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NSABP PROTOCOL C-10: RESULTS

NSABP PROTOCOL C-10: RESULTS. 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. 135,000. Colorectal Cancer. patients per year. 27,000 (20%).

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NSABP PROTOCOL C-10: RESULTS

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  1. NSABP PROTOCOL C-10:RESULTS 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

  2. 135,000 Colorectal Cancer patients per year 27,000 (20%) Stage IV 7000 (5%) 20,000 (15%) Curative Resection Not Resectable (primary + mets) for cure The Problem

  3. The Problem 20,000 (15%) Not Resectable for cure 75% have an asymptomatic primary tumor

  4. The Question Is surgical resection of an asymptomatic primary colorectal tumor beneficial for patients with incurableStage IV disease?

  5. Surgical Goals in a Patient with an Asymptomatic Primary andUnresectable Distant Metastases Prevention of Symptoms of Primary Tumor Bleeding Perforation Obstruction

  6. Medically ManagedUnresected Primary Tumors Bleeding (rare) Perforation (rare) Obstruction 9-29% (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)

  7. Current U.S. Practice Patterns for Stage IV Disease • 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)

  8. Specific Hypothesis for NSABP C-10 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

  9. NSABP C-10 SCHEMA Initial Presentation Stage IV Unresectable Colorectal Cancer Asymptomatic Primary Tumor Good Performance Status Chemotherapy Alone (mFOLFOX6 + Bevacizumab 5mg/kg) Q 14 days Until Excessive Toxicity or Disease Progression

  10. Primary Endpoint • Event rate related to intact primary tumor requiring surgery • Bleeding • Perforation / Fistula formation • Obstruction • Events related to intact primary tumor resulting in patient death

  11. Secondary Endpoints • 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

  12. Statistical Considerations 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

  13. Key Inclusion Criteria • 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

  14. NSABP C-10RESULTS

  15. NSABP C-10: RESULTS

  16. Patient Characteristics

  17. Primary Endpoint 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%) • 10 (11.6%) required surgery • Obstruction - 8 • Perforation - 1 • Pain - 1 • 2 (2.3%) resulted in death • Perforation - 1 • Obstruction – 1

  18. Primary Endpoint • Tumor site • Right (six) • Transverse (one) • Left (five)

  19. Surgery Required Secondary Symptoms at Intact Primary • 10 resections of intact primary tumor required • Bleeding (zero) • Perforation (one) • 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)

  20. Secondary Endpoints 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

  21. Cumulative Incidence of Major Morbidity and Competing Events

  22. Kaplan-Meier Estimates of Overall Survival with 95% CI

  23. CONCLUSIONS (1) • 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 prospectiveclinical trial • Survival does not appear to be compromised by leaving the primary colon tumor intact

  24. CONCLUSIONS (2) • 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

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