Two Cycles of Chemoradiation: 2 Cycles is Enough. Concurrent Chemotherapy / RT Regimens

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1 1 Two Cycles of Chemoradiation: 2 Cycles is Enough Heather Wakelee, M.D. Assistant Professor of Medicine, Oncology Stanford University Concurrent Chemotherapy / RT Regimens Cisplatin 50 mg/m 2 on days 1, 8, 29, 36 Etoposide 50 mg/m 2 on days 1-5, Concurrent thoracic RT (total t dose 61 Gy) 1 Cisplatin 100 mg/m 2 on days 1, 29 Vinblastine 5 mg/m 2 /weekly x 5 Concurrent thoracic RT 60 Gy 2 Paclitaxel mg/m 2 weekly over 1 hour Carboplatin AUC = 2 mg/ml/min over 30 min weekly Concurrent thoracic RT 63 Gy/7 wks/34 fractions 3 (Randomized phase II trial) 2 1. Albain KS, et al. J Clin Oncol. 2002;20: Curran WJ, et al. Proc Am Soc Clin Oncol. 2003;22. Abstract Belani CP, et al. J Clin Oncol. 2005;23:

2 2 Unresectable Stage III Disease: Historical Before 1996 Radiation alone standard of care (50-60Gy) Median 9-11 mo, 10-20% 2 yr, 5-10% 3 years survival 60 Gy better than < 60Gy Meta-analysis XRT +Chemo 9% annual risk of death (13% with Cisplatin) HR 0.87 Radical XRT +/- Chemo 2 yr absolute benefit 4% Perez, Cancer; 59: 1874, 1987 RTOG Perez et al. Cancer 45: , 1980 BMJ 311:899, 1995 Steady Improvements in Unresectable Stage III NSCLC Outcomes Cooperative Group Trial Med Surv 3-Yr Surv (%) (mo) CALGB 8433 (RT) CALGB 8433 (Seq CT->RT) RTOG 9410 (Seq CT/RT) RTOG 9410 (Conc CT->RT)

3 3 Dillman Trial (CALGB 8433): Schema Stage III Unresectable NSCLC N = 155 R A N D O M I Z E XRT 60 Gy/ 30 Fx Cisplatin 100 mg/m2 Vinblastine x 2 cycles XRT 60 Gy/ 30 Fx Dillman NEJM; 323:940,1990 Dillman (CALGB 8433) Trial: Survival Curves Survival 3 yr 7 yr CT + 23% 13% RT RT 11% 6%

4 4 Meta-Analysis: XRT + Chemo Unresectable Stage III Articles (Randomized Phase III) 2589 patients, 14 articles, Cisplatin used 10/14 XRT+Chemo vs XRT Chemo risk for death 1 yr RR 0.88 / 2 yr RR 0.87 / 3 yr RR 0.83 life expectancy 2 months Next Question: Concurrent vs Sequential? Pritchard, Anthony Ann Int Med; 125:723, 1996 RTOG 9410 Trial Design Unresectable Stage III NSCLC N = 592 R A N D O M I Z E Vinblastine Cis 100 mg/m2 x 2 cyclescles Vinblastine Cis 100 mg/m2 x 2 cycles w/concurrent TRT Etoposide PO Cis 100 mg/m2 x 2 cycles w/concurrent BID RT Thoracic RT 63 Gy Curran, PASCO 19: abstr 1891, 2000

5 5 RTOG 9410: Survival Results Sequential Concurrent Hyperfrac Median OS 14.6 m 17.0 m* 15.6 m Median PFS 8.8 m 10.6 m 9.1 m 1 Yr Surv 57% 63% 61% 2 Yr Surv 18% 35% 34% 3 Yr Surv 16% 26% 23% *p = (vs. Seq) Locally Advanced Multimodality Protocol (LAMP) (ACR 427): Trial Design Unresectable Stage III NSCLC N = 268 R A N D O M I Z E Carboplatin AUC 6 Paclitaxel 200 mg/m2 Q3 wk x 2 cycles Carboplatin AUC 6 Paclitaxel 200 mg/m2 Q3wk x 2 cycles XRT QD to 63 Gy, + Carboplatin AUC 2 Paclitaxel 45 mg/m2 weekly x 7 weeks XRT QD to 63 Gy XRT QD to 63 Gy + Carboplatin AUC 2 Paclitaxel 45 mg/m2 weekly x 7 weeks Carboplatin AUC 6 Paclitaxel 200 mg/m2 Q3 wk x 2 cycles Choy, PASCO 21: abstr 1160, 2002

6 6 LAMP Trial: ASCO 2002 Results CT RT CT CT/RT CT/RT CT Med Surv (mo) Yr Surv (%) Yr Surv (%) Med OS 17 mo, 2 yr OS 35% on RTOG 9410 CALGB 39801: Schema Stage III Unresectable NSCLC N = 366 R A N D O M I Z E XRT QD to 66 Gy, + Carboplatin AUC 2 Paclitaxel 50 mg/m2 weekly x 7 weeks Carboplatin AUC 6 Paclitaxel 200 mg/m2 Q3wk x 2 cycles XRT QD to 636 Gy, + Carboplatin AUC 2 Paclitaxel 50 mg/m2 weekly x 7 weeks Vokes, PASCO 22: abstr 7005, 2004

7 mo vs 13.7 mo; NS vs 17 mo on RTOG 9410; 2yr OS 28% vs 32% DISAPPOINTING 24% 3 yr OS on induction arm Vokes, PASCO 22: abstr 7005, 2004 HOG LUN 01-24/USO Schema ChemoRT Cisplatin 50 mg/m 2 IV d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & Concurrent RT 59.4 Gy (1.8 Gy/fr) = 2 cycles Stratification Variables: PS 0-1 vs 2 IIIA vs IIIB CR vs. non-cr Randomize Docetaxel 75 mg/m 2 q 3 wk 3 Observation Hanna PASCO Abs 7512

8 8 HOG Grade 3/4 Toxicities Toxicity PE/XRT Docetaxel OBS *p-value Esophagitis 17.2% Infections 8.9% 11.0% 0.0% Pneumonitis %** 1.4% <0.001 Rx-related death 1.5% 5.5% 0.0% Hospitalized 36.5% 28.8% 8.1% <0.001 RBC transfused 10.3% 5.5% 1.4% *p-value corresponds to comparison of Docetaxel vs. Obs groups **Includes 1 patient death Entry Criteria:ECOG 0-1, IIIA-IIIB, FEV1> 1L, no signif wt loss, no effusions Hanna PASCO Abs 7512 Abs# 7512 HOG : Overall Survival (ITT) Randomized Patients (n=147) Perce ent of patients surviving 100% 75% 50% 25% Observation Docetaxel Consolidation Observation: Median: 24.1 months ( ) 3 year survival rate: 27.6% Docetaxel: Median: 21.5 months ( ) 3 year survival rate: 27.2% P-value: OS13.7 mo 24% 3 yr C % Months since registration Hanna PASCO Abs 7512

9 9 Stage III NSCLC: U.S. Cooperative Group Phase III Trials: (1980 s-2000 s) STUDY YRS CHEMORADIATION XRT No. MST 3 year SCHEMA (Gy) Pts mos surv CALGB P + Vinb XRT % RTOG/ECOG P + Vinb XRT % 8808/4588 RTOG P + Vinb/XRT ~25% CALGB Carbo + Pac CP/XRT % SWOG PE/XRT D +/- Gef NR Current Study PE/XRT +/- D % Hanna PASCO Abs 7512 Results in Inoperable Stage III NSCLC C-CRT Followed by Consolidation or Observation S Phase II S Phase II HOG LUN / USO Phase III 3 CE / RT CE / RT docetaxel Regimen CE / RT CE / RT CE / RT CE / RT docetaxel N Med OS (mo) Med PFS (mo) NR 16 Approx 10 Approx 10 Pneumonitis, gr 3/4 (%) Hospitalization, first weeks (%) Death, first 9 weeks (%) Albain KS, et al. J Clin Oncol. 2002;20: Gandara DR, et al. Clin Lung Cancer. 2006;8: Hanna N, et al. J Clin Oncol. 2008;26:

10 10 Full-Dose C-CRT With 2nd Generation Agents vs Modified- Dose C-CRT With 3rd Generation Agents NSCLC Unresectable Stage IIIA / IIIB ECOG PS 0-1 Age < 75 R A N D O M IZ E Phase III Non-inferiority design Sample size 450 Cisplatin 80 mg/m 2 day 1 Vindesine 3 mg/m 2 days 1 & 8 Mitomycin 8 mg/m 2 day 1 Every 4 weeks x 2 cycles Carboplatin AUC 2 Irinotecan 20 mg/m 2 Days 1, 8, 15, 22, 29, 36 Carboplatin AUC 2 Paclitaxel 40 mg/m 2 Days 1, 8, 15, 22, 29, 36 With RT 60 Gy Cisplatin 80 mg/m 2 day 1 Vindesine 3 mg/m 2 days 1 & 8 Mitomycin 8 mg/m 2 day 1 Every 4 weeks x 2 cycles Carboplatin AUC 5 day 1 Irinotecan 20 mg/m 2 days 1 & 8 Every 3 weeks x 2 cycles Carboplatin AUC 5 day 1 Paclitaxel 200 mg/m 2 day 1 Every 3 weeks x 2 cycles Satouchi M, et al. J Clin Oncol. 2009;27(15s). Abstract Full-Dose C-CRT With 2nd Generation Agents vs Modified-Dose C-CRT With 3rd Generation Agents Non-inferiority not achieved MVP Carb-I Carb-P N Median OS (mo) HR (compared to MVP) % CI P (compared to MVP) Grade 3/4 toxicities (%) Febrile neutropenia Thrombocytopenia Nausea Fatigue Vs Med OS of 23.2 mo on HOG trial; cis/etop x 2 cycles w/ concurrent XRT Satouchi M, et al. J Clin Oncol. 2009;27(15s). Abstract 7504.

11 11 SWOG Maintenance Gefitinib Stage IIIB -Definitive Chemo/XRT ELIGIBLE: IIIB Cisplatin/VP16 +XRT Consolidation Docetaxel RA ND O M I Z E Gefitinib x 2 yrs Placebo x 2 yrs Kelly K, et al. J Clin Oncol. 2008;28: SWOG 0023: Gefitinib Maintenance After Concurrent Cisplatin / Etoposide / RT and Docetaxel Consolidation Overall Survival 100% 80% 60% 40% N Events P = 0.01 Median OS (mo) 1-Yr OS 2-Yr OS Placebo % 59% Gefitinib % 46% 20% 0% Median FU time: 27 months Months After Randomization Kelly K, et al. J Clin Oncol. 2008;28:

12 12 S0023 Causes of Death by Treatment Arm Parameter Gefitinib N = 118 Placebo N = 125 Alive Dead Cancer 61 (86%) 43 (80%) Toxicity 2 (3%) 0 (0%) Other Causes 1 (1%) 3 (6%) Unknown 7 (10%) 8 (15%) No differences in sites of relapse Kelly K, et al. J Clin Oncol. 2008;28: Conclusions Chemotherapy improves RT outcomes in stage III NSCLC Concurrent chemotherapy >> Sequential No improvement in outcome with Induction Carbo/Paclitaxel on CALGB Consolidation Docetaxel on HOG trial Consolidation Gefitinib on SWOG 0023 Aggressive regimens (Japanese trial) no better than US outcomes w/ 2 cycles cisplatin doublet (etoposide) 2 cycles cisplatin doublet, concurrent w/ XRT, is the Standard of Care for Unresectable Stage III NSCLC

13 13 Two Cycles of Chemoradiation: 2 Cycles is Enough: Rebuttal Heather Wakelee, M.D. Assistant Professor of Medicine, Oncology Stanford University Stage III NSCLC: U.S. Cooperative Group Phase III Trials: (1980 s-2000 s) STUDY YRS CHEMORADIATION XRT No. MST 3 year SCHEMA (Gy) Pts mos surv CALGB P + Vinb XRT % RTOG/ECOG P + Vinb XRT % 8808/4588 RTOG P + Vinb/XRT ~25% CALGB Carbo + Pac CP/XRT % SWOG PE/XRT D +/- Gef NR HOG PE/XRT +/- D % MST ~21 mo with 4 cycles of platinum doublet/triplet in Japanese study Until we have targeted agents and know how to target them, 2 cycles cisplatin doublet with concurrent XRT is SOC