Radiol Oncol 2020; 54(2): 209-220. doi: 10.2478/raon-2020-0026 209 research article Care of patients with non-small-cell lung cancer stage III – the Central European real- world experience Milada Zemanova1, Robert Pirker2, Lubos Petruzelka1, Zuzana Zbozínkova3, Dragana Jovanovic4, Mirjana Rajer5, Krisztina Bogos6, Gunta Purkalne7, Vesna Ceriman4, Subhash Chaudhary8, Igor Richter9, Jirí Kufa10, Lenka Jakubikova11, Marius Zemaitis12, Marketa Cernovska13, Leona Koubkova14, Zdenka Vilasova15, Karin Dieckmann16, Attila Farkas17, Jelena Spasic18, Katerina Fröhlich3, Andreas Tiefenbacher2, Virag Hollosi6, Juraj Kultan10, Iveta Kolarová15, Jiri Votruba1 1 1st Faculty of Medicine of Charles University in Prague, Czech Republic 2 Department of Medicine I, Medical University of Vienna, Vienna, Austria 3 Institute of Biostatistic and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic 4 Clinic for Pulmonology, Clinical Centre of Serbia, Belgrade, Serbia 5 Institute of Oncology, Ljubljana, Slovenia 6 National Koranyi Institute of TB and Pulmonology, Budapest, Hungary 7 Pauls Stradins Clinical University Hospital, Riga, Latvia 8 Comprehensive Oncology Center, Nový Jičín, Czech Republic 9 Comprehensive Oncology Center, Liberec, Czech Republic 10 Clinic for Pneumology & Tuberculosis, Faculty of Medicine, Palacký University, Olomouc, Czech Republic 11 Clinic for Pneumology & Tuberculosis, Faculty of Medicine, Masaryk University, Brno, Czech Republic 12 Hospital of LUHS Kauno Klinikos, Kauno, Lithuania 13 Thomayer Hospital, Prague, Czech Republic 14 Department of Pulmonology, University Hospital Motol, Prague, Czech Republic 15 Comprehensive Oncology Center and Multiscan, Pardubice, Czech Republic 16 Department of Radiotherapy, Medical University of Vienna, Vienna, Austria 17 Department of Thoracic Surgery, Semmelweis University, Budapest, Hungary 18 Institute for Oncology and Radiology of Serbia, Belgrade, Serbia Radiol Oncol 2020; 54(2): 209-220. Received 9 January 2020 Accepted 14 April 2020 Correspondence to: Milada Zemanová, Oncology VFN, U Nemocnice 2, 128 08, Prague, Czech Republic. E-mail: milada.zemanova@vfn.cz Disclosure: No potential conflicts of interest were disclosed. Background. Management of non-small-cell lung cancer (NSCLC) is affected by regional specificities. The present study aimed at determining diagnostic and therapeutic procedures including outcome of patients with NSCLC stage III in the real- world setting in Central European countries to define areas for improvements. Patients and methods. This multicentre, prospective and non-interventional study collected data of patients with NSCLC stage III in a web-based registry and analysed them centrally. Results. Between March 2014 and March 2017, patients (n=583) with the following characteristics were entered: 32% fe- males, 7% never-smokers; ECOG performance status (PS) 0, 1, 2 and 3 in 25%, 58%, 12% and 5%, respectively; 21% prior weight loss; 53% squamous carcinoma, 38% adenocarcinoma; 10% EGFR mutations. Staging procedures included chest X-ray (97% of patients), chest CT (96%), PET-CT (27%), brain imaging (20%), bronchoscopy (89%), endobronchial ultrasound (EBUS) (13%) and CT-guided biopsy (9%). Stages IIIA/IIIB were diagnosed in 55%/45% of patients, respectively. N2/N3 nodes were diagnosed in 60%/23% and pathologically confirmed in 29% of patients. Most patients (56%) were treated by combined modalities. Surgery plus chemotherapy was administered to 20%, definitive chemoradiotherapy to 34%, chemotherapy only to 26%, radiotherapy only to 12% and best supportive care (BSC) to 5% of patients. Median survival and progression-free survival times were 16.8 (15.3;18.5) and 11.2 (10.2;12.2) months, respectively. Stage IIIA, female gender, no weight loss, pathological mediastinal lymph node verification, surgery and combined modality therapy were associated with longer survival. Conclusions. The real-world study demonstrated a broad heterogeneity in the management o f stage III NSCLC in Central European countries and suggested to increase the rates of PET-CT imaging, brain imaging and invasive mediastinal staging. Key words: diagnostic procedures; multimodality treatment; non-small-cell lung cancer; stage III Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience210 Introduction Management of locally advanced (stage III) non- small cell lung carcinoma (NSCLC) includes a broad spectrum of diagnostic procedures and therapeutic modalities. Diagnosis is primarily based on computer tomography (CT) scan of chest plus upper abdomen and brain, bronchoscopy and CT-guided biopsies. For more precise exclusion of distant metastases, the evaluation with PET-CT is useful. Detailed locoregional staging is done by means of PET-CT1, endobronchial or endoscopic ultrasound (EBUS/EUS), mediastinoscopy, thora- coscopy, mediastinotomy or other biopsies of sus- pected nodal lesions in order to distinguish early stages (stages I and II) from stage IIIA/IIIB.2 Treatment of NSCLC stage III requires multidis- ciplinary co-operation in order to deliver appro- priate local and systemic therapies for the various subgroups. Occurrence of distant metastases with and without local progression is frequent, thereby leading to 5-year survival rates often less than 20%.3 According to the 7th edition of the TNM classifica- tion3 stage III was subdivided into stage IIIA and IIIB. The 5-year survival rates were 36% and 19%, respectively.4 According to the 8th edition, stage III is divided into IIIA, IIIB and IIIC. The 5-year surviv- al rates are 36%, 26% and 13%, respectively.4 In op- erable stage IIIA, induction or adjuvant chemother- apy improve overall survival5,6 and are established as standard treatments. Important prognostic fac- tors associated with prolonged survival are patho- logical down-staging of mediastinal lymph nodes and/or primary tumors, and complete tumour re- section.7-10 Some trials assessing induction therapy followed by surgery have also included patients with stage IIIB disease and suggested that patients with operable stage IIIB NSCLC have outcomes similar to those with stage IIIAN2 disease.11 For pa- tients with inoperable stage IIIA or stage IIIB and good performance status (PS), definitive chemora- diotherapy is the treatment of choice.2 Concurrent chemoradiotherapy is associated with longer sur- vival at increased toxicity compared to the sequen- tial approach.12 Radiotherapy dose escalation has no clear benefit.13 Sequential chemoradiotherapy or radiotherapy alone remain options for selected patients.2 Consolidation therapy with durvalumab after concurrent chemoradiotherapy has recently been shown to improve survival of patients14 and has been established as standard treatment. There is evidence that management of NSCLC stage III varies between countries, geographical regions, cancer centres and even treating physi- cians. Reasons for these variations include differ- ences in regional standards, access to diagnostic procedures as well as therapeutic modalities, and resources. The aim of the present study was to de- termine diagnostic and therapeutic procedures as well as clinical outcome including survival of pa- tients with NSCLC stage III in the real-world set- ting in Central European countries and to define areas for future improvements in routine manage- ment of these patients. Patients and methods Patients The present study was prospective, observational, non-interventional, multicentric, multinational and registry based. The study had been approved by ethics committees of participating centres and was performed in accordance with the Declaration of Helsinki. Study entry criteria were patients of any age, histological and/or cytological diagnosis of NSCLC stage III according to 7th edition of the TNM classification3 and signed written informed consent. The study allowed enrolling patients who have been treated between March 2014 and March 2017. Follow-up of patients continued until February 2018. Data collection Registration of all data was fully anonymous and performed in an electronic case report form (CRF [eCRF]) by qualified personnel. Patient identifica- tion was in the responsibility of each investiga- tor. The following data were collected: age, gen- der, race, smoking status, PS, weight loss, date of NSCLC diagnosis, histology and mutational status of tumors, staging procedures, method of medias- tinal lymph-node examination, TNM and tumor stage. Data collected on therapeutic procedures were primary therapy, surgical procedures (date, extent, completeness of resection, information on repeated resections), thoracic radiotherapy (date, dose, fractions, technique, energy), prophylactic cranial irradiation, and chemotherapy (dates of start and end, number of cycles, cytotoxic drugs). Combined modality therapy was assessed accord- ing to investigator statement and/or dates of over- lapping therapies. Type of best treatment response, date of recurrence or progression, and dates of death were collected. Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience 211 Statistical analyses Descriptive statistics and frequency tables were used to characterize the sample data set. Statistical significances of differences for categorical and continuous parameters were assessed by means of Fisher’s exact test and Mann-Whitney test, re- spectively. Overall survival (OS) was defined as the time from treatment initiation until death of any cause. Progression-free survival (PFS) was defined as the time from treatment initiation until first documented progression and/or death of any cause. Patients without an event were censored at the time of last follow-up visit. Patients lost to fol- low-up were counted as interval-censored observa- tions. The assumption was made that patients were lost to follow-up due to their treatment failure and that, therefore, no information is available about them. Interval set (interval between visits) was 6 months.15 PFS and OS were estimated by Kaplan- Meier analysis and 95% confidence intervals (95% CI) were provided for all point estimates. Statistical significance of differences in survival between the subgroups was assessed by means of the log-rank test. The multivariable Cox proportional hazard model was used to evaluate the effects of potential prognostic factors on survival measures. Hazard ratios (HR) were complemented with 95% confi- dence intervals and supported with significance levels. Overall response rate (ORR) was defined as the sum of complete response rate (CR) and partial response rate (PR) and disease control rate as ORR plus stable disease rate (SD). All statistical tests were performed at the significance level of P = 0.05. Results Patients A total of 617 patients were enrolled but 34 pa- tients were excluded due to various violations of the study protocol. Thus the study population comprises 583 patients from 16 centres of seven Central European countries: eight centres from Czech Republic (269 patients), two centres from Serbia (109 patients), two centres from Hungary (48 patients) and one centre each from Slovenia (53 patients), Latvia (43 patients), Lithuania (38 pa- tients) and Austria (23 patients). The date for final analysis was February 19, 2018. Minimum follow- up since initial diagnosis was 11 months. Patient characteristics are shown in Table 1: 53.3% aged ≥ TABLE 1. Patient characteristics Characteristic IIIA (N = 321) IIIB (N = 262) IIIA + IIIB (N = 583) P * N (%) N (%) N (%) Age < 65 years ≥ 65 years Mean ± SD (years) Median (years) 155 (48.3) 166 (51.7) 64.8 ± 10.5 65.4 117 (44.7) 145 (55.3) 65.1 ± 10.1 66.0 272 (46.7) 311 (53.3) 64.9 ± 10.3 65.6 0.429 Gender Female Male 92 (28.7) 229 (71.3) 96 (37.0) 166 (63.6) 188 (32.2) 395 (67.8) 0.050 Smoking status Current smoker Former smoker Never smoker Unknown 161 (50.2) 127 (39.6) 26 (8.1) 7 (2.2) 147 (56.3) 92 (35.2) 16 (6.1) 7 (2.7) 308 (52.8) 219 (37.6) 42 (7.2) 14 (2.4) 0.446 Weight loss ≥10% within prior three months No Yes Unknown 243 (75.7) 50 (15.6) 28 (8.7) 163 (62.5) 70 (26.8) 29 (11.0) 406 (69.6) 120 (20.6) 57 (9.8) <0.001 WHO performance status 0 1 2 3 86 (26.8) 194 (60.4) 31 (9.7) 10 (3.1) 60 (23.0) 144 (54.9) 41 (15.7) 17 (6.5) 146 (25.0) 338 (58.0) 72 (12.3) 27 (4.6) 0.025 Histology Squamous cell carcinoma Adenocarcinoma NSCLC NOS Other 176 (54.8) 115 (35.8) 18 (5.6) 12 (3.7) 133 (51.0) 105 (40.0) 18 (6.9) 6 (2.3) 309 (53.0) 220 (37.7) 36 (6.2) 18 (3.1) 0.477 * = Chi-square test for IIIA vs. IIIB; NOS = not otherwise specified; NSCLC = non-small-cell lung cancer; SD = standard deviation Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience212 65 years, 32.2% females, 7.2% never-smokers, 20.6% weight loss (≥ 10% within prior three months), 83% PS WHO 0–1. Stages IIIA and IIIB were diagnosed in 321 (55.1%) and 262 (44.9%) patients, respective- ly. Females, patients with weight loss and patients with poor PS were slightly more frequent among patients with stage IIIB. Squamous cell carcinomas were diagnosed in 309 (53.0%) patients, adenocar- cinomas in 220 (37.7%) patients, NSCLC not oth- erwise specified in 36 (6.2%) patients, and other types (e.g. adeno-squamous, large cell) in 18 (3.1%) patients. Results of molecular analyses were docu- mented for 150 (25.7%) patients (data not shown). EGFR mutations were detected in 14/142 (9.9%) patients, KRAS mutations in 11/31 (35.5%) patients and ALK aberrations in 2/88 (2.3%) patients (data not shown). Staging procedures Diagnostic and staging procedures are summa- rized in Table 2. Widely used procedures were chest x-ray (96%), chest CT scan (97%), bronchos- copy (89%) and upper abdominal CT scan (67%). PET-CT or PET were performed in 28% of patients. Brain imaging by means of CT or MRI was done in 20% of patients. EBUS or EUS were performed in 14% of patients, CT-guided biopsy in 9%, video- assisted thoracoscopic surgery (VATS) in 3%, and mediastinoscopy in 2%. Other procedures includ- ed diagnostic thoracotomy in 5%, radical thoracic surgery with gain of histology in 1%, ultrasonog- raphy (other than abdominal) (1%) and extracra- nial MRI examinations. The frequencies of the pro- cedures showed great variations between centres with particularly great variations for PET or PET- CT (0–78%), brain imaging (0–91%) and EBUS/EUS (0–71%) (Table 2). Stage IIIA and st age IIIB were diagnosed in 55.1% and 44.9% of patients, respectively (Table 1). Subgroups based on T and N descriptors are shown in Table 3. Stages T1–T3 were found in 340 patients (58.3%) mostly having N2 or N3 nodal stage in 301 (51.6%) patients. T4N0, T4N1 and T4N2 tumours were found in 33 (5.7%), 26 (4.5%) and 129 (22.2%) patients, respectively. T3N3 and T4N3 tumours were diagnosed in 29 (5%) and 55 (9.4%) patients, respectively. T3–4N3 tumours (stage IIIC accord- ing to 8th TNM classification) were diagnosed in 84 (14.4%) patients. N2 or N3 lymph nodes were found in 485 (83.2%) patients. Histopathological involvement of mediastinal lymph nodes was con- firmed in 172 (29.5%) patients by surgery (96 pa- tients), transbronchial biopsy (58 patients), medias- TABLE 2. Diagnostic procedures Procedure Patients (N = 583) N (%) range of % in centres Chest CT scan 567 (97) 67 – 100 Chest X-ray 559 (96) 79 – 100 Bronchoscopy 521 (89) 65 – 100 Upper abdominal CT scan 389 (67) 0 – 100 Upper abdominal US 160 (27) 2 – 87 PET-CT or PET scan 163 (28) 0 – 78 Brain CT or MRI 117 (20) 0 – 91 Bone scan 88 (15) 0 – 79 EBUS or EUS 80 (14) 0 – 71 CT-guided biopsy 54 (9) 0 – 31 VATS 19 (3) 0 – 35 Mediastinoscopy 13 (2) 0 – 13 Others 47 (8) 0 – 30 EBUS = endobronchial ultrasound; EUS = endoscopic ultrasound; VATS = video-assisted thoracoscopic surgery T ABLE 3. TNM subgroups (Union for International Cancer Control [UICC] 7) TNM Total patient population Patients undergoing surgery N (%) N % of total population % in stage subgroup IIIA+IIIB 583 (100) 135 32.2 NA IIIA 321 (55.1) 119 20.4 37.1 T4N0 T3N1 T4N1 T1N2 T2N2 T3N2 33 (5.7) 39 (6.7) 26 (4.5) 25 (4.3) 98 (16.8) 100 (17.2) 10 16 7 14 45 27 1.7 2.7 1.2 2.4 7.7 4.6 30.3 41.0 26.9 56.0 45.9 27.0 IIIB 262 (44.9) 16 2.8 6.1 T4N2 T1N3 T2N3 T3N3 T4N3 129 (22.2) 17 (2.9) 32 (5.5) 29 (5.0) 55 (9.4) 15 0 1 0 0 2.6 0 0.2 0 0 11.6 0 3.1 0 0 T stage T1 T2 T3 T4 42 (7.2) 130 (22.3) 168 (28.8) 243 (41.7) 14 46 43 32 2.4 7.9 7.4 5.5 33.3 35.4 25.6 13.1 N stage N0 N1 N2 N3 33 (5.7) 65 (11.1) 352 (60.4) 133 (22.8) 10 23 101 1 1.7 3.9 17.3 0.2 30.3 35.4 28.7 0.8 NA = not applicable Radiol Oncol 2020; 54(2): 209-220. 213Zemanová M et al. / NSCLC stage III – the Central European real-world experience tinoscopy (11 patients) or other types of biopsy (10 patients) (data not shown). Treatment Therapeutic modalities are shown in overview for the total study population in Figure 1, for pa- tients with stage IIIA and those with IIIB in de- tail in Table 4. Time from diagnosis to treatment initiation ranged from 0 to 369 (median 23) days. Combined therapies of any type were delivered to 326 (55.9%) patients. With regard to a single treatment modality only, surgery was delivered to 1.5% thoracic radiotherapy to 11.8%, chemo- therapy to 25.7% and best supportive care (BSC) to 5.0% of patients of the total study population. Prophylactic cranial irradiation was not delivered to any patient. Surgery was performed in 135 (23.2%) patients (119 IIIA, 16 IIIB) and resulted in radical tumour resection in 121 patients and explorative surgery or non-radical resections in 14 patients (Table 4 and Figure 1). The types of surgery included lobectomy (77 patients), bi-lobectomies (6 patients), pneumo- nectomy (32 patients) and atypical radical resec- tions (6 patients) (Table 4). Surgery was delivered as single modality (nine patients), in combination with chemotherapy (77 patients) or radiotherapy (eight patients) or as trimodality therapy (41 pa- tients). Adjuvant chemotherapy was about twice as frequent as pre-operative chemotherapy among patients undergoing surgery. BSC = best supportive care; CT = chemotherapy; pre = preoperative; post = postoperative; peri = perioperative; RT = radiotherapy FIGURE 1. Treatment modalities and combinations. TABLE 4. Therapeutic modalities and combinations Therapeutic modalities IIIA (N=321) IIIB (N=262)N (%) IIIA+IIIB (N=583) Any combination 207 (64.5) 119 (45.4) 326 (55.9) Surgery 119 (37.1) 16 (6.1) 135 (23.2) Surgery alone 9 (2.8) 0 9 (1.5) Surgery plus radiotherapy 7 (2.2) 1 (0.4) 8 (1.4) Surgery plus chemotherapy Preoperative chemotherapy Perioperative chemotherapy Adjuvant chemotherapy 70 (21.8) 22 (6.9) 3 (0.9) 45 (14.0) 7 (2.7) 4 (1.5) 0 3 (1.1) 77 (13.2) 26 (4.4) 3 (0.5) 48 (8.2) Surgery plus RT plus CT (trimodality) Sequential preoperative RT plus CT Concurrent preoperative RT plus CT Sequential postoperative RT plus CT Concurrent postoperative RT plus CT 33 (10.3) 2 (0.6) 3 (0.9) 23 (7.2) 5 (1.6) 8 (3.1) 0 1 (0.4) 3 (1.1) 4 (1.5) 41 (7.0) 2 (0.3) 4 (0.7) 26 (4.5) 9 (1.5) Thoracic RT (including other modalities) Radiotherapy alone 174 (54.2) 37 (11.5) 144 (55.0) 32 (12.2) 318 (54.6) 69 (11.8) Chemoradiotherapy Sequential Concurrent 97 (30.2) 74 (23.1) 23 (7.2) 103 (39.3) 72 (27.5) 31 (11.8) 200 (34.3) 146 (25.0) 54 (9.3) Chemotherapy (including other modalities) Chemotherapy alone 256 (79.7) 58 (18.1) 212 (80.9) 92 (35.1) 468 (80.3) 150 (25.7) Best supportive care alone 9 (2.8) 20 (7.6) 29 (5.0) Type of surgery IIIA (N = 119) IIIB (N = 16) IIIA+IIIB (N = 135) Lobectomy Bi-lobectomy Pneumonectomy Atypical radical resection Non-radical surgery* 74 (62.3) 6 (5.0) 28 (23.5) 5 (4.2) 6 (5.0) 3 (18.7) 0 4 (25.0) 1 (6.2) 8 (50.0) 77 (57.0) 6 (4.5) 32 (23.7) 6 (4.5) 14 (10.4) * = Non-radical surgery (n = 14) as biopsy (n = 4, all IIIB), exploration (n = 7, IIIA = 5, IIIB = 2) or palliative resection (n = 3, IIIA = 1, IIIB = 2); CT = chemotherapy; RT = radiotherapy Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience214 Thoracic radiotherapy was delivered to 318 (54.6%) patients with similar proportions among stage IIIA and stage IIIB (Table 4). Thoracic ra- diotherapy was delivered as single modality (69 patients), as definitive chemoradiotherapy (200 patients) and as trimodality therapy (41 patients). Among patients undergoing definitive chemo- radiotherapy, the sequential administration was much more frequent than the concurrent one (146 versus 54 patients). Among patients undergoing tri- modality therapy, concurrent chemoradiotherapy was delivered in 13 patients (Table 4). Chemotherapy as the most frequent treatment modality was delivered to 468 (80.3%) patients with similar percentages among IIIA and IIIB (Table 4). Chemotherapy was the only treatment modality in 150 patients. Carboplatin was used in 43.6% and cisplatin in 37.4% of patients (data not shown). Platins were combined with vinorel- bine (33%), gemcitabine (22%), etoposide (11%) or paclitaxel (11%). Pemetrexed was used in 7.7% of patients in stage IIIB and 2.5% in stage IIIA. Other drugs including docetaxel, vinblastine and bevaci- zumab were each used in less than 2% of patients. No relevant differences in chemotherapy protocols between stage IIIA and IIIB patients were seen (da- ta not shown). Treatment outcome At a median follow-up time of 30 months, 154 (26.4%) patients were alive, 295 (50.6%) patients were dead and 134 (23%) patients were lost to fol- low-up. Among 334 patients evaluable for overall best response, complete remission, partial remis- FIGURE 2. Overall survival and progression-free survival. Good = PS 0/1 and no weight loss; poor = PS 2/3 and/or weight loss ≥10% within prior three months FIGURE 3. Overall survival and progression-free survival by performance status and weight loss in all patients, stage IIIA and stage IIIB. Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience 215 sion, stable disease and progressive disease were seen in 27.5%, 35.9%, 24.9% and 11.7% patients, respectively. Information on progression during follow-up was available for 338 patients, while no information was available for the other patients due to death (171 patients) or loss to follow-up (74 patients). Eighty-two (24.3%) patients were without progression and 256 (75.7%) patients had progression, either local (40.2%), distant (26.6%) or both (8.9%). Progression after end of treatment was more frequent among patients with stage IIIB than those with stage IIIA (91.2% versus 81.6%). Survival analyses OS and PFS are shown in Table 5, Table 6 and Figure 2. Median OS was 16.8 months and the 3-year OS rate was 21%. Median PFS was 11.2 months and the 3-year PFS rate was 11.5%. OS and PFS were longer among patients with IIIA than among those with IIIB and the corresponding haz- ard ratios were 0.70 (95% CI 0.58–0.85; p < 0.001) and 0.71 (95% CI 0.59–0.85; p < 0.001), respectively (Table 5; Table 6). Among patients with stage IIIA, median OS was 20 months and the 3-year OS rate was 27%. The corresponding values for patients with stage IIIB were 14.4 months and 13.5%, re- spectively. Among patients with T3–4/N3 tumours who are classified as stage IIIC based on the 8th edi- tion of the TNM classification, survival outcome (median OS 11.6 months; 3-year OS rate 9.4%) was worse than the outcome of patients with stage IIIB based on the 7th TNM classification. OS and PFS were longer among patients with PS 0–1 and no weight loss (good prognostic group) than among those with PS 2–3 and/or weight loss ≥ 10% (poor prognostic group) (Table 5; Table 6; Figure 3). These differences were observed in the TABLE 5. Overall survival according to stage and treatment modalities Characteristic N Median 1-year 2-year 3-year Months (95% CI) % (95% CI) IIIA Total* Good Poor 321 223 75 20.0 (17.1; 21.4) 21.4 (20.1; 25.8) 13.3 (11.4; 17.7) 70.7 (65.9; 75.9) 76.3 (70.9; 82.1) 57.3 (47.2; 69.7 39.4 (34.3; 45.2) 45.6 (39.4; 52.8) 23.2 (15.2; 35.2) 27.0 (21.8; 33.3) 33.8 (27.7; 41.3) 9.1 (3.2; 26.0) IIIB Total* Good Poor T3N3 and T4N3** 262 146 97 84 14.4 (13.0; 15.9) 17.8 (14.8; 19.6) 10.4 (8.8; 19.6) 11.6 (9.8; 15.9) 58.2 (52.3; 64.5) 67.0 (59.8; 75.1) 44.1 (35.2; 55.2) 48.5 (38.8; 60.5) 27.5 (22.5; 33.7) 33.1 (26.1; 42.0) 17.3 (11.1; 27.0) 22.6 (15.2; 33.8) 13.5 (9.0; 20.2) 19.6 (13.2; 29.1) 8.1 (3.0; 21.6) 9.4 (3.9; 22.7) IIIA+IIIB Total* Good Poor 583 369 172 16.8 (15.3; 18.5) 20.1 (18.0; 21.5) 11.8 (10.2; 14.2) 65.1 (61.3; 69.1) 72.6 (68.2; 77.3) 50.0 (42.9; 57.9) 34.1 (30.4; 38.2) 40.7 (35.9; 46.2) 19.9 (14.6; 27.0) 21.0 (17.3; 25.4) 28.3 (23.6; 34.0) 8.0 (3.6; 17.8) Surgery All surgeries Alone Surgery plus CT or RT Surgery plus adjuvant CT Trimodality therapy 135 9 85 77 41 29.0 (27.1; NA) 13.9 (3.2; NA) 27.8 (23.6; NA) 28.3 (24.7; NA) Not reached 82.2 (76.0; 88.9) 55.6 (31.0; 99.7) 80.0 (71.9; 89.0) 81.8 (73.6; 90.9) 92.7 (85.0; 100) 60.6 (52.8; 69.6) 22.2 (6.6; 75.4) 57.2 (47.5; 68.9) 60.6 (50.6; 72.7) 76.9 (64.7; 91.5) 43.9 (35.2; 54.8) 22.2 (6.6; 75.4) 37.0 (26.7; 51.3) 38.9 (28.0; 54.0) 64.8 (49.9; 84.2) Non-surgical therapy All non-surgical CT alone RT alone CRT all CRT sequential CRT concurrent 448 150 69 200 146 54 14.6 (13.7; 15.9) 12.7 (11.3; 13.9) 12.7 (9.6; 18.4) 19.6 (17.5; 21.6) 20.5 (17.2; 22.8) 17.9 (14.6; 22.2) 59.9 (55.5; 64.7) 56.5 (49.1; 65.0) 52.2 (41.6; 65.4) 72.9 (67.0; 79.3) 75.2 (68.5; 82.5) 66.7 (55.2; 80.5) 26.0 (22.1; 30.5) 19.1 (13.7; 26.8) 18.8 (11.6; 30.7) 36.9 (30.7; 44.5) 38.8 (31.5; 47.9) 32.0 (21.6; 47.6) 13.8 (10.2; 18.8) 6.2 (2.7; 14.4) 11.8 (5.9; 23.5) 22.6 (16.1; 31.6) 23.5 (16.2; 34.0) 22.5 (12.7; 39.9) HR (95% CI) p-value IIIA vs. IIIB 0.70 (0.58; 0.85) < 0.001 IIIA Good vs. IIIA Poor 0.54 (0.40; 0.73) < 0.001 IIIB Good vs. IIIB Poor 0.57 (0.43; 0.76) < 0.001 IIIA vs. IIIB Good 0.86 (0.68; 1.09) 0.212 Tri-modality vs. Surgery plus adjuvant CT 0.47 (0.25; 0.89) 0.021 CRT sequential vs. concurrent 0.83 (0.57; 1.20) 0.326 Good = performance status 0–1 and no weight loss; Poor = performance status 2–3 and/or weight loss ≥ 10%; CRT = chemoradiotherapy; CT = chemotherapy; RT = radiotherapy * = Total is not sum of Good and Poor, as some patients had no data about weight loss; ** = Stage IIIC in Union for International Cancer Control [UICC] 8 Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience216 TABLE 6. Progression free survival according to stage and risk groups Characteristic N Progression-free survival Median 1-year 2-year 3-year Months (95% CI) % (95% CI) IIIA Total* Good Poor 321 223 75 12.5 (11.3; 13.6) 12.9 (12; 15.2) 11.4 (7.9; 13.2) 52.9 (47.7; 58.7) 55.8 (49.6; 62.7) 45.3 (35.4; 58.1) 24.1 (19.8; 29.3) 27.6 (22.3; 34.3) 14.2 (8.1; 25.0) 16.8 (13.0; 21.7) 19.6 (14.8; 26.0) 8.3 (3.8; 18.1) IIIB Total* Good Poor T3N3 and T4N3** 262 146 97 84 9.9 (9.2; 10.8) 10.7 (9.6; 12.6) 8.6 (7.8; 9.9) 9.4 (7.9; 11.3) 38.5 (33.1; 44.9) 43.8 (36.5; 52.6) 26.8 (19.3; 37.2) 34.5 (25.7; 46.3) 12.8 (9.3; 17.7) 13.6 (9.0; 20.8) 9.9 (5.4; 18.2) 10.7 (5.8; 20.0) 4.3 (1.8; 9.9) 8.6 (4.7; 15.5) 0 2.5 (0.4; 15.1) IIIA+IIIB Total* Good Poor 583 369 172 11.2 (10.2; 12.2) 12.2 (11.0; 13.3) 9.2 (8.3; 10.5) 46.5 (42.6; 50.7) 51.0 (46.2; 56.4) 34.9 (28.4; 42.8) 19.0 (16.0; 22.6) 22.1 (18.2; 26.9) 11.7 (7.7; 17.7) 11.5 (8.9; 14.9) 15.4 (11.9; 19.9) 3.7 (1.3; 10.8) HR (95% CI) p-value IIIA vs IIIB 0.71 (0.59; 0.85) < 0.001 IIIA Good vs IIIA Poor 0.69 (0.52; 0.92) 0.011 IIIB Good vs IIIB Poor 0.69 (0.53; 0.90) 0.006 IIIA vs IIIB Good 0.80 (0.65; 0.99) 0.037 Good = performance status 0–1 and no weight loss; Poor = performance status 2–3 and/or weight loss ≥ 10%; * = Total is not sum of Good and Poor, as some patients had no data about weight loss; ** = Stage IIIC in Union for International Cancer Control [UICC] 8 PS = performance status FIGURE 4. Overall survival by variables. Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience 217 total study population, in IIIA patients and in IIIB patients. Among the good prognostic group of IIIB patients, the survival outcome was similar to the survival outcome of IIIA patients. Additional outcome data are summarized in Tables 5, 6 and 7 and Figures 3 and 4. Univariate analysis demonstrated longer OS for females, nev- er-smokers, good PS, stage IIIA, mediastinal node verification, and for those with PET/CT or PET staging exam. In contrast, OS was not different be- tween patients with adenocarcinomas and those with squamous cell carcinomas. Including these variables into the multivariate survival proportion- al hazard model, the differences in OS remained significant for females versus males, no weight loss versus weight loss, PS 0–1 versus 2–3, stage IIIA versus IIIB, and pathological verification of medi- astinal nodes versus no verification. EGFR muta- tion status was not significant in the multivariate analysis but trend for better survival was found in the univariate model (Table 7). OS was also as- sessed in various treatment subgroups. Significant survival benefits were seen in patients undergoing surgery compared to patients without surgery (HR = 0.43; 95% CI 0.33–0.56; p-value < 0.001) and in patients receiving combined treatment modalities compared to patients with a single treatment mo- dality (Table 5, hazard ratios not shown). The best OS outcome was shown for patients receiving tri- modality therapy (Table 5). A significant OS differ- ence between concurrent and sequential chemora- diotherapy could not be demonstrated. Time from diagnosis to initiation of treatment start had no im- pact on outcome (analysis by quartiles, p = 0.585). Discussion Our observational study demonstrated a large het- erogeneity in both diagnostic procedures and treat- ment modalities among patients with locally ad- vanced NSCLC in the real-world setting in Central European countries. The results were based on 583 patients from 16 cancer centres of seven coun- tries. The patient characteristics of our study were slightly different from those of recent phase 3 tri- als14,16, and these differences might be explained, at least partly, by higher smoking rates in Central European countries compared to other countries and the real-world nature of our study. In our study, two thirds were male, about half of the pa- tients were older than 65 years and 7% were never- smokers. These rates are lower in terms of females and never-smokers than in the PROCLAIM trial16, but similar to those of the PACIFIC trial.14 The ma- TABLE 7. Overall survival according to diagnostic variables Variable N Survival Median Univariate analysis P-value Multivariate analysis P-value months (95% CI) HR (95% Wald CI) HR (95% Wald CI) Stage IIIAIIIB 321 262 20.0 (17.1; 21.4) 14.4 (13.0; 15.9) 0.70 (0.58; 0.85) IIIA vs. IIIB: < 0.001 0.77 (0.62;0.95) 0.017 Gender FemaleMale 188 395 20.4 (16.8; 23.8) 15.4 (14.3; 17.6) 0.76 (0.62; 0.94) Female vs. male: 0.010 0.78 (0.64;0.96) 0.044 Smoking status Current smoker Former smoker Never smoker 308 219 42 15.3 (14.2; 17.7) 18.9 (15.9; 20.6) 27.1 (17.0; NA) Current: 0.54 (0.34; 0.84) Former: 0.61 (0.39; 0.97) Never-smokers 0.007 0.036 vs: Current: 0.71 (0.42;0.22) Former: 0.75 (0.44;1.30) 0.218 0.308 Weight loss ≥ 10% No Yes 406 120 20.0 (17.9; 21.1) 12.7 (10.8; 14.8) 0.54 (0.43; 0.68) No vs. yes: < 0.001 0.68 (0.53;0.88) 0.003 PS 0 1 ≥2 146 338 99 22.4 (17.7; 26.1) 15.4 (13.9; 17.2) 11.6 (8.8; 14.7) 0 vs. ≥ 2: 0.37 (0.28; 0.50) 1 vs. ≥ 2: 0.52 (0.41; 0.66) 0 vs. 1: 0.72 (0.57; 0.92) < 0.001 < 0.001 0.007 0.62 (0.43;0.88) 0.69 (0.52;0.91) 0.90 (0.68;1.17) 0.007 0.009 0.422 Histology Squamous Adenoca NOS/others 309 220 54 16.3 (15.0; 19.0) 18.1 (14.7; 20.6) 15 (10.1; 20.1) Squam: 0.96 (0.79; 1.18) NOS/oth: 0.79 (0.57; 1.11) Adeno vs.: 0.726 0.18 Squam: 0.93(0.68;1.26) NOS/oth:0.96(0.63;1.48) 0.630 0.857 EGFR mutation positivity Positive Negative Not tested 14 128 441 27.1 (20.3; NA) 15.8 (13.9; 19.7) 16.5 (15.0; 18.9) Negative: 0.51 (0.24; 1.10) Not tested: 0.52 (0.25; 1.10) Positive vs: 0.087 0.087 Negative:0.57(0.25;1.28) Not tested:0.83(0.36;1.89) 0.176 0.651 Nodes confirmed No Yes 411 172 14.4 (13.3;15.9) 24.7 (21.0; 28.8) 0.56 (0.45; 0.70) Yes vs. no: < 0.001 0.67 (0.52;0.87) 0.002 PET-CT or PET scan Yes No 163 420 19.6 (17.8; 22.8) 15.4 (14.1; 17.6) 0.73 (0.58–0.91) Yes vs. no: 0.005 0.84 (0.66;1.07) 0.160 NOS = not otherwise specified; oth = others; nodes confirmed = mediastinal lymph-nodes histologically confirmed; PS = performance status Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience218 jority of our patients (53%) had squamous cell car- cinomas and this frequency is slightly higher than the one (47%) of the PACIFIC trial.14 The low rate (6%) of NSCLC not otherwise specified confirms that accurate pathological examination is well es- tablished in Central European countries. Most pa- tients (83%) had good (WHO 0–1) PS and 70% had no weight loss prior to diagnosis. Tumour stages IIIA and IIIB were diagnosed in 55% and 45% of patients, respectively, and these percentages are similar to those of the PACIFIC trial.14 Although not mandatory for patients with stage III NSCLC, molecular analyses were performed in selected pa- tients. The EGFR mutation rate of 10% is consistent with the previously reported rate of 13.8% among patients with advanced NSCLC.17 The percentage of patients with ALK translocations (2%) was in the lower range of stage IV patients18,19, but similar to another study.20 PD-L1 testing was not yet stand- ard for patients with NSCLC stage at the time of our study. Our real-world data can also be compared with those from other recent real-world studies.20-23 All studies were similar in terms of median age (around 65 years), good PS (75–86%), never-smok- ers (4–9%) and percentage of adenocarcinomas (around 40%). In comparison to our study, the proportion of females were slightly higher in the American study (44.8%) and the Canadian study (46%).20,22 The percentages of stage IIIA patients were similar between our and the American study but higher (77%) in the Canadian study.20,22 A major goal of our study was to determine the diagnostic and staging procedures (Table 2). Computer tomography of the chest, supplemented by CT or ultrasonography of the upper abdomen, was performed in most patients. PET-CT (or PET) and brain imaging were performed in only 28% and 20% of patients, respectively. These percent- ages, however, greatly varied between centres and reached almost 100% in some centres (Table 2). In the Canadian real-world study, 58% of patients re- ceived a PET scan as part of staging and 74% had baseline brain imaging.22 Bronchoscopy was per- formed in 89% of patients, thereby being the most frequent intervention for obtaining tumour mate- rial for histopathological diagnosis. Only 13.5% of patients had histopathological mediastinal nodal staging prior to therapy. The American and Canadian real-world studies did not provide data on histopathological assessment of mediastinal lymph nodes prior to treatment.20,22 In a retrospec- tive analysis of 106 patients who had been treated with definitive radiotherapy (plus chemotherapy in most patients), 48.1% of patients had pathologi- cal confirmation of nodal disease.24 Treatment of our patients involved surgery, ra- diotherapy and chemotherapy (Table 4). Surgery with and without any other treatment was per- formed in 23% of all patients, 37.1% and 6.1% of patients with stage IIIA and IIIB, respectively. This percentage is similar to the Canadian study in which 21% of patients underwent surgery, either alone or as part of combined modality therapy. This similarity is somewhat surprising based on the fact that the percentage of our stage IIIB patients was higher than the Canadian one (45% versus 33%). Lobectomy and pneumonectomy were performed in 57% and 24% of patients, respectively. The rates of pneumonectomies were similar between our and the Canadian study (23% versus 18%). Like in the Canadian study22, most of our surgical patients (87%) received chemotherapy, more frequently as adjuvant than induction chemotherapy. Chemoradiotherapy was delivered to 34.3% of our patients (Table 4). The concurrent approach was chosen only in 27% of these patients. This low frequency compared to other studies21,22 may be explained by patients unfit for the concurrent ap- proach, limitations in the infrastructure of several centres including long waiting lists, and a stricter definition of concurrent versus sequential chemora- diotherapy than in other studies. Overall, 80.3% of patients received systemic chemotherapy, either alone or combined with other treatment modalities. Radiotherapy alone and BSC alone were given to 11.8% and 5% of pa- tients, respectively (Table 4). These percentages are in agreement with the percentage of patients with poor (WHO ≥2) performance status. Although the proportion of patients with BSC was small and most likely caused by patient selection, it was simi- lar to another study in which radiotherapy and BSC alone were delivered to 11% and 21% of pa- tients, respectively.24 Our study confirmed tumour stage (IIIA versus IIIB), PS, prior weight loss and gender as prog- nostic factors. OS of patients with adenocarcino- mas did not differ from the one of patients with squamous cell NSCLC. Patients undergoing sur- gery had better survival than those without sur- gery (Table 5). The combination of surgery with chemotherapy and/or radiotherapy was also asso- ciated with improved survival outcome. The lack of a survival benefit for our patients undergoing concurrent chemoradiotherapy compared to those undergoing sequential chemoradiotherapy in our real-world study (Table 5) might be explained by Radiol Oncol 2020; 54(2): 209-220. Zemanová M et al. / NSCLC stage III – the Central European real-world experience 219 the multicentre nature of our study, low number of patients, and the heterogeneity of stage III NSCLC. The survival outcomes were similar between our study and the American real-world study.20 Median OS times were 20.0 and 22.3 months for stage IIIA patients, respectively, and 14.4 and 14.7 months for stage IIIB patients, respectively. The longer median OS of 27.3 months in the Canadian study can, at least partly, be explained by the higher percent- age of stage IIIA patients. The best OS in our study with 64% of patients being alive at three years was seen among patients undergoing trimodal- ity therapy and was consistent with the Canadian study.22 It remains unclear, however, whether this survival benefit is due to treatment or just selection of patients with good prognostic features. In a ran- domized trial, the addition of surgery to chemora- diotherapy failed to improve overall survival.25 Our observational study has several limitations. Firstly, the findings were based on major academic cancer centres and, therefore, might not be repre- sentative for smaller centres. Secondly, there was no even distribution of patients between centres and an abundance of Czech patients was seen. Finally, other patient selection biases including patients lost to follow-up might have also played some role. Our real-world findings also define areas for fu- ture improvements in the management of patients with locally advanced NSCLC in Central Europe. Firstly, the rates of staging by means of PET-CT must be increased, mainly through improving ac- cess to these procedures. Secondly, brain imaging should be implemented prior to treatment in all patients who are planned for aggressive treatments such as surgery or chemoradiotherapy. Thirdly, invasive staging of mediastinal lymph nodes prior to treatment should be performed more fre- quently. In order to achieve these goals, awareness among doctors has to be raised, opportunities for education as well as training of doctors must be in- creased, and the infrastructure of some centres has yet to be improved. Conclusions The present real-world study confirmed known prognostic factors and the broad heterogeneity in diagnostic and therapeutic strategies among pa- tients with stage III NSCLC in Central European countries. Rates of PET-CT staging, invasive stag- ing of mediastinal nodes, and brain imaging prior to combined treatments should be increased in the future. Acknowledgements We would like to thank the heads of the all par- ticipating centres for permission to use data of pa- tients from their respective regional networks and for the support of this project. We are also indebted to all physicians who provided data for the regis- try. 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