ADIOLOGY 1,.11 NCOLOGY September 2000 Vol. 34 No. 3 Ljubljana ISSN 1318-2099 Ni pomembno zgolj preživetje Lilly Onkologija Eli Lilly (Suisse) S. A .. Podružnica v Ljubljani WTC. Dunajska 156. 1113 Ljubljana Telefon, (01) 5688 280. faks, (01) 5691 705 www.lilly.com Dodatne informacije o zdravilu so na voljo v strokovnih publikacijah. ki jih dobite na našem naslovu. . . Editorial office Radiology and Oncology September 2000 Instihlte of Oncology Vol. 34 No. 3 Vrazov trg 4 Pages 217-317 SI-1000 Ljubljana ISSN 1318-2099 Slovenia UDC 616-006 Phone: +386 61 1320 068 CODEN: RONCEM Plwne/Fax: +386 61 1337 410 E-mail: gsersa@onko-i.si Aims and scope Radiology and OncologiJ is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomogmphy, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncologiJ, radiobiology, radiophysics and radia/ion protection. Editor-in-Chief Editor-in-Chief Emeritus GregorSerša Tomaž Benulic Ljubljana, Slovenia Ljubljana, Slovenia Executive Editor Editor Viljem Kovac Uroš Smrdel Ljubljana, Slovenia Ljubljana, Slovenia Editorial board Marija Auersperg Bela Fornet Maja Osmak Ljubljana, Slovenia Budapest, Hu11gary Zagreb, Croatia Nada Bešenski Tullio Giraldi Branko Palcic Zagreb, Croatia Trieste, Italy Va11couve1; Ca11ada Karl H. Bohuslavizki Andrija Hebrang ]urica Papa Hamburg, Germany Zagreb, Croatia Zagreb, Croatia Haris Boka Ltiszl6 Horvtith Dušan Pavcnik Zagreb, Croatia Pecs, Hungary Portland, USA Nataša V. Budilma Berta Jereb Stojan Plesnicar Ljubljana, Slovenia Ljubljana, Slovenia Ljubljana, Slovenia Maijan Budilma Vladimir Jevtic Ervin B. Podgoršak Ljubljana, Slovenia Ljubljana, Slove11ia Montreal, Ca11ada Malte Clausen H. Dieter Kogelnik Jan C. Roos Hamburg, Gemrnny Salzburg, Austria Amsterdam, Netherlands Christoph Clemm Jurij Lindtner Slavko Šimunic Mii11chen, Germany Ljubljana, Slovenia Zagreb. Croatia Mario Corsi Ivan Lovasic Lojze Smid Udine, Italy Rijeka, Croatia Ljublja1.a,Slovenia Christian Dittriclz Marijan Lovrencic Borut Stabuc Viemza, Austria Zagreb, Croatia Ljubljana, S/ovenia Ivan Drinkovic LukaMilas Andrea Veronesi Zagreb, Croatia Houston, USA f:viano, Italy Gillian Duchesne Metka Milcinski Ziva Zupancic Melbourne, Australia Ljubljana, Slovenia Ljubljana, Slove11ia Publishers S/ovenian Medica/ Associatio11 -Slovenian Association of Radiologij, Nuc/ear Medicine Society, Slovenian Society far Radiotherapy a11d Oncology, and Slovenian Cancer Society Croatian Medica/ Association -Croatian Society of Radiology Affiliated with Societas Radiologorum Hungarorum Friu/i-Venezia Giulia regional groups of S.I.R.M. (Italian Society of Medica/ Radiology) Copyright © Radiologij and Oncology. Ali rights reserved. Reader for English Mojca Cakš Key words Eva Klemencic Secretaries Milica Harisch Mira Klemencic Design Monika Fink-Serša Printed by Imprint d.o.o., Ljubljana, S/ove11ia Published quarterly in 700 copies Bank account number 50101 679 901608 Foreign currency account number 50100-620-133-900-27620-978-5152 66/ 6 NLB -Ljubljanska banka d.d. -Ljubljana Subscription fee far institutions $ 100 (16000 SIT), individua/s $ 50 (5000 SIT) The publication of this joumal is subsidized by the Ministry of Science and Technology of the Republic of S/ovenia. lndexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EMBASE / Excerpta Medica This journal is printed on acid-free paper Radiology and Oncology is available on the internet at: http:j /www.onko-i.si/radiolog/nzo.htm ADIOLOGY ANO NCOLOGY .TI. Ljubljana, Slovenia ISSN 1318-2099 September 2000 UDC 616-006 Vol. 34 No. 3 CODEN: RONCEM CONTENTS 2nd International Symposium on ORGAN SPARlNG TREATMENT IN ONCOLOGY September 14-16, 2000 Ljubljana, Slovenia Preface Cufer T, Guest Editor 219 SCIENTIFIC PROGRAM 221 ABSTRACTS OF THE SYMPOSIUM 223 PAPERS OF THE INVITED SPEAKERS Breast and axilla conserving surgery in the management of early-stage breast cancer Blichert-Toft M 251 The intraoperative examination of axillary sentinel nodes ˝.G 2fil Organ sparing for rectum and quality of surgery for preventing local recurrences Temple W J 265 Limb salvage in soft tissue sarcomas Temple W J 269 Quality of life issues related to organ sparing Tannock I F 275 MAGNETIC RESONANCE Old middle cerebral infarction in a neonate Hatzidaki E, Prassopoulos P, Korakaki E, Evangeliou A, Voloudaki A, Giannakopoulou C CLINICAL ONCOLOGY Do we need axillary dissection in early breast cancer? Cufer T 285 Factors influencing rehabilitation in patients with head and neck cancer Hocevar-Boltežar I, Šmid L, Žargi M, Župevc A, Fajdiga I, Fischinger J, Jarc A 289 Ependymomas in adult patients: Results of adjuvant radiotherapy Mayer R, Prettenhofer U, Quehenberger F, Guss H, Hackl A 295 Antibodies to p53 -can they serve as tumor markers in patients with malignant lymphomas? Jezeršek B, Novakovic S 301 REPORT 307 SLOVENIAN ABSTRACTS 309 NOTICES 316 Radiology and Oncology is covered in Bio111edicina Slovenica, Chemical Abstracts, and EMBASE / Excerpta Medica 2nd International Symposium on ORGAN SPARING TREATMENT IN ONCOLOGY September 14-16, 2000 Ljubljana, Slovenia Organised by: Institute of Oncology Ljubljana Scientific committee Tanja Cufer, Chairman Marija Auersperg Marjan Budihna Jožica Cervek Rastko Golouh Hotimir Lesnicar Zvonimir Rudolf Gregor Serša Marko Snoj Branko Zakotnik Matjaž Zwitter Organizing committee Gregor Serša, Chairman Simona Borštnar Tanja Cufer Viljem Kovac Mira Klemencic Ana Žlicar Radio/ 011col 2000; 34(3): 223-49. Radio/ Oncol 2000; 34(3): 219. Preface Tremendous advances have been made in the oncology during the last few decades. The organ sparing treatment approach, which allows for organ preservation leading towards better quality of life without compromising the survival of patients is one of them. New developments in sys­temic treatment together with improved radiation and surgical techniques resulted in even bet­ter survival without the need for extensive and mutilating surgical procedures. Considering the great importance of organ sparing approach we decided to organize an inter­national symposium on this topic back in 1997. The symposium was greatly appreciated by almost a hundred participants from all over Europe and it was decided to make it a repeating event. Therefore the 2nd International Symposium on Organ Sparing Treatment in Oncology, organized by the Institute of Oncology in Ljubljana, will take place on September 2000 in Slovenia. The symposium is dedicated to continuos exchange of knowledge and personal experiences in the organ sparing treatment approach among oncologists and other health professionals involved in the care of cancer patients. We have a nice scientific program including six invited speakers and 26 presenters from different European countries who will present their work and expertise on the organ sparing approach in different cancers as well as on the quality of life of patients. Having in mind the scientific program and the high international reputation of the invited speakers I feel honored to have assumed the responsibility to be the Scientific Chairman of such an important meeting once again. I thank all the members of the Scientific as well as the Organizing Committee who have worked hard to ensure that the 2nd International Symposium on Organ Sparing Treatment in Oncology will take place. Major merit goes to Professor Gregor Serša, the Chairman of the Organizing Committee and the Editor of Radiology and Oncology, who did a great job in orga­nizing this event and who on behalf of the Editorial Board of Radiology and Oncology kindly offered us to publish the material of the symposium in one of their regular issues. You are looking at the issue of Radiology and Oncology in which the manuscripts of five invit­ed speakers at the symposium as well as the abstracts of all 26 presenters are published. Due to tirne pressure we took the liberty of making some editorial changes on the manuscripts in order to adjust them to the requirements of the journal without all the authors having been consulted. Hopefully the authors will not be offended by this. I hope that the participants will enjoy the symposium and that the readers will find this issue of Radiology and Oncology useful, possibly joining us during the next symposium. Tanja Cufer (Guest Editor) Radio/ 011col 2000; 34(3): 221-2. Scientific program znd International Symposium on Organ Sparing Treatment in Oncology BREAST CANCER Breast and axilla conserving surgery in the management of early-stage breast cancer Blichert-Toft M The intraoperative examination of axillary sentinel nodes Viale G Can axillary treatment in selected breast cancer patients be avoided? Majdic E The role of conservative therapy in invasive lobular carcinoma of the breast Vidali C, Amichetti M, Antone/la M, Api P, Aristei C, Bonetta A, Iannone T, Lara O, Neri S, Valli M C, Zini G Sentinel node biopsy in breast cancer Snoj M, Žgajnar], Mavrin T, Golouh R Breast biopsy with needle localization: factors influencing complete excision of nonpalpable carcinoma Bešic N, Hocevar M, Rener M, Fr/covic-Grazio S, Lindtner], Žgajnar], Gazic B History and evolution of endocrine therapy of breast cancer Fahey T ], Jr Intraoperative radiotherapy in breast cancer. How we do it ! Hager E, Forsthuber E, Primi/c F, Sabitzer H, Szalay S 192-Iridium HDR boost in breast cancer treatment ­experience from 644 patients (1984-1995) Hammer ], Trac/c C, Seewald D, Zoidl J The impact of local recurrence on the survival of operable b:reast cancer patients treated conservatively Eržen D, Lindtner J Advanced breast biopsy instrument (ABBI) system Kubista E Breast sparing treatment of mammary cancer Blidaru A, Bordea CI, Viisoreanu C, Balanescu I COLORECTAL CANCER Organ sparing for rectum and quality of surgery for preventing local recurrences Temple W J Scientific program Conservative treatment of anal canal cancer Seewald D, Track C, Hammer J, Zaidi J, Putz E, Labeck W Initiation of sphincter sparing treatment for squamous cell carcinoma of the anal canal in North American Community Hospital Miller R C, Mattson H Cancer of the lower third of the rectum: Dilemas between the low anterior resection and the abdorninoperineal excision Štor Z, Juvan R, Repše S Local excision of pTl and pT2 carcinomas of rectum from 1996 to 1999 Novak] First clinical data of a natura} immunomodulator in colorectal cancer Jakab F, Mayer A, Hoffmann A, Hidvegi M MISCELLANEOUS TUMORS Limb salvage in soft tissue sarcomas Temple W J Surgical treatment of melanoma Mozzillo N Combined application of cisplatin, paclitaxel and radiation for treatment of advanced squamous cell carcinoma of the head and neck Klocker J, Sabitzer H, Raunik W, Wieser S HDR brachytherapy in the treatment of cancer of the uterine cervix: Results and complications in 346 patients (1980 -1995) Hammer J, Track C, Seewald D, Weis E, Zoidl J Sentinel lymph node biopsy in patients with malignant melanoma Hocevar M, Bešic N, Snoj M, Mavrin T Partial nephrectomy in kidney tumors -our 5 years experiences Štrus B, Oblak C Tikhoff -Linberg operation and major resections of the shoulder girdle standard .rocedure for limb salvage in sarcoma patients Spi/er M, Novak J, Sencar M QUALITY OF UFE Quality of life issues related to organ sparing Tannock I F lmproving the quality of life .f patients with TCC by sequential chemoradiotherapy Kragelj B, Sedmak B, Cervek J, Cufer T Factors influencin. rahabititation ": patients with head and neck cancer Hocevar-Boltežar I, Smid L, Zargi M, Zupevc A, Fajdiga I, Fischinger J, Jarc A Radio/ Onco/ 2000; 34(3): 221-2. Abstracts / 2nd Intemational Symposyum on Organ Sparing Treatment Breast and axilla conserving surgery in the management of early-stage breast cancer Mogens Blichert-Toft Department oj Endocrine & Breast Surgery, Rigshospitalet, Copenhagen, Denmark The main incentive to breast conserving therapy (BCT) relates to preserving femininity and avoiding the feeling of Jemale inferiority and a disfigured body image. Some women are even more concerned about pre­serving the breast rather than preserving lije. The preconditions far BCT are satisfactory cosmesis, good physical function, and loco-regional disease control. If the breast is badly disfigured Jollowing BCT, there is little sense in breast conservation. The mainstay of early-stage breast cancer treatment is surgery. One option is breast conservation in case of eligibility. Radicality of the surgical procedure is emphasized whether mastectomy ar breast conservation has been undertaken. Risk factors related to BCT in particular are scrutinized, and especially young age and extensive dueta/ components of the specimen are dealt with as independent risk factors far local control in BCT. BCT in Denmark amounts to about 30% of operations in breast cancer. This is a rather low frequency compared with Jigures from other countries. Consequently, the Danish eligibility criteria are discussed. The reasons Jor axillary dissection are emphasized. Even in small tumors below 10 mm, axillary dissection is indicated due to a considerable involvement oj axillary nodes. The introduction of the sentinel node principle seems to provide a basis Jor conservation oj healthy axillary lymph nodes in node negative patients. Correspondence to: Prof. Mogens Blichert-Toft, M.D., Copenhagen University Hospital, Surgical Department, Rigshospitalet 3104, 2100 Copenhagen, Denmark. Phone: +45 3545 2117; Fax: +45 3545 3642; E-mail: mbt@rh.dk Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd International Symposyum on Organ Sparing Treatment The intraoperative examination of axillary sentinel nodes Giuseppe Viale Department of PathologiJ and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine, Milano, Italy A routine histological examination of axillary sentinel nodes predicts the nonsentinel axillary node status and may allow to spare axillary clearing in patients with breast cancer. To avoid the need for two separate surgical sessions, the results oj sentinel node examination should be known intraoperatively. Routine frozen section examination oj sentinel nodes, however, is liable to yield false-negative results. An extensive intra­operative examination oj frozen sentinel nodes, which would attain sensitivity comparable to, that obtained by routine histological analysis has been therefore devised. The Jrozen sentinel nodes are subserially sec­tioned at 50 mm intervals. Far each level, one section is stained with hematoxylin and eosin (H&E) and the other immunostained far cytokeratins using a rapid immunocytochemical assay. Immunocytochemistry did not increase the sensitivity oj the examination. The general concordance between sentinel and axillary node status was 96. 7%; the negative predictive value oj intraoperative sentinel node examination was 94.1 %. The intraoperative examination oj axillary sentinel nodes is effective in predicting the axillary node status oj breast cancer patients and it may be instrumenta[ in making the decision to spare axillary clearing. Correspondence to: Prof. Giuseppe Viale, M.D., FRCPath, European Institute of Oncology, Department of Pathology, Via Ripamonti 435, 20141 Milano, ltaly. Phone: +39 0257489419; Fax: +39 0257489417; E-mail: giuseppe.viale@ieo.it Radio/ Oncol 2000; 34(3): 223-49. Absh·acts / 2nd International Symposyum on Organ Sparing Treatment Can axillary treatment in selected breast cancer patients be avoided? Elga Majdic Institute oj OncologiJ Ljubljana, Slovenia Purpose. To determine the locoregional control in the patients with invasive breast cancer who had no axil­lary treatment. Patients and methods. Axillary dissection remains an integral part oj breast cancer surgery at our insti­tute; therefore, we can report on only 30 patients with invasive breast cancer who had no axillary treatment from 3.91 till 3.99. The reasons far omitting the axillary treatment were the age and/or the prognostic fac­tors favoring the decision on adjuvant therapy determined by the primary tumor features. Ali patients had clinically negative axillary nodes. 25 were post-and 5 were premenopausal with a mean age oj 64.8 years (range 32-78). Five tumors were pathologically :5 1cm, 13 between 1-2 cm and twelve > 2 cm in diameter. Histologically, 21 carcinomas were dueta/, 8 lobu/ar and 1 papillary; 10 were grade I, 13 grade II and 7 grade III (BREJ. HR were positive in 20 cases. Breast conserving surgery was pe1formed in 24 patients, with post­operative radiotherapy in 18 and mastectomy in 6 patients. Nineteen patients received tamoxifen and 3 chemotherapy. Results. Within a mean follow-up oj 48 months (range 12-108), there were no axillary failures. One had a breast recurrence (treated by tumorectomy without any adjuvant therapy), no patient had distant metas­tases, no one died. Ali patients had a fully functional arm without oedema, paresthesias ar pain. Conclusion. Good regional control in our patients could be explained by the following: In most cases treat­ed by conservation surgery the breast was irradiated postoperatively and the lower portion oj the axilla is usually included within the tangential fields that treat the breast. In mastectomized patients, the Iower axil­lary nodes are usually removed with the breast. Most oj our patients also had systemic therapy as deter­mined by the primary tumor characteristics. Although the number oj our patients is very small, we believe that, in selected NO patients, axillary dissection ar radiotherapy to the axilla with separate fields could be omitted. Morbidity would be greatly diminished, thereby improving the quality oj lije without compromis­ing regional control. The sentinel lymph node detection technique is promising, but cannot yet be used rou­tinely in most centers. Correspondence to: Elga Majdic, M.D., Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 (0)1 232 30 63; Fax: +386 (0)1 431 41 80. Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd Intemational Symposyum on Organ Sparing Treatment The role of conservative therapy in invasive lobular carcinoma of the breast Cristiana Vidali1, Maurizio Amichetti2, Michele Antonello3, Pierluigi Api4, Cynthia Aristei5, Alberto Bonetta6 , Tiziana Iannone7 , Ornella Lora8, Stefano Neri9, Maria Carla Valli10, Giampaolo Zini11 Radiotherapy Departments oj 1 Trieste, 2 Trento, 3Mestre, 4Ferrara, 5Perugia, 6Cremona, 7Belluno, BPadova, 9Bologna, 10Como, 11Reggio E., Italy Introduction. Severa/ studies have shown that conservative surgery (CS) followed by radiation therapy (RT) provides a low incidence of local recurrences (2-4%) in the management oj invasive dueta/ carcinoma (IDC), but the outcome oj invasive lobu/ar carcinoma (ILC) is dijjicult to assess because a high incidence oj ipsilateral recurrences has been reported. The authors reviewed 409 patients with ILC treated by quadran­tectomy and subsequent radiotherapy. Patients and methods. Whole breast external beam irradiation was pe1formed using a cobalt unit or a lin­ear accelerator; the tata/ dose was 46-50 Gy (2 Gy/fr); 325 patients received a boost to the tumor bed (10­20 Gy). Results. Local relapses were observed in 17 patients (4.2%) and the mean time to local jailure was 58.7 months (range 13-130 months); local control was 96% in Tl and 95% in T2 carcinomas. The incidence oj local relapse was higher (5.9% versus 3.2%) in patients with intraductal component (IC). Recurrences underwent salvage mastectomy in 15 cases (88%); 13 of these patients are disease free, 4 developed distant metastases. Conclusion. The difficulties to define the extent of the lesion and the supposed high rate of multicentricity of the tumour have limited the conservative approach to ILC in many institutions. Since ILC are often mul­tifocal and poorly delimited, the excisional biopsy and the lumpectomy may be probably inadequate. The pattern of local recurrences in our series was characterised by a high risk in proximity of the surgical bed despite the primary surgery. Many authors suggest that the presence of an extensive IC could affect the prognosis. In our series IC was found in 134 (32. 7%) cases, but it was extensive only in 77 cases; in these patients the rate of local recurrences was relevant (7.8%). The incidence of synchronous and metachronous bilateral breast recurrences was not significantly higher than in the published data concerning IDC. In con­clusion, this retrospective study indicates that CS in ILC provides a good probability of local control. Correspondence to: Christiana Vidali, M.D., Dept. Radioterapia Ospedale Maggiore Via Piet<1 19, 1-34100 Trieste, ltaly. Phone: +39 040 399 24 02; Fax: +39 040 661 082; E-mail: crisinfo@tin.it Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd Interna/iona/ Symposyum on Organ Sparing Treatment Sentinel node biopsy in breast cancer Marko Snoj, Janez Žgajnar, Tadeja Movrin, Rastko Golouh Institute oj Oncology, Ljubljana, Slovenia Background. Sentinel lymph node (SLN) biopsy is rapidly emerging as the most significant advancement in surgical treatment oj breast cancer since the initiation oj breast conservation treatment. SLN biopsy can accurately identify the node-positive patients who require axillary dissection, and spare node-negative patients an operation from which they would not have any benefit. The procedure is highly multidisciplinary, requiring close cooperation between nuclear medicine, surgery and pathology. It poses a new set oj technical issues far each specialty, oj which none has been completely reso/ved. Therefore, it needs to be cautiously audited during the implementation. It is generally accepted that every surgeon who wants to perform SLN biopsy should do his/her own personal series oj SLN biopsies and backup axillary dissection in at least 30 cases, with a success rate oj at least 90% and false negativity rate oj maximum 3 %. We are presenting the personal series oj a single surgeon (M.S.). Patients and methods. We included 36 Jemale T1_2 N O breast cancer patients in the study. They all received an injection oj 1ml 99mTc sulphur nanocoloid oj 60 MBq activity into and around the tumor. Two hours after the injection the lymphoscintigraphy was done and the projection oj SLN was mar/ced on the skin. The patients were referred to the operating room within 24 hours after the injection at the /atest. There, they were injected again with 1 ml oj Patent Blue peritumorally ar intratumorally. After 3-5 min, an intra­operative gamma probe was used far the identification oj SLN. Surgical incision was made on the spots where the s/cin mar/cs had been made and blue nodes showing afferent and/ or hot nodes were excised. After having retrieved the SLN, the backup axillary dissection was done. Formalinfixed, in tata paraffin embed­ded SLN were cut to three ar five leve/s. The slides were stained, additionally to HE, immunohistochemi­cally by CAM5.2 and CK MNF116. Results. Lymphoscintigraphy was done in all 36 patients. In 4 patients, we could not present SLN preop­eratively. SLNs could be found in all patients after the injection oj B/ue Dye. We retrieved 54 SLNs (aver­age 1.5 SLN/patient); oj these, 36 SLNs were hot and blue, 9 only hot and 9 only blue. Three SLNs in three different patients were in the region oj interna/ mammary artery while the rest were in the axilla. In 17 patients, 19 SLNs were histologically positive and 9 oj tliese had only micrometastases. In all cases, back­ up axillary dissection was done. On average, 16.8 lymph nodes were retrieved per patient. In only five cases oj SLN positive patients, additional positive lymph nodes were found in the axilla. When a negative SLN was found, no positive nodes were detected in the axilla. Conclusion. SLN biopsy in this personal series oj breast cancer patients proved to be a saje and accurate method to predict negative axillary lymph nodes. In our series, there was no false negatives. The identifica­ tion oj SLNs with lymphoscintigraphy and Blue Dye was successful in ali cases. Correspondence to: prof. Marko Snoj, M.O., Ph.D., Institute of Oncology, Zaloška 2, S1-1000 Ljubljana, Slovenia. Phone: +386 (0)1 232 30 63; Fax: +386 (0)1 431 41 80. Radio/ Oncol 2000; 34(3): 223-49. Abslracts / 2nd lntemational Sy111posyu111 on Organ Sparing Trea/ment Breast biopsy with needle localization: f actors influencing complete excision of nonpalpable carcinoma Nikola Bešic, Marko Hocevar, Milj.va Rener, Snežana Frkovic-Grazio, Jurij Lindtner, Janez Zgajnar, Barbara Gazic Institute of Oncologij, Ljubljana, Slovenia Purpose. Biopsy with needle localization oj nonpalpable breast tumor may be diagnostic, lwwever prejer­ably, it should be therapeutic. The latter may be achieved ij tumor is completely excised, i.e. with clear sur­gical margins. Our aim was to jind out the jactors related to complete excision oj nonpalpable tumor. Patients and methods. During a two-year period 215 patients (age range 32-74 years, median 55 years) underwent biopsy ajter needle localization of 222 nonpalpable breast lesions. Marnrnographic, operative and pathologfral jactors were correlated with the outcome of surgery using contingence tables in SPSS sta­tistical sojtware. Results. According to rnarnrnographic jeatures, the biopsy yield rates were 67% in spicular rnasses, 38% in rnicrocalcijications and 35% in tumors. A to tal oj 96 malignant tumors were diagnosed (overa/l biopsy yield rate 43%): 38 in situ and 58 invasive carcinomas. Surgical margins were clear in 44, c/ose in 20 and involved in 32 cases. Margins were likely to be clear ij the tumor was mammographical/y spiculated and smaller than 9 mm, and ij more than 50 g oj tissue was excised. On the contrary, the margins were likely to be involved in micro calcijications, turnors bigger than 9 mm and ij less than 50 g oj tissue was excised. Reoperation was perjormed in 41 cases (22 mastectomy, 19 reexcision) because oj non-clear margins; residu­um was diagnosed in 21 oj them. No residuum was observed ij the tumor was mammographically spiculat­ed; howeve1; it was detected in 17 oj 25 reoperated microcalcijications. Conclusion. Complete excision oj nonpalpable breast malignoma correlates with the 11zammographic jea­tures, tumor size and weight oj excised tissue. Complete removal oj large microcalcijications remain a puz­zling surgical task. Correspondence to: Nikola Bešic, M.D., Ph.D, Institute of Oncology, Zaloska 2, S1-1000 Ljubljana, Slovenia. Phone: +386 (0)1 431 01 65; Fax: +386 (0)1 43 14 180; E-mail: nbesic.•>onko-i.si Radio/ Oncol 2000; 34(3): 223-49. Abstracls / 2nd /11/ernalional Symposyum 011 Organ Sparing Trcatment History and evolution of endocrine therapy of breast cancer Thomas J. Fahey, Jr. Memorial Sloan-Kettering Cancer Cente,. York Avenue, New York, USA The first recorded observation that carcinoma of the breast would respond to hormona/ manipulation was written by Beatson slightly over 100 years ago when he reportcd that surgical oophorectomy induccd a rcmission in a paticnt with mctastatic brcast cancer. Oophorcctomy remained thc most cffective therapy far mctastatic pre-mcnopausal breast canccr for thc first halj oj the 20th Ccntury. The synthcsis of cortisol and other adrenocortical hormone analogues in thc 1950's & 1960's madc possible the cxpansion oj ablative endocrinc surgcry to include adrenalcctomy and hypophysectomy. This "major endocrinc ablation" tech­nique allowcd post-menopausal patients with metastatic brcast cancer to bencfit from hormona! tlzerapy. In large scries reporting thc results of major cndocrine ablations, an avcrage of 30-35% of ali paticnts achieved substantial clinical remissions in thcir diseasc. The discovcry oj hormona/ receptors in brcast cancer tumor cells and the widcspread applications of biochcmical and histochemical receptor tcsting oj pathologic breast cancer specimens in the 1970's -1980's allowed clinicians to predict with 90% certainty which patients would rcspond to endocrine treatmcnts. This developmcnt substantially reduced major surgical procedures in patients who had little chance of rcsponding. The discovery that estrogen receptor blockade with the drug tamox(fen could achieve thc same result as adrcnalcctomy and hypophysectomy in post-menopausal wonzen led to another revolution in the care of patients witlz metastatic breast cancer. Tamoxifen and other estrogen receptor blocking agents, effcctivcly replaced surgical hormona/ ablative treatments in the last third oj the 20th Century. The dcvelopment of c/inically useful blockcrs oj the aromatase pathway oj estrogen synthe­sis in the adrenals, as well as agonists to block pituitary stimulating hormones, made the possibility of total estrogen blockade by non-surgical methods a reality. Algoritluns far the use of these agents in clinical situ­ations wi/1 bc prescnted, and the recent expansion of synthetic estrogen receptor modulators (SERMS) to be used in breast cancer prevention strategies will be discussed. Correspondence to: Prof. Thomas J. Fahey, Jr., M.D., Senior Vice President and Clinical Member, Memorial Sloan­Kettering Cancer Center, 1275 York avenue, NcwYork, New York 10021, USA. Phone: +1 212 639 7275; Fax: +1 212 794 4345. Radio! Oncol 2000; 34(3): 223-49. Abstracts / 2nd International Symposyum on Organ Sparing Treatment Intraoperative radiotherapy in breast cancer. How do we do it? E. Hager, E. Forsthuber, F. Primik, H.Sabitzer, S.Szalay Institute oj Radiotherapy and Radio-Oncology, Department oj Gynaecology, LKH Klagenfurt, Austria Intraoperative radiotherapy consists oj irradiating the tumor bed oj breast cancer during operation. The geo­graphic miss oj the tumor bed is a well documented phenomenon in boost irradiation, demanding adequate techniques oj high quality boost setups. After the tumorectomy including a safety margin oj 1 to 2 cm around the palpable tumor, the lateral sides are sutured side by side to be better included into the applicator. The irradiation must be localized on the tumor bed, constituted by the lateral section areas oj the tumorectomy. The cross-sections oj the applicator are circular with the inner diameters oj 3, 4, 5, and 6 cm. The applicator is fixed in the tumor bed with a foil and is not attached to the collimator oj the linear-accelerator. Our operating table is moveable alowing the transfer oj the patient from the operating room to the radiotherapy treatment room in the best conditions oj asepsis. There, the patient is moved from the operating table to the treatment couch. Anaesthetic surveil­lance oj the patient is ensured by mobile and fixed monitors during the entire period oj transfer and IORT The depth dose presciption is done by CT scan oj the tumor bed. The single dose is 9 Gy with 4 to 12 Me V electrons on the 90% isodose. After the wound is healed, the patients are treated up to 50 Gy (EBRT). No additional boosting is pe1formed. This is why EBRT is two weeks shorter than without IORT There where no early complications associated with the use oj IORT From 5/1999 to 4/2000 conservative surgery was performed on 20 patients with stage I or II breast cancer in a dedicated IORT facility. Correspondence to: E. Hager, M.D., Institute of Radiotherapy and Radio-Oncology, Department of Gy naecology, LKH Klagenfurt, A-9020 Klagenfurt, Austria. Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd Inlernational Symposyunz on Organ Sparing Treatment 192-Iridium HDR boost in breast cancer treatment -experience from 644 patients (1984-1995) Josef Hammer, Christine Track, Dietmar Seewald, Johann Zoidl Department of Radiation Oncology, Barmherzige Schwestern Hospital, Linz, Austria Purpose. Since 1984, HDR Iridium-192 brachytherapy has been used to de/iver an interstitial boost to the primary tumor site in conservative breast cancer treatment. The authors present the survival data and cos­metic results of a prospective treatment method and demonstrate the saje use of Ir-192 high dose rate (HDR) implantations. Patients and methods. Fram 1984 to 1995, 644 patients with 649 tumors have been treated (Tl: 432, T2: 217, N+: 180, N-: 469). The treatment method included external beam radiotherapy (EBRT) of 45 to 50 Gy to the breast (para/le/ opposing portals) followed by one interstitial 10 Gy boost to the tumor bed. Adjuvant systemic therapy was given to ali node-positive patients. Premenopausal patients were given six cycles of CMF (2 to 3 cycles of CMF were administered before radiotherapy and 3 to 4 cycles were continued after­wards), and poshnenopausal estrogen receptor positive patients were treated with Tamoxifen. Mean follow­up of survivors was 77 months (25 to 158). Cosmetic appearance after surgery was evaluated in the first 216 patients using a 4 grade scoring. The clinical and cosmetic results were evaluated according to tumor /oca­tion (medial and central: 11 111/c", lateral: ,,lat"). Results. Five-year actuarial data (10-yr. data in brackets): Overall survival: 89.6 % (75.0 %), /ocal control: 96.5 % (92.0 %), disease free survival: 85.5 % (77.5 %), and disease specific survival: 92.9 % (82.2 %). The /owest local failure rate is given in ER positive patients with 1.4 % after 5 yr., and 5.5 % after 10 yr. Comparing m/c and lat, the survival parameters were highly significant in favour of the /afera/ tumors (p­values: OS 0.0011, DSS 0.009, DFS 0.0001, LC 0.051). There were no severe complications, except in 1 patient with periostitis and neuralgia. To exclude the influence of surgery to the cosmetic results, the mean value of 1. 74 (=before RT) was normalized to 1.00. This postoperative result was compared to the cosmetic result 2 and 5 years after radiotherapy using a simi/ar scoring: The relative value changed to 1.12 after 2 years and to 1.15 after 5 years. The rate of good to excellent results before radiation therapy was 84%, and after 5 years 74%. Normalized to 100 to exclude the influence of surgery, these results represent in 88% the changes in cosmetic appearance due to RT alone. Medial and central tumor /ocations result in a worse cosme­sis compared to lateral tumors: The mean scores after surgery were 1.65 in lat and 2.15 in 111/c (p<0.005). These values had not changed 5 years after RT with 1.69 and 2.13 respectively (p<0.025). Conclusion. Our experience over more than 10 years proves the safety of the use of HDR implantations as a boost of 10 Gy in 1 fraction, delivered with careful attention to the source position far treatment, to the dis­tance of the needles from the skin, and to the treated voh11ne. The 5-year /ocal relapse rate of 3.5 % (10-yr.: S.O %) and survival data are very simi/ar to those reported in literature. The medial and central tumor location in the breast is associated with significant lower survival rates and sign.ficant unfavorable cosmetic results. Correspondence to: Josef Hammer, M.D., Barmherzige Schwestern Hospital, Department of Radiation Oncology, Seilerstaette 4, A-4010 Linz , Austria. Phone: +43732 76 77 7320; Fax: 43732 76 77 7506; E-mail: josef.hammer@bhs.at Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd International Symposyum on Organ Sparing Treatment The impact of local recurrence on the survival of operable breast cancer patients treated conservatively Darja Eržen, Jurij Lindtner Institute oj Oncology, Ljubljana, Slovenia The impact oj local recurrence on survival was studied on 259 patients with operable breast cancer treated at the Institute oj Oncology in Ljubljana in the years 1978-1988. This was a retrospective, non randomized study. All patients had breast conserving surgery (219 patients had quadrantectomy ar wide excision, 40 patients had tumorectomy only). After surgery, 129 patients received postoperative irradiation (50Gy to the breast and mostly 10Gy boost to the tumor bed), and 130 patients had no irradiation. The objective of the study was to evaluate the difference in the recurrence rate in both groups and the impact of recurrence on survival. Fram 130 patients with no irradiation after surgery 41 developed recurrences in contrast to only 16 local recurrences in 129 patients who were irradiated postoperatively (p= 0.00017). Local recurrences were more frequent after tumorectomy in comparison to quadrantectomy ar wide excision (35% vs. 20%, p= 0.02). The survival in the group of patients with loca/ recurrence and in the group of patients without /ocal recur­rence did not differ in the first 5 years after surgery, whereas the difference in the survival of the both groups became highly significant thereafter (p=0.0076) (Figure 1) o Complete + Censored 1,0 0,9 without local recurrence 0,8 C 0,7 c;, .*-t.,.--* 0,6 . C .:l oc:I r:cur:ence + E 0­ g-,. 0,4 P=0,00762 0,3 0,2 0,1 0,0 60 120 180 240 months Figure 1: Survival with local recurrence (68 patients with local recurrence and 190 patients without local recurrence). Correspondence to: Darja Eržen, M.O., M.Se., Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 (0)1 232 30 63; Fax: +386 (0)1 431 41 80. Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd Interna/iona/ Symposyum on Organ Sparing Treatment Advanced breast biopsy instrument (ABBI) system Ernst Kubista University oj Vienna, Women 's Clinic, Department oj Special Gynaecology, Wienna, Austria Severa/ methods have been developed in the last 10-15 years to reduce the extension oj surgery in the treat­ment oj breast cancer. First oj ali, it is well known that breast conservation does not impair the prognosis oj patients with breast cancer and therejore the rate oj brast conserving therapy has been rapidly increas­ing in the countries with high medica/ standard. Far example, in our institution and within the Austrian Co­operative Study Group oj Breast Cance1; the rate oj breast conservation has been raised jrom 35% up to 75% in the last 10 years. This has been mainly due to the jact that postoperative radiation therapy has been improved extensively. Concerning operation in the axilla region the development oj sentinel node technique has brought the oppor­tunity to reduce the extension oj surgery in the axilla and to improve the rate oj postoperative morbidity. Although the logistic problems in pe1forming this technique are evident it is necessary to enhance its use as much as possible. Another new technique is the so-cal/ed ''ABBI-system" (advanced breast biopsy instrument). This procedure is used to remove small lesion under local anaesthesia. It also allows to perjorm the diagnosis and treatment oj minor breast cancers in one step. It is important that these techniques, the sentinel node biopsy and ABBI­system are pe1formed in controlled tria/ conditions to jind out the possibilities and limitations oj this new rnetlwd. Correspondence to: Prof. Ernst Kubista, M.D., Ph.D., University of Vienna, Women · s clinic, Department of Special Gynaecology, Wahringer Giirtel 18-20, 1090 Vienna, Austria. Phone: +43 1 404 002 881; +43 1 406 6749. Radio/ Oncol 2000; 34(3): 223-49. Abstrac/s / 2nd International Symposyum on Organ Sparing Treatment Breast sparing treatment of mammary cancer Alexandru Blidaru, Cristian Ioan Bordea, Cristian Viisoreanu, Ion Balanescu Institute of Oncology „ProfDr. Al. Trestioreanu" Bucharest, Romania Background. Conservative treatment oj breast cancer is a valid alternative to mastectomy in the early stage oj the disease. The purpose oj the paper is to establish the subgroups oj patients best suited far this type oj therapy and the optimum therapeutic protocol. Patients and methods. This is a prospective study that overviews the outcome oj four groups oj patients with stage I and II oj breast cancer treated by the same medica/ team at the Bucharest OncologtJcal Institute: Group A: 123 patients who underwent conservative treahnent as they met the selection criteria far this type oj therapy; Group Bl: 30 patients who underwent conservative treatment because they had refused mastectomy; Group B2: 40 patients who underwent conservative treahnent because oj medica/ contraindication far extended surgery; • Group M: 150 patients by whom mastectomy was pe1formed, although they would have fulfilled the selection criteria far conservative treahnent. The most important selection criteria far conservative treatment were: unilateral, unicentric breast cancer, T<2.5cm, N0-Nl, tumor/breast ratio that would allow proper excision with a convenient cosmetic outcome, and patient's wish. Surgery far the primary tumor consisted oj limited mammary resection, defined as excision oj the tumor together with at least 2 cm oj peritumoural nzammary tissue. The amplitude oj mammary resection depend­ed on the /ocation, size and histopathological type oj the tumor and on the breast size. Axillary dissection was pe1formed far diagnostic purposes and far local control oj the axillary disease. Post-operative radio­therapy is an essential component oj conservative treatment targeting the mammary gland and, under cer­tain circumstances, the regional ganglionar areas. Chemotherapy and/or hormona/ therapy were applied depending on the prognostic factors oj the disease. Results. Loca/ recurrence mtes at 5 years were 6.9% in Group A, 25% in Group Bl, 12.5% in Group B2, 1.3% in Group M. Ovemll survival rate at 5 years was 91.37% in Group A, 70.83% in Group Bl, 62.50% in Group B2, 88.60% in Group M. The cosmetic result oj conservative treatment was good in over 70% oj the cases. Conclusion. Results confirmed that conservative therapy, with due observance oj selection criteria and oj the therapeutical protocol, is an appropriate thempy far a category oj patients with early breast cancer. Correspondence to: Alexandru Blidaru, M.O., Ph.D., Institute of Oncology Bucharest, Sos. Fundeni No. 252, Sector 2, Bucharest, Romania. Phone: 0040 1 650 72 81; Fax: 0040 1 232 60 12; E-mail: bordea@rnc.ro Radio/ Ollcol 2000; 34(3): 223-49. Abstracts / 2nd Intemational Symposyum on Organ Sparing Treatment Organ spar ing for rectum and quality of surgery for prevent ing localrecurrences Walley J. Temple University oj Calgary, Tom Baker Cancer Centre, Calgary, AB Canada The progress in the management oj rectal cancer in the last 100 years has been phenomenal. Fram the days oj Myles abdominal perineal resection at the begi.nning oj the 20th century we have progressed to being able to manage most rectal cancers without the need far a permanent colostomy and from a surgi.cal procedure associated with 40% local recurrence to one with less than 5%. Adjuvant modalities with radiotherapy and chemotherapy have similarly praven useful in advanced disease to improve not only local control but also survival. Particular attention is paid to two aspects: 1) the surgi.cal technique that is so critical in improv­ing survival by improved local control and 2) looking at anal-preserving surgeries far advanced and low rec­tal cancers. It is concluded that a properly done procedure using the TME approach supported by preop radi­a ti on far advanced lesions will result in excellent local control and function in over 90% oj low rectal can­cers. Correspondence to: Prof. Walley J Temple MD FRCSC FACS, University of Calgary/ Tom Baker Cancer Centre, Calgary AB, Canada. Phone: (403) 670 1914; Fax: (403) 283 1651 E-mail: walleyete@cancerboard.ab.ca Radio/ Onco/ 2000; 34(3): 223-49. Abstracts / 2nd International Symposyum on Organ Sparing Treatment Conservative treatment of anal canal cancer Dietmar Seewald, Christine Track, Josef Hammer, Johann Zoidl, Ernst Putz, Werner Labeck Department oj Radiation Oncology, Barmherzige Schwestern Hospital, Linz, Austria Purpose. Sphincter preservation by radiation therapy with ar witlwut simultaneous chemotherapy has become a widely accepted standard treatment far patients with anal cancer. Our experience with 97 patients was analyzed to evaluate local control and late morbidity according to stage and treatment method. Patients and methods. Between January 1983 to December 1999, 97 patients with anal cancer were treat­ed by external beam radiotherapy (EBRT). A median total dose of 50 Gy was delivered to the primary tumor region as well to the perirectal lymph nodes. Patients were staged according the UICC Classification: 40 Tl, 31 T2, 14 T3, 12 T4. Female to male ratio was 79 to 18. Mean age of ali patients was 66 years. Pretreatment procedures included tumor excision ar biopsy, endoscopy, transrectal sonography and examinations to exclude distant metastases. Fifty patients (51.5%) received simultaneous chemotherapy with Mitomycin C and 5-Fluorouracil. An additional boost (electron beam ar implant) to the primary tumor was delivered to 67 patients (69%). Forty-seven patients received external beam therapy followed by interstitial Iridium-192 high dose rate (IR-192 HDR) implantation as boost (5 -7 Gy) in one fraction. We obtained an optimal fix­ation of the needles and precise parallel needle positions with a cylinder applicator far the rectal lumen and a ring fixation system in addition to a semicircular template. To obtain an image of the implant, the patient had to be shifted to the CT-scanner by using a special transportation device. The implanted needles were visualized by CT-scan. Results. Overall survival rate (OS) at 5 and 10 years was 87.3 % and 72.7% respectively, disease-specific survival (DSS) was 88% at 5 years and 10 years, local control rate (LC) was 86% at 5 and at 10 years. Mean follow up of ali survivors was more than 50 months. Conclusion. Radiotherapy is a standard treatment far patients with cancer of the anal canal. Additional chemotherapy showed improved local control rates and overall survival in patients with T3 and T4 tumors. Our results also indicate that the external beam therapy combined with IR-192 HDR brachytherapy as a boost is highly effective in achieving local control without severe grade 3 toxicity. Late toxicity is moderate by delivering boost doses not exceeding a volznne of 60 ccm. Correspondence to: Dietmar Seewald, M.D., Barmherzige Schwestern Hospital, Department of Radiation Oncology, Seilerstaette 4, A-4010 Linz, Austria. Phone: +43732 76 77 7320; Fax: 43732 76 77 7506; E-mail: d.see­wald@netway.at Radio! Oncol 2000; 34(3): 223-49. Abstracts / 2nd International Symposyum on Organ Sparing Treatment Initiation of sphincter sparing treatment for squamous cell carcinoma of the anal canal in a North American Community Hospital Robert C. Miller1 , Heidi Mattson2 1 Division of Radiation Oncologtj, Mayo Clinic and Mayo Foundation, Rocheste1; Minnesota, U.S.A.; 2Department of Medica/ Records, Immanue/-St. Joseph's Hospital-Mayo Health System, Mankato, Minnesota, U.S.A. Objective. In the United States, increasing numbers of patients are choosing to receive oncological therapy in small community cancer centers rather than in academic centers oj excellence. Providing optimal thera­PY far uncommon malignancies such as anal cancer in the community setting can be chal/enging. In a hos­pital-based cancer center located in a rural community oj 35,000, a combined modality approach to the treat­ment oj squamous celi carcinoma oj the anal canal was implemented in 1999. After one yem; the results and toxicity oj treatment were analyzed. Materials and Methods. Patients received an initial 30.6 Gy to 36 Gy oj external bemn radiotherapy (EBRT) to the lower pelvis, inguinal lymph nodes, and anal canal in 1.8 Gy daily fractions, five days/week. A tata/ dose oj 50.4 to 59.4 Gy EBRT was delivered to the primary tumor using 3-D treatment planning and shrinking fields. Tota/ dose was dependent on tumor response and exclusion oj the small bowel from the fina/ boost volume. The regional radiation oncologist, using a dedicated teleradiography system linking the regional center with the primary academic cancer cente1; reviewed ali treatment plans with a sub-specialist radiation oncologist with an interestin GI malignancies. Chemotherapy was delivered concurrently with EBRT Cis-platinum ar Mitomycin-C, at the discretion oj the treating medica/ oncologist, was administered on Day 1 and Day 28. 5-Fluorouracil, delivered as either a 96-hour continuous infusion ar daily bolus injections, was administered on Days 1-4 and Days 28-31. A community surgeon and/or gastroenterologist evaluated the patient eight weeks after completion oj ther­apy. A biopsy was pe1formed at the discretion oj the endoscopist. The treating oncologists also evaluated patients at eight weeks post-treatment and at three-month intervals thereafter. Results. At the time oj presentation, length oj follow up, short term tumor control rates, and acute and delayed toxicity rates will be discussed. Conclusion. A combined modality approach to the treatment oj anal canal malignancies in the community setting is technically feasible with modest, but tolerable, acute toxicity. Difficulties in delivering definitive therapy in an uninterrupted fashion will be addressed at the time oj presentation. Correspondence to: Robert Miller, M.D., Radiation Oncology Mayo Clinic, 200 First St. S.W., 55905 Rochester, Minnesota, USA. Phone: +1 507 345 2960; Fax: +1 507 389 4684; E-mail: Miller.Robert@mayo.edu Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd International Symposyum on Organ Sparing Treatment Cancer of the lower third of the rectum: Dilemmas between the low anterior resection and the abdominoperineal excision Zdravko Štor1 , Robert Juvan2 , Stane Repše3 Clinical Department far Abdominal Surgery, University Medica/ Center, Ljubljana, Slovenia Objective. Sphincter-saving operations are pe1formed with the increasing frequency far patients with car­ cinoma oj the lower third of the rectum. Stapling devices allow a saje resection of lesions closer to the anal verge. Our sh1dy compares the results of the low anterior resection (LAR) using the double stapling tech­ nique and of the abdominoperineal excision (APE) in patients with carcinoma of the lower third of the rec­ tum. Patients and methods. In the period from 1st January 1989 to 31st December 1995, 116 patients with car­ cinoma of the lower third oj the rechm1 underwent potentially curative resection. Five-year survival was estimated by Kaplan-Meier statistical analysis. Patients who died within 30 days after the operation were censored. Differences in survival curves between both groups were assessed by the log rank test. Results. We performed LAR in 44 of 116 (37.9%) patients and APE in 53 of 116 (45.7%). We preserved the sphincter in 52 out of 116 (44.8%)(LAR, local excision). The patients were divided according to the type of operation by the Dukes classification: LAR (A11/44 25%; B16/44 36,4%; C17 /44 38,6%), APE (A12/53 22,6%; B17/53 32,1 %; C24/53 45,3%). Five-year survival rate far patients with Dukes B and C tumors in the lower third of the rechtm is 25% far LAR and 53 % far APE. There was no statistically significant dif­ference oj survival curves between the two operations (p=0.20458, Log ranic). We analyzed our results with regard to positive lymph nodes: LAR (Nl 15.9%; N2 25%; N3 11,4%); APE (Nl 18.9%; N2 22.6%; N3 0%). Lynzphatic spread was found in 23 of 44 (52.3%) oj the patients with LAR and in 22 oj 53 (41.5%) of the patients with APE. Anastomotic leakage became clinically manifest in 8 out of 44 patients (18.2%). Ali the patients required relaparatomy and were h'eated with temporary loop ileostomy. Conclusion. We pe1formed LAR (52,3%) in a higher percentage of patients with lymphatic dissemination than APE (41.5%). Thus the difference in five-year survival rate is not surprising: LAR (25%), APE (53%). A more detailed preoperative staging oj the tumor should be undertaken (endorectal-ultrasonography and size oj the tumor). LAR should be pe1formed in patients with small hmzors ar non advanced carcinoma (T1, T2). In patients where lymphatic dissemination ar more advanced carcinoma (T3,T4) is identified, APE should be performed. Correspondence to: Zdravko Štor M.D., Clinical Department for Abdominal Surgery, University Clinical Center, Zaloška 7, SI-1525 Ljubljana, Slovenia. Phone/Fax: +386 (0)113 01 714, E-mail: zdravko.stor@kclj.si Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd Intemational Symposyum on Organ Sparing Treatment Local excision of pTl and pT2 carcinomas of the rectum from 1996 to 1999 Janko Novak Department far Abdominal Surgery Dr. P. Drzaj Hospital, KC Ljubljana, Slovenia Purpose. Our aim was to present and evaluate local excisions of rectal cancer in view of preserving organ ftmctioning and securing surgery far cure. The current follow-up and results are discussed. Materials and methods. Fram the beginning of 1996 to the end of 1999, we treated 21 patients far rectal cancer by local excision. Ali patients had lesions less than 4 cm in diameter which were not extending beyond the muscularis propria by ELUS examination. Results. At the moment, 13 patients are without recurrence, 3 died of cancer unrelated cause, 4 had anoth­er operation because of recurrence, 1 was last from follow-up far unknown reason. Conclusion. The number of our patients is small and hardly of statistic value. Our opinion is that local exci­sion has its meaning as organ saving procedure if it is supported with good follow up. Correspondence to: Janko Novak, M.D., Department for Abdominal Surgery Dr. P. Drzaj Hospital, KC Ljubljana, Vodnikova 62, SI-1000 Ljubljana, Slovenia. Phone: +386 1 519 32 33. Radio/ Oncol 2000; 34(3): 223-49. Abslracls / 21ld Intematio1Ial Sy111posyu111 011 Orgall Sparillg Tren/111e1II First dinical data of a natura! immunomodulator in colorectal cancer Ferenc Jakab1 , A. Mayer2 , A. Hoffmann3 , M. Hidvegi.4 Department of Surgery and Vascular Surgery, 2 Budapest Center of Onco-Radiology, Llzsoki Teaching Hospital, 3 Biromedicina Co, 4 Department of Biochemistry and Food Technology, Budapest, Hungary Baclcground. MSC (trade-nanze AVEMAR10) is a per os applicable co11Zplex of multiple, biologically active molecules obtained from fer111ented wheat-gerrn extract. Preclinical studies suggest a patent antimetastatic activity and n fnvorable toxicity profile. 011 a pilot-scn/e, this phase TI clinical study was ni111ed to find out whether or not MSC as a support to surgery or plus clzernotherapy ndds any tl!erapeutic benefit compared to the same combinntion zuitlzout MSC in colorectal cancer. Materials and methods. Fram 1998 to June 1999, 18 control patients and 12 consecutive colorectal cnn­cer patients were enro/led into tlzis study. Ali patients underwent curative surgery. The control group (18 patients) received no otlzer therapy or adjuvant che111otherapy alone. The MSC group (12 pntienls) received MSC nlone or plus adjuvmzt clzemotherapy. Until rww, the nzedinn follow-up has been 9 months. Results. The interi111 data of tlze study provide evidence tlznt, in the MSC group, no new 111etastnses, nei­ther hepatic nor other, hnve occurred so fnr. On the contrary, severni new rnetastases have developed in the control group. Conclusion. Orally ad11Zinistered MSC is n potent candidate to be regarded ns n supporlive therapy to surgery or plus che11Zothempy for colorectnl cancer patients. Correspondence to: Prof. Ferenc Jakab, M.O., Uzsoki Teaching Hospital, Department of Surgical and Vascular Surgery, Uzsoki st. 29, H-1l45 13udapest, Hungary. Phone: +36 J 220 9950; Fax: +36 1 220 9950; E-mail: xfjakab@rnail.datanet.hu Rndiol 011col 2000; 34(3): 223-49. Limb salvage in soft tissue sarcomas Walley J. Temple University of Calgary/ Tom Baker Cancer Centre, Calgary AB, Canada In 2000, most paticnts with soff tissue sarcomas oj thc axial or appendicular skeleton can expcct 'to walk away' from tlze surgery. This compares to just 20 ycars ago whcn 11 relatively higlz percentage of patients were trcated with a111putatio11. Now ihe treatrnent has c/rnnged to one oj wide /ocal excision with a 1 cm to 2 cm margin on normal tissues and mz adventitial margin on critical structures such as nerves or vessels, jollowed or preceded by radiotherapy. With the use of adjuvant treatments in co111bination with recon­structive surgery, over 90% oj patients witlz sarco111as of the sojt tissues or bone 111ay be rendered disease jree locally. The only restriction to this approach is when tumor involves the major nerve to a limb or when microscopic, clear margins cannot be ohtained at the lime oj surgery as botlz oj tlzese are hest treated with an amputation. Corrcspondence to: Prof. Walley J Temple MD FRCSC FACS, Univcrsity of Calgary/ Tom Baker Cancer Centre, Calgary AB, Canada. Phone: (403) 670 1914; Fax: (403) 283 1651 E-mail: walleyeteQiJcancerboard.ab.ca Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd International Symposyum on Organ Sparing Treat111ent Combined application of cisplatin, paclitaxel and radiation in the treatment of advanced squamous cell carcinoma of the head and neck J. Klocker1, H. Sabitzer2 , W. Raunik2 , S. Wieser3 1 1 st. Medica! Department, 2 Dept. oj Radiotherapy, 3 Dept. oj Otolaryngology, Klagenjurt General Hospital, Klagenjurt, Austria Objective. Encouraged by the experiences of our prospective tria/ (presented in 1998) and according to the international tendency to combined treatment modalities we designed a further pilot study. Due to the very promising results (phase II tria/s, second line chemotherapy) of the schedules containing taxans against squamous celi carcinomas of the head and neck and the lung, we introduced Paclitaxel into our concept. Paclitaxel is also known as a very effective radiosensitizer. Patients and methods. Between March 1998 and April 2000, about 30 patients with advanced squamous celi carcinoma of the head and neck have been treated. The first cycle of the polychemotherapy consists of 175 mg/1112 Paclitaxel and 75 mg/1112 Cisplatin. The course is repeated every three weeks with reduced doses (135mg/m2 and 60 mg/m2 respectively) three up to five times. Radiotherapy starts immediately after the completion of the second cycle. Standard fractionation radiation therapy with a total dose of 72 Gy is applied. Results. We have seen complete remissions in patients with very advanced carcinomas. This regimen seems to be highly effective against advanced squamous cell cancer of the head and neck. On the other hand, we have to face an increase of adverse side effects as well. Correspondence to: Johann Klocker, M.D., 1 st. Medica! Department, Klagenfurt General Hospital, Brunnengasse 3, A-9020 Klagenfurt, Austria. Phone: +4314 04 00 4429; Fax: +4314 04 00 4451. Radio/ Oncol 2000; 34(3): 223-49. Absh·acts / 2nd Interna/iona/ Symposyum on Organ Sparing Treatmen/ HDR brachytherapy in the treatment of cancer of the uterine cervix: Results and complications in 346 patients (1980 -1995) Josef Hammer, Christine Track, Dietmar Seewald, Eva Weis, Johann Zoidl Department oj Radiation Oncology, Barmherzige Schwestern Hospital, Linz, Austria Purpose. The purpose is to present a saje use oj intrauterine high dose rate (HDR) 192-Iridium applications in the primary treatment oj cervical cancer with a combination oj external beam (EBRT) and HDR brachytherapy (BT). Survival data and side effects will be presented. Material and methods. Fram August 1980 to December 1995, 346 patients with cancer oj the uterine cervix underwent primary irradiation in combination with external beam and HDR intracavitary treahnent at the Deparhnent oj Radiation OncologiJ at the Sisters oj Mercy Hospital in Linz, Austria. Mean age was 60.8 years (range 30.1 to 86.6 years). Ali patients were classified according to the FIGO rules: Stage I 64 patients, stage II 186, stage III 93 and stage IV 3 patients. Eight patients were last to follow up. In EBRT a dose oj 1. 7 to 2 Gy per day was given (4 fields per day) with a mean to tal dose oj 37.4 Gy (range 20 -66 Gy) over a mean time period oj 46,6 days (range 35 -77 days). The mean tata/ BT dose was 29.2 Gy (range 4 -46 Gy), the mean dose per fraction 8.2 Gy (range 4 -10 Gy) and the mean number oj fractions was 3.6 (range 1 to 6 fractions). The mean Jollow up time oj survivors is 134 months. Side effects were evaluated according to the glossary oj Chassagne and Sismondi. Results. A complete remission could be achieved in 322 patients (93.1 %); persistent tumor was found in 24 patients at the first follow-up 3 to 5 months after the completion oj irradiation. The actuarial overa/1 sur­vival probability far ali patients at 5 and 10 years is 60.4% and 44.2 % respectively, the disease specific survival probability is 68.2 % and 62.4%. The local control rate at 5 and 10 years is 75.9 % and 73 %, and the disease-free rate 63.5 % and 58.9 respectively. According to stages I, II, and III & IV, the disease-specif­ic survival at 5 years (event: death with ar from disease) was at 91. 7 %, 69.0 %, and 49.3 %, respectively, and at 10 years, it was 87.7 %, 64.4 % and 39.8 % respectively. The actuarial loca/ control probability far stages I, II, and III & IV was 89.9 %, 75.5 %, and 66.0 %, respectively at 5 years, and 87.9 %, 72.9 %, and 61.2 % at 10 years (Kaplan-Meier calculations). Fram ali 346 patients, 54 (15.6 %) presented with moder­ate ar severe side effects. The actuarial rate far grade 2 complications after 5 years is 11.3 % and far grade 3 5.4 %, and after 10 years 11.9% and 6.7 %, respectively. Conclusion. Intrauterine HDR brachytherapy in addition to external beam irradiation far primary treat­ment oj invasive carcinoma oj the uterine cervix provides excellent treatment results, the same as LDR applications concerning survival data and complication rates as well. Our results are matching with tlwse oj other authors very well. The metlwd described above is a very effective tool far primary irradiation oj cancer oj the uterine cervix, and a saje one in experienced hands. Correspondence to: Josef Hammer, M.D., Barmherzige Schwestern Hospital, Department of Radiation Oncology, Seilerstaette 4, A-4010 Linz, Austria. Phone: +43732 76 77 7320; Fax: 43732 76 77 7506; E-mail: josef.hammer@bhs.at Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd International Symposyum on Organ Sparing Treatment Sentinel lymph node biopsy in patients with malignant melanoma Marko Hocevar, Nikola Bešic, Marko Snoj, Tadeja Movrin Institute oj Oncologi;, Ljubljana, Slovenia Background. The issue of elective lymph node dissection (ELND) in patients with malignant melanoma is one of the most controversial issues in the history of surgical oncology. There have been four randomized prospective surgical tria/s which have at present reached sufficient data maturity to draw relevant conclu­sions. The Intergroup Melanoma Surgical Tria/ recruited the highest number of patients (740) and was from the very beginning designed to identify a subgroup of melanoma patients (selected by different prognostic factors) who might benefit from ELND. The results showed that ELND statistically significantly improved the survival in a group of patients with nonulcerated melanomas with the tumor thickness of 1-2 mm and the h1mor location on the limb. An attractive alternative approach to selection of patients with melanoma based on prognostic factors for ELND came in early 1990's when Morton et al. devised the technique of intraoperative lymphatic mapping, sentinel lymphadenectomy and selective complete lymph node dissection (LM/SL/SeLND). LM/SL/SeLND is today considered by most authorities, as a substitute far ELND if "technological transfer" of LM/SL/SeLND, which requires a multidisciplinary team, is consistently and accurately applied. Therefore it is advised to perform LM and se in ali patients with malignant melanoma of the thickness of 1-4 mm according to Breslow. Patients and methods. Fram January 1999 to June 2000, LM and se were pe1formed in 8 patients (7 male, 1 Jemale) after the excision of primary melanoma with a 2 mm margin. Preoperative lymp/wscintigraphy was pe1formed by using 99111Tc-nanocolloid and radioactive "Hot spots" of regional nodes were marked on the skin. Before the re-excision of the primary lesion, Patent Blue was injected intracutaneously around the skin lesion to help additionally identifying the sentinel lymph nodes. Results. The melanoma was located on the h·unk in seven patients and on the head & neck in one patient. The average tumor thickness according to Breslow was 2.83 mm. The sentinel lymph nodes were located in one lymph node basin in five patients with h·unk melanoma and in two lymph node basins (both axillas) in two patients. In the patient with a scalp melanoma, the lymph nodes were located retroauriculary (1) and on the second lymph node neck leve/ (1). The average number of sentinel lymph nodes was 2.25. We managed to identify 14/18 sentinel lymph nodes. Pathological exam revealed micrometastases in one lymph node in three patients. In ali 3 patients, a complete lymph node dissection was performed and no additional metastases were found. The complete lymph node dissection was performed also in two patients in whom sentinel lymph nodes were not found. One of these two patients had 3 metastatic lymph nodes. Conclusion. LM/SL/SeLND is a valuable substitute far ELND if applied consistently and accurately. It enables more individualized approach to the patients with malignant melanoma and therefore minimizes unnecessary morbidity in patients with negative lymph nodes. Correspondence to: Marko Hocevar, M.D., Ph.D., Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 (0)1 232 30 63; Fax: +386 (0)1 4314 180 Radio/ Onco/ 2000; 34(3): 223-49. Abstrncts / 2nd l11ten111tio11al Sy111posywll 0ll Organ Spnri11g Trcafmrnf nocarcinoma in the years 1990 -1996 is presented. Patients and methods. Rena/ tu111ors in early plzase of growth are often diag11oscd by c/za11ce. 111 tlzc lasi 20 years, 115 (9.8%) oj all 1167 diagnosed nnd operatcd hypernephromas at the Clinical Center oj Ljubljana Ljubljana were treated with partial nephrectomy. Tlze patients inc/uded in thc study lzad ade11ocarcino111a renis. A detailed analysis of the rcsults in thc ycars 1990-1996 is prcsentcd. [11 tlzis 5 ycars, we treated 27 patients with partial ncphrectomy. We looked for clinical data, histo!ogy, /ocatio11 oj tw1101; outcome after 5 years. Results. In 3 cases due to positive histologycal margin, radical nephrectomy was done later. One patient had additional resection oj positive 111argi11. Definitive lzistology after tlzc 211d opcmtion was negative. Others 23 patients were disease.free ajter 5 years. Tlze diameter of tumors in lzistology mnged from 2 -4.5 cm. The /ocation of tumors was both the upper and lower part of the kidney. Tlze preoperative 111casure111e11t of lhe tumor was comparab/e to that found in situ. Conclusion. When tumor is located in proper position mtd is not larger Ihan 3 cm in dia111ete1; partial nephrectomy is a treatment oj choice. Patient needs careful follow-up of locni status in next the years. According to the last reports in literature, the dimneter should be reduced to 2 CIII due to 11111/tifocal growi11g pattem. Correspondence to: Bojan Štrus, M.O., Clinical Center, Surgical clinic, Department of Urology, Zaloška 7, Sl-1525 Ljubljana, Slovenia. Phone/Fax: +386 (0)113 23 298; E-mail: bojan.strusca1kclj.si Radio/ O11col 2000; 34(3): 223-49. Abstracts / 2nd Interna/iona/ Symposyum on Organ Sparing Treatment Tikhoff -Linberg operation and major resections of the shoulder girdle standard procedure for limb salvage in sarcoma patients Marko Špiler, Janez Novak, Mojca Sencar Department of Surgical Oncology , Institute of Oncology Ljubljana, Slovenia Baclcground and objectives. This study was undertaken to clarify the clinical results of limb-sparing TikhoffLinberg procedure and major resections in patients with malignant bone and soft-tissue tumors oj the shoulder girdle in our institute between 1980 and 1999. Patients and methods. Fram 1980 to 1999, 39 patients with malignant bone and soft tissue tumors of the shoulder girdle were treated at the Departrnent of Surgical Oncology, Institute of Oncology Ljubljana. In 27 out of 39 patients, a limb-sparing surgical procedure was possible (19 patients had a TiklwffLinberg proce­dure, and 8 major resection oj bone and soft tissue). There were 15 females and 12 males with age range 14 to 71 (median 40 years). Sixteen patients had bone, 10 soft-tissue sarcomas and one with a large bone metas­tasis of thyroid carcinoma. Five patients had chemotherapy, 2 postoperative irradiation and 4 patients had chemotherapy and irradiation. The follow-up period in limb-sparing group ranged from 4 months to 19 years 9 months (median 6 years 4 months). Results. Currently, 15 patients are alive and disease-free Jrom 1 year 3 months to 19 years (median 7 years 6 months); two died of other diseases, 9 died oj the disease (4 of metastases and 5 of local recurrence and metastases) at a mean (SD) interval of 15 months after surgery (range 6-25 months). One patient was last from fo/low-up 6 months after surgery, because he was not resident of Slovenia. Fram 26 patients, 7 devel­oped local recurrence from 6 months to 10 years 3 nzonths after surgery (median 4 years 8 months) and in 3 of them, mnputation was required. The bone was reconstructed only in 6 patients (in 3 with prosthesis, in 2, vascularised fibular graft was used whereas in one intraoperative extracorporeal autogenous sterilized bone graft). Hand-elbow function was excellent in 11, good in 6 and fair in 2 patients. Conclusion. Classical or modified TikhoffLinberg opemtion is a suitab/e limb sparing procedure far tumors of the shoulder girdle. A good hand-e/bow function can be perserved; howeve1; the problem are local recur­rences occurring in approximately 27 percent in this as well as in the majority oj reported series. Correspondence to: Marko Špiler, M.O., Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 (0)1 232 30 63; Fax: +386 (0)1 43 14 180. Radio/ Oncol 2000; 34(3): 223-49. A/Jstracts / 2nd lnternational Symposyum on Organ Sparing Treatme11t Quality of life issues related to organ sparing lan F. Tannock Princess Margaret Ho spital and Llniversity oj Toronto, Canada Two general methods for assessment of quality of lije (QL) will be described: those based 011 questionnaires and utility-based methods that require choice between different health states. QL must be assessed by patients, and its inclusion in clinical tria/s should be as rigorous as far endpoints such as survival. A pri­nzary measure of QL should be defined: in trials of organ sparing, this should reflect function of the organ that is either last or spared. A hypothesis should be established about maintenance of a defined leve/ of func­tion. The primary QL endpoint should be measured far each patient at baseline and as a function of tilne following treatment. Other measures of QL are important to ensure that maintenance of function is not accompanied by deterioration in more globa/ endpoints. In tria/s comparing radical surgery with organ-sparing approaches, it is not necessary to use QL scales to assess the obvious. If survival is identical, organ-sparing approaches are preferred: a person who can speak has better QL than one who cannot. Assessment of QL is important when loss of function is /ess severe, as in lmast conservation. Here most studies have confirmed better QL with lesser surgery, and anxiety about recurrence in the residual breast was unco111mo11. The c/wice between radical and organ-sparing pro­cedures is more complex if surgery leads to substantial loss of ftmction and organ-sparing to a lower prob­ability of cure. Are patients willing to accept a reduction in the probability of survival in order to maintain organ function? Patients with breast cancer are unwilling to avoid toxic treatment far even a sma/1 deficit in survival, but this may be quite different if patients are faced with more severe /oss of function. The aim of organ sparing procedures is to maintain survival with a leve/ of QL as high as possible. Methods are available far evaluating QL in patients treated by different strategies and should be inc/uded as major endpoints, together with survival, in clinica/ tria/s that investigate organ-sparing strategies. These methods will be useft1/ in decision-aiding and especially in framing choices between improved quality and improved quantity of survival. Correspondence to: lan F. Tannock M.D., Ph.D., FRCPC, Princess Margaret Hospital and University of Toronto, 610 University Avenue, Toronto, ON MSG 2M9 Canada. Te!: 1 416 946 2245; Fax: 1 416 946 2082; E-mail: ian.tan­nock@uhn.on.ca Radio/ Oncol 2000; 34(3): 223-49. Abstracts / 2nd Intemntio11al Sy111posyum 011 Organ Spari11g Trealmenl Improving the quality of life of patients with TCC by sequential chemoradiotherapy Borut Kragelj1, Boris Sedmak2, Jožica Cervek1, Tanja Cufer1 1 Institute of Oncology Ljublja11a, 2 Llniversity Medica/ Center Ljubljana, Department of Llrology, Slovenia Objective. Radiothempy with transurethral resection (TUR) combined either with primary polyche111ot/1er­apy (witlz MTX, VLB, CDDP+/-ADR (MVC-RT) ar concomitant monochenzothempy with VLB (RT + V)) assures a lo11g-ter111 survival 1111d conservation of the bladder in more than haif of the patients with invasive tmnsitional celi carcinoma (TCC) of the urinary bladder. If the primary systemic polychemotherapy is suc­cessful, the targct doses (TD) cmz be reduced from 62-66 Gy to 50-60 Gy. The purpose of this research was to find out wlzether the reduction of TD assures better quality of life to thc patients. Patients and methods. Of 186 patients with TCC of thc bladder treated witlz chemomdiotlzerapy in the period from 1988 to 1994, 34 survivors witlz tlze co11served bladder were entered into the study. They were ali requested to fill in a nzodified EORTC QLQ -C30 forms rcgarding their quality of !ife, to assess t!zeir problcms according to thc enclosed SOMA sca/e and to lrnve cystometrogmphy pe1fonned. Results. We receivcd t/1e filled-in fon11s of 26 paticnts. Of these, 14 were treated with sequential chemora­diothempy (MVC-RT) and received a median TD of 51. 7 Gy, whcrcas the remaining 12 received concomi­tant chemoradiothcmpy (RT+V) and a median TD of 63.6 Gy. Urodynamic examination was pe1fonned in 23 patients; of these, 12 wcre treated with MVC-RT, wlzereas 11 with RT+V In view of physical, role, emo­tional, cognitive and social jiuzctions, genemlly better results were observed in the group with lower TD, though the statistically significant differencc was observed only in thc role functioning score (93 % and 63 % at a higher and lowcr TD, respectively; p=0.028). Moreove1; considering thc symptoms of chronic post-irra­diation /csion of tlzc rectum mzd uri1111ry bladde1; a simi/ar observation was made. Patients having received lower TD presented with general!y less scrious problems, statistically 11111rgi1111I differences were noticed in the micfion mte (p=0.06), lzcmaturia (p=0.119) and thc mtc of uncontrolled defecations (p=0.131). From the cysto111etrogmphy measuremcnts, 11 median 11111xi111u111 capacity of the urinary bladder was assessed to be 348 ml (398 and 294 ml, at a lowcr and higlzer TD, rcspectively; p=0.05). Reduced compliance of the uri­nary bladder was observed in 7 /23 patients (2/12 patients and 5/11 patients at 11 /ower and higher TD, respective!y; p=0193). Hyperactivity 111e11sureme11ts did not show any significant differences. The whole group had high trcatment tolerance (97.1 %: 94.6% MVC-RT and 100% RT+V; p=0.0095). Conclusion. A co111bi1111tion of TUR and MVC-RT with histological co11fir11111tion of CR by biopsy of tumor bed carricd out prior to mdiothempy allows thc irmdiation witlz lower TD, thereby decreasing the toxicity of the trcatment and assuring a better qua!ity of !ife to patients. Correspondence to: Borut Kragelj, M.D., M.Se., Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 (0)1 323 063; Fax: +386 (0)1 13 14 180. Radio/ 011col 2000; 34(3): 223-49. Abstracts / 211d llltcrnnlio11nl Sy111posy11111 011 Orgn11 Spnri11g Tre11/111mt Factors influendng rehabilitation neck cancer Irena Hocevar-Boltežar, Lojze Šmid, Miha Žargi, Avgust Župevc, Igor Fajdiga, Janez Fischinger, Ana Jarc University Medica! Cente,; Department of Otorhinolnryngology nnd Cervicofncial Surgery, Ljub/jn11n, 5/ovenin Purpose. The purpose of the prospcctivc study wns to idcntify t!,e factors adversely i11flue11cing the post. treatment rehabilitation i11 patieJZts with /zead mzd ncck cnncer. Patients and methods. One h1111dred 1111d ten p11tie11ts were examined bejlJre surgicnl treat111e11t in order to find unfavorable factors: impnired hearing acuity, defective tectlz, impnired pul111011ary fw1ctio11, and speec/1 disorders. The rel,11bilitatio11 was plnnned according to t!,e fi11di11gs obtained. TJ,e patie11ts evaluated tlzeir speech, swallowing, and general success oj tl1eir rclwhi/itation (rei11tegratio11 in thcir l10111e e11viro11111e11t) 12 111011ths after tlze treat111e1Zt. The injluence of possible zmfavorab/e jactors, tumor sitc, and surgery extent 011 speech, s,ual/owing and rci11tegratio11 compctcnce was dcternzinate using x2-test. Results. The site of the tumor and the type oj surgery did not i11flue11ce tlze qua!ity oj rehabilitation in gen­eral. Dejective teeth i11jlue11ced the ability oj swallowing, lmt not spcech. Heari11g loss impaired tlzc pntic11t's reintegration in lzis/her home e11viro11111c11t. Impaired p11l111011ary f1mctio11 did not ajject pntient's speec/1. Speech was the poorcst in the lnry11gecto111izcd patients. Howeve,; nhout two thirds of ali pntients wcre sat­ isjicd witlz tlzeir cnpability oj specch, swallowing and tlzeir re/zabilitatio11 in general. Conclusions. Enrly ide11tificntio11 of u11favomble jactors, individually pla1111ed relw/Jilitati011 mu.f i11te11sive help oj dijjerent professionals (ENT surgcon, p/1011iatricia11, speeclz thcmpist) ca11 e11s1!re a proper relzabili­tation oj the affected f1111ctio11s a11d a suitahlc qua!ity oj life for patients tl111t !zave 1111dcrgone surgcry for head a11d neck cnncer. Correspondence to: /\ss. Prof. Irena Hocevar-Boltežar, M.O., l'h.D., Dcparlment of and Cervicofacial Surgery, KC Ljubljana, Zaloška 2, SI-rnoo Ljubljana, Slovenia. Phonc: +386 (0)1 BI (0)1 132 23 50; E-rnail: ircna.hocevar-boltezar(wguest.arnes.si Rndio/ O11col 2000; 34(3): 223-49. Radio/ Oncol 2000; 34(3): 251-9. review Breast and axilla conserving surgery in the management of early-stage breast cancer Mogens Blichert-Toft Department of Endocrine & Breast Surgery, Rigshospitalet, Copenhagen, Demnark The main incentive to breast conserving therapy (BCT) relates to preserving Jemininity and avoiding the feeling oj Jemale inferiority and a disfigured body image. Some women are even more concerned about pre­serving the breast rather than preservi11g lije. The preconditions far BCT are satisfactory cosmesis, good physical Junction, and loco-regional disease control. If the breast is badly disfigured following BCT there is little sense in breast conservation. The mainstay oj early-stage breast cancer treat111ent is surgery. One option is breast conservation in case oj eligibility. Radicality oj the surgical procedure is emphasized whether mastectomy ar breast conservation has been zmdertaken. Risk factors related to BCT in particular are scrutinized, and especially young age and extensive dueta/ components oj the specimen are dealt with as independent risk factors far local control in BCT BCT in Denmark amounts to about 30 % oj operations in breast cancer. This is a rather low frequency co111pared with figures from other countries. Consequently, the Danish eligibility criteria are discussed. The reasons far axi/lary dissection are emphasized. Even in sma/1 tumours below 10 mm, axillary dissection is indicated due to a considerable involvement oj axillary nodes. The introduction oj the sentinel node principle seems to provide a basis far conservation oj healthy axillary lymph nodes in node negative patients. Key words: breast neoplasms -surgery; Iymph node excision; axi/la; breast conserving; self concept Received 28 April 2000 Accepted 10 May 2000 Correspondence to: Prof. Mogens Blichert-Toft, Rigshospitalet 3104, 2100 Copenhagen, Denmark. Phone: +45 3545 2117; Fax: +45 3545 3642; E-mail: mbt«orh.dk Introduction The mainstay of early-stage breast cancer treatment is surgery. The aim of surgical intervention is primarily to ensure loco­regional tumour control. Further, meticulous surgery also embraces the intent to cure potentially curable patients. A radical surgical approach seems most important in early-stage disease due to the limited risk of distant spread in case of small tumours, especially below 2 cm in diameter at Blicizert-Toft M/ Cu11servi11g surgery i11 breast cancer diagnosis.1, 2 Similarly, age at the tirne of diag­nosis turns out to be a considerable risk factor of distant dissemination.2, 3 Recent calcula­tions report the VSO value where the term VSO is the tumour volume far which a distant spread has occurred in half of the patients. Under the age of 35 years at diagnosis, the VSO value was faund to be 11 ml compared to 42 c.cm between 35-45 years and 35 c.cm above 45 years.2 These data are supported by recent DBCG (Danish Breast Cancer Cooperative Group) results showing that young patients below 35 years of age at diagnosis revealed a significantly higher risk of being node positive and significantly fewer patients at that age were faund to harbour tumours of malignancy grade I.3 Further, women below 35 years of age at diagnosis had the worst prognosis with a 1.44 fald increased risk of dying frorn their disease. The assurnption of more aggressive tumours in young patients is further empha­sized by the DBCG observation that low-risk, node-negative patients less than 50 years of age at diagnosis not treated with adjuvant sys­ternic therapy revealed a highly significant risk of dying with decreasing age. However, this trend was not faund in young patients receiving adjuvant systemic therapy.3 There seems to be no doubt that young patients do harbour more aggressive tumo­urs, irrespectively of tumour size. Conse­quently, in order to ensure loco-regional con­trol and cure in potentially curable patients especially the young patients should be offered aggressive therapy whether or not the tumour is sma]J.3 The main question, howev­er, is whether breast conserving therapy can be offered especially the young patients tak­ing into account the peculiarities of the tumours of that particular age group. Breast conserving therapy Breast conserving therapy (BCT) far invasive breast carcinoma comprises a complete exci­ sion of the tumour-bearing part of the breast, axillary dissection if node positivity has been proved, and irradiation of residual breast tis­sue. During the past decade, BCT has been an established and accepted method in manag­ing the invasive breast carcinoma. In June 1990, The National Institute of Health, Bethesda, held a consensus conference aim­ing at the approval of BCT. The Conference concluded that "BCT is an appropriate me­thod of primary therapy far the majority of women with stage I and II breast cancer and is preferable, because it provides survival rates equivalent to those of total mastectomy and axillary dissection while preserving the breast".4 During the tirne elapsed, BCT has been applied widely, but implemented with varying degrees of frequency. With growing experience, the eligibility criteria might shift to become more restrictive.5 Moreover, the possibility of perfarming skin sparing mas­tectomy combined with primary reconstruc­tion of the breast in a one-stage procedure further narrows the indications of BCT. Finally, the lack of mammographic screening far breast cancer reduces the widely use of BCT. What worries many surgeons is the fact that breast conserving surgery (BCS) infrin­ges on the basic surgical principle, viz. to achieve surgical radicality, especially in small tumours in which therapeutic radicality is most important.1 Although the tumour has been entirely removed, there is a high proba­bility that residual cancerous faci are left behind in the breast by undergoing BCS.6,7,8 Incomplete excision of cancerous tissue and close margins increase the risk of local recur­rence in BCT. 8 Further, loco-regional recur­rence has a detrimental effect on survi­ 9,10,11 vaJ. Consequently, the key question about mul­tifacality and multicentricity of the tumour burden remains. In their excellent work on histologic multifacality in Tl-2 invasive carci- Radiol Oncol 2000; 34(3): 251-9. Blichert-Toft M/ Co11servi11g surgery in breast cancer nomas treated by mastectomy, Holland et al.6 concluded that 37 % of tumours were unifacal showing no tumour faci in the mastectomy specimen around the index mass. In 20 %, the tumour faci were present within 2 cm, and in 43, the faci were faund more than 2 cm from the reference tumour. In another study by Sismondi et al.12, multifacality and multicen­tricity prevailed in young patients and in patients of 35 years of age or less compared to elderly patients, viz. 35 % vs. 19 %, 36 % vs. 16%, respectively. Similar results were obta­ined from another study by Anastassiades et al.13 on multicentricity defined as one or more faci of in situ or invasive carcinoma in one or more quadrants other than the one harbouring the reference mass. Multicent­ricity appeared in about half of the patient series and was a frequent finding in patients 55 of years of age or less. Multicentricity pre­vailed in larger tumours, but was demonstrat­ed in 16 % of tumours up to 2 cm. In a failure analysis, Kurtz et al.14 interest­ingly showed that the patients of less than 40 years of age treated far breast carcinoma by BCT had a significantly higher risk of local recurrence compared to older patients, 19 % vs. 9%, after a median fallow-up period of 11 years. Kurtz et al.15 also observed that patients with macroscopically multiple cancers treated by BCT developed recurrence in the treated breast significantly more frequently compared to the patients with a single tumour, viz. 25 % vs. 11 %, after a median fallow-up of 71 months. Further, Voogd et al. pooled the data from two large randomized studies (EORTC and DBCG)16, 17 comparing the outcome of BCT with that of mastectomy. The study group faund that the age below 35 years or less and extensive intraductal component were signifi­cantly associated with an increased risk of local recurrence after BCT. The median fallow­up of patients still alive was 9.7 years. The haz­ard ratio far age was 9.2 (95 % CI 3.7-22) com­pared to the age over 60 years, and far intra­ductal component in association with index mass, the ratio amounted 2.5 (95 % CI 1.3-5.0) (personal communication). Eligibility criteria of BCT in Denmark In Denmark, the application of BCT has car­ried the stamp of cautiousness. During the years from 1983 to 1989, BCT was tested against mastectomy in a clinical randomized tria! recruiting 905 patients faund to be eligi­ble far the study.17 Very few patients had BCT in the 1980's outside the context of the DBCG protocol (82-TM). On a national scale, the per­centage of BCT made up 8 % of surgical pro­cedures in the management of operable breast carcinomas. Approximately one third of the patients below 70 years of age was faund to be eligible far BCS. In the nineties, the perfarmance of BCT has increased. The national figure of BCT fre­quency constituted 24 % of surgical proce­dures in operable breast carcinomas, while mastectomy made up 74 %. In 2 %, the proce­dure was not registered in the DBCG data base. The development of applying the BCT as a surgical option in Denmark is apparent from Figure l. Generally speaking, the frequency is low. However, the incidence has increased over tirne. Further, the frequency of BCT vari­es among centers being highest in areas with mammographic screening far breast cancer and in the centers where the surgeon works as an integral part of a specialist breast team. In Denmark, the treatment of breast can­cer is organized and conducted by the DBCG by running nationwide predetermined proto­cols. Approximately 95 % of ali newly diag­nosed breast cancer cases are registered on case report farms and processed within the DBCG data base. 18 All of the disciplines involved in breast cancer management work within the frame of DBCG according to the agreed guidelines in order to ensure and maintain high professional standards. Radio/ 011col 2000; 34(3): 251-9. Blichert-Toft M/ Conserving surgery in breast cancer Per cent 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 County (1-15) Figure l. The distribution of BCT in Denmark from 1983 to 1997 divided into 5-year periods related to individual counties. The decision-making whether or not to perform BCS is based on the knowledge of the natura! history of breast cancer and the updated results of BCT as mentioned earlier. Consequently, grave concern is given to surgi­cal radicality, notably in small tumours, young age, extensive intraductal components, multifocality, and multicentricity. DBCG recommendations far BCT 1) Small tumours allowing complete excision with free margins verified histologically. In unifocal tumours with no tumour foci around the reference mass, approximately a 5mm free margin is required. In tumours with tumour foci (invasive or intraductal) present in the vicinity of the reference mass, approxi­mately a 10 mm distance from the edge of the tumour area to the nearest margin is advised. In Denmark, the national figure of tumour size has not changed considerably over the past 20 years and is on average 26 mm, mea­sured histologically. A relatively large tumour diameter at the tirne of diagnosis puts a limit to the performance of BCS. Radio/ Oncol 2000; 34(3): 251-9. 2) An excellent to good cosmetic outcome is mandatory for the execution of BCS. To obtain a satisfactory cosmetic result, the ratio of tumour size to breast volume is decisive. A relatively large tumour size in Danish pati­ents constitutes an obstacle to limited surgery in the management of breast carcinomas. 3) Tumour location. The preferable tumour location for BCS is in the periphery of the breast. Tumours located close to the nipple areola complex are less fit for resection and radicality is difficult to safeguard if cosmesis has to be valued. Tumours located in the lower half of the breast might also create dif­ficulties from a cosmetic point of view. In such cases, primary breast reconstruction mi­ght constitute an alternative surgical option. 4) Patient's preference plays a role in the deci­sion-making. The decision may be influen­ced by the wish to avoid radiotherapy which might not be employed in case of mastectomy. Maybe radiotherapy facilities are not available and the patient has to trave! a long distance. The patient has a genuine preference for mas­ Blichert- Toft M/ Conserving surgery in breast cancer tectomy owing to safety reasons although ful­filling the eligibility criteria of BCT. 5) Surgeons preference. Undoubtedly, the surgeon' s own experience, training, and firm belief has an impact on the decision wheth­er or not to remove the breast. This factor might contribute to the varying frequency of BCT executed in the various regions in Den­mark. 6) Age, definitely, influences the decision­making. Due to abundant and dense breast tissue in young age, the tumour might be dif­ficult to delimit. Further, there is an increased risk of multifocality and multicentricity in young age as previously stated. These issues taken together with more tumour aggressive­ness underline the necessity of radical and meticulous surgical removal of tumour. Un­der these conditions, surgeons might prefer mastectomy to BCT. 7) The policy of primary chemotherapy in large tumours to make the tumour diminish has a bearing on employing BCT. In Den­mark, primary chemotherapy is employed in case of locally advanced breast cancer, but not as an up-front therapy prior to BCT. Advantage and outcome of BCT The main incentive to BCT relates to retaining femininity and avoiding the feeling of female inferiority and a disfigured body image. The most important prerequisites for achieving these goals in BCT are a satisfactory cosme­sis, good physical function, and loco-regional disease control. On the other hand, preserv­ing the breast does not by itself prevent emo­tional sequelae as seen in postmastecto­my.19,20 In particular, the younger patients undergoing mastectomy score clearly lower on body image compared to BCT.20 The dilem­ma is obvious. The younger patients most in need of breast preservation are those less eli­gible for the procedure. Today, BCT is an accepted method in the management of potentially curable patients found to be eligible for the method.21 How­evei. eligibility criteria differ between centers and even among countries and there is a con­siderable geographic variation in the utiliza­tion rates of BCT. The influence of these diver­sities upon routine BCT outcome is not thor­oughly reported. However, tirne to loco-regi­onal recurrence, tirne to distant progression, and overall survival are found to be equal in most major randomized trials comparing BCT with mastectomy, viz. NSABP-B-06, Milan I, EORTC 10801, DBCG 82TM.16,17,21 Tumour size, nodal status, histological grade, and vas­cular invasion are prognostic factors for poor outcome and of the same magnitude regard­ing BCT and mastectomy. However, in ran­domized trials young age and extensive intra­ductal components seem to increase the risk of local recurrence in the BCT series compared with mastectomy (personal communication). Loco-regional recurrence after BCT The prognosis related to loco-regional recur­rence (LR) after mastectomy is well known, while the situation in BCT is less clarified. A study combining the results from the EORTC16 and DBCG17 randomized trials on BCT vs. mastectomy revealed that LR occur­red significantly earlier in the mastectomy group, on an average 1.2 years.22 Approx­imately 8 % of the series had LR as the first event in a 10-year of follow-up. Overall, 49 % with LR as a first event died within 74 months of follow-up after salvage treatment. The survival curves were compara­ble with 5-year survival rate of 58 % in mas­tectomy and 59 % in BCT. The most common local therapy of LR in BCT was salvage mas­tectomy and in mastectomy excision with or without radiotherapy. Radio/ Onco/ 2000; 34(3): 251-9. Bliclzert-Toft M/ Conserving surgery in breast ca11cer Overall, 35 % of patients with LR as the first event developed a subsequent LR .. There was no significant difference between the actuarial curves of BCT and maste,ctomy pre­senting 5-year actuarial LR rates of 62 % in the mastectomy group and 63 % in BCT. Ali sub­sequent LR appeared within a tirne span of 5.5 years after salvage therapy. The study seems to indicate that LR as the first event after initial BCT or mastectomy basically harbours the same biological poten­tial of spread and consequently bears the same bad prognosis. Conservation of axillary lymph nodes At the St. Gallen Conference, 1998, the In­ternational Consensus Panel advanced the statement that the most relevant factor for the assessment of risk in breast cancer remains the axillary nodal status and the number of nodes involved.23 Further, agreed European guidelines claim that histological node status should be obtained in the women with inva­sive cancer having a planned curative opera­tion. 24,25 Minimal requirements are four nodes retrieved and examined if a sampling procedure is done, otherwise 10 nodes exam­ined are preferable in level I-II dissections. The prime objectives of axillary surgery in the management of potentially curable breast carcinomas are 1) accurate staging, 2) treat­ment to cure, and 3) quantitative information of metastatic lymph node involvement for prognostic purposes and allocation to adju­vant treatment protocols.26 It is agreed that no physical examination of the axilla, no imaging techniques, and no molecular biologic markers can today replace axillary surgery for staging purposes. Under­staging the axilla is detrimental to fina! out­ 26,27,28 come. The extent of axillary dissection has a bearing on all three outcome measures men­tioned above, why "adequate" surgery gener- Radiol 011co/ 2000; 34(3): 251-9. ally is recommended. Normally, adequate surgery means the dissection of axillary leve! I and II, -and leve! III if suspicious nodes are palpated at that leve! during operation. It is important to avoid axillary failure. Ordinarily, a total axillary dissection (level I-III) provides a low risk of subsequent axillary failure, less than 1-2 %. On the other hand, if less than a total dissection has been done, the risk of axillary failure turns out to be inversely pro­portional to the number of nodes retrieved.27 Axillary recurrence seems to reduce survival probabilities, causes significant patient mor­bidity, is difficult to salvage, and might lead to uncontrollable axillary disease.29 It is well established that the frequency of axillary lymph node involvement is directly proportional to tumour size. The proposal has been put forward that, in small tumours, the axillary dissection can be avoided. This sug­gestion seems not to be supported by the recent Danish national figures on the fre­quency of axillary spread based on the results from 16,660 DBCG patients below 75 years of age operated upon during the period 1990­1997 and with at least four axillary nodes removed.26 Overall, 44 % of patients had axil­lary nodal spread. The percentage of node Per cent axil. pos. I-10mm 11-20mm 21-30mm 31-mm Tumour dimnctcr Figure 2. Distribution of node positivity by axillary dissection in operable breast carcinoma patients relat­ed to tumour size. Blic/1ert-Toft M/ Co11servi11g surgery in brcast cancer positivity increased from 21 % in tumours 1­10 mm in diameter as measured by the pathologist up to 72 % in tumours more than 30 mm in diameter (Figure 2). In Tla tumours, 5 mm or less, node positivity reached 16 % and in Tlb, 6-10 mm, the value was 23 %. Further, it appeared that the percentage of patients with four or more positive nodes (N=7,631) increased from 23 % in node posi­tive tumours of 1-10 mm up to 59 % in node positive tumours of more than 30 mm in diameter (Figure 3).26 The tumour burden seems to be high even in case of small tumours. Consequently, the avoidance of axil­lary dissection seems not advisable, and espe­cially not from the point of view that radical surgery seems most important in the man­agement of the very early stages of breast can­cer.1 ,2 Pcr cent of axil. pos. pts. 3 pos. nodes 31-mm 1-lOmm 11-20mm 21.30mm Tumour diamcter Figure 3. Percentage of patients with four or more pos­itive axillary nodes related to tumour size in node-pos­itive patients with operable breast carcinoma. Se11ti11el 11ode Whether or not to clear the axilla stili repre­sents a dilemma. The procedure carries a cer­tain morbidity and functional sequelae. Further, no advantage is gained by removing healthy lymph nodes in node negative axillas, rather on the contrary. The introduction of the sentinel node pro­cedure may salve the problem and contribute to the lymph node conservation in surgical oncology. The basic principle encompasses lymphatic mapping of the axilla and selective lymphadenectomy with the intention to iden­tify a particular lyrnph node in a regional lyrn­phatic basin assurned to be the first node in a direct drainage pathway. This particular node is described as the sentinel node.30,31 If the sentinel node retains metastatic spread, the risk of involvement of non-sentinel nodes in the axilla cannot be neglected and the axilla should be dissected. If the sentinel node is not involved, no further action seerns to be taken and no additional surgery is needed. The eligibility criteria for the usage of the sentinel node method in the management of breast cancer are not yet completely agreed upon. Most commonly, the criteria laid down are tumours with a diameter less than 4 cm, unifocal lesions, and palpatory negative axil­las, also negative by ultrasound and fine nee­dle biopsy. However, in many institutions the criteria are handled more strictly. The method is so far not yet widely implemented, and a more liberal access to the procedure needs the gathering of breast cancer surgery on fewer hands in order to keep up experience, training, and high professional standards. A crucial point for routine use of the method is documented expertise demonstrat­ing a sufficient high detection rate of the sen•• tinel node (preferably approximately 90 %) and an acceptable low rate of false negative node (preferably below 5 %), i.e. metastatic spread to axillary non-sentinel nodes while the node appointed the sentinel node is proved without metastasis. The detection rate of sentinel node varies with the technique used and values below 90 % are in fact given. In most institutions of excellence the sen­ tinel node method has been adopted as a rou­ tine procedure. The method is stili under eval­ uation and intensive research projects are Rndiol Oncol 2000; 34(3): 251-9. Blichert-Toft M/ Conserving surgery i11 breast cancer launched. It is beyond the scope of this pre­sentation to cover this vast field of research and progress. Undoubtedly, the sentinel node will change the policy of managing the axilla and will provide a basis for conservation of healthy lymph nodes in node negative patients. References l. Hellman S. Natura! history of small breast can­cers. J Ciin 011co/ 1994; 12: 2229-34. 2. Tubiana M, Koscielny S. The rationale for early diagnosis of cancer. The example of breast cancer. Acta O11col 1999; 38: 295-303. 3. Kroman N, Jensen M-B, Wohlfahrt J, Mouridsen HT, Andersen PK, Melbye M. Factors influencing the effect of age on prognosis in breast cancer. Population based study. Br Med J 2000; 320: 474-8. 4. NIH consensus conference. Treatment of early­stage breast cancer. JAMA 1991; 265: 391-5. 5. Voogd AC, Repelaer vDOJ, Roumen RMH, Crommelin MA, Beek vMWPM, Coebergh JWW. Changing attitudes towards breast conserving treatment of early breast cancer in the Southeastem Netherlands: Results of a survey among surgeons and a registry-based analysis of pattem of care. Eur J Surg Oncol 1997; 23: 134-8. 6. Holland R, Veling SHJ, Mravunac M, Hendriks JHCL. Histologic multifocality of Tis, Tl-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Ca11cer 1985; 56: 979­90. 7. Schnitt SJ, Connolly JL, Khettry U, Mazoujian G, Brenner M, Silver B et al. Pathologic findings on re-excision of the primary site in breast cancer patients considered for treatment by primary radi­ation therapy. Ca11cer 1987; 59: 675-81. 8. Harris JR, Connolly JL, Schnitt SJ, Cady B, Love S, Osteen RT et al. The use of pathologic features in selecting the extent of surgical resection necessary for breast cancer patients treated by primary radi­ation therapy. Ann Surg 1985; 201: 164-9. 9. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F et al. Postoperative radio­therapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl] Med 1997; 337: 949-55. 10. Overgaard M, Jensen M-B, Overgaard J, Hansen PS, Rose C, Andersson M et al. Postoperative radiotherapy in high-risk postmenopausal breast cancer patients given adjuvant tamoxifen: DBCG 82C randomised tria!. Lonce/ 1999; 353: 1641-8. 11. Shukla HS, Melhuish J, Mansel RE, Hughes LE. Does local therapy affect survival rates in breast cancer. Ann Surg Onco/ 1999; 6: 455-60. 12. Sismondi P, Bordon R, Arisio R, Genta F. Local recurrences after breast conserving surgery and radiotherapy: correlation of histopathological risk factors with age. Breast 1994; 3: 8-13. 13. Anastassiades O, Iakovou E, Stavridou N, Gogas J, Karameris A. Multicentricity in breast cancer. A study of 366 cases. Am] Ciin Pa/ho/ 1993; 99: 238­43. 14. Kurtz JM, Spitalier J-M, Amalric R, Brandone H, Ayme Y, Bressac C et al. Mammary recurrence in women younger than forty. lili J Radia/ Onco/ Biol Phys 1988; 15: 271-6. 15. Kurtz JM, Jacquemier J, Amalric R, Brandone H, Ayme Y, Hans D et al. Breast conserving therapy for macroscopically multiple cancers. Amz Surg 1990; 212: 38-44. 16. Dongen vJA, Bartelink H, Fentiman IS, Lerut T, Mignolet F, Olthuis G et al. Randomized clinical tria! to assess the value of breast-conserving ther­apy in stage I and II breast cancer, EORTC 10801 tria!. J Noti Cancer lllst Monogr 1992; 11: 15-8. 17. Blichert-Toft M, Rose C, Andersen JA, Overgaard M, Axelsson CK, Andersen KW et al. Danish ran­domized tria! comparing breast conservation ther­apy with mastectomy: Six years of life-table analy­sis. J Na// Cancer Inst Monogr 1992; 11: 19-25. 18. Fischerman K, Mouridsen HT. Danish Breast Cancer Cooperative Group, DBCG. Structure and results of the organization. Acta Oncol 1988; 27: 593-6. 19. Meyer L, Aspegren K. Lang-term psychological sequelae of mastectomy and breast conserving treatment for breast cancer. Acta Onco/ 1989; 28: 13-8. 20. Poulsen B, Graversen HP, Beckmann J, Blichert­Toft M. A comparative study of post-operative psy­chosocial function in women with primary opera­ble breast cancer randomized to breast conserva­tion therapy or mastectomy. Eur] Surg Oncol 1997; 23: 327-34. 21. Morris AD, Morris RD, Wilson JF, White J, Steinberg S, Okunieff P et al. Breast-conserving therapy vs mastectomy in early-stage breast can- Radio/ Onco/ 2000; 34(3): 251-9. Blichert-Toft M/ Co11servi11g surgery in /Jreast cm1cer cer: A meta-analysis of 10-year survival. Cancer J Sci Alll 1997; 3: 6-12. 22. Tienhoven vG, Voogd AC, Peterse HL, Nielsen M, Mignolet F, Andersen KW et al. Prognosis after treatment for loco-regional recurrence in two ran­domized trials comparing rnastectorny with breast conserving therapy, EORTC 10801, DBCG-TN82. Eur J Cancer 1999; 35: 32-8. 23. Goldhirsch A, Glick JH, Gelber RD, Senn H-J. International consensus panel on the treatrnent of prirnary breast cancer V: Update 1998. In: Senn H­J, Gelber RD, Goldhirsch A, ThLrlimann B, edi­tors. Adjuvanl therapy of primary breast cancer VI. Berlin: Springer-Verlag; 1998. p.481-97. 24. The British association of surgical Oncology, BASO. The guidelines for surgeons in the manage­ment of symptornatic breast disease in the UK. Eur J Surg Onco/ 1998; 24: 464-76. 25. Blichert-Toft M, Smola MG, Cataliotti L, O'Higgins N, on behalf of the European society of surgical oncology. Principles and guidelines for surgeons -rnanagement of symptomatic breast cancer. Eur ] Surg Onco/ 1997; 23: 101-9. 26. Blichert-Toft M. Axillary surgery in breast cancer management: Background, incidence and extent of nodal spread, extent of surgery and accurate axillary staging, surgical procedures. Acta Oncol 2000 (in press). 27. Graversen HP, Blichert-Toft M, Andersen JA, Zedeler K. Breast cancer: Risk of axillary recur­rence in node negative patients following partial dissection of the axilla. Eur J Surg Oncol 1988; 14: 407-12. 28. Grabau DAa, Jensen M-B, Blichert-Toft M, Andersen JA, Dyreborg U, Carstensen B et al. The importance of surgery and accurate axillary stag­ing for survival in breast cancer. Eur J Surg Oncol 1998; 24: 499-507. 29. Recht A, Pierce SM, Abner A, Vidni F, Osteen RT, Love SM et al. Regional nodal failure after conser­vative surgery and radiotherapy for early-stage breast carcinoma. J Ciin Oncol 1991; 9: 988-96. 30. Rutgers EJTh, Jansen L, Nieweg OE, Vries Jd, Koops HS, Kroon BBR. Technique of sentinel node biopsy in breast cancer. Eur J Surg Oncol l998; 24: 316-30. 31. Cox CE, Bass SS, Boulware D, Ku NNK, Berman C, Reintgen DS. Implementation of new surgical technology: Outcome measures for lymphatic mapping of breast carcinoma. Ann Surg Onco/ 1999; 6: 553-61. Radio/ Oncol 2000; 34(3): 251-9. Radio/ Oncol 2000; 34(3): 261-4. revtew The intraoperative examination of axillary sentinel nodes Giuseppe Viale Department of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine, Milano, Italy Routine histological examination of axillary sentinel nodes predicts the nonsentinel axillary node status and may allow to spare axillary clearing in patients with breast cancer. To avoid the need far two separate sur­gical sessions the results of sentinel node examination should be known intraoperatively. Routine frozen sec­tion examination of sentinel nodes, howeve1; is liable to yield false-negative results. An extensive intraop­erative examination of frozen sentinel nodes which wou/d attain a sensitivity comparable to that obtained by routine histological analysis has been therefore devised. The frozen sentinel nodes are subserially sec­tioned at 50 µm intervals. Far each leve/, one section is stained with hematoxylin and eosin (H&E) and the other immunostained far cytokeratins using a rapid immunocytochemica/ assay. Immunocytochemistry did not increase the sensitivity of the examination. The general concordance between sentinel and axillary node status was 96. 7 %; the negative predictive value of intraoperative sentinel node examination was 94.1 %. The intraoperative examination of axillary sentinel nodes is effective in predicting the axillary node status of breast cancer patients and it may be instrumenta/ in making the decision to spare axillary c/earing. Key words: breast neoplasms -surgery; lymph node excision; axilla; lymph nodes -patlwlogy; intraoper­ative period; immunohistochemistry Introduction The axillary sentinel node biopsy (i.e. the biopsy of the first node draining the lymph from the tumour) in patients with small pri­mary breast carcinomas and clinically unin­volved axillary nodes is rapidly gaining wide Received 10 May 2000 Accepted 5 June 2000 Correspondence to: Giuseppe Viale, MD, FRCPath, Via Ripamonti 435, 20141 Milano, ltaly. Phone: +39 0257489419; Fax: +39 0257489417; E-mail: giuseppe.viale@ieo.it 4 diffusion.1-_Severa! investigations have docu­mented that this procedure has a very high (96 to 100 %) negative predictive value with res­pect to the status of the remaining nonsen­tinel axillary nodes, and may avoid unneces­sary axillary lymph node dissection (ALND) in patients with negative sentinel nodes.5­ Axillary lymph node status is the most powerful prognostic parameter in breast car­cinoma patients, and dictates the choice of the post-surgical adjuvant treatment. Because it is not possible to assess the node status clinically or by imaging techniques, ALND Viale G / Intraoperative examination of sentinel nodes with the removal of at least part of the axillary nodes has represented till now the treatment of choice in ablative or conservative breast surgery. ALND, however, may lead to several com­plications, like oedema, numbness, pain and weakness of the arm. Furthermore, mammo­graphic screenings and women's conscious­ness have resulted in an ever increasing pre­valence of patients being treated with ALND for very small primary tumours. Accordingly, these patients are less likely to have already developed axillary node metastases. Indeed, ALND will yield uninvolved lymph nodes in approximately 65-70 % of patients with small (pTl) primary tumours.5-7 Also, it should be taken into account that approximately 25 % of the patients who have undergone ALND and are without histopa­thological evidence of axillary metastases (pN0) will experience disease progression. This is most likely due to an inaccurate sam­pling or examination of all the nodes removed by ALND with the missing of (micro)metasta­tic foci. Indeed, the re-examination of axillary nodes by serial sectioning or use of more sophisticated techniques (e.g. immunocyto­chemistry for cytokeratins) allows to identify the missed metastases and to up-stage a simi­lar percentage of patients. The SNB may spare ALND in patients with uninvolved sentinel nodes, and at the same tirne enables the pathologists to extensively examine individual (or very few) lymph nodes by serial sectioning and use of immunocyto­chemical techniques. This results in the high­est likelihood of detecting even the smallest metastatic deposits with a more correct stag­ing of the disease. Indeed, the prevalence of sentinel lymph node metastases in patients with small (pTl) primaries is much higher than expected, almost reaching 35 % of the ca­ses. In approximately 40 % of these patients, the sentinel nodes are the only involved axil­lary nodes, thus reinforcing the validity of the SNB concept.8-10 Though the short follow-up period does not allow to evaluate the clinical course of the disease in patients with uninvolved sentinel nodes, it is likely that the SNB procedure will allow to identify true pN0 patients with a very favourable prognosis. The histopathological examination of axil­lary sentinel nodes To be effective in the management of breast carcinoma patients, SNB must rely upon an extremely careful and extensive histological examination of the sentinel nodes, which must be entirely and serially sectioned at reduced intervals. Both, computer simula­tions and the current practice have docu­mented that to identify small micrometastatic foci (2 mm in size or less) the sentinel nodes must be sectioned at 50-200 microns inter­vals, with the examination of up to 60 or more sections per node. 7,11 The histological examination of the axil­lary sentinel nodes may be performed on per­manent sections of formalin-fixed, paraffin­embedded tissue, or intraoperatively on frozen sections. This latter procedure has the advantage of enabling to complete the surgi­cal treatment of the primary tumour and of the ALND in a single session. Again, even in the case of an intraoperative examination of the sentinel nodes, the nodes must be entire­ly and serially sectioned. Indeed, the exami­nation of few frozen sections of only a moiety of the node (as routinely done for other pur­poses) will lead to an unacceptably high number of false negative diagnoses. To overcome this drawback, we have devised a procedure for the extensive intraop­erative examination of the axillary sentinel nodes.7 The nodes are bisected and both moi­eties are frozen in isopentane chilled by liq­uid nitrogen. Fifteen pairs of frozen sections are then cut at 50 microns intervals from each moiety. Whenever lymph node tissue is left, Radio/ Onco/ 2000; 34(3): 261-4. Viale G / Intraoperative examination of sentinel nodes additional pairs of sections are cut at 100 micron intervals, until the complete examina­tion of the node. One section of each pair is routinely stained with haematoxylin and eosin (H&E), while the other is kept unstained for the possible use of immunocy­tochemical reactions for cytokeratins. These are done to assess the malignant nature of suspicious cells identified in the correspond­ing H&E-stained sections. In our case, the general concordance between the intraoperative examination of sentinel nodes and axillary-node status was 96.77%, the true false-negative rate 3.22 %, the sensitivity 93.3 % and the negative predic­ tive value 94.1 %. The tirne required for such an extensive examination of the sentinel nodes is approximately 40 minutes, which are normally spent by the surgeon to complete ablative or conservative mastectomy (having done the SNB first). Irnmunocytochemistry and molecular biology in the examination of axillary sentinel nodes Many reports have emphasised the role of immunocytochemistry in the accurate identi­fication of (micro)metastases in the sentinel nodes and have recommended to perform immunoreactions for specific epithelial mark­ 14 ers (cytokeratins) in all sentinel nodes.12-It must be considered, however, that the use of immunocytochemistry does not overcome the need for an extensive sectioning of the node, which must be entirely sampled. To keep the tirne required and the costs of the examina­tion of the sentinel nodes as low as possible, the use of immunocytochemistry may be con­fined to those cases which cannot be confi­dently diagnosed on purely morphological grounds. This holds particularly true for sin­gle-cell metastases commonly occurring in invasive lobular carcinomas. The percentage of cases subjected to immunocytochemistry depends upon the training and expertise of the examining pathologist on the one side, and upon the quality of the tissue sections on the other. Even more recently, the possible role of the amplification by PCR of specific mRNA mol­ecules to detect sentinel node metastases has been exploited.15,16 In these procedures, RNA molecules are extracted from fresh/frozen lymph nodes, and complementary DNA is synthesised by reverse transcription. Epitheli­al-specific markers (cytokeratin 19, CEA, MUCl, maspin, mammaglobin, etc) are then amplified by PCR. These techniques are effec­tive in identifying a single metastatic cell among 1,000,000 normal lymphoid cells in in vitro experiments. In vivo results, however, have been less impressive thus far. Indeed, the sensitivity of these techniques often does not reach the expected 100 % of cases known to harbour metastases (most likely due to the problems with the sampling procedures). Even more important, however, is their low specificity, with several false-positive results when the techniques are applied to unin­volved lymph nodes or to lymph nodes from patients without any neoplastic disease. The clinical implications of micrometastases in axillary sentinel nodes A most debated issue in the SNB procedure is related to the clinical implications of the occurrence of micrometastases in the sentinel nodes. It has been formerly discussed whe­ther these small metastases have an impact on patients' survival, and many investigations -but not all-on the subject have documented a prognostic implication of the axillary micro­metastases in the patients with long-term fol­low-up. In the contest of the SNB, however, it is important to assess whether the detection of micrometastatic disease in the sentinel nodes is predictive of the occurrence of additional Radio/ Oncol 2000; 34(3): 261-4. Viale G / Intraoperative examination oj sentinel nodes metastases in the nonsentinel axillary nodes. Contrary to the findings of other groups17,18, in our experience, approximately 25 % of 150 patients with micrometastases in the axillary sentinel nodes harbour additional axillary metastases. In 75 % of these cases, the addi­tional metastases are larger than 2 mm, and their prognostic value is undisputed. Accor­dingly, we suggest that patients with micrometastatic disease in the sentinel nodes undergo ALND, unless they are enrolled in randomized clinical trials specifically desig­ned to address the question of the proper sur­gical management of the axilla. Reference s 1. Albertini JJ, Lyman GH, Cox C, Yeatman T, Balducci L, Ku N, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276: 1818-22. 2. Giuliano AE, Jones RC, Brennan M, and Statman R. Sentinel lymphadenectomy in breast cancer. J Ciin Onco/ 1997; 15: 2345-50. 3. Guenther JM, Krishnamoorthy M, Tan LR. Sentinel lymphadenectomy far breast cancer in a community managed care setting. Cancer J Sci Am 1997; 3: 336-40. 4. Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida S, Bedoni Let al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clin­ically negative lymph-nodes. Lancet 1997; 349: 1864-7. 5. Turner RR, Ollila DW, Krasne DL, Giulino AE. Histopathologic validation of the sentinel lymph node hypothesis far breast carcinoma. Ann Surg 1997; 226: 271-8. 6. Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer lnst 1999; 91: 368-73. 7. Viale G, Bosari S, Mazzarol G, et al. Intraoperative examination of axillary sentinel lymph nodes in breast carcinoma patients. Cancer 1999; 85: 2433-8. 8. Turner RR, Ollia DW, Krasne DL, Giuliano AE. Histopathologic validation of the sentinel lymph node hypothesis far breast carcinoma. Ann Surg 1997; 226: 271-8. Radio/ Onco/ 2000; 34(3): 261-4. 9. Port ER, Tan LK, Borgen PI, Van Zee KJ. Incidence of axillary lymph node metastases in Tla and Tlb breast carcinoma. Ann Surg Oncol 1998; 5: 23-7. 10. Bass SS, Dauway E, Mahatme A, Ku NN, Berman C, Reintgen D, et al. Lymphatic mapping with sen­tinel lymph node biopsy in patients with breast cancers <1 centimeter (Tla-Tlb). Am Surg 1999; 65: 857-62. 11. Meyer JS. Sentinel lymph node biopsy: strategies far pathologic examination of the specimen. J Surg Onco/ 1998; 69: 212-8. 12. Czerniecki BJ, Scheff AM, Callans LS, et al. Immunohistochemistry with pancytokeratins improves the sensitivity of sentinel lymph node biopsy in patients with breast carcinoma. Cancer 1999; 85: 1098-103. 13. Pendas S, Dauway E, Cox CE, Giuliano R, Ku NN, Schreiber RH, et al. Sentinel node biopsy and cytokeratin staining far the accurate staging of 478 breast cancer patients. Am Surg 1999; 65: 500-6. 14. Dowlatshahi K, Fan M, Bloom KJ, Spitz DJ, Pate! S, Snider Jr HC. Ocenit metastases in the sentinel lymph nodes of patients with early stage breast carcinoma. Cancer 1999; 86: 990-5. 15. Noguhi S, Aihara T, Nakamori S, et al. The detec­tion of breast carcinoma micrometastases in axil­lary lymph nodes by means of reverse transcrip­tase-polymerase chain reaction. Cancer 1994; 74: 1595-600. 16. Noguhi S, Aihara T, Motomura K, Inaji H, lmaoka S, Koyama H. Detection of breast cancer micrometastases in axillary lymph nodes by means of reverse transcriptase-polymerase chain reaction.Comparison between MUCI mRNA and keratin 19 mRNA amplification. Am J Pat/zal 1996; 148: 649-56. 17. Reynolds C, Mick R, Donohue JH, et al. Sentinel lymph node biopsy with metastasis: can axillary dissection be avoided in some patients with breast cancer. J Ciin Onco/ 1999; 17: 1720-6. 18. Chu KU, Turner RR, Hansen NM, Brennan MB, Bilchik A, Giuliano AE. Do ali patients with sen­tinel node metastasis from breast carcinoma need complete axillary node dissection? Ann Surg 1999; 229: 536-41. Radio/ Onco/ 2000; 34(3): 265-8. review Organ sparing for rectum and quality of surgery for preventing local recurrences Walley J. Temple University oj Calgary/ Tom Baker Cancer Centre, Calgary AB, Canada The progress in the management oj rectal cancer in the last 100 years has been phenomenal. Fram the days oj Myles abdominal perinea/ resection at the beginning oj the 20th century we have progressed to being able to manage most rectal cancers without the need far a permanent colostomy and from a surgical procedure associated with 40% loca/ recurrence to one with less than 5%. Adjuvant modalities with radiotherapy and chemotherapy have similarly praven useful in advanced disease to improve not only local control but also survival. In the manuscript the particular attention is paid to two aspects: 1) the surgical technique that is so critical in improving survival by improved local control and 2) looking at anal-preserving surgeržes far advanced and low rectal cancers. It is concluded that a properly done procedure using the TME approach supported by preop radiation far advanced lesions will result in excelle11t /ocal control a11d function in over 90% oj low rectal cancers. Key words: rectal neoplasms -surgery; neoplasms recurrence, local prevention and control The progress in the management of rectal cancer in the last 100 years has been phe­nomenal. From the days of Myles abdominal perineal resection at the beginning of the 20th century we have progressed to being able to manage most rectal cancers without the need for a permanent colostomy and from a surgi­cal procedure associated with 40 % local re­currence to one with less than 5 %. Adjuvant modalities with radiotherapy and chemo- Received 25 June 2000 Accepted 30 June 2000 Correspondence to: Walley J Temple MD FRCSC FACS, University of Calgary / Tom Baker Cancer Centre, Calgary AB, Canada. Phone: (403) 670 1914; Fax: (403) 283 1651 E-mail: walleyete@cancerboard.ab.ca therapy have similarly proven useful in advanced disease to improve not only local control but also survival. In my presentation I wish to particularly look at two aspects: 1) the surgical technique that is so critical in improving survival by improved local control and 2) looking at anal­preserving surgeries for advanced and low rectal cancers. In the last 20 years, there have been a num­ber of prospective studies that have identified the surgeon as a prognostic factor in rectal cancer outcome. This implies that surgical techniques are critical in providing local con­trol than the biology of the disease. Philips published the first of these in the early 1980's. Temple W] / Recta/ cancer & quality of surgery In the prospective data base of the UK Large Bowel Project, over 1000 procedures were analyzed. Far the 20 surgeons who had done greater than 30 patients and as many as 100 patients, the local recurrence varied between 5 % and 20 %. There was no difference betwe­en the local recurrence whether it was done by the resident working far the consultant or by the consultant. In another prospective data base published from Edinburgh which looked at 13 surgeons who had treated 645 rectal cancer patients, they noticed not only a major difference in postoperative morbidity, cura­tive resection and leak rate but they also saw the local recurrence vary between O and 21 % as well. Ten-year survival varied between 20 % and 63 %. The Swedish Rectal Tria! has also been analyzed and it has been shown that similarly in the 11 surgeons who had done greater than 25 procedures, in other words, experienced surgeons, far a tata! of 464 patients, the percent of abdominal perineal rate changed varied between 40 % and 80 % and the 3-year local recurrence varied between O and 41 %. The analysis showed that local recurrence was lower in the patients who had surgery at the university hospitals and the death was lower in specialists who had been practicing far more than 10 years. Finally, in the rectal cancer study in Germany, Hermanek has shown that local recurrence was different according to the departments the surgery was perfarmed in. It also varied by the surgeon and was affected by low vol­ume. There seems to be no question that in fact the surgeon is the prognostic factor in this disease in terms of local recurrence and function. What is encouraging is that local recurrence significantly influences survival. If in fact we could identify what makes the difference, then the appropriate techniques can be taught. It is no wonder that results are so variable if we look at the standards of surgery far this disease if we look at the quality control of the NSABP R-01 Study with adjuvant treatments. Radio/ Oncol 2000; 34(3): 265-8. The only requirements were that the tumor must be completely resected, margins tumor free, mesentery should be removed with the specimen, and the levators should be tran­sected at the pelvis wall when possible. With our knowledge today of good rectal cancer surgery, this is a totally inadequate measure of what constitutes a proper rectal operation. In the early 80's we became interested in local recurrence of rectal cancer and took advantage of our prospective Cancer Registry to see if the quality of surgery made a differ­ence as determined by the pathology and sur­gical record. Using this data base in a retro­spective manner the only things we could determine were whether the specimen was removed intact, whether the tumor was tran­sected during the procedure, and whether there was a 2.5 cm R2+50 Gy 84 mos 2mos R0 + 54 Gy 111 mosNED ? R0 46 mos R2 +54 Gy 77 mos lnfield 91mos osM 2days R0 + 54 Gy 41mosNEo 17 mos R0 74 mas R1 + 54 Gy 86 mos Outfield(Th5·5J RX Outfield (Th2•3l R1 + 52.2G 146 mosAwo 44 mos 18 supratentorial 1 Headache Vertigo Neck stiffness 30 supratentorial cell.l -11 Headache Nausea, Emesis Th12-S1 1 Dysbasla Hemiparesis 44 TH12-L1 myxopap.11 Low back pain Hemiparesis 55 L3-4 pap.11 Low back pain 44 Th10-L1 pap.l ? 30 L3-4 anapl .lll Hemiparesis 52 L2-L4 pap.l Low back pain mos: months; celi: cellulary; myxopap: myxopapillary; pap: papillary; anapl: anaplastic AWD: Alive with disease, NED: No evidence of disease, DOD: Dead of disease, DSM: Dead of second malignancy R0: Radical surgery; R1: Microscopically incomplete surgery; R2: Macroscopically incomplete surgcry; RX: unknown radicality Follow up The median follow-up was 101 months (range, 12-146 months). Patients were seen in follow-ups every 3 months for 3 years and every 6-12 months thereafter. Follow up investigations included myelography in earli­er years, later on, computed tomography or /magnetic resonance imaging were per­formed. Data analysis Estimates of rates for overall and disease-spe­cific survival were calculated using the Kaplan-Meier product limit method.17 The timing of all events was calculated from the last day of radiotherapy. hair and/or moderate skin erythema; no late side-effects were observed. All patients were evaluable for survival and local control. Overall 5-year survival was 100 %. The median disease-free survival was 86 months, the 5-year disease-free survival was 86%. Two patients failed locally within the radi­ation field. In one patient with an intracranial ependymoma, radiosurgery was performed for salvage, the other patient received no fur­ther treatment; he died secondary to primary pancreatic cancer. Initially, both patients had been irradiated for local recurrence. Two patients with spinal cord tumours developed outfield failures. Details are summarised in Table 1. No distant failures were observed. Results Discussion Radiation treatment was well tolerated. Acute Failure to control disease at the primary site discomfort included reversible focal loss of seems to be the major problem. Most patients Radio/ Oncol 2000; 34(3): 295-300. Mayer et al. / Adjuvant mdiothempy far ependymomas with intracranial ependymomas who develop spina! metastases also fail locally and die of their local disease. In rare cases, distant metastases have been reported.14, 1s Prognostic factors ,13 Clinical variables like age,2,3,12gender,3,13 tumour grade, 4,7,11-13 histological subtype1,4 and tumour location,3,6,12 have been discu­ssed to be potential prognostic factors. Some reports have seen no significant difference in survival rates based on age, 2,3,13 others have found a trend for better progression-free su­rvival 7,12 or a significant better actuarial sur­vival in patients older than 16 years of age7. While some authors3 have found no signif­icant correlation with gender and survival, Vanuytsel et al.13 obtained a significant better overall and progression-free survival in fema­le patients. Tumour grade has been most fre­quently identified as significant variable. 4,7,11,13 Seven out of eight of our patients with spinal and intracranial ependymomas had low/intermediate-grade tumours with a 5­year disease-specific survival rate of 86 %; the­se numbers are in keeping with the results of other reviews.2,4,11 Tumour location was the only factor that influenced absolute survival in a review of Me. Laughlin et al.6, these find­ings have not been confirmed by others.3,12 Another possible prognosticator which was evaluated by some authors is the duration of symptoms prior to diagnosis.11,14 The clinical presentation of ependymoma depends on the location of the tumour; it can be unspecific like headache or low-back pain, which may lead to delayed diagnosis. Wen et al.14 report a median duration tirne of 18 months in patients with spina! ependymomas, 40% of the patients had symptoms for more than 3 years prior to their initial visit. Median length of symptoms of 14 months was noted by Waldron et al.11, but this clinical variable had no impact on recurrence-free and cause-spe­cific survival on multivariate analysis. Intracranial ependymoma Surgical resection and radiotherapy are accep­ted as standard treatment, but it remains dis­agreement regarding the volume that should be irradiated. For the treatment of high-grade supratentorial ependymoma with no evidence of dissemination, some authors recommend craniospinal irradiation (CSI),12 others howev­er, saw no benefit of the use of CSI and found whole brain irradiation with boost a justifiable approach.7,13 Craniospinal irradiation remains standard treatment when spina! seeding is radiographically or pathologically evident. For localised supratentorial low-grade tumours general agreement exists on local confined fields 7, 13 either generous local irradiation or whole-brain irradiation with boost. The spread to the subarachnoidal space is considered to be higher for tumours arising in the posterior fossa and for high-grade tumours. Therefore, for high-grade infratento­rial tumours, CSI is considered as treatment of choice by most authors.2 , 7,12 In case of low­grade infratentorial tumours, treatment poli­ 13 cies include local fields 7 , and CSI.12 Local infield failure occurred in one of our two patients with intracranial ependymomas 77 months after macroscopically incomplete resection of local recurrent tumour and post­operative radiotherapy (50 Gy); stereotactic radiosurgery was performed for salvage in this patient. Spina/ ependymoma Spina! ependymomas have a long natura! his­tory. Both, the length of symptoms prior to diagnosis as discussed above and the devel­opment of late recurrences illustrate this. Re­currences later than 10 years following initial diagnosis and therapy have been reported11 therefore long-term follow-up is needed to assess treatment results. Surgical resection is the mainstay of treat­ment for the majority of these tumours; with the improvement of neurosurgical instrumen- Radio/ Oncol 2000; 34(3): 295-300. Mayer et a/. / Adjuvant radiotherapy far epe11dy1110111as tation, the morbidity of the radical approach has decreased extremely. However, radical surgery is not possible in all cases. The role of postoperative radiotherapy is controversial for the patients with spinal ependymomas. Some authors consider surgery alone to be efficient9 , others recommend postoperative radiotherapy only for intermediate/high­grade tumours8,11 or after incomplete resec­tion;5,6,8,11,14 generally, a local field irradiation is considered sufficient.6,10,11 Wen et al.14 rec­ommend a dose of 45-50 Gy if the tumour has been incompletely resected or if it has been removed in a piecemeal fashion and not in an en bloc fashion. If the tumour has been removed in a piecemeal fashion the authors recommend a thecal sac irradiation addition­ally. Waldron et al.11 also suggest postopera­tive irradiation of intermediate or poorly dif­ferentiated tumours, irrespective of the degree of resection, as well as in incomplete­ly resected tumours. Given the dose limita­tions by the spinal cord tolerance levels, the radiation doses reported in the literature 7 range between 40 and 54 Gy.2, , 8,12,14 A report by Stuben et al. 7 showed a significant differ­ence in progression free survival (PFS) proba­bility between the patients treated with doses up to 45 Gy and those patients receiving more than 45 Gy (36 % vs. 54 % 5-year PFS). In our patients with spinal ependymoma, a mean dose of 53 Gy was used and infield failure was obtained in one patient. He had been irradiated for local recurrence after macro­scopically incomplete surgery; the patient died due to pancreatic cancer. In two patients, one papillary and one myxopapilary subtype, outfield failures were seen. (Table 1). One may argue, that larger fields might have reduced the risk of these events. Conclusion Adjuvant radiotherapy either after incom­plete surgery and/or local recurrence and/or high-grade tumours seems to be efficient to prolong local control in this rare disease. References 1. Schwartz TH, Kirn S, Glick RS, Bagiella E, Balmaceda C, Fetell MR, et al. Supratentorial ependymomas in adult patients. Neurosurgery 1999; 44: 721-31. 2. Schiiller P, Schafer U, Micke O, Willich N. Radiotherapy for intracranial and spina! ependy­momas. Strahlenther Onkol 1999; 175: 105-11. 3. Abdel Wahab M, Corn B, Wolfson A, Raub W, Gaspar LE, Curran W Jr, et al. Prognostic factors and survival in patients with spina! cord gliomas after radiation therapy. Am J Ciin Oncol 1999; 22: 344-51. 4. Schild SE, Nisi K, Scheithauer BW, Wong WW, Lyons MK, Schomberg PJ, et al. The results of radio­therapy for ependymomas: The Mayo clinic experi­ence. In/ J Rad Oncol Biol Plzys 1998; 42: 953-8. 5. Lee TI, Gromelski EB, Green BA, Weidner A. Surgical treatment of spina! ependymoma and post-operative radiotherapy. Acta Neurochir 1998; 140: 309-13. 6. McLaughlin MP, Marcus RB Jr, Buatti JM, Me Collough WM, Mickle JP, Kedar A, et al. Ependymoma: Results, prognostic factors and treatment recommendations. Int] Radiat Oncol Biol Phys 1998; 40: 845-50. 7. Stiiben G, Stuschke M, Kroll M, Havers W, Sack H. Postoperative radiotherapy of spina! and intracranial ependymomas: Analysis of prognostic factors. Radiotlzer Oncol 1997; 45: 3-10. 8. Shirata H, Kamada T, Hida K, Koyanagi I, Iwasaki Y, Miyasaka K, et al. The role of radiotherapy in the management of spina! cord glioma. Int J Rad Oncol Biol Phys 1995; 33: 323-8. 9. Epstein FJ, Farmer JP, Freed D. Adult intrame­dullary spina! cord ependymomas: the result of surgery in 38 patients. J Neurosurg 1993; 79: 204-9. 10. Clover LL, Hazuka MB, Kenzie JJ. Spina! cord ependymomas treated with surgery and radiation therapy: A review of 11 cases. Am J Ciin Oncol 1993; 16: 350-3. 11. Waldron JN, Laperriere NJ, Jaakkimainen L, Simpson WJ, Payne D, Milosevic M, et al. Spina! cord ependymomas: A retrospective analysis of 59 cases. lili J Rad Oncol Biol Plzys 1993; 27: 223-9. Radio/ Oncol 2000; 34(3): 295-300. Mayer et a/. / Adjuvant mdiotherapy far ependymomas 12. Grabenbauer GG, Barta B, Erhardt J, Buchfelder M, Thierauf P, Beck JD, et al. Ependymornas: Prognostic factors and results of surgery and radiotherapy. Onkol 1992; 168: 679-85. 13. Vanuytsel LJ, Bessell EM, Ashley SE, Bloom JG, Brada M. Intracranial ependymoma: Long-terrn results of a policy of surgery and radiotherapy. Int J Rad Oncol Biol Phys 1992; 23: 313-9. 14. Wen B-C, Hussey DH, Hitchon PW, Schelper RL, Vigliotti AP, Doornbos JF, et al. The role of radio­therapy in the rnanagernent of ependyrnomas of the spina! cord. Int J Rad Onco/ Biol Phys 1991; 20: 781-6. 15. Levin VA, Sheline GE, Gutin PH. Ependyrnorna. In: de Vita V Jr, Hellrnan S, Rosenberg SA, editors. Cancer: Principles and practice oj oncology, Philadelphia: J.B. Lippincott; 1989. p.1588-9. 16. Molina OM, Colina JL, Luzardo GD, Mendez OE, Cardozo D, Velasquez HS, et al. Extraventricular cerebral anaplastic ependymornas. Surg Neurol 1999; 51: 630-5. 17. Kaplan EL, Meier P. Nonpararnetric estirnation from incomplete observations. J Am Stat Assoc 1958: 53: 457-81. 18. Graf M, Blaeker H, Otto HF. Extraneural metasta­sizing ependyrnorna of the spina! cord. Pathol Oncol Res 1999; 5: 56-60. Radio! Onco/ 2000; 34(3): 295-300. Radio/ Onco/ 2000; 34(3): 301-6. Antibodies to p53 -can they serve as tumor markers in patients with malignant lymphomas? Barbara Jezeršek1 and Srdjan Novakovic 2 1 Department of Medica/ Oncology, 2Department of Tumor Biology, Institute of Oncology, Ljubljana, Slovenia Background. Tumor suppressor gene p53 is mutated in approximately 21 % oj patients with nonHodgkin's lymphomas (the percentage varying from O up to 67 % depending upon the histological type). Most oj the mutations are point missense mutations resulting in nuclear accumulation oj altered protein. Roughly one third oj patients with overexpression oj p53 protein develop circulating anti p53 antibodies. The present study was aimed at defining the usefulness oj serial serological determinations oj autoantibodies to p53 far clinical follow up oj NHL patients. Patients and methods. Serum leve/s oj antibodies to p53 were determined in various time intervals in three lymphoma patients (who had elevated serum leve/s at the time oj diagnosis) far maximum huo years using the commercially available ELISA kit p53-Autoantikoerper ELISA 2. Generation. Results. In ali three cases the temporal patterns oj anti p53 antibodies reflected accurately disease pro­gression ar regression, and even foretold a relapse ten months in advance. The reflection oj disease regres­sion by autoantibodies lagged approximately three months behind the morphological disappearance oj the disease due to a long halj lije oj the antibodies. Conclusion. Our results confirmed the usefulness oj antibodies to p53 as tumor markers far follow up oj lymphoma patients, yet the subset oj patients that could be appropriately followed up with this method is very limited due to the low proportion oj patients that develop immune response to p53 protein. Key words: lymplwma, non-Hodgkin; tumor markers, biological ; protein p53 Received 19 April 2000 Accepted 21 May 2000 Correspondence to: Barbara Jezeršek, M.D., M.Se. Dept. of Medica! Oncology, Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Tel.: +386 1 323 063 ext. 29 33, Fax: +386 1 4314 180, E-mail: snovakovic@onko-i.si Introduction p53 is a tumor suppressor gene the alter­ations of which are among the most frequent genetic changes detected in human neo­plasms. Normal p53 acts as a "guardian of the genome" by preventing the proliferation of cells with damaged DNA. This function is achieved by the production of normal (wild type) p53 protein which acts on downstream Jezeršek B et al. / Antibodies to p53 in NHL patients genes to arrest the cell cycle until the DNA damage is repaired, or if the damage is irre­versible, to cause apoptosis.1, 2 The loss of wild type function usually occurs by a two­step mechanism comprising mutation of one copy of the p53 gene and deletion or inactiva­tion of the remaining wild type allele. The outcome of the mutation is the synthesis of a protein with a changed conformation, a longer half life, and disordered function in terms of cellular growth. 3 The incidence of p53 mutations in nonHodgkin's lymphomas (NHL) varies according to histological type and disease stage -it is high in aggressive lymphomas (Burkitt's and diffuse large B cell lymphomas) and lower in intermediate and indolent lym­phomas. Regardless of the type -the inci­dence is generally higher in case of a relapse or after progression. Most of the mutations are missense mutations clustered in exons 5 to 8 of one p53 allele and are usually associ­ated with deletion of the other allele, through 17p deletion.4 Different authors5-11 reported that p53 pro­tein can become immunogenic in various human tumors in vivo, indicating that alter­ations in the expression or properties of p53 associated with tumor development can be detected by screening the sera of cancer patients for anti p53 antibodies. The forma­tion of autoantibodies to p53 is directed against two immunodominant regions locat­ed at the carboxy and amino termini of the protein outside the central mutational hot spot region 7 and is observed only in patients with p53 missense mutations that express detectable levels of p53 protein in their tumor cells. 8 The p53 specific immune response does not develop in cancer patients bearing stop, splice/stop, splice or frameshift muta­tions of p53 gene in tumor cells.8 According to the literature autoantibodies to p53 were identified in 2.6 % 10 up to 21 % 6 of the tested sera of NHL patients. In our pre­vious study the percentages of p53 antibody positive sera also varied greatly" between dif­ferent histological subtypes of NHL. In this paper we present a small study examining the usefulness of serial serological determina­tions of autoantibodies to p53 for clinical fol­low up of NHL patients. Materials and methods Patients Three patients (two male and one female patient, ages 25, 64, and 47 years, respective­ly) with different types of NHL (REAL classi­fication)12 in which autoantibodies to p53 were detected at the tirne of diagnosis were followed up for maximum two years. In all three patients also p53 protein overexpres­sion (indicating an underlying mutation of p53 gene) was identified immunohistochemi­cally. Sample col/ection Blood was collected in variable tirne intervals over a maximum two year period and sera were separated from the dot by centrifuga­tion. The sera were then aliquoted and stored at -2O°C until analysis. The samples were diluted in sample dilution buffer before assaying (so that the measurement results fell inside the area of a standard curve) and the determinations were executed according to manufacturer's instructions. Serum determinations Serial determinations of autoantibodies to p53 were performed using the commercially available ELISA kit p53-Autoantikoerper ELISA 2. Generation (Dianova, Hamburg, Germany). The assay is based on a sandwich technique with human recombinant p53 pro­tein coated to the microtiter plate wells which binds the anti p53 autoantibodies of the Radio/ Oncol 2000; 34(3): 301-6. Jezeršek B et al. / Antibodies to p53 in NHL patients serum sample and a goat anti human IgG antibody (as the detection antibody) conju­gated to peroxidase. The bound enzymatic activity is determined by addition of a chro­mogenic substrate and by measuring the resulting colored solution with a spectropho­tometer. The concentration of the sample or the standard is directly proportional to the absorbance value measured. Results Patient A was diagnosed with Burkitt's lym­phoma stage IV and was treated with aggres­sive chemotherapy that included high