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 Protocol Chair:Laurence E. McCahill, MD Protocol Officer:Nicholas Petrelli, MD Medical Oncology Officer:Saima Sharif, MD MS Protocol Statistician:Greg Yothers, Ph NSABP Chairman:Norman Wolmark, MD

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

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

The Question Is surgical resection of an asymptomatic primary colorectal tumor beneficial for patients with incurable Stage IV disease?

Surgical Goals in a Patient with an Asymptomatic Primary and Unresectable Distant Metastases Prevention of Symptoms of Primary Tumor Bleeding Perforation Obstruction

Medically Managed Unresected 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)

Current U.S. Practice Patterns for Stage IV Disease SEER Database 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)

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

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 NSABP C-10 SCHEMA

Primary Endpoint Event rate related to intact primary tumor requiring surgeryEvent rate related to intact primary tumor requiring surgery –Bleeding –Perforation / Fistula formation –Obstruction Events related to intact primary tumor resulting in patient deathEvents related to intact primary tumor resulting in patient death

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

Statistical Considerations Primary Endpoint: Event rate of 25% related to intact primary requiring surgery is considered acceptableEvent rate of 25% related to intact primary requiring surgery is considered acceptable 85% power to r/o 40% primary endpoint event rate85% power to r/o 40% primary endpoint event rate

Key Inclusion Criteria Asymptomatic primary colon cancerAsymptomatic 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)Radiographic evidence of distant metastatic disease (Stage IV at presentation) Metastases considered unresectable by treating physician/surgeonMetastases considered unresectable by treating physician/surgeon

NSABP C-10 RESULTS

NSABP C-10: RESULTS Characteristic No. of Patients Percent Registered (3/06-6/09)90100 Ineligible33.3 With follow-up Analysis cohort (elig & with f/u) Median follow-up (Months, elig & with f/u) 20.7N/A

Patient Characteristics Characteristic No of Patients Percent AGE: ≤ 59 ≥ 60 Median N/A SEX:MaleFemale RACE:WhiteBlackAsian Native American ECOG PS:

Primary Endpoint Surgical resection required for symptoms or death from complications from intact primary tumor 12 cases (14%) of major morbidity12 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%)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 (2.3%) resulted in death Perforation - 1 Obstruction – 1

Primary Endpoint Tumor site –Right (six) –Transverse (one) –Left (five)

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)

Secondary Endpoints Four patients met secondary endpoint criteria –3 obstructions 2 required stent placement2 required stent placement 1 resolved with conservative management1 resolved with conservative management –1 required percutaneous abscess drainage Median survival was 19.9 mo (95% CI )Median survival was 19.9 mo (95% CI ) Other surgeries on primary tumor - 13Other 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

CONCLUSIONS (1) The primary endpoint of the trial was metThe 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 trialUtilizing 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 intactSurvival does not appear to be compromised by leaving the primary colon tumor intact

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