eastern cooperative oncology group impact of bevacizumab dose reduction on clinical outcomes for...

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Impact of Bevacizumab Dose Reduction on Clinical Outcomes for Patients Treated

on the Eastern Cooperative Oncology Group’s Study E3200.

Impact of Bevacizumab Dose Reduction on Clinical Outcomes for Patients Treated

on the Eastern Cooperative Oncology Group’s Study E3200.

Bruce J. Giantonio, Paul J. Catalano, Peter J. O’Dwyer, Neal J. Meropol, and Al B. Benson III.

University of Pennsylvania, Philadelphia, PA, Dana-Farber Cancer Institute, Boston, MA Fox Chase Cancer Center, Philadelphia, PA, Northwestern University, Chicago, IL

eastern cooperative oncology groupeastern cooperative oncology group

Bevacizumab dose reduction/discontinuation Bevacizumab dose reduction/discontinuation criteriacriteria

Dose reductions of bevacizumab to 5mg/kg were permitted for the following:

1. Hypertension, bleeding, and thrombosis Grade 2,2. Proteinuria of < 2 grams/24 hours that resolved to < 0.5

grams/24 hrs,3. Liver function test abnormalities grade 3 that resolved to

Grade 1.

Discontinuation of bevacizumab was required for:1. any of the above events that occurred at a grade in excess of

that which didn’t meet criteria for reduction, or 2. that did not resolve to the specified grade required for

continuation.

Note, the occurrence of Grade 3 thrombosis (defined as requiring anticoagulation) required discontinuation of bevacizumab

Dose reductions of bevacizumab to 5mg/kg were permitted for the following:

1. Hypertension, bleeding, and thrombosis Grade 2,2. Proteinuria of < 2 grams/24 hours that resolved to < 0.5

grams/24 hrs,3. Liver function test abnormalities grade 3 that resolved to

Grade 1.

Discontinuation of bevacizumab was required for:1. any of the above events that occurred at a grade in excess of

that which didn’t meet criteria for reduction, or 2. that did not resolve to the specified grade required for

continuation.

Note, the occurrence of Grade 3 thrombosis (defined as requiring anticoagulation) required discontinuation of bevacizumab

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MethodsMethods

1. Data on the application of dose reduction and discontinuation were obtained from a post study survey of institutions for all study participants who were treated with bevacizumab.

2. Median overall survival, median progression free survival, and hazard ratios were computed for patients who either had their bevacizumab discontinued (provided at least one cycle was administered), dose reduced, or dose reduced followed by discontinuation.

1. Data on the application of dose reduction and discontinuation were obtained from a post study survey of institutions for all study participants who were treated with bevacizumab.

2. Median overall survival, median progression free survival, and hazard ratios were computed for patients who either had their bevacizumab discontinued (provided at least one cycle was administered), dose reduced, or dose reduced followed by discontinuation.

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E3200: Study DesignE3200: Study Design

FOLFOX4 +Bevacizumab

(10 mg/kg, q 2 weeks)

FOLFOX4

Bevacizumab (10mg/kg, q 2 wks)

Previously treated metastatic CRC

PD

PD

PD

Stratification factors:Stratification factors:

ECOG PS: 0 vs 1, 2ECOG PS: 0 vs 1, 2

Prior XRTPrior XRT

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Dose Modification/Reduction SurveyDose Modification/Reduction Survey

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Survey Response DemographicsSurvey Response Demographics

FOLFOX + bevacizumab

Bevacizumab alone

Returned Questionnaires 246 (84%) 205 (84%)

Male 59.1% 58.5%Median Age 62 60

Median PS (%; 0/1/2) 49.2/47.9/2.9 47.8/44.4/7.8

Median Cycles (range) 11 (1,49) 4 (1,48)

Median Cycles with reduction 42% 52%

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Survey ResponsesSurvey Responses

FOLFOX + bevacizumab

Bevacizumab alone

Reponses:No reduction or discontinuation

109 124

Discontinuation w/o reduction 60 43

Reduction w/o discontinuation 48 31

Reduction then discontinuation 29 7

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Dose Reductions by ToxicityDose Reductions by Toxicity

Arm A Arm CReduction (any grade) n=246 n=205Hypertension 27 15

Thromboembolism 1 0

Proteinuria 63 33Bleeding 6 4SGOT/SGPT 2 0

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Discontinuations by ToxicityDiscontinuations by Toxicity

Arm A Arm CDiscontinuation (any grade) n=246 n=205Hypertension 17 12

Thromboembolism 8 1

Proteinuria 7 6Bleeding 5 3SGOT/SGPT 2 0

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Outcomes by reduction/discontinuation of Outcomes by reduction/discontinuation of bevacizumabbevacizumab

Med OS and PFS by ARM w/ or w/o Dose Reduction (Red)/Discontinuation (DC)

Arm A Arm C No Re d/DC

(n=106) Red/D C (n=134)

No Re d/DC (n=128)

Red/DC (n=7 7)

OS (mos) 12.9 13.6 9.2 10.1 PFS (mos ) 7.3 7.4 2.0 3.6

Hazard Ratio s for Re ductio n/Discontinuatio n versu s No Redu ction/Disco ntinuat ion

Arm A Arm C HR P HR P OS .82 .17 .85 .30 PFS .81 .14 .65 .0070

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ConclusionsConclusions

1. Study specified dose reduction and/or discontinuation of bevacizumab was performed for adverse events in 56% and 38% of patients treated in Arms A and C who responded to the questionnaire.

2. Hypertension and proteinuria were the most common reasons for bevacizumab dose reduction or discontinuation.

3. Overall survival and progression free survival were not compromised for patients who underwent dose reductions or discontinuation of bevacizumab.

4. Randomized clinical trials will be required to determine the optimal dose of bevacizumab used in combination with chemotherapy for the treatment of colorectal cancer.

1. Study specified dose reduction and/or discontinuation of bevacizumab was performed for adverse events in 56% and 38% of patients treated in Arms A and C who responded to the questionnaire.

2. Hypertension and proteinuria were the most common reasons for bevacizumab dose reduction or discontinuation.

3. Overall survival and progression free survival were not compromised for patients who underwent dose reductions or discontinuation of bevacizumab.

4. Randomized clinical trials will be required to determine the optimal dose of bevacizumab used in combination with chemotherapy for the treatment of colorectal cancer.

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