1. Is surgical resection of an asymptomatic primary colorectal tumor beneficial for patients with incurable Stage IV disease? 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 The Question The Problem Bleeding (rare) Perforation (rare) Obstruction 9-29% Medically Managed Unresected Primary Tumors Current U.S. Practice Patterns for Stage IV Disease Abstract #3527  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)  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 CONCLUSIONS Protocol Chair:Laurence E. McCahill, MD Protocol Officer:Nicholas Petrelli, MD Medical Oncology Officer:Saima Sharif, MD, MS Protocol Statistician:Greg Yothers, PhD NSABP Chairman:Norman Wolmark, MD 7000 (5%) Curative Resection (primary + mets) 27,000 (20%) Stage IV 135,000 Colorectal Cancer patients per year 20,000 (15%) Not Resectable for cure The Problem 20,000 (15%) Not Resectable for cure 75% have an asymptomatic primary tumor (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) 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 Specific Hypothesis for NSABP C-10 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 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 Endpoints 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 Statistical Considerations  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 Key Inclusion Criteria NSABP C-10 Study Information Characteristic # Patients% Registered (3/06-6/09) 90100 Ineligible 33.3 With follow-up 8998.9 Analysis cohort (elig & with f/u) 8695.6 Median follow-up (Months, elig & with f/u) 20.7N/A RESULTS Patient Characteristics Characteristic# Patients% AGE: ≤ 59 ≥ 60 Median 46 40 58 53.5 46.5 N/A SEX: Male Female 41 45 47.7 53.2 RACE: White Black Asian Native American 69 10 5 2 80.2 11.6 5.8 2.3 ECOG PS: 0 1 56 30 65.1 34.9 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) Primary Endpoint 2 (2.3%) resulted in death Perforation - 1 Obstruction – 1 10 (11.6%) required surgery Obstruction - 8 Perforation - 1 Pain – 1  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) Surgery Required Secondary Symptoms at Intact Primary 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 Cumulative Incidence of Major Morbidity and Competing Events Kaplan-Meier Estimates of Overall Survival with 95% CI Months Percent 0612182430 0 20 40 60 80 100 Median OS = 19.9 95% CI (15.0-27.2) 95% CI Prevention of Symptoms of Primary Tumor Bleeding Perforation Obstruction Surgical Goals in a Patient with an Asymptomatic Primary and Unresectable Distant Metastases Major Morbidity Curative Resection Other Resection Death Major Morbidity=16.3%