NSABP PROTOCOL C-10:NSABP PROTOCOL C-10:RESULTSRESULTS

A Phase II Trial of 5-Fluorouracil, Leucovorin and A Phase II Trial of 5-Fluorouracil, Leucovorin and Oxaliplatin Oxaliplatin (mFOLFOX6)(mFOLFOX6) Plus Bevacizumab Plus Bevacizumab

for Patients with Unresectable Stage IV Colon Cancer for Patients with Unresectable Stage IV Colon Cancer and Synchronous Asymptomatic Primary Tumorand 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

135,000Colorectal Cancerpatients 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 TumorPrevention of Symptoms of Primary TumorBleeding

Perforation

Obstruction

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)

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) 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 PresentationStage IV Unresectable Colorectal Cancer

Asymptomatic Primary TumorGood Performance Status

Chemotherapy Alone(mFOLFOX6 + Bevacizumab 5mg/kg)

Q 14 daysUntil Excessive Toxicity or Disease Progression

NSABP C-10 NSABP C-10 SCHEMASCHEMA

Primary Endpoint

• Event rate related to intact primary tumor Event rate related to intact primary tumor requiring surgeryrequiring surgery– BleedingBleeding– Perforation / Fistula formationPerforation / Fistula formation– ObstructionObstruction

• Events related to intact primary tumor Events related to intact primary tumor resulting in patient death 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 Event rate of 25% related to intact primary

requiring surgery is considered acceptablerequiring surgery is considered acceptable

• 85% power to r/o 40% primary endpoint 85% power to r/o 40% primary endpoint event rateevent rate

Key Inclusion Criteria

• Asymptomatic primary colon cancerAsymptomatic primary colon cancer– >12 cm from anal verge on endoscopy>12 cm from anal verge on endoscopy– No clinical evidence of obstruction or No clinical evidence of obstruction or

perforationperforation– No bleeding requiring active transfusionsNo bleeding requiring active transfusions

• Radiographic evidence of distant metastatic Radiographic evidence of distant metastatic disease (Stage IV at presentation)disease (Stage IV at presentation)

• Metastases considered unresectable by Metastases considered unresectable by treating physician/surgeontreating physician/surgeon

NSABP C-10RESULTS

NSABP C-10: RESULTSNSABP C-10: RESULTS

CharacteristicCharacteristic No. of PatientsNo. of Patients PercentPercent

Registered (3/06-6/09) 90 100

Ineligible 3 3.3

With follow-up 89 98.9

Analysis cohortAnalysis cohort(elig & with f/u)(elig & with f/u) 8686 95.695.6

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

20.7 N/A

Patient CharacteristicsPatient CharacteristicsCharacteristicCharacteristic No of PatientsNo of Patients PercentPercent

AGE:AGE:≤ ≤ 5959≥ ≥ 6060

MedianMedian

464640405858

53.553.546.546.5N/AN/A

SEX:SEX:MaleMale

FemaleFemale41414545

47.747.753.253.2

RACE:RACE:WhiteWhiteBlackBlackAsianAsian

Native AmericanNative American

696910105522

80.280.211.611.65.85.82.32.3

ECOG PS:ECOG PS:0011

56563030

65.165.134.934.9

Primary Endpoint Primary Endpoint

Surgical resection required for symptoms or Surgical resection required for symptoms or death from complications from intact primary tumor death from complications from intact primary tumor • 12 cases (14%) of major morbidity12 cases (14%) of major morbidity• Estimated Cumulative Incidence of Major Morbidity Estimated Cumulative Incidence of Major Morbidity

related to the intact primary tumor at 24 months is related to the intact primary tumor at 24 months is 16.3% (95% CI 7.6%-25.1%)16.3% (95% CI 7.6%-25.1%)

10 (11.6%) required surgery10 (11.6%) required surgeryObstruction - 8Obstruction - 8Perforation - 1Perforation - 1Pain - 1Pain - 1

2 (2.3%) resulted in death2 (2.3%) resulted in deathPerforation - 1Perforation - 1Obstruction – 1Obstruction – 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 EndpointsSecondary Endpoints

Four patients met secondary endpoint criteriaFour patients met secondary endpoint criteria– 3 obstructions 3 obstructions

• 2 required stent placement2 required stent placement• 1 resolved with conservative management1 resolved with conservative management

– 1 required percutaneous abscess drainage1 required percutaneous abscess drainage

• Median survival was 19.9 mo (95% CI 15.0-27.2)Median survival was 19.9 mo (95% CI 15.0-27.2)

• Other surgeries on primary tumor - 13Other surgeries on primary tumor - 13– Attempted cure - 10Attempted cure - 10– Other - 3Other - 3

Cumulative Incidence of Major Morbidity Cumulative Incidence of Major Morbidity and Competing Events and Competing Events

Months

Perc

ent

Major MorbidityCurative ResectionOther ResectionDeath

Major Morbidity=16.3%

0 6 12 18 24

010

20

30

40

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

Months

Perc

ent

0 6 12 18 24 30

020

40

60

80

100

Median OS = 19.9

95% CI (15.0-27.2)

CONCLUSIONS (1)CONCLUSIONS (1)

• The primary endpoint of the trial was metThe primary endpoint of the trial was met

• Utilizing mFOLFOX6 + Bev does Utilizing mFOLFOX6 + Bev does NOTNOT result in result in unacceptable rates of obstruction, perforation, unacceptable rates of obstruction, perforation, bleeding, or death related to the intact primary bleeding, or death related to the intact primary colon tumor in this colon tumor in this prospectiveprospective clinical trialclinical trial

• SurvivalSurvival does not appear to be compromised does not appear to be compromised by leaving the primary colon tumor intactby leaving the primary colon tumor intact

CONCLUSIONS (2)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