2011结直肠癌更新课件

ASCO 2011 - Updates in Colorectal Cancer - Axel Grothey Professor of Oncology Mayo Clinic Rochester Noteworthy at ASCO for CRC? No practice-changing information, but confirmation of standards of care Early rectal cancer: Capecitabine can be used as radiosensitizer in neoadjuvant therapy Addition of oxaliplatin more toxic, no increase in pCR rate Is there a role for TNT (Total Neoadjuvant Therapy)? Noteworthy at ASCO for CRC? Early colon cancer: Value of oxaliplatin as adjuvant therapy in stage II cancers debatable Palliative therapy of CRC: IGF-R1 inhibitors conclusively ineffective Not all KRAS mutations are created equal Aflibercept (VEGF-TRAP) is active and improves OS in 2nd line added to FOLFIRI (to be presented in Barcelona) The Impact of Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Patients with Carcinoma of the Rectum: NSABP R-04 MS Roh, GA Yothers, MJ OConnell, RW Beart, HC Pitot, AF Shields, DS Parda, S Sharif, CJ Allegra, NJ Petrelli, JC Landry, DP Ryan, A Arora, TL Evans, GS Soori, L Chu, RV Landes, M Mohiuddin, S Lopa, N Wolmark 1400 Patients 1.Compare the rate of local-regional relapse in patients receiving preoperative capecitabine with RT to patients receiving preoperative CVI 5-FU with RT 2.Compare the rate of local-regional relapse in patients receiving preoperative oxaliplatin with those not receiving preoperative oxaliplatin NSABP R-04 Primary Aims Roh et al. ASCO 2011 Group 4 Capecitabine 825 mg/m2 PO BID + Oxaliplatin 50 mg/m2/week X 5 + 4600cGy + 540-1080cGy Adenocarcinoma of rectum amenable to surgical resection located =5mm=N1 4 or more 10mm nodes=N2 Study Schema No Progression Progression FOLFOX x 6Restage5FUCMTTMEFOLFOX x 2 TMEFOLFOX x 6 TMEFOLFOX x 8 RANDOMIZE: 1:1 “selective arm” “standard arm” 5FUCMT Value of Oxaliplatin as Part of Adjuvant Therapy in Stage II Colon Cancer? - Pooled Analysis of NSABP Trials - Yothers et al. ASCO 2011 Adjusted* KM-Estimate of DFS Stage II Yothers et al. ASCO 2011 Oxaliplatin HR by Risk Group Stage II Yothers et al. ASCO 2011 5-Year Adjusted Estimates Yothers et al. ASCO 2011 Decision Algorithm in Adjuvant Therapy Resected Colon Ca Stage IIStage III FOLFOX XELOX High-Risk dMMR No therapy! 5-FU/LV or Capecitabine * * *pts not considered candidates for oxaliplatin T4 and/or 80% for all components Median f/u: 22.3 mos (863 deaths) Van Cutsem, et al. WCGC 2011 VELOUR: Side effects Grade 3/4 Adverse Events with 2% higher incidence in AFL vs PL arm: Diarrhea, asthenia/ fatigue, stomatitis/ ulceration, infection, hypertension, GI/ abdominal pain, neutropenia/ neutropenic complications, proteinuria AEs leading to treatment discontinuation: AFL: 26.6% PL: 12.1% Van Cutsem, et al. WCGC 2011 VELOUR: Results Van Cutsem, et al. WCGC 2011 Comparison VELOUR vs E3200 VELOURE3200 Prior TxOxaliplatin-based Irinotecan-based (IFL) Prior BEV 30%none ArmsFOLFIRI + PL FOLFIRI + AFL HR p-value FOLFOX + PL FOLFOX + BEV HR p-value mOS (mos) 12.0613.50.817 0.0032 10.812.90.75 0.0011 mPFS (mos) 4.676.90.758 0.00007 1 6 mos) 1:1 mCRC after failure FP/oxaliplatin + BEV regimen R 525 pts Ramucirumab IV + FOLFIRI q 2 weeks 525 pts Placebo + FOLFIRI q 2 weeks 65 Primary EP: OS PIs: Tabernero, Grothey Cytokine increase on BEV therapy Kopetz et al., JCO 2010 Regorafenib A Multi-Kinase Inhibitor Cellular Phosphorylation AssaysIC50 nM VEGFR-2 Phosphorylation, 293 Cells8 TIE2-Receptor Phosphorylation, CHO Cells 31 PDGFR- Phosphorylation, Aortic SM Cells90 mVEGFR3 Phosphorylation, 293 Cells150 Mutant RET Phosphorylation, Thyroid TT Cells 10 Mutant c-KIT Phosphorylation, GIST 882 Cells20 FGF-10 FGFR MCF-7 Cells 150-300 MAPK ERK-P HCC, HepG2 Cells500 Cell Proliferation AssaysIC50 nM VEGF/HuVEC (2% FCS) BrdU4 bFGF/ HuVEC (2% FCS) BrdU120 PDGFBB/Aortic SM (0.1% BSA) BrdU121 Thyroid TT RET C643W (10% FCS) 33 GIST 882 KIT K642E (10% FCS) 45 Breast, MDA MB 231 (10% FCS)570 Melanoma, A375 (10% FCS)900 HCC HepG2 (10% FCS)560 Regorafenib Salvage Therapy Registration Trial Primary endpoint OS: increase OS from 4.5 to 6.0 months; HR = 0.75 Significance level/power: 0.025 (one-sided)/90% Accrual period (months): 26 ( accrual rate 30 pat./month) Study duration (months): 31.5 Total number of e