Is surgical resection of an asymptomatic primary colorectal tumor beneficial for patients with

1. Major Morbidity Curative Resection Other Resection Death 100 135,000 Colorectal Cancer patients per year 80 Initial Presentation Stage IV Unresectable Colorectal Cancer Asymptomatic Primary Tumor Good Performance Status 27,000 (20%) Stage IV 60 Percent 7000 (5%) Curative Resection (primary + mets) 20,000 (15%) Not Resectable for cure 40 Chemotherapy Alone (mFOLFOX6 + Bevacizumab 5mg/kg) Q 14 days Until Excessive Toxicity or Disease Progression 20 0 0 6 12 18 24 30 Months 20,000 (15%) Not Resectable for cure 95% CI 75% have an asymptomatic primary tumor Major Morbidity=16.3% A Phase II Trial of 5-Fluorouracil, Leucovorin and Oxaliplatin (mFOLFOX6) Plus Bevacizumab for Patients with Unresectable Stage IV Colon Cancer and Synchronous Asymptomatic Primary Tumor: Results of NSABP C-10 L.E. McCahill, G.A. Yothers, S. Sharif, N.J. Petrelli, S. Lopa, M.J. O'Connell, N. Wolmark NSABP; Lacks Cancer Center, Grand Rapids, MI; NSABP Operations/Biostatistical Centers; University of Pittsburgh, Grad School of Public Health, Dept of Biostatistics, Pittsburgh, PA; NSABP; Allegheny General Hospital, Pittsburgh, PA; NSABP; Helen F. Graham Cancer Center, Newark, DE; NSABP Biostatistical Center; University of Pittsburgh Graduate School of Public Health Dept of Biostatistics, Pittsburgh, PA; NSABP, Pittsburgh, PA Surgical Goals in a Patient with an Asymptomatic Primary and Unresectable Distant Metastases NSABP C-10 Schema RESULTS NSABP C-10 Study Information Surgery Required Secondary Symptoms at Intact Primary Kaplan-Meier Estimates of Overall Survival with 95% CI Prevention of Symptoms of Primary Tumor Bleeding Perforation Obstruction • 10 resections of intact primary tumor required • Bleeding (0) • Perforation (1) • Obstruction (8) • Pain (1) • Bevacizumab had been discontinued (6) • Progressed on protocol (5) • Bev held for scheduled procedure (1) • On Bevacizumab at time of surgery (4) • 3 with primary anastomosis, no leak • 1 with loop transverse colostomy (extensive metastases) The Problem Medically ManagedUnresectedPrimary Tumors Bleeding (rare) Perforation (rare) Obstruction 9-29% Endpoints Patient Characteristics (Information derived from stage IV CRC treated with a two-drug chemotherapy regimen (fluorouracil and leucovorin), for which response rates are much lower than response rates for currently available chemotherapy) PRIMARY • Event rate related to intact primary tumor requiring surgery • Bleeding • Perforation / Fistula formation • Obstruction • Events related to intact primary tumor resulting in patient death SECONDARY • Morbidity related to intact primary requiring active treatment other than surgery • Stent placement • Transfusions for active GI bleed • NCI CTCAE v3.0 Grade 3, 4, 5 toxicities • Overall Survival Median OS = 19.9 95% CI (15.0-27.2) Secondary Endpoints Current U.S. Practice Patterns for Stage IV Disease • Four patients met secondary endpoint criteria • 3 obstructions • 2 required stent placement • 1 resolved with conservative management • 1 required percutaneous abscess drainage • Median survival was 19.9 mo (95% CI 15.0-27.2) • Other surgeries on primary tumor - 13 • Attempted cure - 10 • Other - 3 The Problem • SEER Database 2000 (1988-2000) • 26,764 patients presenting with Stage IV colorectal cancer • 66% had primary tumor resected • Resection more commonly performed: • for younger patients • colon >> rectal • right >> left Cook & McCahill, Ann Surg Oncology 2005: 12(8) CONCLUSIONS • The primary endpoint of the trial was met • Utilizing mFOLFOX6 + Bev does NOT result in unacceptable rates of obstruction, perforation, bleeding, or death related to the intact primary colon tumor in this prospective clinical trial • Survival does not appear to be compromised by leaving the primary colon tumor intact • Majority of the patients 72/86 (84%) were spared an initial non-curative resection of their primary colon tumor • Initial treatment of this patient population with chemotherapy + bevacizumab is a reasonable standard of care Cumulative Incidence of Major Morbidity and Competing Events Statistical Considerations Specific Hypothesis for NSABP C-10 Primary Endpoint • Event rate of 25% related to intact primary requiring surgery is considered acceptable • 85% power to r/o 40% primary endpoint event rate Primary Endpoint The elimination of initial surgery for patients receiving 3-drug systemic chemotherapy + bevacizumab will not lead to unacceptable morbidity related to the intact primary tumor Surgical resection required for symptoms or death from complications from intact primary tumor • 12 cases (14%) of major morbidity • Estimated Cumulative Incidence of Major Morbidity related to the intact primary tumor at 24 months is 16.3% (95% CI 7.6%-25.1%) • Tumor site • Right (six) • Transverse (one) • Left (five) Key Inclusion Criteria The Question • Asymptomatic primary colon cancer • >12 cm from anal verge on endoscopy • No clinical evidence of obstruction or perforation • No bleeding requiring active transfusions • Radiographic evidence of distant metastatic disease (Stage IV at presentation) • Metastases considered unresectable by treating physician/surgeon Is surgical resection of an asymptomatic primary colorectal tumor beneficial for patients with incurableStage IV disease? 10 (11.6%) required surgery Obstruction - 8 Perforation - 1 Pain – 1 • 2 (2.3%) resulted in death • Perforation - 1 • Obstruction – 1 Abstract #3527