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 ManagedUnresected Primary Tumors

Current U.S. Practice Patternsfor 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

135,000Colorectal Cancer patients per year

20,000 (15%)Not Resectable

for cure

The Problem

20,000 (15%)Not Resectable

for cure

75% have anasymptomatic primary tumor

(Information derived from stage IV CRC treated with atwo-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 PresentationStage IV Unresectable Colorectal Cancer

Asymptomatic Primary TumorGood Performance Status

Chemotherapy Alone(mFOLFOX6 + Bevacizumab 5mg/kg)

Q 14 daysUntil 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) 90 100

Ineligible 3 3.3

With follow-up 89 98.9

Analysis cohort(elig & with f/u) 86 95.6

Median follow-up(Months, elig & with f/u) 20.7 N/A

RESULTS

Patient Characteristics

Characteristic # Patients %

AGE:≤ 59≥ 60

Median

464058

53.546.5N/A

SEX:Male

Female4145

47.753.2

RACE:WhiteBlackAsian

Native American

691052

80.211.65.82.3

ECOG PS:01

5630

65.134.9

Surgical resection required for symptoms or deathfrom 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 deathPerforation - 1Obstruction – 1

10 (11.6%) required surgeryObstruction - 8Perforation - 1Pain – 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 Morbidityand Competing Events

Kaplan-Meier Estimates ofOverall Survival with 95% CI

Months

Pe

rce

nt

0 6 12 18 24 30

02

04

06

08

01

00

Median OS = 19.995% CI (15.0-27.2)

95% CI

Prevention of Symptoms of Primary TumorBleeding

PerforationObstruction

Surgical Goals in a Patient with an Asymptomatic Primary and

Unresectable Distant Metastases

Major MorbidityCurative ResectionOther ResectionDeath

Major Morbidity=16.3%