陈逸恒大肠癌化疗进展课件

Recent progress of chemotherapy for colorectal cancer,Yi-heng Chen The Fist Affiliated Hospital of Guangxi University of Traditional Chinese Medicine,Contents,Neoadjuvant chemotherapy,Metastatic Colorectal Cancer: Liver Metastases: Final results of the EORTC Intergroup randomized phase III study 40983 EPOC evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases,EORTC 40983: Study Design,RANDOMIZE,Surgery,FOLFOX4,FOLFOX4,Surgery,6 cycles (3months),N=364,6 cycles (3 months),Primary endpoint: PFS Secondary endpoint: Safety,Nordlinger et al. ASCO 2007. Abstract LBA5.,Patients with colorectal cancer with resectable liver metastases; WHO/ECOG PS 0-2,EORTC 40983: Toxicity,Good compliance with perioperative chemotherapy Most patients (78.6%) received all 6 cycles of FOLFOX4 Treatment well tolerated Most notable toxicities included grade 3 diarrhea (8.2%), grade 3 sensory neuropathy (2.3%), and grade 3/4 neutropenia (18.1%) No toxic deaths occurred during this time period Slightly more postoperative complications observed in chemotherapy-plus-surgery arm vs surgery-alone arm (25.2% vs 15.9%) Postoperative deaths comparable between arms (1 vs 2 patients),Nordlinger B, et al. ASCO 2007. Abstract LBA5.,EORTC 40983: Results,Nordlinger et al. ASCO 2007. Abstract LBA5.,EORTC 40983: Key Messages,Three months of FOLFOX4 is safe for doing liver resection Addition of chemotherapy significantly improved PFS, particularly for patients who actually had metastases resected,Adjuvant chemotherapy,Adjuvant FOLFOX4 in Stage II-III Colon Cancer: Final MOSAIC Trial Results Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years,MOSAIC: Study Design,Primary endpoint: disease-free survival (DFS) Secondary endpoints: safety, overall survival,n=2246 Enrollment: Oct 1998Jan 2001 (146 centers; 20 countries) Completely resected colon cancer Stage II, 40%; Stage III, 60% Age 1875 years KPS 60 No prior chemotherapy,De Gramont et al. ASCO 2007. Abstract 4007.,MOSAIC: Disease-Free Survival,1. Andre, et al. N Engl J Med 2004;350:23432351 De Gramont et al. ASCO 2007. Abstract 4007.,MOSAIC: DFS,Data cut-off: June 2006,*Not powered for stage II!,3.8%,7.5%,p=0.258,p=0.005,De Gramont et al. ASCO 2007. Abstract 4007.,MOSAIC: OS,Data cut-off: January 2007,FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III,0.1%,4.4%,p=0.996,p=0.029,MOSAIC: Key Messages,The DFS benefit at 3 years was maintained at 5 years Significant OS benefit in stage III patients 20% reduction in risk of death MOSAIC trial did not show clear survival benefit with the addition of oxaliplatin to adjuvant 5-FU/LV in patients with stage II disease Individualized treatment decisions for stage II patients,“high-risk“ patients,T4 bowel obstruction/perforation poorly differentiated tumors lymphatic/vascular invasion fewer than 12 examined nodes indeterminate or positive margins,Hickish T et al. ESMO 2004; Abstract 284 P,Chemotherapy for advanced /metastatic disease,Optimizing Treatment Sequences: Combination vs Sequential Therapy Chemotherapy holiday? Integration of targeted therapies,Combination vs Sequential Therapy,CAIRO Study: Sequential compared to combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (ACC): A Dutch Colorectal Cancer Group (DCCG) phase III study.,CAIRO: Study Design,*Dosages (all 3-wk cycles) Capecitabine: Days 1-14 twice daily Monotherapy: 1250 mg/m2 Combination: 1000 mg/m2,Irinotecan: Day 1 Monotherapy: 350 mg/m2 Combination: 250 mg/m2 Oxaliplatin: Day 1 130 mg/m2,Capecitabine (n = 397),Patients with advanced colorectal cancer and no previous treatment (N = 795),Irinotecan (n = 251),Capecitabine + Oxaliplatin (n = 143),Sequential,Combination,First Line*,Second Line*,Third Line*,Capecitabine + Irinotecan (n = 398),Capecitabine + Oxaliplatin (n = 213),CAIRO: Survival,Combination treatment did not prolong OS compared with sequential therapy First-line treatment: PFS higher in combination arm (7.8 mos) vs sequential arm (5.8 mos) (P = .0002),Punt CJ, et al. ASCO 2007. Abstract 4012.,Survival (Mos),Survival Probability,0.0,0.2,0.4,0.6,0.8,1.0,P = .33,Combination treatment: 17.4 mos (15.2-19.2),Sequential treatment: 16.3 mos (14.3-18.2),Median OS,CAIRO : Toxicity,Punt CJ, et al. ASCO 2007. Abstract 4012.,CAIRO : Key Messages,Combination therapy does not significantly improve OS compared with sequential therapy. Both treatment strategies are valid options for pts with ACC.,Chemotherapy holiday?,OPTIMOX2: Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study,OPTIMOX2: Study Design,Patients with metastatic colorectal cancer (N = 202),Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.,Until progression,OPTIMOX1 (n = 100),OPTIMOX2 (n = 102),Started before tumor progression reached baseline measurements,Chemotherapy- free interval*,mFOLFOX7 6 cycles,s5-FU/LV2,mFOLFOX7 6 cycles,mFOLFOX7 6 cycles,mFOLFOX7 6 cycles,Primary endpoint: duration of disease control (DDC) *Median duration: 20 weeks,OPTIMOX2: PFS and OS,Trend toward improved PFS (P = .08) and OS (P = .0549) with maintenance therapy Median PFS Maintenance Therapy (OPTIMOX1): 36 wks CFI (OPTIMOX 2): 29 wks Median OS Maintenance Therapy: 26 mos CFI: 19 mos No statistically significant difference in median PFS after FOLOFOX 7 reintroduction for OPTIMOX 2 vs OPTIMOX 1 (17 vs 18 wks),Goebel F, et al. ASCO 2007. Abstract 4013.,OPTIMOX2: Toxicity Results,Incidence of grade 3 neuropathy similar between arms,Maindrault-Goebel F, et al. ASCO 2007. Abstract 4013.,OPTIMOX2: Key Messages,Maintenance LV5FU2 associated with prolonged OS and extended duration of disease control vs CFI After FOLFOX7 reintroduction, no difference in PFS observed between maintenance LV5FU2 and CFI approaches Break in chemotherapy not recommended CFI can be recommended only in selected patients without adverse prognostic factors,Maindrault-Goebel F, et al. ASCO 2007. Abstract 4013.,Integration biologics,The CRYSTAL trial: Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC) XELOX-1/ NO16966: Bevacizumab (Bev) in combination with XELOX or FOLFOX4: Updated efficacy results from XELOX-1/ NO16966, a randomized phase III trial in first-line metastatic colorectal cancer,CRYSTAL: Study Design,R,FOLFIRI,FOLFIRI + cetuximab*,N = 1217,*400 mg/m2 initial dose, then 250 mg/m2/wk,Objective: Evaluate first-line cetuximab + irinotecan/5-FU/LV Primary endpoint: PFS Secondary endpoints: OS, response, disease control, QOL, safety,Van Cutsem et al. ASCO 2007: Abstract 4000.,Untreated EGFR-expressing inoperable metastatic CRC,CRYSTAL Trial : PFS Results,PFS significantly prolonged with addition of cetuximab to FOLFIRI,Van Cutsem E, et al. ASCO 2007. Abstract 4000.,CRYSTAL Trial:Toxicity,Combination of cetuximab and FOLFIRI generally well tolerated,Van Cutsem, et al. ASCO 2007. Abstract 4000.,CRYSTAL: PFS,Progression-free survival time (months),PFS estimate,1.0,HR = 0.851; 95% CI = 0.726-0.998,Stratified log-rank p-value = 0.0479,8.9 mo,8.0 mo,1-year PFS rate 23% vs 34%,Van Cutsem et al. ASCO 2007: Abstract 4000.,CRYSTAL: Key Messages,Cetuximab in combination with FOLFIRI significantly increases response rate and significantly prolongs PFS in the first-line treatment of pts with mCRC Although statistically significant, is the PFS difference (0.9 months) clinically meaningful? Cetuximab combined with chemotherapy can lead to a higher resection rate in selected patients with liver metastases.,XELOX + placebo n=350,FOLFOX4 + placebo n=351,XELOX + bevacizumab n=350,FOLFOX4 + bevacizumab n=350,XELOX n=317,FOLFOX4 n=317,Initial 2-arm open-label study (N=634),Protocol amended to 2x2 placebo-controlled design after bevacizumab Phase III data1 became available (N=1 401),NO16966: Study Design,Cassidy et al, ESMO 2006,Co-primary objectives (primary end point=PFS): Superiority of chemotherapy + bevacizumab vs chemotherapy + placebo Non-inferiority of XELOX vs FOLFOX Secondary endpoints: OS, response, safety,XELOX vs FOLFOX,NO16966: PFS (ITT),Saltz et al. ASCO 2007: Abstract 4028.,XELOX/FOLFOX + bevacizumab n = 699 (513 events) XELOX/FOLFOX + placebo n = 701 (547 events),HR = 0.83 (97.5% CI 0.72 0.95) P = 0.0023,8.0 mo,9.4 mo,The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS,Months,0,5,10,15,20,25,0,0.2,0.4,0.6,0.8,1.0,PFS estimate,NO16966: Overall Survival (ITT),Saltz et al. ASCO 2007: Abstract