Neo-adjuvant chemotherapy in NSCLC

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1 SCLC Epidemiology eo-adjuvant chemotherapy in SCLC Sarita Dubey sst Professor, Medical ncology, UCSF UCSF/UC Davis Thoracic conference ovember 8, 2008 Statistics for 2008 Cancer Incidence Deaths Colon 108,070 49,960 Breast 184,450 40,930 Prostate 186,320 28,660 Total 478, ,550 Lung 215, ,840 Jemal, C Cancer J Clin 2008; 58: 71 Lung Cancer Stage Distribution at Time of Diagnosis Peter Jennings Stage III 25% Stage IV 45% Stage I/II Unstaged 14% ational Cancer Institute: SEER Cancer Statistics Review,

2 ISLC Staging Project: Proposed Changes 6th Edition Descriptor Current definition M1 (contralateral lung) M1a IV IV IV IV 5 Goldstraw P et al. J Thorac ncol. 2007;2: Proposed T/M Stage Based on Proposed T/M Definitions T1 ( 2 cm) T1a I II III IIIB T1 (2 3 cm) T1b I II III IIIB T2 ( 5 cm) T2a IB II III IIIB T2 (5 7 cm) T2b II IIB III IIIB T2 (> 7 cm) T3 IIB III III IIIB T3 invasion T3 IIB III III IIIB T4 (same lobe nodules) T3 IIB III III IIIB T4 (extension) T4 III III IIIB IIIB M1 (ipsilateral lung) T4 III III IIIB IIIB T4 (pleural dissemination) M1a IV IV IV IV M1 (distant) M1b IV IV IV IV SCLC: Staging & Prognosis Pathologic Survival Relapse (%) Stage 5 yr (%) Local Distant I T1M IB T2M II T11M IIB T21M T3M 38 III T31M T1-32M 23 Mountain CF. Chest.1997;111: ; Feld R, et al. J Clin ncol. 1984;2: ; Pairolero PC, et al. nn Thorac Surg. 1984;38: ; Martini, Melamed MR. J Thorac Cardiovasc Surg. 1980;30: ; Thomas P, Rubinstein L. nn Thorac Surg. 1990;49: ; Goldstraw P, et al. J Thorac ncol. 2007;2: dvantages of Induction Therapy Improving survival rates with chemotherapy Systemic therapy in a local disease Earlier elimination of micrometastatic disease improved survival Chemotherapy better tolerated before major surgery than after Downstaging of 2 disease survival In vivo evaluation of chemo effects 2

3 dvantages of Induction Therapy Induction Chemotherapy phase III trials Earlier elimination of micrometastatic disease improved survival Chemotherapy better tolerated before major surgery than after Possible downstaging of 2 disease ssessment of chemosensitivity Trial Design Stage n Chemo S9900 RCT IB-II 354 Carbo/paclitaxel LU-22 RCT I-III 519 Platinum-doublet Burdett Meta-analysis I-III 988 Platinum chemo Ch.E.S.T. RCT IB-III 270 Cis/gemcitabine TCH RCT I-III 600 Carbo/paclitaxel merican RCT I-III closed Cis/docetaxel S 9900 S9900 Patient Characteristics IB-III R D M I Z E PCLITXEL CRBPLTI (PCb) x 3 cycles SURGERY SURGERY (n = 167) PCb (n = 168) IB + II 71% 70% CR / PR 3% / 38% R0 resection (ITT) Pneumonectomy Lobectomy 84% 68% 84% 68% Surgical mortality 2.5% 4.5% Mediastinoscopy if L > 1 cm on CT Pisters K, et al. J Clin ncol. 2005;23(16S). bstract Closed 2004 because of adjuvant data Final accrual 354/ ineligible o difference in : Surgical morbidity Pneumonectomy rates Pisters K, et al. J Clin ncol. 2005;23(16S). bstract 7012 and virtual presentation at Vallieres E, et al. Lung Cancer. 2005;49(suppl 2). bstract

4 SWG 9900: Updated Survival Results MRC LU22 / VLT / ERTC PRGRESSI-FREE SURVIVL HR = 0.77 ( ), P = 0.07 (2005: HR = 0.80 [ ], P = 0.14) VERLL SURVIVL HR = 0.81 ( ), P = 0.19 (2005: HR = 0.84 [ ], P = 0.32) IB - III 100% 80% 60% 40% 20% 0% % 80% 60% 40% 20% 0% Months fter Registration Pisters K, et al. J Clin ncol. 2007;25(18S). bstract PCb Induction chemotherapy =258 Chemotherapy: MVP Cisplatin/vinorelbine 45% Cisplatin/gemcitabine 25% Carboplatin/docetaxel 12% Gilligan D, et al. Lancet. 2007;369: =261 76% received all 3 cycles of chemotherapy 4% CR 45% PR Closed early MRC LU22 / VLT / ERTC (n = 261) + Chemo (n = 258) I/IB 15% / 44% 19% / 45% R0 resection Pneumonectomy Lobectomy 79% 28% 50% 81% 23% 56% Surgical Morbidity 43% 38% 2-yr PFS 52% 53% (HR = 0.96) 5-yr S 45% 44% (HR = 1.02) Chemotherapy for Early Stages Trial (Ch.E.S.T.) Stratification IB/II vs. IIB/III (T31 excluding superior sulcus) Mediastinoscopy for ML >1cm R D M IZ TI rm 1: rm 2: Cisplatin/ Gemcitabine F LL WŪ P o difference in : Survival outcome Surgical morbidity Pneumonectomy rates Gilligan D, et al. Lancet. 2007;369: Cisplatin 75 mg/m2, d.1 Gemcitabine 1250 mg/m2 d.1&8, Q 3wks x 3 cycles 1 objective : 3-PFS CLSED ERLY ccrual 270 / 700 Scagliotti, SC 2008,#

5 Ch.E.S.T PFS: Subset analysis by stage only Chemotherapy + Stage IB-II (n) Median PFS (yrs) yr PFS 56% 50% Stage IIB-III (n) Median PFS (yrs) yr PFS (95% CI) 36% (24%-49%) 55% (42%-67%) Log-rank p-value = Ch.E.S.T Progression-Free Survival Events Median PFS (yrs) 3-yr PFS only (=141) 55% % Log-rank p-value* CT+ (=129) 49% % Hazard ratio 95% CI p-value** 0.71 (0.50, 0.99) Pts at risk at years only: CT+: * unadjusted treatment 95 p-value **global 52 model 33 p-value Ch.E.S.T S: Subset analysis by stage only Chemotherapy + Stage IB-II (n) Median S (yrs) 3-yr S 70% 65% Stage IIB-III (n) Median S (yrs) yr S (95% CI) 47% (33%-59%) 70% (57%-80%) Log-rank p-value = Events Median S (yrs) 3-yr S Ch.E.S.T verall Survival only (=141) 42% % Log-rank p-value* CT+ (=129) 34% unestimated 67% Hazard ratio 95% CI p-value** 0.63 (0.42, 0.93) Patients at risk at years only: CT+: * unadjusted treatment p-value **global model p-value 5

6 Meta-analyses on neoadjuvant therapy dvantages of Induction Therapy verall survival Berghmans Lung Ca 2005, 49,13-23 Huang PSC 2005; 23 bstr # RCT s =590 8 RCT s =1965 HR 0.66 (CI ) in favor of neoadjuvant chemo HR 0.68 (CI ) Higher quality trials HR 0.80 (CI ) Earlier elimination of micrometastatic disease improved survival Chemotherapy better tolerated before major surgery than after Possible downstaging of 2 disease Burdett JT 2006, 1: RCT s =988 5yr S 6% HR 0.82 (CI ) P=0.02 ssessment of chemosensitivity eoadjuvant Trials djuvant Trials Chemotherapy delivery Cisplatin dose intensity Betticher JC 2003;21 IT Lancet nc 2006;7 # of chemotherapy cycles 95.6 Depierre JC 2002;20 Rosell EJM1994; Scagliotti SC JBR10 EJM 2005;352 CLGB SC % 2 preop cycles 84% 2 postop cycles 100% of 3 preopcycles 85% 3 preop cycles 58% of 3 or more cycles 55% 4cycles at full dose Better patient tolerability of chemotherapy in pre-op rather than post-op dvantages of Induction Therapy Earlier elimination of micrometastatic disease improved survival Chemotherapy better tolerated before major surgery than after Downstaging of 2 disease survival ssessment of chemosensitivity 6

7 Median survival by L status at time of surgery in III 2 SCLC Study pcr S0139 lbain PSC 2005,23 #7014 ERTC Van Meerbeeck PSC 2005,23# mo 26 mo 26mo 40mo eoadjuvant chemotherapy and impact on type of surgery Betticher JC 2003, 21: 1752 R 35mo 16mo R Downstaging of mediastinal lymph nodes at time of surgery improves survival!! Pre-op chemo does not increase surgical complications or pneumonectomy rates Conclusions S9900 LU22/VLT R0 resection Pneumonectomy Lobectomy Surgical mortality R0 resection Pneumonectomy Lobectomy Surgical Morbidity 84% 68% chemo 84% 68% 2.5% 4.5% 79% 28% 50% 81% 23% 56% 43% 38% eoadjuvant chemotherapy is a promising modality to improve outcomes in early lung cancer Results are blunted by early closure of clinical trials Downstaging of mediastinal lymph nodes with induction therapy improves survival Better tolerability of chemotherapy preoperatively Induction chemotherapy does not increase surgical morbidity and does not decrease rate of pneumonectomies 7

8 ngoing trials eoadjuvant or djuvant chemotherapy Targeted agents Chemotherapy or chemoradiation eoadjuvant or djuvant chemotherapy IB - III TC X3 TC x 3 T : Paclitaxel 200mg/m2 C:Carboplatin UC 6 Q 3 weeks TCH Trial (Spain) eodjuvant Taxol Carboplatin Hope trial ngoing trials Targeted agents eoadjuvant Chemo vs chemoradiation in 2 disease- RTG 0412 Cis / Doc / bevacizumab surgery Cis / Doc / erlotinib surgery Pazopanib surgery IB-III IB-III ever or <15pk yr I R D M I Z E Cisplatin 75mg/m2 D1,22 Docetaxel 75mg/m2 D1,22 Cisplatin 50mg/m2 D1,8,22,29 Docetaxel 20mg/m2 D1, 8,15,22,29 TRT 50.4Gy o PD Consolidation: Docetaxel 75mg/m2 D1, 22, 43 Stratification L levels: 1vs 2 odal involvement: Micro vs clinical T stage: T1 vs T2/3 Primary objectives: S Secondary: PFS, ERCC1, XRCC1,serum proteomics, Post treatment PET 8

9 eoadjuvant Chemo vs chemoradiation in 2 disease- Korea R D M I Z E Cisplatin 40mg/m2 D1,8 Taxol 90 mg/m2 D1,8 X2 cycles Cisplatin 40mg/m2 D1,8 Taxol 90 mg/m2 D1,8 X2 cycles TRT 45Gy 25Fx Cisplatin 40mg/m2 D1,8 Taxol 90 mg/m2 D1,8 X2 cycles Primary objectives: Time to recurrence VEMBER Lung Cancer wareness Month Secondary: S pcr 9