Three dimensional conformal radiotherapy and concurrent chemotherapy for unresectable stage III non-small cell lung cancer

Three dimensional conformal radiotherapy and concurrent chemotherapy for unresectable stage III non-small cell lung cancer

Combined Modali~ Therapy~Small there was a response in 79% in 24 evaluable pts (19 PR, 2 SD, 3 PD and 4 NE) and 68% in all. One and two-year overall s...

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Combined Modali~ Therapy~Small there was a response in 79% in 24 evaluable pts (19 PR, 2 SD, 3 PD and 4 NE) and 68% in all. One and two-year overall survival were 55% and 43%, respectively, with a median survival of 15 months. To conclude, in this group of patients with advanced disease, 76% had stage IIIb, a high response rate was achieved with manageable toxicity and promising survival data.

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Neoadjuvant therapy with Docetaxel (TAX) and Cisplatin (ClS) in patients (pts) with non-small cell lung cancer (NSCLC), stage IliA, N2 is highly active with few toxicities

D.C. Betticher, S.-F. Hsu Schmitz, Y. Gauthier, C. yon Briel, A. Roth, A. Spiliopoulos, M Pless, R. Stahel, W. Weder, M. TStsch, T. Cerny, H.B. Ris. For the Swiss Group for Clinical Cancer Research (SAKK),

Switzerland Neoadjuvant therapy in locally advanced NSCLC has become a standard in the majority of centres. Mitomycin C is often used leading frequently to postoperative pulmonary complications with a mortality of 5-15% of pts. Study Design: Multi-institutional (10 centres), prospective, nonrandomised study; pts: cT < 4, pN2 NSCLC pathologically confirmed by mediastinoscopy; chemotherapy: 3 cycles of TAX (85 mg/m2, dl) and CIS (40 mg/m 2 [36 pts] - 50 mg/m 2 [23 pts], dl + d2), qSw followed by surgery (except of PD). Radical resection included mediastinal lymphadenectomy. Postoperative radiotherapy (60 Gy) was given in case of incomplete resection and/or positive first mediastinal lymph node. Pts: N = 59, age (median/range): 59 y (39-76), PS: 0 = 36, 1 = 23. Histology (according to WHO classification 1999): squamous cell 43%, adeno- 41%, large cell carcinomas and others 16%. T1 = 5, T2 = 37, T3 = 17. N2 detectable on CT scan and by mediastinoscopy: 49; positive by mediastinoscopy only: 10 pts. Results: Actual dose intensity (median): TAX: 84 mg/m2/3w (range 49--90), CIS 80-98 mg/m2/3w (40-103). Response rate (3 inevaluable pts): 68% (Ch 54-80%), with 9% CR, 59% PR, 28% NC and 4% PD. 53 pts underwent surgery, 24 received postoperative radiotherapy. Pathological (path) CR was found in 16% with fibrosis beside necrosis being an important feature. Squamous cell carcinomas had a better path response with median necrosis/fibrosis of 80% vs. 43% for other histological subtypes (p = 0.002). Downstaging with NO and N1 at surgery occurred in 21% and 26% of pts, respectively. Complete tumour resection was possible in 77% of pts. Median remission duration (RD) was 11.2 months and did not correlate with clinical response. However, RD correlated with path response: 75% RD was 9.8 months for >60% necrosis/fibrosis vs. 7.2 months for pts with <60% (p = 0.04). Toxicity: chemotherapy: 34% of cycles were tolerated without any nonhematological toxicity except for nausea (_<1) and alopecia (<3). There was one fatal gastric bleeding on d8 of an inevaluable pt on steroids. Surgery: no postoperative pulmonary complications. The postoperative mortality was 1.7% (1 pt died due to heart attack on day 4). Conclusion: Combined TAX and CIS, as used in the study, is an efficacious and well tolerated regimen for locally advanced NSCLC with a promising clinical and pathological response rate, comparable to previous regimens but with less postoperative pulmonary toxicity often seen after Mitomycin C.

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Induction (I) and concurrent (C) carboplatinlpaclitaxel (C/P) with dose escalated thoracic conformal radiotherapy (TCRT) in stage IIIAJB non-small cell lung cancer (NSCLC): A phase IIII trial

MA. Socinski, J. Halle, M. Schell, J. Clark, S. Limentani, W. Mitchell, R. Fraser, J. Rosenmann. University of North Carolina at Chapel Hill,

Chapel Hill; Multidisciplinary Thoracic Oncology Program, University of North Carolina, Chapel Hill, North Carolina, USA The optimal strategy in the combined modality approach to stage IIIA/B NCSLC remains undefined. In this study, 2 cycles of I C/P (AUC 6 and 225 mg/m2/3 h q21d) were followed on d43 by weekly

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C C/P (AUC 2 and 45 mg/m2/3 h × 6) and TCRT (2 Gy qd). 3D computer-assisted planning techinques were utilized. 50 Gy was delivered to the original tumor volume and mediastinum with a 1.02.0 cm margin. Boost volumes included the pdmary tumor volume and all radiographically positive nodes with a 1.0 cm margin. Dose of TCRT was escalated in 4 cohorts: 60, 66, 70, 74 Gy 62 patients (pts) were entered (39 M:23 F; IlIA/B, 27:35; PSO-I:2, 61:1; % >5% wt loss, 32: adeno 58%, squam 35%, other 7%). Response to I C/P - 40% PR, 42% SD, 13% PD (10% local (L), 3% distant (D)), 5% NE. No unusual toxicity during I C/P was seen. 48/62 pts (77%) began TCRT and C C/P on d 43-14 pts did not - 8 PD, 2 early deaths, 2 refused, 1 P gr4 hypersensitivity reaction, 1 co-morbidity. No dose-limiting toxicity during TCRT dose-escalation was seen. 31/32 (97%) pts treated at 74 Gy completed therapy to 74 Gy. Toxicity (%) -esophagitis- RTOG gr 1/2/3/4 = 561331813: gr 2/3/4 neutropenia 19/14/0, anemia 31/2/0, pits 6/4/0, lymphocytopenia 4/35/46, NN 10/0/2.% wt change from baseline to end of therapy was -2.3% (+/-0.07%) (p = .002). One gr 2 pneumonitis (at 60 Gy), 3 (6%) late esophageal strictures (gr 2) and 1 gr 3 pericardial effusion have occurred thus far. Overall response to all therapy (n = 62): 50% (3% CR, 47% PR), 24% SD, 16% PD, 10% NE. 30 pts have failed - 46% L, 8% L + D, 46% D only (50% of the D were brain only). Survival (including all 62 pts) - median = 26 mos; 1-, 2-, 3-yr survival probabilities (95% CI) are 0.74 (0.62, 0.86), 0.52 (0.36, 0.69) and 0.47 (0.31, 0.65), respectively. Conclusions: 1) Sequential and concurrent delivery of chemotherapy (C/P) with dose-escalated TCRT to 74 Gy is a novel strategy in the management of unresectable stage IIIA/B NSCLC, 2) The toxicity of this aggressive strategy utilizing TCRT is acceptable, and 3) Survival is notable with possible explanations being sequential and concurrent delivery of chemotherapy, enhanced tumor targeting utilizing conformal techniques, and dose escalation of TCRT with an acceptable rate of toxicity.

dimensional conformal radiotherapy and concurrent [32• Three chemotherapy for unresectable stage III non-small cell lung cancer E. Choi, K. Shin, S. Ahn, B. Yi, H.S. Chang 1, C.W. Suh 2, J.S. Lee2, S.H. Kim2, Y.S. Koh2, W.S. Kim2, D.S. Kim2, W.D. Kirn2. Dept. of

Radiation Oncology, Seoul; 1DepL of Radiation Oncology; 2Internal Medicine, Asan Medical Center, College of Medicine, University of U/san, Seoul, Korea This phase II study has been conducted to determine the feasibility, toxicity, response rate, local control, distant metastasis, and survival of hyperfractionated 3D conformal radiotherapy and concurrent chemotherapy with mitomycin C, vinblastine, and cisplaatin in unresectable stage III non-small cell lung cancer (NSCLC), and also to find the most ideal 3D conformal radiotherapy technique. From Aug 1993, 161 patients with unresectable stage III NSCLC were entered into this trial and 146 (91%) completed the treatment. Hyperfractionated radiotherapy was given to a total dose of 85-70 Gy (120 cGy/fx, bid) with concurrent 2 cycles of MVP chemotherapy (Mitomycin C 6 rag/m2 d2 & d29, Vinblastine 6 mg/m2 d2 & d29, Cisplatin 60 rag/m2 dl & d28). Of these 146 patients who completed the treatment, 78 received noncoplanar 3D conformal radiotherapy using 4-6 fields and 17 received coplanar segmented conformal radiotherapy. Clinical tumor response was assessed one month after the completion of radiotherapy by computerized tomography (CT) scan. Toxicity was graded by RTOG and SWOG criteria. Normal tissue complication probability (NTCP) for lung was calculated to find the correlation with radiation pneumonitis. Nineteen (13%) had stage Ilia and 127 (87%) had IIIb disease including 16 with pleural effusion and 20 with supraclavicular lymph node metastasis. Response rate was 74%, including 20% complete response and 54% partial response. With a minimum follow up of 42 months, overall survival was 51.2% at 1 year, 25.1% at 2 years and 13.6% at 4 years and median survival was 15 months. Patients achieving a complete response (n = 29) had a 2-year overall survival of 43.8% and 4 year of 31.9% compared to 22.9% and 12.4% for partial responders (n = 79) (p = 0.0001). Actuarial

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local progression free survival was 65.4% at 1 year, 42.1% at 2 years and 36.3% at 4 years. Actuarial distant free survival was 58.4% at 1 year, 48.8% at 2 years and 41.1% at 4 years. Severe weight loss (more than 10%) occurred in 20 patients (13.7%) during treatment. Forty two patients (29%) showed radiation pneumonitis; 29 showed grade 1 and 13 other showed grade 2. The average NTCP value of the patients who showed radiation pneumonitis was significantly higher than that of the patients without pneumonitis (66.0% vs. 26.4). Four patients died of treatment related toxicity. This hyperfractionated 3D conformal radiotherapy and concurrent chemotherapy is a well tolerated regimen with acceptable toxicity. This study showed a higher local control rate, and better survival at 2 and 4 years compared to our previous trial of hyperfractionated radiotherapy following 3 cycles of induction chemotherapy.



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phase IIII study of Docetaxel (Taxotere) combined with concurrent radiation therapy in locally advanced non-small cell lung cancer (NSCLC)

S Aamdal I , G. Lauvvang I , K Owre 1, R. Hatlevoll 1, J. Armellini 2 I Norwegian Radium Hospital, Montebello, Oslo, Norway, 2Aventis, Antony, France Concurrent radiation and chemotherapy play an important role in the treatment of unresectabte NSCLC. We performed a phase 1/11study of Docetaxel (D), 1 h i.v. infusion given at days 1, 8, 22, 29 with concurrent radiotherapy of 2 Gy, 5 days/week (wk) for 5 wks in patients (pts) who were chemotherapy and radiotherapy naive with unresectable stage III NSCLC. Results: 42 pts entered the study, M/F ratio: 27/15, median age: 59 (41-71), median WHO PS: 1 (0-1), histology: squamous 45%, adenocarcinoma 38%, other 17%. 12 pts entered the phase I, the maximum tolerated dose was reached at D 40 mg/m 2, reversible oesophagitis was the dose limiting toxicity. 33 pts have been treated at the recommended dose of D 30 mg/m 2, 1 pt was ineligible (kidney metastasis). Among the 24 pts evaluable for response, an objective response rate (ORR) of 62.5% (95% CI: 40.6-81.2) was observed (8 CR, 7 PR) and confirmed by external expert review. At the recommended dose, the median survival time is 13.6 months (95% Ch 8.2-24.8), the one-year survival is 59.4% (95% CI: 40.6-76.3) and the median time to progression is 12 months (95% CI: 5.1-36.0). The median duration of response (ORR) is 104.6 wks (95% CI: 52.0156.3). The median follow-up period is 9 months (95% Ch 3.3-33.2). 122 cycles were administered (median = 4, range 1-4). The median relative dose intensity was 100%. All pts (N = 33) were evaluable for safety. No grade 3-4 hematological toxicity was observed. Nonhematological side effects: 78% of pts experienced mild to moderate dysphagia, grade 3-4:1 infection, 1 stomatitis, 1 myocardial infarction (recovered), 1 dyspnea, 1 nausea and 1 neuropathy were observed. Conclusion: Docetaxel 30 mg/m 2 weekly for 4 weeks with concurrent radiotherapy (50 Gy) is effective and well tolerated. The simplicity of this chemoradiation regimen facilitates its use for standard stage Ill NSCLC chemotherapy na'~'vepts radiation treatment routines. A phase III randomized comparative trial is ongoing.

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Combined

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Outcome results of long term follow up, for population based cohort of patients with stage Ilia NSCLC treated with aggressive combined modality treatment approach in a prospective study

S El-Sayed, A Leylek, M Akra, C. Mihalcioiu. University of Manitoba, Winnipeg, Canada

Introduction: Lung cancer is the leading cause of cancer deaths worldwide, historically Radiotherapy was the standard treatment for locally advanced NSCLC producing 5 years disease free survival of around 5%. Recent studies have shown that AGGRESSIVE COMBINED MODALITY treatment is superior to radiotherapy alone in prolonging survival. Objectives: To evaluate the feasibility and potential value of concomitant radiation and chemotherapy followed with surgery in improving the outcome of patients with stage IliA NSCLC in a prospective study setting. The primary end point of the study is Toxicity of the combined modality treatment. Methods: ELIGIBILITY: Patients selected for the study were deemed to have stage IliA, histologically confirmed NSCLC. performance status (KPS) of = or >70%, acceptable pulmonary and renal functions, and signed informed consent. TREATMENT REGIMEN: Treatment included Radiotherapy of 5000 cgy/20 F, days 1-28 in case of small volume or 3500 cgy/10 F, days 1-14 in case of large volume, combined with concomitant chemotherapy with cisplatinum 50 mg/m2 IVI day 1-5, 21-25. Results: From July 1991 to November 1995, 30 patients were accrued with age range of 40-71 years and average age of 59 years. Histology: 14 patients with adenocarcinoma, 8 with squamous cell carcinoma and 8 with poorly differentiated tumors. The majority of the patients presented with cough and dyspnea, some were asymptomatic at presentation. Most of the patients received the planned chemo/radiotherapy. While 9 patients had radical surgery (Iobectomy or pneumonectomy). Toxicity While all patients have required hospitalization for the 5 days of concomitant chemo-radiation, overall, the toxicity of the treatment was mild with no treatment-related death or delay in radiotherapy treatments. SURVIVAL Out of the 30 patients 28 died of their disease and 2 lost to follow up after 15 and 25 months. The median survival is 16 months. Conclusions: The treatment protocol is practical and feasible. The treated patients were more advanced than the average. No doubt that aggressive combined modality treatment prolong survival but distant metastasis remains the main cause of treatment failure. Long term disease free survival remains poor. It is possible that more aggressive chemo/radiotherapy schedules could produce better results. ~ - 9 - ] Early whole brain concomitant radiotherapy-chemotherapy for non-small cell lung cancer (NSCLC) brain metastases. A phase 2 study C. Ngo Quy 1, M.-A. Hailer 1, A. Darut-Jouve 2, G. Jolimoy2, D. Spa~th 3, V. Beckendorf3, T. Bazarbachi 1, E. Luporsi 3, B. Coudert 2, Y. Martinet 1. I Fed6ration de Pneumologie, H6pital de Brabois, Nancy; 2Service d'Oncologie Medicale, Centre Anticancereux G.F. Leclerc, Dijon; 3 Centre Anticancereux A. Vautrin, Vandoeuvre-les-Nancy, France Brain is a frequent secondary location in NSCLC. The combination of chemotherapy (CT) and radiotherapy could increase treatment efficiency by interfering with the cell ability to repair the specific injuries induced by each treatment.