Phase III Study of Concurrent Chemotherapy and Radiotherapy (CT/RT) versus CT/RT followed by Surgical Resection for Stage IIIA(pN2) NSCLC Outcomes Update.

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Phase III Study of Concurrent Chemotherapy and Radiotherapy (CT/RT) versus CT/RT followed by Surgical Resection for Stage IIIA(pN2) NSCLC Outcomes Update of North American Intergroup Trial 0139 (R9309) Conducted by: RTOG (chair), SWOG, NCIC CTG, ECOG, CALGB and NCCTG Radiation Therapy Oncology Group

Lung Intergroup Trial 0139 Rationale Patients with stage III NSCLC and clinically- evident N2 disease have poor outcomes with surgery or radiotherapy (RT) alone Chemotherapy (CT) plus RT is standard for pathologically-confirmed N2 nodes (pN2) Surgical resection after CT/RT, although promising in phase II trials, is controversial due to increased morbidity and mortality

Lung Intergroup Trial 0139 Objectives 1.Determine if resection after CT/RT results in improved outcome compared to CT plus full-course RT (arms based on SWOG 8805 and SWOG 9019) 2.Analyze progression-free, overall, and long-term survival; toxicity; and patterns of failure

Lung Intergroup Trial 0139 Eligibility Criteria T1-3, pN2, M0 non-small cell lung cancer Resection technically feasible FEV1 >2.0 liters, or, predicted post-resection FEV1  800 cc Medically fit

Lung Intergroup Trial 0139 Study Design STRATIFY KPS vs T1 vs T2 vs T3 RANDOMIZE RE-EVALUATE RE-EVALUATE 2-4 weeks after 7 days before completion of RT completion of RT Induction CT/RT Cisplatin, 50 mg/m 2 IV d1, 8, 29, 36 Etoposide, 50 mg/m 2 IV d1-5, Thoracic RT, 45 Gy (1.8 Gy/d), begin d1

Lung Intergroup Trial 0139 Study Design No progression at re-evaluation Surgical Resection Continue RT to 61 Gy without interruption CONSOLIDATION cisplatin plus etoposide X 2 cycles

Lung Intergroup Trial 0139 Statistical Considerations Sample size assumed 25% 2-year survival for CT/RT and 10% absolute improvement by the addition of surgery 80% statistical power and 0.05 significance level Final accrual 484 eligible patients

Lung Intergroup Trial 0139 Results Opened 3/94 and closed 11/01 Accrual longer than planned with more events, thus closure allowed at n = 429 First analysis in 2003 reported better PFS, but not OS, for surgical arm Second planned analysis this report: Median follow-up: 81 months All patients followed >2.5 years

Lung Intergroup Trial 0139 Patient and Tumor Characteristics* Randomized/Eligible CT/RT/S CT/RT Female Age median yrs/  70 KPS Weight loss  5 kg T3 tumors Squamous histology LDH abnormal 429/396 (93%) (36%) 60/63 (16%) 48 (12%) 84 (21%) 48 (12%) 129 (33%) 72 (18%) *balanced in both arms

Lung Intergroup Trial 0139 Eligible for thoracotomy177 (88%) Thoracotomy performed164 (81%) Complete resection144 (71%) Incomplete resection 11 (5.5%) No resection 9 (4.5%) Eligible for consolidation CT/RT 179 (92%) Commenced consolidation155 (80%) Treatment Delivered ARM 1 (n=202) ARM 2 (n=194)

Lung Intergroup Trial 0139 Treatment CT/RT/S CT/RT p-value (n=202) (n=194) Induction 191 (95%) 177 (92%) NS chemotherapy Consolidation 112 (56%) 144 (75%) p< chemotherapy Radiotherapy 193 (96%) 154 (79%) p< Treatment Delivered* *Per protocol or with an acceptable variation (study chair review)

INT 0139 Grade 3/4 Toxicity from CT/RT *p= NeutropeniaPneumonia/respiratory CT/RT/S (n=202) CT/RT (n=194) Nausea/emesisEsophagitis* Percent (%)

Lung Intergroup Trial 0139 During induction none, either arm CT/RT/S total 16 (7.9%) 30 d ays postop. 10 (5.0%) misc. other 6 (2.9%) CT/RT (during or 4 (2.1%) after consolidation) Treatment-Related Mortality

INT 0139 Treatment-Related Deaths on CT/RT/S Arm (n=16) Type of Total Deaths Surgery (of n=202) n (% total) Cause of Death None 38 1 (3%) Pneumonitis Exploration only Wedge Lobectomy 98 1 (1%) ARDS Pneumonectomy (26%) ARDS/respiratory 11; miscellaneous, 3 (R) simple 17 5 (29%) (R) complex 12 6 (50%) (L) simple 6 0 (L) complex 19 3 (16%)

Lung INT 0139: Patterns of Failure Site of First Arm 1 Arm 2 p-value Progression (CT/RT/S) (CT/RT) Local relapse only 10% 22% primary 2% 14% nodes 7% 3% both 1% 5% Brain only 11% 15% 0.29 All distant metastases 37% 42% 0.35

INT 0139 Pathologic T and N Status at Time of Surgery pT/N N % Thoracotomies % Total (n=164) (n=202) T0N0(pCR) 29 18% 15% T1N % 15% T2-4N % 8% Tany N % 38% N1-3 or 88* 54% 43% unknown *3 were unknown

Intergroup 0139/RTOG 9309 Progression-Free Survival by Treatment Arms CT/RT/S 159/202 CT/RT 172/194 Logrank p = Hazard ratio = 0.77 (0.62, 0.96) % Alive without Progression / / // / / // / / ///// // / / / / / // // Months from Randomization Failed/Total

INT 0139/RTOG 9309 Survival Endpoints Endpoint CT+RT+S CT+RT Progression-Free Survival* Median 12.8 months 10.5 months 5-year (  95% CI) 22.4% (6) 11.1% (5) Overall Survival* Median 23.6 months 22.2 months 5-year (  95% CI) 27.2% (6) 20.3% (6) *crossing survival curves due to treatment-related deaths, 96 (24.2%) alive/censored

INT 0139 Survival Data CT/RT/S: more alive without progression (21% vs 11%, p =.008), but more died without progression (18% vs 10%, p =.02) Survival curves indistinguishable through year 2, then separate By year 5, absolute survival benefit of 7% favors surgical arm: odds ratio 0.63 (0.36, 1.10), p = 0.10; no other factor predicted 5-yr survival by logistic regression

Intergroup 0139/RTOG 9309 Overall Survival by Treatment Arms CT/RT/S 145/202 CT/RT 155/194 Logrank p = 0.24 Hazard ratio = 0.87 (0.70, 1.10) % Alive Months from Randomization Dead/Total

INT 0139 Cox Stepwise Selection Model for Overall Survival Variable* Hazard Ratio p-value (95% CI) Weight loss 1.54 (1.16, 2.05) <5 kg vs  5 kg Female vs male 1.42 (1.09, 1.84) N2 station 1.38 (1.04, 1.83) positive vs  2 CT/RT/S vs CT/RT 1.07 (0.84, 1.36) 0.61 *Not significant: age, KPS, T stage, LDH, histology

INT 0139 Trimodality Arm (n=202) Survival by Pathologic Status at Surgery T/N Median Survival Subset (months) 5-year Tany N0* 34 41% Tany N % or unknown No surgery 8 8% *29 of these = T0N0 (pCR): MS, 40 months; 5-year, 42%

Intergroup 0139 Trimodality Arm Overall Survival by Pathologic Nodal Status No surgery (n=38) Pathologic N0 (n=76) Pathologic N1-3, unknown (n=88) p < % Alive Months from Randomization

INT 0139 Exploratory Survival Analysis All but 1 postoperative death followed a pneumonectomy Hypothesized survival advantage for CT/RT/S if lobectomy performed and for CT/RT if pneumonectomy Patients on CT/RT/S were matched with those on CT/RT arm on 4 prestudy factors (KPS, age, sex, T stage); match feasible for 90/98 lobectomies and 51/54 pneumonectomies

INT0139 Overall Survival of the Lobectomy Subset versus Matched CT/RT Subset % Alive Months from Randomization /// /// / //// /// / / // // / // Logrank p = CT/RT/S 57/90 CT/RT 74/90 Dead/Total MS 34 mos. 22 mos. 5 yr OS 36% 18% CT/RT/S CT/RT

Lung Intergroup Trial 0139/RTOG 9309 Both approaches have median and 5-year survivals better than predicted from phase II data in stage IIIA(pN2) NSCLC Longer follow-up confirms significantly improved PFS, but not OS, when surgery follows CT/RT There is a trend for increased 5-year survival with trimodality therapy Conclusions

Lung Intergroup Trial 0139/RTOG 9309 N0 status at surgery significantly predicts greater 5-year survival The trimodality approach is not optimal when a pneumonectomy is required due to high mortality risk Surgical resection after CT/RT can be considered for fit patients if lobectomy is feasible Conclusions

Radiation Therapy Oncology Group INT 0139 Acknowledgements Study Chairs: Kathy S. Albain, M.D. – Medical Oncology Valerie R. Rusch, M.D. – Thoracic Surgery Andrew T. Turrisi, III, M.D. – Radiation Oncology Biostatisticians: R. Suzanne Swann, Ph.D. Rebecca Paulus, B.S.

Radiation Therapy Oncology Group INT 0139 Acknowledgements Other Coauthors: Frances A. Shepherd, M.D. Colum Smith, M.D. David R. Gandara, M.D. David H. Johnson, M.D. Mark R. Green, M.D. Robert C. Miller, M.D. Yuhchyau Chen, M.D., Ph.D. Robert B. Livingston, M.D. Gail Darling, M.D. William T. Sause, M.D. James D. Cox, M.D.

Radiation Therapy Oncology Group INT 0139 Other Acknowledgements Additional Protocol Discipline Chairs: Yvon Cormier, M.D. Mark Krasna, M.D. Claude Deschamps, M.D. Randolph Marks, M.D. Bahman Emami, M.D. Tom Rice, M.D. David Ettinger, M.D. Stephen Seagren, M.D. Richard Feins, M.D. Henry Wagner, M.D. Daniel Ihde, M.D. Major Thoracic Surgical Support: Willard Fry, M.D. RTOG Headquarters: Joanne Ley, R.N., C.C.R.P.