expenditure of other activities is expressed in mul- tiples of METs. A 3 MET activity expends 3 times the energy used at rest. The MET model is used in epidemiological studies and provides general medical thresholds and guidelines for a popula- tion.4 Based on the MET hours/week (MET h/w) mod- el, physical activity can be classified as occupation- al physical activity (OPA) or leisure time physical activity (LTPA). OPA is low for sitting work, mod- erate for standing and walking work and high for manual work. LTPA is low for activities < 3MET, moderate for activities approximately 3–6 MET and vigorous or high intensity for activities > 6 MET.13 (Figure 1). A recent study by Matthews et al., provides strong evidence that current recom- mendation levels of LTPA, both moderate to vig- orous (7.5–15 MET h/w or 150–300 minutes/week) provide cancer (colon, breast, endometrial, kidney, myeloma, liver, non-Hodgkin lymphoma) protec- tion in a dose dependent manner.4 Minor incidence of some cancer types seems to be correlated with vigorous LTPA. 4 Actual knowledge on the association between physical activity and cancer Several studies have been performed to assess the effect of LTPA in lowering cancer risk. There is con- vincing evidence of the beneficial effect of physical activity on the risk of colon and breast cancer and probable evidence for other cancers.4,6,7 Original scientific articles and systematic reviews (based largely on epidemiological studies consisting of large cohorts and case controls) have demonstrat- METs = metabolic equivalents FIGURE 1. Levels of physical activity intensity (sedentary behaviour, low, moderate and vigorous or high). Radiol Oncol 2021; 55(1): 7-17. Jurdana M / Physical activity and cancer 9 ed a dose–response relationship between physical activity and cancer risk.4,14 Breast cancer In 1980 it was hypothesized that physical activity protects against breast cancer and many studies have confirmed this association risk.15 Physical activity is associated with a reduced risk of breast cancer incidence and better survival rates among women with breast cancer diagnosis.16 Physically active women had up to 20% lower risk incidence of breast cancer in comparison to inactive women, providing evidence that physical activity influences sex hormones, insulin resistance, and in- flammatory adipokines.17,18 Another early case con- trol study demonstrated a clear reduction of breast cancer in younger women during the reproductive period, who engaged in the recommended level of physical activity (3–6 MET h/w).19 Similarly, obser- vational evidence suggests that regular physical activity reduces the risk of breast cancer incidence and mortality among obese menopausal and post- menopausal women.20-23 The Nurses’ Health Study collected information over 29 years and reported that moderate or vigor- ous physical activity for 7 or more hours per week (> 6 MET h/w) compared to those who reported less than 1 hour per week (< 3 MET h/w) resulted in a 20 % reduction in developing breast cancer. The association was similar in both premenopausal and postmenopausal women.24,25 Campbell et al. state that regular exercise in as- sociation with weight reduction decreases the lev- els of sex hormones, as well as reducing breast can- cer risk.26 In this study, more than 400 overweight to obese sedentary women, aged 50–75 years, were assigned to one of the following groups: a) moder- ate to vigorous intensity aerobic exercise only, b) diet only, c) moderate to vigorous intensity aerobic exercise and diet, and d) control. They found that physical activity among postmenopausal women might lower breast cancer risk by reducing fat mass, alongside a significantly greater decrease of estrogen and significantly increased sex hormone– binding globulin (SHBG)27 which regulates the availability of free estrogen to hormone sensitive tissue by binding biologically active estrogen. Taken together, these findings suggest that weight loss is the key factor linking alterations in diet or exercise to sex hormone changes. In the study conducted by Niehoff et al. 2019 the associa- tion between physical activity and breast cancer risk was examined in a large population of women with a family history of breast cancer. This demon- strated that physical activity was associated with reduced postmenopausal, but not premenopausal, breast cancer risk.28 The diversity of available data of physical activity and cancer association is due to population heterogeneity and the influence of breast cancer modifiable and non-modifiable fac- tors, such as genetics, early age menarche, nul- liparity, older age at first childbirth and breast- feeding.29 Although there is a proven link between physical activity and breast cancer, the type and dose of physical activity may have a varied effect. Physical activity can reduce the risk of breast can- cer in women who engaged with moderate inten- sity levels. In addition, a greater decreased risk was found for vigorous intensity levels of physical ac- tivity with a stronger association in postmenopau- sal women.4 Risk reduction was observed among women who participated in physical activity dur- ing all periods in their lives. Colon and rectal cancer To date, the most definitive epidemiological stud- ies have provided consistent evidence that physi- cal activity is associated with a lower risk of colon cancer.8,30,31 A meta-analysis of numerous prospective stud- ies, examining the association between physical activity of various intensity levels and the risk of developing colon and rectal cancer have been evaluated, showing that increased levels of physi- cal activity considerably decreases the colon and rectal cancer risk.32 Moreover, others reported that higher levels of physical activity in colon cancer survivors have a minor possibility of cancer recur- rence and improved survival compared to inactive survivors.33 Risk reduction for colon cancer in physically ac- tive individuals was greater in case control stud- ies (24%) in comparison with cohort studies (17%). Similar results were found for OPA (22%) and LTPA (23%).34 The association between colon cancer and physical activity in case control studies showed an equally significant risk reduction for men and women (24%) while in cohort studies this asso- ciation was greater for men than for women.4,35,36 The effects of physical activity on colon and rectal cancer may be influenced by different parameters; physical activity type, intensity, frequency and du- ration, as well as vary by sex and race/ethnicity.37 The large multiethnic cohort study conducted by Park et al., demonstrated an inverse association be- Radiol Oncol 2021; 55(1): 7-17. Jurdana M / Physical activity and cancer10 tween moderate/vigorous activity and colorectal cancer risk, which appears to be stronger in men, especially among men with longer sitting time.10 A possible explanation of the diverse benefits be- tween the sexes may reflect hormonal differences.10 The case–control study of Boyle considered 870 colorectal cancers cases (proximal colon, dis- tal colon and rectal), compared 996 age and sex matched healthy controls, and analysed the tim- ing and intensity of physical activity on sub site specific colorectal cancer risk, showing a strong reduction of distal colon cancer risk.38 Authors of this study demonstrated that physical activity with more than 6 MET h/w was associated with a lower distal colon cancer risk by about 40%, while an in- crease of physical activity to 18 MET h/w further increased the percentage of cancer risk reduction. An association between physical activity and rec- tal cancer in participants exercising 6 MET h/w or more was also observed. In general, the overall da- ta show no association between the total physical activity level and recreational physical activity and rectal cancer. Recently, it was found that LTPA was associated with a lower risk of both, colon and rec- tal cancer.22 A health initiative observational study found an inverse association between leisure time physical activity and rectal cancer, particularly, in postmenopausal women.39 Another case control study revealed that partici- pants who spent more than ten years in sedentary work presented a greater risk of distal colon can- cer and rectal cancer compared to those who never held sedentary work.40 However, the risk was sig- nificantly reduced in participants who performed jobs requiring heavy activity.40 The health benefits of moderate to vigorous physical activity have been recently proposed to prevent colorectal cancer among people with long- er sitting times.10 In addition, others confirm the protective role of moderate physical activity with the risk of the polyp’s development and adeno- mas.41 Other cancer sites Many studies reported on the association be- tween physical activity and lower risk of several other site-specific types of cancer.9,42 Evidence is less consistent than for breast and colorectal can- cer and can be classified as probable or possible. Regardless, patient data from nine cohort studies (US, European and Australian cohorts) including adult engagement in the recommended amounts of LTPA (moderate to intense activity) demonstrate, in addition to colon and breast cancer, also lower risk levels for endometrial and kidney cancer, liver cancer, lung, gastric and non-Hodgkin lymphoma (women only).4,42 Endometrial cancer Previous meta-analysis studies of endometrial can- cers found evidence of a decreased risk in mod- erately to vigorously physically active women.43 Many other studies investigated the influence of physical activity and body mass, since obesity is a strong risk factor for endometrial cancer as it is related to physical inactivity.44 Bladder cancer The meta-analysis of many cohort studies and several case-control studies reported lower rates of bladder cancer for individuals with the highest level of recreational or OPA than those who were the least physically active.45 The LTPA of over one million individuals was associated with a reduced risk of bladder and kidney cancer.22 Lung cancer Lung cancer has been less well studied than the cancers described above, but some epidemiologi- cal studies have revealed an association between physical activity and reduced cancer risk among former and current smokers.46 Prostate cancer Evidence suggesting that physical activity can reduce prostate cancer risk is on the increase. Although rigorous physical activity may be need- ed to influence hormone levels involved in the eti- ology of this cancer.47 The data for several other cancers are limited and further research is needed in order to strength- en the hypothesis that physical activity reduces the development of cancer.22 Preliminary evidence suggests that higher levels of physical activity may influence cancer risk at several of these sites.22 Potential biological mechanisms in the relation between physical activity and cancer risk The most commonly hypothesized mechanisms proposed for physical activity and reduced cancer Radiol Oncol 2021; 55(1): 7-17. Jurdana M / Physical activity and cancer 11 risk are presented below. Moreover, the associa- tion between physical activity and gut microbiota composition in relation to cancer is described. The effects of physical activity on cancer prevention are summarized in Figure 2. Anti-inflammatory action of muscle derived myokines Skeletal muscle plays an important role in coun- teracting pro-inflammatory effects. During the past decade, it was identified as a secretory or- gan.48 Cytokines or other peptides that are pro- duced, expressed and released by skeletal muscle and exert autocrine, paracrine or endocrine effects should be classified as ‘myokines’. It has been sug- gested that myokines may contribute to exercise- induced protection against several chronic dis- eases.48 Inflammation is a normal component of host defence; however, chronic low-grade inflam- mation is a key contributor in a range of chronic diseases and plays a critical role in cancer devel- opment and is crucial for the sustenance of the processes of tumorigenesis.49 Interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) are inflammatory cytokines that have been measured in relation to cancer.49 Increased levels of pro-inflammatory cytokines and a decrease in anti-inflammatory cytokines have been linked to increased cancer risk and a permanent presence of inflammatory cytokines also maintains an en- vironment in which cancer cells can proliferate.49 Evidence suggests that regularly performed LTPA, moderate to vigorous may reduce markers of sys- temic inflammation.50 However, there is a sub- stantial body of evidence that high-intensity or prolonged endurance training leads to increased oxidative stress that may result in a pro-inflamma- tory response from the immune system to protect the host tissue.51 In addition, an increase in the expression of pro-inflammatory cytokines can be crucial for long-term adaptive responses to exer- cise training.52 Although high-intensity endurance training can increase antioxidant enzyme activity and reduce markers of training-induced oxida- tive stress, very high training loads of elite and non-elite athletes participating in ultra-endurance competitions are associated with an acute reduc- tion in antioxidant capacity and an increase in markers of oxidative stress.53 SHBG = sex hormone–binding globulin FIGURE 2. The effects of physical activity on cancer prevention. Moderate to vigorous physical activity improves immune function, total antioxidant capacity, increases SHBG production and anti-inflammatory plasma adiponectin and improves gut microbiota composition. In addition, moderate to vigorous physical activity decreases systemic inflammation, oxidative stress, reduces adipose tissue and hyperinsulinemia, decreases inflammatory hormone leptin and regulates sex hormone levels. Radiol Oncol 2021; 55(1): 7-17. Jurdana M / Physical activity and cancer12 Skeletal muscle is an important source of anti- inflammatory myokines, including muscle derived interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 15 (IL-15), and interleukin 1 receptor antagonist (IL-1ra), which act as antagonists to the generally pro-inflammatory cytokines.54 The pro-inflammatory TNF-α plays an impor- tant role in cancer promotion.55 TNF-α was origi- nally identified as a factor that caused tumor ne- crosis in high concentrations; its activity at moder- ate levels can promote tumor growth. One of the key functions for TNF-α is to activate the pro-in- flammatory transcription factor (NFκB), involved in cancer pathogenesis.56 Interestingly, IL-6 produced by monocytes or macrophages acts as a pro-inflammatory response, whereas skeletal muscle derived IL-6 acts as an anti-inflammatory response by reducing TNF-α concentration or NFκB activation.57 It turns out that regenerative or anti-inflam- matory activities of interleukin-6 are mediated by classic signalling, whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans signaling.58 In classic signaling, interleukin-6 stimulates target cells via a membrane bound in- terleukin-6 receptor (IL-6R), which upon ligand binding associates with the signalling receptor pro- tein gp130 and trigger the activation of the JAK/ STAT signalling pathway. In cells that express only gp130 but not IL-6R, IL-6 binds to the soluble IL-6R (sIL-6R) and the complex in turn binds to gp130 to trigger activation of intracellular signalling, known as trans signaling.58 Skeletal muscle IL-6 was the first identified myokine and, to date, the most studied myokine which is produced and released by contracting skeletal muscle fibres, exerting extensive anti- inflammatory effects in other organs via an in- flammatory (TNF-α) independent pathway.59 IL-6 was discovered as a myokine because of the ob- servation that IL-6 increases up to 100-fold in the circulation during and after physical activity.59 Therefore, the exercise release of IL-6 induces an increase in anti-inflammatory IL-1ra and IL-10. In most exercise-related studies, TNF-α does not change and is likely to be suppressed by the mus- cle derived IL-6, as demonstrated by a modest de- crease of TNF-α after exercise.48 This confirms that anti-inflammatory effects of regular exercise can protect against systemic low-grade inflammation. The anti-inflammatory effects can be mediated by a reduction in visceral fat and body fat as well as by an anti-inflammatory environment through the release of myokines.59,60 Another skeletal muscle myokine, IL-15, has been identified as an anabolic factor in muscle growth and it appears to play an important role in fat metabolism.60 Interestingly, a negative as- sociation between plasma IL-15 concentration and abdominal fat mass was established, which sup- ports the idea that muscle-expressed IL-15 may be involved in the reduction of visceral fat mass and may play an important role in the decrease of many cancer risks.57 Skeletal muscle is an endocrine organ, which, in addition to releasing myokines, also produces and secretes microRNAs into circulation.61 Loss of function microRNA experiments demonstrated that microRNAs have significant roles in the regu- lation of protein function in cancer, cancer cell pro- liferation and survival.61 Immune function It has been demonstrated that moderate physical activity may enhance the immune function by in- creasing the number and activity of immune func- tion cells such as neutrophils, eosinophils, mono- cytes and lymphocytes, and stimulate an increase in natural killer cells which have an important role in tumor suppression.5,62 Interestingly, regular moderate physical activity can increase the total antioxidant capacity of defence and be responsi- ble for the elimination of reactive oxygen species (ROS).5 These highly reactive species are responsi- ble for oxidative stress and play an important role in the progression of various types of human can- cer.63 Moderate to vigorous physical activity can also provide a higher number of mitochondria in skeletal muscles that consequently provide a great- er capacity to reduce oxidative stress.64 Indeed, each mitochondrion has a reduced oxidative load, and, as such, more electrons are directed to cy- tochrome oxidase instead of producing reactive oxygen species.65 Hormones Regular moderate to vigorous intensities of physi- cal activity influences the levels of biologically available sex hormones and decreases the incidence of hormone-related cancers, including breast can- cer, endometrium, ovaries, and prostate cancer.66,67 Many studies have concluded that physical activ- ity modifies metabolic hormone levels by lowering circulating fat, which produces the sex hormones responsible for the stimulatory effect on mammary glands and increases SHBG production, reducing Radiol Oncol 2021; 55(1): 7-17. Jurdana M / Physical activity and cancer 13 their ability to influence target tissue. During men- opause, the concentration of estrogens declines, but adipose tissue in obese women still produces estrogens after menopause.68 Physical activity re- sponsible for reducing body fat mass, counteracts adipose tissue and is crucial for the reduction of breast cancer risk.68 Another study performed on premenopausal women demonstrated that regular physical activity and high LTPA reduce the concen- tration of estradiol and increase SHBG independ- ent of obesity, thus indicating that the protective effect of exercise is not completely mediated by the changes in adiposity.69 Furthermore, excess levels of some androgens in men have been suggested to increase the risk of prostate cancer. Increased pro- duction of SHBG during physical activity may pre- vent prostate cancer development by decreasing the levels of biologically available testosterone.47 Regular moderate to vigorous physical activ- ity affects cancer risk by reducing the levels of in- sulin and insulin growth factor-1 (IGF-1).70 High levels of (IGF-1) and insulin resistance have been responsible for an increased risk of various cancer types.70 The epidemiological evidence between insulin levels and cancer risk is associated with hyperinsulinemia. Insulin is a powerful mitogen and is involved in glucose metabolism enhancing tumor development. Hyperinsulinemia promotes the synthesis and activity of (IGF-1), a mitogen that increases cellular proliferation, differentia- tion and transformation and inhibits apoptosis.71 Intervention strategies including regular physi- cal activity reduce insulin levels, fasting glucose levels, decrease hepatic and muscle insulin resist- ance, and total IGF-1, increase glucose transporter protein and mRNA, increase activity of glycogen synthase and hexokinase, decrease release and in- crease clearance of free fatty acids, increase muscle glucose delivery because of increased muscle cap- illary density, and effect changes in muscle com- position to increase glucose disposal.72 This proves that the mechanism involved is directly associated with skeletal muscle contraction during exercise. Adiposity Chronic low-grade inflammation in adiposity is associated with a higher risk of several cancer types.73-75 Adipose tissue as an endocrine organ which produces and releases a variety of pro- inflammatory cytokines such as (IL- 6), (TNF-α), (CRP), leptin, and anti-inflammatory adiponectin. During exercise, in particular resistance training, skeletal muscle cells produce and express anti- inflammatory myokines, belonging to distinctly different families, responsible for reducing pro- inflammatory leptin, (IL-6) and (TNF-α) secretion and significantly increase the adiponectin level.76 Some pro-inflammatory cytokines, such as the obesity hormone leptin, have a potential role in the development of a large variety of malignan- cies and are currently at the centre of the obesity- cancer link.77 In humans, excessive adipose tissue is directly associated with elevated levels of leptin, which is significantly higher in women than in men, even after the adjustment for total body fat mass.78,79 One explanation for this tendency is a differential regulation of leptin expression by sex hormones; estrogens were observed to increase leptin levels, while testosterone was observed to decrease leptin levels.80 Leptin, in addition, can act as a mitogen and can increase the expression of anti-apoptotic proteins, inflammatory (TNF-α and IL-6), and angiogenic factors (VEGF). Interestingly, the effects of exercise, and particularly resistance exercise, can reduce leptin concertation, exerting an anti-inflammatory response.76, 81-83 To date, the evidence that leptin can indeed be involved in the neoplastic processes has been provided by studies on breast and colorectal cancer, while limited stud- ies are available for other cancer types.84 Moreover, adipose tissue adiponectin levels have been shown to exert anti-inflammatory ac- tions and may thus counteract the increased can- cer risk seen in obesity-induced inflammation.85 Plasma adiponectin levels are known to be associ- ated with insulin sensitivity and the risk of devel- oping metabolic disorders and malignancy.86 As exercise training improves insulin sensitivity and prevents the development of obesity related dis- eases, it has been proposed that exercise-induced improvement in insulin sensitivity is mediated through the regulation of plasma adiponectin lev- els. In addition, low serum adiponectin levels and high serum leptin levels are independent risks for cancer metastasis.87 Since physical inactivity is strongly linked with excess weight/obesity, and both are important risk factors for cancer develop- ment, regular physical activity appears to be im- portant for the prevention of cancer development through reduction adiposity, in particular the met- abolically active abdominal fat both of which are known to contribute to systemic inflammation.83 The role of microbiota composition The human gastrointestinal tract (GIT) is colonized by trillions of microbial cells, and numerous studies Radiol Oncol 2021; 55(1): 7-17. Jurdana M / Physical activity and cancer14 have shown the importance of gut microbiota com- position in several physiological and pathological processes, including local gastrointestinal cancer, as well as others such as distal cancer (head and neck, breast, oesophageal, pancreatic, and prostate cancer).88 A microbial imbalance or dysbiosis can be caused by several risk factors, such as aging, smoking, having an unhealthy diet, and inflam- mation that increases the host’s risk for neoplastic transformation.89 Gut microbiota provides nutri- ents, regulates epithelial development, and affects the immune system. Additionally, an augmented microbial diversity is associated with improve- ment in the health status and the immune system.90 It has been demonstrated that gut microbiota can be modulated by different factors. Recently, hu- man and animal studies have revealed that aerobic exercise increases microbiota diversity, altering the bacterial composition and influencing the produc- tion of important metabolites of gut bacteria.91 Regular aerobic physical activity affects colon motility, provides a positive effect on the gut by reducing transient stool time and contact time be- tween pathogens and the gastrointestinal mucosa layer.92 Physical activity may reduce prostaglan- dine production and inflammation and protect the integrity of the intestine. In this manner, physical activity prevents the risk of many diseases such as colon cancer, diverticulosis and other inflamma- tory diseases.93 Other possible positive effects of exercise include elevated short-chain fatty acids (SCFAs) and immunoglobulin production and an increase in butyrate concentration. The increase of fecal butyrate has anti-carcinogenic and anti-in- flammatory properties.94 In addition, exercise can prevent obesity and induce changes in microbiota composition and diversity, and potentially con- tribute to reducing weight and obesity-associated pathologies.95 Recently, it has been demonstrated that aerobic exercise training alters the gut micro- biota and microbial-derived SCFA in sedentary lean and obese adults without any changes to di- etary patterns.96 This evidence supports the idea that regular physical activity appears to be an im- portant environmental factor that induces changes in microbial composition benefits for the host, and stimulates gut bacteria to produce substrates that protect against GIT disorders and colon cancer. Conclusions The epidemiological data for the beneficial effects of physical activity and cancer risk are being gath- ered rapidly and several possible mechanisms have been proposed to explain the link between physi- cal activity and cancer. Physical activity can reduce the risk of various types of cancers by mechanisms including: decreasing markers of systemic inflam- mation by releasing anti-inflammatory myokines, improving insulin resistance, reducing leptin lev- els and hyperinsulinemia, increasing adiponectin levels and function of immune cells, decreasing circulating estrogen and androgen levels, and decreasing transient stool time and contact time between pathogens and the gastrointestinal mu- cosa layer. Discovering that skeletal muscle is an endocrine organ elucidated some of the proposed mechanisms. Based on the current level of knowledge, some unexplained factors remain: existing evidence is limited to be able to support a specific dose of physical activity among a specific population sub- group, tailored for site-specific cancer reduction; how to measure precise physical activity; and how different type, dose and intensities of exercise are attributed to lowering certain cancer risks. General guidelines recommend 150 minutes of moderate physical activity or at least 75 of vigorous physi- cal activity per week.11, 97 The second report by the World Cancer Research Fund (WRCF) states that “more physical activity is better”. Although any dose of physical activity is important for the reduc- tion of cancer risk; to date, data from numerous studies have reported that higher levels of physical activity (150–300 minutes per week or 7–15 MET h/w) in particular, making vigorous is important for cancer prevention.4 References 1. Vainio H, Kaaks R, Bianchini F. 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Med Sci Sports Exerc 2019; 51: 1252-61. doi: 10.1249/MSS.0000000000001937 Radiol Oncol 2021; 55(1): 18-25. doi: 10.2478/raon-2020-0069 18 research article Clinical relevance of 18F-FDG PET/CT in the postoperative follow-up of patients with history of medullary thyroid cancer Jelena Saponjski1, Djuro Macut2, Dragana Sobic Saranovic3, Branislava Radovic1, Vera Artiko3 1 Center for Nuclear Medicine, Clinical Center of Serbia, Belgrade, Serbia 2 Clinic for Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, Belgrade, Serbia 3 Center for Nuclear Medicine, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Radiol Oncol 2021; 55(1): 18-25. Received 6 August 2020 Accepted 17 October 2020 Correspondence to: Prof. Vera Artiko, M.D., Ph.D., Director, Center for Nuclear Medicine, Clinical Center of Serbia, Visegradska 26, 11 000 Belgrade, Serbia. E-mail: vera.artiko@gmail.com Disclosure: No potential conflicts of interest were disclosed. Background. The aim of the study was evaluation of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computed tomography (PET/CT) in the detection of active disease in the patients with suspected recurrence of the medullary thyroid carcinoma (MTC). Patients and methods. 18F-FDG PET/CT investigation was performed in 67 patients, investigated from 2010 to 2019. Follow up was performed from 6 to 116 months after surgery (median 16.5 months, x _ ± SD = 29±28.9 months). Twenty five of 67 patients underwent 99mTc-dimercaptosuccinic acid (99mTc-DMSA) scintigraphy, 11 underwent somatostatin receptor scintigraphy (SRS) with 99mTc-HYNIC TOC while 11 123I-metaiodobenzylguanidine (MIBG) scintigraphy. Results. From 67 patients, 35 (52.2%) had true positive 18F-FDG PET/CT findings (TP). Average maximal standardized uptake value (SUVmax) for all TP lesions was 5.01+3.6. In 25 (37.3%) patients findings were true negative (TN). Four (6%) patients had false positive (FP) findings while three (4.5%) were false negative (FN). Thus, sensitivity of the 18F-FDG PET/ CT was 92.11%, specificity 86.21%, positive predictive value 89.74%, negative predictive value 89.29% and accuracy 89.55%. In 27 patients (40%) 18F-FDG PET/CT finding influenced further management of the patient. Conclusions. 18F-FDG PET/CT has high accuracy in the detection of metastases/recurrences of MTC in patients after thyroidectomy as well as in evaluation and the appropriate choice of the therapy. Key words: 18F-FDG PET/CT; medullary thyroid carcinoma; follow up; postoperative Introduction Medullary carcinoma of thyroid gland (MTC) is a malignant neuroendocrine tumor originated from the para-follicular C cells. The incidence is 1 to 2% of thyroid malignancies. It may occur as sporadic or hereditary form as a part of type 2 multiple en- docrine neoplasia (MEN2) syndromes with surgery representing the primary therapeutic modality.1,2 C cells secrete specifically calcitonin and procalciton- in which are considered as specific tumor markers.3 Carcinoembryonic antigen (CEA) is not specific marker for this tumor but is useful in follow up of the treatment. Both calcitonin and CEA doubling times are considered as prognostic predictors in pa- tients with persistent disease after surgery.4 Diagnosis of MTC during management of thy- roid nodular disease could be established by fine needle aspiration cytology, immunocytochemical staining against calcitonin and/or its measurement in the needle washouts or additional immunostain- ing against specific biomarkers such as calcitonin, CEA, chromogranin A. Elevated basal values of serum calcitonin especially when greater than 100 pg/ml, or calcitonin levels obtained during calcium stimulation test are used for diagnosis of MTC.5 Radiol Oncol 2021; 55(1): 18-25. Saponjski J et al. / FDG PET/CT in medullary cancer 19 Total thyroidectomy and neck dissection is con- sidered as the first line and curative treatment. In the treatment of progressive MTC, surgery, imag- ing-guided local treatments and tyrosine kinase inhibitors can be used and combined.1 In the diag- nosis of MTC, different anatomical and functional imaging procedures may be used. Ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) are used in staging of the disease before primary surgery. The role of nuclear medicine methods is reserved for detection and lo- calization of recurrent disease when serum tumor marker levels are elevated and when the findings of morphologic imaging methods are inconclu- sive.6,7 The most frequently used radiopharmaceuticals for the diagnosis and follow up of MTC, labelled with γ emitting radionuclides, are metaiodoben- zylguanidine (MIBG) labelled either with 131I or 123I, 99mTc-pentavalent dimercaptosuccinic acid (99mTc(V)-DMSA), 111In-pentetreotide (Octreoscan) and 99mTc-EDDA/HYNIC-Tyr3-octreotide (Tektrotyd).8-13 The radiopharmaceuticals labelled with a positron-emitting radionuclides suitable for positron emission tomography with computed tomography (PET/CT) are 18F-fluorodeoxyglucose (18F-FDG), 18F-fluorodihydroxyphenylalanine (18F-DOPA), and 68Ga-labelled somatostatin ana- logues (68Ga- DOTATATE or DOTATOC). According to the literature, overall sensitivity of conventional nuclear medicine methods γ emitting radionuclides is lower in comparison to conventional anatomic imaging (i.e. US, CT, MRI) and positron emission tomography/computed tomography.7,8 However, still, application of PET/CT in the nuclear medicine worldwide is limited. Radiopharmaceuticals track different metabolic pathways or receptor expres- sion/functioning, and proved to be useful in detect- ing MTC recurrences/metastasis. Nuclear medicine methods may help guiding the appropriate choice of the therapy but also offer possibility of radionu- clide therapy with radiolabeled somatostatin ana- logues or metaiodobenzylguanidine. The aim of our study was to examine specificity and sensitivity of 18F-FDG PET/CT in comparison to other available nuclear imaging methods used for the follow-up of MTC patients treated with the first-line radical thyroidectomy. Patients and methods In this cohort retrospective study, 18F-FDG PET/ CT investigation was performed in 67 consecutive patients (32 males and 35 females, 52.2±16.2 years of age) in a period from 2010 to 2019. Follow up was performed from 6 to 116 months after surgery (median 16.5 months, x _ ± SD = 29±28.9 months), in order to detect active disease after total thyroidec- tomy and estimate the effect of adjuvant medical or radiotherapy. The majority of patients (56) had increased serum concentration of calcitonin (45- 8526 pg/ml) while 16/67 had increased concentra- tion of CEA. All the patients underwent radiologi- cal imaging methods (CT, NMR, US). In addition to 18F-FDG PET/CT investigation, 25 patients under- went 99mTc-DMSA scintigraphy, 11 somatostatin re- ceptor scintigraphy (SRS) with 99mTc- HYNIC TOC and 11 99mTc-MIBG scintigraphy. The patients underwent 18F-FDG PET/CT ex- amination on a 64-slice PET/CT scanner (Biograph, TruePoint64, Siemens Medical Solutions Inc. USA). Radiopharmaceutical (5.5MBq/kg) was injected to the patient after fasting for at least 6 hours. Afterwards, patients rested in a quiet and dark- ened room for 60 min, after which images of PET/ CT were obtained. Low-dose non-enhanced CT scans (120 kV with automatic, real-time dose mod- ulation amperage, slice thickness of 5 mm, pitch of 1.5 and a rotation time of 0.5 s) and 3-dimensional PET scans (6-7 fields of view, 3 min/field) were ac- quired from the base of the skull to the mid-thigh. Non-corrected and attenuation-corrected CT, PET and fused PET/CT images were displayed for anal- ysis on a Syngo Multimodality workplace (Siemens AG). The FDG uptake was analyzed visually and quantitatively using SUVmax index. FDG PET/ CT findings were considered positive in the case of higher accumulation FDG in comparison to sur- rounding parenchyma, mediastinal blood vessels and the liver. For assessment of glucose metabo- lism level in metastasis, SUVmax was used. Tumor lesions were defined by volume of interest placed around every suspected focus of intense FDG up- take, with 50% threshold. The measurements of SUVmax, were done on reconstructed images, after using ordered subsets expectation maximization as statistical reconstruction method, but no absolute cut-off value of SUVmax was used for the diag- nosis. Images were interpreted separately by two nuclear medicine physicians, unaware of results of other imaging modalities. In cases of discrepancy, images were presented to multidisciplinary team and experts’ opinion was adopted. In addition to 18F-FDG PET/CT investigation, when required, whole body scintigraphy, single photon emission computed tomography (SPECT) imaging and, if necessary spot views were per- Radiol Oncol 2021; 55(1): 18-25. Saponjski J et al. / FDG PET/CT in medullary cancer20 formed with 99mTc(V)-DMSA, 99mTc-HYNIC-TOC), and 123I-MIBG using ECAM gamma camera and computer (ESOFT). The patient underwent an intravenous injection of 740 MBq 99mTc(V)--DMSA and after 2 h 30 min, a whole body scintigraphy was performed (scanning speed 10 cm/min). Somatostatin receptor scintigraphy (SRS) of the whole body was performed 2 h and 24 h after i.v. administration of 740 MBq 99mTc-HYNIC-TOC. Before study therapy with somatostatin analogs was withdrawn, mild laxatives were introduced, patients were fasting and were well hydrated. Scintigraphy with 123I-MIBG was performed 24 h after slow intravenous injection of no less than 80 MBq. Whole-body planar images were acquired at scanning speeds of 5cm/min. Each spot view was acquired for a maximum of 10 min (about 500 kcounts). Investigation was followed by SPECT of particu- lar region. It was performed using 360º orbit, step and shoot mode, at 30 sec per view. The acquired data were collected in a 128 x 128 computer matrix and reconstructed using filtered back-projections with a Butterworth filter (cut-off 0.6 cycles/pixel, order 5) and iterative reconstruction. Whole body and SPECT images were first evalu- ated visually by two experienced nuclear medicine physicians. Visual appearance of an increased fo- cal uptake of tracer in the suspected tumor site was considered a positive finding. Reference standards for active disease were sur- gery, biopsy and follow up of 5 years. Descriptive statistical methods were used such as mean value, standard deviation, sensitivity, specificity, positive predictive value, negative pre- dictive value and accuracy, as well as the percent- age. Progression- free survival was assessed by Kaplan Meier survival analyses. Ethical consideration All the patients gave the informed consent for the investigation and the study was approved by Ethical Committee of Clinical Center of Serbia (668/6/2018) and Ethical Committee of Faculty of Medicine University of Belgrade (1550/V-9/2019). Results The results of PET/CT findings are shown in the Table 1. From 67 patients 35 (52.2%) had positive 18F-FDG PET/CT findings (TP): 15 in the neck lymph nodes (42.9%), 13 in mediastinal lymph nodes (37.1%), 2 (5.7%) in mediastinal and abdominal lymph nodes and lungs, 2 (5.7%) in thyroid neck re- gion and 3 on multiple localizations in bones, lungs and mediastinum (8.6%), with SUVmax 5.01+3.6. In 25 (37.3%) patients accumulation of FDG was physi- ological (TN). Four (6%) patients were false positive (FP), 3 with enlarged jugular lymph nodes and neg- ative pathohistological finding and one with hilar lymphadenopathy which has not been visualized on control PET/CT scans. Three (4.5%) were false negative (FN), two of which with increased calci- tonin levels (above 1000 pg/ml) and one because of the recently finished chemotherapy and slight accumulation in the neck lymph node which was considered as reactive (4.7%). In 27 patients (40%) FDG PET/CT finding influenced further therapeu- tic management of the patient. TABLE 1. 18F-FDG PET/CT findings in medullary thyroid carcinoma patients with calcitonin levels Findings Number % Increased calcitonin levels Calcitonin levels above 1000 pg/ml TP 35/67 52.2 35/35 (100%) 18/35 (51%) TN 25/67 37.3 18/25 (72%) 0 FP 4/67 6 2/4 (50%) 0 FN 3/67 4.5 2/3 (66%) 2/3 (66%) Sensitivity 92.11% (95% CI 78.62% to 98.34%) Specificity 86.21% (95% CI 68.34% to 96.11%) Positive predictive value 89.74% (95% CI 77.81% to 95.62% Negative predictive value 89.29% (95% CI 73.59% to 96.14%) Accuracy 89.55% (95% CI 79.65% to 95.70%) 18F-FDG = 18F-fluorodeoxyglucose; CI = confidence interval; FN = false negative; FP = false positive; TN = true negative; TP = true positive Radiol Oncol 2021; 55(1): 18-25. Saponjski J et al. / FDG PET/CT in medullary cancer 21 The results of 99mTc(V)-DMSA scintigraphy are shown in the Table 2. In the patients who under- went 99mTc-DMSA scintigraphy, there were 4 TP, 13 TN, 3 FP (after surgery) and 5 FN (small lesions). In 11/14 (78.6%) TN patients 18F-FDG PET/CT and 99mTc-DMSA findings were concordant. Concordance of the 18F-FDG PET/CT findings with the results of other radionuclide methods in selected number of MTC patients are shown in Table 3 and Figures 1–3. When patients were FDG PET true negative, they were also negative (TN) or FP with other modalities which emphasized the value of FDG PET in comparison to other methods. However, sometimes, additional information was obtained by other methods. Thus, in one TP patient with FDG PET/CT, because of lymph node metas- tases and suspicious but not obvious liver metas- tases, scintigraphy with 123I-MIBG showed obvi- ous liver metastases, i.e. accomplished the PET/CT finding, while scintigraphy with two other meth- ods (DMSA, Tektrotyd) was FN. In another two TP patients on FDG PET/CT, expression of somatosta- tin receptors was very high, so the corresponding therapy was ordered. Kaplan Meier progression-free survival analysis in FDG TP patients showed median survival of 15 months (95% CI 11.14+18.85 months), while me- dian survival in TN (disease free patients) at the moment of investigation was 30 months (95% CI 1.08+58.92 months) (Figure 4). Discussion Our results point out very high sensitivity (92. 11%) of 18F-FDG PET/CT in the detection of recurrence or metastases of MTC, relatively high positive (89.74%) and negative predictive value (89.29%) as well as accuracy (89.55%). Specificity was 86.21%. The main reason for FP and FN results was subjec- tive assessment of the size and the uptake in the lymph nodes after the therapy, which emphasized the importance of follow up in order to avoid FP and FN results. According to our results, 18F-FDG PET/CT can be used in the follow-up period of pa- tients with elevated plasma calcitonin in order to detect recurrence and residual disease after the pri- mary operation. The results of other investigators for sensitivity vary from 47 to 93% while specificity ranged from 67-92%.14-18 Like in our study, where 18F-FDG PET/ CT contributed significantly in 40% of the cases, other authors revealed that 18F-FDG PET/CT pro- vides additional information important for the further management of the patients in a significant number of cases (up to 54%).19-21 Other studies also showed that 18F-FDG PET/CT positive finding may influence the management of recurrent MTC when hypermetabolic lesions are detected. 22-24 In all our TP patients serum calcitonin levels were increased, and in 51% of them were higher than 1000 pg/ml, while 72% of TN had increased calcitonin levels but none of them higher than 1000 pg/ml. However, in 2/3 FN findings calcitonin level was increased above 1000 pg/ml. This is in accordance with the data of other investigators who proved that there is a positive relationship between serum levels of calcitonin and CEA and the sensitivity of 18F-FDG PET/CT. Moreover, it was shown that sensitiv- ity of 18F-FDG PET/CT improves in patients with shorter serum calcitonin and CEA doubling times. This is confirming the usefulness of 18F-FDG PET/ CT method in patients with more aggressive forms TABLE 2. 99mTc-DMSA scintigraphy findings in medullary thyroid carcinoma patients Findings Number % TP 4 TN 13 FP 3 FN 5 Sensitivity 44.44% (95% CI 13.70% to 78.80%) Specificity 81.25% (95% CI 54.35% to 95.95%) Positive predictive value 57.14% (95% CI 27.55% to 82.38%) Negative predictive value 72.22% (95% CI 58.07% to 83.00%) Accuracy 68.00% (95% CI 46.50% to 85.05%) 99mTc(V)-DMSA = 99mTc-pentavalent dimercaptosuccinic acid; CI = confidence interval; FN = false negative; FP = false positive; TN = true negative; TP = true positive TABLE 3. Concordance of the 18F-FDG PET/CT findings with the results of other radionuclide methods in selected number of medullary thyroid carcinoma patients 18F-FDG PET/CT 99mTc(V)-DMSA 99mTc-HYNIC-TOC 123I-MIBG 14 TP (100%) 4 TP (28.6%)4 FN (28.6%) 5 TP (35.7%) 3 FN (21.4%) 3 TP (21.4%) 2 FN (14.3%) 14 TN (100%) 11 TN (78.6%)2 FP (14.3%) 1 FP (7%) 1 TN (7%) 3 TN (21.4%) 2 FP (14.3%) 4 FP (100%) 1 FP (25%)2 TN (50%) 1 FP (7%) 1 FN (100%) 1 FN (100%) 1 FN (100%) 123I-MIBG = metaiodobenzylguanidine; 18F-FDG = 18F-fluorodeoxyglucose; 99mTc(V)-DMSA = 99mTc- pentavalent dimercaptosuccinic acid; FN = false negative; FP = false positive; PET/CT = positron emission tomography with computed tomography; Tektrotyd = 99mTc-EDDA/HYNIC-Tyr3-octreotide; TN = true negative; TP = true positive Radiol Oncol 2021; 55(1): 18-25. Saponjski J et al. / FDG PET/CT in medullary cancer22 FIGURE 1. Patient with diagnosis of MTC after total thyroidectomy. (A, B) FDG PET/CT confirmed high uptake metastases in the mediastinal lymph nodes and uneven distribution of FDG in the liver. (C) 99mTc-DMSA spot view scintigraphy finding is negative. (D) 99mTc - tektrotyd SPECT finding is negative. (E) 123I – MIBG WB finding showed high uptake in multiple liver metastases. (F) 123I – MIBG SPECT finding showed high uptake in multiple liver metastases. A B C D E F A B C of disease in comparison to those with slowly pro- gressive disease.4,25-26 Furthermore, 18F-FDG PET/ CT is able to accurately identify MTC patients with poor prognosis and life expectancy, and to evalu- ate response to targeted therapies in patients with advanced metastatic disease.27 Our investigation showed that progression-free survival in FDG TP patients showed median sur- vival of 15 months in the patients with recurrences and metastases, while median progression-free survival in disease free patients at the moment of investigation was 30 months. This is in accordance with the results of other authors. Thus, Fox et al. obtained that progression free survival was 19.2 months, while Elisei et al. obtained that progres- sion free survival was, in dependence of the ther- apy 11.2 vs 4.0 months.28,29 Our results obtained with 99mTc(V)-DMSA showed in general slightly lower sensitivity in the detection of metastatic or recurrent disease (44.4%) in comparison to majority of other others authors. Thus Verga et al. reported a sensitivity rate of 50%, Ugur et al. even 95%, while the study of Adams et al., revealed 65% and Howe et al. 71.4%.30-33 However, relatively large number of TN patients in FIGURE 2. Patient with diagnosis of MTC after total thyroidectomy. (A, B) FDG PET/ CT confirmed high uptake metastases in the lymph nodes of the neck, mediastinum and abdomen. (C) 99mTc- DMSA planar spot view scintigraphy showed uptake only in the few lymph nodes in the neck and mediastinum. Radiol Oncol 2021; 55(1): 18-25. Saponjski J et al. / FDG PET/CT in medullary cancer 23 our study leads us to conclusion that DMSA scin- tigraphy could be used together with 18F-FDG PET/ CT to rule out residual or metastatic disease. A wide range of sensitivity could be explained by dif- ferent commercial kits used, with different stability of the isomeric composition.34 Taking this into con- sideration, DMSA scintigraphy should not be the best option in preoperative setting in comparison to postoperative detection of residual disease pre- sumably when calcitonin level starts to increase.7,34 Taking into consideration our results and those of other investigators, 18F-FDG PET/CT showed higher sensitivity in patients with MTC when compared to single photon emission tracers.18-20 In our group of MTC patients who had both 18F-FDG PET/CT and DMSA just a small number under- went MIBG and SRS scintigraphy, and statisti- cal analysis could not be made. However, a small number of cases on the management of recurrent and metastatic MTC implicated that the sensitivity of 123Ι/131Ι-MIBG and Octreoscan used for this indi- cation is low and ranged between 30% and 71%.7 However, the advantage of MIBG and SRS scintig- raphy is the possibility of radionuclide therapy in the cases with high uptake. Similar to our findings, Rubello et al. concluded that 18F-FDG PET had the highest sensitivity in localizing metastatic disease in comparison to 99mTc(V)-DMSA scintigraphy, 111In-DTPA-octreotide, US, CT and MRI.21 Szakall et al. showed that 18F-FDG PET was superior with bet- ter sensitivity than CT, MRI, and 131I-MIBG in lo- calizing lymph node involvement in patients with known MTC and postoperatively elevated calci- tonin levels.34 These authors also found that while FDG PET was superior in comparison to anatomic modalities in the lesions in neck, supraclavicular and mediastinal, CT had advantage in detection of liver and lung metastases, while FDG PET and MR were similar.34 Although there is no single imaging method sensitive enough to reveal all MTC recurrences, our results confirmed an advantage of 18F-FDG PET/CT in comparison to gamma emitting radiopharma- ceuticals. Positron emitting radiopharmaceuticals beyond FDG, such as fluorine-18 dihydroxypheny- lalanine (18F-FDOPA) and somatostatin analogues labelled with gallium-68 (68Ga-SSA) tracks different metabolic pathways or receptor expression/func- tioning, and proved to be useful in detecting MTC recurrences/metastasis. According to the literature data, PET/CT imaging with available radiopharma- ceuticals is suggested when serum calcitonin exceed 150 pg/mL or calcitonin doubling time is shortened (i.e. < 24 months).36-38 If available, 18F-FDOPA PET/ CT is preferred, but if the finding is negative or this radiopharmaceutical unavailable, 18F-FDG PET/CT should be performed, in particular if calcitonin and CEA levels are rapidly rising (i.e. doubling time < FIGURE 3. Patient with diagnosis of MTC after total thyroidectomy. (A) FDG PET/CT confirmed high uptake in metastases in the mediastinal lymph nodes. (B) 99mTc- tektrotyd scintigraphy confirmed high uptake in metastases in the mediastinal lymph nodes. (C) 99mTc-DMSA planar spot view scintigraphy finding was negative showed uptake only in the few lymph nodes in the neck and mediastinum. A B C FIGURE 4. Kaplan Meier progression-free survival curve in positive FDG patients with median survival of 15 months (95% CI 11.14 ± 18.85 months), while median survival in disease free patients was 30 months (95% CI 1.08+58.92 months). Radiol Oncol 2021; 55(1): 18-25. Saponjski J et al. / FDG PET/CT in medullary cancer24 1 year) or an aggressive behavior of the disease is expected (e.g. CEA levels disproportionately high compared with calcitonin levels).27,39 According to Kushchayev et al., functional imaging, primar- ily PET/CT with 18F-FDOPA and 18F-FDG, plays a crucial role in the evaluation and management of MTC and has proven to be an efficient tool for the detection of metastases in patients with elevated calcitonin levels.40 Furthermore, 68Ga-SSA PET/CT could be considered in the cases with inconclusive anatomic imaging, 18F-FDOPA and 18F-FDG PET/ CT results as well to assess the feasibility of pep- tide receptor radionuclide therapy.27 18F-FDG PET/CT is a useful method with high diagnostic accuracy in the detection of second- ary deposits of MTC in patients after radical thy- roid surgery. It can be used alone or in line with other nuclear medicine methods as it is 99mTc(V)- DMSA especially in the cases when other position emitting radiopharmaceuticals are not available (18F-FDOPA and 68Ga-SSA). Conclusions 18F-FDG PET/CT has high accuracy in the detection of metastases/recurrences of MTC in patients with elevated calcitonin level after thyroidectomy and is superior to radionuclide single photon imaging modalities for identifying true positive disease. References 1. Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25: 567-610. doi: 10.1089/thy.2014.0335 2. Trimboli P, Seregni E, Treglia G, Alevizaki M, Giovanella L. Procalcitonin for detecting medullary thyroid carcinoma: a systematic review. Endocr Relat Cancer 2015; 22: R157-164. doi: 10.1530/ERC-15-0156 3. Trimboli P, Giovanella L. 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Thyroid Res 2019; 7: 1893047. doi: 10.1155/2019/1893047 Radiol Oncol 2021; 55(1): 26-34. doi: 10.2478/raon-2020-0071 26 research article Radiological evaluation of ex novo high grade glioma: velocity of diametric expansion and acceleration time study Roberto Altieri1,2,3, Francesco Certo2, Giuseppe La Rocca4, Antonio Melcarne5, Diego Garbossa5, Alberto Bianchi6, Salvatore Crimi6, Alessandro Pluchino7, Simone Peschillo1, Giuseppe M.V. Barbagallo1,2 1 Division of Neurosurgery, Department of Neurosciences, Policlinico “G. Rodolico”, University Hospital, Catania, Italy 2 Multidisciplinary Research Center on Brain Tumors Diagnosis and Treatment, University of Catania, Catania, Italy 3 PhD program at Department of Neuroscience, University of Turin, Turin, Italy 4 Division of Neurosurgery, Catholic University School of Medicine, Rome, Italy 5 Department of Neuroscience, University of Turin, Turin, Italy 6 Department of General Surgery and Medical Surgery Specialties, University of Catania, Catania, Italy 7 Department of Physics and Astronomy “E. Maiorana”, University of Catania, Catania, Italy Radiol Oncol 2021; 55(1): 26-34. Received 15 July 2020 Accepted 16 October 2020 Correspondence to: Roberto Altieri, M.D., Department of Neurosurgery, Policlinico “G. Rodolico” University Hospital, Via Santa Sofia, 78, 95125 Catania, Italy. Phone: +39 953 781 143; E-mail: roberto.altieri.87@gmail.com Disclosure: No potential conflicts of interest were disclosed. Background. One of the greatest neuro-oncological concern remains the lack of knowledge about the etiopatho- genesis and physiopathology of gliomas. Several studies reported a strict correlation between radiological features and biological behaviour of gliomas; in this way the velocity of diametric expansion (VDE) correlate with lower grade glioma aggressiveness. However, there are no the same strong evidences for high grade gliomas (HGG) because of the lack of several preoperative MRI. Patients and methods. We describe a series of 4 patients affected by HGG followed from 2014 to January 2019. Two patients are male and two female; two had a pathological diagnosis of glioblastoma (GBM), one of anaplastic astrocytoma (AA) and one had a neuroradiological diagnosis of GBM. The VDE and the acceleration time (AT) was calculated for fluid attenuated inversion recovery (FLAIR) volume and for the enhancing nodule (EN). Every patients underwent sequential MRI study along a mean period of 413 days. Results. Mean VDE evaluated on FLAIR volume was 39.91 mm/year. Mean percentage ratio between peak values and mean value of acceleration was 282.7%. Median appearance time of EN after first MRI scan was 432 days. Mean VDE was 45.02 mm/year. Mean percentage ratio between peak values and mean value of acceleration was 257.52%. Conclusions. To our knowledge, this is the first report on VDE and acceleration growth in HGG confirming their strong aggressiveness. In a case in which we need to repeat an MRI, time between consecutive scans should be reduced to a maximum of 15–20 days and surgery should be executed as soon as possible. Key words: acceleration time; glioblastoma; anaplastic astrocytoma; high grade glioma; radiological growth; veloc- ity of diametric expansion Introduction High grade glioma (HGG) still represent a chal- lenge for the medical community worldwide.1-4 Currently, average survival rates reported for ana- plastic astrocytoma (AA) and glioblastoma (GBM) are 3–4 years and 10–16 months, respectively.5 One of the greatest concerns remains the lack of knowl- edge about the etiopathogenesis and pathophysiol- ogy of gliomas. The new WHO classification tried Radiol Oncol 2021; 55(1): 26-34. Altieri R et al. / Radiological evaluation of high grade glioma growth 27 to explain the biological behavior of these tumors, analyzing their metabolic and genetic pathways.5 However, such classification has determined fur- ther fragmentation of our knowledge, in a time when we need a minimum common denomina- tor to solve this terrible puzzle.6,7 In recent years, research focused on glioma neuroradiological fea- tures trying to relate these with their biological behavior.8-15 As a consequence, many preoperative information about low grade gliomas (LGG) came from analysis of velocity of diametric expansion (VDE). Pallud and Mandonnet16-19 reported a strict correlation between VDE and glioma aggressive- ness: growth values under 4 mm between two consecutive MRI studies suggest a low invasive- ness rate and thus lower malignancy.20,21 However, the same evidences are not available for HGG be- cause of the lack of several preoperative MRI and no growth patterns have been standardized for HGG. We report a series of four patients in whom HGG growth and evolution were radiologically analyzed thanks to a long preoperative follow-up since tumor diagnosis until treatment. Patients and methods We describe a series of 4 patients followed by the first author from 2014 to January 2019. Two pa- tients are male, two are female, two had a patho- logical diagnosis of GBM, one of AA and one re- ceived a neuroradiological diagnosis of GBM. Every patient was radiologically followed through almost three pre-operative MRI scans, focusing on T1 with gadolinium and T2/fluid attenuated inver- sion recovery (FLAIR) sequences. Tumor volume was calculated by neurosurgeons with experience in neuro-oncological field, using Horos software for MacOs for manual segmentation of T1 and FLAIR 3D volumetric images in each MRI scan.22 For each patient’s MRI scans mean tumor diameter (MTD)20 was calculated through the following for- mula, starting from FLAIR-altered region’s and en- hancing nodule’s (EN) volume (V), and expressed in millimeters (mm): [eq. 1]. It represents the reverse formula of ellipsoid volume formula calculation: assuming the three diameters as equivalent. Variation of MTD ( ) between two consecu- tive MRI scans of each patient, was calculated as follows: [eq. 2] Where n is the ordinal number of MRI scan for each patient. Velocity of diametric expansion (VDE)18,20, or MTD difference over time (days) between two con- secutive MRI scans, was calculated as: VDE = [eq. 3] where ∆T is the number of days between two consecutive MRI scans. VDE is reported as mil- limeters on days (mm/dd). Assuming a linear VDE growth, VDE for each interval of time was then cal- culated respect to 1-solar-year, as follow: Annual VDE = VDE [eq. 4] For each patient, mean acceleration (Acc) or VDE variation over time, was calculated as follows: Acc = [eq. 5] Where n is the ordinal number of MRI scan for each patient; ∆T is the number of days between two consecutive MRI scans. VDE is expressed in mm/ dd, thus Acc results as mm/dd2. In order to evaluate variation of VDE and Acc along observation time, further analysis were con- ducted for any patient. In particular, we observed peak of VDE and Acc values in all patients. About VDE, we quantified these peaks high- est value of VDE /mean VDE value ratio (listed in Table 3) in every patient along observation period, expressed as percentage [eq. 6]: VDE peak = [eq. 6]. Where v is the VDE value; vmax is the highest val- ue of VDE recorded for any patient along all obser- vation period; n total number of MRI scans for each patient; i the ordinal number of MRI scan. In Acc peak analysis, we evaluated ratio be- tween highest Acc value and mean Acc value for any patient (listed in table 4), expressed as percent- age, as follows: Acc peak = [eq. 7]. Where α is the Acc value; αmax is the highest val- ue of Acc recorded for any patient along all obser- vation period; n total number of MRI scans for each patient, i the ordinal number of MRI scan. Radiol Oncol 2021; 55(1): 26-34. Altieri R et al. / Radiological evaluation of high grade glioma growth28 Further analysis evaluated EN/FLAIR volumes ratio (EFVR) (eq. 8), EN/FLAIR MTD ratio (EFMR) and their evolution over observation time (eq. 10 and 11), as follows: EFVR = [eq. 8]; EFMR = [eq. 9]; EFVR on single interval of time between conse- quent MRI scan = [eq. 10]; EFVR on total interval of time between first and last MRI scan of each patient = [eq. 11]; EFMR on single interval of time between conse- quent MRI scan = [eq. 12]; EFMR on total interval of time between first and last MRI scan of each patient = [eq. 13]; Where n is the ordinal number of MRI scan for each patient; n0 and nf are the first and last MRI scan for each patient, respectively. Every analysis was conducted for whole-tumor FLAIR volume and for single EN. The analysis and graphic representation were carried out with Microsoft Office Excel® software. In addition, a literature review was performed using PubMed MEDLINE database and searching for “radiological glioma growth”, “glioma radio- logic follow-up”, “glioma volume growth”. Ethical standards All procedures performed in studies involving hu- man participants were in accordance with the ethi- cal standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or compa- rable ethical standards. Informed consent was ob- tained from all individual participants included in the study. Results Case 1 A 39 y.o. male patient was under radiological fol- low-up since 5 years after meningioma resection. MRI scan was obtained once a year. After 5 years of negative post-operative MRI, the exam showed hyperintensity in the right hippocampal and para- hippocampal areas on T2/FLAIR sequences, with- out enhancement after gadolinium infusion. MTD was 35.5 mm. For the sake of a closer follow-up, a new MRI scan with spectroscopy was sched- uled 3 months later. In this second MRI scan, the FLAIR hyperintense lesion MTD was 39.7 mm, with no enhancement after gadolinium injection. Spectroscopy showed a peak in N-acetyl-aspartate (NAA), choline (Cho) and Creatinine (Cr) values. Both data suggested a likely diagnosis of ex novo HGG. Despite strong recommendation to undergo surgery, the patient delayed surgical treatment by 3 months. The new MRI scan, obtained the day before surgery for surgical planning, showed a MTD of 45 mm and contrast enhancement on T1-weighted sequences. The post-operative MRI showed a complete resection of the enhancing tu- mor. After resection, histopathologic diagnosis re- vealed AA, wild-type (WT) for IDH1. All values of ΔMTD, VDE and Acc calculated according to equa- tions [2], [4,] [5], [6], [7] are listed in Table 1. After tumor gross total resection, the patient underwent the Stupp regimen for adjuvant treatment and died 16 months later. Case 2 A 37 y.o. male patient, after an episode of dysar- thria, underwent a neuroradiological workout. MRI images showed a left fronto-parieto-insular en- hancing lesion suspicious for ex novo GBM. FLAIR and EN MTD were respectively 56.59 mm and 42.02 mm. After a week, he repeated the MRI with spec- troscopy showing elevation of Cho and reduction of NAA values, elevation of Cho/NAA ratio, mild elevation of lactate signal. At the same time, cen- tral necrosis was visible. A diagnosis of GBM was made. FLAIR and EN MTD were 59.83 cc and 48 cc respectively. VDE was 169.23 mm/year for FLAIR tumor volume, whilst for EN was 311.81 mm/year. Due to poor neurological condition and tumor loca- tion, surgery was avoided. Following further neu- rological deterioration, he underwent a new MRI scan 2 weeks later. FLAIR tumor MTD was 72.60 mm, EN MTD was 52.16 mm. At this point, chemo- therapy with temozolmide (TMZ) started. About two months later, a repeat MRI study showed good response. MTD was 67.37 mm for FLAIR tumor vol- ume and 43.80 mm for EN, in which TMZ effect was higher (Figure 1). In fact, ΔMTD was - 5.22 mm and - 9.36 on FLAIR and EN nodule volume, respec- tively. Values of ΔMTD, VDE and Acc calculated according to equations [2], [4,] [5], [6], [7] for every Radiol Oncol 2021; 55(1): 26-34. Altieri R et al. / Radiological evaluation of high grade glioma growth 29 respectively. MTD of FLAIR-altered regions were 35.73, 41.68 and 41.68 mm, respectively (Figure 2). At the end complete resection of EN was obtained; histopathological diagnosis was compatible with GBM, IDH1 WT. She underwent adjuvant therapy according to the Stupp regimen and remains alive 31 months after the index surgery. All values of ΔMTD, VDE and Acc calculated according to equa- tions [2], [4,] [5], [6], [7] for every MRI scan are list- ed in Table 1, divided for FLAIR and EN volumes. TABLE 1. Data about patient #1, #2, #3, #4 #Patient #MRI Days after previous MRI V FLAIR (cc) MTD (mm) ΔMTD (mm) VDE (mm/ day) VDE (mm/ year) Acc (VDE/ dd) V EN MTD (mm) ΔMTD (mm) VDE (mm/ day) VDE (mm/ year) Acc (VDE/ dd) 1 1 0 0 0 0 0 0.00 0.0000 2 365 22.53 35.5 35.5 0.0973 35.50 0.0003 3 90 31.47 39.7 4.2 0.0467 17.03 0.0005 4 60 45.65 45 5.3 0.0883 32.24 0.0015 2 1 0 90.6 56.59 0.00 0.00 0.00 0.0000 37.1 42.02 0.00 0.00 0.00 0.0000 2 7 107.1 59.83 3.25 0.46 169.23 0.0662 55.3 48.00 5.98 0.85 311.81 0.1220 3 18 191.3 72.60 12.76 0.71 258.82 0.0394 75.1 53.16 5.16 0.29 104.54 0.0159 4 36 152.9 67.37 -5.22 -0.15 -52.97 -0.0040 42 43.80 -9.36 -0.26 -94.91 -0.0072 3 1 0 0 0 0 0.000 0 0.0000 0 0 0 0 0 0 2 465 4.8 21.25 21.25 0.046 16.68 0.0001 0 0 0 0.00 0 0 3 277 9.1 26.30 5.05 0.018 6.66 0.0001 0 0 0 0.00 0 0 4 48 16.4 32.01 5.71 0.119 43.39 0.0025 0.3 8.43 8.43 0.18 64.14 0.0037 5 21 22.8 35.73 3.72 0.177 64.59 0.0084 0.7 11.19 2.75 0.13 47.84 0.0062 6 14 36.2 41.68 5.95 0.425 155.18 0.0304 2.7 17.54 6.36 0.45 165.74 0.0324 7 29 36.2 41.68 0.00 0.000 0.00 0.0000 4.9 21.40 3.86 0.13 48.53 0.0046 4 1 0 0.2 7.37 0.00 0.00 0.00 0.0000 0 0 0 0 0 0 2 160 1 12.60 5.23 0.03 11.93 0.0002 0.2 7.37 7.37 0.05 16.81 0.0003 3 36 1 12.60 0.00 0.00 0.00 0.0000 0.3 8.43 1.07 0.03 10.81 0.0008 4 27 1 12.60 0.00 0.00 0.00 0.0000 0.3 8.43 0.00 0.00 0.00 0.0000 Mean values 5.405 39.91 0.0077 2.11 45.02 0.0119 Acc = acceleration; MRI = magnetic resonance imaging; MTD = mean tumor diameter; ΔMTD = variation of MTD respect to previous value; VDE = velocity of diameter expansion; V EN = volume of enhancing nodule post gadolinium; V FLAIR = volume of fluid attenuated inversion recovery altered regions TABLE 2. Data on fluid attenuated inversion recovery (FLAIR) tumor and enhancing nodule (EN) volume velocity of diameter expansion (VDE). Reported as mm/year #Patient Mean FLAIR VDE DS FLAIR VDE Mean EN VDE DS EN VDE 1 21.19 16.26 2 93.77 145.21 80.36 174.48 3 40.93 55.88 46.61 59.19 4 2.98 5.97 6.90 8.34 Total mean value 39.9 45.02 MRI scan are listed in Table 1, divided for FLAIR and EN volumes. 6 months after initial diagnosis the patient remains alive. Case 3 A 72 y.o. female patient, after a seizure, underwent MRI workout without pathological findings. She repeated a MRI scan after 15 months and a FLAIR alteration in the left motor areas was seen. MTD was 21.25 mm. She refused any treatment. MRI scan was repeated further 9 months later show- ing a bilateral alteration of FLAIR signal in the frontal lobes. MTD was 26.30 mm. However, the patient chose to undergo neuroradiological follow- up rather than surgery. After two months, a new MRI scan showed an EN in the right frontal lobe. MTD of EN was 8.43 mm, MTD of FLAIR altered regions was 32.01 mm. Neurosurgeons suggested excision of the EN, but the patient refused again. Further MRI scans at 2, 6 and 10 weeks were ob- tained. MTD of EN were 11.19, 17.54 and 21.40 mm, Radiol Oncol 2021; 55(1): 26-34. Altieri R et al. / Radiological evaluation of high grade glioma growth30 Case 4 A 56 y.o. female patient underwent MRI for per- sisting headache. An incidental slight alteration of FLAIR signal in the left gyrus rectus was discov- ered. MTD was 7.37 mm. She repeated an MRI 5 months later to evaluate tumor evolution and an EN appeared in the previously FLAIR-altered ar- ea. MTD of the EN was 7.37 mm, whereas MTD of FLAIR-altered area was 12.6 mm and there were no further changes in the next MRIs. An MRI with spectroscopy was obtained one month later and this suggested a GBM. The new MTD of the EN was 8.43 mm. Surgical treatment was then proposed. She underwent preoperative MRI for neuronavi- gation one month later. MTD of the EN was 8.43 mm (Figure 3). Complete resection of EN was car- ried out and histopathological diagnosis revealed GBM IDH1 WT. She underwent adjuvant therapy with Stupp regimen and is still alive 12 months after surgery. All values of ΔMTD, VDE and Acc calculated according to equations [2], [4,] [5], [6], [7] for every MRI scan are listed in Table 1, divided for FLAIR and EN volumes. General evaluations Each patient underwent sequential MRI studies, with an average number of 4 scans along a mean period of 413 days. ENs were evident only in pa- tient 2 on the first MRI study, whereas appeared at fourth, fourth and second MRI scan in patients n. 1, 3 and 4, respectively. No common time correlation between evidence of first FLAIR alteration and EN appearance was found. Median appearance time after first MRI scan was 432 days. Final mean tumor volume, evaluated on each patient’s last T2/FLAIR MRI sequences, was 59 cc, with a median volume variation along sequential MRIs of 6.4 cc. A B C FIGURE 1. MRI scans in Patient 2 at 0 (A), 18 (B) and 54 (C) days. (T1 with gadolinium sequences). FIGURE 2. MRI scans in Patient 3 at 0 (A), 465 (B), 742 (C), 790 (D), 811 (E), 825 (F) and 854 (G) days (fluid attenuated inversion recovery [FLAIR] and T1 with gadolinium sequences). A B C D E F G Radiol Oncol 2021; 55(1): 26-34. Altieri R et al. / Radiological evaluation of high grade glioma growth 31 Mean MTD at last MRI was 41,66 mm and 24.54 mm for FLAIR and EN volume, respectively, whilst median ΔMTD along the observation period was 5.4 mm and 2.11 mm, for FLAIR and EN volume, respectively (Table 1). Mean VDE was 39.9 mm/year and 45.2 mm/year for FLAIR volume and EN, respectively (Table 1, 2). VDE analysis revealed peak in variation along time. Mean percentage maximal VDE/mean VDE ratio, calculated according to eq. 6, was 221.49% and 259.47% for FLAIR and EN volumes, respec- tively (Table 3). Acceleration analysis according to [eq. 5] re- vealed a mean value of 0.0077 mm/dd2 and 0.0119 mm/days2 for FLAIR and EN volume, respectively. Mean percentage ratio between peak values and mean value of acceleration was 282.7% for FLAIR volume and 257.52% for EN, respectively (table 4). In patient n. 1 late occurrence of the EN didn’t al- low complete evaluation of MTD variation, VDE and Acc (Figure 4). Analysis of EFVR and EFMR, according to eq. 8–13 did not show significant results. Discussion Ex novo HGG diagnosis usually becomes evident when the tumor mass is wide and resection must be carried out as soon as possible. Thus, for each patient no many preoperative MRI scans are avail- able for mathematical analysis of tumor growth. In the past decades, imaging studies on LGG evo- lution23,24 let neurosurgeons to change their mind on treatment: from a “wait-and-see” approach to an early resection one, due to the understand- ing of malignant transformation risk.17,18 Indeed, Mandonnet et al. published in 200819 a pioneering A B C D FIGURE 3. MRI scans in Patient 4 at 0 (A), 160 (B), 196 (C) and 223 (D) days (fluid attenuated inversion recovery [FLAIR] and T1 with gadolinium sequences). FIGURE 4. Velocity of diameter expansion (VDE) variation of mean tumor diameter (MTD) for fluid attenuated inversion recovery [FLAIR] and enhancing nodule (EN) volumes for each patient. Plus the case reported by Mandonnet et al. as specified in Discussion paragraph. Graphic shows variation of acceleration (Acc) based on VDE (mm/days2) for FLAIR tumor volume and EN volume along time. Except obvious similar variation for two types of volume considered, peaks are easily notable. VDE of patient #1 is covered by patient #4. VDE variation for FLAIR and EN volumes Radiol Oncol 2021; 55(1): 26-34. Altieri R et al. / Radiological evaluation of high grade glioma growth32 paper on the role of VDE in LGG and Pallud, few years later, reported that a VDE over 8 mm/year is an independent negative prognostic factor for survival in LGG patients.20 In the past, few studies reported mathematical models of growth based on simple exponential growth of Volume Doubling Time (VDT)25,26 or linear growth of tumor radius.27 In 2015 Stensjoen et al. analyzed tumor’s growth curve in 106 patients, considering two consecutive MRI scans, and reported the Gompertzian growth to be the most reliable mathematical model to pre- dict tumor mass evolution; and this had already been reported by previous studies.9,28,29 As seen in LGG, valuable evaluations of malignancy and evo- lutions could come from MTD analysis and its vari- ation among sequential MRI studies. Mandonnet et al. reported an incidental insular tumor, followed for 9 months: VDE was 12 and 14 mm/year at 5 and 9 months, respectively. Histopathologic analysis then revealed an AA.21 Cochereau et al. reported a secondary GBM, in which VDE after evolution was 13 mm/year.30 In such cases, authors suggest that an annual VDE value over 8 mm/year should represent an alarm for HGG suspect. Our experience with ex novo HGG, shows even higher mean values for an- nual VDE: 39.91 and 45.02 mm/year for FLAIR and TABLE 3. Raw data about velocity of diameter expansion (VDE) of fluid attenuated inversion recovery (FLAIR) and enhancing nodule (EN) volume. Mean percentage maximal VDE/mean VDE ratio could help in early high grade gliomas (HGG) diagnosis Interval of consecutive MRI VDE Pt #1 FLAIR VDE Pt #2 FLAIR VDE Pt #2 EN VDE Pt #3 FLAIR VDE Pt #3 EN VDE Pt #4 FLAIR VDE Pt #4 EN Mean Values 1 35.50 169.23 311.81 16.68 0.00 11.93 16.81 2 17.03 258.82 104.54 6.66 0.00 0.00 10.81 3 32.24 -52.97 -94.91 43.39 64.14 0.00 0.00 4 64.59 47.84 5 155.18 165.74 6 0.00 48.53 Mean Values 28.26 125.03 107.15 47.75 54.37 3.98 9.21 FLAIR VDE Peak/ VDE mean value ratio (percentage) 125.63 135.36 324.99 300.00 221.49 EN VDE Peak/ VDE mean value ratio (percentage) 291.02 304.81 182.57 259.47 Mean Values 240.48 TABLE 4. Raw data of mean acceleration (Acc) based on velocity of diameter expansion (VDE) of fluid attenuated inversion recovery (FLAIR) and enhancing nodule (EN) volume. Mean percentage maximal Acc/mean Acc ratio of each patient could help in early high grade gliomas (HGG) diagnosis Interval of consecutive MRI Acc Pt #1 FLAIR Acc Pt #2 FLAIR Acc Pt #2 EN Acc Pt #3 FLAIR Acc Pt #3 EN Acc Pt #4 FLAIR Acc Pt #4 EN Mean Values 1 0.0003 0.0662 0.1220 0.00010 0 0.0002 0.0003 2 0.0005 0.0394 0.0159 0.00007 0 0.0000 0.0008 3 0.0015 -0.0040 -0.0072 0.00248 0.0037 0.0000 0.0000 4 0.00843 0.0062 5 0.03037 0.0324 6 0.00000 0.0046 Mean Values 0.0008 0.0339 0.0436 0.0069 0.0078 0.0001 0.0004 FLAIR Acc Peak/ Acc mean value ratio (percentage) 195.6695 195.5808 439.7477 300 282.7495 EN Acc Peak/ Acc mean value ratio (percentage) 280.0617 414.7516 77.74935 257.5209 Mean Values 270.1352 Radiol Oncol 2021; 55(1): 26-34. Altieri R et al. / Radiological evaluation of high grade glioma growth 33 EN volume, respectively, enforcing previous find- ings and suggesting a more aggressive behaviour of an ex novo HGG respect the secondary ones. Wide differences in VDE values between our cases and cases reported by other authors, might come from different pathogenisis (primary versus secondary HGG), different observation times and biological features of the brain tumors. However, we want to underline how the VDE variate along the observa- tion time. FLAIR VDE shows peaks, particularly in patients n.3 and n.4, with a ratio between peak and mean VDE value of 324.99% (n = 3.25 mm/dd) and 300% (n = 3 mm/dd), respectively. As shown in Figure 1, VDE variations follow a similar pat- tern in FLAIR and EN volume: progressive growth reach the highest value and then a rapid decrease is registered. Even if such peaks happen in dif- ferent moments for each patients, such difference may be caused by different starting observation time. Speculating the possibility to follow growth curves of different HGG, all with the same onset time, peaks and following decrease could all hap- pen in the same interval of time. Similar pattern, as in our cohort, could be found even in Mandonnet et al. case report.21 Moreover the reported mean VDE of the EN is higher than FLAIR volume VDE sug- gesting the higher biological aggressiveness of the enhancing regions. In addition, not yet reported to our knowledge, mean Acc values show differ- ent peaks along tumor life. In our experience mean percentage ratio between peak and mean Acc val- ues was 270.13%. Last data could improve early di- agnosis of suspected primary or secondary HGG, even if a consensus about MRI timing doesn’t ex- ist. Follow-up MRI scans could be proposed every 4 months31 to patients with early-detected LGG. Pallud et al. proposed a timing between 6 weeks and 3 months according to Chang score.16 However, the wait and see policy in suspected HGG can let tumors grow and induce deficits. Thus, 3 months interval between two consecutive MRIs could be proposed when tumors could be misdiagnosed. Conversely, if strong suspect for HGG exists, obser- vation could be carried out monthly. Indeed, Acc peak over 270% or VDE peak over 240% in com- parison to mean values, for both FLAIR and EN volume, could help in diagnosis. Moreover, no long interval time is needed between MRIs: in our expe- rience Acc variation could be seen even after 15–20 days. Obviously, at least three consecutive MRI scans are needed for VDE and Acc analysis. In sum- mary, even if large series should confirm these data, we strongly propose surgical treatment in case of Acc peak and rapid VDE evolution, due to the high probability that MRI alterations refer to HGG. Such analysis could be helpful as prognostic factor and evolution parameter in case of surgical untreatable patients, i.e. due to poor general conditions or pa- tient refusing surgery. However, sudden changes in VDE and Acc values do not have known causes. A clue could come from evolution of secondary gli- omas, in which a previous LGG has been reported. By now, accumulation of mutation in LGG genes, particularly on chromatin modelling system, let a more aggressive phenotype acquisition. Maybe, as no long observation time has been obtained for HGG, our data could report a crucial moment of HGG evolution. Such peaks could refer to gain of mutation in high percentage of proliferating cells. Thus, MTD could increase in EN and FLAIR due to peripheral disposition of viable glioma cells. Such an expansion would not be compensated by core necrosis. However, too many different factors, i.e. mechanical, growth-factors-related, neo-angio- genesis, supervene in HGG infiltration and evolu- tion. This could also explain our different results in time of peak presentation since first diagnosis, associated with the unknown time of tumor onset. It would be interesting to analyze such variation in animal models, even if inoculation of glioma cells is an important bias in infiltration pattern study. A sudden increase in MTD as reported by VDE and Acc analysis, a biopsy and genetic analysis could be investigated and related if possible. Conclusions To our knowledge, this is the first study describ- ing parameters of acceleration and VDE peak in a retrospective series of ex novo HGG. Through se- quential MRIs and evaluation of these parameters, an early diagnosis of HGG could be done. In addi- tion, time between consecutive MRI scans could be reduced to 15–20 days. This work represent a pilot study on new findings of HGG growth curve, never investigated, due to short observation time in case of HGG suspect. Despite limitations in number of patients and observation time, if our data are con- firmed in larger series, such values could be help- ful as prognostic factors in non-surgical patient. 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Herraiz1 1 Women’s Health Institute José Botella Llusiá, Hospital Clínico San Carlos, Fundación de Investigación del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain 2 Service of Gynecology Oncology. MD Anderson Cancer Center Madrid, Spain 3 Service of Radiology. Hospital Clínico San Carlos, Madrid, Spain 4 Service of Obstetrics and Gynecology, Hospital Sanitas La Zarzuela, Universidad Francisco de Vitoria, Madrid, Spain Radiol Oncol 2021; 55(1): 35-41. Received 16 May 2020 Accepted 5 October 2020 Correspondence to: Pluvio J. Coronado, M.D., Ph.D., Instituto de Salud de la Mujer, Hospital Clinico San Carlos, C/Martín Lagos s/n, 28040, Madrid, Spain. E-mail: pcoronadom@sego.es Disclosure: No potential conflicts of interest were disclosed. Background. The aim of the study was to determine if the endometrial tumor volume (TV) measured by magnetic resonance imaging (MRI-TV) is associated with survival in endometrial cancer and lymph nodes metastases (LN+). Patients and methods. We evaluated the MRI imaging and records of 341 women with endometrial cancer and preoperative MRI from 2008 to 2018. The MRI-TV was calculated using the ellipsoid formula measuring three perpen- dicular tumor diameters. Tumor myometrial invasion was also analyzed. Results. Higher MRI-TV was associated with age ≥ 65y, non-endometrioid tumors, grade-3, deep-myometrial invasion, LN+ and advanced FIGO stage. There were 37 patients with LN+ (8.8%). Non-endometrioid tumors, deep-myometrial invasion, grade-3 and MRI-TV ≥ 10 cm3 were the factors associated with LN+. Using a receiver operating characteristic [ROC] curve, the MRI-TV cut-off for survival was 10 cm3 (area under curve [AUC] = 0.70; 95% CI: 0.61–0.73). 5 years disease-free (DFS) and overall survival (OS) was significantly lower in MRI-TV ≥ 10 cm3 (69.3% vs. 84.5%, and 75.4% vs. 96.1%, respectively). MRI-TV was considered an independent factor of DFS (HR: 2.20, 95% CI: 1.09–4.45, p = 0.029) and OS (HR: 3.88, 95% CI: 1.34–11.24, p = 0.012) in multivariate analysis. Conclusions. MRI-TV was associated with LN+, and MRI-TV ≥ 10 cm3 was an independent prognostic factor of lower DFS and OS. The MRI-TV can be auxiliary information to plan the surgery strategy and predict the adjuvant treatment in women with endometrial cancer. Key words: tumoral volume; magnetic resonance image; endometrial cancer; recurrence; survival Introduction Endometrial cancer (EC) is the most common ma- lignant tumor of the female reproductive tract in developed countries. Its prevalence has increased worldwide in the last years.1,2,3 In Spain, EC is the third most common cancer in women and the most common tumor of the female genital tract.4 Patient prognosis depends on different factors, including stage, depth of myometrial invasion (DMI), lymphovascular space invasion, grade, and nodal status. Besides molecular alterations, DMI is one of the most important morphologic prognos- tic factors, correlating with tumor grade, presence of lymph node (LN) metastases and survival.5,6 Preoperatively, magnetic resonance imaging (MRI) can accurately assess the DMI4, whereas histologic type and grade only can be determined with endo- metrial tumor sampling. Radiol Oncol 2021; 55(1): 35-41. Coronado PJ et al. / Tumoral volume is related to survival in endometrial cancer36 Standard surgical therapy for localized EC in- cludes hysterectomy with bilateral salpingo-oo- phorectomy (HT & BSO); however, the criteria for selecting patients for lymphadenectomy (LND) are still controversial.7,8 During the last two decades many authors have attempted to identify prog- nostic factors for stratifying women with EC into risk categories, in order to tailor the surgical and adjuvant treatment on the basis of estimated risk of tumor dissemination and recurrence.7 Different investigators have defined low-risk groups con- sistent with disease confined to the uterine corpus, histologic grade 1 or 2, endometriod histologic subtype, less than 50% DMI and tumor diameter of 2 cm or less to avoid LND.7,9,10 The LN evalua- tion is recommended in intermediate and high-risk EC.8 However, recent matched-pair studies have observed a lack of survival benefit of the systematic LND in those types of EC.11,12 Although tumor size is a factor that determines the stage of disease in many types of cancer (head and neck, breast, lung, renal, uterine cervix, vulva, uterine sarcoma, melanoma and soft tissue sar- coma), it is not involved in defining the stage of EC.13 Different authors have been trying to dem- onstrate the relationship between tumor diameter in resected uterine specimens and prognosis in EC.9,10 Naturally, postoperative assessment is not suitable for taking decisions of the better surgical approach and for selecting patients for neoadju- vant therapies. Therefore, preoperative assessment impacts the planning for surgery.14 Hence, some recent Japanese studies measured preoperatively tumor volumes by MRI, concluding that it is ef- fective for predicting LN metastases and planning the LND.15,16 However, there is no good evidence about the role of tumor volume (TV) measured by MRI in the patient’s prognosis. The aim of this study was to determine if the tumor volume measured in the preoperative MRI study (MRI-TV) has a relationship with disease- free survival (DFS) as a primary objective and with overall survival (OS) and LN involvement as sec- ondary goals. Patients and methods A historical cohort of women diagnosed of EC between 2008 and 2018 was analyzed in Hospital Clinico San Carlos in Madrid, Spain. We includ- ed all women diagnosed of EC who underwent a presurgical MRI. All the patients had undergone HT & BSO. Pelvic or pelvic and para-aortic LND were always performed by the same oncological team. Women diagnosed with uterine sarcomas or concomitant neoplasm, those who had been treated with primary chemo and/or radiotherapy or had been operated without presurgical MRI were excluded. The study was approved by the lo- cal Institutional Review Boards (No. 16/443-E). All patients were managed according to the guidelines approved by the Spanish Society of Gynecology and Obstetrics and all of them signed a specific consent form.17 All MRI studies were performed in 1.5T mag- nets (Signa Excite and Signa HDx, General Electric Medical Systems) using a standard protocol. High- resolution T2 weighted images were acquired in three perpendicular planes and then contrast en- hanced T1 fat suppressed series were acquired in two or three different planes. Diffusion weighted sequences (b ≥ 800 s/mm2) were acquired in most, but not in all the cases. All MR images were ana- lyzed in the Radiology Service of the center by ex- pert radiologists. The maximum tumor diameters were measured in three perpendicular axes, on the images that showed better the tumor-to-myometri- um contrast (usually on the gadolinium enhanced series, having the T2 and diffusion images as ref- erences). The tumoral volume was calculated us- ing the ellipsoid volume formula (length × height × width × [π/6]). In addition, DMI was assessed following the standardized criteria using unenhanced T2 and gadolinium enhanced T1 series. DMI was defined as the distance between the myometrial interface and the deeper invasion point. Deep myometrial invasion was considered when the tumor affected 50% or more of the myometrial thickness. In 237 cases in which it was the retrieved ultra- sound reports, there was information about the DMI that was recorded and included. DMI was assessed during a real-time two-dimensional ex- amination, and deep myometrial invasion was measured as the distance between endometrium- myometrium junction and maximum tumor depth. In our center, intraoperative frozen section eval- uation (FSE) of DMI is routinely performed. This information was available and recorded in 189 cas- es. Two pathologists with wide experience in gy- necological cancers where the ones that performed the intraoperative assessment of myometrial inva- sion and histological grade in all of the samples. Continuous variables were described as median and interquartile range [p25-p75] and were com- pared using the T-test in normal distributions or the Mann-Whitney test in non-parametrical dis- Radiol Oncol 2021; 55(1): 35-41. Coronado PJ et al. / Tumoral volume is related to survival in endometrial cancer 37 tributions. Discrete variables were represented with absolute frequencies and percentages, and they were compared by the Chi-squared test or the Fisher’s exact test in case of small cell comparisons. The McNemar test was used to assess the differenc- es among the techniques evaluating the deep myo- metrial invasion. Receiver operating characteristic (ROC) curve was calculated to analyze the relation between the tumoral volume measured by MRI and the recurrence in order to identify the tumoral volume cut-off predicting the relapse. For survival analysis, Cox’s method was used in order to assess which factors were directly associated with surviv- al. Multivariate modeling using Cox’s proportional hazard models, including the significant variables in univariate analysis, was performed to obtain a subset of independent predictors of DFS and OS. Hazard ratio (HR) with a 95% confidence interval (CI) was calculated. The Kaplan-Meier method was used to estimate the survival distribution depend- ing on the tumoral volume using the cut-off cho- sen. The Log-Rank (Mantel-Cox) test was used to calculate the statistical signification between the groups in relation to disease recurrence and death. All statistical tests were 2-sided and statistical sig- nificance was defined as a p-value lower than 0.05. All computations were performed using IBM SPSS Statistic version 22.0 for Windows. Results The series baseline is shown in the Table 1. The highest accuracy for detecting DMI was the intra- operative FSE (sensitivity 94%, 95% CI: 88–100%) The MRI had sensitivity of 75%, 95% CI: 66–84% and transvaginal ultrasound 58%, 95% CI: 47–69 %, respectively. FSE was significantly more sensitive in detecting deep myometrial invasion than MRI (p = 0.049). The median of MRI-TV was 8.2 cm3 (interquartile range [IQR]: 1.9–20.4). We found that higher MRI- TV was associated with advanced age, the highest histological grade 3, deep myometrial invasion, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, LN involvement, dis- ease recurrence and death (Table 2). In order to identify a MRI-TV cut-off that could be considered a risk factor in EC, we performed a ROC curve. The more efficient cut-off in detection of tumor recurrence was a TV = 10 cm3, showing a 72.5% sensitivity and 59.8% specificity detecting the tumor recurrence (area under curve [AUC] = 0.70; 95% CI: 0.61–0.73). Analyzing only the 216 cases in which LND was performed, we found that the LN involvement was associated with the histological subtype, grade 3 and DMI. MRI-TV ≥ 10 cm3 was significantly as- sociated with LN metastases (Table 3). After a median follow-up of 30.5 months (IQR 18.5-46.2), 51 (15.0%) women presented a relapse and 29 (8.5%) deceased. Among the relapsed pa- tients, 8 were alive and free of disease, 22 were alive with disease, and 21 died. Among the deceased pa- tients, 21 women had disease-related death, and 8 died due to other causes. TABLE 1. Baseline patient´s characteristics Variable N=341 Age (years) < 65y ≥ 65y 65.7 [58.0–74.0] 186 (54.5%) 155 (45.5%) BMI (kg/m2) < 30 ≥ 30 29.3 [24.8–33.0] 200 (58.7%) 141 (41.3%) Histologic subtype Endometrioid Mucinous Squamous Serous Papillary Clear cells Mixed mesodermal tumors Undifferenced 278 (81.5%) 5 (1.5) 6 (1.8%) 23 (6.7%) 13 (3.8%) 12 (3.5%) 1 (0.3%) Histological Grade G1 G2 G3 159 (46.6%) 86 (25.2%) 96 (28.25%) Myometrial invasion < 50% ≥ 50% 207 (60.7%) 134 (39.3%) FIGO stage I II III IV 270 (79.2%) 15 (4.4%) 45 (13.2%) 11 (3.2%) Surgical treatment HT & BSO alone With pelvic lymphadenectomy With pelvic & paraaortic lymphadenectomy 96 (37.4%) 74 (28.8%) 87 (33.9%) Lymph nodes status (N = 216) Negatives Positives 179 (82.9%) 37 (17.1%) Adjuvant treatment None Irradiation Chemotherapy Irradiation and Chemotherapy 150 (44.0%) 146 (42.8%) 9 (2.6%) 36 (10.6%) Follow-up (months) 30.5 (18.5–46.2) Recurrence 51 (15.0%) Decrease 29 (8.5%) Data are given as median and [interquartile range, p25-p75] or number (percentage). BMI = body mass index; FIGO = International Federation of Gynecology and Obstetrics; HT & BSO = hysterectomy with bilateral salpingo- oophorectomy Radiol Oncol 2021; 55(1): 35-41. Coronado PJ et al. / Tumoral volume is related to survival in endometrial cancer38 A B FIGURE 1. Kaplan Meier curves representing the survival in relation of tumoral volume measured by magnetic resonance. (A) Disease-free survival; (B) Overall Survival. Survival analysis showed a 5-year DFS of 69.3% in tumors ≥ 10 cm3, which was significantly lower than in tumors of < 10 cm3 (84.5%, Log Rank test: 0.001) (Figure 1A). In relation to OS, 5-year OS sur- vival was lower in tumors ≥ 10 cm3 in comparison with tumors < 10 cm3 (75.4% vs. 96.1%, Log Rank test: 0.002) (Figure 1B). Cox’s univariate analysis identified the age (p < 0.001), MRI-TV (p = 0.001), non-endometrioid tumors (p = 0.006), grade-3 (p < 0.001), myometrial invasion (p = 0.009) and ad- vanced stage (p < 0.001) as predicting factors of TABLE 2. Relation between tumor volume measured by magnetic resonance and pathological factors in 341 endometrial cancer Variables MR tumor volume cm3 p value* Tumoral volume 8.2 (1.9–20.4) - Age (years) < 65 ≥ 65 5.4 (1.5–15.4) 11.0 (2.8–30.0) 0.001 BMI (kg/m2) < 30 ≥ 30 9.1 (2.3–22.3) 7.5 (1.6–23.6) 0.525 Histologic subtype Endometrioid Non endometrioid 7.9 (1.8–20.4) 12.4 (3.3–40.1) 0.859 Histological Grade G1–G2 G3 6.7 (1.3–17.2) 13.8 (4.6–41.0) < 0.001 Myometrial invasion < 50% ≥ 50% 4.6 (1.2–15.4) 14.1 (5.7–35.1) < 0.001 FIGO stage I–II III–IV 7.6 (1.5–19.6) 15.6 (6.5–44.7) < 0.001 Lymph node status (N = 216) Negatives Positives 9.3 (3.3–20.9) 15.6 (6.3–40.7) 0.008 Recurrence No Yes 7.6 (1.7–17.4) 22.4 (5.6–49.2) < 0.001 Overall Survival Alive Death 8.0 (1.8–18.6) 30.5 (9.6–56.4) < 0.001 Data are gives as median (p25–p75). * = Mann-Whitney U independent sample test; BMI = body mass index; FIGO = International Federation of Gynecology and Obstetrics recurrence (Table 4). MRI-TV (p = 0.029), grade 3 (p < 0.001) and advanced stage (III–IV) (p = 0.047) were the independent factors of recurrence in the multivariate analysis (Table 5). In relation with OS, the age (p < 0.001), MRI-TV (p = 0.005), grade-3 (p = 0.001) and advanced stage (p = 0.001) were the pre- dictor factors of mortality (Table 4). In multivariant analysis, MRI-TV (p = 0.012) and grade-3 (p = 0.011) were the independent factors of OS. Discussion In woman with EC, the preoperative MRI-TV cor- relates with the LN involvement and is an inde- pendent prognostic factor for DFS and OS in this series. A cut-off of 10 cm3 determines properly the cases that might present with positive LN and should undergo LND. It also adds information about poor prognosis and the need for adjuvant treatment. The relation between relapse and MRI- Radiol Oncol 2021; 55(1): 35-41. Coronado PJ et al. / Tumoral volume is related to survival in endometrial cancer 39 TV in EC has been described by other studies. A Japanese study in 667 women with EC and us- ing a volume index defined as the product of the maximum diameter in the 3 planes (longitudinal, anteroposterior and horizontal), found a MRI-TV ≥ 36 cm3 as an independent prognostic factor of OS (HR 2.0; 95% CI:1.3–3.1).18 This study used as cut- off a fixed value of MRI-TV based on other study from the same group16, and considered the vol- ume of the endometrial cavity as a single measure of three measures. In our study, the endometrial cavity was considered as ellipsoid, more like the real shape of the endometrial tumor. However, both studies have similar outcomes, suggesting the MRI-TV is an independent prognostic factor to take in consideration in the preoperative assess- ment of women diagnosed of EC. In addition, the MRI-TV in the Japanese study was significantly associated with LN involvement, especially when TV was ≥ 125 cm3. Similar finding was also found in our study when we analyzed the MRI-TV both as continuous variable and as qualitative using 10 cm3 as cut-off value. The differences in the cut-off may be because of the different method to measure the endometrial cavity. A Japan-Korea cooperative study with the same methodology, found similar results in 327 cases, showing a MRI-TV > 36 cm3 as an independent prognostic factor of LN metas- tases.19 Other studies analyzing the preoperative metabolic volume by PET/CT and MRI found the tumor volume as an independent prognostic fac- tor for DFS and it was significantly associated with recurrence in patients with endometrioid EC.20 MRI has been considered as the best technique to diagnose deep myometrial invasion. However, in our series, the best option was FSE. A recent study found a higher performance using fusion of T2-weighted magnetic with diffusion-weighted MR images, with a sensitivity of 92.3% and speci- ficity of 95.5% for deep myometrial invasion detec- tion.21 In relation to ultrasound, we obtained a poor result in order to detect the deep myometrial in- vasion. A recent study analyzing 210 women with proven EC found that both subjective assessment and objective ratios were significant predictors of the myometrial invasion, but subjective assess- ment was confirmed as the most reliable method to assess myometrial invasion (sensitivity 79% and specificity 73%).22 A meta-analysis of 35 studies with 6387 women diagnosed of EC found that FSE had a significantly better diagnostic performance than intraoperative gross evaluation (sensitivity 84% vs. 71%) for the intraoperative diagnosis of deep myometrial invasion. The tumoral size has been associated with sever- al classic prognostic factors and it has been consid- ered as a prognostic factor in many human tumors, including gynecological tumors such as cervix, vulva and breast, but not in ovarian and EC.13 The Mayo clinic criteria in EC9, suggested the tumoral size > 2 cm as high risk of LN metastases. In our series, the MRI-TV was associated with the classi- cal prognostic factors in the EC. This finding was also found by other authors.18,19 High-risk clinico- TABLE 3. Predictor factors of lymph node metastases in 216 cases of endometrial cancer with known lymph node status Variables No lymph node metastases N = 179 Lymph node metastases N = 37 p value Age (years) < 65 ≥ 65 78 (43.6%) 101 (56.4%) 12 (32.4%) 25 (67.6%) 0.211 Histologic subtype Endometrioid Non endometrioid 147 (82.1%) 32 (17.9%) 23 (62.2%) 14 (37.8%) 0.007 Histological Grade G1–G2 G3 118 (56.9%) 61 (43.1%) 13 (35.1%) 24 (64.9%) < 0.001 Myometrial invasion < 50% ≥ 50% 90 (50.3%) 89 (49.7%) 8 (21.6%) 29 (78.4%) 0.001 Maximum tumor size < 2 cm ≥ 2 cm 43 (24.0%) 136 (76.0%) 6 (16.2%) 31 (83.8%) 0.390 MR tumor volume < 10 cm3 ≥ 10 cm3 61 (34.1%) 118 (65.9%) 5 (13.5%) 32 (86.5%) 0.013 TABLE 4. Analysis of disease-free and overall survival using Cox regression model Variables Disease-free p value overall p value Age (continue, years) 1.06 (1.03–1.09) < 0.001 1.09 (1.05–1.13) < 0.001 MRI tumor volume < 10 cm3 ≥ 10 cm3 1 2.99 (1.50–5.99) 0.001 1 4.50 (1.56–12.93) 0.005 Histologic subtype Endometrioid Non endometrioid 1 2.55 (1.30–5.01) 0.006 1 2.40 (0.97–5.95) 0.052 Histological Grade G1–G2 G3 1 4.02 (2.31–6.98) < 0.001 1 3.55 (1.71–7.37) 0.001 Myometrial invasion < 50% ≥ 50% 1 2.10 (1.20–3.64) 0.009 1 1.89 (0.91–3.93) 0.088 FIGO stage I–II III–IV 1 6.70 (3.83–11.72) < 0.001 1 3.94 (1.79–8.68) 0.001 Data are given in Hazard Ratio (95% confidence interval). FIGO = International Federation of Gynecology and Obstetrics; MRI = magnetic resonance image Radiol Oncol 2021; 55(1): 35-41. Coronado PJ et al. / Tumoral volume is related to survival in endometrial cancer40 pathological features (such as deep myometrial invasion, histological grade and non-endometrioid subtypes), LN involvement and advanced FIGO stages were increased with higher MRI-TV, sug- gesting a positive correlation between it and the adverse outcomes. Sentinel node biopsy is a good way to have LN status information and to avoid the complete LND.23 However, this procedure is not free of com- plications and a preoperative information predict- ing the LN involvement could help in the process of making the decision of whether or not to per- form the LN assessment. Based on our results, we suggest performing a LN assessment in EC with large TV. Nevertheless, we cannot set the best TV cut-off from which assess the LN status. In our study, the TV was measured by different radiologist, and even though we used the same cri- teria, it could be a limitation because of the inter- observer variability that can alter the endometrial measures. On the other hand, the type of adjuvant treatment and the type of surgery could differ be- tween the cases and this could have influenced the patients’ survival. The main strength of this study, with respect to others that also analyzed the TV, is the use of an ellipsoid to measure the TV, because is the shape more similar to endometrial cavity, and the result of the product of three single meas- ures results on a cubic shape. Conclusions In conclusion, the TV measured by MRI is a pre- dictor of high-risk pathological factors, and it is positively associated with LN involvement. The TV higher than 10 cm3 is related with poor prog- nosis in univariate and multivariate analysis. 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Milam MR, Java J, Walker JL, Metzinger DS, Parker LP, Coleman RL. Gynecologic Oncology Group. Nodal metastasis risk in endometrioid endometrial cancer. Obstet Gynecol 2012; 119: 286-92. doi: 10.1097/ AOG.0b013e318240de51 15. Todo Y, Sakuragi N, Nishida R, Yamada T, Ebina Y, Yamamoto R, Fujimoto S. Combined use of magnetic resonance imaging, CA 125 assay, histologic type, and histologic grade in the prediction of lymph node metastasis in endometrial carcinoma. Am J Obstet Gynecol 2003; 188: 1265-72. doi: 10.1067/mob.2003.318 16. Todo Y, Okamoto K, Hayashi M, Minobe S, Nomura E, Hareyama H, et al. A validation study of a scoring system to estimate the risk of lymph node metastasis for patients with endometrial carcinoma for tailoring the indica- tion of lymphadenectomy. Gynecol Oncol 2007; 104: 623-8. doi: 10.1016/j. ygyno.2006.10.002 TABLE 5. Multivariant analysis of disease-free and overall survival using Cox regression model with the classic histological prognostic factors Variables Disease-freesurvival p value Overall survival p value MRI tumor volume < 10 cm3 ≥ 10 cm3 1 2.20 (1.09–4.45) 0.029 1 3.88 (1.34–11.24) 0.012 Histologic subtype Endometrioid Non endometrioid 1 1.06 (0.50–2.24) 0.873 1 1.16 (0.43–3.16) 0.766 Histological Grade G1–G2 G3 1 3.60 (1.95–6.66) < 0.001 1 3.07 (1.47–6.41) 0.003 Myometrial invasion < 50% ≥ 50% 1 1.77 (1.01–4.46) 0.047 1 1.51 (0.72–3.17) 0.279 Data are given in Hazard Ratio (95% confidence interval). MRI = magnetic resonance image Radiol Oncol 2021; 55(1): 35-41. Coronado PJ et al. / Tumoral volume is related to survival in endometrial cancer 41 17. Oncoguía SEGO (ES). [Guide of practice clinic in cancer gynaecology and senology]. [Spanish]. Madrid: Publicaciones SEGO; 2010. 18. Todo Y, Watari H, Okamoto K, Hareyama H, Minobe S, Kato H, et al. 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Frühauf F, Zikan M, Semeradova I, Dundr P, Nemejcova K, Dusek L, et al. The diagnostic accuracy of ultrasound in assessment of myometrial invasion in endometrial cancer: subjective assessment versus objective techniques. Biomed Res Int 2017; 2017: 1318203. doi: 10.1155/2017/1318203 23. Ruiz R, Gorostidi M, Jaunarena I, Goiri C, Aguerre J, Lekuona A. Sentinel node biopsy in endometrial cancer with dual cervical and fundal indocya- nine green injection. Int J Gynecol Cancer 2018; 28: 139-44. doi: 10.1097/ IGC.0000000000001151 Radiol Oncol 2021; 55(1): 42-49. doi:10.2478/raon-2021-0003 42 research article Trends in population-based cancer survival in Slovenia Vesna Zadnik1, Tina Zagar1, Katarina Lokar1, Sonja Tomsic1, Amela Duratovic Konjevic2, Branko Zakotnik1 1 Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Institute of Oncology Ljubljana, Ljubljana, Slovenia Radiol Oncol 2021; 55(1): 42-49. Received 2 January 2021 Accepted 10 January 2021 Correspondence to: Prof. Vesna Zadnik, M.D., Ph.D., Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: vzadnik@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. The aim of our study was to describe the survival of Slovenian cancer patients diagnosed in the last twenty years. An insight is given into the improvement made in different cancer types, population groups and prog- nostic factors. Materials and methods. The principal data source was the population-based Slovenian Cancer Registry. The survival analysis included patients diagnosed with cancer in twenty years period from 1997 to 2016, which has been divided into four consecutive five-year periods. In addition, the analysis was stratified by cancer type, gender, age and stage. The survival was estimated using net survival calculated by the Pohar-Perme method and the complete approach has been applied. Results. The survival of Slovenian cancer patients has been increasing over time. During the 20 years observed, five- year net survival increased by 11 percentage points. Significantly higher growth was observed in men. Age and stage at diagnosis are still crucial for the survival of cancer patients. Five-year net survival is lowest in those over 75 years of age at diagnosis but has also improved by seven percentage points over the past 20 years. The five-year net survival of patients in the localized stage increased by ten percentage points over the 20 years under observation. Survival of patients in the distant stage has not been improving. In both sexes, survival for melanoma, colorectal and lung cancers have increased significantly over the last 20 years. Progress has also been made in the two most common gender specific cancers: breast cancer in women and prostate cancer in men. Still, the significant progress in prostate cancer is probably mostly due to lead-time bias as during the study period, Slovenia used indiscriminate PSA testing, which probably artificially prolonged survival. Conclusions. The survival of Slovenian cancer patients has been increasing over time, which gives us a basis and an incentive for future improvements. To monitor the effectiveness of managing the cancer epidemic, the cancer burden needs to be monitored also in the future, using quality data and scientifically justified methodological ap- proaches. In this process a well organised population-based cancer registries should play a key role. Key words: cancer burden; cancer survival; time trend; Slovenian Cancer Registry Introduction Global health indicators show that cancer is an epidemic of modern times. Epidemiological in- dicators from Slovenian Cancer Registry confirm similar situation also in Slovenia. Among all causes of death, it ranks 1st in men and 2nd in women. In recent years, 15,000 Slovenes per year have devel- oped cancer, and slightly over 6,000 have died of cancer. There are more than 120,000 people living in Slovenia who had ever been diagnosed with can- cer. Since cancer is more common among the el- derly (only a third of patients are younger than 65 years at the time of diagnosis), and the Slovenian Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia 43 population is ageing, it is expected that the burden of this disease will increase, even if the level of risk factors remains the same as today.1,2 Continuous and systematic collection, storage and analysis of data on all cancer patients in a de- fined population is the basis for controlling this major public health problem – a key role is played by population-based cancer registries. One of their main purpose is to collect accurate and complete cancer data that can be used to plan and evaluate the National Cancer Control Programmes, specifi- cally in the fields of primary and secondary pre- vention, diagnostics, treatment and rehabilitation and palliative care, to plan the capacities and re- sources needed to manage cancer (staff, medical equipment, hospital and rehabilitation facilities).3 Incidence, mortality and survival are the main cancer burden indicators that are reported by the population-based cancer registries. Cancer mortal- ity is the primary indicator of the cancer burden worldwide, since it is available for the largest num- ber of countries. Mortality depends on the number of new patients (incidence) on one hand and on their survival on the other. Survival itself does not depend on the incidence, as it considers only those who have already fallen ill, so it indirectly indi- cates the success of diagnosis and treatment (in pa- tients with earlier diagnosed disease and prompt treatment according to guidelines, a better survival is expected) and is considered as the most power- ful indicator. The population survival of cancer pa- tients, as shown by cancer registries is, therefore, a composite indicator. It reflects the characteristics of patients as well as the organization, accessibil- ity, quality, and efficiency of the healthcare system. Clinical studies usually present the results of sur- vival of groups of patients with a specific disease and for specific well-defined treatment, where strict entry criteria for the study group are defined, such as stage, performance status 0 or 1, normal organ function, age under 70 years etc. Population data on survival significantly differs from that. Population survival is affected, for example, by the disease stage at diagnosis, which depends on the time length from the first signs to the visit of gen- eral practitioner and further to the time of diagno- sis. This time may be reduced through informing the population about when to visit a physician in case of health problems and the ability of general practitioners to consider the possibility of a serious disease, through increasing the availability of di- agnostic tests, and minimising waiting times. The availability of screening programmes with proved benefit further increases the chances of cure or at least better survival, as they detect precancerous le- sions or early-stage of the disease. Once diagnosed, the success of treatment depends on the type of cancer, the patient’s characteristics (age, comorbid- ities, general physical performance, etc.) and also on the availability of multidisciplinary treatment and the qualifications of the medical team. All of these diverse factors that determine population survival must be considered by the researcher or clinician who interprets the results of population survival studies, and even more so when compar- ing survival between countries.4 In this study we are presenting the survival of Slovenian cancer patients diagnosed in the last twenty years. An insight is given into the improve- ment that was made in different cancer types, dif- ferent population groups (gender and age) and stage at diagnosis. The survival improvements support reported ongoing progress achieved by Slovenian oncology and Slovenian healthcare sys- tem. The results of survival analysis are further discussed in the comprehensive report, which con- tains also insights from clinical experts who are in- volved in specific treatment of cancer patients in Slovenia.5 Materials and methods The principal data source for the analysis is the population-based Slovenian Cancer Registry (SCR). Thus, the data refer to all cancer patients, residents of Republic of Slovenia at the time of di- agnosis, irrespective of where they have been diag- nosed, treated or where they have died. The SCR’s quality and completeness indices prove that can- cer registration in Slovenia adequately covers the entire population.6 To assure completeness and to obtain additional information on registered cancer cases, SCR is linked with several governmental and health databases. Synchronisation of data between different sources is based on unique personal iden- tification number, which is assigned to every resi- dent in Slovenia and recorded in every state regis- try including SCR. Using unique personal identifi- cation number guaranties data integrity, data qual- ity and prevents duplication. SCR is linked with the Central Register of Population through secure on-line connection (24/7 availability) and daily up- dates information on vital status and address for each person registered by SCR. The electronic link- age to the national Mortality Database and to the breast, colorectal and cervical screening registries is performed at least once per year.6,7 Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia44 The data on gender, date of diagnosis, age at diagnosis, code of primary site according to the International classification of Diseases (10th edi- tion), stage at diagnosis (general categorization into localized, regional or distant stage) and vital status with the date of end of follow-up (date of death, date of lost to follow-up or date of the end of study) were extracted from the SCR’s database for all cancer cases. The survival analysis included pa- tients who were diagnosed with cancer in the years from 1997 to 2016. The entire observed period has been divided into four consecutive five-year peri- ods. The patients older than 95 years of age were excluded from survival analysis. Separate analyses were made for children (0–14 years), adolescents (15–19 years) and adults (20–94 years). All analyses were performed on data registered in the SCR database on 1st September 2019 and 234,827 cases of cancer were extracted from the database. Among them, there were 37,917 non- melanoma skin cancer patients. Because this is a frequent but almost completely curable disease, we excluded these patients from the analysis. Further, we excluded 1,711 cases of cancer being registered by death certificate only, since the date of diag- nosis is unknown, 4,470 cases in which the date of registration was the same as the date of death (mostly they are diagnosed at autopsy), and 668 cases in which the person was 95 years of age or older. The vital status of patients was last checked on 31st August 2019. At the end of the observation period, the person can be alive, dead or lost from the vital statistics records. Between 1997 and 2001, 26 persons with no follow-up data in the Central Register of Population were registered in the SCR (0.06% of 45,390 new cancer cases during this pe- riod) and only 3 persons with no follow-up data between 2002 and 2016 (0.002% of 189,437). In the group of patients, the survival is interpret- ed as the proportion of patients who are still alive after a certain time from the diagnosis. Survival time is defined as the time between the date of can- cer diagnosis and the date of the end of follow-up. The survival was estimated using net survival cal- culated by the Pohar-Perme method. Net survival is the survival that would be observed if the only cause of death was the disease we are studying, i.e. causal specific survival. For example, a net survival of 30% over five years tells us that in a hypotheti- cal case where patients would die only from cancer and no other causes, 70% of those patients would die within five years from diagnosis.8,9 Because all the included patients were not followed-up for five years we have applied the complete approach in the survival calculation.10 For the calculation, we used the relsurv library for the R software environment.11 Results and discussion There were 191,154 patients aged 20 to 94 years di- agnosed between 1997 and 2016 with any cancer (non-melanoma skin cancer excluded). Throughout the observed period, slightly more men than wom- en were diagnosed, of which most were aged from 50 to 74 years. In solid tumours, the disease was mostly detected in the localized stage. The five most frequent cancers in Slovenia – non-melanoma skin, prostate, colorectal, breast and lung cancer – account for 60% of all new cancer cases.1 Survival of cancer gradually increased in rela- tion to the year of diagnosis. Over the 20-year peri- od, five-year net survival increased by slightly less than 11 percentage points (Figure 1). The rise is in concordance to observed in our last three reports on survival of Slovenian cancer patients diagnosed with cancer between 1963–1990, 1983–1997 and 1995–2005.12,13,14 According to the CONCORD-3 study which compared the five-year net survivals of adult patients with 15 different cancers between 2010 and 2014 in 26 European countries, in most cases the survivals of Slovenian cancer patients are below the European average.14 As presented in Table 1, in the first observed period, between 1997 and 2001, the net five-year survival for all cancers combined was much bet- ter for women than for men, with a difference of 16 percentage points. In the 20-year period signifi- cantly higher growth was observed in men, where five-year net survival increased by 17 percentage points (from 38% to 56%). In women, five-year net survival increased by six percentage points (from 54% to 60%). At a first glance, it seems that men have started to take better care of their health and that the ‘macho’ male population (refusing to see a doctor) is disappearing. Undoubtedly, breast and prostate cancer, which represent as many as a fifth of all cancer patients in men and women, contrib- ute the most to reducing the gap between the gen- ders. A large proportion of the increase in survival in men can be attributed to the survival of patients with prostate cancer, where it rose by as much as 21 percentage points (Table 1). However, this significant progress in prostate cancer survival is probably mostly artificial (lead time bias), since we used indiscriminate PSA testing in Slovenia quite uncritically during the study period, with which we also detected those prostate cancers that devel- Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia 45 FIGURE 1. Five-year net survival (with a 95% confidence interval) of adult patients (20–94 years) with selected cancers, Slovenia 1997–2001 and 2012–2016. Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia46 op slowly and would not cause health problems for men during their lifetime. This artificially prolongs survival, as the disease is detected earlier, but the course of the disease is not changed.15 However, the most common cancer in women, breast cancer, has not seen such a large improvement in survival (Table 1). The breast cancer screening programme was introduced across the whole country only in 2018, so it could not make a significant contribu- tion to the results of our current analysis.16 In both sexes, survival for other three common cancers have increased significantly over the last 20 years: colorectal cancer (by 14 percentage points, from 48% to 62%), cutaneous melanoma (by 11 percentage points, from 79% to 90%), and lung cancer (by 8 percentage points, from 10% to 18%) (Figure 1). These results reflect earlier diagnostics and advances in systemic treatment. Despite treat- ment progress, the survival of lung cancer patients remains low. There are some other cancers where almost no progress over time was observed and in which survival remains low including pancreatic, oesophageal, gallbladder and bile duct, liver and brain cancers. TABLE 1. Five-year net survival (with a 95% confidence interval) of adult patients (20–94 years) with selected cancers by sex, Slovenia 1997–2001 and 2012–2016 Cancer type Male Female 1997–2001 2012–2016 1997–2001 2012–2016 Five- year net survival 95% confidence interval Five- year net survival 95% confidence interval Five- year net survival 95% confidence interval Five- year net survival 95% confidence interval C00-C14 Mouth and pharynx 34.4 31.6-37.3 43.6 40.6-46.8 61.1 53.8-69.4 65.2 58.5-72.8 C32 Larynx 59.4 54.4-64.9 62.1 56.3-68.4 67.9 55.2-83.5 51.5 38.6-68.5 C15 Oesophagus 5.1 3.2-8.1 10.5 7.5-14.9 8.2 3.7-18.3 14.2 8.0-25.1 C16 Stomach 20.7 18.4-23.4 31.6 28.8-34.7 25.4 22.4-28.9 30.7 27.3-34.7 C18-C20 Colon and rectum 47.1 44.9-49.5 63.1 61.1-65.2 48.7 46.3-51.2 59.7 57.4-62.1 C22 Liver and intrahepatic bile ducts 2.9 1.3-6.4 12.3 9.5-15.9 3.4 1.0-11.6 9.1 4.8-17.1 C23-C24 Gallbladder and billiary tract 11.9 8.0-17.5 14.7 11.2-19.3 6.5 4.3-9.9 13.7 10.6-17.8 C25 Pancreas 4.3 2.7-4.8 4.7 3.4-6.6 2.8 1.7-4.8 6.0 4.5-8.0 C33-C34 Trachea, bronchus and lung 9.6 8.6-10.7 15.5 14.3-16.8 11.4 9.5-13.6 22.1 20.2-24.1 C38.0, C47-C49 Connective and soft tissue 61.3 51.1-73.7 58.0 48.9-68.7 55.0 45.1-67.0 52.0 44.8-60.3 C40-C41 Bone 66.7 52.3-85.1 65.7 48.9-88.3 66.0 50.7-86.1 51.8 36.5-73.3 C43 Malignant melanoma of skin 75.4 70.9-80.3 90.0 87.0-93.2 81.8 77.9-85.8 90.8 88.0-93.7 C50 Breast - - - - 77.5 76.0-79.0 87.6 86.3-88.9 C53 Cervix uteri - - - - 73.1 70.2-76 69.0 64.7-73.7 C54 Corpus uteri - - - - 79.8 77.1-82.6 80.6 78.0-83.3 C56 Ovary - - - - 47.9 44.5-51.6 40.4 36.7-44.5 C61 Prostate 71.1 68.4-73.8 92.3 91.0-93.7 - - - - C62 Testis 96.4 94.2-98.7 97.6 95.9-99.3 - - - - C64-C65 Kidney with renal pelvis 56.5 52.1-61.3 64.6 61.1-68.3 61.4 56-67.4 69.3 64.8-74.1 C67 Bladder 48.5 44.1-53.2 55.3 51.3-59.6 50.5 42.9-59.4 44.4 38.4-51.3 C70-C72 Central and autonomic nervous system 13.2 9.8-17.9 15.8 12.4-20.1 18.7 14.2-24.7 15.0 11.4-19.7 C73 Thyroid gland 88.1 79.5-97.7 90.6 85.1-96.4 86.6 82.1-91.4 95.3 92.7-97.9 C81 Hodgkin's lymphoma 78.3 69.3-88.5 78.3 69.2-88.5 79.0 69.5-89.7 85.7 77.3-95.1 C82-C85 non-Hodgkin's lymphoma 55.1 49.8-60.9 65.7 61.9-69.8 54.7 49.8-60.1 61.3 57.6-65.2 C90 Multiple myeloma and malignant plasma cell neoplasms 36.8 28.9-46.9 38.9 32.6-46.4 32.8 26.4-40.7 44.0 37.5-51.5 C91-C95 Leukaemias 49.8 44.7-55.4 46.0 41.8-50.6 41.6 36.2-47.9 47.2 41.9-53.0 C00-C96 (but C44) All sites, but skin 38.4 37.6-39.2 55.8 55.0-56.5 54.3 53.4-55.1 59.9 59.1-60.6 Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia 47 Age and stage at diagnosis are prognostic fac- tors for disease development and treatment out- come and also for the survival of cancer patients. The survival of persons aged 20 to 49 was better in the last two periods compared to other age groups and improved by 15 percentage points in period 2012 to 2016 compared to the period 1997 to 2001 (Figure 2). Five-year net survival is lowest in those over 75 years of age but also in this age group has improved by seven percentage points over the last 20 years. The number of older patients with cancer is increasing in Slovenia, for example, the number of patients aged over 75 has more than doubled in the analysed period.17 It is precisely these patients who most frequently have comorbidities that can severely limit attainability of specific oncological treatment, which explains why the proportion of patients without specific oncological treatment re- mained roughly the same through time despite the increasingly complex treatments available - around 20% according to the last SCR’s report on cancer patient’s survival.5 We can conclude that doctors equally often decide to treat elderly patients, al- though more complex treatments are often accom- panied by many more side effects. Consequently, as seen from our analysis in the last three time pe- riods, the five-year net survival of the oldest group of patients still remained almost the same, while in the younger groups it increases steadily and signif- icantly. Apparently, the age and concomitant dis- eases are a wall that we cannot scale with today’s treatments. The importance of the stage at diagnosis can- not be overemphasised. The five-year net survival of patients diagnosed with solid tumours in local- ized stage increased by 10 percentage points over the 20 years of observation and reached 85% in the last period. Five-year net survival of patients di- agnosed with cancer in regional stage approaches 55%, whereas in patients diagnosed with cancer in distant stage it is only slightly below 25% and does not improve statistically significantly through time (Figure 3). Despite a number of new insights into prognostic and predictive factors and with the advancement of molecular biology which enabled more effective treatments, the classical stage of TNM remains the basic predictor of disease pro- gression and survival (together with the age of can- cer patient). Reporting the stage in cancer registries is historically simplified into three groups: local- ized, regional, and distant disease. Results show, that nowadays the disease is more frequently diag- nosed in the localized stage and less often in the re- gional stage; the percentage of patients with distant disease remains the same. This is partly due to more accurate and accessible diagnostic methods that al- low detecting more and smaller distant lesions de- spite on a whole the diagnostic is done earlier. From our analysis, we can conclude that the im- provement in survival can be explained by the dis- ease being diagnosed at an earlier stage and is not just the consequence of the stage-shift described above. This is certainly the case for the last period for colorectal and breast cancers. For all patients who respond to the screening invitation, the five- year risk of death is four to five times lower than for those who do not respond to the invitation, due to the disease being diagnosed at a lower stage.18 Of course, survival is not a measure of the success of a screening programme (it’s biased due to time advantage), but treatment of the disease at an ear- lier stage undoubtedly affects recovery and conse- quently cause specific mortality. Successful screen- ing programmes and high population responsive- ness are therefore improving survival. Although rarely, cancer is diagnosed in children as well. In the present survival analysis, we included FIGURE 2. Five-year net survival of patients with cancer (all sites but non-melanoma skin cancer) by age group, Slovenia 1997–2016. FIGURE 3. Five-year net survival of patients with cancer (all solid tumours but non- melanoma skin cancer) by stage at diagnosis, Slovenia 1997–2016. Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia48 1,379 children and adolescents (aged 0 to 19 years) diagnosed in Slovenia in the target period 1997 to 2016. The net survival has been gradually increasing with respect to the year of diagnosis. For example, the five-year net survival for all childhood cancers combined increased by almost 8 percentage points and exceeded 85% in the last period 2012–2016 com- pared to the first period 1997–2001 and being less than 30% fifty years ago.12,19 There is a significant difference in the survival among patients with dif- ferent cancer sites: patients with malignant brain tu- mours survived five years in 70%, those diagnosed with leukaemia in 88%, but all of those diagnosed with lymphomas survived five years in 98%. The 20-year improvement was the highest in lympho- mas – for 12 percentage points. Clearly, the malig- nant diseases in children are heterogeneous group and a retrospective analysis of factors contributing to the observed improvement in survival is difficult. In Slovenia, all children suspected of having cancer undergo a diagnostic workup and treatment in a single national paediatric centre, which positively affects their survival along with developments in diagnostics and treatment.19,20 Similarly, as in adults, boys achieve slightly lower survivals than girls, but the gap between the sexes has been narrowing over time (Table 2). Five-year net survival was similar in children and in adolescents in all observed periods (Figure 2, Table 2). In the first two observed periods, be- tween 1997 and 2006, it was slightly better in the 0 to 14 years age group, and in the last two peri- ods, between 2007 and 2016, it was reversed being better in the 15–19 age group. In the last observed period, from 2012 to 2016, it reached 85 and 91% for children and adolescents, respectively. The five-year net survival of children and adolescents with solid tumours with localized and regional stage disease exceeds 85% in the last ten years. In children and adolescents with distant disease at diagnosis, the five-year net survival approaches 70% (Table 2). Conclusions Population-based cancer survival is a composite indicator reflecting the characteristics of patients as well as the organisation, accessibility, quality, and efficiency of the healthcare system. This analysis is the starting point of our fourth comprehensive re- port on the survival of Slovenian cancer patients5 and shows the progress of Slovenian oncology and healthcare, as well as Slovenian general attitude to- wards cancer over the last twenty-year period. As we determined, the survival of Slovenian cancer patients has been increasing over time, which gives us a basis and an incentive for future improve- ments. In addition, the lag in survival of Slovenian cancer patients in comparison with the patients from other European health systems identified in some cancers in the CONCORD-3 study14 and in the last EUROCARE study21provides us with a le- gitimate basis for considering improvements in the future. The National Cancer Control Programme deliv- ers a comprehensive set of activities in the fields of primary and secondary prevention, diagnostics, treatment and rehabilitation, as well as palliative care. Therefore, in order to reduce the cancer bur- den and improve the quality of life and economic sustainability, all evidence-based primary and secondary prevention programmes must be estab- lished and used, and evidence-based treatment im- plemented in scientifically acceptable time frames. The development of medical science, oncology and molecular biology in the last 20 years has brought many revolutionary insights into the field of on- cology, which undoubtedly have had an impact and will have an even more significant impact on the survival of cancer patients in the future. To monitor the effectiveness of managing the cancer epidemic of today, also in the future the burden of cancer will need to be monitored based on qual- ity data and scientifically justified methodological approaches both provided by established cancer TABLE 2. Five-year net survival of children (0–14 years) and adolescences (15–19 years) with cancer by period of diagnosis, sex, age group and stage at diagnosis for solid tumours, Slovenia 1997–2016 Period of diagnosis Gender Age at diagnosis Stage (C00-C80) All Male Female 0–4 year 5–9 year 10–14 year 15–19 year Localized Regional Distant 1997 – 2001 205 146 93 48 78 132 116 59 20 351 2002 – 2006 180 149 96 49 51 133 114 52 21 329 2007 – 2011 170 161 89 53 69 120 126 33 18 331 2012 – 2016 200 168 104 74 56 134 144 53 27 368 Radiol Oncol 2021; 55(1): 42-49. Zadnik V et al. / Trends in population-based cancer survival in Slovenia 49 registries. Further on, cooperation between onco- logical epidemiologists and clinical specialists is crucial for a comprehensive review and prepara- tion of proposals for improvement. Acknowledgements The authors thank the staff of the Slovenian Cancer Registry whose endless efforts to collect accurate and complete data have made this report possible. 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Radiol Oncol 2021; 55(1): 50-56. doi: 10.2478/raon-2020-0056 50 research article Completely resected stage III melanoma controversy - 15 years of national tertiary centre experience Barbara Peric1,2, Sara Milicevic1, Andraz Perhavec1,2, Marko Hocevar1,2,3, Janez Zgajnar1,2 1 Department of Surgery, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Faculty of Medicine, University of Maribor, Maribor, Slovenia Radiol Oncol 2021; 55(1): 50-56. Received 28 May 2020 Accepted 24 July 2020 Correspondence to: Assist. Prof. Barbara Perić, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: bperic@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. Two prospective randomized studies analysing cutaneous melanoma (CM) patients with sentinel lymph node (SLN) metastases and rapid development of systemic adjuvant therapy have changed our approach to stage III CM treatment. The aim of this study was to compare results of retrospective survival analysis of stage III CM patients’ treatment from Slovenian national CM register to leading international clinical guidelines. Patients and methods. Since 2000, all Slovenian CM patients with primary tumour ≥ TIb are treated at the Institute of Oncology Ljubljana and data are prospectively collected into a national CM registry. A retrospective analysis of 2426 sentinel lymph node (SLN) biopsies and 789 lymphadenectomies performed until 2015 was conducted using Kaplan-Meier survival curves and log-rank tests. Results. Positive SLN was found in 519/2426 (21.4%) of patients and completion dissection (CLND) was performed in 455 patients. The 5-year overall survival (OS) of CLND group was 58% vs. 47% of metachronous metastases group (MLNM) (p = 0.003). The 5-year OS of patients with lymph node (LN) metastases and unknown primary site (UPM) was 45% vs. 21% of patients with synchronous LN metastasis. Patients with SLN tumour burden < 0.3 mm had 5-year OS similar to SLN negative patients (86% vs. 85%; p = 0.926). The 5-year OS of patients with burden > 1.0 mm was similar to the MLNM group (49% vs. 47%; p = 0.280). Conclusions. Stage III melanoma patients is a heterogeneous group with significant OS differences. CLND after posi- tive SLNB might still remain a method of treatment for selected patients with stage III. Key words: cutaneous melanoma; sentinel node biopsy; completion lymph node dissection; overall survival Introduction Since Morton has introduced the concept of senti- nel lymph node (SLN) biopsy, the procedure had been a central part of cutaneous melanoma (CM) treatment. The information about SLN metastases is considered as one of the most important indica- tors of recurrence and survival of CM patients.1,2 Completion lymph nodes dissection (CLND) was offered to patients with positive SLN despite sig- nificant morbidity which is only slightly lower in case of CLND compared to therapeutic lymphad- enectomy.3 Common belief was that at least 20% of patients with positive non-SLN would benefit from that kind of treatment.4 Despite all attempts to prove otherwise, two prospective randomised studies conducted in re- cent years have shown that CLND does not im- prove survival of patients with positive SLN com- pared to follow up of the nodal basin with ultra- sound (US).5,6 Although there was no significant improvement of overall survival (OS), the MSLT-2 study did in- dicate, that immediate CLND offers better regional Radiol Oncol 2021; 55(1): 50-56. Peric B et al. / Resected stage III melanoma controversy 51 control and that non-SLN burden is an independ- ent prognostic indicator for recurrence (hazard ra- tio [HR]: 1.78; p = 0.005).5 In years to follow, studies comparing systemic adjuvant treatment of CM to those receiving place- bo after surgical treatment have shown improved regional relapse free survival (RFS) and OS in pa- tients with targeted therapy.7-9 That knowledge combined with results of MSLT-II and DeCOG led clinicians to belief, that CLND in patients with pos- itive SLN is no longer warranted.10 But group of stage III patients is one of the most heterogeneous groups with expected 5-year OS ranging from 30–60% and adjuvant systemic therapy is potentially toxic and costly.11,12 In case of first reported adjuvant systemic therapy trial, 43% of patients receiving ipilimumab had grade 3 or 4 side effects but in later studies, the percentage has dropped to approximately 14%.7,8 Toxicity rates have dropped and at the same time 1-year RFS has increased to 70.5% in completely resected stage III CM patients treated with anti-PD-1 agent nivolum- ab and 75.4% in case of adjuvant pembrolizumab.13 But one has to keep in mind that individual costs of adjuvant immunotherapy treatment in our coun- try can reach up to 67.000 Euros per year. How to make adjuvant systemic treatment combined with suitable follow up of regional lymph node basin available to all patients are nowadays concerns of many clinicians. Perhaps additional piece of information is hid- ing in the SLN burden. Studies in the past have as- sociated SLN burden of > 1 mm with significantly worse outcome and a need for adjuvant systemic treatment. On the other hand different studies were not able to confirm the minimal SLN burden as reproducible factor for excellent survival at all sites. Despite that it seems, that burden of < 0.1 mm is associated with 5-year survival of 83–91%, with non-SLN positivity rates between 0 and 12%.14 The aim of our study was to compare survival based on retrospective analyse of stage III CM from national CM base to current understanding of lymph node surgery. Patients and methods Data of CM patients treated at the Institute of Oncology Ljubljana (OI) were prospectively col- lected into clinical melanoma registry. Data of SLN biopsy procedures were collected since January 2000, the year of the SLN biopsy introduction in Slovenia. Complete lymph node dissection data were registered since 2003. In Slovenia all CM sur- gical procedures (with exclusion of skin biopsy) are performed at the OI. Clinical melanoma regis- try of the OI serves as a substitute of the national CM database. Data of 2426 patients with CM (CM ≥ TIb based on confirmed histology) undergoing SLN biopsy at the OI between 2000 and 2015 were analysed. The SLN biopsy procedure was performed according to established recommendations.15 During described period, gross and microscopic examination of SLN was performed by 4 dedicated pathologists at the institute using SLN protocol that has been adopted by the EORTC as the standard procedure for path- ological handling of SLN for CM.16 The false nega- tive rate (FNR) was defined as false negative/true positive combined with false negative. All patients with positive SLN and performance status ECOG 0–2, who agreed to further surgical treatment, un- derwent CLND. Altogether there were 455 patients with positive SLN and CLND. To that number we added the analysis of 149 pa- tients with synchronous primary CM and clinically detected regional lymph node metastasis (SLNM), 121 patients with metachronous primary CM and regional lymph node metastasis (MLNM), and 64 patients with melanoma of unknown primary site (UPM). Synchronous metastases were defined as metastases detected clinically prior to surgery or occurring within 6 months of the initial CM diag- nosis. Patients with first recurrence of the disease in the regional lymph node basin later in course of the disease were classified to the MLNM group. UPM was defined as clinically detected and his- tologically confirmed nodal melanoma metastases with no evidence of primary lesion. Patients with synchronous nodal and in-transit metastases were excluded from the study as were patients with previously excised pigmented skin lesion without proper histological evaluation. Finally, data of 789 patients after complete lymph node dissection di- vided in four groups (CLND, SLNM, MLNM and UPM) operated between 2003 and 2015 were retro- spectively analysed. The date of study closure was January 15th 2019. Data were summarized as mean ± SD, un- less otherwise specified. Chi-square test was used for categorical variables while quantitative vari- ables were compared using Kruskal-Wallis test. Overall survival (OS) time was calculated from the date of the excision of primary lesion (or the date of lymph node dissection in the case of UPM) to the date of death and censored at the closing date for survivors. Survival analyses were performed Radiol Oncol 2021; 55(1): 50-56. Peric B et al. / Resected stage III melanoma controversy52 by constructing Kaplan-Meier survival curves and compared using log-rank tests. Comparisons between groups of patients undergoing complete lymph node dissection (CLND, MLNM, SLNM and UPM) for each parameter were calculated us- ing χ2 or nonparametric Kruskal-Wallis analysis as indicated. Statistical analysis was performed using SPSS for Windows, version 22.0. A p-value < 0.05 was considered statistically significant. Ethical considerations The study was approved by the Institutional Review Board Committee and was conducted in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki. TABLE 1. Demographics of sentinel lymph node biopsy (SLNB) group Negative SLN No. (%) Positive SLN No. (%) Unfound SLN No. (%) All SLNB No. (%) Number of patients 1837(75.7) 519 (21.4) 70 (2.9) 2426 (100.0) Tumour site Head 174 (9.5) 34 (6.6) 21 (30.0) 229 (9.4) Neck 30 (1.6) 6 (1.2) 7 (10.0) 43 (1.8) Trunk 857 (46.7) 268 (51.6) 30 (42.9) 1155 (47.6) Limbs 776 (42.2) 211 (40.7) 12 (17.1) 999 (41.2) Breslow thickness (mm) < 1.5 757 (41.2) 67 (12.7) 24 (32.9) 848 (34.8) 1.5–3.5 735 (40.0) 226 (43.5) 26 (37.1) 987 (40.7) 3.5 323 (17.6) 224 (43.2) 20 (28.6) 567 (23.4) Unknown 20 (1.1) 3 (0.6) 1 (1.4) 24 (1.0) Ulceration Yes 554 (30.2) 234 (45.1) 40 (57.1) 828 (34.1) No 1054 (57.4) 232 (44.7) 22 (31.4) 1308 (53.9) Unknown 229 (12.5) 53 (10.2) 8 (11.4) 290 (12.0) Tumour subtype SSM 260 (14.2) 62 (11.9) 9 (12.9) 331 (13.6) NM 277 (15.1) 129 (24.9) 10 (14.3) 416 (17.1) LMM 14 (0.8) 1 (0.2) 1 (1.4) 16 (0.7) ALM 29 (1.6) 10 (1.9) 0 (0.0) 39 (1.6) Other 105 (5.7) 25 (4.8) 2 (2.9) 132 (5.4) Unknown 1152 (62.7) 292 (56.3) 48 (68.6) 1492 (61.5) ALM = acral lentiginous melanoma; LMM = lentigo malignant melanoma; NM = nodular melanoma; SLN = sentinel lymph node; SLNB = sentinel lymph node biopsy; SSM = superficial spreading melanoma Results Between 2000 and 2015, 2426 CM patients had SLN biopsy procedures at the OI. Positive SLN was found in 519 (21.4%) patients, of these 13 (2.5%) had metastatic lymph nodes in two nodal basins. The size of SLN metastasis was recorded (in mm) in 91.7% of cases. SLN biopsy procedure was unsuccessfully per- formed in 70 patients (70/2426, 2.9%). Preoperative lymphoscintigraphy failed to detect the SLN in 23/2426 (0.9%) patients. Unsuccessful surgical re- trieval was recorded in 47/2426 (1.9%) patients. Lymph node basin with the highest percentage of unsuccessful surgery was neck 24/310 (7.7%), fol- lowed by interval lymph nodes 6/115 (5.2%), axilla 13/1238 (1.1%) and groin 4/693 (0.6%). In 455 patients with positive SLN, CLND was performed. Patients with unsuccessfully retrieved SLN or negative SLN and lymph node recurrence discovered during follow up (88/1837; 4.7%) were considered as false negative (FN). According to that the FNR was 14.5%. In addition, there were 33 patients with only wide local excision who de- veloped nodal recurrence. Since there was no sta- tistically significant difference in OS between the two subgroups of patients (p = 0.373) they were in further analysis merged together as MLNM. Demographics of patients undergoing SLN biopsy are depicted in Table 1. Demographics of four groups of patients un- dergoing complete lymph node dissection (CLND, SLNM, MLNM, UPM) are summarized in Table 2. Median follow-up of patients after lymphad- enectomy was 47 months (range 20 days - 198 months). At the time of data cut-off, 60.1% of pa- tients died. The 5-year OS of CLND group was 58%, MLNM 47%, SLNM 21% and UPM 45%, while 10-year OS was as follows: 45% for CLND, 29% for MLNM, 19% for SLNM and 40% for UPM group (Figure 1). The 5-year OS of MLNM group was significant- ly worse than survival of CLND group (47% vs. 58%; p = 0.003). However, the 5-year OS of CLND group was heterogeneous based on different tu- mour burden in SLN: < 0.3 mm 86%, 0.3–0.69 mm 72%, 0.7–1.0 mm 61% and > 1.0 mm 49% (Figure 2). Patients with SLN tumour burden < 0.3 mm had the 5-year OS similar to SLN negative group (86% vs. 85%; p = 0.926). The 5-year OS of patients with SLN tumour burden > 1.0 mm was comparable to the MLNM group (49% vs. 47%; p = 0.280). The percentage of positive non-SLN differed according to the size of the SLN tumour burden; Radiol Oncol 2021; 55(1): 50-56. Peric B et al. / Resected stage III melanoma controversy 53 3.2% (2/63) of patients with SLN metastasis < 0.3 mm, 7.4% (5/68) of patients with SLN metastasis 0.3–0.69 mm, 11.9% (7/59) of patients with SLN metastasis 0.7–1.0 mm, 23.0% (51/222) of patients with SLN metastasis > 1 mm and 32.6% (14/43) of patients with SLN metastasis of unknown size had positive non-SLN. Discussion Data of 2426 patients with CM undergoing SLN biopsy and 789 patients after CLND treated at the Institute of Oncology Ljubljana during 15-year period were retrospectively analysed. The results have shown that 5-year OS of patients with SLN tumour burden < 0.3 mm is comparable to OS of patients with negative SLN (p = 0.926). On the other end of spectrum were patients with SLN tumour burden of > 1 mm with survival com- parable to patients with metachronous regional lymph node metastasis (5-year OS 49% vs. 47%, p = 0.280). Patients with CLND after positive SLN had significantly improved survival compared to those with dissection after delayed dissection (p = 0.003). In last two decades three prospective rand- omized studies have addressed the management of regional lymph nodes in CM patients.2,5,6 The result of the first, MSLT-I, confirmed the critical role of the SLN biopsy although it did not demon- strate the melanoma specific survival (MSS) ben- efit. Despite that, the results did show that early removal of lymph node metastases in intermediate thickness CM could improve survival. 10-year dis- tant disease free survival was 54.8% in the group with intermediate thickness CM following CLND after positive SLN biopsy and 35.6% in the case of observation and nodal recurrence. According to our analysis 10-year OS was 45% in CLND group compared to the 29% OS of the MLNM group which had the characteristics similar to the true observational group. The survival difference was slightly smaller in our population in comparison to MSLT-1 trial which can be explained by popula- tion differences. MSLT-I included 81.6% of patients with intermediate thickness CM with median thickness of 1.8 mm in biopsy group, while median thickness in our population was 3 mm. One third of patients had SLN tumour burden > 1 mm.2,11 In our population the percentage was 48.8%. The observed differences in survival indicate that the benefit of the CLND is not limited only to patients with intermediate thickness CM. TABLE 2. Demographics of the four groups with lymph node dissection CLND No. (%) MLNM No. (%) SLNM No. (%) UPM No. (%) p Number of patients 455 (57.7) 121 (15.3) 149 (18.9) 64 (8.1) Age (years) 0.005 Mean 56 60 59 58 Median 56 64 61 61 Gender 0.198 F 206 (45.3) 63 (52.1) 65 (43.6) 23 (36.0) M 249 (54.7) 58 (47.9) 84 (56.4) 41 (64.0) Primary tumour site 0.254 Head 29 (6.4) 16 (13.2) 25 (16.8) - Neck 5 (1.1) 4 (3.3) 2 (1.3) - Trunk 235 (51.6) 48 (39.7) 64 (43.0) - Limbs 186 (40.9) 53 (43.8) 58 (39.0) - Breslow thickness (mm) < 0.001 Mean ± SD 3.9 ± 0.1 3.5 ± 0.3 8.5 ± 0.8 - Median 3.0 2.6 6.0 - < 1.5 60 (13.2) 28 (23.1) 12 (8.1) - 1.5–3.5 202 (44.4) 54 (44.6) 21 (14.1) - > 3.5 190 (41.8) 35 (28.9) 105 (70.5) - Unknown 3 (0.7) 4 (3.3) 11 (7.4) - Clark level < 0.001 II 2 (0.4) 1 (0.8) 1 (0.7) - III 87 (19.1) 32 (26.4) 16 (10.7) - IV 234 (51.4) 50 (41.3) 63 (42.3) - V 41 (9.0) 7 (5.8) 33 (22.1) - Unknown 91 (20.0) 31 (25.6) 36 (24.2) - Ulceration Present 197 (43.4) 47 (38.8) 91 (61.1) - < 0.001 Absent 213 (46.8) 52 (43.0) 18 (12.1) - Unknown 45 (9.9) 22 (18.2) 40 (26.8) - Number of positive nodes < 0.001 Mean ± S.D. 1.6 ± 1.8 3.3 ± 4.0 4.3 ± 5.4 4.5 ± 7.0 Median 1 2 2 2 Diameter of the largest lymph node metastases (mm) < 0.001 Mean ± S.D. 3.5 ± 5.7 35.3 ± 30.7 20.8 ± 14.2 46.0 ± 27.2 Median 1.4 28 16 47 CLND = completion lymph nodes dissection; MLNM = metachronous lymph node metastasis; SLNM = synchronous lymph node metastasis; UPM = unknown primary site metastases Radiol Oncol 2021; 55(1): 50-56. Peric B et al. / Resected stage III melanoma controversy54 Studies following MSLT-I and addressing the question of improved OS survival after the CLND included small proportion of patients with SLN tumour burden > 1 mm (two thirds of patients in each DeCOG study arm had SLN tumour burden ≤ 1 mm) which would, together with exclusion of patients with head and neck CM and those with extracapsular extension, indicate selection bias during study accrual.5,6,11 One interesting notion comparing our results to the results of the MSLT- II is, that they have include approximately 6% less patients with ulceration (37.0% of CLND com- pared to our 43.3%) and 20% less patients with thick melanoma (21.8% MSLT-II vs. 41.8%). The percentage of patients with SLN tumour burden > 1 mm was 21.7% in MSLT-II CLND group and 48.8% in our study respectively. The comparison imposes a question whether one can rely on the prospective randomized trials while facing a spe- cific real life population? Differences in our na- tional results indicate that direct implementation of the conclusions of randomised trials may not always be suitable. Results of DeCOG and MSLT- II studies failed to prove the OS survival benefit of the CLND. In case of our cohort the 5-year OS of patients following CLND was improved by 11% compared to the MLNM group (58% vs. 47%, p = 0.003) with no signifficant difference in the Breslow thicknes or presence of ulceration be- tween the two groups. Intriguing relationship between Breslow thick- ness and nodal burden was observed. In our study the worst OS survival was associated with SLNM group with only 21% alive after 5 years. The group of SLNM patients had substantially thicker CM yet their nodal burden was smaller compared to MLNM group (35.3 ± 30.7 mm MLNM vs. 20.8 ± 14.2 mm) indicating different primary tumour bi- ology but also indicating the effect of the delayed lymphadenectomy on the size of the nodal burden. If the timing of lymphadenectomy is a vital part of treatment the concern about possible loss of re- gional control during observation after SLN biopsy is raised. Many clinicians are aware that unresect- able regional disease is a serious clinical problem in CM. At the moment it is not known in how many cases observation and sequential regional relapse would actually cause loss of regional control.11 But not only regional control, other results could also be influenced by timing, as indicated in the Delgado meta-analysis. They concluded that there appears to be a time-dependent disease specific survival advantage related to early or immediate surgery regardless of the extent of the procedure compared to delayed or none in the case of nodal metastases.17 Can we reassure our patient that it is safe to leave the possible CM metastases in lymph node basin in cases where SLN biopsy is not followed by CLND? Many would argue that in the case of high risk for disease progression, small tumour burden in lymph node basin makes no change.6,11 Interestingly that is in contrast to some basic re- search showing that especially in CM models stem- like tumour cells have been found to reside in the vessels in the vicinity of lymphatic nodes, suggest- FIGURE 1. Overall survival (OS) of groups with completion lymph nodes dissection (CLND), synchronous lymph node metastasis (SLNM), metachronous lymph node metastasis (MLNM), unknown primary site metastases (UPM). FIGURE 2. Overall survival (OS) according to sentinel lymph node (SLN) tumour burden. Radiol Oncol 2021; 55(1): 50-56. Peric B et al. / Resected stage III melanoma controversy 55 ing that there is a kind of ‘lymphovascular’ stem cell niche which is not removed without CLND. It is speculated that these stem-like tumour cells might ‘hibernate’ for a long time span within the lymphovascular niche, and may form new tumours even years after surgical removal of the primary tumour. Similarly, the persistence of metastatic tu- mour cells in non-SLN subcapsular sinuses might also relate to a tumour cell survival supporting function of lymphatic vessels, which could play a role in premetastatic lymphatic niches as well.18 On the other hand, lymphatic endothelial cells (LEC) are expressing PD-L1 surface receptors that direct- ly interface with leukocytes and causes dysfunc- tional T cell activation, so one would speculate that the risk of tumour progression can be minimized with adjuvant immunotherapy. Studies aimed at adjuvant therapy in CM patients did show less re- lapses compared to placebo group and indicated that adjuvant systemic therapy can lead to sus- tained and durable survival benefit. However ad- ditional validation of this approach with extended follow-up in patients receiving adjuvant systemic therapy for CM is warranted, including correla- tion with OS data.19 It is important to note that tri- als that influenced our understanding of stage III melanoma treatment (MSLT-1, MSLT-2, DeCOG) included patients with completely resected CM and SLN burden > 1 mm.11 With results of MSLT-II and underpowered DeCOG trial indicating no benefit from CLND after positive SLN we can expect, that only a small num- ber of patients will be advised to have CLND in the future. It will be up to clinicians to decide, who with stage III disease should receive adjuvant sys- temic therapy and the decision will be based only on information gathered from SLN biopsy instead on information gathered from CLND available for adjuvant trials. Unfortunately, until new conclu- sions are available, results from previous adjuvant trials cannot simply be extrapolated to patients who only had SLN biopsy. The information about the non-SLN status might be lacking.20 Our own results show that 17.4% of patients (79/455) had positive non-SLN and with that possible decision influencing information. The issue of additional information gained from CLND was addressed by Verver and colleagues. They used a retrospective cohort of SN-positive patients previously collected and described to con- struct a model of risk stratification based solely on primary CM and SLN biopsy information. Their model is based on presence or absence of the ul- ceration and SLN burden of > 1 mm or ≤ 1 mm. They concluded that CLND upstaged 19% of pa- tients in the N-category and 5% of patients in AJCC stage 8Th edition (6% AJCC stage upstaging in the 7th edition). The survival analysis showed signifi- cant difference between low risk group (absent ul- ceration and SLN burden ≤ 1 mm) with 5-year MSS of 82.4% and intermediate risk (ulceration present and SLN ≤ 1 mm or ulceration absent and SLN > 1 mm) with survival around 67.6% and substantial gap between intermediate and high risk group (ul- ceration present and SLN > 1 mm) with 44% 5-year MSS in the later.20 Verver’s model is a significant step to understanding the stage III survival het- erogeneity but if tumor burden is an important prognostic indicator, four group prognostication sounds somehow crude. In our analysis we defined groups according to SLN burden. The OS survival analysis done according to the four group strati- fication caused previously described CLND curve to fan out. The analysis proved that group of pa- tients with SLN burden > 1 mm are high risk pa- tients with 5-year OS of 49%. In fact, their survival did not differ statistically from the MLNM group. On the other side of the spectrum are patients with SLN burden < 0.3 mm with excellent prognosis and 5-year OS of 86% similar to the group with nega- tive SLN. In the middle are those with SLN bur- den > 0.3 mm and ≤ 1 mm with 60–70% 5-year OS. Additional analysis showed that 9.4% of these pa- tients had metastases in non-SLN. Based on current recommendations those patients would not receive any additional adjuvant treatment. For those CM patents not receiving adjuvant systemic treatment and not being able to undergo regular nodal ba- sin US, surgery remains a treatment option, which should be taken under consideration. Conclusions Stage III melanoma patients are extremely hetero- geneous group with significant survival differenc- es. Since not all of them can be treated with systemic adjuvant therapy, CLND after positive SLNB may be offered to selected CM patients. Considering adjuvant treatment, CLND provides independent prognostic information that at the moment cannot be replaced satisfactorily by other variables. Authors‘ contribution BP contributed to the conception of the study, drafted the work and interpretated the data. SM Radiol Oncol 2021; 55(1): 50-56. Peric B et al. / Resected stage III melanoma controversy56 performed data acquisition, analysis and contrib- uted to data interpretation. AP contributed to in- terpretation of data and substantively revised the manuscript. MH made substantial contributions to the conception and design of the work and added critical remarks to the revised version. JZ contrib- uted to the conception, interpretation of data and substantively revised the manuscript. References 1. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19: 3622-34. doi: 10.1200/JCO.2001.19.16.3622 2. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final trial report of sentinel-node biopsy versus nodal observation in mel- anoma. N Engl J Med 2014; 370: 599-609. doi: 10.1056/NEJMoa1310460 3. Moody JA, Botham SJ, Dahill KE, Wallace DL, Hardwicke JT. Complications following completion lymphadenectomy versus therapeutic lymphadenec- tomy for melanoma - a systematic review of the literature. Eur J Surg Oncol 2017; 43:1760-7. doi: 10.1016/j.ejso.2017.07.003 4. van Akkooi AC, de Wilt JH, Verhoef C, Schmitz PI, van Geel AN, Eggermont AM, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol 2006; 17: 1578-85. doi: 10.1093/annonc/mdl176 5. Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, et al. Completion dissection or observation for sentinel-node me- tastasis in melanoma. N Engl J Med 2017; 376: 2211-22. doi: 10.1056/ NEJMoa1613210 6. Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer NH, Berking C, et al. Final analysis of DeCOG-SLT trial: No survival benefit for complete lymph node dissection in patients with melanoma with positive sentinel node. J Clin Oncol 2019; 37: 3000-8. doi: 10.1200/JCO.18.02306 7. Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resec- tion of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer 2019; 119: 1-10. doi: 10.1016/j. ejca.2019.07.001 8. Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated mela- noma. N Engl J Med 2017; 377: 1813-23. doi: 10.1056/NEJMoa1708539 9. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017; 377: 1824-35. doi: 10.1056/NEJMoa1709030 10. Franke V, van Akkooi ACJ. The extent of surgery for stage III melanoma: how much is appropriate? Lancet Oncol 2019; 20: e167-e174. doi: 10.1016/ S1470-2045(19)30099-3 11. Bello DM, Faries MB. The landmark series: MSLT-1, MSLT-2 and DeCOG (management of lymph nodes). Ann Surg Oncol 2020; 27: 15-21. doi: 10.1245/s10434-019-07830-w 12. Gershenwald JE, Scolyer RA. Melanoma staging: American Joint Committee on Cancer (AJCC) 8th edition and beyond. Ann Surg Oncol 2018; 25: 2105- 10. doi: 10.1245/s10434-018-6513-7 13. Blankenstein SA, van Akkooi ACJ. Adjuvant systemic therapy in high- risk melanoma. Melanoma Res 2019; 29: 358-64. doi: 10.1097/ CMR.0000000000000604 14. Madu MF, Wouters MW, van Akkooi AC. Sentinel node biopsy in melanoma: Current controversies addressed. Eur J Surg Oncol 2017; 43: 517-33. doi: 10.1016/j.ejso.2016.08.007 15. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for ear- ly stage melanoma. Arch Surg 1992; 127: 392-9. doi: 10.1001/arch- surg.1992.01420040034005 16. Cook MG, Green MA, Anderson B, Eggermont AM, Ruiter DJ, Spatz A, et al. The development of optimal pathological assessment of sentinel lymph nodes for melanoma. J Pathol 2003; 200: 314-9. doi: 10.1002/path.1365 17. Delgado AF, Delgado AF. Complete lymph node dissection in melanoma: A systematic review and meta-analysis. Anticancer Res 2017; 37: 6825-9. doi: 10.21873/anticanres.12143 18. Ma Q, Dieterich LC, Detmar M. Multiple roles of lymphatic vessels in tumor progression. Curr Opin Immunol 2018; 53: 7-12. doi: 10.1016/j. coi.2018.03.018 19. Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandala M, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600- mutant stage III melanoma. J Clin Oncol 2018; 36: 3441-9. doi: 10.1200/ JCO.18.01219 20. Verver D, van KD, van Akkooi ACJ, Rutkowski P, Powell BWEM, Robert C, et al. Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations. Eur J Cancer 2018; 96: 25-33. doi: 10.1016/j.ejca.2018.02.022 Radiol Oncol 2021; 55(1): 57-65. doi: 10.2478/raon-2020-0067 57 research article Surgical resection of synchronous liver metastases in gastric cancer patients. A propensity score-matched study Tomaz Jagric1, Matjaz Horvat2 1 Department of General and Abdominal Surgery, University Medical Centre Maribor, Slovenia 2 Faculty of Medicine, University of Maribor, Slovenia Radiol Oncol 2021; 55(1): 57-65. Received 25 June 2020 Accepted 15 October 2020 Correspondence to: Assist. Prof. Tomaž Jagrič, M.D., Ph.D., Department of General and Abdominal Surgery, University Medical Centre Maribor; Ljubljanska ulica 5; 2000 Maribor. E-mail: tomaz.jagric@gmail.com Disclosure: No potential conflicts of interest were disclosed. Background. The aim of the study was to determine the value of synchronous liver resection in patients with oligo- metastatic gastric cancer and the prognostic factors in these patients. Patients and methods. We compared the results of 21 gastric patients with liver metastases and synchronous liver resection (LMR) to 21 propensity score-matched patients with gastric cancer and liver metastases in whom liver resection was not performed (LM0) and to a propensity score-matched control group of 21 patients without liver me- tastases and stage III and IV resectable gastric cancer (CG). Results. The overall 5-year survival of LMR, LM0 and CG were 14.3%, 0%, and 19%, respectively (p = 0.002). Five-year survival was 47.5% for well-differentiated tumour compared to 0% in patients with moderate or poor tumour differen- tiation (p = 0.006). In addition, patients with R0 resection and TNM stage N0–1 had a significantly better survival com- pared to patients with TNM N stage N2–3 (5-year survival: 60% for N0–1 vs. 7.7% for N2–3; p = 0.007). Conclusions. The results presented in the study support synchronous liver resections in gastric patients and provide additional criteria for patient selection. Key words: gastric cancer; liver metastases; synchronous resection; propensity score Introduction Liver metastases occur in 3.5–14% of gastric cancer patients.1-8,12,15-17 Surgical resection has been shown to be a viable option in selected cases of gastric cancer patients with liver metastases. Since no randomised controlled trials are yet available re- garding the treatment of liver metastases in gastric cancer1-8, no clear-cut recommendations exist as to which patient could benefit the most from such treatment. The aim of our study was to determine the value of synchronous liver resection in patients with oligometastatic gastric cancer and to deter- mine the prognostic factors in these patients. We compared the results of propensity score-matched gastric cancer patients with and without liver re- sections as well as with a control group of stage III and IV patients without liver metastases. Patients and methods Patients Patient and tumour characteristics, preoperative di- agnostics and laboratory data, types of operations, perioperative complications and mortality from 1546 patient data has been included in our database since 1991. Histopathological descriptions were handled in accordance with the International Union Against Cancer 8th TNM classification of gastric cancer.11 Postoperative complications were defined according to the Clavien–Dindo classification.9 Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer58 Chemotherapy schemes varied during the study period. The administered preoperative and postop- erative regimens included: epirubicin + oxaliplatin, capecitabine + fluorouracil, capecitabine + oxalipl- atin, or 5-fluorouracil + leucovorin. For our analysis, only the patients who had synchronous liver me- tastases and gastric resection with curative intent (LMR) were selected. The results of these operations were compared to propensity score-matched (PSM) patients with liver metastases who had gastric can- cer resection, in whom the surgeon did not opt for additional liver resection (LM0). The decision regarding liver metastasis resection was obtained on the preoperative tumour board and during the operation at surgeon’s discretion. Patients were se- lected for liver resection, if they met the following criteria: (i) three or less metastases (oligometastatic gastric cancer); (ii) no distant metastases; (iii) resect- able primary tumour; (iv) good general health. The nomenclature of hepatic anatomy and resection was used according to the Brisbane 2000 system.10 Since we could not determine retrospectively whether pa- tients’ general state or advanced disease precluded liver metastases resection in LM0 group, we select- ed an additional PSM control group (CG). For CG, the propensity score-matched stage III and IV gas- tric cancer patients without having liver metastases resected with curative intent were used for estima- tion of treatment benefit. Follow-up was carried out by surgeons and oncologists. Informed consent was obtained from all individual participants included in the study. The study was approved by the local ethics committee of the University Medical Centre Maribor in Slovenia (UKC-MB-KME-58/20). Propensity score-matching The data from 1546 patients prospectively stored in our database was used for PSM. Patients were matched using the propensity score method as described by Rosenbaum and Rubin.18,19 The pro- pensity score for an individual was calculated on the given covariates of preoperative haemoglobin levels, age, American Society for Anaesthesiology (ASA) score and the International Union against Cancer (UICC) stage using the multivariate logistic regression model. With this method three groups of PSM patients containing 21 patients each was formed: (i) Patients with liver metastases and no liver resection (LM0); (ii) Patients with liver metas- tases and liver resection (LMR); (iii) Patients with stage III and IV gastric cancer and no liver resec- tion (CG). In all patients a gastrectomy with local curative intent was performed. Statistical analysis Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as percentage. Continuous variables were com- pared with Student’s t-test for normally distribut- ed variables; nonparametric variables were tested with Mann-Whitney’s U-test. The cut-off levels of continuous variables were determined by means of receiver operator curves with cut-off value of AUC above 0.75 and p value of less than 0.05. Variables above the threshold p value of 0.1 were included for multivariate analysis. The Cox regression model was used for primary analysis. Estimates of treatment effect were expressed as hazard ratios with 95% confidence interval. Kaplan-Meier curves were constructed to determine time-to-event end- points. Differences in survivals between groups were determined with the Log-rank and Breslow tests. P value of >0.05 was selected as the level of significance. All statistical analyses were per- formed on SPSS for Windows 10 v. 22 (IBM). Results Patients In the final analysis 63 patients resected for gastric cancer were included. The characteristics of these patients, their tumours, and operations are pro- vided in Table 1. All three groups were balanced according to age, gender, tumour location, opera- tions, UICC and TNM stage and number of resect- ed lymph nodes. In the LM0 group, significantly less patients received chemotherapy compared to LMR and CG group (4.8% vs. 42.9% vs. 42.9%; p = 0.004). A D2 lymphadenectomy was performed significantly more often in the LMR and CG com- pared to patients in the LM0 group (LM0: 19%, LMR: 76.2% and CG: 81%; p < 0.0001). The number of harvested lymph nodes (LNs) per operation was significantly higher in LMR and CG compared to LM0 group (LM0: 18 ± 9 LNs, LMR: 27.6 ± 14.6 LNs; CG: 26 ± 17 LNs; p = 0.028). All patients in LM0 had locally microscopically negative resection margins. In LMR patients a R0 resection could be obtained in 85.7% compared to 100% in the CG (p = 0.076). LM0 patients had significantly more liver metasta- ses compared to LMR patients (p < 0.0001). Most of LM0 patients had more than three metastases (71.4%) compared to one liver metastasis usually present in LMR patients (90.5%). Patients with liver metastases (LM0 and LMR) had a tumour location almost exclusively in the middle and lower third Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer 59 TABLE 1. Patients’, tumour and operations characteristics of the included patients All patients PSM groups p LM0 LMR CG Age [years ± SD] 64.43 ± 9.9 64.9 ± 6.9 65.5 ± 10 62.7 ± 12.5 NS Gender [n(%)] Male Female 50(79.4) 13(20.6) 17(81) 4(19) 16(76.2) 5(23.8) 17(81) 4(19) NS CA 19-9 [ng(IQR)] 13(64.7) 20(32) 7(62) 5.5(351.7) NS CEA [ng(IQR)] 4(6.5) 3.5(26.7) 4(6) 3(17.25) NS Hb [g/l(IQR)] 112.5(28.25) 117.5(25) 105(41) 107(27.5) NS Chemotherapy [n(%)] Yes No 19(30.2) 44(69.8) 1(4.8) 20(95.2) 9(42.9) 12(57.1) 9(42.9) 12(57.1) 0.004 Dindo-Claviene 0 II IIIa IIIb V 50(79.4) 3(4.8) 1(1.6) 2(3.2) 7(11.1) 16(76.2) 1(4.8) 0(0) 0(0) 4(19) 18(85.7) 1(4.8) 0(0) 1(4.8) 1(4.8) 16(76.2) 1(4.8) 1(4.8) 1(4.8) 2(9.5) NS TNM T stage [n(%)] 1 2 3 4a 4b 5(7.9) 1(1.6) 36(57.1) 8(12.7) 13(20.6) 0(0) 0(0) 17(81) 2(9.5) 2(9.5) 2(9.5) 0(0) 8(38.1) 3(14.3) 8(38.1) 3(14.3) 1(4.8) 11(52.4) 3(14.3) 3(14.3) NS TNM N stage [n(%)] 0 1 2 3a 3b 6(11.1) 5(9.3) 15(27.8) 9(16.7) 19(35.2) 0(0) 3(23.1) 3(23.1) 1(7.7) 6(46.2) 3(14.3) 2(9.5) 8(38.1) 3(14.3) 5(23.8) 3(15) 0(0) 4(20) 5(25) 8(40) NS UICC stage [n(%)] IIIa IIIc IV 2(3.2) 4(6.3) 57(90.5) 0(0) 0(0) 21(100) 1(4.8) 2(9.5) 18(85.7) 1(4.8) 2(9.5) 18(85.7) NS Positive LNs [n(IQR)] 7(17.7) 11(23) 5.5(18.7) 12.5(12.2) All LNs [n±SD] 28.2±11.5 18±9 27.6±14.6 26±17 0.028 Grade [n(%)] Well Moderate Poor 6(12.5) 13(27.1) 29(60.4) 2(16.7) 4(33.3) 6(50) 2(10) 5(25) 13(65) 2(12.5) 4(25) 10(62.5) NS Type of gastrectomy [n(%)] Subtotal Total Total with distal esophagectomy Distal esophagectomy & proximal gastrectomy Stump resection 22(34.9) 34(54) 4(3.2) 2(1.6) 1(1.6) 12(57.1) 8(38.1) 0(0) 1(4.8) 0(0) 6(28.6) 14(66.7) 0(0) 1(4.8) 0(0) 4(19) 12(57.1) 4(19) 0(0) 1(4.8) NS Location [n(%)] Stump Entire Proximal Middle Distal 1(1.6) 6(9.5) 10(15.9) 20(31.7) 26(41.3) 0(0) 2(9.5) 2(9.5) 6(28.6) 11(52.4) 0(0) 9(42.9) 9(42.9) 2(9.5) 1(4.8) 1(4.8) 3(14.3) 6(28.6) 5(23.8) 6(28.6) 0.045 ASA score [n(%)] I II III 16(25.4) 32(50.8) 15(23.8) 6(28.6) 9(42.9) 6(28.6) 6(28.6) 12(57.1) 3(14.3) 4(19) 11(52.4) 6(28.6) NS Lymphadenectomy [n(%)] D1 D2 26(41.3) 37(58.7) 17(81) 4(19) 5(23.8) 16(76.2) 4(19) 17(81) < 0.0001 R0 [n(%)] 39(61.9) 0(0) 18(85.7) 21(100) < 0.0001 Number of liver metastases [n(%)] 1 2–3 > 3 23(54.8) 4(9.5) 15(35.7) 4(19) 2(9.5) 15(71.4) 19(90.5) 2(9.5) 0(0) 0(0) 0(0) 0(0) < 0.0001 Grade [n(%)] Well Moderate Poor 6(9.5) 13(27.1) 29(60.4) 2(16.7) 4(33.3) 6(50) 2(10) 5(25) 13(65) 2(12.5) 4(25) 10(62.5) NS Hospital stay [n(IQR)] 13(8.5) 12(6.5) 13.5(8) 14(12.7) NS ASA = American Society for Anaesthesiology; Ca 19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; CG = patients without liver metastases and stage III and IV resectable gastric cancer; Hb = serum hemoglobin levels; IQR = interquartile range; LM0 = patients with gastric cancer and liver metastases in whom liver resection was not performed; LMR = patients with synchronous liver metastases and gastric resection with curative intent; LNs = lymph nodes; NS = not significant; PSM = propensity score-matched; UICC = International Union against Cancer Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer60 of the stomach, while the tumour location in CG was evenly distributed in the whole stomach (p = 0.045). Surgery, morbidity and mortality There were no significant differences in the perio- perative mortality between the three groups. The perioperative morbidity in the LM0, LMR and CG was 23.8%, 14.3%, and 23.8%, respectively. Major morbidity (Dindo-Claviene > IIIb) was observed in 16.7%, 9.6%, and 14.3% in the LM0, LMR and CG group, respectively. The 30-day mortality was 9.5%, 4.8% and 9.5% in the LM0, LMR, and CG group, respectively. Although the differences were insignificant, the patients in the LMR group had the lowest perioperative morbidity and mortality. The results of surgical treatment are presented in Table 1. The characteristics of liver resections in LMR group are presented in Table 2. Metastasectomy of single metastasis was performed in most cases (57.1%), followed by segmental resection of a sin- gle metastasis (14.3%) and metastasectomy of more than 1 metastasis (14.3%). Major resection was performed only in one case (4.8%), and radio frequency ablation was performed in two cases (9.5%). The liver resections for 21 included cases, the involved liver segments and recurrence sites are documented in Table 3. The most frequent re- currence site was the liver followed by peritoneum. Notably 47.6% of cases did not have a documented recurrence after liver resection. In Table 4 the types of operations in the CG are presented. Additional resection of an involved or- gan was undertaken in 47.6% of cases. The most commonly infiltrated other organ was the tail of the pancreas (2 cases) and the local peritoneum of the bursa omentalis (8 cases). The most frequent additional resection in CG was the local peritonec- tomy, followed by left splenopancreatectomy with segmental colon resection and left splenopan- createctomy with left adrenal resection. Left pan- createctomy was associated with most morbidity, while mortality was the highest in patients with no additional resection. Multivariate analysis From the included predictors, age, gender, ASA score, Ca 19-9 serum levels, haemoglobin serum levels, additional liver resection, tumour grade, UICC stage, and TNM nodal stage were signifi- cantly associated with survival. The hazard ratios, 95% confidence intervals, and the p-values are list- ed in Table 5. Survival analysis None of the patients in the LM0 group survived 5 years. Their survival was significantly shorter com- pared to patients in the LMR group a cumulative FIGURE 1. Cumulative survivals of patients with liver metastases without resection, with liver resection and in the control group respectively. TABLE 2. Characteristics of liver resections in the group of patients with synchronous liver metastases and gastric resection with curative intent (LMR) n(%) Segment involvement I II II/III III IV V VI VII VIII 0(0) 2(8.6) 3(13) 9(39.1) 2(8.6) 2(8.6) 0(0) 3(13) 2(8.6) Liver resection Metastasectomia of 1 metastasis Metastasectomia of >1 metastasis Segmental resection Hepatectomy Radio frequency ablation 12(57.1) 3(14.3) 3(14.3) 1(4.8) 2(9.5) Dindo-Claviene morbidity 0 II IIIa IIIb V 18(85.7) 1(4.8) 0(0) 1(4.8) 1(4.8) Number of metastases 1 metastasis 2–3 metastasis > 3 metastasis 19(90.5) 2(9.5) 0(0) Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer 61 5-year survival of 14.3% (p = 0.002). The survival of LMR patients was comparable to the survival of CG patients who had a 5-year survival rate of 19%. The median survival was 4.2 months, 9.3 months and 10.2 moths in the LM0, LMR and CG group respectively. The survival plots for the cumulative survival of patients in each group are shown in Figure 1. The multivariate analysis identified age, gender, ASA score, carbohydrate antigen 19-9 (Ca 19-9) se- rum levels, haemoglobin serum levels, additional liver resection, tumour grade, UICC stage, and TNM nodal stage as significant predictors for sur- vival. These predictors were used to determine cut- off levels and determine the subgroup of patients with the greatest benefit of liver resection. With the ROC analysis we determined the cut-off for serum levels of Ca19-9, age, haemoglobin serum levels. Patients with Ca19-9 levels above 10 ng/ml had sig- nificantly worse survival (5-year survival: 0% vs. 15.4%; p = 0.003). The survival advantage was lost for R0 resections. Patients with TNM stage N0–1 had an insignificantly better survival compared to patients with TNM stage N2–3. If only R0 patients were included, patients with TNM stage N0–1 had a significantly better survival compared to patients with TNM N stage N2–3 (5-year survival: 60% for N0–1 vs. 7.7% for N2–3; p = 0.007). Patients with a A B C D E FIGURE 2. Survival of subgroups. Overall survival according age (A), tumour differentiation (B), serum CA-19 level (C), N stage of TNM (D) and serum haemoglobin (E). Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer62 was more pronounced in patients with R0 resec- tion. Five-year survival in these patients was 47.5% for well-differentiated tumours compared to 0% in patients with moderate or poor tumour differen- tiation (p = 0.006). Patients younger than 64 years had a 5-year survival of 15.6% compared to 3.8% in patients older than 64 years (p = 0.029). R0 re- sected patients with serum haemoglobin levels be- low 100 g/l before the operation had a significantly worse 5-year survival compared to patients with higher haemoglobin levels (5-year survival: 14.3% vs. 20.8%; p = 0.09). The multivariate analysis also determined gender and ASA score to be significant predictors for survival; however, we could not de- termine any cut-off levels for patient stratification. The survival plots of different subgroups are pre- sented in Figure 2. Discussion Liver metastases in gastric cancer patients usu- ally occur as part of a systemic failure and rarely present as isolated disease suitable for resec- tion.1-8,12,15-17 In the present study liver resection has only been performed in 1.36% of patients operated for gastric cancer. As a result of low incidence of resectable liver metastases prospective large-scale randomised controlled trials are not feasible and at present no clear-cut recommendations exist for liver resection of gastric cancer metastases.1-8,12,15-17 To evaluate potential benefits and prognostic fac- tors for synchronous liver metastases resections in gastric cancer patients we performed a retrospec- tive propensity score-matched study. The treatment of stage IV gastric cancer patients is still the subject of heated debates. The results of the REGATTA trial suggest that palliative resection in addition to chemotherapy does not improve sur- vival for stage IV gastric cancer patients compared to chemotherapy alone, putting in question the value of surgery in oligometastatic gastric cancer.21 However, in the REGATTA trail only palliative gastrectomies were performed limiting the value of these results in gastric cancer patients with po- tentially resectable liver metastases. In the light of emerging evidence proving benefits of liver mes- tastases resections in oligometastatic gastric cancer patients, we performed a retrospective analysis of stage IV gastric cancer patients with liver metasta- ses. The data from the present study is in accord- ance with the results of studies that show a signifi- cant increase in long-term survival in patients with liver resections in gastric cancer patients.1-8,12,15-17 TABLE 3. Characteristics of liver metastases and recurrence sites in the group of patients with synchronous liver metastases and gastric resection with curative intent (LMR) Case No. Involved segment Number of metastases Type of resection Recurrence site 1 II 1 Segmentectomy 0 2 IV 1 Metastasectomy 0 3 III 1 Segmentectomy Peritoneal carcinomatosis 4 II/III 1 Segmentectomy Liver metastases 5 III 1 Metastasectomy 0 6 VII 1 Metastasectomy 0 7 III 1 Metastasectomy Local recurrence 8 III 1 Segmentectomy Peritoneal carcinomatosis 9 VIII 1 Metastasectomy Liver metastases 10 III 1 Segmentectomy 0 11 V 1 Metastasectomy Local recurrence 12 IV, II 3 Metastasectomy Liver metastases 13 II/III 1 Metastasectomy Liver metastases 14 III 1 Metastasectomy 0 15 II/III 1 Left lateral secienectomy 0 16 III 1 Metastasectomy 0 17 III 1 Metastasectomy Peritoneal carcinomatosis 18 V, VIII 2 Metastasectomy Liver metastases 19 VII 1 Radio frequency ablation Liver metastases and peritoneal carcinomatosis 20 VII 1 Radio frequency ablation 0 21 III 1 Segmentectomy 0 TABLE 4. Morbidity and mortality of additional resections in in the control group of patients without liver metastases and stage III and IV resectable gastric cancer (CG) N (%) Morbidity (%) Mortality (%) Gastrectomy Subtotal Total Total with distal esophagectomy Stump resection 4(19) 12(57.1) 4(19) 1(4.8) 0(0) 2(16.6) 1(25) 0(0) 1(25) 1(25) 0(0) 0(0) Additional resection No additional resection Local peritonectomy Left splenopancreatectomy and segmental colon resection Left splenopancreatectomy and left adrenal resection 11(52.4) 8(4.8) 1(4.8) 1(4.8) 1(9.1) 1(12.5) 0(0) 1(100) 2(18.2) 0(0) 0(0) 0(0) well differentiated tumour had a significantly bet- ter survival compared to patients with moderate and poor tumour differentiation. This difference Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer 63 The multivariate analysis confirmed that liver resection is a significant predictor for long-term survival. Median overall survival of 4.2 months in LM0 group was similar to other studies that re- ported median survival of 0 to 15 months with un- resectable liver metastases.8 In contrast, the median overall survival in LMR group was significantly longer compared to LM0 group. In our study long- term survival of gastric cancer patients was only possible when liver metastases were resected. The comparison of results from the LM0 and LMR group might support the claim that liver re- sections have a positive impact on long-term sur- vival8,12,15-17; however, the retrospective nature of the study carries some risk of biased selection de- spite the PSM. At least six patients in LM0 group had potentially resectable metastases. Because we could not determine retrospectively the precise rea- sons for unresectability of liver metastases in these LM0 patients, local advanced stage, poor general state, anatomical location of the metastasis or some other factor not included in the propensity score calculation might have precluded a safe resection the time of operation. In order to better evaluate the potential benefit of liver resection in gastric cancer patients we compared the results of LMR patients to PSM control group of UICC stage III and IV gas- tric cancer patients (CG). In both groups, patients were well-balanced according to patients’ and tu- mour characteristics. In addition, no difference was observed in the adjuvant treatment between LMR and CG group. The long-term survival of patients in LMR was comparable to patients in CG. Based on these results, we concluded that liver resection offered a survival benefit comparable to propensity score-matched patients with stage III and IV dis- ease a R0 resection and without liver metastases. An important aspect of treatment effect evalua- tion is the safety of the procedure. The periopera- tive morbidity and mortality in the LMR group was 14.3% and 4.8% that compares favourably to results published in other studies.1-8,12-17 Notably, perioperative morbidity in LMR group was signifi- cantly better compared to CG group. This discrep- ancy in perioperative morbidity could in part be explained in the additional multivisceral resections in the CG. Pancreatic resections have been identi- fied in previous studies to increase morbidity and mortality.13,14 In fact, we observed that the pancreas tail resection was associated with 50% morbidity in the CG. This might explain a lower complication rate in the LMR group compared to CG group. The 5-year survival of LMR patients in our study was 14.3% which was comparable to other studies that reported the 5-year survival of 0% to 42% after liver resection.1-8,12,15-17 In their seminal multi-centric retrospective analysis of stage IV gastric cancer in Western patients Ministrini et al. reported 5-year survival of 11.8%.22 Although our results compare favourably to results of Ministrini et al., some stud- ies reported better long-term survival of up to 32% to 59%.12, 20 An important reason for better survival after liver resection in these repots might be that patients with metachronous liver resections were included. Metachronous resections have been de- termined to be a significant prognostic factor.7 In other studies patients proceeded to liver resection only after a course of chemotherapy, while patients in whom disease progression was determined might have been excluded. In the present report, only synchronous resections have been analysed. It was therefore impossible to exclude patients at risk for progression. In fact, patient selection is the most critical aspect of liver metastases treat- ment in gastric cancer patients. Unfortunately, no clear recommendations for patients’ selection exist yet. In our study, the multivariate analysis identi- fied age, gender, ASA score, Ca 19-9 serum levels, haemoglobin serum levels, additional liver resec- tion, tumour grade, UICC stage, and TNM nodal stage as significant predictors for long-term sur- vival in LMR patients. The most powerful predic- tor for long-term survival was the TNM N stage of the primary tumour. The 5-year survival of LMR patients with N0-1 stage was 47.5% and even 60% in patients with TNM stage N0-1 and R0 resec- tion. These results are comparable even to results TABLE 5. Cox proportional hazard model for survival after gastric cancer resection with liver metastases HR 95% CI p Lower Upper Age 1.497 1.213 1.846 <0.0001 Gender 55.237 4.626 659.594 0.002 ASA score 0.049 0.009 0.261 <0.0001 Ca 19-9 1 1 1.001 0.02 Hb 0.918 0.864 0.974 0.005 Additional liver resection 0.001 0 0.029 <0.0001 Tumour grade 8.276 1.971 34.753 0.004 UICC stage 0 0 0.003 0.002 TNM N stage 0.386 0.163 0.917 0.031 ASA = American Society for Anaesthesiology; Ca 19-9 = carbohydrate antigen 19-9; CI = confidence interval; Hb = serum hemoglobin levels [g/l]; HR = hazard ratio; UICC = International Union against Cancer Radiol Oncol 2021; 55(1): 57-65. Jagric T and Horvat M / Resection of synchronous liver metastases in gastric cancer64 published by Tasubayashi et al. who reported a 5-year overall survival of 59%.12 Our results sug- gest that patients with a higher nodal stage of the primary tumour were at higher risk for systemic recurrence. They would probably progress after adjuvant treatment and would not be candidates for metachronous resection. Therefore, high nodal stage might be a valuable negative selection criteri- on when considering synchronous liver resection. As we further stratified patients, we deter- mined additional subgroups with the greatest sur- vival benefit. Patients with serum levels of Ca 19- 9 below 10 ng/ml had a 5-year survival of 15.4%. Similar long-term survival was observed in pa- tients younger than 64 years (15.6%). Patients with preoperative haemoglobin levels of more than 100 g/l had a 5YS of 20.8%. Next to the TNM N stage, tumour grade was found to have the most signifi- cant impact on long-term survival. Patients with a well-differentiated tumour had a 5-year survival of 47.5% compared to 0% in moderate to poor dif- ferentiated tumour. As these predictors are linked to inherent tumour biology, probably the most im- portant determinants for behaviour of liver metas- tases are intrinsic tumour properties that have yet to be determined in future studies. Our study has some limitations. It is a retrospec- tive study with a limited number of included pa- tients. Secondly, although the patients were select- ed with propensity score-matching, some selection bias could have still been present, since not all se- lection criteria have been included in the propensi- ty score calculation. And finally, only synchronous metastases have been included in the analysis. Conversely, since isolated liver metastases occur only in small number of resectable gastric cancer, most of the presently published studies have only a small number of cases. Still, these studies have a significant merit as they help build recommenda- tions for the treatment of liver metastases in gas- tric cancer patients. In the present paper we could show that synchronous liver resection in selected cases is beneficial since patients might expect simi- lar long-term survival as R0 resected stage IV gas- tric cancer patients without liver metastases. The liver resection was identified as an independent prognostic factor on multivariate analysis. Based on results of our study, we determined selection criteria for liver resection of synchronous gastric cancer metastases. Conclusions In conclusion, our results confirm that synchro- nous liver resection in gastric cancer patients is safe and offers significant survival benefit compared to chemotherapy alone. Moreover, after resection of liver metastases with curative intent, patients might expect similar long-term survival as PSM pa- tients with stage III and IV gastric cancer without liver metastases and R0 resection. In addition, we determined that patients benefiting the most from synchronous liver resection are patients younger than 64 years, with less than three liver metastases, Ca 19-9 serum levels below 10 ng/ml, well-differ- entiated primary tumours, and TNM N0–1 stage, provided an R0 resection can be obtained. Future prospective randomized studies will have to con- firm the value of these selection factors to provide clear-cut guidelines for treatment of gastric cancer patients with liver metastases. References 1. Takemura N, Saiura A, Koga R, Arita J, Yoshioka R, Ono Y, et al. Long-term outcomes after surgical resection for gastric cancer liver metastasis: an analysis of 64 macroscopically complete resections. Langenbecks Arch Surg 2012; 397: 951-7. doi: 10.10007/s00423-012-0959-z 2. Sarel AI, Yelluri S. Gastric adenocarcinoma with distant metastasis: is gastrectomy necessary? Arch Surg 2007; 142: 14349. doi: 10.1001/arch- surg.142.2.143 3. 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Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J Hepatobiliary Surg 2005; 12: 351-5. doi: 10.1007/s00534-005-0999-7 11. Jiu-Yang Liu, Chun-Wei Peng, Xiao-Jun Yang, Chao-Qun Huang, Yan Li. The prognosis role of AJCC/UICC 8th Edition staging system in gastric cancer, a retrospective analysis. Am J Transl Res 2018; 10: 292-303. PMID: 29423014 12. Tatsubayashi T, Tanizawa Y, Miki Y, Tokunaga M, Bando E, Kawamura T, et al. Treatment outcomes of hepatectomy for liver metastases of gastric cancer diagnosed using contrast-enhanced magnetic resonance imaging. Gastric Cancer 2017; 20: 387-93. doi: 10.1007/s10120-016-0611-7 13. Hartgrink HH, van de Velde CJ, Putter H, Bonenkamp JJ, Klein Kranenbarg E, Songun I, et al. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol 2004; 22: 2069-77. doi: 10.1200/JCO.2004.08.026 14. Cuschieri A, Fayers P, Fielding J, Craven J, Bancewicz J, Joypaul V, et al. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: Preliminary results of the MRC randomised controlled surgical trial. The surgical cooperative group. Lancet 1996; 347: 995-9. doi: 10.1016/ s0140-6736(96)90144-0 15. Jung JO, Nienhüser H, Schleussner N, Schmidt T. Oligometastatic gas- troesophageal adenocarcinoma: molecular pathophysiology and current therapeutic approach. Inter J Mol Sciences 2020; 21: 3-24. doi: 10.3390/ ijms21030951 16. Oki E, Tokunaga S, Emi Y, Kusumoto T, Yamamoto M, Fukuzawa K, et al. Kyushu Study Group of Clinical Cancer. Surgical treatment of liver metasta- sis of gastric cancer: a retrospective multicenter cohort study (KSCC1302). Gastric Cancer 2016; 19: 968-76. doi: 10.1007/s10120-015-0530-z 17. Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet 2016; 17: 309-18. doi: 10.1016/S1470- 2045(15)00553-7 18. Rosenbaum PR, Rubin DB. The central role of the propensity score in ob- servational studies for causal effects. Biometrika 1983; 70: 41-55. 10.1093/ biomet/70.1.41 19. Li M. Using the propensity score method to estimate causal effects: a review and practical guide. Organ Res Methods 2012; 15: 1-39. doi: 10.1177/1094428112447816 http://orm.sagepub.com 20. Makino H, Kunisaki C, Izumisawa Y, Tokuhisa M, Oshima T, Nagano Y, et al. Indication for hepatiec resection in treatment of liver metastasis from gastric cancer. Anticancer Res 2010; 30: 2367-76. doi: 10.1016/S1470- 2045(15)00553-7 21. Fujitani K, Yang HK, Mizusawa J, Terashima M, Han SU, Iwasaki Y, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, ran- domised controlled trial. Lancet Oncol 2016; 17: 1-10. doi: 10.1016/S1470- 2045(15)00553-7 22. Ministrini S, Bencivenga M, Solaini L, Cipollari C, Sofia S, Marino E, et al. Stage IV gastric cancer: The surgical perspective of the Italian Research Group on Gastric Cancer. Cancers 2020; 12: 1-14. doi: 10.3390/can- cers12010158 Radiol Oncol 2021; 55(1): 66-76. doi: 10.2478/raon-2020-0070 66 research article Postoperative radiotherapy for patients with completely resected pathological stage IIIA-N2 non-small cell lung cancer: a preferential benefit for squamous cell carcinoma Cuimeng Tian1,2, Guimei Liu1, Yongxiang Xu1, Guangrong Xia1, Tongmei Zhang3, Jiaqiang Huang4, Hui Jiang5, Ji Ming Wang2, Baolan Li3 1 Department of Radiation Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute / Beijing Chest Hospital, Capital Medical University, Beijing, China 2 Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, USA 3 Department of General Medicine, Beijing Tuberculosis and Thoracic Tumor Research Institute / Beijing Chest Hospital, Capital Medical University, Beijing, China 4 Department of Cellular and Molecular Biology, Beijing Tuberculosis and Thoracic Tumor Research Institute / Beijing Chest Hospital, Capital Medical University, Beijing, China 5 Division of Technology, Beijing Tuberculosis and Thoracic Tumor Research Institute / Beijing Chest Hospital, Capital Medical University, Beijing, China Radiol Oncol 2021; 55(1): 66-76. Received 21 July 2020 Accepted 6 October 2020 Correspondence to: Dr. Baolan Li, Department of General Medicine, Beijing Tuberculosis and Thoracic Tumor Research Institute / Beijing Chest Hospital, Capital Medical University, No.9, Beiguan Street, Tongzhou District, Beijing, 101149, China. E-mail: libaolan1109@163.com Conflict of interest: No potential conflicts of interest were disclosed. Background. The beneficial effect of postoperative radiotherapy (PORT) on completely resected pathological IIIA-N2 (pIIIA-N2) non-small cell lung cancer (NSCLC) has been a subject of interest with controversy. The aim of the study was to distinguish the clinical efficacy of PORT on lung adenocarcinoma (LADC) and lung squamous cell car- cinoma (LSCC) among pIIIA-N2 NSCLC. Patients and methods. Between October 2010 and September 2016, 288 consecutive patients with completely resected pIIIA-N2 NSCLC at Beijing Chest Hospital were retrospectively analyzed, which consisted of 194 cases of LADC and 85 cases of LSCC. There were 42 (21.6%) patients treated with PORT in LADC cases and 19 (22.3%) patients treated with PORT in LSCC cases. The 5-year overall survival (OS), loco-regional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The prognostic factors were deter- mined using Cox’s regression model. Results. Among 194 cases of LADC, the 1-, 3-, and 5-year OS in the PORT group were 95.2%, 61.9% and 40.0%, respec- tively, while in the non-PORT group were 90.1%, 63.3% and 45.0% (p = 0.948). The use of postoperative chemotherapy (POCT) and smoking index ≥ 400 were both prognostic factors of 5-year rates of OS, LRFS and DMFS. On the other hand, among 85 cases of LSCC, the 1-, 3-, and 5-year OS in the PORT group were 94.7%, 63.2% and 63.2%, respectively, whereas in the non-PORT group were 86.4%, 48.5% and 37.1% (p = 0.026). In this group, only the use of PORT was a favorable prognostic factor for 5-year OS, LRFS and DMFS. Conclusions. Due to clinicopathological differences among completely resected pIIIA-N2 NSCLC, PORT may not be suitable to all patients. Our study distinguishes pIIIA-N2 LSCC from LADC by their positive responses to PORT. Key words: lung squamous cell carcinoma; lung adenocarcinoma; pIIIA-N2; postoperative radiotherapy Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC 67 Introduction Lung cancer is the leading cause of cancer-related deaths worldwide.1 Non-small cell lung cancer (NSCLC) accounts for 80–85% of all cases of this cancer type. Stage IIIA-N2 NSCLC is a heterogene- ous combination of the diseases with poor prognosis even after surgical resection.2 Therefore, for patients with IIIA-N2 NSCLC, comprehensive treatment is advocated by many institutions.3 Postoperative ra- diotherapy (PORT) has been explored to improve treatment outcomes for IIIA-N2 NSCLC patients. A meta-analysis of randomized trials published in 1998 did not reveal a beneficial effect of PORT on N2 NSCLC, except for its safety.4 A new meta-anal- ysis of eight randomized/controlled trials (RCTs) and eight retrospective studies reported that the addition of PORT (with or without chemotherapy) significantly reduced local recurrence and increased the survival of patients with resected IIIA-N2 NSCLC.5 To obtain further supportive evidence for the safety and efficacy of PORT, the Lung Adjuvant Radiotherapy Trial (LungART) is conducting a mul- ticenter European prospective phase III trial with resected N2-NSCLC (with a goal of recruiting 700 patients). The trial presented at ESMO 2020 explor- ing the role of modern mediastinal PORT showed no benefit on disease free survival (DFS).6 Evaluation of the risks and benefits of PORT thus remains an issue of intense interest. Some studies suggested that subgroups of different clinicopatho- logical NSCLC may affect the efficacy of PORT. N2 status and other factors including smoking, large primary tumor and male sex played an important role in determining the efficiency of PORT.7-12 In addition, histological subtypes of NSCLC may also contribute to the sensitivity to PORT. Lung adeno- carcinoma (LADC) and squamous cell carcinoma (LSCC) are the most frequent subtypes of NSCLC, accounting for 50% and 30% of the cases, respec- tively.13 During the past decades, LADC received additional treatments with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and anaplastic lymphoma kinase (ALK) inhibitors with significantly improved patient prognosis.14 Unfortunately these inhibitors did not show thera- peutic effect on LSCC.15 Since compared with LADC, LSCC had a higher rate of local recurrence (21% vs. 14% for LADC) and lower rate of distant metasta- sis (7% vs. 11% for LADC) in patients with resected NSCLC, rigorous local treatment using PORT may more effectively eradicate micro-residual LSCC to improve the patient OS.16,17 These considerations prompted us to analyze the effect of PORT on the outcome of a cohort of pIIIA-N2 LADC and LSCC patients who received complete surgical resection. Patients and methods Patients Between October 2010 and September 2016, 288 consecutive patients with pathologically con- firmed T1–3N2M0 stage IIIA NSCLC, according to the American Joint Committee on Cancer (AJCC) 7th lung cancer TNM classification, who underwent surgery at the Department of Thoracic Surgery at Beijing Chest Hospital were included in the present retrospective study. The eligibility criteria of the patients included the following: (1) demonstrating an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; (2) not having re- ceived neo-adjuvant chemotherapy or chemoradi- otherapy; (3) information about tumor characteris- tics, pathology and follow-up data being available. All patients survived at least 4 months after radical resection in Beijing Chest Hospital. The medical re- cords and follow-up data of the patients were retro- spectively analyzed, including gender, age, smok- ing index, histology, pathological T stage, types of surgery, types of N2 (N2a1 N2a2, N2b) were based on The Eighth Edition Lung Cancer Stage Classification, number of positive nodes, positive lymph nodes ratio (PLNR), number of N2 stations, postoperative chemotherapy (POCT), PORT, pat- terns and times of recurrence, and survival status.18 Ethics approval and consent to participate The ethics committee of Academic Research Project Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University approved this study and consent was obtained from all participants. Surgery Radical resection was performed as follows: (1) either sleeve resection, lobectomy or pneumonec- tomy; (2) microscopically negative resection mar- gins; (3) mediastinal lymphadenectomy or system- atic mediastinal LN sampling. Postoperative chemotherapy (POCT) POCT was administered with a cisplatin- or car- boplatin-based regimen, used within 4 weeks af- Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC68 ter the surgery. Patients excluded from POCT in- cluded asthenia condition, refusal of the therapy or based on physicians’ decision. Postoperative radiotherapy (PORT) PORT, based on radiation oncologists’ decision or surgeon’s referral, was administered within 6 months after the surgery during or after the POCT cycles. Extensive mediastinal lymph node involve- ment was the main indication for PORT. Clinical target volume (CTV) included surgical margin, ipsilateral hilum, and high-risk ipsilateral medi- astinal drainage lymph area. The planning target volume (PTV) was defined as the CTV plus 0.5–0.8 cm margins. Therapy with EGFR TKIs or ALK inhibitors Patients with EGFR or ALK mutations in NSCLC were also treated with EGFR TKIs or ALK inhibi- tors given when tumors relapsed or metastasized. EGFR TKIs included erlotinib, gefitinib or icotinib. ALK inhibitor used was crizotinib. Follow-Up The patients were followed up every 3 months after surgery for the first 2 years and every 6–12 months thereafter. The last follow-up time was December 2019. Regular follow-up included physical exami- nation, hematology tests, chest CT scans, ultra- sound of supraclavicular region, ultrasound or CT scanning of the abdomen, and other imaging pro- cedures based on the requirement. Treatment fail- ures were determined by the physicians based on the available information, including clinical assess- ments, imaging results and/or pathological exami- nation. Follow-up information was also obtained by telephone surveys and reviewing electronic medical records. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered as local-regional failure (LRF). Tumors appeared at other sites, including the supraclavic- ular zone, contralateral hilum and distant organs, were considered distant metastasis (DM). Data analysis SPSS statistical software (version 23.0; SPSS Inc., Chicago, IL) was used for the statistical analyses. Loco-regional recurrence-free survival (LRFS) was defined from the day of surgery to the day of docu- mented LRF or the last follow-up. Distant metasta- sis-free survival (DMFS) was defined from the day of surgery to the day of documented DM or the last follow-up. Overall survival (OS) was measured from the day of surgery to the date of death from any cause or the last follow-up. A χ2 test was used to determine the distribution of patient character- istics within the PORT group and the non-PORT group. The 5-year OS, LRFS and DMFS were cal- culated using the Kaplan-Meier method. To deter- mine prognostic value, study variables were com- pared with the survival measures using log-rank tests. The prognostic factors were determined us- ing Cox’s regression model. A statistically signifi- cant difference was set at p < 0.05. Results Patient characteristics Detailed patient clinical and pathological charac- teristics are presented in Tables 1 with 194 cases of LADC and 85 cases of LSCC. Among 194 cases of LADC, the median age was 58 years. The median numbers of lymph nodes resected was 18 (range: 2–57). There were 170 (87.6%) patients treated with POCT and 42 (21.6%) patients treated with PORT. The clinicopathological features of the patients were comparable between PORT and non-PORT groups, with the exception that in the PORT group, there were more patients with T1–2 tumors, treat- ed with lobectomy and POCT. Among 85 cases of LSCC, the median age was 60 years. The median numbers of lymph nodes resected was 21 (range: 5–66). There were 72 (84.7%) patients treated with POCT and 19 (22.3%) treated with PORT. Among 61 PORT cases, the techniques used included three- dimensional conformal radiotherapy (3D-CRT, 21 cases) and intensity modulated radiotherapy (IMRT, 40 cases). The therapies were administered with a linear accelerator using 6–8 MV x-ray at 180–200 cGy per fraction, 5 days per week, to an average total radiation dose of 5918 cGy. PORT was used 4.38 months after surgery as an average and after 2 or 4 cycles of POCT. Survival Among 194 cases of LADC, the median survival time was 44.50 months. A total of 112 (57.7%) pa- tients succumbed during follow-up. The 1-, 3-, and 5-year OS rates in the PORT group were 95.2, 61.9 and 40.0%, respectively, whereas the non-PORT group exhibited 1-, 3- and 5-year OS rates of 90.1, Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC 69 63.3 and 45.0%, respectively (p = 0.948; Figure 1A). On the other hand, among 85 cases of LSCC, the median survival time was 38.00 months. A total of 52 (61.2%) patients succumbed during follow-up. The 1-, 3-, and 5-year OS rates in the PORT group were 94.7, 63.2 and 63.2%, respectively, whereas the non-PORT group exhibited 1-, 3- and 5-year OS rates of 86.4, 48.5 and 37.1%, respectively (p = 0.026; Figure 1B). Univariate analyses Univariate analyses were performed to determine the association between clinicopathological fac- tors and the patients’ 5-year OS, LRFS and DMFS FIGURE 1. The survival of 194 lung adenocarcinoma (LADC) cases with or without postoperative radiotherapy (PORT). (A) Overall survival (OS) of PORT and non-PORT patients. (B) OS of 85 lung squamous cell carcinoma (LSCC) cases with PORT or non-PORT. TABLE 1. Patient characteristics Characteristic LADC ( N = 194 ) LSCC ( N = 85 ) Total, n (%) Non-PORT, n (%) PORT, n (%) P Total, n (%) Non-PORT, n (%) PORT, n (%) P Gender 0.262 0.593 Female 96(49.5) 72(47.4) 24(57.1) 7(8.2) 6(9.1) 1(5.3) Male 98(50.5) 80(52.6) 18(42.9) 78(91.8) 60(90.9) 18(94.7) Age (yr) 0.058 0.814 < 65 139(71.6) 104(68.4) 35(83.3) 60(70.6) 47(71.2) 13(68.4) ≥ 65 55(28.4) 48(31.6) 7(16.7) 25(29.4) 19(28.8) 6(31.6) Smoking Index 0.199 0.058 < 400 127(65.5) 96(63.2) 31(73.8) 18(21.2) 11(16.7) 7(36.8) ≥ 400 67(34.5) 56(36.8) 11(26.2) 67(78.8) 55(83.3) 12(63.2) Type of surgery 0.028 0.211 Lobectomy 178(91.8) 136(89.5) 42(100) 57(84.0) 42(63.6) 15(78.9) Pneumonectomy 16(8.2) 16(10.5) 0(0.0) 28(16.0) 24(36.4) 4(21.1) Pathological T stage 0.044 0.167 T1–2 166(85.6) 126(82.9) 40(95.2) 56(65.9) 46(69.7) 10(52.6) T3 28(14.4) 26(17.1) 2(4.8) 29(34.1) 20(30.3) 9(47.4) Type of pN2 0.228 0.989 a1 46(23.7) 38(25.0) 8(19.0) 31(36.5) 24(36.4) 7(36.8) a2 62(32.0) 44(28.9) 18(42.9) 26(30.6) 20(30.3) 64(31.6) b 86(44.3) 70(46.1) 16(38.1) 28(32.9) 22(33.3) 6(31.6) N of positive nodes 0.090 0.581 1–3 87(44.8) 73(48.0) 14(33.3) 45(52.9) 36 (54.5) 9(47.4) ≥ 4 107(55.2) 79(52.0) 28(66.7) 40(47.1) 30(45.5) 10(52.6) PLNR 0.060 0.832 < 20% 80(41.2) 68(44.7) 12(28.6) 51(60.0) 40(60.6) 11(57.9) ≥ 20% 114(58.8) 84(55.3) 30(71.4) 34(40.0) 26(39.4) 8(42.1) N of N2 stations 0.422 0.970 Single 46(23.7) 38(25.0) 8(19.0) 31(36.5) 24(36.4) 7(36.8) Multiple 148(76.3) 114(75.0) 34(81.0) 54(63.5) 42(63.6) 12(63.2) POCT 0.026 0.512 No 24(12.4) 23(15.1) 1(2.4) 13(15.3) 11(16.7) 2(10.5) Yes 170(87.6) 129(84.9) 41(97.6) 72(84.7) 55(83.3) 17(89.5) LADC = lung adenocarcinoma; LSCC = lung squamous cell carcinoma; PORT = postoperative radiotherapy; PLNR = positive lymph nodes ratio; POCT = postoperative chemotherapy A B Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC70 in LADC and LSCC cases. The results of 194 cases of LADC are presented in Table 2. The 5-year OS in this patient group was significantly increased with a smoking index < 400 (p = 0.001), a lower T stage (p = 0.032), lower rate (or a single) N2 station me- tastasis (p = 0.001), lower number of positive nodes (p = 0.000), and lower percentage of positive nodes (p = 0.000). In addition, a lower smoking index < 400 (p = 0.001), a lower T stage (p = 0.020), lower number (or a single) N2 station metastasis (p = 0.002), lower number of positive nodes (p = 0.000), and lower percentage of positive nodes (p = 0.001) were as- TABLE 2. Univariate analyses of the factors affecting overall survival (OS), loco-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) of lung squamous cell carcinoma (LADC) patients (N = 194) Characteristics No. OS LRFS DMFS 5-year OS, % P 5-year LRFS, % P 5-year DMFS, % P Gender 0.071 0.085 0.139 Female 96 48.2 46.9 44.1 Male 98 39.6 37.1 30.6 Age(yr) 0.751 0.811 0.494 < 65 139 43.6 41.6 34.5 ≥ 65 55 45.0 42.8 41.3 Smoking Index 0.001* 0.001* 0.006* < 400 127 50.4 49.4 44.5 ≥ 400 67 31.0 27.4 22.7 Types of surgery 0.468 0.158 0.319 Lobectomy 178 44.1 42.3 36.5 Pneumonectomy 16 41.7 38.5 37.5 Pathologic T stage 0.032* 0.020* 0.001* pT1–2 166 46.3 44.0 40.4 pT3 28 29.5 28.0 15.5 Types of pN2 0.001* 0.002* 0.000* a1 46 60.9 58.3 58.8 a2 62 37.9 38.8 37.8 b 86 38.7 35.4 22.5 N of positive nodes 0.000* 0.000* 0.000* 1–3 87 56.6 54.7 53.4 ≥ 4 107 33.3 31.4 20.4 PLNR 0.000* 0.001* 0.000* < 20% 80 54.8 52.7 51.8 ≥ 20% 114 35.7 34.0 26.9 N of N2 stations 0.001* 0.002* 0.001* Single 46 60.9 58.3 58.8 Multiple 148 38.3 36.9 29.0 POCT 0.169 0.280 0.541 No 24 34.4 36.5 37.5 Yes 170 44.9 43.0 36.6 PORT 0.948 0.723 0.440 No 152 45.0 43.0 38.8 Yes 42 40.0 40.0 28.7 Kaplan-Meier method was used to calculate 5-year OS, LRFS and DMFS. Log-rank tests were used to analyze differences between patient groups. A statistically significant difference was set at p < 0.05, represented by “*”. PLNR = positive lymph nodes ratio; PORT = postoperative radiotherapy; POCT = postoperative chemotherapy Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC 71 sociated with improved 5-year LRFS. Furthermore, the 5-year DMFS were significantly increased in pa- tients with lower smoking index < 400 (p = 0.006), lower T stage (p = 0.001), lower (or a single) N2 sta- tion metastasis (p = 0.000), lower number of positive nodes (p = 0.000), and lower percentage of positive nodes (p = 0.000). The results of 85 cases of LSCC are presented in Table 3. It was noteworthy that on- ly PORT improved the 5-year OS, LRFS and DMFS, with p values of 0.026, 0.008 and 0.018 respectively. TABLE 3. Univariate analyses of the factors affecting overall survival (OS), loco-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) of lung adenocarcinoma (LSCC) patients (N = 85) Characteristics No OS LRFS DMFS 5-year OS, % P 5-year LRFS, % P 5-year DMFS, % P Gender 0.670 0.784 0.762 Female 7 42.9 42.9 42.9 Male 78 43.2 39.1 41.3 Age(yr) 0.362 0.617 0.447 < 65 60 46.4 40.8 43.9 ≥ 65 25 36.0 36.0 36.0 Smoking Index 0.713 0.659 0.767 < 400 18 55.6 44.4 50.0 ≥ 400 67 39.6 37.8 39.0 Type of surgery 0.283 0.375 0.498 Lobectomy 57 47.6 42.4 45.5 Pneumonectomy 28 34.1 33.2 33.9 Pathologic T stage 0.341 0.289 0.237 pT1–2 56 46.4 44.1 47.1 pT3 29 37.0 30.3 31.8 Type of N2 0.625 0.596 0.882 a1 31 50.6 44.4 44.8 a2 26 41.3 37.8 41.2 b 28 35.2 34.3 38.1 N of positive nodes 0.115 0.161 0.431 1–3 45 49.2 45.2 46.1 ≥ 4 40 36.7 34.1 36.1 PLNR 0.152 0.154 0.265 < 20% 51 48.7 43.8 46.9 ≥ 20% 34 34.4 33.0 33.1 N2 stations 0.367 0.363 0.654 Single 31 50.6 44.4 44.8 Multiple 54 38.9 36.9 39.7 POCT 0.316 0.371 0.525 No 13 30.8 30.8 30.8 Yes 72 45.3 40.9 43.5 PORT 0.026* 0.008** 0.018* No 66 37.7 32.5 35.3 Yes 19 63.2 63.2 63.2 Kaplan-Meier method was used to calculate 5-year OS, LRFS and DMFS. Log-rank tests were used to analyze differences between patient groups. A statistically significant difference was set at p < 0.05, represented by “*”. PLNR = positive lymph nodes ratio; PORT = postoperative radiotherapy; POCT = postoperative chemotherapy Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC72 Multivariate analyses Multivariate analyses using Cox’s regression model were performed to determine independent prognostic factors for patient survival and disease control. The results of 194 cases of LADC were pre- sented in Table 4. Use of POCT (HR, 0.417; 95% CI, 0.230–0.757; p = 0.004), multiple N2 stations (HR, 2.065; 95% CI, 1.148–3.714; p = 0.015) and smok- ing index ≥ 400 (HR, 2.172; 95% CI, 1.471–3.207; p = 0.000) were identified as significant independ- ent predictors of OS. The use of POCT (HR, 0.524; 95% CI, 0.291–0.942; p = 0.031), multiple N2 sta- tions (HR, 1.818; 95% CI, 1.010–3.272; p = 0.046) and smoking index ≥ 400 (HR, 2.098; 95% CI, 1.421– 3.099; p = 0.000) were identified as significant in- dependent predictors of LRFS. Likewise, use of POCT (HR, 0.554 95% CI, 0.310–0.992; p = 0.047), T3 stage (HR, 2.120; 95% CI, 1.308–3.435; p = 0.002) and smoking index ≥ 400 (HR, 1.739; 95% CI, 1.181– 2.560; p = 0.005) were identified as significant in- dependent predictors of DMFS. The results of 85 cases of LSCC were presented in Table 5, which indicates that only patients with the use of PORT showed significantly improved OS (HR, 0.364; 95% CI, 0.159–1.832; p = 0.017), LRFS (HR, 0.308; 95% CI, 0.133–0.712; p = 0.006) and DMFS (HR, 0.349; 95% CI, 0.152–0.802; p = 0.013) (Figure 2). Toxicities associated with PORT Twelve patients (19.6%) experienced Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade 2 (10 patients) or Grade 3 (2 patients) acute pneumonitis. No patients experienced Grade 4 or higher acute pneumonitis. There were 46 pa- tients (75.4%) experiencing CTCAE v4.0 Grade 1 (35 patients) or higher acute esophagitis (10 with Grade 2 and 1 with Grade 3 toxicity). No patients experienced Grade 4 or higher acute esophagitis. TABLE 4. Multivariate analyses of the factors affecting overall survival (OS), loco-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) of lung squamous cell carcinoma (LADC) patients (N = 194) Characteristics OS LRFS DMFS HR (95% CI) P HR(95% CI) P HR (95% CI) P Smoking Index 0.000* 0.000* 0.005* < 400 1 1 1 ≥ 400 2.172(1.471–3.207) 2.098(1.421–3.099) 1.739(1.181–2.560) Pathologic T stage 0.074 0.156 0.002* pT1–2 1 1 1 pT3 1.560(0.958–2.542) 1.428(0.873–2.337) 2.120(1.308–3.435) N of positive nodes 0.255 0.234 0.134 1–3 1 1 1 ≥ 4 1.403(0.783–2.512) 1.441(0.789–2.632) 1.624(0.861–3.062) PLNR 0.392 0.435 0.471 < 20% 1 1 1 ≥ 20% 1.313(0.704–2.447) 1.291(0.680–2.452) 1.283(0.651–2.528) N of N2 stations 0.015* 0.046* 0.141 Single 1 1 1 Multiple 2.065(1.148–3.714) 1.818(1.010–3.272) 1.565(0.863–2.839) POCT 0.004* 0.031* 0.047* No 1 1 1 Yes 0.417(0.230–0.757) 0.524(0.291–0.942) 0.554(0.310–0.992) PORT 0.759 0.737 0.444 No 1 1 1 Yes 1.074(0.680–1.697) 0.924(0.584–1.463) 1.196(0.756–1.891) Multivariable Cox proportional hazard models were used to adjust risk factor distributions between patient groups. A statistically significant difference was set as p < 0.05, represented by “*”. PLNR = positive lymph nodes ratio; PORT = postoperative radiotherapy; POCT = postoperative chemotherapy; HR = hazard ratio; CI = confidence interval Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC 73 TABLE 5. Multivariate analyses of the factors affecting overall survival (OS), loco-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) of lung adenocarcinoma (LSCC) patients (N = 85) Characteristics OS LRFS DMFS HR (95% CI) P HR(95% CI) P HR (95% CI) P Smoking Index 0.789 0.823 0.563 < 400 1 1 1 ≥ 400 0.905(0.436–1.880) 0.922(0.454–1.874) 0.806(0.389–1.672) Pathologic T stage 0.208 0.149 0.151 pT1–2 1 1 1 pT3 1.436(0.817–2.522) 1.524(0.860–2.701) 1.522(0.858–2.699) N of positive nodes 0.257 0.296 0.664 1–3 1 1 1 ≥ 4 1.618(0.704–3.715) 1.556(0.679–3.563) 1.194(0.537–2.657) PLNR 0.440 0.454 0.330 < 20% 1 1 1 ≥ 20% 1.322(0.650–2.689) 1.308(0.648–2.643) 1.428(0.697–2.925) N of N2 stations 0.922 0.963 0.813 Single 1 1 1 Multiple 1.043(0.447–2.436) 0.979(0.409–2.343) 0.903(0.385–2.114) POCT 0.127 0.224 0.496 No 1 1 1 Yes 0.523(0.227–1.202) 0.595(0.258–1.374) 0.751(0.328–1.715) PORT 0.017* 0.006* 0.013* No 1 1 1 Yes 0.364(0.159–1.832) 0.308(0.133–0.712) 0.349(0.152–0.802) Multivariable Cox proportional hazard models were used to adjust risk factor distributions between patient groups. A statistically significant difference was set at p < 0.05, represented by “*”. PLNR = positive lymph nodes ratio; PORT = postoperative radiotherapy; POCT = postoperative chemotherapy; HR = hazard ratio; CI = confidence interval FIGURE 2. The effect of postoperative radiotherapy (PORT) on the survival of 85 lung squamous cell carcinoma (LSCC) patients. (A) Overall survival (OS). (B) loco-regional recurrence-free survival (LRFS). (C) Distant metastasis-free survival (DMFS). PORT alone was a significant positive prognostic factor for OS (p = 0.017) (A); LRFS (p = 0.006 (B); and DMFS (p = 0.013) (C). A B C Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC74 All patients completed symptomatic radiotherapy with planned doses. As late radiation toxicity, 2 patients (3.2%) were observed with pulmonary fi- brosis. Discussion With advancement of the technology, PORT plays an important role in improving the survival of resected pN2-NSCLC patients with no exces- sive increase in the risk of intercurrent deaths.19,20 However, the newest result of the first European randomized study evaluating modern PORT after complete resection reported no benefit for DFS.6 In general, in patients with different clinicopatho- logical features, only selected patients benefit from PORT.21 Several clinicopathological factors such as number of N2 status, smoking history, tumor size and sex have been reported to be associated with patient survival rates.7-12 Therefore, the estimate of the benefit of PORT for pIIIA-N2 NSCLC should be individualized. The aim of this study was to assess the potential effect of PORT on histologi- cally different subgroups of completely resected pIIIA-N2 NSCLC. Traditionally, although both LADC and LSCC were categorized as NSCLC, we regard them as different cancer types due to distinct cells of origin, unique molecular charac- teristics and dissimilar clinical responses to treat- ments. LSCC typically originates from bronchial epithelium of larger and more proximal airways (basal cells), mostly from central lung and etiologi- cally are more closely associated with smoking and chronic inflammation.22,23 Patients with LSCC tend to have lower rates of distant dissemination than those of LADC.24 Therefore, the main therapeutic objective for LSCC patients is to eradicate residual microscopic tumors with tumor-negative resection margin and clearance of mediastinal node areas. In addition, new treatments (i.e., EGFR tyrosine kinase and ALK inhibitors) failed to shown ben- efits for patients with LSCC, which are also gener- ally chemotherapy-insensitive.15, 25 However, use of PORT is associated with a significantly lower loco- regional recurrence rate in a randomized study of 366 patients with resected pN1-N2 NSCLC.26 Another randomized study of 230 patients with resected stage II or stage III LSCC showed sig- nificantly lower overall recurrence rate by use of PORT in patients bearing N2 disease.27 PORT was also beneficial for patients with resected pIIIA-N2 LSCC.28 A comprehensive analysis of our pIIIA-N2 LSCC patient cohort demonstrates that PORT im- proves 5-year OS, LRFS, and DMFS, supporting the advantage of PORT for pIIIA-N2 LSCC. LADCs, originating from the bronchiolar or alveolar epithelium (Clara cells or type II pneu- mocytes), mainly locate in the peripheral smaller airways with glandular histology features with biomarkers consistent with tissues of the distal lung.22,23 The great risk of distant metastasis shown by LADCs exceeds that of local recurrence at every disease stage, highlighting the systemic threat of the disease.29 Platinum-based doublets have been the standard postoperative adjuvant therapy for resected stage IB–IIIA NSCLC patients during the past years.30 In our study of 194 LADC cases, Cox’s regression model shows POCT as an independent predictor of OS, LRFS and DMFS. The last decade has seen significant advances in understanding of lung cancer biology and management. EGFR is one of the most important molecular biomarkers in NSCLC, mainly in LADC, in which mutations strongly predict the efficacy and sensitivity to EGFR TKIs.31 In fact, TKIs have become the first- line treatment choice for patients with advanced NSCLC with EGFR mutations.32-34 Due to lower toxicity and improved quality of patient life, ad- juvant EGFR-TKI therapy is a priority option for completely resected stage II–IIIA (N1–N2) EGFR- mutant NSCLC, resulting in superior disease-free survival.35 The EGFR-TKI inhibitors may not be curative, but as adjuvant they do provide clini- cal benefit for most patients with EGFR-mutant tumors.36 However, in our study, EGFR-TKIs did not demonstrate superior effect on LDAC after sur- gery, most likely due to targeted therapy is used as a salvage treatment rather than a postoperative adjuvant treatment. LADC and LSCC are thought to have different cell origin and distinct molecular characteristics. Tobacco smoke is a major risk factor for NSCLC, but LSCCs are more highly associated with tobacco smoke exposure and more often seen in male. In contrast, LADCs occurs more often in women and people who do not have a smoke history.37 In addi- tion, significant differences were found in microen- vironment, dysregulations of miRNAs, epigenetic modifications, cell signal transduction proteins and target genes in various stages of LADC and LSCC.38 Recent studies have proposed exploring mitochondrial respiratory gene expression profiles in LADC versus LSCC to improve the diagnosis and treatment of patients.39 One report focusing on the efficacy of PORT in patients with pN2 EGFR wild type LADC and LSCC concludes that female LADC (wild type EGFR) and male LSCC patients Radiol Oncol 2021; 55(1): 66-76. Tian C et al. / Postoperative radiotherapy for resected stage IIIA-N2 NSCLC 75 benefited from PORT combined with platinum- based POCT.40 In our study, pIIIA-N2 LSCC is distinguishable from LADC in their sensitivity to PORT with improved survival. Our study is based on a relatively smaller da- ta set from patient cohort of a single institution. Further randomized studies of a larger number of patients through multi-institutional collaborations are warranted to more precisely evaluate the thera- peutic significance of PORT in NSCLC, especially in LSCC. Conclusions It is clear that PORT is not suitable to all patients of completely resected stage IIIA-N2 NSCLC. Rather, PORT displayed its benefit for IIIA-N2 LSCC. Acknowledgements and funding The authors thank Xu Zhang and Zhouguang Hui for technical assistance. 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Int J Surg 2019; 72: 34-42. doi: 10.1016/j.ijsu.2019.10.013 Radiol Oncol 2021; 55(1): 82-87. doi: 10.2478/raon-2020-0065 82 research article Clinical and volumetric predictors of local control after robotic stereotactic radiosurgery for cerebral metastases: active systemic disease may affect local control in the brain Sławomir Blamek1, Magdalena Stankiewicz2, Bogusław Maciejewski1 1 Department of Radiotherapy, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland 2 Department of Brachytherapy, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland Radiol Oncol 2021; 55(1): 82-87. Received 24 August 2020 Accepted 30 September 2020 Correspondence to: Sławomir Blamek, M.D., Ph.D., Department of Radiotherapy, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, ul. Wybrzeże AK 15, 44-102 Gliwice, Poland. E-mail: slawomir.blamek@io.gliwice.pl Disclosure: No potential conflicts of interest were disclosed. Background. The aim of the study was to assess the association between physical and biological dose normalized to volume of the metastatic tumor as well as clinical factors with local control in patients with brain metastases who underwent robotic stereotactic radiosurgery. Patients and methods. A cohort of 69 patients consecutively treated with robotic radiosurgery between 2011 and 2016 was analyzed. The patients were treated with either single fraction radiosurgery or hypofractionated regimens. Biologically effective dose (BED) was calculated assuming alpha/beta value = 10 and both physical dose and BED were normalized to the tumor volume to allow dose-volume effect evaluation. Moreover, clinical and treatment- related variables were evaluated to asses association with local control. Results. A total of 133 tumors were irradiated and their volumes ranged between 0.001 and 46.99 cm3. Presence of extracranial progression was associated with worse local control whereas higher total dose, BED10 > 59 Gy and single metastasis predicted statistically significantly better local outcome. BED10/cm3 > 36 Gy, and BED2 > 60 Gy negatively affected local control in univariate analysis. In multivariate analysis performed on all these variables, presence of a single metastasis, BED10 > 59 Gy and extracranial progression retained their significance. Excluding a priori the BED2/ cm3 parameter resulted with a Cox model confirming significance of all remaining variables. Conclusions. Hypofractionated treatment schemes have similar efficiency to single fraction treatment in terms of local control and the effect depends on BED irrespective of fractionation schedule. Effective control of extracranial sites of the disease is associated with higher probability of local control in the brain which in turn is consistently lower in patients with multiple lesions. Key words: brain metastases; radiosurgery; radiobiology; local control Introduction Although the number of studies focusing on over- all survival after radiosurgery for brain metastases is impressive, much less is known about factors af- fecting local control. Tumor volume/diameter, vol- ume of edema, large (> 15) number of lesions, con- current chemotherapy and other factors are listed by various authors but without consistency and the findings usually are not reproduced by others.1-5 Of course, assuming that metastatic tumors contain a constant number of clonogenic cells per volume unit, there is indeed a risk that larger tumors may be treated less effectively. This is because lower doses are used to kill larger number of cancer stem cells per tumor. According to the RTOG 9005 protocol, brain metastases exceeding 3 cm in diameter were treated with a single dose of 15 Gy as opposed to 24 Radiol Oncol 2021; 55(1): 82-87. Blamek S et al. / Robotic stereotactic radiosurgery for cerebral metastases 83 Gy for tumors smaller than 2 cm.6 This results with almost five times more stem cells treated with less than two thirds of the dose delivered to a smaller tumor. Alternatively, fractionated schemes of still uncertain efficacy can be implemented. Their pos- tulated equivalence to single fraction schedules in terms of biological dose is based on radiobiological calculations but the assumptions taken, need con- firmation in clinical studies. The first studies aimed at detailed analysis of the effect of the dose normal- ized to volume of the lesion and probability of lo- cal control were made by Amsbaugh et al. but they analyzed single fraction regimens only.7,8 The aim of our study was to assess the associa- tion between physical and biological dose deliv- ered per volume unit of a metastatic tumor as well as clinical factors with local control in patients with brain metastases after robotic stereotactic radiosur- gery. Patients and methods All patients treated with the CyberKnife system for cerebral metastases between 2011 and 2016 were retrospectively evaluated to find those with follow-up imaging studies allowing for evaluation of local control. No selection was made in terms of pathology of the tumor, prior treatment or primary tumor status. This resulted with identification of 69 patients for further evaluation. Patients were immobilized with thermoplas- tic masks for treatment. CT and MR images were made and the target volume and critical structures were defined on registered images. Usually, no ad- ditional margin was added to the GTV. Patients were qualified to a single fraction or hypofrac- tionated treatment after individual assessment of the target volume and proximity of organs at risk. Single doses were prescribed following the RTOG 9005 study. If V12 exceeded 10 cm3 or dose con- straints for critical structures were violated, frac- tionated treatment was prescribed. The dose was specified to isodose encompassing the target, usu- ally between 78 and 90%. All patients were treated with the CyberKnife VSI system. Biologically effective dose (BED) was calculat- ed assuming the alpha/beta value of 10. The total physical dose (TD) and BED were normalized to the tumor volume to allow better evaluation of the dose effect. Prescription dose was taken as refer- ence for calculation. Threshold values of BED and BED/cm3 were determined after a stepwise analysis and further included into statistical analysis as cat- egorical variables. Age, gender, pathology, prima- ry tumor status, WBRT use and other variables po- tentially associated with local control and survival were also analyzed. MR imaging after treatment was performed usually every 3-4 months during the first year and every 6-12 months thereafter. Local control (LC) was defined as lack of progres- sion (complete or partial response or stable dis- ease) of the irradiated lesion. Any increase in lesion size without evidence of radiation-induced necro- sis was qualified as local progression. Local pro- gression-free survival (LPFS) was defined as time between treatment and the first imaging showing progression of the irradiated lesion. Local progres- sion (LP) was defined as growth of the irradiated lesion irrespective of the status of other lesions. Distant progression-free survival defined as time to development of new brain metastases (outside the irradiated lesions) was not evaluated. TABLE 1. Basic characteristics of the study population Median (range) Age 58 (32–84) KPS 80 (70–100) Number of lesions (1-9) 1 2 3 4 5 6 9 1 (1–9) Number of patients 40 12 9 4 1 2 1 Gender (M/F) 22/47 WBRT before SRS Yes No 34 35 Location of the primary tumour Lung Breast Kidney Skin (melanoma) Colon Unknown primary Uterine corpus Other* 23 20 5 5 3 3 2 8 Disease status Stable/NED Progressive 42 27 Primary tumor controlled Yes No 62 7 Extracranial metastases Present No 39 30 * = One case of each: intestinal sarcoma, thyroid cancer, uterine cervix carcinoma, esophageal, gastric, oral cavity, ovarian, and bladder cancer; F = female; KPS = Karnofsky performance status; M = male; NED = no evidence of disease; SRS = stereotactic radiosurgery; WBRT = whole brain radiotherapy Radiol Oncol 2021; 55(1): 82-87. Blamek S et al. / Robotic stereotactic radiosurgery for cerebral metastases84 Kaplan-Meier method and log-rank test were used for calculations and intergroup comparisons. Kaplan-Meier estimations were calculated per le- sion (progression of the index lesion was an event). If a new lesion occurred, the patient was censored TABLE 2. Dosimetric and volumetric characteristics of the group Variable Median (range) p Total dose in SRS 18 Gy (5–24) p = 0.0036* Total dose in HSRT 20 Gy (12–30) Dose per fraction in HSRT 7.25 Gy (6–13 ) BED10 in SRS 50.4 (7.5–81.6) p = 0.0237* BED10 in HSRT 35.7 (19.2–60) Lesion volume 1.74 cm3 (0.001–46.99) Single metastasis 4.68 cm3 (0.05–39.2) p = 0.0002* Multiple metastases 0.96 cm3 (0.001–46.99) Total tumor volume 4.9 cm3 (0.05–63.95) Single metastasis volume 4.68 cm3 (0.05–39.2) p = 0.0371* Multiple metastases volume 4.90 cm3 (0.48–63.95) *= comparison between groups, Mann-Whitney U test; BED10 = biologically effective dose for alpha/ beta =10; HSRT = hypofractionated stereotactic radiotherapy; SRS – stereotactic radiosurgery TABLE 3. Association of selected variables with local control Variable p univariate Multivariate Single vs. multiple lesions 0.00001 0.0161 Gender 0.2508 Total dose* 0.0011 0.0886 BED10* 0.7026 BED10 > 59 Gy 0.0026 0.0105 Fractionation (SRS vs. HSRT) 0.1265 Tumor volume¶ 0.1777 Total tumor volume¶ 0.8950 Chemotherapy before SRS/HSRT 0.3785 Chemotherapy after SRS/HSRT 0.2174 Chemotherapy before and after SRS/HSRT 0.2606 Time between diagnosis of primary and metastases* 0.6551 BED10 per 1 ml tumor volume > median (24.3 Gy) 0.3709 BED10 per 1 ml tumor volume > 36 Gy 0.0281 0.3032 Total dose/ml tumor volume > median (11 Gy) 0.3882 Extracranial metastases 0.3130 Control of primary tumor 0.8681 Extracranial progression** 0.0078 0.0011 RPA class 0.8627 WBRT use 0.3918 BED2/cm3 > 60 0.0392 0.8638 * = above vs. below or equal median; ** = progression of primary tumor or any of extracranial metastases; SRS = stereotactic radiosurgery; HSRT = hypofractionated stereotactic radiotherapy; BED10, BED2 = biologically effective dose for alpha/beta =10 and 2, respectively; WBRT = whole brain radiotherapy; RPA = recursive partitioning analysis for the purpose of the analysis (only the irradiated lesions were the subject of analysis and it was as- sumed that dose delivered to an existing lesion will not affect the probability of progression elsewhere in the brain). Patients dying without evidence of progression of the irradiated lesion were censored at the time of death. Cox regression was used for multivariate analysis which was performed on the set of variables significant in the univariate analy- sis. Mann-Whitney U test was used for intergroup comparisons. The p value < 0.05 was considered significant. The study follows the principles of the Declaration of Helsinki. Results A total of 133 tumors in 69 patients were irradiated and their volumes ranged between 0.001 and 46.99 cm3 (median 1.86). Basic patient characteristics is shown in Table 1. Median total intracranial tumor volume was 4.1 cm3. The doses used resulted with BED10 values of 11.9 – 81.6 Gy (median 46.2 Gy). Physical doses and BED per 1 cm3 of tumor volume ranged between 0.3 - 1322 Gy (median 11), and 4.6-119733.5 Gy (me- dian 24.3), respectively. Detailed dosimetric char- acteristics is shown in Table 2. Median LPFS was 10.7 months. Actuarial 1-year local progression-free survival was 46%. No asso- ciation between the volume of the tumor and lo- cal control could be found. Total dose, BED10 above 59 Gy (Figure 1), presence of a single metastasis (Figure 2), and extracranial progression (Figure 3) were significantly associated with LC variables. Presence of extracranial progression was associ- ated with worse local control whereas higher TD, BED10 > 59 Gy and single metastasis predicted bet- ter local outcome. Moreover, negative association with BED10/cm3 (Figure 4), and BED2/cm3 and LC was identified (Table 3). In multivariate analysis only presence of a single metastasis, BED10 > 59 Gy and extracranial progres- sion retained their significance. Excluding a priori the BED2/cm3 parameter, which can be considered redundant in construction of the Cox model result- ed with confirmation of significance of all of the remaining. The results of analysis prompted to check also the difference in local control between patients with 1-3 and more metastases which was also high- ly significant (p = 0.0000), with median LPFS of 7.1 and 17.1 months, respectively. All patients with Radiol Oncol 2021; 55(1): 82-87. Blamek S et al. / Robotic stereotactic radiosurgery for cerebral metastases 85 FIGURE 4. Local progression-free survival according to biologically effective dose (BED)10 normalized to tumor volume. Exceeding the threshold value of 36 Gy10/cm3 (red, dashed line) was associated with reduced chances of maintaining local control. FIGURE 1. Local progression-free survival according to biologically effective dose (BED)10. Doses above 59 Gy10 (red, dashed line) were associated with significantly longer local progression-free survival (LPFS) (median 7.5 vs. 18.4 months). FIGURE 2. Local progression-free survival according to number of metastases. Presence of a single metastasis (blue, solid line) was a favorable prognostic factor. FIGURE 3. Local progression-free survival according to systemic disease status. Extracranial progression (red, dashed line) was an adverse prognostic factor. more than 3 metastases failed locally before one year whereas actuarial 1-year LPFS in the group with 1-3 metastases was 68%. Discussion To the best knowledge of the authors this is the first study in which dose normalized to tumor volume is analyzed as a prognostic factor for local control for both single-fraction and hypofraction- ated regimens. Amsbaugh et al. used the dose per lesion diameter and dose per volume parameters to construct dose-volume response relationships.7,8 They found strong correlation between doses and volumes of the tumor which was quite obvious be- cause all patients in their series were treated with single fraction, so the larger the volume, the small- er total dose was used. This resulted with worse results in patients with larger metastases who were treated with lower doses. Similar patients in ours were treated with fractionated regimens which theoretically should result with similar effective- ness like after a large, single fraction. And indeed, no clear association between tumor volume and outcome could be identified here as opposed to increasing rates of local control corresponding to maximum dose per mm of tumor diameter (80%, 85%, and 90% for 1.67 Gy/mm, 2.86 Gy/mm, and 4.4 Gy/mm, respectively) reported in the Amsbaugh’s paper.7 They identified also a relationship between mean dose per volume and local control. Finally, they observed that patients with fewer number of metastases had worse local control (OR: 0.815, Radiol Oncol 2021; 55(1): 82-87. Blamek S et al. / Robotic stereotactic radiosurgery for cerebral metastases86 95% CI: 0.72-0.93).8 Similar observation was made by Yamamoto et al. in their study on stereotactic radiosurgery for multiple brain metastases.9 They observed significant difference in local recurrence ratio and need for repeat treatment between group with 2-9 metastases (more recurrences) and group with 10 and more lesions. At the same time they ad- mitted that the reason for that finding remains ob- scure. Contrary to their findings, in our series pa- tients with larger number of metastases had worse local control than patients treated for single lesion. This is not an obvious finding whatsoever, espe- cially knowing that the median volume of the tu- mor was significantly larger in patients with single lesion (median 4.68 cm3) than in patients with mul- tiple metastases (median 0.96 cm3). Nevertheless, the effect was stunning which was confirmed by secondary analysis showing that all patients with more than 3 metastases fail locally before one year. BED above 59 Gy10 was associated with im- proved chances of local control. This parameter re- tained significance in multivariate analysis indicat- ing that appropriate biologically effective dose in- creases the probability of local control irrespective of the fractionation method. What is more intrigu- ing, biological doses normalized to tumor volume above 36 Gy10/cm3 (the threshold value calculated for the nervous tissue - BED2 was 60 Gy2/cm3 and was also significant) resulted with significantly worse local control. This phenomenon did not re- tain significance in multivariate analysis including all variables significant in the univariate analysis. However, in an additionally constructed model without incorporating BED2/cm3 it did. Amsbaugh et al. did not identify a threshold dose per cm3 of tumor volume associated with plateau of local ef- fect or local control decrease. The exact meaning of this finding is uncertain and it may be just a statis- tical artifact. One could also speculate that it may indicate existence of some kind of threshold dose and after reaching the optimal dose level its fur- ther escalation might facilitate concurrent negative processes. In situ recurrence of the radiosurgically ablated tumor due to damage of the surrounding tissues resulting with easier penetration of the cir- culating tumor cells may be one of possible expla- nations. Local progression was significantly associ- ated also with extracranial progression which may further support this theory of re-seeding of the site of previously ablated tumor by circulating cells originating from extracranial foci. The concept of radiation-induced metastases, and more generally – treatment-induced metastases (TIM), although described in the 50—ties of the XX-th century, was mostly forgotten but regained attention in recent years.10–12 In this specific case it would be rather treatment-induced/facilitated local recurrence as- sociated with exceeding a safe dose for local micro- environment. Of course we cannot provide a proof of sterilization of the irradiated tumor or distinct characteristics of the progressing lesion but we believe our observation is worth further studies. Radiation resistance associated with general resist- ance to the treatment also can be an explanation and presumably should be given first, as a more probable one. In this case, in spite of delivering high doses to low-volume lesions, we would face local failure without prior elimination of the lesion. Currently, it can be only concluded that patients with systemic progression are more likely to pro- gress also in the brain. Better outcome after larger single dose in terms of probability of local control was confirmed for example by Mohammadi et al. They found that tumors smaller than 2 cm of diameter are better controlled with 24 Gy than lower doses.13 This finding supports the assumption that there is a dose-response relationship but, on the other hand, it shows the drawbacks of using a single fraction in case of tumors which cannot be treated with sufficiently large doses. In our series, the dose- response relationship was also identified but was best seen when the dose exceeded 59 Gy10, irre- spective of the fractionation method and tumor volume. Interestingly, some authors did not find any correlation between local control and dosimet- ric or clinical factors.5 The only factor significantly associated with local control in the study by Loo et al. for example, was the total volume of edema, not volume of the tumors or dose delivered.2 Our study has drawbacks typical for retrospec- tive evaluations. We cannot exclude patient selec- tion bias and we did not have follow-up imaging available for every patient treated in our center which limited the study sample. We realize also that metastases in a single patients share a lot of common properties important for the prognosis and their independent analysis may be somewhat misleading. On the other hand, it should facilitate demonstration of the dose and volume effect be- cause lesions of various sizes in one patient were often irradiated with different doses. Our results suggest that local control in the brain can depend on several factors including those not directly related to the local treatment and may be associated also with systemic progression. In turn, this may influence overall survival in much more complex way than we assume. The results suggest Radiol Oncol 2021; 55(1): 82-87. Blamek S et al. / Robotic stereotactic radiosurgery for cerebral metastases 87 also that escalating the dose above certain limits may not be beneficial. The threshold dose for this effect calculated for the nervous tissue is similar to the dose of 60 Gy used in conventional radiother- apy for primary brain tumors. Further escalation did not prove beneficial but was associated with increased risk of adverse effects.14 Conclusions Hypofractionated treatment schemes have similar efficiency to single fraction treatment in terms of local control and the effect depends on BED, irre- spective of fractionation schedule. Effective con- trol of extracranial sites of the disease is associated with probability of local control in the brain which is consistently lower in patients with multiple le- sions. References 1. Chon H, Yoon K, Kwon DH, Kim CJ, Kim M-S, Cho YH. Hypofractionated stereotactic radiosurgery for pituitary metastases. J Neurooncol 2017; 132: 127-33. doi: 10.1007/s11060-016-2346-z 2. Loo M, Pin Y, Thierry A, Clavier JB. Single-fraction radiosurgery versus fractionated stereotactic radiotherapy in patients with brain metastases: a comparative study. Clin Exp Metastasis 2020; 37: 425-34. doi: 10.1007/ s10585-020-10031-5 3. Eaton BR, Gebhardt B, Prabhu R, Shu H-K, Curran WJ, Crocker I. Hypofractionated radiosurgery for intact or resected brain metastases: defining the optimal dose and fractionation. Radiat Oncol 2013; 8: 135. doi: 10.1186/1748-717X-8-135 4. Greto D, Livi L, Bonomo P, Masi L, Detti B, Meattini I, et al. Cyberknife ste- reotactic radiosurgery for the re-irradiation of brain lesions: a single-centre experience. Radiol Medica 2014; 119: 721-6. doi: 10.1007/s11547-014- 0383-2 5. Remick JS, Kowalski E, Khairnar R, Sun K, Morse E, Cherng HR, et al. A multi-center analysis of single-fraction versus hypofractionated stereotactic radiosurgery for the treatment of brain metastasis. Radiat Oncol 2020; 15: 128. doi: 10.1186/s13014-020-01522-6 6. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tu- mors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 2000; 47: 291-8. doi: 10.1016/s0360-3016(99)00507-6 7. Amsbaugh M, Pan J, Yusuf MB, Dragun A, Dunlap N, Guan T, et al. Dose- Volume response relationship for brain metastases treated with frameless single-fraction linear accelerator-based stereotactic radiosurgery. Cureus 2016; 27; 8: e5. doi: 10.7759/cureus.587 8. Amsbaugh MJ, Yusuf MB, Gaskins J, Dragun AE, Dunlap N, Guan T, et al. A dose-volume response model for brain metastases treated with frameless single-fraction robotic radiosurgery: seeking to better predict response to treatment. Technol Cancer Res Treat 2017; 16: 344-51. doi: 10.1177/1533034616685025 9. Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Watanabe S, et al. Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2-9 versus 10 or more tumors. J Neurosurg 2014; 121(Suppl): 16-25. doi: 10.3171/2014.8.GKS141421 10. Kaplan HS, Murphy ED. The effect of local roentgen irradiation on the biologi- cal behavior of a transplantable mouse carcinoma; increased frequency of pulmonary metastasis. J Natl Cancer Inst 1949; 9: 407-13. 11. Ebos JML. Prodding the beast: assessing the impact of treatment-induced metastasis. Cancer Res 2015; 75: 3427-35. doi: 10.1158/0008-5472.CAN-15- 0308 12. Brown JM, Marsa GW. Effect of dose fractionation on the enhancement by radiation or cyclophosphamide of artificial pulmonary metastases. Br J Cancer 1978; 37: 1020-5. doi: 10.1038/bjc.1978.148 13. Mohammadi AM, Schroeder JL, Angelov L, Chao ST, Murphy ES, Yu JS, et al. Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases. J Neurosurg 2017; 126: 735-43. doi: 10.3171/2016.3.JNS153014 14. Lee SW, Fraass BA, Marsh LH, Herbort K, Gebarski SS, Martel MK, et al. Patterns of failure following high-dose 3-D conformal radiotherapy for high- grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 1999; 43: 79-88. doi:10.1016/S0360-3016(98)00266-1 Radiol Oncol 2021; 55(1): 88-96. doi: 10.2478/raon-2020-0075 88 research article Prospective evaluation of probabilistic dose-escalated IMRT in prostate cancer Daniel Wegener1, Bernhard Berger2, Zhoulika Outtagarts1, Daniel Zips1,3, Frank Paulsen1, Martin Bleif4, Daniela Thorwarth5, Markus Alber6, Oliver Dohm5, Arndt-Christian Müller1 1 Department of Radiation Oncology, University Hospital Tübingen, Germany 2 Clinic for Radiation Oncology, St. Elisabethen-Clinic, Ravensburg, Germany 3 German Cancer Consortium (DKTK), Partner Site Tübingen; and German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Clinic for Radiology and Radiation Oncology, Alb Fils Clinic Göppingen, Germany 5 Section for Biomedical Physics, Department of Radiation Oncology, University Hospital Tübingen, Germany 6 Clinic for Radiation Oncology, University Hospital Heidelberg, Germany Radiol Oncol 2021; 55(1): 88-96. Received 31 August 2020 Accepted 2 November 2020 Correspondence to: Daniel Wegener, Department of Radiation Oncology, University Hospital Tübingen, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen. E-Mail: daniel.wegener@med.uni-tuebingen.de Disclosure: No potential conflicts of interest were disclosed. We mention the cooperation with Siemens Healthcare, Philips, Elekta and PTB Braunschweig in another research project (DW, DZ, DT, ACM). Background. Cure- and toxicity rates after intensity-modulated radiotherapy (IMRT) of prostate cancer are dose- and volume dependent. We prospectively studied the potential for organ at risk (OAR) sparing and compensation of tumor movement with the coverage probability (CovP) concept. Patients and methods. Twenty-eight prostate cancer patients (median age 70) with localized disease (cT1c–2c, N0, M0) and intermediate risk features (prostate-specific antigen [PSA] < 20, Gleason score ≤ 7b) were treated in a prospective study with the CovP concept. Planning-CTs were performed on three subsequent days to capture form changes and movement of prostate and OARs. The clinical target volume (CTV) prostate and the OARs (bladder and rectum) were contoured in each CT. The union of CTV1–3 was encompassed by an isotropic margin of 7 mm to define the internal target volume (ITV). Dose prescription/escalation depended on coverage of all CTVs within the ITV. IMRT was given in 39 fractions to 78 Gy using the Monte-Carlo algorithm. Short-term androgen deprivation was recommended and given in 78.6% of patients. Results. Long-term toxicity was evaluated in 26/28 patients after a median follow-up of 7.1 years. At last follow-up, late bladder toxicity (Radiation Therapy Oncology Group, RTOG) G1 was observed in 14.3% of patients and late rectal toxicities (RTOG) of G1 (7.1%) and of G2 (3.6%) were observed. No higher graded toxicity occurred. After 7.1 years, biochemical control (biochemically no evidence of disease, bNED) was 95.5%, prostate cancer-specific survival and the distant metastasis-free survival after 7.1 years were 100% each. Conclusions. CovP-based IMRT was feasible in a clinical study. Dose escalation with the CovP concept was associ- ated by a low rate of toxicity and a high efficacy regarding local and distant control. Key words: probabilistic planned IMRT; coverage probability concept; prostate cancer; IMRT; dose escalation Background Cure- and toxicity rates after intensity modu- lated radiotherapy (IMRT) of prostate cancer are dose-dependent.1 Dose-escalated radiotherapy (RT) up to 80 Gy is a standard RT-technique2 and performed with (daily) image-guided RT (IGRT) combined with rapid treatment administration us- ing volumetric modulated arc therapy (VMAT) or comparable techniques.2-4 Current improvements in regard to outcome and toxicity focus either on dose escalation or margin adaption. Dose escala- Radiol Oncol 2021; 55(1): 88-96. Wegener D et al. / Coverage-probability based dose-escalated IMRT of prostate cancer 89 tion can be performed by using hypofractionated schedules of the whole prostate or of the domi- nant lesion alone5, Margin adaption i.e. reduction to reduce toxicity +/- dose-escalation is performed by target tracking or (online) adaptive strategies. However, these techniques require not only mod- ern RT instruments, which are not available yet for the majority of radiooncology departments, but also more time consumption per patient.6 Also, planning target volume (PTV) margins still need to account for intra- and interfraction prostate motion to prevent target miss, while re- specting the surrounding organs at risk (OAR), es- pecially bladder and rectum. Therefore, alternative concepts which are applicable in width and which combine both dose escalation and toxicity reduc- tion are of interest. A promising concept to achieve a favorable PTV- coverage while individually sparing OARs rep- resents Coverage probability based IMRT which does not need daily imaging due to its pre-adap- tive planning approach.7-9 We studied the potential for Organ at Risk (OAR) sparing and compensa- tion of tumor movement of the Coverage probabil- ity (CovP) concept within a prospective study and report 7-year outcome and toxicity rates. Patients and methods The coverage probability concept was investigated within a prospective study to evaluate in inter- mediate-risk prostate cancer patients’ feasibility, toxicity and outcome parameter. The study was approved by the research board of the University Clinic of Tuebingen on 06/27/2007 (project-number: 257/2007B01). Patient enrollment Inclusion criteria were histopathologically con- firmed adenocarcinoma of the prostate, intermedi- ate-risk in D`Amico classification, age ≤ 85 years at enrollment, Karnofsky-performance-status ≥ 70%, localized disease (bone scan, abdominal/pelvic CT) and informed consent. Exclusion criteria were prior prostatectomy, prior transurethral resection (TURP) or previous irradiation of pelvis, a second malignancy or another severe, clinically prominent illness (e.g. decompensated heart insufficiency, chronic inflammatory bowel disease, blood coagu- lation restrictions etc.). Coverage probability concept A planning CT (pCT; SOMATOM Sensation 64, Siemens Healthcare, Erlangen) was performed daily over three days with a rectum- and bladder protocol in use. The pCT`s were registered with Oncentra Masterplan® (Theranostic GmbH, Solingen, Germany), then target volume and organ at risks (OAR’s) were contoured in each pCT. The clinical target volume’s (CTV) of each pCT (prostate + 1 cm seminal vesicle) were merged to create a CTVunion, FIGURE 1. Coverage probability (CovP) concept: an example case is shown to indicate CovP-internal target volume (ITV) and planning organ at risk volumes (PRVs). A B C D E F Radiol Oncol 2021; 55(1): 88-96. Wegener D et al. / Coverage-probability based dose-escalated IMRT of prostate cancer90 which was expanded by 7 mm to define an internal target volume (CovP-internal target volume [ITV]). The same margin of 7 mm was added to the merged OARs (rectum and bladder) to create planning OAR volumes (PRV). The coverage-probability approach uses spatially variable weight factors for “cost func- tions” for both ITV and OAR’s. These weight factors are based on the probabilities of systematic organ shifts, estimated by the three planning CTs. For RT planning, “class solutions“ were employed includ- ing OAR constraints, aimed target doses, optimal gantry angles as described elsewhere.7-9 (Figure 1). Treatment RT was performed as step-and-shoot IMRT with 78 Gy in 39 fractions. Planning software were Hyperion® versions 2.2.5, 2.2.6 and 2.3 (University Tuebingen, Germany; based on Monte Carlo algo- rithm). All patients were treated in supine position on a 15 MV linear accelerator (Elekta Synergy S, Elekta Oncology Systems®, Crawley, UK) equipped with a 4 mm multileaf collimator. Cone-beam CT (CBCT) was initially performed daily for three days and then the average positioning error was calculated and corrected for the next fraction. Thereafter, CBCT was routinely performed twice weekly to account for random positioning errors. In case of a positioning error of >3 mm, CBCT was repeated at the next RT treatment. Additional short term androgen depri- vation therapy (ADT) for six months was recom- mended according to national guidelines. Further treatment specifications are given elsewhere.9,10 Patient follow-up and evaluation For each patient, baseline parameters for genitouri- nary (GU) and gastrointestinal (GI) functions were assessed and acute- and late toxicities were scored by a physician using common terminology crite- ria for adverse events (CTCAE)10 and/or Radiation Therapy Oncology Group (RTOG) Classification.11 Initially, CTCAE version 2.0 was used, which was transferred in 2009 into version 4.0 for comparabil- ity.12 A physical examination, combined with scor- ing of late toxicity and measurement of features prostate-specific antigen (PSA)-level, was per- formed three months after RT and then once a year. Primary outcome parameter was relapse-free survival (biological no evidence of disease, bNED). Biochemical relapse was defined by the Phoenix- criteria.13 Secondary outcome parameters were overall survival (OS), prostate-cancer specific sur- vival (PCSS) and distant metastasis-free survival (DMFS). The outcome parameters were calculated from start of radiotherapy. Statistical analysis Descriptive statistics were performed with Microsoft Excel 2010 (Version 14.0.7145.5000). Further calcula- tions, graphs and Kaplan-Meier estimations were performed with SPSS (Statistical Package for Social Sciences ‘IBM SPSS Statistics for Windows, Version 24.0 (IBM Corp., Armonk, N.Y., USA)). Results Patient characteristics and treatment Twentyeight patients were treated between 09/2008 and 10/2010 in this prospective study. Patient char- acteristics are given in Table 1. Dose escalation to 78 Gy was performed in all patients, the coverage probability concept was realized in 27/28 patients. In one patient, the study therapy was not accom- plished due to unknown reasons (but a “standard” step-and shot IMRT to 78 Gy was performed based on one pCT). Neoadjuvant ADT was administered to 78.6% of patients with a mean duration of 8.9 months. Survival endpoints Median follow-up (FU) time was 7.4 years (range 0.7–9.3 years; mean 7.1 years). Median FU for PSA- control was 7.0 years (range 3.3–9.1 years; mean 6.8 years). PSA-nadir was reached on average after 2.7 TABLE 1. Patient characteristics of the study cohort Parameter Mean (min.-max.) Median n (%) Age at treatment (years) Duration of radiotherapy (weeks) 70 (56–83) 7.9 (7.4–8.7) 70 7.9 Gleason-Score (n, %) 6 7a (3+4) 7b (4+3) 4 (14.3 %) 15 (53.6 %) 9 (32.1 %) cTNM (n, %) cT1c cT2a cT2b cT2c 8 (28.6 %) 8 (28.6 %) 3 (10.7 %) 9 (32.1 %) Neoadjuvant ADT (n, %) Duration of ADT (months, range) Initial PSA peak in ng/ml (range) 8.9 (3.0–27.0) 9.1 (1.9–19.8) 6.0 8.3 22 (78.6 %) PSA-peak by subgroup 0 < x ≤ 5 5 < x ≤ 10 10 < x ≤ 15 15 < x ≤ 20 3 (10.7 %) 15 (53.6 %) 8 (28.6 %) 2 (7.1 %) ADT = androgen deprivation therapy; PSA = prostate-specific antigen Radiol Oncol 2021; 55(1): 88-96. Wegener D et al. / Coverage-probability based dose-escalated IMRT of prostate cancer 91 years (min.: 0.2 years; max.: 8.3 years; median: 1.3 years). Biochemical control is shown in Figure 2. Two patients developed a biochemical recurrence. PCSS and DMFS after 7 years were 100% each. One patient died after a FU of 4.5 years due to a metastatic GIST which was detected 51 months af- ter RT and located outside of the treated RT-field. Another patient was lost to FU. Acute toxicity Acute toxicity was defined as toxicity occurring from start of RT until the first FU-investigation ≤ 90 days after end of RT. Weekly RTOG scoring results as well as maximum toxicity scores for GI- and GU-toxicity are given in Supplement Figure 3. 46.4% of patients developed acute GU toxicity of maximum grade 1 and 42.9% developed acute GU toxicity of maximum grade 2. No higher graded toxicity occurred. Acute GI toxicity of maximum grade 1 and 2 was found in 46.4% and 35.7% of pa- tients, respectively. No higher graded GI-toxicity occurred. Maximal GI- and GU-toxicity was seen in week 7 and 8 of radiotherapy. Additionally, CTCAE urinary incontinence was assessed: most patients (n = 22; 78.6%) did not develop inconti- nence. At first FU, two patients (7.1%) reported grade 1 toxicity (no pads necessary) and no higher toxicity was reported. Skin erythema of RTOG grade 1 or 2 was present towards the end of radio- therapy in 78.6% (n = 22) of patients and no higher graded skin toxicity occurred. At first FU, only one patient still suffered from RTOG grade 1 skin tox- icity. Late toxicity Long-term toxicity was evaluated in 26/28 patients after a median FU of 7.4 years (range 0.7–9.3 years; mean 7.1 years). Toxicity was scored as cumulative maximum over study period and as toxicity at last follow-up (LFU). FIGURE 2. Survival outcomes: Kaplan-Meier curves of biochemically no evidence of disease (bNED), overall survival (OS), distant metastasis-free survival (DMFS) and prostate-cancer specific survival (PCSS). A B C D Radiol Oncol 2021; 55(1): 88-96. Wegener D et al. / Coverage-probability based dose-escalated IMRT of prostate cancer92 Late GU-toxicity Most late GU-toxicity occurred 3–5 years post RT and seemed to decrease in prevalence towards LFU. Mild late bladder toxicity (RTOG G1) at LFU was observed in 14.3% of patients and no higher toxicity occurred (Figure 3). At LFU, 14.3% and 10.7% of patients reported urinary frequency of CTC grades 1 and 2, respectively and no higher toxicity occurred. A urinary retention of CTC grade 1 and 2 was seen in 21.4% and 7.1% of patients at LFU (Figure 3). Urinary urgency of CTC grade 1 and 2 at LFU was present in 10.7% and 3.6% of pa- tients showing no increase in prevalence over time. Urinary incontinence of CTC grade 1 (no pads needed) was reported by 21.4% of patients at LFU. Incontinence peaked 4–5 years after RT and then showed a decrease over time (supplement data). GI Toxicity Late rectal toxicities (RTOG) at LFU of grade 1 (7.1% of patients) and of grade 2 (3.6%) were observed (Figure 4). A peak in late GI-toxicity (RTOG) of grade 1 was seen 4 years post RT and then seemed to decrease again in prevalence. Gastrointestinal grade 3 toxicity, presenting with rectal bleeding, was observed in two patients (RTOG GI late, CTC rectal hemorrhage and CTC proctitis due to over- lapping toxicity scoring). Both patients had pre-ex- isting hemorrhoids and hemorrhoidal operations in their medical history. This occurred 9 months and 19 months post RT, respectively. After treat- ment with Argon-Plasma-Coagulation, no further grade 3 toxicity occurred in these two patients or others. Mild rectal hemorrhaging (CTC grade 1) was present in 14.3% of patients at LFU. Proctitis FIGURE 3. Late genitourinary (GU) toxicity items Radiation Therapy Oncology Group (RTOG) bladder late, common terminology criteria (CTC) urinary frequency and CTC urinary obstruction scored over the follow up (FU) period (left). Y-axis: percentage of patients reporting the toxicity item. Top X-axis: number n of patients with data available. Lower X-axis: years after radiotherapy. Right column: maximum late toxicity summed up by grade A B C Radiol Oncol 2021; 55(1): 88-96. Wegener D et al. / Coverage-probability based dose-escalated IMRT of prostate cancer 93 of CTC grade 1 (2) was present in 10.7% (7.1%) of patients at LFU (Figure 4). Diarrhea of CTC grade 1 and 2 were present in 10.7% and 3.6% of patients, respectively. While diarrhea symptoms subsided 2 years post RT, it was reported again in one patient 8 years after radiotherapy (supplement data). Fecal incontinence of grade 1 and 2 occurred each in one patient (3.6%), undulating over the FU period with no increase of severity of the symptom (supple- ment data). Dose-volume-histogram parameter Mean V70 PRV-bladder was 11.08% with this ap- proach (accepted threshold: V70 bladder <35%). Mean V70 PRV-rectum was 13.03% (accepted threshold: V70 rectum <15%). These constraints were based on the QUANTEC data and adjusted according to house standard. Due to these con- straints, the mean CovP-ITV dose was 75.40 Gy (V78 = 26.77%). Discussion In this prospective study, we report the feasibility and safety of a probabilistic planning concept for radiotherapy of intermediate risk prostate cancer patients based on the coverage probability. Dose- escalation to 78 Gy was aimed with this technique showing very high long-term biochemical control rates and excellent survival rates. The toxicity pro- file was moderate with 85% of patients presenting without any GU/GI-toxicity at last follow-up in- FIGURE 4. Late gastrointestinal (GI) toxicity items Radiation Therapy Oncology Group (RTOG) rectum late, common terminology criteria (CTC) proctitis and CTC rectal hemorrhage scored over the follow up (FU) period (left). Y-axis: percentage of patients reporting the toxicity item. Top X-axis: Number n of patients with data available. Lower X-axis: years after radiotherapy. Right column: maximum late toxicity summed up by grade. A B C Radiol Oncol 2021; 55(1): 88-96. Wegener D et al. / Coverage-probability based dose-escalated IMRT of prostate cancer94 dicating that CovP is a robust plan optimization achieving both low toxicity and favorable outcome. In the planning phase of this study in 2007, dose escalation to 78 Gy was a novel concept in need of evaluation of safety and superiority to the former “standard” therapies of 3D-RT or IMRT of the pros- tate up to 70 Gy. Meanwhile, several studies could show a benefit to PCSS of dose escalation14-17 and a total dose of 74 to 80 Gy is the current standard of care and recommended in national guidelines.2,3 Our study concept on probabilistic treatment plan- ning is substantiated by excellent bNED-rates of 95.5% after 7.1 years (DMFS: 100%, OS: 96.4%). Two patients developed a biochemical recurrence. In one of these two patients, PSMA-PET-CT showed a local recurrence in the prostate. This patient had not received ADT due to cardiac diseases. In the other patient, a biochemical recurrence occurred at LFU and no further information on staging was available at the time of analysis of this study. Large studies of similar patient cohorts reached bNED- rates of 55–90% and DMFS of 88-100% (in the dose- escalated study arms treated with normofraction- ated RT with 74-86.4 Gy total dose) after 5 years of FU.14-16,18-20 Compared to the 7.1 years FU of this study, only the M.D. Anderson trial could provide a longer FU period of 8.7 years in the mean.16 Our results are especially interesting in regard to the achieved mean ITV-dose of 75.40 Gy (V78 = 26.7%) because this dose is in the lower dose range of the mentioned studies. Therefore, it could be hypothe- sized that robust treatment planning implementing probabilities of target volumes and OARs might be more relevant than dose-escalation to at least 78 Gy. And the standard one-CTV/PTV approach might be more at risk for target miss compared to a robust ITV concept, as was examined in another publication by our deparmenten.9 However, there are restrictions in comparability due to differences in the included tumor stages, ADT (no information about ADT in the study of Goldner et al.; no ADT in the M.D. Anderson trial.16,20 Taken together, the study treatment compares well to current standard treatments in PCSS and bNED. The toxicity of this treatment approach is a central quality parameter, especially considering the potentially larger target volume (CovP-ITV) compared to a one-pCT approach. Acute GU- and GI-toxicity was acceptable with only grade 1 and grade 2 (RTOG, CTC scores) and no grade 3+ toxicity. While certain items showed a peak after 3 weeks of RT (RTOG bladder acute) or 5 weeks (CTC urinary Incontinence, RTOG GI acute), most items showed an increase of toxicity prevalence towards the end of RT and the early peaks most likely origin in coincidental accumulation due to the limited patient size of the study. Towards the first FU-examination 3 months post RT, mostly grade 1 toxicity persisted. It is noteworthy that us- ing the CTC-classification probably overestimates the item urinary incontinence in comparison to other studies since for example in the PROTECT- study, incontinence of grade 1 was defined as need of ≥1 pad per day which equals CTC incontinence of grade 2.21 In contrast, CTC incontinence of grade 1 – as measured in this study - is defined as oc- casional incontinence (pressure, coughing) not re- quiring pads. Interestingly, late GU-toxicity of grade 1 or 2 (RTOG bladder late, CTC incontinence, CTC ur- gency) occurred only temporarily in this study population and decreased in prevalence after 5 years after RT. To date, consensus understanding of radiation biology is the continuous increase of late effects over time.22 No further data describ- ing decreasing late toxicity after pelvic radiation is known to the authors.23,24 Due to the small sample size, random distribution of data and/or psycho- logical factors such as patient habituation or recall bias cannot be ruled out. Late GI-toxicity also showed no sign of increment over time and was generally rare: At LFU RTOG grade 2 toxicity was only present in one patient. Regarding rectal hemorrhaging, we suppose that the predisposition of hemorrhoids in those patients who developed this toxicity can be regarded as the (established) major risk factor.25 Taken together, the low toxicity rates in this cohort compare well to larger studies and demonstrate a favorable thera- peutic window of the CovP-concept.14-16,18,20,23,26,27 The coverage concept has been described before in detail.7,8,9 The advantages include a safe margin with high PTV coverage, based on the individual OAR- and prostate motion of each patient, and measured by three planning-CTs. The idea behind the concept is a foreseen adaption of intra- and in- terfractional motion and deformation and there- fore reduced verification intervals are needed. The efficacy of this method could be demonstrated in this study. Additionally, toxicity rates were not increased compared to standard techniques. The CovP-concept with 7 mm margin does not require daily image guidance due to its robustness as shown elsewhere.9 This might save radiation dose and on-table time for the department. Especially in patients who cannot undergo fiducial implementa- tion or other invasive procedures such as rectum spacers4,28 or patients with larger positional varia- Radiol Oncol 2021; 55(1): 88-96. Wegener D et al. / Coverage-probability based dose-escalated IMRT of prostate cancer 95 tion of the prostate, this technique presents a useful and safe alternative.7 This study has several limitations: Further eval- uation of outcome data in a larger study popula- tion is necessary. Additionally, there was no con- trol group to compare toxicity and outcome to. In one patient, the study therapy was not accom- plished due to unknown reasons. Three planning- CTs are necessary for this method, causing extra burden on staff and patient, including additional radiation dose for the latter. However, we believe that the benefits, especially the reduced need for image verification or implantation of fiducials etc., outweigh the disadvantages and might even save radiation dose to the patient. Lastly, the performed step-and-shoot IMRT technique is mainly replaced by VMAT-techniques which leave slightly more options for OAR dose reduction and target dose escalation.9 However, the excellent late toxicity data and bNED rates support the relevance of this approach leading to an implementation in current study protocols.29 Conclusions Coverage probability-based IMRT was feasible in a clinical study. Dose escalation with the CovP- concept was associated with a low rate of toxic- ity and a high efficacy regarding local and distant control, comparing well to studies with similar pa- tient cohorts. Benefits include reduced target miss due to inclusion of potential inter- and intrafrac- tion motion and reduced radiation dose due to less need for verification images. Utilization in other tumor entities and/or with contemporary RT tech- niques is being currently tested (NCT03617133). Availability of data and material and authors contributions The datasets used and/or analyzed during the cur- rent study are available from the corresponding author on reasonable request. BB, MA. OD, FP and MB were responsible for the creation of the study protocol, ethical approval, patient enrollment and study therapy. DW, ZO and ACM were responsible for data acquisition, statistical analysis and writing of the manuscript. DT, DZ, FP and MA were responsible for manu- script revision and proof reading. References 1. Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, con- trolled trials. Int J Radiat Oncol Biol Phys 2009; 74: 1405-18. doi: 10.1016/j. ijrobp.2008.10.091 2. National Comprehensive Cancer Network I. NCCN Clinical Practice Guidelines in Oncology. Prostate cancer. 2018; Version 4.2018. August 15, 2018: 34. 3. Deutsche Krebsgesellschaft DK, AWMF. Leitlinienprogramm Onkologie. Interdisziplinäre leitlinie der qualität s3 zur früherkennung, diagnose und therapie der verschiedenen stadien des prostatakarzinoms 2018; Langversion 5.0:394. 4. Wegener D, Zips D, Thorwarth D, Weiß J, Othman AE, Grosse U, et al. Precision of T2 TSE MRI-CT-image fusions based on gold fiducials and repetitive T2 TSE MRI-MRI-fusions for adaptive igrt of prostate cancer by using phantom and patient data. Acta Oncol 2019; 58: 88-94. doi: 10.1080/0284186X.2018.1518594 5. Monninkhof EM, van Loon JWL, van Vulpen M, Kerkmeijer LGW, Pos FJ, Haustermans K, et al. Standard whole prostate gland radiotherapy with and without lesion boost in prostate cancer: toxicity in the flame rand- omized controlled trial. Radiother Oncol 2018; 127: 74-80. doi: 10.1016/j. radonc.2017.12.022 6. Schroeck FR, Jacobs BL, Bhayani SB, Nguyen PL, Penson D, Hu J. Cost of new technologies in prostate cancer treatment: systematic review of costs and cost effectiveness of robotic-assisted laparoscopic prostatectomy, intensity- modulated radiotherapy, and proton beam therapy. Eur Urol 2017; 72: 712-35. doi: 10.1016/j.eururo.2017.03.028 7. Baum C, Alber M, Birkner M, Nüsslin F. Robust treatment planning for inten- sity modulated radiotherapy of prostate cancer based on coverage probabil- ities. Radiother Oncol 2006; 78: 27-35. doi: 10.1016/j.radonc.2005.09.005 8. Baum C, Birkner M, Alber M, Paulsen F, Nüsslin F. Dosimetric consequences of the application of off-line setup error correction protocols and a hull- volume definition strategy for intensity modulated radiotherapy of prostate cancer. Radiother Oncol 2005; 76: 35-42. doi: 10.1016/j.radonc.2005.06.006 9. Outaggarts Z, Wegener D, Berger B, Zips D, Paulsen F, Bleif M, et al. Target miss using PTV-based IMRT compared to robust optimization via coverage probability concept in prostate cancer. Acta Oncol 2020; 59: 911-7. doi: 10.1080/0284186X.2020.1760349. 10. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003; 13: 176-81. doi: 10.1016/ S1053-4296(03)00031-6 11. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995; 31: 1341-6. doi: 10.1016/0360-3016(95)00060-C 12. National Cancer Institute USDOHAHS. Common terminology criteria for ad- verse events (CTCAE) Version 4.0. NIH Publication No 09-5410 2009: 1-196. 13. Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Ph 2006; 65: 965-74. doi: 10.1016/j.ijrobp.2006.04.02 14. Dearnaley DP, Jovic G, Syndikus I, Khoo V, Cowan RA, Graham JD, et al. Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial. Lancet Oncol 2014; 15: 464-73. doi: 10.1016/S1470-2045(14)70040-3 15. Peeters ST, Heemsbergen WD, Koper PC, van Putten WL, Slot A, Dielwart MF, et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006; 24: 1990-6. doi: 10.1200/ JCO.2005.05.2530 16. Kuban DA, Tucker SL, Dong L, Starkschall G, Huang EH, Cheung MR, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008; 70: 67-74. doi: 10.1200/JCO.2005.05.2530 Radiol Oncol 2021; 55(1): 88-96. Wegener D et al. / Coverage-probability based dose-escalated IMRT of prostate cancer96 17. Hall MD, Schultheiss TE, Smith DD, Tseng BP, Wong JY. The impact of increas- ing dose on overall survival in prostate cancer. Radiat Oncol 2015; 10: 115. doi: 10.1186/s13014-015-0419-3 18. Zietman AL, Bae K, Slater JD, Shipley WU, Efstathiou JA, Coen JJ, et al. Randomized trial comparing conventional-dose with high-dose con- formal radiation therapy in early-stage adenocarcinoma of the pros- tate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol 2010; 28: 1106-11. doi: 10.1200/ JCO.2009.25.8475 19. Zietman AL, DeSilvio ML, Slater JD, Rossi CJ Jr, Miller DW, Adams JA, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized con- trolled trial. JAMA 2005; 294: 1233-9. doi: 10.1001/jama.294.10.1233 20. Goldner G, Dimopoulos J, Kirisits C, Pötter R. Moderate dose escalation in three-dimensional conformal localized prostate cancer radiotherapy: single-institutional experience in 398 patients comparing 66 Gy versus 70 Gy versus 74 Gy. Strahlenther Onkol 2009; 185: 438-45. doi: 10.1007/s00066- 2009-2033-5. 21. Donovan JL, Hamdy FC, Lane JA, Mason M, Metcalfe C, Walsh E, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016; 375: 1425-37. doi: 10.1056/ NEJMoa1606221 22. Dorr W, Hendry JH. Consequential late effects in normal tissues. Radiother Oncol 2001; 61: 223-31. doi: 10.1016/s0167-8140(01)00429-7 23. Di Franco R, Borzillo V, Ravo V, Ametrano G, Cammarota F, Rossetti S, et al. Rectal/urinary toxicity after hypofractionated vs. conventional radiotherapy in high risk prostate cancer: systematic review and meta analysis. Eur Rev Med Pharmacol Sci 2017; 21: 3563-75. doi: 10.26355/eur- rev_201708_13266 24. Carvalho IT, Baccaglini W, Claros OR, Chen FK, Kayano PP, Lemos GC, et al. Genitourinary and gastrointestinal toxicity among patients with localized prostate cancer treated with conventional versus moderately hypofraction- ated radiation therapy: systematic review and meta-analysis. Acta Oncol 2018; 57: 1003-10. doi: 10.1080/0284186X.2018.1478126 25. Valdagni R, Kattan MW, Rancati T, Yu C, Vavassori V, Fellin G, et al. Is it time to tailor the prediction of radio-induced toxicity in prostate cancer patients? Building the first set of nomograms for late rectal syndrome. Int J Radiat Oncol Biol Phys 2012; 82: 1957-66. doi: 10.1016/j.ijrobp.2011.03.028 26. Aluwini S, Pos F, Schimmel E, Krol S, van der Toorn PP, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (hypro): late toxicity results from a randomised, non-inferiori- ty, phase 3 trial. Lancet Oncol 2016; 17: 464-74. doi: 10.1016/S1470- 2045(15)00567-7 27. Jolnerovski M, Salleron J, Beckendorf V, Peiffert D, Baumann AS, Bernier V, et al. Intensity-modulated radiation therapy from 70 Gy to 80 Gy in prostate cancer: six- year outcomes and predictors of late toxicity. Radiat Oncol 2017; 12: 99. doi: 10.1186/s13014-017-0839-3 28. Eckert F, Alloussi S, Paulsen F, Bamberg M, Zips D, Spillner P, et al. Prospective evaluation of a hydrogel spacer for rectal separation in dose- escalated intensity-modulated radiotherapy for clinically localized prostate cancer. BMC Cancer 2013; 13: 27. doi: 10.1186/1471-2407-13-27. 29. Ramlov A, Assenholt MS, Jensen MF, Grønborg C, Nout R, Alber M, et al. Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer. Radiother Oncol 2017; 123: 158-63. doi: 10.1016/j.radonc.2017.01.015 Radiol Oncol 2021; 55(1): 97-105. doi: 10.2478/raon-2020-0062 97 research article Effect of the oral intake of astaxanthin on semen parameters in patients with oligo- astheno-teratozoospermia: a randomized double-blind placebo-controlled trial Senka Imamovic Kumalic1,2, Irma Virant Klun1,2, Eda Vrtacnik Bokal1,2, Bojana Pinter1,2 1 Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Radiol Oncol 2021; 55(1): 97-105. Received 17 August 2020 Accepted 14 September 2020 Correspondence to: Assoc. Prof. Bojana Pinter, M.D., Ph.D., M.S. (Econ), Specialist in Obstetrics and Gynecology, University Medical Centre Ljubljana, Division of Obstetrics and Gynecology; Faculty of Medicine University of Ljubljana, Šlajmerjeva 3, 1000 Ljubljana, Slovenia. E-mail: bojana.pinter@guest.arnes.si Disclosure: No potential conflicts of interest were disclosed. Background. Higher concentrations of seminal reactive oxygen species may be related to male infertility. Astaxanthin with high antioxidant activity can have an impact on the prevention and treatment of various health conditions, including cancer. However, efficacy studies on astaxanthin in patients with oligospermia with/without astheno- or teratozoospermia (O±A±T) have not yet been reported. Our aim was to evaluate the effect of the oral intake of astaxanthin on semen parameters. Patients and methods. In a randomized double-blind trial, 80 men with O±A±T were allocated to intervention with 16 mg astaxanthin orally daily or placebo. At baseline and after three months basic semen parameters, sperm de- oxyribonucleic acid (DNA) fragmentation and mitochondrial membrane potential (MMP) of spermatozoa and serum follicle-stimulating hormone (FSH) value were measured. Results. Analysis of the results of 72 patients completing the study (37 in the study group, 35 in the placebo group) did not show any statistically significant change, in the astaxanthin group no improvements in the total number of spermatozoa, concentration of spermatozoa, total motility of spermatozoa, morphology of spermatozoa, DNA frag- mentation and mitochondrial membrane potential of spermatozoa or serum FSH were determined. In the placebo group, statistically significant changes in the total number and concentration of spermatozoa were determined. Conclusions. The oral intake of astaxanthin did not affect any semen parameters in patients with O±A±T. Key words: antioxidant; male infertility; oligo-astheno-teratozoospermia; semen quality; DNA fragmentation; cancer Introduction Currently, almost every seventh couple is infertile. The male factor as the single or additional reason for infertility is presented in nearly 50% of infertile couples.1 World Health Organization (WHO) de- fines oligo-astheno-teratozoospermia (OAT) as the concentration and the proportions of motile and morphologically normal spermatozoa below the reference values.2 One of the many pathophysiological factors of male infertility are higher concentrations of seminal reactive oxygen species (ROS).3 The un- controlled production of these molecules may be harmful to cells and different biomolecules such as carbohydrates, amino acids, proteins, lipids, and deoxyribonucleic acid (DNA), which can be damaged. ROS can have a negative influence on sperm function and quality4-7 due to the reduced motility of spermatozoa8, DNA damage9-11 and the Radiol Oncol 2021; 55(1): 97-105. Imamovic Kumalic S et al. / Oral intake of astaxanthin and semen parameters in infertile patients98 impaired integrity of the cellular membrane.7,12,13 It was revealed that infertile men with low semen concentration, poor semen motility, and a high pro- portion of morphologically abnormal spermatozoa were associated with an increased risk of testicular cancer.14,15 Several antioxidants are present within the ejaculate as protection against excessive ROS- induced lipid peroxidation.16 It has been confirmed that antioxidant capacity in semen is decreased in infertile men and men with testicular cancer with a high ROS proportion, compared to men with a normal proportion of ROS.17–19 Sperm function tests have arisen as a supplement to standard semen analysis.20 The DNA integrity of spermatozoa has a critical impact in determining sperm competence21,22 which is related to ROS lev- els9,10 and can be measured by sperm DNA frag- mentation (SDF) assays.21,22 A recent meta-analysis of 28 studies demonstrated that SDF is more ac- curate in determining the function of spermatozoa compared to conventional semen parameters.23 A study of apoptotic DNA fragmentation in human spermatozoa found a significant increase in apop- totic SDF in the semen of testicular cancer patients post-orchiectomy and in OAT patients compared to a control group of healthy men.24 In addition to DNA integrity, mitochondria have an important impact on cell function25, and the sperm mitochon- drial membrane potential (MMP) contributes some benefit to male fertility potential and sperm qual- ity.26 Combined SDF and MMP may act as better predictors of natural conception than standard se- men parameters.27 Regarding the role of seminal antioxidant capac- ity in male infertility, several trials on the impact of antioxidants on semen characteristics have been performed. The review of randomized and place- bo-controlled trials affirmed the favorable impact of some types of antioxidants on different semen characteristics.28 Several studies have shown fa- vorable effects, especially on the motility of sper- matozoa.29-34 In some trials, antioxidant combina- tions (coenzyme Q10, vitamin C, vitamin E, sele- nium, zinc, L-carnitine, etc.) were assessed.35–40 The most recent Cohrane review shows that for couples attending fertility clinics, pregnancy rates and live births may be improved with antioxidant supple- mentation in subfertile males.41 As one of many antioxidants, ketocarotenoid astaxanthin has the potential to prevent and treat various diseases, including diabetes, liver and re- nal diseases, cancer, chronic inflammatory diseas- es, cardiovascular diseases, eye and skin diseases, metabolic syndrome, gastrointestinal diseases, and neurodegenerative diseases.42 Astaxanthin accumulates in the microalga Haematococcus plu- vialis, and compared to vitamin E, this compound has up to 100 times higher antioxidant activity.43 Astaxanthin is a food supplement and widely available over-the-counter. Until now, there were two “in vitro” studies that first showed the posi- tive effect of astaxanthin on sperm capacitation in 24 healthy, fertile men44; subsequently, the positive effect on sperm capacitation in 27 men from cou- ples who did not succeed to conceive after at least twelve months of regular unprotected intercourse was confirmed.45 On the other hand, there has been only one clinical trial investigating the influence of astaxanthin on male fertility published until now. The trial included a low number of patients with a history of male infertility – 11 patients in the study group and 19 patients in the placebo group; how- ever, these patients were enrolled without regard for semen characteristics.46 Favorable changes in inhibin B concentration, sperm linear velocity and ROS levels, and pregnancy rate were determined. However, the efficacy of astaxanthin oral intake on semen parameters in OAT patients treated for in- fertility has not yet been reported. The aim of this prospective randomized double- blind placebo-controlled clinical trial was to assess the effect of three-month intake of astaxanthin in infertile men with oligospermia with/without astheno- or teratozoospermia (O±A±T) on basic semen parameters, DNA fragmentation and mi- tochondrial membrane potential of spermatozoa, and serum level of follicle-stimulating hormone (FSH). Patients and methods The prospective randomized double-blind place- bo-controlled trial was performed from November 2014 to January 2019 at the outpatient infertility clin- ic, Department of Human Reproduction, Division of Obstetrics and Gynecology of the University Medical Centre Ljubljana, Slovenia. The study was approved by the Slovenian National Medical Ethics Committee (consent number 145/02/14) and was registered at ClinicalTrials.gov, NCT02310087. All participants were enrolled after they provided written informed consent to participate in the trial. Participants A total of 80 infertile men with O±A±T were en- rolled after they signed a written informed consent Radiol Oncol 2021; 55(1): 97-105. Imamovic Kumalic S et al. / Oral intake of astaxanthin and semen parameters in infertile patients 99 to participate in this trial. They were considered O±A±T after at least two previous semen analysis (seminogram) and andrological examination in the frame of their infertility treatment after their part- ner being unable to conceive for at least 12 months of unprotected sexual intercourse or after a failed assisted conception procedure. Semen quality was defined as O±A±T according to the WHO 2010 guidelines: oligospermia (O) − sperm concentra- tion < 15 million/ml; asthenozoospermia (A) − pro- gressive motility of spermatozoa < 32%; terato- zoospermia (T) − < 4% spermatozoa with normal morphology.20 The exclusion criteria were smoking more than 20 cigarettes per day, genetic causes of infertility, endocrinopathies, genital tract infec- tions, undescended testis, systemic diseases, his- tory of testicular cancer and treatment with other drugs and food supplements, such as antioxidants, during the last three months before enrolling in this study. Intervention and methods Eighty eligible infertile men with O±A±T were al- located at random to daily intake of 16 mg of astax- anthin capsules (Astasan) or placebo capsules, both produced by the same manufacturer (Sensilab). Astaxanthin capsules contained astaxanthin, vita- min E as a stabilizer, safflower oil, gelatin, water and glycerine. Placebo capsules were identical both in appearance and taste, containing gelatine, water and glycerine only. A computerized randomiza- tion table was used for the purpose of randomi- zation. A random allocation sequence was gener- ated and participants were enrolled and assigned to interventions by a third party, thus ensuring that both the enrolled participants and researchers were blinded. At baseline and after three months of treatment, all participants answered a question- naire about their age, height, weight, smoking sta- tus and the history of current occupational expo- sure to high temperatures, ultraviolet or radiology radiation, chemicals, or a predominant sedentary job in order to exclude the potential effect of these factors on semen quality. The semen samples were obtained by masturbation after 2−5 days of sexual abstinence. Semen quality was assessed according to the WHO guidelines.20 The total number, con- centration, motility and morphology were deter- mined by international standard laboratory micro- scopic analyses.47 Sperm DNA fragmentation in our study was evaluated using a TUNEL assay – measuring DNA fragmentation in spermatozoa using terminal de- oxyribonucleotidyl transferase (TdT)-mediated dUTP nick-end labelling.48 The calculated threshold value for the TUNEL assay to distinguish between normal and abnormal semen samples in men was 20%.49 MMP was measured by means of 3,3’-dihex- yloxacarbocyanine iodide (DiOC6(3)) staining as an indicator of mitochondrial membrane integrity and the mitochondrial potential capacity to gener- ate ATP by oxidative phosphorylation.50 Propidium iodide (PI) was used as a supravital fluorescent dye and stained spermatozoa were analyzed by flow cytometry. MMP was considered to be normal in our laboratory setting when the proportion of spermatozoa with normal MMP (attributed to cells with high fluorescence signals) was higher than 60%.27 The serum level of FSH was measured by a solid-phase, two-site chemiluminescent immuno- metric assay. The normal FSH values for males in our laboratory setting were 0.7−11.1 IU/L. Sample size calculation To estimate the sample size for the study, we an- ticipated an increase in sperm concentration in the astaxanthin group, as reported in the only clinical study until now.46 With the assumption of a 34% increase as reported, with alpha 0.05 and power 80%, 32 cases were needed in each group. To ac- count for drop-outs, we aimed to recruit 40 cases in each group. Statistical analysis Statistical analysis was carried out using the Statistical Package for the Social Science (SPSS), version 25, IBM Corp, Armonk, NY, USA. An in- dependent Student’s t-test was used to analyze normally distributed data, and the Mann-Whitney test was used to analyze data that were not distrib- uted normally. A paired t-test or the Wilcoxon test were applied to analyze the differences in the se- men variables within groups. The chi-square test was applied to compare the exposure to occupa- tional factors between groups. The results of con- tinuous variables were expressed as the mean ± SD. P-values < 0.05 were considered significant. Results A group of 256 men was assessed for eligibility; half (126 men, 49.2%) declined to participate, and 50 did not meet the inclusion criteria; 80 men were eligible and willing to participate and these indi- Radiol Oncol 2021; 55(1): 97-105. Imamovic Kumalic S et al. / Oral intake of astaxanthin and semen parameters in infertile patients100 viduals were randomized. Eight patients in both groups (10%) dropped out for personal reasons during the treatment, and thus, 72 patients com- pleted the trial. No adverse effects during the treat- ment were reported. Finally, we analyzed the effect of treatment in 37 patients in the astaxanthin and 35 patients in the placebo group (Figure 1). Five patients were not included in the statisti- cal analyses on changes in sperm total number and concentration and 27 patients were not included in the statistical analyses on the motility of sper- matozoa as in these patients only a few mobile or immobile spermatozoa in the semen sample were present. At baseline, all patients in the astaxanthin group were in accordance with WHO criteria for OAT. In the placebo group, all patients were in ac- cordance with the WHO criteria for oligo-teratozo- ospermia and two-thirds for asthenozoospermia. The epidemiological and semen characteristics of the included patients are summarized in Table 1. There were no statistically significant differences between all parameters of both groups of patients upon enrollment. In addition, exposure of patients to chemicals, ultraviolet rays, X-ray radiation, high temperature, and a sedentary job according to their history (questionnaire) have not been related to the semen parameters in the studied population of men. FIGURE 1. CONSORT flow chart of study presenting the inclusion criteria, randomization and follow-up of participants. Radiol Oncol 2021; 55(1): 97-105. Imamovic Kumalic S et al. / Oral intake of astaxanthin and semen parameters in infertile patients 101 The pre- and post-treatment semen parameters and hormonal levels of both groups of patients are displayed in Table 2. The three-month treatment of patients with astaxanthin did not affect the se- men parameters or serum FSH levels in any way. Interestingly, the significant change after the three- month period was the increased total number (16.0 ± 21.1 vs. 38.4 ± 69.2 million/ejaculate, p = 0.002) and concentration (5.7 ± 5.9 vs. 10.2 ± 15.7 million/ml, p = 0.024) of spermatozoa in the placebo group, but not in the astaxanthin group (24.6 ± 28.6 vs. 31.7 ± 33.4 million/ejaculate, p = 0.186, and 7.0 ± 5.6 vs. 9.2 ± 7.9 million/ml, p = 0.100). To address the increase in the concentration of spermatozoa in the placebo group, we separately analyzed the seasonal inclusion of patients into the trial to review the potential seasonal changes of se- men quality. Nineteen patients in the astaxanthin group and 18 patients in the placebo group were enrolled in the study during the winter/spring pe- riod, and 18 patients in the astaxanthin group and 17 patients in the placebo group were enrolled dur- ing the summer/fall seasons. There was no signifi- cant difference in the seasonal inclusion of patients in the trial (p = 0.995). Discussion The present study is the first study of astaxanthin efficacy on semen parameters in oligo-astheno- teratozoospermic patients who were treated for infertility. Our results did not show any significant improvements in the basic semen parameters or at the cellular level (SDF, MMP) or serum FSH val- ues after oral intake of astaxanthin. In previously published studies on the effects of antioxidants in semen quality28,32,38,39, the semen quality was de- fined according to the WHO 1999 guidelines. On the other hand, our patients were included based on their semen quality in line with the WHO 2010 guidelines, which have lower threshold values. Therefore, our patients were enrolled in the study with considerably poorer semen quality compared to patients in previous studies, which followed old- er WHO guidelines. Considering cancer patients, both chemotherapy and radiation have measur- able effects on the sperm number, motility, mor- phology, and DNA integrity.51 Although treatment usually represents the greatest threat to the fertil- ity of male survivors, the underlying malignancy may additionally affect semen production and quality. In cases of testicular cancer, the rates of oligospermia and azoospermia at presentation are 50% and 10%, respectively.52–55 Similarly, Hodgkin Lymphoma is associated with oligospermia and azoospermia before the treatment, and depending on the treatment regimen, also after.56–58 According to poor starting values of basic sperm parameters in our patients, in addition to their low MMP and very high DNA fragmentation, it can be concluded that our patients, in general, had poorer semen quality as subjects in the previous studies due to the lower threshold of the new WHO guidelines. TABLE 1. Comparison of baseline characteristics of patients in astaxanthin and placebo groups Characteristic Astaxanthin (n = 37) Placebo (n = 35) p-value Age (years) 35.0 ± 5.2 36.4 ± 5.5 0.276 BMI (kg/m2) 25.9 ± 3.8 27.1 ± 4.6 0.162 Smoking (no. of cigarettes smoked / day) 4.8 ± 6.8 3.6 ± 6.8 0.264 Sperm concentration (million /ml)* 6.9 ± 5.7 5.4 ± 5.8 0.297 Total sperm number (million/ejaculate)* 23.9 ± 28.4 15.6 ± 21.0 0.164 Total sperm motility (%)** 29.9 ± 14.8 38.2 ± 14.8 0.063 Progressive sperm motility (%)** 25.1 ± 14.5 33.3 ± 14.6 0.063 Sperm morphology (%) 1.8 ± 2.1 1.9 ± 2.0 0.663 Sperm head defect (%) 95.1 ± 16.2 97.5 ± 3.3 0.936 Sperm neck + midpiece defect (%) 2.9 ± 16.4 0.2 ± 0.8 0.981 Sperm tail defect (%) 0.2 ± 0.6 0.5 ± 1.0 0.424 Leukocytes with peroxidase (million/ml) 0.3 ± 0.3 0.5 ± 0.8 0.976 Mitochondrial membrane potential (%)*** 27.5 ± 18.5 26.9 ± 15.3 0.888 DNA fragmentation (%) 50.5 ± 23.9 45.8 ± 21.8 0.424 FSH (IU/l) 9.7 ± 7.8 9.2 ± 5.8 0.919 Chemicals at work (% exposed) 5.4 14.3 0.204 Ultraviolet rays at work (% exposed) 2.7 0 0.327 X-ray at work (% exposed) 0 11.4 0.051 High temperature at work (% exposed) 13.5 14.3 0.925 Sedentary job (% exposed) 45.9 40.0 0.611 Results are presented as average (± SD) or percentage (%). Differences at baseline assessed with independent Student t-test, Mann-Whitney U-test or Chi-square test, as appropriate. * = the analysis for total sperm number and sperm concentration was made for 34/37 patients from the astaxanthin group and 35/35 patients from the placebo group, since the excluded patients only had a few mobile or immobile spermatozoa in the semen sample; ** = the analysis for total and progressive sperm motility was made for 25/37 patients from the astaxanthin group and 20/35 patients from placebo group, since the excluded patients only had a few mobile or immobile spermatozoa in the semen sample; ***= the proportion of spermatozoa with normal MMP; BMI = body mass index; DNA = deoxyribonucleic acid; FSH = follicle-stimulating hormone Radiol Oncol 2021; 55(1): 97-105. Imamovic Kumalic S et al. / Oral intake of astaxanthin and semen parameters in infertile patients102 Under these conditions, our study revealed that antioxidant astaxanthin could not improve semen quality in cases of very poor semen quality, which could also be of great importance for cancer pa- tients. Our results are in contrast to a previous study by Comhaire, which determined favorable changes in the inhibin B concentration, sperm linear veloc- ity and ROS levels, and pregnancy rate after astax- anthin treatment in the same dosage of astaxanthin as in our study. However, the study enrolled a low number of infertile males (11 in the study group and 19 in the placebo group) and was not based on semen analysis but rather on a more than twelve months’ infertility history of female partners hav- ing no verifiable cause of infertility.46 Interestingly, another recent study, similar to our study, showed that different antioxidants did not affect the se- men quality in a larger group of infertile patients.59 Similar results of no effect of antioxidants were found in some other studies.38,60–63 These data show that antioxidants are interesting, but the clinical data should be comprehended with prudence. The improved total number and concentrations of spermatozoa after three months of treatment with a placebo could reflect the beneficial psycho- logical effect of placebo on patients. In the litera- ture, the strength of expectations is connected to the degree of the placebo effect.64,65 The appearance of a medication, past experience, verbal informa- tion, and relationship between a patient and phy- sician may influence the patient’s expectations.66 However, previously published reviews on the effects of oral antioxidants on semen quality did not show any positive effect of the placebo in the placebo-controlled studies.28,67 On average, the FSH value in the studied popu- lation was relatively high thus indicating the im- balance of the pituitary-gonadal endocrine axis and hypogonadism with a serious damage of sper- matogenesis. In infertile men, a higher concentra- tion of FSH is considered to be a reliable indicator of germinal epithelial damage, and was shown to be associated with azoospermia and severe oligo- zoospermia.68 This indicates that the studied popu- lation of men in our study was facing severe male infertility (severe OAT). TABLE 2. Comparison of basic semen parameters, sperm MMP, DNA fragmentation, serum FSH values in astaxanthin and placebo groups after three-month treatment period Parameter Astaxanthin (n = 37) Placebo (n = 35) Baseline After 3 months p-value Baseline After 3 months p-value Sperm concentration (million /ml)* 7.0 ± 5.6 9.2 ± 7.9 0.100 5.7 ± 5.9 10.2 ± 15.7 0.024 Total sperm number (million/ejaculate)* 24.6 ± 28.6 31.7 ± 33.4 0.186 16.0 ± 21.1 38.4 ± 69.2 0.002 Total sperm motility (%)** 32.3 ± 14.0 37.9 ± 14.7 0.172 38.0 ± 15.0 43.1 ± 12.8 0.164 Progressive sperm motility (%)** 27.3 ± 14.0 33.0 ± 14.7 0.171 33.1 ± 14.7 38.1 ± 12.8 0.176 Sperm morphology (%) 1.8 ± 2.1 1.6 ± 1.4 0.471 1.9 ± 2.0 2.0 ± 1.7 0.913 Sperm head defect (%) 95.1 ± 16.2 97.8 ± 2.2 0.785 97.5 ± 3.3 97.2 ± 2.7 0.836 Sperm neck + midpiece defect (%) 2.9 ± 16.4 0.2 ± 0.7 0.916 0.2 ± 0.8 0.3 ± 0.8 0.472 Sperm tail defect (%) 0.2 ± 0.6 0.4 ± 0.9 0.253 0.5 ± 1.0 0.5 ± 0.9 0.872 Leukocytes with peroxidase (million/ml) 0.3 ± 0.3 0.5 ± 0.7 0.155 0.5 ± 0.8 0.6 ± 0.9 0.365 Mitochondrial membrane potential (%)*** 27.5 ± 18.5 26.3 ± 18.5 0.375 26.9 ± 15.3 27.1 ± 15.9 0.925 DNA fragmentation (%) 50.5 ± 23.9 51.2 ± 17.9 0.958 45.8 ± 21.8 49.8 ± 16.9 0.116 FSH IU/l) 9.7 ± 7.8 10.0 ± 8.3 0.200 9.2 ± 5.8 9.7 ± 6.5 0.345 Results presented as average (±SD) or percentage (%). Differences within groups between baseline and after 3 months assessed with paired t-test and Wilcoxon test, as appropriate. * = the analysis for total sperm number and sperm concentration was made for 33/37 patients from the astaxanthin group and 34/35 patients from the placebo group, since the excluded patients only had a few mobile or immobile spermatozoa in the semen sample; ** = the analysis for total and progressive sperm motility was made for 22/37 patients from the astaxanthin group and 16/35 patients from the placebo group, since the excluded patients only had a few mobile or immobile spermatozoa in the semen sample; ***: the proportion of spermatozoa with normal sperm mitochondrial membrane potential (MMP); DNA = deoxyribonucleic acid; FSH = follicle-stimulating hormone Radiol Oncol 2021; 55(1): 97-105. Imamovic Kumalic S et al. / Oral intake of astaxanthin and semen parameters in infertile patients 103 The advantage of our prospective, double-blind study includes the good randomization of patients for astaxanthin or placebo treatment. At baseline, both groups were comparable by their characteris- tics. We included patients based on their previous seminograms, and they were all clinically exam- ined by an experienced andrologist. Additionally, strict exclusion criteria were used. Besides, this is the first clinical study of the efficacy of astaxan- thin oral intake on semen parameters in severe oligo-astheno-teratozoospermic patients treated for infertility. The number of patients included is higher compared to similar placebo-controlled studies of other antioxidants.32,39,69,70 Astaxanthin group was homogenous because all patients ac- corded with WHO 2010 criteria for O+A+T. In the placebo group, two-thirds of patients also met the criteria for O+A+T; the average progressive motil- ity of spermatozoa was just above the reference value (33.1 ± 14.7%), but the average total motil- ity of spermatozoa was below the reference value. Therefore, the placebo group was also considered to be homogenous. Nevertheless, our study had some limitations, since one-third of patients had only a few mobile or immobile spermatozoa dur- ing the semen analysis; therefore, the measure- ments and statistical analysis for the total number, concentration and motility of spermatozoa in these patients were not possible. In addition, a relatively high proportion of patients declined to participate in this study. As our study was performed with humans who gave consent to participate, it is our ethical obliga- tion to also report the results with no evidence of an effect.71,72 Also, our study delivers an important fact that the clinical study on the astaxanthin effect in oligo-astheno-teratozoospermia was carried out. Unreported or unpublished negative findings in- troduce a bias in meta-analysis.73 Last but not least, the results could be an important part of future sci- entifically fair and flawless meta-analyses and re- views of the effects of antioxidants in infertile men. Conclusions In conclusion, the oral intake of 16 mg astaxan- thin daily for three months did not significantly improve the semen parameters in patients with oligo-astheno-teratozoospermia compared to pla- cebo. Our findings are important for the treatment and counselling on possible improvements in se- men quality and fertilizing potential in infertile, and also post-testicular cancer patients. As a wide range of different antioxidant supplements is avail- able, including astaxanthin, these findings are also significant concerning the efficacy of supplements in the treatment of male infertility. Acknowledgments The authors would like to thank Branko Zorn, Saso Drobnic, Mojca Kolbezen Simoniti, Ivan Verdenik, Natasa Petkovsek, Sara Hajdarevic, and registered nurses of the Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, Slovenia, and Andreja Natasa Kopitar from the Institute for Microbiology and Immunology, Faculty of Medicine, University of Ljubljana for their assistance in the study. The authors are grate- ful to manufacturer Sensilab, Ljubljana, Slovenia, for the donation of astaxanthin and placebo cap- sules. References 1. Sharlip ID, Jarow JP, Belker AM, Lipshultz LI, Sigman M, Thomas AJ, et al. Best practice policies for male infertility. Fertil Steril 2002; 77: 873-82. doi: 10.1016/s0015-0282(02)03105-9 2. 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Review of clinical trials on effects of oral antioxidants on basic semen and other parameters in idiopathic oligoasthenoteratozoospermia. Biomed Res Int 2014; 2014: 426951. doi: 10.1155/2014/426951 29. Piomboni P, Gambera L, Serafini F, Campanella G, Morgante G, De Leo V. Sperm quality improvement after natural anti-oxidant treatment of as- thenoteratospermic men with leukocytospermia. Asian J Androl 2008; 10: 201-6. doi: 10.1111/j.1745-7262.2008.00356.x 30. Safarinejad MR. Effect of pentoxifylline on semen parameters, reproductive hormones, and seminal plasma antioxidant capacity in men with idiopathic infertility: a randomized double-blind placebo-controlled study. Int Urol Nephrol 2011; 43: 315-28. doi: 10.1007/s11255-010-9826-4 31. Safarinejad MR, Safarinejad S, Shafiei N, Safarinejad S. Effects of the reduced form of coenzyme Q10 (ubiquinol) on semen parameters in men with idi- opathic infertility: a double-blind, placebo controlled, randomized study. J Urol 2012; 188: 526-31. doi: 10.1016/j.juro.2012.03.131 32. Alizadeh F, Javadi M, Karami AA, Gholaminejad F, Kavianpour M, Haghighian HK. Curcumin nanomicelle improves semen parameters, oxidative stress, inflammatory biomarkers, and reproductive hormones in infertile men: a randomized clinical trial. Phytother Res 2018; 32: 514-21. doi: 10.1002/ ptr.5998 33. Banihani SA. Effect of ginger (Zingiber officinale) on semen quality. Andrologia 2019; 51: e13296. doi: 10.1111/and.13296 34. Jannatifar R, Parivar K, Roodbari NH, Nasr-Esfahani MH. Effects of N-acetyl- cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men. Reprod Biol Endocrinol 2019; 17: 24. doi: 10.1186/s12958-019-0468-9 35. Lipovac M, Bodner F, Imhof M, Chedraui P. Comparison of the effect of a combination of eight micronutrients versus a standard mono preparation on sperm parameters. Reprod Biol Endocrinol 2016; 4: 84. doi: 10.1186/ s12958-016-0219-0 36. Tremellen K, Miari G, Froiland D, Thompson J. A randomized control trial examining the effect of an antioxidant (Menevit) on pregnancy outcome during IVF-ICSI treatment. Aust N Z J Obstet Gynaecol 2007; 47: 216-1. doi: 10.1111/j.1479-828X.2007.00723.x 37. Ghanem H, Shaeer O, El-Segini A. Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. Fertil Steril 2010; 93: 2232-5. doi: 10.1016/j.fertnstert.2009.01.117 38. Raigani M, Yaghmaei B, Amirjannti N, Lakpour N, Akhondi MM, Zeraati H, et al. The micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men. Andrologia 2014; 46: 956-62. doi: 10.1111/and.12180 39. Yamamoto Y, Aizawa K, Mieno M, Karamatsu M, Hirano Y, Furui K, et al. The effects of tomato juice on male infertility. Asia Pac J Clin Nutr 2017; 26: 65- 71. doi: 10.6133/apjcn.102015.17 40. Busetto GM, Agarwal A, Virmani A, Antonini G, Ragonesi G, Del Giudice F, et al. Effect of metabolic and antioxidant supplementation on sperm pa- rameters in oligo-astheno-teratozoospermia, with and without varicocele: a double-blind placebo-controlled study. Andrologia 2018; 50: e12927. doi: 10.1111/and.12927 41. Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev 2019; 3: CD007411. doi: 10.1002/14651858.CD007411.pub4 42. Yuan JP, Peng J, Yin K, Wang JH. Potential health-promoting effects of astax- anthin: a high-value carotenoid mostly from microalgae. Mol Nutr Food Res 2011; 55: 150-65. doi: 10.1002/mnfr.201000414 43. Miki W. Biological functions and activities of animal carotenoids. Pure Appl Chem 1991; 63: 141-6. doi: 10.1351/pac199163010141 44. Dona G, Kozuh I, Brunati AM, Andrisani A, Ambrosini G, Bonanni G, et al. Effect of astaxanthin on human sperm capacitation. Mar Drugs 2013; 11: 1909-19. doi: 10.3390/md11061909 45. Andrisani A, Donà G, Tibaldi E, Brunati AM, Sabbadin C, Armanini D, et al. Astaxanthin improves human sperm capacitation by inducing lyn dis- placement and activation. Mar Drugs 2015; 13: 5533-51. doi: 10.3390/ md13095533 46. Comhaire FH, El Garem Y, Mahmoud A, Eertmans F, Schoonjans F. Combined conventional/antioxidant “Astaxanthin” treatment for male infertil- ity: a double blind, randomized trial. Asian J Androl 2005; 7: 257-62. doi: 10.1111/j.1745-7262.2005.00047.x 47. Björndahl L, Barratt CLR, Mortimer D, Jouannet P. ‘How to count sperm properly’: checklist for acceptability of studies based on human semen analysis. Hum Reprod 2016; 31: 227-32. doi: 10.1093/humrep/dev305 48. Franco JG Jr, Baruffi RL, Mauri AL, Petersen CG, Oliveira JB, Vagnini L. Significance of large nuclear vacuoles in human spermatozoa: implica- tions for ICSI. Reprod Biomed Online 2008; 17: 42-5. doi: 10.1016/s1472- 6483(10)60291-x 49. Sergerie M, Laforest G, Bujan L, Bissonnette F, Bleau G. Sperm DNA frag- mentation: threshold value in male fertility. Hum Reprod 2005; 20: 3446-51. doi: 10.1093/humrep/dei231 50. Armstrong JS, Rajasekaran M, Chamulitrat W, Gatti P, Hellstrom WJ, Sikka SC. Characterization of reactive oxygen species induced effects on human spermatozoa movement and energy metabolism. Free Radic Biol Med 1999; 26: 869-80. doi: 10.1016/s0891-5849(98)00275-5 Radiol Oncol 2021; 55(1): 97-105. Imamovic Kumalic S et al. / Oral intake of astaxanthin and semen parameters in infertile patients 105 51. Colpi GM, Contalbi GF, Nerva F, Sagone P, Piediferro G. Testicular function following chemo-radiotherapy. Eur J Obstet Gynecol Reprod Biol 2004; 13(Suppl 1): S2-6. doi: 10.1016/j.ejogrb.2003.11.002 52. Pont J, Albrecht W. Fertility after chemotherapy for testicular germ cell cancer. Fertil Steril 1997; 68: 1-5. doi: 10.1016/s0015-0282(97)81465-3 53. Fossa SD, Aass N, Molne K. Is routine pre-treatment cryopreservation of semen worthwhile in the management of patients with testicular cancer? Br J Urol 1989; 64: 524-9. doi: 10.1111/j.1464-410x.1989.tb05292.x 54. Horwich A, Nicholls EJ, Hendry WF. Seminal analysis after orchiectomy in stage I teratoma. Br J Urol 1988; 62: 79-81. doi: 10.1111/j.1464-410x.1988. tb04272.x 55. Berthelsen JG. Sperm counts and serum follicle-stimulating hormone levels before and after radiotherapy and chemotherapy in men with testicular germ cell cancer. Fertil Steril 1984; 41: 281-6. doi: 10.1016/s0015- 0282(16)47605-3 56. Rueffer U, Breuer K, Josting A, Lathan B, Sieber M, Manzke O, et al. Male gonadal dysfunction in patients with Hodgkin’s disease prior to treatment. Ann Oncol 2001; 12: 1307-11. doi: 10.1023/a:1012464703805 57. Van der Kaaij MA, Heutte N, Echten AJV, Raemaekers JMM, Carde P, Noordijk EM, et al. Sperm quality before treatment in patients with early stage Hodgkin’s lymphoma enrolled in EORTC-GELA lymphoma group trials. Haematologica 2009; 94: 1691-7. doi: 10.3324/haematol.2009.009696 58. Viviani S, Ragni G, Santoro A, Perotti L, Caccamo E, Negretti E, et al. Testicular dysfunction in Hodgkin’s disease before and after treatment. Eur J Cancer 1991; 27: 1389-92. doi: 10.1016/0277-5379(91)90017-8 59. Steiner A, Hansen K, Diamond MP, Coutifaris C, Cedars M, Legro R, et al. Antioxidants in the treatment of male factor infertility: results from double blind, multi-center, randomized controlled males, antioxidants, and infertil- ity (MOXI) trial. [abstract O-064]. In: Abstracts of the 34th annual meeting of the European Society of Human Reproduction and Embryology; 2018. Hum Reprod 33(Supp 1): i30. 60. Donnelly ET, McClure N, Lewis SE. Antioxidant supplementation in vitro does not improve human sperm motility. Fertil Steril 1999; 72: 484-95. doi: 10.1016/s0015-0282(99)00267-8 61. Safarinejad MR, Shafiei N, Safarinejad S. A prospective double-blind ran- domized placebo-controlled study of the effect of saffron (Crocussativus Linn.) on semen parameters and seminal plasma antioxidant capacity in infertile men with idiopathic oligoasthenoteratozoospermia. Phytother Res 2011; 25: 508-16. doi: 10.1002/ptr.3294 62. Rafiee B, Morowvat MH, Rahimi-Ghalati N. Comparing the effectiveness of dietary vitamin C and exercise interventions on fertility parameters in normal obese men. Urol J 2016; 13: 2635-9. PMID: 27085565 63. Bozhedomov VA, Lipatova NA, Bozhedomova GE, Rokhlikov IM, Shcherbakova EV, Komarina RA. Using L- and acetyl-L-carnintines in com- bination with clomiphene citrate and antioxidant complex for treating idiopathic male infertility: a prospecitive randomized trial. Urologia 2017; 3: 22-32. doi: 10.18565/urol.2017.3.22-32 64. Kirsch I. How expectancies shape experience. Washington: American Psychological Association; 1999. 65. Bjørkedal E, Flaten MA. 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BMJ 2012; 344: d7202. doi: 10.1136/bmj.d7202 Radiol Oncol 2021; 55(1): 106-115. doi: 10.2478/raon-2020-0073 106 research article Semi-supervised planning method for breast electronic tissue compensation treatments based on breast radius and separation Alexander R. Podgorsak1,2, Lalith K. Kumaraswamy1,2 1 State University of New York at Buffalo, Department of Medical Physics, Buffalo, New York, United States 2 Roswell Park Comprehensive Cancer Center, Department of Radiation Medicine, Buffalo, New York, United States Radiol Oncol 2021; 55(1): 106-115. Received 24 July 2020 Accepted 19 October 2020 Correspondence to: Alexander R. Podgoršak, Ph.D., 8052 Clinical Translational Research Center, 875 Ellicott Street, Buffalo, New York 14203. E-mail: arpodgor@buffalo.edu Disclosure: No potential conflicts of interest were disclosed. Background. The aim of the study was to develop and assess a technique for the optimization of breast electronic tissue compensation (ECOMP) treatment plans based on the breast radius and separation. Materials and methods. Ten ECOMP plans for 10 breast cancer patients delivered at our institute were collected for this work. Pre-treatment CT-simulation images were anonymized and input to a framework for estimation of the breast radius and separation for each axial slice. Optimal treatment fluence was estimated based on the breast radius and separation, and a total beam fluence map for both medial and lateral fields was generated. These maps were then imported into the Eclipse Treatment Planning System and used to calculate a dose distribution. The distribu- tion was compared to the original treatment hand-optimized by a medical dosimetrist. An additional comparison was performed by generating plans assuming a single tissue penetration depth determined by averaging the breast radius and separation over the entire treatment volume. Comparisons between treatment plans used the dose homogene- ity index (HI; lower number is better). Results. HI was non-inferior between our algorithm (HI = 12.6) and the dosimetrist plans (HI = 9.9) (p-value > 0.05), and was superior than plans obtained using a single penetration depth (HI = 17.0) (p-value < 0.05) averaged over the 10 collected plans. Our semi-supervised algorithm takes approximately 20 seconds for treatment plan generation and runs with minimal user input, which compares favorably with the dosimetrist plans that can take up to 30 minutes of attention for full optimization. Conclusions. This work indicates the potential clinical utility of a technique for the optimization of ECOMP breast treatments. Key words: electronic compensation; dose homogeneity index; plan optimization Introduction It is estimated that approximately 276,480 new cases of invasive breast cancer will be diagnosed in women in the United States by the end of 2020.1 One of the techniques used for breast radiation therapy employs two electronically compensated tangent x-ray fields. Such a technique has been found to minimize irradiation of the surround- ing lung and cardiac tissue, while improving the homogeneity of the delivered dose within the breast.2-4 This is important as it is reported that women treated for breast cancer have higher inci- dence of coronary artery disease and myocardial infarction.5-7 Additionally, dose inhomogeneity reduction has been shown to reduce adverse ef- fects such as acute radiation toxicity, particularly in women with large breast size.8,9 Electronic compensation (ECOMP) is a forward- planned intensity modulated radiation therapy technique which can account for variation in the breast size and shape in both the anterior-posterior Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method 107 and cranio-caudal direction.10-14 It achieves its im- provement in dose homogeneity through dynamic multi-leaf collimator motion. Within the Eclipse (Varian Medical Systems, Palo Alto, United States) treatment planning software (TPS), the irregular compensation surface is defined by a transmis- sion penetration depth (TPD). The TPD is the point along every ray in the field that tissue compensa- tion occurs. If the TPD is reduced, the compensa- tion surface is moved closer to the surface of the breast. Clinically, the TPD is currently selected based on prior knowledge of the treatment plan- ner. Dose profiles are computed within the TPS, and the homogeneity is improved via manual edit- ing of the x-ray fluence maps. This can be a time- consuming process, with large variability between users depending on the skill or experience of the planner. Published work exists which attempted to cor- relate the size and shape of the breast to the TPD which yielded the most homogenous dose distri- bution. Friend et al. reported the use of a constant TPD rule depending on breast separation, TPD of 40% if separation is greater than 24 cm, TPD of 50% otherwise.15 Emmens and James reported the use of smaller TPD with larger breast separation producing a more homogenous dose distribution, yet the full breast volume should be used to attain the most homogenous distribution.11 These works used a single TPD for all axial breast slices, ignor- ing the variation in breast size and shape in the cranio-caudal direction. Alghufaili et al. correlated the full contour of the breast to the optimal TPD in-terms of achieving a homogenous dose distribu- tion.16 Three TPDs were output for three regions of the breast (superior, middle, inferior) using the average breast separation and radius in those re- gions. Our work looks to extend this idea, but use the breast size and shape in each axial slice to deter- mine the optimal TPD slice-by-slice. Materials and methods Figure 1 shows how the breast radius and sepa- ration may change in the cranio-caudal direction for an example patient. Figure 2 shows the hand- calculated optimal TPD over each axial slice in the cranio-caudal direction using the model proposed FIGURE 1. Left shows how the breast radius varies in the cranio-caudal direction, right shows how the breast separation varies in the cranio-caudal direction for the same collected patient breast. FIGURE 2. Variation in the optimal transmission penetration depth (TPD) over all slices in the cranio-caudal direction compared with the TPD considering a constant TPD or a TPD using the three-region breast approach. Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method108 by Alghufaili, compared with averaging the opti- mal TPD considering one (constant TPD) and three breast regions. Attempting to select a single or few optimal TPDs over the entire cranio-caudal direc- tion is difficult. With this variation in breast shape and size, and the optimal TPD in the cranio-caudal direction, it seems likely that improvements in ECOMP treatment planning may be realized with a higher-resolution correlation of breast shape and size to the optimal x-ray beam fluence. We look to do this optimal TPD selection with a weakly super- vised framework that will estimate the breast sepa- ration and radius from input CT-simulation data. To this end, 10 ECOMP breast plans for 10 breast cancer patients delivered at our institute with a Varian Trilogy LINAC and millennium model 120 multi-leaf collimators were retrospectively collect- ed. CT-simulation data were anonymized for each patient and used to develop our semi-supervised framework for measurement of breast size and sep- aration. Two left-sided and 1 right-sided treatment were used for hand-measurement of the breast sep- aration and radius at each axial location within the treatment volume determined by the placement of superior and inferior markers prior to simulation. It should be noted that a breath hold technique was employed in the left-sided breast cases, both during imaging and treatment. We defined breast separa- tion as the distance along the posterior edge of the breast, and breast radius as the distance from the chest wall to the anterior apex of the breast. Hand measurements were used to assess the accuracy of the semi-supervised breast separation and radius measurement framework. The first step of the framework is the identifi- cation of medial and ipsilateral platinum markers placed prior to CT-simulation. Two square regions are required as input for marker identification. That is the only user supervision the algorithm re- quires. If the medial marker is found to be to the right of the ipsilateral marker (by x-position), it is a left-sided treatment, otherwise it is a right-sided treatment. A vector is created connecting the me- dial and ipsilateral markers, extrapolated out to the image boundary, and all image structure beneath the vector is removed from the image data leav- ing only the targeted breast. An ellipse is fitted to the remaining breast structure using the elliptical Hough transform.17 The major axis of the fitted el- lipse is the estimated breast separation; half of the minor axis is the estimated breast radius. Figure 3 shows an example axial CT-simulation slice with the fitted ellipse and the estimated (yellow) and hand-measured (blue) separation and radius meas- urement in cm overlaid. For each axial slice in the three breast volumes, the hand-measured separa- tion and radius were compared with the automati- cally estimated separation and radius using the av- erage percent difference between them. Previous work has correlated the breast separa- tion and radius to the TPD which will yield the most homogenous dose distribution.11,15,16 The TPS is still required to compute the fluence profile to deliver the prescribed TPD. We looked to correlate the breast size and shape to that optimal fluence profile, such that the x-ray fluence map needed to achieve the most homogenous dose could be attained without the use of the TPS. To do this, uniform semi-elliptical phantoms simulating axial slices of the breast with varying separation and radius ranging from a separation of 12 cm to 24 cm and a radius of 5 cm to 12 cm were generated. These phantoms were input to Eclipse TPS, and the TPD was set in accordance with the model proposed by Alghufaili et al.16 The TPS was used to measure the x-ray fluence needed to deliver the homogenous dose profile, and correlate it with the breast size and shape. A mathematical model computing the optimal fluence as a function of breast separation and radius was acquired using a least-squares minimization bilateral fitting to the individual fluence measurements. This model can then be used to compute a mapping of the x-ray fluence at the surface of the breast needed to de- liver the most homogenous dose, across all axial slices in the treatment volume. It is important to note that this model is dependent on beam energy. As each ray passes through the breast volume, we FIGURE 3. CT-simulation axial slice with fitted ellipse (red) and breast radius and separation estimation (yellow) and hand-measurement (blue) of left breast overlaid. Included is the location of the hand measurement for radius and separation in blue. Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method 109 assumed exponential drop-off of the fluence gov- erned by the Beer-Lambert-Bouguer Law.18-20 In this way, we created 2D x-ray fluence maps need- ed to deliver the most homogenous dose profile, considering each axial slice in the treatment vol- ume, using a semi-supervised processing frame- work. The 10 retrospectively collected ECOMP breast plans were re-planned within Eclipse using x-ray fluence maps generated with our proposed semi- supervised framework. The resultant dose distri- butions were compared with those from the origi- nal plans created and optimized by an experienced dosimetrist. Two additional comparisons were car- ried out with plans generated in Eclipse, the first by assuming a single TPD determined over the entire treatment volume (current model in Eclipse TPS), and no manual editing of the fluence maps to correct any dose inhomogeneities. The second is using Alghufaili’s three-region breast model, where three TPD’s are used, the optimal TPD for the superior, medial, and inferior portions of the treatment volume. Quantitative comparison be- tween the four plans across the ten patients used the dose homogeneity index (HI, lower is better)21, mathematically described in Equation 1 as [eq. 1] where D2 and D98 represent doses to 2% and 98% of the PTV respectively, and Dp represents the prescription dose, along with Pearson correlation coefficients22, and single-tailed heteroscedastic t- tests to assess the significance of any differences between plans (p-value < 0.05). Our goal was to achieve a more homogenous dose profile using our semi-supervised algorithm compared with the use of a single TPD over all axial slices in the treatment volume or the 3-region breast model of Alghufaili, and to achieve a statistically non-inferior dose ho- mogeneity compared with the dosimetrist treat- ment plans. Our institute places constraints on ECOMP plans which mandate global maximum dose less than 108% the prescription and treatment volume dose greater than 95% the prescription. We compared how each of the four techniques created plans which met these dose constraints or other- wise. The weakly-supervised breast radius and sepa- ration estimation process, fitting of the x-ray beam fluence to the mathematical models, and statistical analyses were all done in MATLAB. Results Treatment plans were generated in around 20 sec- onds by our proposed algorithm. This number includes the time it takes for breast radius and separation estimation, and compares well with the medical dosimetrist plans which can take up to 30 minutes due to the iterative and manual process of editing the fluence maps to bring the generated plans within institutional dose constraints. It is also important to note that our proposed algorithm re- quires much less user input than the fully-super- vised forward-planned iterative method, indicat- ing an improvement in the clinical workflow. TABLE 1. Agreement between breast radius and separation hand-measurements and automatic algorithm measurement in centimeter (cm) difference and percent difference Radius Number % Difference Difference (cm) 1 9.6 [9.3–9.9] 0.70 [0.68–0.72] 2 6.2 [5.7–6.7] 0.40 [0.39–0.41] 3 22.0 [21.5–22.5] 1.00 [0.98–1.02] Average 12.6 [10.4–14.8] 0.69 [0.59–0.79] Separation Number % Difference Difference (cm) 1 6.1 [5.0–7.2] 1.13 [1.11–1.15] 2 4.2 [4.1–4.3] 0.71 [0.68–0.74] 3 5.3 [5.1–5.5] 0.91 [0.71–1.11] Average 5.2 [5.1–5.3] 0.92 [0.79–1.05] FIGURE 4. Correlation between breast separation and radius with the x-ray fluence needed to deliver homogenous dose distribution to the breast treatment volume using a 6 MV beam. Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method110 Average percent difference and average distance in cm between the automatic-algorithm-measured and hand-measured breast radius and separation over the three test volumes can be found in Table 1. Average percent difference between the breast ra- dius measurements over the three test volumes was 12.6% (95% confidence interval 10.4% – 14.8%), corresponding to an actual measurement error of 0.69 cm (0.59 cm – 0.79 cm). Average percent differ- ence between the breast separation measurements over the three test volumes was 5.2% (95% confi- dence interval 5.1% – 5.3%), corresponding to an actual measurement error of 0.92 cm (0.79 cm – 1.05 cm). It should be noted that the reconstructed voxel size was 1.269 mm, hence these errors are below 8 pixels at a measurement error value of 1 cm. Figure 4 displays the correlation between the breast separation and radius with the optimal transmission fluence at the breast surface needed to deliver the most homogenous dose distribution to the breast volume using a 6 MV x-ray beam. This plot indicates an increase in the x-ray fluence needed as the breast separation decreases and the radius increases. Following the fitting of a plane to the model, the relationship in Equation 2 was ac- quired, where f is the optimal fluence for the axial slice with a radius and separation measurement from the semi-supervised framework. [eq. 2] f (radius, separation, 6 MV) = 0.753 + 0.006 * radius – 0.005 * separation These results are in agreement with the work of Emmens11 and Alghufaili16, which reported corre- lation between a decreasing separation and an in- crease in radius with the TPD. The TPD is related with x-ray fluence, in that more fluence is needed to attain a deeper penetration depth. The mathe- matical relationship between breast size and shape and the optimal fluence for a 23 MV beam can be found in Equation 3. To simplify the number of pa- rameters in the Equation and improve the general- izability of the model, we assumed a bilinear fit for each of the three models. [eq. 3] f (radius, separation, 23 MV) = 0.888 + 0.006 * radius – 0.007 * separation Figure 5 shows optimal fluence maps generated using a single TPD throughout the treatment vol- ume, using three TPDs assuming a three-region A B C FIGURE 5. Optimal fluence maps from (A) assuming a single penetration depth, from (B) assuming a three-region breast model, and (C) our proposed model. Colorbar shows beam fluence. TABLE 2. Summary of dose homogeneity indices (HI) for all ten collected treatment courses. Compared are the treatments generated with our proposed algorithm, plans created using the 3-region breast model proposed by Alghufaili, those plans optimized by a medical dosimetrist, and plans generated by assuming a single transmission penetration depth (TPD) within the treatment planning software Number Proposed Work HI 3-region breast model Dosimetrist Optimized HI Single TPD HI 1 26.7 22.4 16.5 23.0 2 17.8 19.2 14.1 19.1 3 10.6 15.2 11.2 17.2 4 11.8 14.6 9.51 13.3 5 8.49 7.87 3.32 8.04 6 8.79 14.1 6.64 12.6 7 4.59 7.44 3.82 8.19 8 7.57 21.5 8.84 23.5 9 11.3 17.9 8.29 18.7 10 10.6 16.0 10.5 17.8 Average 12.6 15.6 9.87 17.0 Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method 111 TABLE 3. Summary of global dose maximum and clinical target volume (CTV) minimum values for all ten collected treatment courses. Compared are the treatments generated with our proposed algorithm, plans created using the 3-region breast model proposed by Alghufaili, those plans optimized by a medical dosimetrist, and plans generated by assuming a single transmission penetration depth (TPD) within the treatment planning software Global dose max (%) CTV dose min (%) Number Proposed work 3-region breast model Dosimetrist optimized Single TPD Proposed work 3-region breast model Dosimetrist optimized Single TPD 1 107.7 108.5 109.1 113.3 96.9 97.3 104.1 96.0 2 109.7 111.3 106.5 111.8 74.4 75.0 76.9 74.2 3 107.4 108.1 107.5 112.7 95.5 88.7 95.3 89.1 4 107.5 110.4 105.9 109.8 95.5 95.2 95.0 96.8 5 107.7 109.7 104.0 105.0 95.1 95.9 98.1 87.8 6 107.5 108.7 105.5 111.4 97.9 96.0 99.3 97.4 7 108.0 114.2 105.9 116.3 95.4 95.4 95.7 95.4 8 107.6 112.6 106.6 114.6 95.3 92.8 97.8 94.1 9 107.5 115.5 106.0 118.1 95.6 95.6 95.1 95.0 10 107.5 108.6 107.8 114.4 86.1 81.6 87.8 87.2 Average 107.8 111.2 106.5 112.7 92.7 91.4 94.5 91.3 TABLE 4. Summary of mean dose to the heart and ipsilateral lung V20 Gy for all ten collected courses. Compared are the treatments generated with our proposed algorithm, plans created using the 3-region breast model proposed by Alghufaili, those plans optimized by a medical dosimetrist, and plans generated by assuming a single transmission penetration depth (TPD) within the treatment planning software Mean dose to the heart (cGy) Ipsilateral lung V20 Gy (%) Number Proposed Work 3-region breast model Dosimetrist Optimized Single TPD Proposed Work 3-region breast model Dosimetrist Optimized Single TPD 1 11.0 15.0 13.7 13.4 0.42 2.30 2.41 2.05 2 298 296 294 327 18.2 18.3 16.7 20.3 3 177 165 109 160 5.12 4.91 3.56 4.65 4 271 267 149 250 9.09 9.03 8.07 7.93 5 40.8 44.9 39.7 42.0 16.6 16.8 15.8 16.2 6 113 112 108 111 8.95 8.84 8.33 8.59 7 47.0 52.4 47.7 51.7 9.56 11.2 9.9 10.9 8 26.9 28.9 26.5 28.7 11.4 11.2 11.4 10.9 9 95.9 128 89.5 125 9.18 10.8 7.8 10.6 10 406 402 159 397 18.7 18.5 12.4 18.2 Average 149 151 104 151 10.7 11.2 9.65 11.0 breast model, and using a different TPD for each slice throughout the treatment volume. It should be noted that the resolution of these maps is con- sistent with that of the imaging (1.269 mm). Table 2 summarizes the HI for each of the col- lected ECOMP plans comparing the original medi- cal dosimetrist plans, plans from our proposed al- gorithm, plans generated using the 3-region breast model proposed by Alghufaili, and plans from the use of a single TPD over the entire treatment vol- ume. Over the collected plans, there is no statistical difference between the medical dosimetrist plans and our algorithm’s plans in terms of the dose ho- mogeneity index. Table 3 summarizes the global Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method112 dose maximum and treatment volume dose mini- mum for each of the 10 collected plans. Compared with the use of a single TPD, our algorithm is able to generate fluence maps which yield global maxi- mum doses and treatment volume dose minimums that are within our institution’s constraints that is in better agreement with the medical dosimetrist plans. Table 4 summarizes the mean dose to the heart and summarizes the volume percent above 20 Gy for the ipsilateral lung (V20 Gy) over the 10 collected plans. There is no statistical difference between the medical dosimetrist plans and our al- gorithm plans in terms of the heart mean dose or the ipsilateral lung V20 Gy. Figure 6 demonstrates isodose color washes in the axial, sagittal, and coronal planes, one set gen- erated from fluence maps generated with our pro- posed algorithm, the other from the current model utilized in the Eclipse TPS that assumes a constant TPD over the entire treatment volume. Our pro- posed algorithm creates a plan that has more ho- mogenous coverage of the breast and a reduced anterior hotspot. This specific case had a HI of 10.6 from the plan generated using our proposed algo- rithm and 17.2 from the plan assuming a constant TPD of 30% throughout the breast volume. Using the 3-region breast model to generate the treatment plan yielded an HI of 15.2. Discussion This study proposed a semi-supervised scheme for the determination of the optimal x-ray fluence map needed to deliver the most homogenous dose distribution to the breast volume in ECOMP treat- ment plans. Our algorithm takes as input the CT- simulation data from pre-treatment imaging and A B C D E F FIGURE 6. (A, C, E) axial, coronal, and sagittal views of the breast treatment volume showing the isodose color washes from the treatment plan generated with the proposed algorithm. (B, D, F) axial, coronal, and sagittal views of the breast treatment volume showing the isodose color washes from the treatment plan generated by assuming a constant transmission penetration depth of 30%. Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method 113 uses the breast radius and separation measure- ment over the entire treatment volume to output tangential maps of the x-ray fluence that describes how to deliver the most homogenous dose profiles such that acute late effects due to radiation toxicity caused by radiation dose in-homogeneities can be reduced. This fluence determination takes into con- sideration the variation in breast separation and ra- dius in the cranio-caudal direction, and extends on previous work by using each axial slice in the vol- ume to optimize the homogeneity instead of just a single or a couple slices. Figures 1, 2, and 5 empha- size the importance in considering this variation in the size and shape of the breast in the cranio-caudal direction. The three fluence maps in Figure 5 show how the optimal fluence maps change when the breast is broken up into finer resolution sections, from a single uniform shape in Figure 5A, three uniform shapes in Figure 5B, to estimating the ex- act shape at each axial slice in Figure 5C. Our re- sults indicate that the proposed algorithm can cre- ate plans that are statistically non-inferior in terms of the dose homogeneity to those plans manually edited by a dosimetrist. Additionally, our algo- rithm is able to produce plans that are within our institution’s dose constraints for the global dose maximum and target dose minimum. A comparison of the isodose color washes in Figure 6 show a better coverage of the green color wash over more of the treatment volume when the proposed algorithm is used instead of a constant TPD of 30%. In the axial slice (Figure 6 A and 6B), the green wash extends closer to the posterior edge of the breast volume against the lung volume. The sagittal view (Figure 6E and 6F) shows an advan- tage to our proposed algorithm in the coverage of the green wash towards the inferior portion of the breast volume. In all three anatomical planes, the green wash is more homogenous throughout the treatment volume, as confirmed with the homoge- neity index for this specific case (10.6 for the pro- posed algorithm, 17.2 for the constant TPD). There is also a reduction in the anterior hot spot that is prevalent in all three of the views from the single TPD treatments. The mathematical models fitted for the 6 MV and 23 MV beams (Equations 2 & 3, respectively), are both dominated by the 0th degree additive con- stant. The breast radius and separation play a role (additive for the radius, subtractive for the separa- tion), but it is small. With breasts of small radius and separation, our semi-supervised size measurement algorithm tends to overestimate the radius and separation of the breast, thereby generating plans that have regions where the dose potentially would exceed the maximum dose constraint. It would be these cases where manual optimization by the medical dosimetrist would still be necessary to reduce the hotspots potentially present in the dose profile. Patients 1 and 5 in Table 2 are examples of this. They both had overestimations in the breast radius and separation, causing the homogeneity to be worse compared with the medical dosimetrist plans due to the presence of several local dose hotspots that didn’t go above the 108% global maximum dose constraint, but still reduced homogeneity. This work can be thought of as a more homog- enous starting point for the iterative optimization process of the medical dosimetrist. Currently, a single TPD is empirically selected within Eclipse and the resultant fluence maps are manually ed- ited to improve the homogeneity of the computed dose profiles to bring the plan within institutional dose constraints. Our work has shown that an al- gorithm that measures the breast separation and radius over the entire breast volume and relates them to the optimal x-ray fluence maps can lead to more homogenous plans than the use of a single TPD. It seems possible that these improvements were realized with the higher-resolution correla- tion of breast size and shape to the x-ray beam flu- ence. This work may lead to a quicker, less manu- ally intensive process for the dosimetrist to bring the ECOMP plans within dose constraints. In every collected case, some combination of the global dose maximum being too high or treatment volume minimum dose being too low led to the necessity of optimization of the single TPD plans by the dosi- metrist. In the cases that met dose constraints with dosimetrist editing, our algorithm was able to cre- ate plans that met dose constraints with no manual editing required. There still may be manual edit- ing required to achieve equivalent dose homoge- neity with the dosimetrist-edited plans, however compared with the use of a single TPD or a three- region breast model, the plans from our algorithm attain a higher level of homogeneity and are more deliverable when considering institutional dose constraints. Our work extends on the literature in this prob- lem space in several important ways. Firstly, our work accounts for the variation in breast radius and separation in the cranio-caudal direction, axial slice by axial slice, by estimating the breast radi- us and separation at each slice and correlating it with the optimal (in terms of beam homogeneity) beam penetration using the TPD value. Secondly, Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method114 we took this TPD value and determined a math- ematical model, which governed what beam flu- ences would be needed to deliver parallel-opposed beams of the prescribed TPD. In this manner, the TPS would not be needed to obtain the optimized x-ray fluence map. A limitation of this current work is our model assumes exponential drop-off of the beam gov- erned by the Beer-Lambert-Bouguer Law. This as- sumes a homogenous material that the x-rays are traveling through, and will not be the case in the breast volume. This may cause the assumed fluenc- es to not be exactly what would be achieved with the delivery of a particular TPD deemed optimal for the breast separation and radius slice-by-slice. An additional limitation is in cases where there is skin folding at the breast surface, as may occur in the case of a large, pendulous breast. A challeng- ing situation is created in that the breast radius and separation would not be impacted, yet the optimal TPD and x-ray fluence would be changed. Such a condition was not included in the development of our model, so it may lead to the creation of sub- optimal plans. One final limitation is at this point, our algorithm still requires an operator for medial and ipsilateral marker identification. The supervi- sion amount is low compared to the current clinical workflow, however a fully automated framework would improve the clinical applicability of this al- gorithm. Conclusions This work indicates the advantages to the consid- eration of the full volumetric shape of the breast to determine the optimal TPD needed to deliver a homogenous dose distribution to the breast treat- ment volume. This volumetric shape is defined by the measurement of the breast separation along the posterior edge and radius from the isocenter at the posterior border to the apex anteriorly, consider- ing all axial slices in the cranio-caudal direction. This work also detailed a method for the semi-su- pervised determination of this volumetric shape, resulting in the output of the x-ray fluence needed for the delivery of the optimal dose distribution. We envision this process used to attain a more ho- mogenous, consistent starting point for the medi- cal dosimetrist as they optimize the ECOMP treat- ment plans, compared with assuming a constant shape of the breast in the cranio-caudal direction. References 1. American Cancer Society I. Breast Cancer Facts & Figures 2019-2020. Atlanta; 2019. 2. Aref A, Thornton D, Youssef E, He T, Tekyi-Mensah S, Denton L, et al. Dosimetric improvements following 3D planning of tangential breast irra- diation. Int J Radiat Oncol Biol Phys 2000; 5: 1569-74. doi: 10.1016/S0360- 3016(00)00808-7 3. Donovan EM, Johnson U, Shentall G, Evans PM, Neal AJ, Yarnold JR. Evaluation of compensation in breast radiotherapy: a planning study us- ing multiple static fields. Int J Radiat Oncol Biol Phys 2000; 3: 671-9. doi: 10.1016/S0360-3016(99)00388-0 4. Kestin LL, Sharpe MB, Frazier RC, Vicini FA, Yan D, Matter RC, et al. Intensity modulation to improve dose uniformity with tangential breast radiothera- py: initial clinical experience. Int J Radiat Oncol Biol Phys 2000; 5: 1559-68. doi: 10.1016/S0360-3016(00)01396-1 5. Correa CR, Litt HI, Hwang W-T, Ferrari VA, Solin LJ, Harris EE. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol 2007; 21: 3031-7. doi: 10.1200/ JCO.2006.08.6595 6. Harris EER, Correa C, Hwang W-T, Liao J, Litt HI, Ferrari VA, et al. Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 2006; 25: 4100-6. doi: 10.1200/ JCO.2005.05.1037 7. Recht A. Which breast cancer patients should really worry about radiation- induced heart disease – and how much? J Clin Oncol 2006; 25: 4059-61. doi: 10.1200/JCO.2006.07.7909 8. Goldsmith C, Haviland J, Tsang Y, Sydenham M, Yarnold J. Large breast size as a risk factor for late adverse effects of breast radiotherapy: Is re- sidual dose inhomogeneity, despite 3D treatment planning and delivery, the main explanation? Radiother Oncol 2011; 2: 236-40. doi: 10.1016/j. radonc.2010.12.012 9. Moody AM, Mayles WPM, Bliss JM, A’Hern RP, Owen JR, Regan J, et al. The influence of breast size on late radiation effects and association with radiotherapy dose inhomogeneity. Radiother Oncol 1994; 2: 106-12. doi: 10.1016/0167-8140(94)90063-9 10. Chui CS, Hong L, Hunt M, McCormick B. A simplified intensity modulated radiation therapy technique for the breast. Med Phys 2002; 4: 522-9. doi: 10.1118/1.1460875 11. Emmens D, James H. Irregular surface compensation for radiotherapy of the breast: correlating depth of the compensation surface with breast size and resultant dose distribution. Brit J Radiol 2010; 986: 159-65. doi: 10.1259/ bjr/65264916 12. James H, Poynter A, Crosbie J, MacKenzie L, Boston S, LeVay J. Electronic compensation for CT planned breast treatments. Radiother Oncol 2002; S133-4. 13. James H, Scrase C, Poynter A. Practical experience with intensity-modulated radiotherapy. Brit J Radiol 2004; 913: 3-14. doi: 10.1259/bjr/14996943 14. LeVay J, James H, Poynter A, MacKenzie L, Boston S. Optimising the delivery of radiotherapy for early breast cancer by the use of IMRT. Clin Oncol 2003; S14. 15. Friend M. An overview of electronic tissue compensation (ECOMP) for breast radiotherapy. 2014 Combined Scientific Meeting. Vienna, Austria; 2014. 16. Alghufaili AH, Shanmugarajah L, Kumaraswamy LK. Correlating the depth of compensation to the 3-D shape of the breast to achieve homogeneous dose distribution using the electronic tissue compensation treatment technique. Med Dosim 2019; 1: 30-4. doi: 10.1016/j.meddos.2018.01.001 17. Xie Y, Ji Q. A new efficient ellipse detection method. In: Object recogni- tion supported by user interaction for service robots. Troy, New York: IEEE, Rensselaer Polytechnic Institute; 2002. doi: 10.1109/ICPR.2002.1048464 18. Beer A. Bestimmung der absorption des rothen lichts in farbigen flussig- keiten. Ann Physik 1852; 78-88. doi: 10.1002/andp.18521620505 19. Bouguer P. Essai d’optique sur la gradation de la lumière. chez Claude Jombert, ruë S. Jacques, au coin de la ruë des Mathurins, à l …; 1729 Radiol Oncol 2021; 55(1): 106-115. Podgorsak AR and Kumaraswamy LK / Radius and separation based electronic compensation planning method 115 20. Lambert JH. Photometria sive de mensura et gradibus luminis, colorum et umbrae. Augsburg: Christoph Peter Detleffsen for the widow of Eberhard Klett; 1760 21. Wu Q, Mohan R, Morris M, Lauve A, Schmidt-Ullrich R. Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced head-and-neck squamous cell carcinomas. I: dosimetric results. Int J Radiat Oncol Biol Phys 2003; 56: 573-85. doi: 10.1016/s0360-3016(02)04617-5 22. Koo TK, Li MY. A guideline of selecting and reporting intraclass correlation coefficients for reliability research. J Chiropr Med 2016; 2: 155-63. doi: 10.1016/j.jcm.2016.02.012 Radiol Oncol 2021; 55(1): 116-120. doi: 10.2478/raon-2020-0044 116 research article Efficacy of breast shielding during head computed tomography examination Nika Zalokar, Nejc Mekis University of Ljubljana, Faculty of Health Sciences, Medical Imaging and Radiotherapy Department, Ljubljana, Slovenia Radiol Oncol 2021; 55(1): 116-120. Received 20 May 2020 Accepted 16 June 2020 Correspondence to: Nejc Mekiš, Ph.D., Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia. E-mail: nejc.mekis@zf.uni-lj.si Disclosure: No potential conflicts of interest were disclosed. Background. Female breasts are exposed to scattered radiation regardless of not being included in the primary field during head CT. This study aimed to investigate whether the use of lead shielding is beneficial in dose reduction to the breasts during head CT. Patients and methods. The study was performed in two different hospitals on two different CT units and included 120 patients. Half of the measurements (n = 60) was conducted without the use of lead shielding and the other half (n = 60) with the use of lead shielding of 0.5 mm equivalent thickness. Results. Significant skin dose reduction to the breasts during head CT in both hospitals with the use of lead shield- ing was discovered; 81% (338.2 ± 43.7 µGy to 64.3 ± 18.8 µGy) in Hospital A and 74% (from 253.1 ± 35.1 µGy to 65.3 ± 16.9 µGy) in Hospital B. Conclusions. Considering the assumed carcinogenic effect of low doses of radiation, high frequency of the head CT scans and the significant reduction of radiation doses to the highly radiosensitive breasts, the use of lead shielding is highly recommendable. Key words: scatter radiation; head CT; lead shielding; breasts; dose reduction Introduction Computed tomography (CT) is a valuable diag- nostic tool for many conditions.1 According to the International Atomic Energy Agency (IAEA) an in- dividual receives 2.4 mSv of the total annual dose of natural radiation2 and the typical effective radia- tion dose received during a standard CT scan rang- es from 1 to 14 mSv.3 Head CT is one of the most frequently performed examinations4,5 and accounts for 50% of all CT scans and 25% of the collective radiation dose from CT.5 High effective doses re- ceived during CT examinations raise concerns1,6, so an effort to minimize it is crucial.1 Due to concerns over radiation exposure, the very valuable princi- ple ‘‘as low as reasonably achievable’’ (ALARA) was established to stress the importance of mini- mizing radiation exposure.7 Many CT shielding techniques have been developed as a result, among them radiation protection shields, which are one of the simplest mechanisms by which radiation dose can be reduced.3 The use of lead shielding is a long-accepted method to minimize the dose from scatter radia- tion in radiographic procedures.1,8 In head CT, the head as the main target under investigation is in- cluded in the primary beam, while radiosensitive organs such as the breasts are located outside the primary beam. Radiosensitive structures that lie in the primary beam cannot be easily protected, while the organs outside the primary beam, which are mainly exposed to scattered radiation, can be eas- ily protected against it. Scattered radiation distrib- utes caudally through patient’s neck thereby in- evitably exposing the breasts. However, scattered radiation produced in gantry and patient’s head reaching the breasts from outside can be effectively diminished by the lead shielding.8 Radiation dose Radiol Oncol 2021; 55(1): 116-120. Zalokar N and Mekis N / Breast shielding efficacy in head CT 117 to the breasts is significant enough to be a matter of concern9 regardless of all the current dose reduc- tion techniques.5 Female breast tissue is highly sensitive to ra- diation’s carcinogenic effects. Its tissue weighting factor has risen from 0.05 to 0.12.7 The exposure of breasts to ionising radiation is a strong risk fac- tor for breast cancer. The study by Preston et al.10 showed that the increased risk is directly propor- tional to the radiation dose received and inversely related to age at irradiation. The use of radiation shields, if applied properly, is one of the simplest implementations by which radiation dose can be diminished without the negative impact on diag- nostic image quality.3 The benefit of shielding to radiosensitive organs in many diagnostic procedures has been acknowl- edged in many studies.1,5,8,11-13 Brnić et al.8 recom- mend lead shielding of the breasts during head CT since a recognizable reduction (57%) of the exposure was found. The study by Williams and Adams5 also discovered a significant dose reduc- tion (58–47%) with a lead bib protecting the thyroid. Beaconsfield et al.11 also claim a significant dose re- duction (76%) during head CT due to lead shielding of breasts. However, Brnić et al.8 measured the ex- posure with thermoluminescent dosimeters (TLD) during shielding of only one breast while the other remained unshielded, the study by Williams and Adams5 performed measurements while investi- gating the benefit of thyroid shielding on an anthro- pomorphic phantom and Beaconsfield et al.11 have performed only 20 measurements with the use of breast shielding during axial head CT examination. For the above-mentioned reasons and given the high frequency of head CT scans and high sensi- tivity of breasts to ionising radiation, the purpose of this study was to determine the effectiveness of breast shielding during the routine helical head CT scan in real clinical practice with an electronic do- simeter and a lead apron of 0.5 mm lead equivalent, which is the most commonly used protective shield in Slovenia. Lead shielding is not routinely used in the breast area during head CT examination so the results could clarify the dilemma whether the shielding is beneficial in protecting the breasts. Possible changes in clinical practice might be ex- pected in the future. Patients and methods The study was performed in two major hospi- tals in Slovenia. The sample size was calculated based on the study performed by Brnić et al.8, with the G*Power 3.1 (Allgemeine Psychologie und Arbeitspsychologie, University Dusseldorf) pro- gramme. 120 female patients referred to a spiral head CT scan participated in our study (age range 23–92 years with average age of 67.9 ± 16.7 years). 60 measurements were conducted in Hospital A on Siemens Somatom Definition (Siemens Medical Systems, Germany) CT unit and 60 measure- ments in Hospital B with Toshiba Aquilion 64 slice (Toshiba Medical Systems, Otawara, Japan) CT unit. All results of the quality assurance tests for both CT units, performed prior to the study by the medical physicist, were under the remedial level. Half of the measurements in each hospital (n = 30) were performed with the use of lead shielding and half of the measurements (n = 30) without the lead shielding. Randomized sampling was used in this study. The Unfors EDD 30 (Unfors, Sweden) unit was used to measure the skin dose at the surface of the breast in real time during CT of the head. According to the manufacturer, the dosimeter of- fers a dose range from 1 nGy to 9999 Gy with the start trigger level at 0.05 mSv/h. The manufacturer also claims that the EDD 30’s inaccuracy is ± 6% at calibration point with 80 kVp, 2 mm of Cu and 4 mm of Al. The dosimeter was tested and showed the best and consistent response of the dosimeter when it was in alignment to the horizontal plane and the cable of the dosimeter was positioned away from the source of scattered radiation (not contained in the scanning area). The dose was read on the display. Acquisition parameters are shown in Table 1. Same protocols as used in clinical practice in each hospital were used during the study. The sensor of the dosimeter was attached to the centre of the breast in the alternating order, in a way that the dosimeter was always in alignment with the examination table to ensure minimal ef- fect of the angulation dependence of the dosim- eter. The breast area was wrapped with lead apron (Mavig, Germany) of 0.5 mm equivalent lead TABLE 1. Acquisition parameters Hospital A B Pitch 0.55 0.656 Rotation time (s) 1 0.6 kV 120 120 mA 480 200 Radiol Oncol 2021; 55(1): 116-120. Zalokar N and Mekis N / Breast shielding efficacy in head CT118 thickness as tightly as possible around the patient (shoulders were not draped). The example of the shielding position is presented on Figure 1 using an anthropomorphic phantom. Our study was approved by the hospital’s Ethics Committee and by the National Medical Ethics Committee prior to the initiation. A writ- ten informed consent was obtained from all pa- tients. All the measurements were processed with the IBM SPSS STATISTICS version 25 (IBM, USA). The Shapiro-Wilk test was used to check the nor- mal distribution of the sample. A student T-test was performed to determine the statistical signifi- cance of the difference of the skin dose between the shielded and unshielded breasts in each hospital. A significance of p < 0.05 was used for all the tests. Results In Hospital A the mean skin dose to the breast was 338.2 ± 43.7 µGy without the lead shielding and 64.3 ± 18.8 µGy when the lead shielding was used. The difference between the doses was statis- tically significant (p < 0.001) with the dose reduc- tion of approximately 81%. In Hospital B, the mean skin dose to the unprotected breasts was 253.1 ± 35.1 µGy compared to 65.3 ± 16.9 µGy to the breasts protected with the lead shielding. The dose reduc- tion of 74% was statistically different (p < 0.001). Table 2 and Figure 2 summarize the results. Discussion This study provides evidence, that lead shielding significantly reduced the amount of scatter radia- tion to the breasts in both Hospitals. Radiosensitive structures that lie in the primary field cannot be easily protected, meanwhile the structures outside the CT scanning plane, such as the breasts during the head CT examination, can be easily protected against the scatter radiation. During the head CT examination the use of lead shielding can significantly reduce the exposure from scattered radiation generated in patient’s head and in gantry.8,14 Our results showed that the breast exposure in Hospital A and B was reduced by 81% and 74%, respectively, with the use of 0.5 mm lead shield- ing. Nevertheless, a noticeably higher mean skin dose to breasts without the shielding in Hospital A, compared to Hospital B has been detected. This TABLE 2. Mean measured skin dose to the breasts in both investigated hospitals Hospital A Hospital B unshielded shielded unshielded shielded Mean skin dose to breast (µGy) 338.2 ± 43.7 64.3 ± 18.8 253.1 ± 35.1 65.3 ± 16.9 Dose reduction 81% 74% FIGURE 1. Presentation of the shielding position used in the study. Radiol Oncol 2021; 55(1): 116-120. Zalokar N and Mekis N / Breast shielding efficacy in head CT 119 difference might be the result of the higher mA set- ting, longer scan lengths (were not noted) and the angular dependence of the dosimeter. Further in- vestigation could be made. The study from Beaconsfield et al.11 reported an average 76% dose reduction using a 0.5 mm lead equivalent thickness, which is similar to our study. They used the axial imaging technique of the head CT examination and not the spiral, as did we in our study. The axial imaging technique was also used in the study by Brnić et al.8, which reported lower reduction in dose; 57%. However, their study used a 0.35 mm lead shield, and only one breast was shielded during the measurements, so a lower dose reduction is expected. However, Williams and Adams5 did use the same CT imaging technique – the spiral scanning. They have investigated the impact of thyroid shielding on dose to the patient during head CT. They have measured a 58% dose reduction on the thyroid during the spiral head CT examination. The thyroid, however, cannot be pro- tected from the X-rays scattered from within the patient.11 All mentioned studies used thermo-lumi- nescent dosimeters to measure the radiation dose. In contrary, our study used an electronic dosimeter so the skin dose on the breasts was read out on the display as soon as the scanning was finished. The International Commission on Radiological Protection (ICRP) has published new tissue weighting factors for the breast and other organs in 2007. The breast tissue weighting factor was in- creased from 0.05 to 0.12.7 One of the strongest risk factors for breast cancer is the radiation exposure at a young age.10,15 According to the ALARA prin- ciple all effort should be made to reduce irradia- tion of the breasts using shielding. In addition to breast shielding some other radiosensitive tissues will also be protected against the external scatter radiation, particularly bone marrow (42% of bone marrow is found in the thorax).8,11 Based on the ICRP1037, bone marrow is a radiosensitive organ with the same tissue weighting factor as the breasts – 0.12, however, the effect of shielding on the bone marrow was not investigated in our study. The study was conducted on female patients and not on an anthropomorphic phantom as the study by Williams and Adams5, so the measurements were performed on real body tissue in real clinical circumstances. In addition, patient positioning and diverse body geometry of the patients influenced the shielding possibilities. Shielding in the present study was wrapped around the chest of the patient so both breasts were shielded simultaneously and not one breast only like in the study by Brnić et al.8 Wrapped-around shielding is also the routine way of shielding in CT diagnostics’ clinical practice, and not covering only one radiosensitive organ. Since shielded and unshielded measurements on the same patient could not be performed, a large sample was necessary for statistical accuracy. In total, 60 measurements of radiation dose to the breasts under the shielding were performed com- pared to the 20 measurements performed in the study by Beaconsfield et al.11 In the present study the measurements were performed in two different institutions on two different CT units with differ- ent exposure parameters. All the above contributes to the additional value of the present work. Our study has proven that the use of lead shielding significantly reduced the skin dose to the breasts. Nevertheless, special attention still needs to be payed to the positioning of the apron. The lead shielding must be positioned so it does not enter the primary field. If the shielding enters the primary field of imaging, it would produce signifi- cant image artefacts or, if the automatic exposure control is used, the system would drastically in- crease the tube output in order to compensate the absorption in lead. Caution must also be taken to wrap the shielding around the patient as tightly as possible, so there is no air gap between the chest and the shielding. This study was performed with a lead shield, which is the most commonly used form of shielding in Slovenia. New shielding materials are emerging, among them the Antimony-Bismuth shields, which FIGURE 2. Mean skin dose to breast in both hospitals with and without the shielding. Radiol Oncol 2021; 55(1): 116-120. Zalokar N and Mekis N / Breast shielding efficacy in head CT120 are positioned in the primary field and only par- tially block the beam. Further investigation could be performed. Nevertheless, the breasts are located outside the primary field so the lead shielding can be applied to reduce the scattered radiation to the breasts. This study showed that the lead shielding sig- nificantly reduced the amount of scatter radiation irradiating the breasts. The dose was reduced by a minimum of 74% and a maximum of 81%. Head CT is one of the most frequently performed CT examinations and the breasts are one of the most radiosensitive organs so patients undergoing a head CT scan will benefit significantly when lead shielding is used. Our work could be continued by investigating the efficiency of the newly emerging shielding materials, its efficiency in correlation to material thickness and the frequency of using the shielding in different departments. References 1. Akhlaghi P, Miri-Hakimabad H, Rafat-Motavalli L. Effects of shielding the radiosensitive superficial organs of ORNL pediatric phantoms on dose reduction in computed tomography. J Med Phys 2014; 39: 238-46. doi: 10.4103/0971-6203.144490 2. International Atomic Energy Agency. Radiation in everyday life. [cited 2020 Mar 20]. Available at: https://www.iaea.org/Publications/Factsheets/ English/radlife. 3. Safiullah S, Patel R, Uribe B, Spradling K, Lall C, Zhang L, et al. Prevalence of protective shielding utilization for radiation dose reduction in adult patients undergoing body scanning using computed tomography. J Endourol 2017; 31: 985-91. doi: 10.1089/end.2017.0294 4. European Commission. Radiaton protection N° 180 medical radiation ex- posure of the European population. Part 1 & Part 2; 2015. [cited 2020 mar 20]. Available at: https://ec.europa.eu/energy/content/rp-180-medical- radiation-exposure-european-population-part-1-part-2_en 5. Williams L, Adams C. Computed tomography of the head: an experimental study to investigate the effectiveness of lead shielding during three scanning protocols. Radiography 2006; 12: 143-52. doi: 10.1016/j.radi.2005.05.001 6. Pace I, Zarb F. A comparison of sequential and spiral scanning techniques in brain CT. Radiol Technol 2015; 86: 373-8. PMID: 25835403 7. Valentin EJ, Boice Jr J, Meinhold C, Alexakhin R. Annals of the ICRP Publication 103: The 2007 Recommendations of the International Commission on Radiological Protection; 2007. 8. Brnić Z, Vekić B, Hebrang A, Anić P. Efficacy of breast shielding during CT of the head. Eur Radiol 2003; 13: 2436-40. doi: 10.1007/s00330-003-1945-1 9. Sowby FD. Annals of the ICRP. Ann ICRP 1981; 6: 1. doi: 10.1016/0146- 6453(81)90127-5 10. Preston DL, Mattsson A, Holmberg E, Shore R, Hildreth NG, Boice JD. Radiation effects on breast cancer risk: a pooled analysis of eight cohorts. Radiat Res 2002; 158: 220-35. doi: 10.1667/0033-7587(2002)158[0220:reo bcr]2.0.co;2 11. Beaconsfield T, Nicholson R, Thornton A. Would thyroid and breast shielding be beneficial in CT of the head? Eur Radiol 1998; 8: 664-7. doi: 10.1007/ s003300050456 12. Ngaile JE, Uiso CBS, Msaki P, Kazema R. Use of lead shields for radiation pro- tection of superficial organs in patients undergoing head CT examinations. Radiat Prot Dosimetry 2008; 130: 490-8. doi: 10.1093/rpd/ncn095 13. Chung JJ, Cho ES, Kang SM, Yu JS, Kim DJ, Kim JH. Usefulness of a lead shield- ing device for reducing the radiation dose to tissues outside the primary beams during CT. Radiol Med 2014; 119: 951-7. doi: 10.1007/s11547-014- 0421-0 14. Zalokar N, Mekiš N. A phantom study showing the importance of breast shielding during head CT. Radiat Prot Dosimetry 2020; 186: 507-12. doi: 10.1093/rpd/ncz305 15. Cardis E, Hall J, Tavtigian SV. Identification of women with an increased risk of developing radiation-induced breast cancer. Breast Cancer Res 2007; 9: 1-9. doi: 10.1186/bcr1668 16. Mekis N, Zontar D, Skrk D. The effect of breast shielding during lumbar spine radiography. Radiol Oncol 2013; 47: 26-31. doi: 10.2478/raon-2013-0004 Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. I Radiol Oncol 2021; 55(1): 1-6. doi: 10.2478/raon-2020-0068 Umetna inteligenca v mišičnoskeletni onkološki radiologiji Vogrin M, Trojner T, Kelc R Izhodišča. Primarni kostni tumorji so razmeroma redki, zato njihova obravnava pogosto terja izkuše- nega mišičnoskeletnega radiologa. Želimo čim natančneje prepoznavati novotvorbe ter zmanjševati verjetnost človeškega dejavnika in napak, zato v zadnjih letih pospešeno razvijamo in implementiramo sisteme umetne inteligence v klinično prakso. Predstavljamo najbolj obetavne sisteme za diagnostiko primarnih in sekundarnih kostnih tumorjev ter novotvorbe dojke, pljuč in črevesja. Zaključki. Navkljub pomanjkanju dolgoročnih raziskav, ki bi potrdile učinkovitost in superiornost raču- nalniških ekspertnih sistemov, imajo le-ti velik potencial pri diagnostiki kostnih tumorjev in tumorjev mehkih tkiv. Radiol Oncol 2021; 55(1): 7-17. doi: 10.2478/raon-2020-0063 Telesna aktivnost in tveganje za pojavnost raka. Sodobna znanja in možni biološki mehanizmi Jurdana M Izhodišča. Številne raziskave potrjujejo, da telesna aktivnost zmanjša tveganje za razvoj raka. Biološki mehanizmi, ki povezujejo zaščitni vpliv telesne aktivnosti na pojavnost raka vključujejo znižanje: sistemske- ga vnetja, hiperinzulinemije, inzulinu podobnega rastnega dejavnika (IGF-I), spolnih hormonov, vnetnega leptina in drugih mediatorjev vnetja, povezanih z debelostjo. Poleg omenjenega, telesna aktivnost zvišuje vrednosti protivnetnega adiponektina, izboljša imunski odziv ter sestavo in raznolikost bakterijskih vrst, ki so del črevesne bakterijske združbe. Zmerna telesna aktivnost dokazano preprečuje tveganje za razvoj raka, večje učinke pa povezujejo s telesno aktivnostjo višje intenzivnosti. Za preprečevanje nekaterih vrst raka bodo potrebne nadaljnje raziskave o vrsti, intenzivnosti in trajanju telesne aktivnosti ter oblikovanje natančnih priporočil za posamezne vrste raka. Zaključki. Obstajajo prepričljivi dokazi, da zmerna do intenzivna telesna aktivnost ščiti pred rakom debelega črevesa in rakom dojk. Prav tako so opazni pozitivni učinki telesne aktivnosti v preventivi pred drugimi raki. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. II Radiol Oncol 2021; 55(1): 18-25. doi: 10.2478/raon-2020-0069 Klinični pomen preiskave 18F-FDG PET/CT za pooperativno spremljanje bolnikov z medularnim rakom ščitnice Šaponjski J, Macut D, Šobić Šaranović D, Radović B, Artiko V Izhodišča. Cilj raziskave je bil oceniti pomen 18-fluor deoksiglokoze (18F-FDG) pozitronske emisijske tomografije z računalniško tomografijo (PET/CT) za odkrivanje aktivne bolezni pri bolnikih s sumom na ponovitev medularnega raka ščitnice. Bolniki in metode. V obdobju od 2010 do 2019 smo preiskavo 18F-FDG PET/CT naredili pri 67 bolnikih, nato pa jih spremljali od 6 do 116 mesecev po operaciji (srednja vrednost 16,5 meseca, x_ ± standardna deviacija [SD] = 29 ± 28,9 meseca). 25 od 67 bolnikom smo opravili scintigrafijo z 99m-tehnecij dimer- kaptosucinsko kislino (99mTc-DMSA), 11 scintigrafijo somatostatinskega receptorja z 99mTc-HYNIC TOC, medtem ko smo pri 11 bolnikih opravili scintigrafijo z 123I-meta-jod-benzil-gvanidinom (123I-MIBG). Rezultati. Od 67 bolnikov je imelo 35 (52,2 %) resnično pozitivnih 18F-FDG PET/CT ugotovitev. Povprečna maksimalna standardizirana vrednost prevzema (SUVmax) za vse resnično pozitivne lezije je bila 5,01 + 3,6. Ugotovitve pri 25 (37,3 %) bolnikov so bile resnično negativne. Štirje bolniki (6 %) so imeli lažno pozi- tivne ugotovitve, trije (4,5 %) pa lažno negativne. Tako je bila občutljivost preiskave 18F-FDG PET/CT 92,11 %, specifičnost 86,21 %, pozitivna napovedna vrednost 89,74 %, negativna napovedna vrednost 89,29 % in natančnost 89,55 %. Pri 27 bolnikih (40,0 %) je ugotovitev 18F-FDG PET/CT vplivala na nadaljnje vodenje bolnika. Zaključki. 18F-FDG PET/CT ima visoko natančnost pri odkrivanju metastaz/recidivov medularnega raka ščitnice pri bolnikih po tiroidektomiji, pa tudi pri oceni učinkovitosti in izbiri ustreznega zdravljenja. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. III Radiol Oncol 2021; 55(1): 26-34. doi: 10.2478/raon-2020-0071 Radiološka ocena novonastalega glioma visoke stopnje malignosti. Proučevanje hitrosti diametričnega širjenja in pospešitvenega časa Altieri R, Certo F, La Rocca G, Melcarne A, Garbossa D, Bianchi A, Crimi S, Pluchino A, Peschillo S, Barbagallo GMV Izhodišča. Spoznavanje etiopatogeneze, fiziologije in patologije gliomov ostaja pomemben izziv so- dobne nevroonkologije. Številne raziskave so pokazale jasno povezavo med radiološkimi značilnostmi in biološkimi lastnostmi gliomov. Znano je, da je hitrost diametrične ekspanzije povezana z agresivnostjo nizko malignih gliomov. Pri visoko malignih gliomih enako močnih dokazov nimamo, saj je število predo- perativnih MRI preiskav manjše. Bolniki in metode. Predstavljamo skupino štirih bolnikov (dva moška in dve ženski) z visoko malignim gliomom, ki smo jih sledili od 2014 do januarja 2019. Dva sta imela histološko potrjen glioblastom, eden anaplastični astrocitom, en bolnik pa je imel nevroradiološko diagnozo glioblastoma. Hitrost diametrične ekspanzije in pospešitveni čas smo izračunali za prostornino tumorja in za nodul. Pri izračunu za pro- stornino tumorja smo uporabili slikanje z magnetno resonančno metodo z izločanjem signalov tekočin (angl. fluid attenuated inversion recovery, FLAIR) pri izračunu za nodul pa postkontrastni ojačani signal. Povprečen razmik med zaporednimi MRI je bil 413 dni. Rezultati. Povprečna hitrost diametrične ekspanzije za povečanje prostornine tumorja na FLAIR je bila 39,91 mm/leto. Povprečno odstotno razmerje med najvišjimi vrednostmi in povprečno vrednostjo pospe- šitve je bilo 282,7 %. Srednji čas od prve MRI do pojava postkontrastnega ojačanega signala je bil 432 dni. Povprečna hitrost diametrične ekspanzije za postkontrastni ojačani signal je bila 45,02 mm/leto, pov- prečno odstotno razmerje med najvišjimi vrednostmi in povprečno vrednostjo pospešitve pa 257,52 %. Zaključki. Po našem vedenju je to prvo poročilo o hitrosti diametrične ekspanzije in pospeševanju rasti pri visoko malignih gliomih, ki potrjuje njihovo agresivno naravo. V primerih, ko moramo ponoviti predoperativ- no MRI, je potrebno čas med zaporednimi slikanji skrajšati na največ 15–20 dni in operacijo izvesti čim prej. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. IV Radiol Oncol 2021; 55(1): 35-41. doi: 10.2478/raon-2020-0064 Volumen tumorja, izmerjen predoperativno z magnetnoresonančnim slikanjem, je povezan s preživetjem pri bolnicah z rakom endometrija Coronado PJ, de Santiago-López J, de Santiago-García J, Méndez R, Fasero M, Herraiz MA Izhodišča. Namen raziskave je bil ugotoviti, ali je tumorski volumen pri raku endometrija, izmerjen z ma- gnetnoresonančnim slikanjem, povezan s preživetjem bolnic in metastaziranjem v bezgavke. Bolnice in metode. Ocenili smo predoperativni MRI in podatke 341 bolnic z rakom endometrija, ki smo jih zdravili od leta 2008 do 2018. Z MRI smo izračunali tumorski volumen in uporabili elipsoidno formulo, ki je upoštevala tri pravokotne premere tumorja. Dodatno smo analizirali invazijo tumorja v miometrij. Rezultati. Z MRI izmerjen večji tumorski volumen je bil povezan s starostjo ≥ 65 let, ne-endometrioidni- mi tumorji, gradusom 3, globoko miometrijsko invazijo, metastaziranjem v bezgavke in napredovalim stadijem FIGO. 37 (8,8 %) bolnic je imelo metastaze v bezgavkah. Ne-endometrioidni tumorji, globoka miometrijska invazija, gradus 3 in tumorski volumen ≥ 10 cm3 so bili dejavniki povezani z metastaziranjem v bezgavke. Z analizo krivulje ROC smo postavili mejo tumorskega volumna 10 cm3 (površina pod krivuljo = 0,70; 95 % interval zaupanja [CI]: 0,61–0,73). To je meja, ki je pomembna za preživetje bolnic. Pet-letno preživetje brez bolezni (DFS) in celokupno preživetje (OS) bolnic je bilo pri magnetnoresonančnem tumor- skem volumnu ≥ 10 cm3 bistveno nižje v primerjavi s tistim pod to mejo (69,3 % proti 84,5 % in 75,4 % proti 96,1 %). Magnetnoresonančni tumorski volumen se je v multivariatni analizi izkazal kot neodvisni dejavnik za DFS (razmerje obetov [HR]: 2,20, 95 % CI: 1,09–4,45, p = 0,029) in OS (HR: 3,88, 95 % CI: 1,34–11,24, p = 0,012). Zaključki. Z MRI izmerjen tumorski volumen je bil povezan z metastaziranjem v bezgavke. Vrednost magnetnoresonančnega tumorskega volumna ≥ 10 cm3 je bila neodvisni napovedni dejavnik za DFS in OS. Informacija o z MRI izmerjenem tumorskem volumnu lahko pomaga pri načrtovanju kirurškega in dodatnega zdravljenja žensk z rakom endometrija. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. V Radiol Oncol 2021; 55(1): 42-49. doi: 10.2478/raon-2021-0003 Časovni trend preživetja bolnikov z rakom v Sloveniji Zadnik V, Žagar T, Lokar K, Tomšič S, Duratović Konjević A, Zakotnik B Izhodišča. Namen raziskave je opisati preživetje slovenskih bolnikov z rakom, diagnosticiranih v zadnjih dvajsetih letih. Prikazujemo izboljšanje preživetij pri različnih vrstah raka, populacijskih skupinah in napo- vednih dejavnikih. Metode. Osnovni vir podatkov je Register raka Republike Slovenije. V analizo preživetja smo vključili bolnike, ki jim je bila diagnoza rak postavljena med leti 1997 in 2016. Dvajsetletno obdobje smo razdelili na štiri zaporedna petletna obdobja. Poleg tega je bila analiza narejena še ločeno glede na vrsto raka, spol, starost in stadij bolezni ob diagnozi. Preživetje smo ocenili s čistim preživetjem, izračunanim po me- todi Pohar-Perme, za vključevanje podatkov pa smo uporabili popolno metodo. Rezultati. Preživetje slovenskih bolnikov z rakom se s časom povečuje. V opazovanih dvajsetih letih se je petletno čisto preživetje povečalo za 11 odstotnih točk. Znatno bolj se je izboljšalo preživetje pri moških. Starost in stadij ob diagnozi sta še vedno ključna za preživetje bolnikov z rakom. Petletno čisto preživetje je najnižje pri osebah starejših od 75 let ob diagnozi, vendar se je v zadnjih dvajsetih letih tudi pri najsta- rejših izboljšalo za sedem odstotnih točk. Petletno čisto preživetje bolnikov diagnosticiranih z omejeno boleznijo se je v dvajsetih letih povečalo za deset odstotnih točk. Preživetje bolnikov z razsejano boleznijo ob diagnozi se ni izboljševalo. Pri obeh spolih se je preživetje bolnikov z melanomom, rakom debelega črevesa in danke ter s pljučnim rakom v zadnjih dvajsetih letih značilno izboljšalo. Napredek je bil dosežen tudi pri dveh, pri vsakem na spol vezanih, najpogostejših rakih: raku dojke pri ženskah in raku prostate pri moških. Kljub vsemu pa je pomemben napredek pri raku prostate verjetno predvsem posledica pristra- nosti časa prednosti, saj je Slovenija v obdobju raziskave precej nekritično uporabljala testiranje PSA, kar je verjetno umetno podaljšalo preživetje. Zaključki. Izboljšanje preživetja slovenskih bolnikov z rakom, ki ga opazujemo v zadnjih letih, predstavlja osnovo in spodbudo za nadaljnje izboljšave. Učinkovitost obvladovanja epidemije raka je smiselno tudi v prihodnje spremljati z uporabo kakovostnih podatkov in znanstveno utemeljenih metodoloških pristopov. V tem procesu imajo ključno vlogo dobro organizirani populacijski registri raka. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. VI Radiol Oncol 2021; 55(1): 50-56. doi: 10.2478/raon-2020-0056 Zdravljenje regionalnih zasevkov kožnega melanoma. 15 let izkušenj terciarnega centra Perić B, Miličević S, Perhavec A, Hočevar M, Žgajnar J Izhodišča. Na podlagi rezultatov dveh randomiziranih prospektivnih raziskav ter razvoja dopolnilnega zdravljenja se je temeljito spremenila obravnava bolnikov s kožnim melanomom po biopsiji varovalne be- zgavke (angl. sentinel lymph node). Namen raziskave je bil primerjati retrospektivne rezultate zdravljenja slovenskih bolnikov s kožnim melanomom III. stadija s sedanjimi mednarodnimi priporočili. Bolniki in metode. Vse bolnike s kožnim melanomom stadija ≥ TIb zdravljene na Onkološkem inštitutu Ljubljana smo od leta 2000 dalje prospektivno vključevali v podatkovno bazo. Opravili smo retrospektivno analizo podatkov bolnikov zdravljenih do leta 2015. Med njimi jih je bilo 2426 takih po opravljeni biopsiji varovalne bezgavke ter 789 bolnikov po limfadenektomiji bezgavčne lože. Izrisali smo Kaplan-Meierjeve krivulje preživetja in rezultate primerjali z log-rank testom. Rezultati. Izmed 2426 bolnikov je bil zasevek v varovalni bezgavki odkrit pri 519 (519/2426, 21.4 %) bolnikih, 455 bolnikov jih je zdravljenje nadaljevalo z limfadenektomijo. Celokupna 5-letna preži- vetja glede na zasevke v regionalnih bezgavkah so bila: po dokončanju limfadenektomije 58 %, z metahronimi zasevki v bezgavkah in limfadenektomijo 47 % (p = 0,003) ter z regionalno bolezni- jo neznanega izvora 45 % in ob sinhronih regionalnih zasevkih 21 %. Celokupno preživetje bolni- kov z zasevki varovalne bezgavke < 0.3 mm je bilo primerljivo s tistimi brez zasevka (86 % vs. 85 %, p = 0,926). Bolniki s zasevkom > 1 mm so imeli preživetje primerljivo s tistimi, ki so imeli metahrone zasevke v bezgavkah (49 % vs. 47 %, p = 0.280). Zaključki. Preživetja bolnikov s III. stadijem kožnega melanoma se znatno razlikujejo. Dokončanje lim- fadenektomije po odkritju zasevka v varovalni bezgavki ostaja učinkovito zdravljenje v skrbno izbranih primerih. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. VII Radiol Oncol 2021; 55(1): 57-65. doi: 10.2478/raon-2020-0067 Sinhrona odstranitev jetrnih metastaz pri bolnikih z rakom želodca. Primerjava uravnoteženih skupin bolnikov Jagrič T, Horvat M Izhodišča. Cilj raziskave je bil ugotoviti pomen sinhronih odstranitev jetrnih metastaz pri bolnikih z oligo- metastatskim rakom želodca in določiti napovedne dejavnike za napoved poteka bolezni. Bolniki in metode. Primerjali smo rezultate sinhrone odstranitve jetrnih metastaz in želodca pri 21 bolni- kih z rakom želodca (LMR) z rezultati 21 uravnoteženih bolnikov z rakom želodca in metastazami v jetrih, kjer smo odstranili le želodec (LM0). Kot kontrolno skupino smo vključili uravnotežene bolnike z rakom želodca in stadijem III in IV brez jetrnih metastaz (CG). Rezultati. Celokupno 5-letna preživetja bolnikov skupin LMR, LM0 in CG so bila 14.3 %, 0 % in 19 % (p = 0.002). Celokupno 5-letno preživetje bolnikov z operacijo jetrnih zasevkov in dobro diferenciranim rakom želodca je bilo 47,5 %, pri bolnikih z zmerno in slabo diferenciranim rakom pa 0 % (p = 0.006). Pri bolnikih z R0 operacijo jetrnih zasevkov in s stadiji primarnega tumorja TNM N0–1 je bilo celokupno 5-letno preživetje bistveno boljše kot pri bolnikih s stadiji primarnega tumorja TNM N2–3 (5-letno preživetje: 60 % pri N0–1 in 7,7 % pri N2–3; p = 0.007). Zaključki. Rezultati raziskave podpirajo sinhrone odstranitve jetrnih zasevkov pri bolnikih z rakom želod- ca in podajajo kriterije za izbor primernih kandidatov za takšno zdravljenje. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. VIII Radiol Oncol 2021; 55(1): 66-76. doi: 10.2478/raon-2020-0070 Pooperativno obsevanje za bolnike s popolno reseciranim nedrobnoceličnim pljučnim rakom patološkega stadija IIIA-N2. Večja korist za ploščatocelični rak Tian C, Liu G, Xu Y, Xia G, Zhang T, Huang J, Jiang H, Wang J, Li B Izhodišča. Ugoden učinek pooperativnega obsevanja pri popolni patološki resekciji nedrobnocelične- ga pljučnega raka in s stadijem IIIA-N2 (pIIIA-N2) je še vedno diskutabilen. Namen raziskave je bil oceniti klinično učinkovitost pooperativnega obsevanja pri nedrobnoceličnem pljučnem raku pIIIA-N2 ločeno za žlezni rak in ploščatocelični rak. Bolniki in metode. Analizirali smo 288 zaporednih bolnikov, ki smo jih zdravili med oktobrom 2010 in septembrom 2016 v Pekinški bolnišnici. Vsem bolnikom smo radikalno operirali nedrobnocelični rak pljuč stadija pIIIA-N2. 194 bolnikov je imelo žlezni rak in 85 ploščatoceličnega. Med bolniki z žleznim rakom je bilo 42 (21,6%) zdravljenih s pooperativnim obsevanjem, med bolniki s ploščatoceličnim pa 19 (22,3%). Petletno celokupno preživetje, preživetje brez loko-regionalne ponovitve bolezni in preživetje brez od- daljenih metastaz smo izračunali z metodo Kaplan-Meier. Napovedne dejavnike smo določili z uporabo Coxovega regresijskega modela. Rezultati. Med 194 bolniki z žleznim rakom je bilo 1-, 3- in 5-letno celokupno preživetje v skupini poope- rativno obsevanih 95,2 %, 61,9 % in 40,0 %; v skupini brez pooperativnega obsevanja pa 90,1 %, 63,3 % in 45,0 % (p = 0,948). Pooperativna kemoterapija, pozitivne bezgavke v več regijah in indeks kajenja ≥ 400 so bili napovedni dejavniki petletnih preživetij tako za celokupno preživetje, kot tudi za preživetje brez loko-regionalne ponovitve bolezni in preživetje brez oddaljenih metastaz. Po drugi strani je bilo med 85 bolniki s ploščatoceličnim rakom 1-, 3- in 5- letno celokupno preživetje v skupini pooperativno obsevanih 94,7 %, 63,2 % in 63,2 %, medtem ko je bilo v skupini brez pooperativnega obsevanja 86,4 %, 48,5 % in 37,1 % (p = 0,026). V tej skupini je bila le uporaba pooperativnega obsevanja ugoden napovedni dejav- nik za 5-letno celokupno preživetje, preživetje brez loko-regionalne ponovitve bolezni in preživetje brez oddaljenih metastaz. Zaključki. Zaradi klinično-patoloških razlik med radikalno operiranimi bolniki z nedrobnoceličnim rakom pljuč stadija pIIIA-N2 verjetno pooperativno obsevanje ni primerno za vse bolnike. Pričujoča raziskava je pokazala, da bi lahko imeli bolniki s ploščatoceličnim rakom stadija pIIIA-N2 večjo korist od pooperativ- nega obsevanja kot bolniki z žleznim rakom. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. IX Radiol Oncol 2021; 55(1): 77-81. doi: 10.2478/raon-2020-0074 Z obsevanjem povezan angiosarkom v področju dojke, rekonstruirane s telesu lastnim tkivom in zdravljen z elektrokemoterapijo Cencelj-Arnež R, Novak J, Klevišar Ivančič A, Bošnjak M, Čemažar M, Snoj M Izhodišča. Z radioterapijo povezan angiosarkom dojke je redek kasni zaplet obsevanja, ki ga je pogosto težko prepoznati. Napoved bolezni je slaba. Največkrat se kaže kot vijolično obarvana koža, eritem ali hitro rastoča tipna rezistenca, ki jo lahko zamenjamo z drugimi benignimi kožnimi lezijami. Bolniki in metode. Po pregledu literature smo po mastektomiji in rekonstrukciji dojk s telesu lastnim tki- vom našli opisane le 4 takšne primere z radioterapijo povezanega angiosarkoma. Predstavljeni primer je prvi, ki prikazuje zdravljenje z elektrokemoterapijo. Predstavljamo bolnico s sekundarnim angiosarkomom dojke, pet let po mastektomiji z rekonstrukcijo dojke in dopolnilno radioterapijo. Rezultati. Elektrokemoterapija je bila izvedljiv, varen in učinkovit način zdravljenja angiosarkoma po- vezanega z obsevanjem. Večina zdravljenih lezij je v več zaporednih zdravljenjih z elektrokemoterapijo popolnoma odgovorila na zdravljenje, vendar so se na nezdravljenem področju večkrat pojavile nove lezije. Zaključki. Bolnice z rakom dojk po mastektomiji z ohranitvijo kože in takojšnjo rekonstrukcijo dojk, ki so bile obsevane, potrebujejo redno dolgotrajno spremljanje in takojšnjo biopsijo kakršnekoli sumljive lezije. Elektrokemoterapija se je izkazala kot eden izmed možnih načinov zdravljenja z radioterapijo povezane- ga angiosarkoma. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. X Radiol Oncol 2021; 55(1): 82-87. doi: 10.2478/raon-2020-0065 Klinični in volumetrični napovedniki za lokalno kontrolo bolezni po robotski stereotaktični radioterapiji možganskih matastaz. Aktivna sistemska bolezen lahko vpliva na lokalno kontrolo bolezni v možganih Blamek S, Stankiewicz M, Maciejewski B Izhodišča. Namen raziskave je bil ugotoviti povezavo med fizikalno in biološko dozo normalizirano na volumen metastatskega tumorja ter kliničnimi faktorji, ki vplivajo na lokalno kontrolo tumorja pri bolnikih z možganskimi metastazami, ki smo jih zdravili z robotsko stereotaktično radioterapijo. Bolniki in metaode. Analizirali smo skupino 69 bolnikov, ki smo jih zdravili z robotsko radiokirurgijo v ča- su med 2011 in 2026. Obsevanje je bilo enodozno ali hipofrakcionirano. Biološko učinkovito dozo (angl. biologically effective dose; BED) smo izračunali na osnovi predpostavke za razmerje alfa/beta = 10. Fizikalno dozo in BED smo normalizirali na velikost tumorja in tako omogočili analizo učinka doza-volumen. Dodatno smo analizirali klinične parametre povezane z zdravljenjem, da bi jih povezali z učinkom lokalne kontrole tumorjev. Reultati. Obsevali smo 133 tumorjev velikosti 0,001 do 46.99 cm3. Napredovanje bolezni izven glave je bilo povezano s slabšo lokalno kontrolo bolezni, med tem ko so bili višja skupna doza, BED10 > 59 Gy in posamezne mezastaze statistično značilno povezani z daljšo lokalno kontrolo. BED10/cm3 > 36 Gy in BED2 > 60 Gy sta negatvno vplivali na lokalno kontrolo bolezni. V multivariatni analizi vseh spremenljivk so prisotnost ene metastaze, BED10 > 59 Gy in napredovanje bolezni izven glave ohranili statistično značilno razliko. Če smo izključili napovednik BED2/cm3, pa so v Cox-ovem modelu tudi vse preostale spremenljiv- ke ohranile statistično zančilno povezavo z lokalno kontrolo bolezni. Zaključki. Hipofrakcionacija je imela podoben učinek, kot enodozno obasevanje pri lokalni kontroli mezastaz, je pa bil učinek obeh režimov obsevanj odvisen od BED. Učinkovita kontrola bolezni izven glave je povezana z večjo verjetnostjo lokalne kontrole bolezni, vendar je učinek veliko slabši pri multiplih lezijah. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. XI Radiol Oncol 2021; 55(1): 88-96. doi: 10.2478/raon-2020-0075 Prospektivna ocena verjetne dozno eskalirajoče intenzitetno modulirane radioterapije (IMRT) pri raku prostate Wegener D, Berger B, Outaggarts Z, Zips D, Paulsen F, Bleif M, Thorwarth D, Alber M, Dohm O, Müller AC Izhodišča. Stopnja ozdravitve in toksičnosti po intenzitetno modulirani radioterapiji (IMRT) raka prostate je odvisna od sevalne doze in obsevalnega volumna. Prospektivno smo ugotavljali možnost koncepta verjetnosti pokritja (ang. Coverage Probability, CovP) za zaščito kritičnih organov in kompenzacijo pre- mikov tumorja. Bolniki in metode. 28 bolnikov (srednja starost 70 let) z lokaliziranim rakom prostate (cT1c–2c, N0, M0) in srednje stopnje tveganja (PSA < 20, seštevek po Gleasonu ≤ 7b) smo zdravili v prospektivni raziskavi s konceptom CovP. Planirne slike CT-ja smo naredili v treh zaporednih dneh, da bi registrirati spremembe oblike ter premike prostate in kritičnih organov. Na vsakem CT-ju smo obkrožili klinični tarčni volumen (CTV, prostata) ter kritične organe (mehur in danko). Vsoti CTV1–3 smo dodali izotropni rob 7 mm, ki je opredelil notranji tarčni volumen (ITV). Predpisana/eskalirana doza je bila odvisna od pokritja vseh CTV- jev znotraj ITV-ja. Bolniki so prejeli IMRT v 39 frakcijah do 78 Gy, pri čemer smo uporabili algoritem Monte- Carlo. Priporočili smo kratkotrajno androgenska odtegnitev, ki smo jo izvedli pri 78,6 % bolnikov. Rezultati. Kasno toksičnost smo ocenili pri 26/28 bolnikih po srednjem času sledenja 7,1 let. Ob zadnjem pregledu so bili kasni neželeni učinki na mehurju (po klasifikaciji angl. Radiation Therapy Oncology Group, RTOG) G1 ugotovljeni pri 14,3 % bolnikov ter kasna črevesna toksičnost (RTOG) G1 pri 7,1 % in G2 pri 3.6% bolnikov. Toksičnost višjih stopenj se ni razvila. Po 7,1 letih je bila biokemična kontrola bolezni (biokemično brez znakov bolezni) 95,5 %, za raka prostate specifično preživetje in preživetje brez oddaljenih zasevkov pa sta bila 100%. Zaključki. IMRT, ki temelji na konceptu CovP, je izvedljiva v klinični raziskavi. Eskalacijo doze so spremljali nizka toksičnost, ter učinkovita kontrola lokalne in oddaljene bolezni. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. XII Radiol Oncol 2021; 55(1): 97-105. doi: 10.2478/raon-2020-0062 Vpliv peroralnega jemanja astaksantina na kakovost semena pri bolnikih z oligoastenoteratozoospermijo. Randomizirana dvojno slepa, s placebom kontrolirana raziskava Imamović Kumalić S, Virant Klun I, Vrtačnik Bokal E, Pinter B Izhodišča. Višje koncentracije reaktivnih kisikovih spojih so lahko vzrok za moško neplodnost. Astaksantin z močnim antioksidativnim delovanjem ima potencialno zdravju koristne učinke za preprečevanje in zdravljenje različnih bolezni, tudi raka. Vpliv astaksantina na kakovost semenčic pri neplodnih moških s slabo kakovostjo semena, vključno z oligo- z/brez asteno- z/brez teratozoospermijo (O±A±T) doslej še ni bila raziskovan. Namen raziskave je bil preučiti vpliv peroralnega jemanja astaksantina na kakovost semena. Bolniki in metode. V klinično prospektivno randomizirano dvojno slepo raziskavo smo vključili 80 moških, pri katerih je bila diagnosticirana O±A±T in so jemali bodisi 16 mg astaksantina ali placebo. Ob vstopu v raziskavo in po treh mesecih jemanja zdravila ali placeba smo pri vseh bolnikih določili parame- tre spermiograma, mitohondrijski membranski potencial semenčic, fragmentacijo deoksiribonukleinske kisline (DNK) semenčic in nivo folikle stimulirajočega hormona (FSH) v serumu. Rezultati. Analiza rezultatov 72 preiskovancev, ki so zaključili raziskavo (37 v študijski skupini in 35 v kontrolni skupini) ni pokazala statistično pomembnih razlik. V študijski skupini nismo ugotovili sprememb v koncentraciji semenčic, skupnem številu semenčic, skupni gibljivosti semenčic, morfologiji semenčic, mitohondrijskem membranskem potencialu semenčic, fragmentaciji DNK ali v serumskih nivojih FSH. V kontrolni skupini smo našli statistično pomembne spremembe v koncentraciji semenčic in v skupnem številu semenčic. Zaključki. Peroralno jemanje astaksantina ni vplivalo na nobenega od parametrov kakovosti semena pri pacientih z O±A±T. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. XIII Radiol Oncol 2021; 55(1): 106-115. doi: 10.2478/raon-2020-0073 Delno nadzorovana načrtovalna metoda za obsevanje dojk ob upoštevanju njihovega polmera in medsebojne razdalje ter elektronske kompenzacije tkiva Podgoršak AR, Kumaraswamy LK Izhodišča. Namen raziskave je bil razviti in oceniti tehniko za optimiziranje obsevalnih načrtov za obse- vanje dojk, ki temelji na polmeru dojk in na njuni medsebojni razdalji, upoštevaje elektronsko kompen- zacijo tkiva. Bolnice in metode. Za raziskavo smo uporabili deset obsevalnih načrtov za obsevanje dojk, izdelanih na našem inštitutu, pri čemer smo upoštevali elektronsko kompenzacijo tkiva. Za oceno polmera dojk in določitev medsebojno razdalje med dojkama smo uporabili aksialne reze simulacijskih računalniškoto- mografskih slik. Vse uporabljene podatke smo predhodno anonimizirali. Optimalni obsevalni načrt smo določili na podlagi medsebojne razdalje med dojkama in polmera dojke ter fluenčne mape za vsa obsevalna polja. Fluenčne mape smo uvozili v načrtovalni sistem Eclipse in jih uporabili za izračun dozne porazdelitve. Izračunano dozno porazdelitev smo primerjali z dozno porazdelitvijo pri obsevalnem načrtu, ki ga je izdelal dozimetrist z ročno optimizacijo. Za primerjavo obsevalnih načrtov smo uporabili indeks dozne homogenosti HI, pri čemer smo upoštevali, da je nižja vrednost HI boljša. Rezultati. Primerjava povprečnih vrednosti HI desetih obsevalnih načrtov ni pokazala pomembnih razlik (p-vrednost > 0,05) med našim algoritmom (HI = 12,6) in obsevalnimi načrti, ki jih je izdelal dozimetrist (HI = 9,9). Ob uporabi delno nadzorovanega algoritma smo za izdelavo obsevalnega načrta potrebovali približno 20 sekund, medtem ko je dozimetrist potreboval 30 minut za izdelavo optimiziranega obseval- nega načrta. Zaključki. Raziskava nakazuje potencialno klinično uporabnost opisane tehnike optimizacije obseval- nih načrtov z upoštevanjem elektronske kompenzacije tkiva. Slovenian abstracts Radiol Oncol 2021; 55(1): I-XIV. XIV Radiol Oncol 2021; 55(1): 116-120. doi: 10.2478/raon-2020-0044 Vpliv uporabe svinčene zaščite na sevalno dozo, ki jo prejmejo dojke med slikanjem glave z računalniško tomografijo Zalokar N, Mekiš N Izhodišča. Med računalniško tomografijo (CT) glave dojke niso v primarnem polju slikanja, vendar so izpostavljene dozi sipanega sevanja. Namen raziskave je bil ugotoviti, ali uporaba svinčene zaščite po- membno vpliva na prejeto dozo na dojke med slikanjem glave s CT-jem v dveh slovenskih bolnišnicah. Pacientke in metode. V raziskavo smo vključili 120 pacientk, polovico (n = 60) iz bolnišnice A in polo- vico iz bolnišnice B. Uporabili smo dva različna CT aparata s spiralno tehniko slikanja. Polovico meritev smo izvedli brez uporabe svinčene zaščite, polovico meritev pa s svinčeno zaščito 0,5 mm ekvivalentne debeline svinca, ki smo jo ovili okoli trupa pacientke. Za merjenje doze smo uporabili elektronski dozime- ter EDD 30. Rezultati. Kožna doza na dojke se je ob uporabi svinčene zaščite statistično značilno pomembno zni- žala v obeh bolnišnicah. V bolnišnici A za 81 % (iz 338,2 ± 43,7 µGy na 64,3 ± 18,8 µGy), v bolnišnici B pa za 74 % (iz 253,1 ± 35,1 µGy na 65,3 ± 16,9 µGy). Zaključki. Glede na visoko povprečno statistično značilno znižanje sevalne doze na dojke (78 %), ško- dljive učinke ionizirajočega sevanja, vedno bolj pogostih doznoobremenjujočih slikanj glave s CT-jem in visoko občutljivost dojk na učinke ionizirajočega sevanja priporočamo uporabo svinčene zaščite med slikanjem glave s CT-jem. Fundacija "Docent dr. J. Cholewa" je neprofitno, neinstitucionalno in nestrankarsko združenje posameznikov, ustanov in organizacij, ki želijo materialno spodbujati in poglabljati raziskovalno dejavnost v onkologiji. Dunajska 106 1000 Ljubljana IBAN: SI56 0203 3001 7879 431 Activity of "Dr. J. Cholewa" Foundation for Cancer Research and Education – a report for the first quarter of 2021 Doc. Dr. Josip Cholewa Foundation for cancer research and education continues with its planned ac- tivities in the first quarter of 2021 and is commencing to prepare for the activities the whole year. Its primary focus remains the provision of grants and scholarships and other forms of financial assistance for basic, clinical and public health research in the field of oncology. An analysis of the ongoing activi- ties in the last year was made in order to make an assessment of the impact of Foundation's activities, thus providing a basis for developing new strategies and approaches in its scope of fight against cancer. The Foundation continues to provide support for »Radiology and Oncology«, a quarterly scientific magazine with a respectable impact factor that publishes research and review articles about all aspects of cancer. The magazine is edited and published in Ljubljana, Slovenia. »Radiology and Oncology« is an open access journal available to everyone free of charge. Its long tradition represents a guarantee for the continuity of international exchange of ideas and research results in the field of oncology for all in Slovenia that are interested and involved in helping people affected by many different aspects of cancer. The Foundation makes great efforts to provide financial and other kinds of support for the organisation of various forms of meetings to extend and broaden the knowledge about prevention of cancer, early detection of various types of cancer, its treatment and rehabilitation of cancer patients. The advances in knowledge of all aspects of dealing with cancer should be in Foundation's opinion available to all the professionals that treat cancer patients, to the patients themselves and their closest relatives and friends, and finally also to the general public. The problems associated with cancer affect more and more people and their relatives in Slovenia and elsewhere. The Foundation will therefore continue with its activities in the years to come. Treatment of cancer is ever more successful with many patients surviving decades after the start of their treatment and many new problems and challenges have thus come into place. Longer survival of an increasing number of patients with previously incurable cancer conditions adds many new dimensions to their life and to the life of their families. It also confronts cancer specialists, all the other experts and lay public dealing with cancer with new challenges and new goals to achieve. Andrej Plesničar, M.D., M.Sc. Viljem Kovač M.D., Ph.D. Borut Štabuc, M.D., Ph.D. Za lajšanje bolečine in oteklin v ustni votlini in žrelu, ki so posledica radiomukozitisa PR /B SI /B EN /2 01 9/ 01 2 Bistvene informacije iz Povzetka glavnih značilnosti zdravila Tantum Verde 1,5 mg/ml oralno pršilo, raztopina Tantum Verde 3 mg/ml oralno pršilo, raztopina Sestava 1,5 mg/ml: 1 ml raztopine vsebuje 1,5 mg benzidaminijevega klorida, kar ustreza 1,34 mg benzidamina. V enem razpršku je 0,17 ml raztopine. En razpršek vsebuje 0,255 mg benzidaminijevega klorida, kar ustreza 0,2278 mg benzidamina. Sestava 3 mg/ml: 1 ml raztopine vsebuje 3 mg benzidaminijevega klorida, kar ustreza 2,68 mg benzidamina. V enem razpršku je 0,17 ml raztopine. En razpršek vsebuje 0,51 mg benzidaminijevega klorida, kar ustreza 0,4556 mg benzidamina. Terapevtske indikacije: Samozdravljenje: Lajšanje bolečine in oteklin pri vnetju v ustni votlini in žrelu, ki so lahko posledica okužb in stanj po operaciji. Po nasvetu in navodilu zdravnika: Lajšanje bolečine in oteklin v ustni votlini in žrelu, ki so posledica radiomukozitisa. Odmerjanje in način uporabe: Odmerjanje 1,5 mg/ml: Odrasli: 4 do 8 razprškov 2- do 6-krat na dan (vsake 1,5 do 3 ure). Pediatrična populacija: Mladostniki, stari od 12 do 18 let: 4-8 razprškov 2- do 6-krat na dan. Otroci od 6 do 12 let: 4 razprški 2- do 6-krat na dan. Otroci, mlajši od 6 let: 1 razpršek na 4 kg telesne mase; do največ 4 razprške 2- do 6-krat na dan. Odmerjanje 3 mg/ml: Uporaba 2- do 6-krat na dan (vsake 1,5 do 3 ure). Odrasli: 2 do 4 razprški 2- do 6-krat na dan. Pediatrična populacija: Mladostniki, stari od 12 do 18 let: 2 do 4 razprški 2- do 6-krat na dan. Otroci od 6 do 12 let: 2 razprška 2- do 6-krat na dan. Otroci, mlajši od 6 let: 1 razpršek na 8 kg telesne mase; do največ 2 razprška 2- do 6-krat na dan. Starejši bolniki, bolniki z jetrno okvaro in bolniki z ledvično okvaro: Uporabo oralnega pršila z benzidaminijevim kloridom se svetuje pod nadzorom zdravnika. Način uporabe: Za orofaringealno uporabo. Zdravilo se razprši v usta in žrelo. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Posebna opozo- rila in previdnostni ukrepi: Če se simptomi v treh dneh ne izboljšajo, se mora bolnik posvetovati z zdravnikom ali zobozdravnikom, kot je primerno. Benzidamin ni priporočljiv za bolnike s preobčutljivostjo nasalicilno kislino ali druga nesteroidna protivnetna zdravila. Pri bolnikih, ki imajo ali so imeli bronhialno astmo, lahko pride do bronhospazma, zato je potrebna previdnost. To zdravilo vsebuje majhne količine etanola (alkohola), in sicer manj kot 100 mg na odmerek. To zdravilo vsebuje metilpar- ahidroksibenzoat (E218). Lahko povzroči alergijske reakcije (lahko zapoznele). Zdravilo z jakostjo 3 mg/ml vsebuje makrogolglicerol hidroksistearat 40. Lahko povzroči želodčne težave in drisko. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Študij medsebojnega delovanja niso izvedli. Nosečnost in dojenje: O uporabi benzidamina pri nosečnicah in doječih ženskah ni zadostnih podatkov. Uporaba zdravila med nosečnostjo in dojenjem ni priporočljiva. Vpliv na sposobnost vožnje in upravljanja strojev: Zdravilo v priporočenem odmerku nima vpliva na sposobnost vožnje in upravljanja strojev. Neželeni učinki: Neznana pogostnost (ni mogoče oceniti iz razpoložljivih podatkov): anafilaktične reakcije, preobčutljivostne reakcije, odrevenelost, laringospazem, suha usta, navzea in bruhanje, angioedem, fotosenzitivnost, pekoč občutek v ustih. Neposredno po uporabi se lahko pojavi občutek odrevenelosti v ustih in v žrelu. Ta učinek se pojavi zaradi načina delovanja zdravila in po kratkem času izgine. Način in režim izdaje zdravila: BRp-Izdaja zdravila je brez recepta v lekarnah in specializiranih prodajalnah. Imetnik dovoljenja za promet: Aziende Chimiche Riunite Angelini Francesco – A.C.R.A.F. S.p.A., Viale Amelia 70, 00181 Rim, Italija Datum zadnje revizije besedila: 14. 10. 2019 Pred svetovanjem ali izdajo preberite celoten Povzetek glavnih značilnosti zdravila. Samo za strokovno javnost. Datum priprave informacije: november 2019 Odgovoren za trženje: Bonifar d.o.o. C M Y CM MY CY CMY K Tantum_Verde_Radiology&Oncology-final-corr06.11._Version_3_PRINT.pdf 3 08/11/2019 14:35 References: 1. Keytruda EU SmPC SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih značilnosti zdravila! Ime zdravila: KEYTRUDA 25 mg/ml koncentrat za raztopino za infundiranje vsebuje pembrolizumab. Terapevtske indikacije: Zdravilo KEYTRUDA je kot samostojno zdravljenje indicirano za zdravlje- nje: napredovalega (neoperabilnega ali metastatskega) melanoma pri odraslih; za adjuvantno zdravljenje odraslih z melanomom v stadiju III, ki se je razširil na bezgavke, po popolni kirurški odstranitvi; metastatskega nedrobnoceličnega pljučnega raka (NSCLC) v prvi liniji zdravljenja pri odraslih, ki imajo tumorje z ≥ 50 % izraženostjo PD-L1 (TPS) in brez pozitivnih tumorskih mutacij EGFR ali ALK; lokalno napredovalega ali metastatskega NSCLC pri odraslih, ki imajo tumorje z ≥ 1 % izraženostjo PD-L1 (TPS) in so bili predhodno zdravljeni z vsaj eno shemo kemoterapije, bolniki s pozitivnimi tumorskimi mutacijami EGFR ali ALK so pred prejemom zdravila KEYTRUDA morali prejeti tudi tarčno zdravljenje; odraslih bolnikov s ponovljenim ali neodzivnim klasičnim Hodgkino- vim limfomom (cHL), pri katerih avtologna presaditev matičnih celic (ASCT) in zdravljenje z brentu- ksimabom vedotinom (BV) nista bila uspešna, in odraslih bolnikov, ki za presaditev niso primerni, zdravljenje z BV pa pri njih ni bilo uspešno; lokalno napredovalega ali metastatskega urotelijskega raka pri odraslih, predhodno zdravljenih s kemoterapijo, ki je vključevala platino; lokalno napredova- lega ali metastatskega urotelijskega raka pri odraslih, ki niso primerni za zdravljenje s kemoterapijo, ki vsebuje cisplatin in imajo tumorje z izraženostjo PD-L1 ≥ 10, ocenjeno s kombinirano pozitivno oceno (CPS); ponovljenega ali metastatskega ploščatoceličnega raka glave in vratu (HNSCC) pri odraslih, ki imajo tumorje z ≥ 50 % izraženostjo PD-L1 (TPS), in pri katerih je bolezen napredovala med zdravljenjem ali po zdravljenju s kemoterapijo, ki je vključevala platino. Zdravilo KEYTRUDA je kot samostojno zdravljenje ali v kombinaciji s kemoterapijo s platino in 5-fluorouracilom (5-FU) indicirano za prvo linijo zdravljenja metastatskega ali neoperabilnega ponovljenega ploščatocelič- nega raka glave in vratu pri odraslih, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 1. Zdravilo KEYTRUDA je v kombinaciji s pemetreksedom in kemoterapijo na osnovi platine indicirano za prvo linijo zdravljenja metastatskega neploščatoceličnega NSCLC pri odraslih, pri katerih tumorji nimajo pozitivnih mutacij EGFR ali ALK; v kombinaciji s karboplatinom in bodisi paklitakselom bodisi nab- -paklitakselom je indicirano za prvo linijo zdravljenja metastatskega ploščatoceličnega NSCLC pri odraslih; v kombinaciji z aksitinibom je indicirano za prvo linijo zdravljenja napredovalega raka ledvič- nih celic (RCC) pri odraslih. Odmerjanje in način uporabe: Testiranje PD-L1 pri bolnikih z NSCLC, urotelijskim rakom ali HNSCC: Za samostojno zdravljenje z zdravilom KEYTRUDA je priporočljivo opraviti testiranje izraženosti PD-L1 tumorja z validirano preiskavo, da izberemo bolnike z NSCLC ali predhodno nezdravljenim urotelijskim rakom. Bolnike s HNSCC je treba za samostojno zdravljenje z zdravilom KEYTRUDA ali v kombinaciji s kemoterapijo s platino in 5-fluorouracilom (5-FU) izbrati na podlagi izraženosti PD-L1, potrjene z validirano preiskavo. Odmerjanje: Priporočeni odmerek zdravila KEYTRUDA za samostojno zdravljenje je bodisi 200 mg na 3 tedne ali 400 mg na 6 tednov, apliciran z intravensko infuzijo v 30 minutah. Priporočeni odmerek za kombinirano zdravljenje je 200 mg na 3 tedne, apliciran z intravensko infuzijo v 30 minutah. Za uporabo v kombinaciji glejte povzetke glavnih značilnosti sočasno uporabljenih zdravil. Če se uporablja kot del kombiniranega zdravljenja skupaj z intravensko kemoterapijo, je treba zdravilo KEYTRUDA aplicirati prvo. Bolnike je treba zdraviti do napredovanja bolezni ali nesprejemljivih toksičnih učinkov. Pri adjuvantnem zdra- vljenju melanoma je treba zdravilo uporabljati do ponovitve bolezni, pojava nesprejemljivih toksičnih učinkov oziroma mora zdravljenje trajati do enega leta. Če je aksitinib uporabljen v kombinaciji s pembrolizumabom, se lahko razmisli o povečanju odmerka aksitiniba nad začetnih 5 mg v presledkih šest tednov ali več. Pri bolnikih starih ≥ 65 let, bolnikih z blago do zmerno okvaro ledvic, bolnikih z blago okvaro jeter prilagoditev odmerka ni potrebna. Odložitev odmerka ali ukinitev zdravljenja: Zmanjšanje odmerka zdravila KEYTRUDA ni priporočljivo. Za obvladovanje neželenih učinkov je treba uporabo zdravila KEYTRUDA zadržati ali ukiniti, prosimo, glejte celoten Povzetek glavnih značilnosti zdravila. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Povzetek posebnih opozoril, previdnostnih ukrepov, interakcij in neželenih učinkov: Imunsko pogojeni neželeni učinki (pnevmonitis, kolitis, hepatitis, nefritis, endokrinopatije, neželeni učinki na kožo in drugi): Pri bolnikih, ki so prejemali pembrolizumab, so se pojavili imunsko pogojeni neželeni učinki, vključno s hudimi in smrtnimi primeri. Večina imunsko pogojenih neželenih učinkov, ki so se pojavili med zdravljenjem s pembrolizumabom, je bila reverzibilnih in so jih obvladali s prekinitvami uporabe pembrolizumaba, uporabo kortikosteroidov in/ali podporno oskrbo. Pojavijo se lahko tudi po zadnjem odmerku pembrolizumaba in hkrati prizadanejo več organskih sistemov. V primeru suma na imunsko pogojene neželene učinke je treba poskrbeti za ustrezno oceno za potrditev etiologije oziro- ma izključitev drugih vzrokov. Glede na izrazitost neželenega učinka je treba zadržati uporabo pem- brolizumaba in uporabiti kortikosteroide – za natančna navodila, prosimo, glejte Povzetek glavnih značilnosti zdravila Keytruda. Zdravljenje s pembrolizumabom lahko poveča tveganje za zavrnitev pri prejemnikih presadkov čvrstih organov. Pri bolnikih, ki so prejemali pembrolizumab, so poročali o hudih z infuzijo povezanih reakcijah, vključno s preobčutljivostjo in anafilaksijo. Pembrolizumab se iz obtoka odstrani s katabolizmom, zato presnovnih medsebojnih delovanj zdravil ni pričakovati. Uporabi sistemskih kortikosteroidov ali imunosupresivov pred uvedbo pembrolizumaba se je treba izogibati, ker lahko vplivajo na farmakodinamično aktivnost in učinkovitost pembrolizumaba. Vendar pa je kortikosteroide ali druge imunosupresive mogoče uporabiti za zdravljenje imunsko pogojenih neželenih učinkov. Kortikosteroide je mogoče uporabiti tudi kot premedikacijo, če je pembrolizumab uporabljen v kombinaciji s kemoterapijo, kot antiemetično profilakso in/ali za ublažitev neželenih učinkov, povezanih s kemoterapijo. Ženske v rodni dobi morajo med zdravljenjem s pembrolizuma- bom in vsaj še 4 mesece po zadnjem odmerku pembrolizumaba uporabljati učinkovito kontracepcijo, med nosečnostjo in dojenjem se ga ne sme uporabljati. Varnost pembrolizumaba pri samostojnem zdravljenju so v kliničnih študijah ocenili pri 5.884 bolnikih z napredovalim melanomom, kirurško odstranjenim melanomom v stadiju III (adjuvantno zdravlje- nje), NSCLC, cHL, urotelijskim rakom ali HNSCC s štirimi odmerki (2 mg/kg na 3 tedne, 200 mg na 3 tedne in 10 mg/kg na 2 ali 3 tedne). V tej populaciji bolnikov je mediani čas opazovanja znašal 7,3 mesece (v razponu od 1 dneva do 31 mesecev), najpogostejši neželeni učinki zdravljenja s pembro- lizumabom so bili utrujenost (32 %), navzea (20 %) in diareja (20 %). Večina poročanih neželenih učinkov pri samostojnem zdravljenju je bila po izrazitosti 1. ali 2. stopnje. Najresnejši neželeni učinki so bili imunsko pogojeni neželeni učinki in hude z infuzijo povezane reakcije. Varnost pembrolizuma- ba pri kombiniranem zdravljenju s kemoterapijo so ocenili pri 1.067 bolnikih NSCLC ali HNSCC, ki so v kliničnih študijah prejemali pembrolizumab v odmerkih 200 mg, 2 mg/kg ali 10 mg/kg na vsake 3 tedne. V tej populaciji bolnikov so bili najpogostejši neželeni učinki naslednji: anemija (50 %), navzea (50 %), utrujenost (37 %), zaprtost (35%), diareja (30 %), nevtropenija (30 %), zmanjšanje apetita (28 %) in bruhanje (25 %). Pri kombiniranem zdravljenju s pembrolizumabom je pri bolnikih z NSCLC pojavnost neželenih učinkov 3. do 5. stopnje znašala 67 %, pri zdravljenju samo s kemoterapijo pa 66 %, pri kombiniranem zdravljenju s pembrolizumabom pri bolnikih s HNSCC 85 % in pri zdravljenju s kemoterapijo v kombinaciji s cetuksimabom 84 %. Varnost pembrolizumaba v kombinaciji z aksiti- nibom so ocenili v klinični študiji pri 429 bolnikih z napredovalim rakom ledvičnih celic, ki so prejemali 200 mg pembrolizumaba na 3 tedne in 5 mg aksitiniba dvakrat na dan. V tej populaciji bolnikov so bili najpogostejši neželeni učinki diareja (54 %), hipertenzija (45 %), utrujenost (38 %), hipotiroidizem (35 %), zmanjšan apetit (30 %), sindrom palmarno-plantarne eritrodisestezije (28 %), navzea (28 %), zvišanje vrednosti ALT (27 %), zvišanje vrednosti AST (26 %), disfonija (25 %), kašelj (21 %) in zaprtost (21 %). Pojavnost neželenih učinkov 3. do 5. stopnje je bila med kombiniranim zdravljenjem s pembrolizumabom 76 % in pri zdravljenju s sunitinibom samim 71 %. Za celoten seznam neželenih učinkov, prosimo, glejte celoten Povzetek glavnih značilnosti zdravila Način in režim izdaje zdravila: H – Predpisovanje in izdaja zdravila je le na recept, zdravilo se uporablja samo v bolnišnicah. Imetnik dovoljenja za promet z zdravilom: Merck Sharp & Dohme B.V. , Waarderweg 39, 2031 BN Haarlem, Nizozemska. Merck Sharp & Dohme inovativna zdravila d.o.o., Šmartinska cesta 140, 1000 Ljubljana, tel: +386 1/ 520 42 01, fax: +386 1/ 520 43 50 Pripravljeno v Sloveniji, September 2020; SI-KEY-00145 EXP: 09/2022 Samo za strokovno javnost. H - Predpisovanje in izdaja zdravila je le na recept, zdravilo pa se uporablja samo v bolnišnicah. Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih značilnosti zdravila Keytruda, ki je na voljo pri naših strokovnih sodelavcih ali na lokalnem sedežu družbe. (pembrolizumab, MSD) Melanom1 Hodgkinov limfom1 Nedrobnocelični pljučni rak1 Rak ledvičnih celic1 Ploščatocelični karcinom glave in vratu1 Urotelijski karcinom1 Razvrščeno na listo bolnišničnih zdravil Ime zdravila: Polivy 30 mg prašek za koncentrat za raztopino za infundiranje in Polivy 140 mg prašek za koncentrat za raztopino za infundiranje. Kakovostna in količinska sestava: Polivy 30 mg: Ena viala s praškom za koncentrat za raztopino za infundiranje vsebuje 30 mg polatuzumaba vedotina. Po rekonstituciji en mililiter vsebuje 20 mg polatuzumaba vedotina. Polivy 140 mg: Ena viala s praškom za koncentrat za raztopino za infundiranje vsebuje 140 mg polatuzumaba vedotina. Po rekonstituciji en mililiter vsebuje 20 mg polatuzumaba vedotina. Polatuzumab vedotin je konjugat protitelesa in zdravila, sestavljen iz antimitotičnega sredstva monometil-avristatina E (MMAE), kovalentno konjugiranega na monoklonsko protitelo, ki je usmerjeno proti CD79b. Terapevtske indikacije: Zdravilo Polivy je v kombinaciji z bendamustinom in rituksimabom indicirano za zdravljenje odraslih bolnikov z difuznim velikoceličnim limfomom B (DVCLB), ki se na prejšnje zdravljenje niso odzvali ali pa se je bolezen pri njih ponovila in niso primerni za presaditev krvotvornih matičnih celic. Odmerjanje in način uporabe: Odmerjanje: Priporočeni odmerek zdravila Polivy je 1,8 mg/kg v intravenski infuziji na 21 dni v kombinaciji z bendamustinom in rituksimabom v trajanju 6 ciklov. Način uporabe: Zdravilo Polivy je namenjeno intravenski uporabi. Začetni odmerek zdravila Polivy je treba dati v 90-minutni intravenski infuziji. Bolnike je treba med infundiranjem in vsaj še 90 minut po končani infuziji začetnega odmerka nadzorovati glede reakcij, povezanih z infundiranjem in preobčutljivostnih reakcij. Če je bolnik prejšnje infundiranje dobro prenesel, je mogoče nadaljnje odmerke zdravila Polivy dati v 30-minutni infuziji, bolnika pa je treba nadzirati med infundiranjem in vsaj še 30 minut po končani infuziji. Zdravilo Polivy je treba rekonstituirati in razredčiti z upoštevanjem aseptičnega postopka in pod nadzorom zdravstvenega delavca. Treba ga je aplicirati v intravenski infuziji po namenski infuzijski liniji, opremljeni s sterilnim nepirogenim filtrom, ki malo veže beljakovine in s katetrom. Zdravila Polivy se ne sme aplicirati kot hiter intravenski odmerek ali bolus. Previdnostni ukrepi, potrebni pred ravnanjem z zdravilom ali dajanjem zdravila: Zdravilo Polivy vsebuje citotoksično komponento, ki je kovalentno vezana na monoklonsko protitelo. Upoštevajte ustrezen postopek za ravnanje in odstranjevanje. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Posebna opozorila in previdnostni ukrepi: Sledljivost: Z namenom izboljšanja sledljivosti bioloških zdravil je treba jasno zabeležiti ime in številko serije uporabljenega zdravila. Mielosupresija: Pri bolnikih, zdravljenih z zdravilom Polivy, so poročali o resni in hudi nevtropeniji in febrilni nevtropeniji že v prvem ciklu zdravljenja. Treba je razmisliti o profilaktični uporabi granulocitnega rastnega dejavnika (G-CSF), saj je bila med kliničnim razvojem zdravila potrebna njegova uporaba. Med uporabo zdravila Polivy se lahko pojavi tudi trombocitopenija ali anemija 3. ali 4. stopnje. Pred vsakim odmerkom zdravila Polivy je treba kontrolirati celotno krvno sliko. Pri bolnikih z nevtropenijo in/ali trombocitopenijo 3. ali 4. stopnje je treba pretehtati opravljanje pogostejših laboratorijskih kontrol in/ali odložitev ali ukinitev uporabe zdravila Polivy. Periferna nevropatija: Pri bolnikih, zdravljenih z zdravilom Polivy, so poročali o periferni nevropatiji že v prvem ciklu zdravljenja; tveganje se povečuje z zaporednimi odmerki. Bolnikom z že obstoječo periferno nevropatijo se nevropatija lahko poslabša. Bolnike je treba nadzorovati glede simptomov periferne nevropatije. Bolnikom, pri katerih se pojavi novonastala periferna nevropatija ali se poslabša obstoječa periferna nevropatija, bo morda treba odmerek zdravila Polivy odložiti, zmanjšati ali uporabo zdravila Polivy ukiniti. Okužbe: Pri bolnikih, zdravljenih z zdravilom Polivy, so poročali o resnih, življenje ogrožajočih ali smrtnih okužbah, vključno z oportunističnimi okužbami. Poročali so tudi o ponovni aktivaciji latentnih okužb. Bolnike je treba med zdravljenjem skrbno nadzorovati glede znakov bakterijskih, glivnih ali virusnih okužb; če se pojavijo znaki in simptomi okužbe, mora bolnik poiskati zdravniško pomoč. Razmisliti je treba o profilaksi z zdravili proti okužbam v celotnem obdobju zdravljenja z zdravilom Polivy. Zdravila Polivy se ob prisotnosti aktivne hude okužbe ne sme aplicirati. Pri bolnikih, pri katerih se pojavijo resne okužbe, je treba ukiniti zdravilo Polivy in sočasno kemoterapijo. Imunizacija: Sočasno z zdravljenjem se bolnikom ne sme dajati živih in živih oslabljenih cepiv. Progresivna multifokalna levkoencefalopatija (PML): Med zdravljenjem z zdravilom Polivy so poročali o pojavu PML. Bolnike je treba skrbno nadzorovati glede novonastalih nevroloških, kognitivnih ali vedenjskih sprememb, ki nakazujejo na PML, oziroma glede poslabšanja takšnih sprememb. V primeru suma na PML je treba uporabo zdravila Polivy in morebitne sočasne kemoterapije odložiti, v primeru potrjene diagnoze pa ukiniti. Sindrom razpada tumorja: Bolniki z velikim tumorskim bremenom in hitro proliferirajočim tumorjem imajo lahko večje tveganje za sindrom razpada tumorja. Pred zdravljenjem z zdravilom Polivy je treba uporabiti ustrezne profilaktične ukrepe v skladu z lokalnimi smernicami. Bolnike je treba med zdravljenjem z zdravilom Polivy skrbno spremljati glede pojava sindroma razpada tumorja. Reakcije, povezane z infundiranjem: Zdravilo Polivy lahko povzroči reakcije, povezane z infundiranjem, vključno s hudimi primeri. Zapoznele reakcije, povezane z infundiranjem, so se pojavile tudi 24 ur po prejetju zdravila Polivy. Pred zdravilom Polivy je treba aplicirati antihistaminik in antipiretik in skrbno spremljati bolnike ves čas infundiranja. Če se pojavi reakcija, povezana z infundiranjem, infundiranje prekinite in ustrezno ravnajte oziroma zdravite. Embrio-fetalna toksičnost: Glede ne mehanizem delovanja in rezultate predkliničnih študij lahko pri nosečnici uporabljeno zdravilo Polivy škoduje plodu. Nosečnicam je treba svetovati glede tveganja za plod. Ženskam v rodni dobi je treba svetovati, naj uporabljajo učinkovito kontracepcijo med zdravljenjem z zdravilom Polivy in še vsaj 9 mesecev po zadnjem odmerku. Moškim, ki imajo partnerke v rodni dobi, je treba svetovati, naj uporabljajo učinkovito kontracepcijo med zdravljenjem z zdravilom Polivy in še vsaj 6 mesecev po zadnjem odmerku. Plodnost: Za moške, ki se bodo zdravili z zdravilom Polivy, je priporočljivo pred zdravljenjem shraniti seme. Starejši bolniki: Bolniki, stari 65 let ali več, so imeli podobno incidenco resnih neželenih učinkov kot bolniki, mlajši od 65 let. Klinične študije z zdravilom Polivy niso vključevale zadostnega števila bolnikov, starih 65 let ali več, da bi lahko določili, ali se odzovejo drugače od mlajših bolnikov. Hepatotoksičnost: Pri bolnikih, zdravljenih z zdravilom Polivy, so se pojavili resni primeri hepatotoksičnosti. Predhodna bolezen jeter, izhodiščno zvišani jetrni encimi in uporaba sočasnih zdravil lahko tveganje povečajo. Kontrolirati je treba raven jetrnih encimov in bilirubina. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Namenskih kliničnih študij medsebojnega delovanja zdravil s polatuzumabom vedotinom pri človeku niso izvedli. Pri sočasnem zdravljenju z zaviralcem CYP3A4 je potrebna previdnost. Bolnike, ki sočasno prejemajo močne zaviralce CYP3A4, je treba skrbneje nadzorovati glede znakov toksičnosti. Močni induktorji CYP3A4 lahko zmanjšajo izpostavljenost nekonjugiranemu MMAE. Sočasna uporaba polatuzumaba vedotina ne vpliva na farmakokinetiko rituksimaba in bendamustina. Neželeni učinki: Najpogosteje zabeleženi neželeni učinki pri bolnikih, zdravljenih z zdravilom Polivy v kombinaciji z BR, so bili anemija, trombocitopenija, nevtropenija, driska, navzea in periferna nevropatija. O resnih neželenih učinkih so poročali pri 42,4 % bolnikov, zdravljenih z zdravilom Polivy in BR. Najbolj pogosti neželeni resni učinki, o katerih so poročali pri > 5 % bolnikov, so bili febrilna nevtropenija, sepsa, z infundiranjem povezane reakcije, pljučnica in zvišana telesna temperatura. Poročanje o domnevnih neželenih učinkih: Poročanje o domnevnih neželenih učinkih zdravila po izdaji dovoljenja za promet je pomembno. Omogoča namreč stalno spremljanje razmerja med koristmi in tveganji zdravila. Od zdravstvenih delavcev se zahteva, da poročajo o katerem koli domnevnem neželenem učinku zdravila na: Javna agencija Republike Slovenije za zdravila in medicinske pripomočke, Sektor za farmakovigilanco, Nacionalni center za farmakovigilanco, Slovenčeva ulica 22, SI-1000 Ljubljana, Tel: +386 (0)8 2000 500, Faks: +386 (0)8 2000 510, e-pošta: h-farmakovigilanca@jazmp.si, spletna stran: www.jazmp.si. Za zagotavljanje sledljivosti zdravila je pomembno, da pri izpolnjevanju obrazca o domnevnih neželenih učinkihzdravila navedete številko serije biološkega zdravila. Režim izdaje zdravila: H. Imetnik dovoljenja za promet: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Nemčija. Verzija: 3.0/20 Informacija pripravljena: januar 2021 DODATNE INFORMACIJE SO NA VOLJO PRI: Roche farmacevtska družba d.o.o., Stegne 13G, 1000 Ljubljana SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA POLIVY Samo za strokovno javnost M -S I-0 00 00 20 5 Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi varnosti. Zdravstvene delavce naprošamo, da poročajo o katerem koli domnevnem neželenem učinku zdravila. Kako poročati o neželenih učinkih, si poglejte skrajšani povzetek glavnih značilnosti zdravila POLIVY pod "Poročanje o domnevnih neželenih učinkih". Referenci: 1. Povzetek glavnih značilnosti zdravila POLIVY. Dostopano (30.07.2020) na https://www.ema.europa.eu/en/documents/product- information/POLIVY-epar-product-information_sl.pdf. 2. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol 2020;38:155-165. R/R – ponovitev bolezni ali neodzivnost na zdravljenje • DVCLB – difuzni velikocelični limfom B • BR – bendamustin, rituksimab • IZ – interval zaupanja • P – p vrednost Zdravilo POLIVY (polatuzumab vedotin) je v kombinaciji z bendamustinom in rituksimabom (BR) indicirano za zdravljenje odraslih bolnikov z difuznim velikoceličnim limfomom B (DVCLB), ki se na prejšnje zdravljenje niso odzvali ali pa se je bolezen pri njih ponovila in niso primerni za presaditev krvotvornih matičnih celic.1 1,00 0 2 4 6 8 10 12 14 16 18 20 22 24 26 ve rje tn os t O S (c el ok up no p re ži ve tje ) 0,60 0,80 0,40 0,20 0 čas (meseci) RAZMERJE OGROŽENOSTI (HR), 0,42; 95 % IZ, 0,24 do 0,75 P = ,002 Bolniki s tveganjem: POLIVY + BR (N=40) BR (N=40) 40 40 36 27 33 17 30 11 25 10 22 7 19 7 16 7 16 6 15 6 12 5 9 4 138 33 34 25 30 15 27 10 24 7 21 7 17 7 16 6 15 6 13 5 9 4 5 3 3 3 2 1 4,7 meseca 12,4 meseca Zdravilo POLIVY v kombinaciji z bendamustinom in rituksimabom za več kot 2x podaljša celokupno preživetje.1,2 *30 mg viale ni na voljo na slovenskem trgu. ONIVYDE: IZDELAN POSEBEJ ZA BOJ PROTI RAKU TREBUŠNE SLINAVKE ONIVYDE JE PEGILIRANI LIPOSOM Z IRINOTEKANOM, IZDELAN POSEBEJ ZA UČINKOVITO ZDRAVLJENJE TE AGRESIVNE BOLEZNI2–5 KLINIČNI PODATKI ŠTUDIJE 3. FAZE POTRJUJEJO EDINSTVENO KLINIČNO VREDNOST ZDRAVILA ONIVYDE V KOMBINACIJI S 5-FU/LV: ∞ skladni podatki o učinkovitosti pri vseh opazovanih dogodkih: pomembno podaljšanje preživetja in povečana stopnja odziva6–8 ∞ ohranjena kakovost življenja6,9 ∞ dobro poznan varnostni profil1,6,7 POMEMBNA UČINKOVITOST ONIVYDE + 5-FU/LV JE POTRJENA V KLINIČNI PRAKSI10–12 ONIVYDE + 5-FU/LV PRIPOROČAJO VSE GLAVNE MEDNARODNE SMERNICE13–16 LITERATURA: 1. Povzetek glavnih značilnosti zdravila ONIVYDE. 2. Lamb YN, Scott LJ. Drugs. 2017;77:785–792. 3. Drummond DC et al. Cancer Res. 2006;66:3271–3277. 4. Kalra AV et al. Cancer Res. 2014;74:7003–7013. 5. Carnevale J, Ko AH. Future Oncol. 2016;12:453–464. 6. Wang-Gillam A et al. Lancet. 2016;387:545–557. 7. Wang-Gillam A et al. Eur J Cancer. 2019;108:78–87. 8. Chen LT et al. Eur J Cancer. 2018;105:71–78. 9. Hubner RA et al. Eur J Cancer. 2019;106:24–33. 10. Kieler M et al. Ther Adv Med Oncol. 2019;11:1–13. 11. Yoo C et al. Ther Adv Med Oncol. 2019;11:1–9. 12. Pellino A et al. ESMO. 2019;P660. 13. Ducreux M et al. Ann Oncol. 2015;25(suppl 5):v56–v68. 14. eUpdate Cancer of the Pancreas Treatment Recommendations. Published June 20, 2019. ESMO Guidelines Committee. Available at: https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Cancer-of-the- Pancreas/eUpdate-Treatment-Recommendations. Last accessed June 2020. 15. Okusaka T et al. Pancreas. 2020;49(3):326–335. 16. NCCN Guidelines Version 1, 2020. Pancreatic Adenocarcinoma. Available at https://www2.tri-kobe.org/nccn/guideline/ pancreas/english/pancreatic.pdf. Published November 26, 2019. Last accessed June 2020. Samo za strokovno javnost. Datum priprave informacije: avgust 2020. ONI AD1 C1 20-21 ONIVYDE pegylated liposomal je odobren za zdravljenje metastatskega adenokarcinoma trebušne slinavke v kombinaciji s 5-fluorouracilom (5-FU) in levkovorinom (LV) pri odraslih bolnikih, pri katerih je bolezen po zdravljenju na osnovi gemcitabina napredovala.1 SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA ONIVYDE pegylated liposomal 4,3 mg/ml SESTAVA*: ONIVYDE pegylated liposomal 4,3 mg/ml koncentrat za disperzijo za infundiranje: ena viala z 10 ml koncentrata vsebuje 43 mg brezvodnega irinotekana (v obliki irinotekanijeve soli saharoznega oktasulfata v pegilirani liposomski formulaciji). TERAPEVTSKE INDIKACIJE*: Zdravljenje metastatskega adenokarcinoma trebušne slinavke v kombinaciji s 5-fluorouracilom (5-FU) in levkovorinom (LV) pri odraslih bolnikih, pri katerih je bolezen po zdravljenju na osnovi gemcitabina napredovala. ODMERJANJE IN NAČIN UPORABE*: ONIVYDE pegylated liposomal (irinotekan) smejo bolnikom predpisati in dajati samo zdravstveni delavci, ki imajo izkušnje pri uporabi zdravil za zdravljenje raka. Priporočeni odmerek in režim odmerjanja zdravila ONIVYDE pegylated liposomal je 70 mg/m2  intravensko 90 minut, čemur sledi LV 400 mg/m2 intravensko 30 minut in nato 5FU 2400 mg/m2 intravensko 46 ur, vsaka 2 tedna. Zdravilo ONIVYDE pegylated liposomal se ne daje kot samostojno zdravilo. Pri bolnikih z znano homozigotnostjo za alel UGT1A1*28 je treba razmisliti o manjšem začetnem odmerku zdravila ONIVYDE pegylated liposomal 50 mg/m2. Če zdravilo bolniki dobro prenašajo, lahko v naslednjih ciklih razmislimo o odmerku zdravila ONIVYDE pegylated liposomal 70 mg/m2. Prilagajanje odmerkov se priporoča za obvladovanje toksičnosti 3. ali 4. stopnje, povezane z zdravilom ONIVYDE pegylated liposomal. KONTRAINDIKACIJE*: Anamneza hude preobčutljivosti na irinotekan ali katero koli pomožno snov. Dojenje. OPOZORILA*: Zdravilo ONIVYDE pegylated liposomal (irinotekan) ni enakovredno drugim neliposomskim formulacijam irinotekana, zato jih ne smemo zamenjevati. Mielosupresija/nevtropenija: Med zdravljenjem se priporoča nadziranje celotne krvne slike. Bolniki se morajo zavedati tveganja za nevtropenijo in pomena povišane telesne temperature. Febrilno nevtropenijo je treba nujno zdraviti v bolnišnici s širokospektralnimi intravenskimi antibiotiki. Pri bolnikih, ki doživijo hude hematološke neželene učinke, se priporoča zmanjšanje odmerka ali prekinitev zdravljenja. Bolnikov s hudo odpovedjo kostnega mozga ne smemo zdraviti z zdravilom ONIVYDE pegylated liposomal. Imunosupresivni učinki in cepiva: Dajanje živih ali atenuiranih cepiv bolnikom z oslabljenim imunskim sistemom lahko povzroči resne ali smrtne okužbe. Bolniki azijskega porekla imajo večje tveganje za hudo in febrilno nevtropenijo. Posamezniki s homozigotnostjo 7/7 za alel UGT1A1*28 imajo povečano tveganje za nevtropenijo. Interakcije z močnimi induktorji encima CYP3A4, močnimi zaviralci encima CYP3A4 in močnimi zaviralci encima UGT1A1: Zdravila ONIVYDE pegylated liposomal ne smemo dajati skupaj z močnimi induktorji encima CYP3A4 (kot so antikonvulzivi, rifampicin, rifabutin in šentjanževka), močnimi zaviralci encima CYP3A4 (npr. grenivkinim sokom, klaritromicinom, indinavirjem, itrakonazolom, lopinavirjem, nefazodonom, nelfinavirjem, ritonavirjem, sakvinavirjem, telaprevirjem, vorikonazolom) ali z močnimi zaviralci encima UGT1A1, razen če ni drugih terapevtskih možnosti. Zdravljenje z močnimi zaviralci encima CYP3A4 moramo prekiniti vsaj 1 teden pred začetkom zdravljenja z zdravilom ONIVYDE pegylated liposomal. Driska: Pri bolnikih, ki doživijo zgodnji pojav driske (v ≤ 24 urah po začetku zdravljenja z zdravilom ONIVYDE pegylated liposomal), je treba razmisliti o terapevtskem in profilaktičnem zdravljenju z atropinom, razen če je kontraindicirano. Bolnike je treba opozoriti na tveganje za zapoznelo drisko (> 24 ur), ki je izčrpavajoča in v redkih primerih tudi življenjsko nevarna. Če driska traja tudi, ko bolnik prejema loperamid več kot 24 ur, je treba razmisliti o dodatni peroralni antibiotični podpori. Zdravljenje z zdravilom ONIVYDE pegylated liposomal je treba odložiti, dokler se driska ne umiri do ≤ 1. stopnje (2–3 odvajanja/dan več kot pred zdravljenjem). Zdravila ONIVYDE pegylated liposomal ne smemo dajati bolnikom z zaporo črevesja ali kronično vnetno črevesno boleznijo, dokler se ta ne pozdravi. Holinergične reakcije: Zgodnjo drisko lahko spremljajo rinitis, povečano slinjenje, zardevanje, diaforeza, bradikardija, mioza in hiperperistaltika. Uporabiti je treba atropin. Akutne infuzijske in povezane reakcije: V primeru hudih preobčutljivostnih reakcij je treba zdravljenje z zdravilom ONIVYDE pegylated liposomal prekiniti. Predhodna Whipplova operacija: Večje tveganje za resne okužbe. Bolnike je treba spremljati glede znakov okužbe. Žilne bolezni: Zdravilo ONIVYDE pegylated liposomal je bilo povezano s trombemboličnimi dogodki, kot so pljučna embolija, venska tromboza in arterijska trombembolija. Treba je pridobiti podrobno zdravstveno anamnezo, da bi prepoznali bolnike z več dejavniki tveganja poleg osnovne neoplazme. Bolnike je treba obvestiti o znakih in simptomih trombembolije in jim svetovati, da se v primeru katerega od teh znakov ali simptomov takoj obrnejo na svojega zdravnika ali medicinsko sestro. Pljučna toksičnost: Pri bolnikih, ki so prejemali neliposomski irinotekan, so se pojavili dogodki, podobni intersticijski pljučni bolezni (IPB), ki so vodili do smrtnih primerov. Pri bolnikih z dejavniki tveganja (obstoječo pljučno boleznijo, uporabo pnevmotoksičnih zdravil, kolonije stimulirajočimi dejavniki ali predhodnim zdravljenjem z obsevanjem) je treba pred zdravljenjem z zdravilom ONIVYDE pegylated liposomal in po njem skrbno nadzirati respiratorne simptome. Dokler ni opravljena diagnostična ocena, je treba ob pojavu nove ali napredovale dispneje, kašlja in povišane telesne temperature zdravljenje z zdravilom ONIVYDE pegylated liposomal začasno prekiniti. Pri bolnikih s potrjeno diagnozo IPB moramo zdravljenje z zdravilom ONIVYDE pegylated liposomal dokončno prekiniti. Jetrna okvara: Bolniki s hiperbilirubinemijo so imeli povišane koncentracije skupnega SN-38, zato je tveganje za nevtropenijo povečano. Pri bolnikih z vrednostjo skupnega bilirubina 1,0–2,0 mg/dl je treba redno nadzirati celotno krvno sliko. Previdnost je potrebna pri bolnikih z jetrno okvaro (bilirubin > 2-kratna zgornja meja normalnih vrednosti [ULN]; aminotransferaze > 5-kratna ULN). Ledvična okvara: Uporaba zdravila pri bolnikih s pomembno ledvično okvaro ni bila ocenjena. Bolniki s premajhno telesno maso (indeks telesne mase < 18,5 kg/m2): Potrebna je previdnost. Pomožne snovi: En mililiter zdravila ONIVYDE pegylated liposomal vsebuje 0,144 mmol (3,31 mg) natrija. INTERAKCIJE*: Previdnostni ukrepi: Sočasno dajanje z induktorji encima CYP3A4 lahko zmanjša sistemsko izpostavljenost zdravilu ONIVYDE pegylated liposomal. Sočasno dajanje z zaviralci encima CYP3A4 ali encima UGT1A1 (npr. atazanavirja, gemfibrozila, indinavirja, regorafeniba) lahko poveča sistemsko izpostavljenost zdravilu ONIVYDE pegylated liposomal. PLODNOST* NOSEČNOST*: Uporaba ni priporočljiva. DOJENJE*: Zdravilo je kontraindicirano. KONTRACEPCIJA*: Ženske v rodni dobi morajo med zdravljenjem in še 1 mesec po zdravljenju uporabljati učinkovito kontracepcijo. Moški morajo med zdravljenjem in 4 mesece po zdravljenju uporabljati kondome. VPLIV NA SPOSOBNOST VOŽNJE IN UPRAVLJANJA STROJEV*: Bolniki morajo biti med zdravljenjem pri vožnji in upravljanju strojev previdni. NEŽELENI UČINKI*: Zelo pogosti: nevtropenija, levkopenija, anemija, trombocitopenija, hipokaliemija, hipomagneziemija, dehidracija, zmanjšan apetit, omotica, driska, bruhanje, navzea, bolečine v trebuhu, stomatitis, alopecija, pireksija, periferni edem, vnetje sluznic, utrujenost, astenija, zmanjšana telesna masa. Pogosti: septični šok, sepsa, pljučnica, febrilna nevtropenija, gastroenteritis, oralna kandidoza, limfopenija, hipoglikemija, hiponatriemija, hipofosfatemija, nespečnost, holinergični sindrom, dizgevzija, hipotenzija, pljučna embolija, embolija, globoka venska tromboza, dispneja, disfonija, kolitis, hemoroidi, hipoalbuminemija, akutna ledvična odpoved, z infuzijo povezana reakcija, edem, zvišana raven bilirubina, zvišana raven alanin-aminotransferaze, zvišana raven aspartat-aminotransferaze, zvišano mednarodno umerjeno razmerje. Občasni: biliarna sepsa, preobčutljivost, tromboza, hipoksija, ezofagitis, proktitis, makulopapulozni izpuščaj, obarvanje nohtov. PREVELIKO ODMERJANJE*: Za preveliko odmerjanje zdravila ni znanega antidota. Treba je uvesti maksimalno podporno nego, s katero preprečimo dehidracijo zaradi driske in zdravimo zaplete zaradi okužb. FARMAKODINAMIČNE LASTNOSTI*: Učinkovina zdravila ONIVYDE pegylated liposomal je irinotekan (zaviralec topoizomeraze I), inkapsuliran v vezikel z lipidnim dvoslojem oziroma liposom. Irinotekan je derivat kamptotecina. Kamptotecini delujejo kot specifični zaviralci encima DNA-topoizomeraza I. Irinotekan in njegov aktivni presnovek SN-38 se reverzibilno vežeta na kompleks topoizomeraze I in DNA ter sprožita poškodbe v enoverižni DNA, kar zaustavi replikacijske vilice pri podvajanju DNA in povzroča citotoksičnost. Irinotekan se presnavlja s karboksilesterazo do SN-38. SN-38 je približno 1.000-krat močnejši zaviralec topoizomeraze I, očiščene iz tumorskih celičnih linij človeka in glodavcev, kot irinotekan. PAKIRANJE*: Pakiranje vsebuje eno vialo z 10 ml koncentrata. NAČIN PREDPISOVANJA IN IZDAJE ZDRAVILA: Rp/Spec. DATUM ZADNJE REVIZIJE BESEDILA: avgust 2020. Imetnik dovoljenja za promet: Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, Francija. Številka dovoljenja za promet z zdravilom: EU/1/16/1130/001. *Pred predpisovanjem preberite celoten povzetek glavnih značilnosti zdravila. Celoten povzetek glavnih značilnosti zdravila in podrobnejše informacije so na voljo pri: Servier Pharma d.o.o., Podmilščakova ulica 24, 1000 Ljubljana, tel: 01 563 48 11, www.servier.si. 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In vitro maturation of monocytes in squamous carcinoma of the lung. Br J Cancer 1981; 43: 486-95. doi: 10.1038/bjc.1981.71 Chapman S, Nakielny R. A guide to radiological procedures. London: Bailliere Tindall; 1986. Evans R, Alexander P. Mechanisms of extracellular killing of nucleated mammalian cells by macrophages. In: Nelson DS, editor. Immunobiology of macrophage. New York: Academic Press; 1976. p. 45-74. Authorization for the use of human subjects or experimental animals When reporting experiments on human subjects, authors should state whether the procedures followed the Helsinki Declaration. Patients have the right to privacy; therefore the identifying information (patient’s names, hospital unit numbers) should not be published unless it is essential. In such cases the patient’s informed consent for publication is needed, and should appear as an appropriate statement in the article. Institutional approval and Clinical Trial registration number is re- quired. 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The statement of disclosure must be in the Cover letter accompany- ing the manuscript or submitted on the form available on www.icmje.org/coi_disclosure.pdf Page proofs Page proofs will be sent by E-mail to the corresponding author. It is their responsibility to check the proofs carefully and return a list of essential corrections to the editorial office within three days of receipt. Only grammatical corrections are ac- ceptable at that time. Open access Papers are published electronically as open access on https://content.sciendo.com/raon, also papers accepted for publication as E-ahead of print. instructions Pfizer Luxembourg SARL, GRAND DUCHY OF LUXEMBOURG, 51, Avenue J. F. Kennedy, L-1855 Pfizer, podružnica Ljubljana, Letališka cesta 29a, Ljubljana BISTVENI PODATKI IZ POVZETKA GLAVNIH ZNAČILNOSTI ZDRAVILA IBRANCE 75 mg, 100 mg, 125 mg trde kapsule(1) IBRANCE 75 mg, 100 mg, 125 mg filmsko obložene tablete(2) Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi varnosti. Zdravstvene delavce naprošamo, da poročajo o kateremkoli domnevnem neželenem učinku zdravila. Glejte poglavje 4.8 povzetka glavnih značilnosti zdravila, kako poročati o neželenih učinkih. Sestava in oblika zdravila: (1) Ena trda kapsula vsebuje 75 mg, 100 mg ali 125 mg palbocikliba in 56 mg, 74 mg ali 93 mg laktoze (v obliki monohidrata). (2) Ena filmsko obložena tableta vsebuje 75 mg, 100 mg ali 125 mg palbocikliba. Indikacije: Zdravljenje lokalno napredovalega ali metastatskega na hormonske receptorje (HR – Hormone Receptors) pozitivnega in na receptorje humanega epidermalnega rastnega faktorja 2 (HER2 – Human Epidermal growth factor Receptor 2) negativnega raka dojk: v kombinaciji z zaviralcem aromataze ali v kombinaciji s fulvestrantom pri ženskah, ki so prejele predhodno endokrino zdravljenje. Pri ženskah v pred- in perimenopavzi je treba endokrino zdravljenje kombinirati z agonistom gonadoliberina. Odmerjanje in način uporabe: Zdravljenje mora uvesti in nadzorovati zdravnik, ki ima izkušnje z uporabo zdravil za zdravljenje rakavih bolezni. Priporočeni odmerek je 125 mg enkrat na dan 21 zaporednih dni, sledi 7 dni brez zdravljenja (shema 3/1), celotni cikel traja 28 dni. Zdravljenje je treba nadaljevati, dokler ima bolnik od zdravljenja klinično korist ali dokler se ne pojavi nesprejemljiva toksičnost. Pri sočasnem dajanju s palbociklibom je treba zaviralec aromataze dajati v skladu s shemo odmerjanja, ki je navedena v Povzetku glavnih značilnosti zdravila (PGZZ). Pri sočasnem dajanju s palbociklibom je priporočeni odmerek fulvestranta 500 mg intramuskularno 1., 15. in 29. dan ter nato enkrat na mesec, glejte PGZZ za fulvestrant. Prilagajanja odmerkov: Za prilagajanja odmerkov zaradi hematološke toksičnosti glejte preglednico 2, zaradi nehematološke toksičnosti pa preglednico 3 v PGZZ-ju. Pri bolnikih s hudo intersticijsko boleznijo pljuč (ILD)/pnevmonitisom je treba zdravljenje trajno prekiniti. Posebne skupine bolnikov: Starejši: Prilagajanje odmerka ni potrebno. Okvara jeter ali ledvic: Pri bolnikih z blago ali zmerno okvaro jeter ali blago, zmerno ali hudo okvaro ledvic prilagajanje odmerka ni potrebno. Pri bolnikih s hudo okvaro jeter je priporočeni odmerek 75 mg enkrat na dan po shemi 3/1. Pediatrična populacija: Varnost in učinkovitost pri otrocih in mladostnikih, starih < 18 let, nista bili dokazani. Način uporabe: Peroralna uporaba. (1) Jemanje s hrano, priporočljivo z obrokom. (2) Tablete se lahko jemlje s hrano ali brez nje. (1, 2) Ne smemo jemati z grenivko ali grenivkinim sokom. Kapsule oz. tablete zdravila je treba pogoltniti cele. Kontraindikacije: Preobčutljivost na učinkovino ali katerokoli pomožno snov. Uporaba pripravkov s šentjanževko. Posebna opozorila in previdnostni ukrepi: Ženske v pred- in perimenopavzi: Kadar zdravilo uporabljamo v kombinaciji z zaviralcem aromataze je obvezna ovarijska ablacija ali supresija z agonistom gonadoliberina. Hematološke bolezni: Pri nevtropeniji stopnje 3 ali 4 je priporočljiva prekinitev odmerjanja, zmanjšanje odmerka ali odložitev začetka ciklov zdravljenja, bolnike pa je treba ustrezno spremljati. ILD/pnevmonitis: Pri bolnikih se lahko pojavita huda, življenjsko ogrožajoča ali smrtna ILD in/ali pnevmonitis, kadar zdravilo jemljejo v kombinaciji z endokrinim zdravljenjem. Bolnike je treba spremljati glede pljučnih simptomov, ki kažejo na ILD/pnevmonitis (npr. hipoksija, kašelj, dispneja), in pri pojavu novih ali poslabšanju respiratornih simptomov oz. sumu na ILD/pnevmonitis zdravljenje prekiniti. Okužbe: Zdravilo lahko poveča nagnjenost k okužbam, zato je bolnike treba spremljati glede znakov in simptomov okužbe ter jih ustrezno zdraviti. Okvara jeter ali ledvic: Pri bolnikih z zmerno ali hudo okvaro jeter ali ledvic je treba zdravilo uporabljati previdno in skrbno spremljati znake toksičnosti. (1) Laktoza: Vsebuje laktozo. Bolniki z redko dedno intoleranco za galaktozo, odsotnostjo encima laktaze ali malabsorpcijo glukoze-galaktoze ne smejo jemati tega zdravila. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Učinki drugih zdravil na farmakokinetiko palbocikliba: Zaviralci CYP3A: Sočasni uporabi močnih zaviralcev CYP3A, med drugim klaritromicina, indinavirja, itrakonazola, ketokonazola, lopinavirja/ritonavirja, nefazodona, nelfinavirja, posakonazola, sakvinavirja, telaprevirja, telitromicina, vorikonazola in grenivke ali grenivkinega soka, se je treba izogibati. Induktorji CYP3A: Sočasni uporabi močnih induktorjev CYP3A, med drugim karbamazepina, enzalutamida, fenitoina, rifampicina in šentjanževke, se je treba izogibati. Učinek zdravil za zmanjševanje kisline: (1) Če palbociklib zaužijemo s hrano, klinično pomembnega učinka na izpostavljenost palbociklibu ni pričakovati. (2) Klinično pomembnega učinka na izpostavljenost palbociklibu ni pričakovati. Učinki palbocikliba na farmakokinetiko drugih zdravil: Pri sočasni uporabi bo morda treba zmanjšati odmerek občutljivih substratov CYP3A z ozkim terapevtskim indeksom (npr. alfentanil, ciklosporin, dihidroergotamin, ergotamin, everolimus, fentanil, pimozid, kinidin, sirolimus in takrolimus), saj IBRANCE lahko poveča izpostavljenost tem zdravilom. Študije in vitro s prenašalci: Palbociklib lahko zavira prenos, posredovan s P-gp v prebavilih in beljakovino odpornosti pri raku dojk (BCRP). Uporaba palbocikliba z zdravili, ki so substrati P-gp (npr. digoksin, dabigatran, kolhicin) ali BCRP (npr. pravastatin, rosuvastatin, sulfasalazin) lahko poveča njihov terapevtski učinek in neželene učinke. Palbociklib lahko zavira privzemni prenašalec organskih kationov OCT1. Plodnost, nosečnost in dojenje: Med zdravljenjem in vsaj 3 tedne (ženske) oziroma 14 tednov (moški) po koncu zdravljenja je treba uporabljati ustrezne kontracepcijske metode. Zdravila ne uporabljajte pri nosečnicah in ženskah v rodni dobi, ki ne uporabljajo kontracepcije. Bolnice, ki prejemajo palbociklib, ne smejo dojiti. Zdravljenje s palbociklibom lahko ogrozi plodnost pri moških. Pred začetkom zdravljenja naj moški zato razmislijo o hrambi sperme. Vpliv na sposobnost vožnje in upravljanja s stroji: Ima blag vpliv na sposobnost vožnje in upravljanja strojev. Potrebna je previdnost. Neželeni učinki: Zelo pogosti: okužbe, nevtropenija, levkopenija, anemija, trombocitopenija, pomanjkanje teka, stomatitis, navzea, diareja, bruhanje, izpuščaj, alopecija, suha koža, utrujenost, astenija, pireksija, povečane vrednosti ALT/AST. Način in režim izdaje: Rp/Spec - Predpisovanje in izdaja zdravila je le na recept zdravnika specialista ustreznega področja medicine ali od njega pooblaščenega zdravnika. Imetnik dovoljenja za promet: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgija. Datum zadnje revizije besedila: 09.11.2020 Pred predpisovanjem se seznanite s celotnim povzetkom glavnih značilnosti zdravila. PP-IBR-EEP-0188 Datum priprave: januar 2021. Samo za strokovno javnost. HR+/HER2- = pozitiven na hormonske receptorje in negativen na receptorje humanega epidermalnega rastnega faktorja 2. Literatura: Povzetek glavnih značilnosti zdravila Ibrance, 9.11.2020. Za zdravljenje lokalno napredovalega ali metastatskega HR+/HER2- raka dojk: • v kombinaciji z zaviralcem aromataze, • v kombinaciji s fulvestrantom pri ženskah, ki so prejele predhodno endokrino zdravljenje. Pri ženskah v pred- in perimenopavzi je treba endokrino zdravljenje kombinirati z agonistom gonadoliberina (LHRH – Luteinizing Hormone–Releasing Hormone). ZAUPANJE, ZGRAJENO NA MOČI R a d io lo g y a n d O n c o lo g y I V o lu m e 5 5 I N u m b e r 1 I P a g e s 1 -1 2 0 I M a r c h 2 0 2 1 march 2021 vol.55 no.1