NSABP PROTOCOL C-10: RESULTS A Phase II Trial of 5-Fluorouracil, Leucovorin and Oxaliplatin...
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Transcript of NSABP PROTOCOL C-10: RESULTS A Phase II Trial of 5-Fluorouracil, Leucovorin and Oxaliplatin...
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
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-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
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