Is the Neo-adjuvant Approach Better than Adjuvant Approach? Comparative Levels of Evidence: Randomized Trials

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1 Is the Neo-adjuvant Approach Better than Approach? Virginie Westeel University Hospital Besançon, France Perspectives in Lung Cancer Amsterdam, 5-6 March 2010 Comparative Levels of Evidence: Randomized Trials Neo-adjuvant 2 randomized trials >300 pts 1 early discontinuation (based on adjuvant data) 354 & 373 pts 0 positive study 3 recent meta-analyses on published data 6 randomized trials >300 pts testing adjuvant platinumbased chemo 307 to 1867 patients 2 positive studies 1 recent meta-analysis on individual pt data 1

2 The last Meta-analysis +5.4% at 5 yr Pignon JP, J Clin Oncol 2008; 26: LACE: Stage J Clin Oncol 2008 : Pignon; 26:

3 The Last Neo- Meta-analysis + 5% at 5 yr Burdett, J Thorac Oncol 2006;1: Gilligan, Lancet 2007;369: The Very Last Neo- Meta-analysis 3224 patients p=.0001 Stage III: 0.84 (95%CI= ) Song, J Thorac Oncol 2010;5 to be published in April 3

4 TCH Phase III Arm 1 : N=212 Surgery 624 patients IA (>2 cm), IB, II, T3N1 R Arm 2 : N=201 Arm 3 : N=211 Pacli/Carbo 3 cycles Surgery Surgery Pacli/Carbo 3 cycles Paclitaxel 200 mg/m² + carboplatin AUC 6 q3wk Main objective: PFS at 5 yr chemotherapy vs surgery Felip. ASCO 2009, Abs WLCC 2009 Abs. PRS.3 TCH : Progression-Free Survival Chemotherapy Probability Surgery Adj CT Surgery At risk: Adj CT Surgery Time (years) Adj CT Median PFS (mo) yr PFS 34.1% 36.6% HR=0.96; 95% CI ( ); p =

5 TCH : Progression-Free Survival Neo-adjuvant Chemotherapy Probability At risk: Surgery Preop CT Median PFS 25.1 mo 31.5 mo 5-year PFS 34.1% 38.3% HR=0.92; 95% CI ( );p=0.176 Preop CT Surgery Preop CT Surgery Median Follow up 51 Months Time (years) TCH : Overall Survival Probability At risk: Neoadj Adj Surg T1 N0 8% 14% 10% T2 N0 66% 63% 64% Median OS (mo) yr OS 46.6% 45.5% 44% Preop CT Adj CT Surgery Time (years) Surg vs Adj: HR=0.99 ( ); p= Surg vs neo-adj: HR=0.96 ( ); p=0.56 5

6 Neo-adjuvant or? no direct comparison + 5% at 5 yrs Higher level of evidence Neo-adjuvant or? no direct comparison + 5% at 5 yrs Higher level of evidence 1 point 6

7 Neo-adjuvant or? no direct comparison + 5% at 5 yrs Higher level of evidence 2 points What Benefit in Daily Practice? 100 patients fit for chemotherapy + surgery 100 patients fit for surgery + chemotherapy 7

8 What Benefit in Daily Practice? 100 patients fit for chemotherapy + surgery 61 patients receive adjuvant chemotherapy Saint-Jacques, J Thorac Oncol 2008;3: What Benefit in Daily Practice? 98 patients receive neoadjuvant chemotherapy 61 patients receive adjuvant chemotherapy Depierre, J Clin Oncol 2002;20: Saint-Jacques, J Thorac Oncol 2008;3:

9 What Benefit in Daily Practice? 93 patients undergo surgery 61 patients receive adjuvant chemotherapy Depierre, J Clin Oncol 2002;20: Saint-Jacques, J Thorac Oncol 2008;3: What Benefit in Daily Practice? 93 patients undergo surgery 61 patients receive adjuvant chemotherapy pts to treat for 1 to benefit regarding OS (Bria, Lung Cancer 2009;63:50-57) Depierre, J Clin Oncol 2002;20: Saint-Jacques, J Thorac Oncol 2008;3:

10 What Benefit in Daily Practice? 3% patients benefit in terms of OS 2% patients benefit in terms of OS pts to treat for 1 to benefit regarding OS (Bria, Lung Cancer 2009;63:50-57) Neo-adjuvant or? no direct comparison : larger + 5 % at 5 yrs Higher level of evidence 2 points 10

11 Neo-adjuvant or? no direct comparison : larger + 5 % at 5 yrs Higher level of evidence 1 point 2 points Chemotherapy Compliance Trials At least 1 cycle 2 cycles 3 cycles 4 cycles ALPI IALT ANITA JBR10 TCH adj 90% 92% 90% 95.5% 66% 72% 64% 69% 61% 55% 61% 50% 45% Depierre TCH neoadj Gilligan SWOG % 97% 96% 90% 89% 90% 96% 79% 11

12 Chemotherapy Compliance Trials At least 1 cycle 2 cycles 3 cycles 4 cycles ALPI IALT ANITA JBR10 TCH adj Depierre TCH neoadj Gilligan SWOG % 92% 90% 95.5% 66% 98% 97% 96% 72% 64% 90% 89% 69% 61% 55% 61% 90% 96% 79% 50% 45% IFCT 0002 Stage I II NSCLC GP: TC: GEM: 1250 mg/m 2, D1 8 q3wk CDDP: 75 mg/m 2, D1 q3wk PAC: 200 mg/m 2, D1 q3wk Carbo: AUC 6, D1 q3wk Responders PERI GP1 TC1 GP2 TC2 E V L U SURGERY GP3 TC3 GP4 TC4 A PRE GP1 TC1 GP2 TC2 T I O N GP3 TC3 GP4 TC4 SURGERY Westeel ASCO 2009 Abstr 7530, Quoix WLCC 2009 Abstr B4.1 12

13 Chemotherapy Compliance No. cycles % patients Receiving cycles PRE PERI p 1 & NS 3 & 4 (Responders) Neo-adjuvant or? no direct comparison : higher Compliance: better 1 point Higher level of evidence Compliance 2 points 13

14 Neo-adjuvant or? no direct comparison : higher Compliance: better 2 points Higher level of evidence Compliance 2 points Survival and Time to Chemotherapy in Colon Cancer Time to chemo No. patients Survival HR (95%CI) > 30 days 1122 (26%) 1 30 to 60 days 2391 (55%) 1.1 ( ) 60 to 90 days 454 (10%) 1.4 ( ) > 90 days 415 (9%) 1.6 ( ) Hershman D. Cancer 2006 ;107:

15 Time to Chemotherapy ALPI = Randomization within 42 days IALT = Median delay of 40 days (6.6% > 60 days) BR 10 = Randomization within 42 days Chemotherapy within 2 days ANITA = Inclusion within 42 days In daily practice: median 52 days (43-70 days) Saint-Jacques, J Thorac Oncol 2008;3: Neo-adjuvant or? no direct comparison : higher Compliance: better Time to chemotherapy: shorter (Goldie & Coldman) 2 points Higher level of evidence Compliance Time to chemotherapy 2 points 15

16 Neo-adjuvant or? no direct comparison : higher Compliance: better Time to chemotherapy: shorter (Goldie & Coldman) 3 points Higher level of evidence Compliance Time to chemotherapy 2 points ERCC Olaussen, N Engl J Med 2006; 355:

17 Personalized Chemotherapy IFCT 0801 ARM A (Control) CDDP pemetrexed Stage II-IIIA non-n2 resected non-squamous carcinomas ARM B (Experimental) customized EGFR mutated EGFR wt ou I ERCC1+ ERCC1- ou I Erlotinib Observation CDDP-Pemetrexed Neo-adjuvant or? Survival : higher Compliance: better Time to chemotherapy: shorter Pathological analysis higher level of evidence Compliance Time to chemotherapy Pathological analysis: biological markers for personalized approach 3 points 2 points 17

18 Neo-adjuvant or? Survival : higher Compliance: better Time to chemotherapy: shorter Pathological analysis higher level of evidence Compliance Time to chemotherapy Pathological analysis: biological markers for personalized approach 3 points 3 points Neo-adjuvant or? Survival : higher Compliance: better Time to chemotherapy: shorter Pathological analysis 3 points higher level of evidence Compliance Time to chemotherapy Pathological analysis: biological markers for personalized approach Better staging 3 points 18

19 Neo-adjuvant or? Survival : higher Compliance: better Time to chemotherapy: shorter Pathological analysis 3 points higher level of evidence Compliance Time to chemotherapy Pathological analysis: biological markers for personalized approach Better staging 4 points EORTC 08941: Design Non-resectable IIIA pn2 All non-squamous N2 SCC: for right-sided tumors N2 > 4R, for left-sided tumors N2> 5-6 N2 found at thoracotomy could be resectable Cisplatin or Carboplatin + other x 3 Van Meerbeeck JNCI 2007;99:

20 EORTC 08941: Survival RT Surgery p Median survival 17.5 mo mo. At 2 yr 41% 35% At 5 yr 14% 15.7% 0.6 Median PFS 11.3 mo. 9 mo. At 2 yr 24% 27% 0.6 Van Meerbeeck JNCI 2007;99: Lung intergroup trial 0139 : Design Resectable stage IIIA pn2 RAOMIZATION Induction Cisplatin 50 mg/m² D1,8,29,36 Etoposide 50 mg/m² D1-5, RT, 45 Gy, from D1 No progression Surgery RT to 61 Gy Consolidation CDDP + VP16 x 2 Albain Lancet 2009;374:

21 Lung int trial 0139 : Results RT 213 Surgery 216 Median survival 22.2 mo 23,6 mo 5 yr 20 % 27 % 0.1 Median PFS 10.5 mo 12.8 mo 5 yr 11 % 22 % Local relapse 22 % 10 % Albain, Lancet 2009;374: p Lung int trial 0139 : Exploratory analysis Lobectomy Pneumonectomy Matched according to age, sex, PS, ct Survival RT Surg p Lobectomy Median 21.7 mo mo. At 5 yr 18% 36% Pneumonectomy Median 29.4 mo mo. At 5 yr 24% 22% NS Albain, Lancet 2009;374:

22 Neo-adjuvant or? Survival : higher Compliance: better Time to chemotherapy: shorter Pathological analysis N2: Surgery after response for nonresectable tumors: no higher level of evidence Compliance Time to chemotherapy Pathological analysis Response to chemotherapy 3 points 4 points Neo-adjuvant or? Survival : higher Compliance: better Time to chemotherapy: shorter Pathological analysis N2: Surgery after response for nonresectable tumors: no In resectable tumors, surgery after conc CT-RT if lobectomy 3 points higher level of evidence Compliance Time to chemotherapy Pathological analysis N2 4 points 22

23 Neo-adjuvant or? Survival : higher Compliance: better Time to chemotherapy: shorter Pathological analysis N2: Surgery after response for nonresectable tumors: no In resectable tumors, surgery after conc CT-RT if lobectomy 4 points higher level of evidence Compliance Time to chemotherapy Pathological analysis N2 4 points Conclusions No direct comparison of neoadjuvant vs adjuvant The highest level of evidence is in favor of adjuvant chemotherapy Comparable survival benefit? Practical advantages in favor of each 23