Transcript Slide 1

Vascular issues associated
with bevacizumab
Stuart M. Lichtman, MD, FACP
65+ Clinical Geriatric Program
Associate Attending
Memorial Sloan-Kettering Cancer Center
New York
Bevacizumab
• Improved survival in first line metastatic
colorectal cancer with chemotherapy
• Improved survival in previously treated
metastatic colorectal cancer
• Improved survival in previously untreated
nonsquamous nonsmall cell lung cancer
• Improved PFS in previously untreated
metastatic breast cancer
Bevacizumab
• In pivotal trial of metastatic colorectal
cancer 3.3% vs. 1.0% (placebo)
experienced arterial thrombotic event
• No increased incidence of venous
thromboembolism
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ATE
• angina pectoris, arterial thrombosis,
cerebral infarct, cerebral ischemia,
cerebrovascular accident, myocardial
infarction, and myocardial ischemia.
Exclusions
Within 1 year of study entry
1. un -controlled hypertension
2. myocardial infarction
3. unstable angina
4. congestive heart failure NYHA class II or higher
5. serious cardiac arrhythmia requiring medication
6. grade 2 or higher peripheral vascular disease
any history of
1. stroke
2. chronic daily treatment with aspirin (>325 mg/day)
3. nonsteroidal anti-inflammatory medications at doses known to inhibit
platelet function
4. Current full-dose anticoagulation (within 10 days before treatment)
ATE
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Patients
• 1745 patients
– Colorectal cancer
– Breast cancer
– Non small cell lung
69%
25%
6%
– Fluoropyrimidine based therapy
– Bevacizumab
• 5 mg/kg/week
• 2.5 mg/kg/week
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31%
69%
94%
ATE
Overall
• Difference in ATE
– 3.8% vs. 1.7%
• Rate per 100 person years
– 5.5 vs. 3.1
• ATE causing death
– 0.62% vs. 0.26%
• VTE
– 9.97% vs. 9.85%
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Time to First ATE
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Risk Factors
• Evaluated:
– Exposure to bevacizumab
– Age >65 years
– Hypertension at baseline
– History of ATE
– History of atherosclerosis
– History of myocardial infarction
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Risk Factors
• Evaluated:
– Exposure to bevacizumab (P=0.04)
– Age >65 years (P=0.01)
– Hypertension at baseline
– History of ATE (P<0.001)
– History of atherosclerosis
– History of myocardial infarction
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Risk Factors
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Elderly Patients and the Risk of
Arterial Thromboembolic Events
(ATEs)
Percent
Chemotherapy
Alone
(n=782)
bevacizumab
+
Chemotherapy
(n=963)
ATEs (overall)*
1.7
3.8
<65 years
1.4
2.1
65 years
2.5
7.1
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Elderly Patients and the Risk of
Arterial Thromboembolic Events
(ATEs)
Percent
Chemotherapy
Alone
(n=782)
bevacizumab
+
Chemotherapy
(n=963)
ATEs (overall)*
1.7
3.8
<65 years
1.4
2.1
65 years
2.5
7.1
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ATE Incidence by Risk
Group
% of ATE
Baseline risk factor
(% of population)
Control
(n/N)
BV
(n/N)
All patients
(100)
1.7
(13/782)
3.8
(37/963)
None
(63)
1.0
(5/490)
1.8
(11/602)
Age >65 years*
(35)
2.5
(7/279)
7.1
(24/339)
History of ATEs*
(8.5)
3.4
(2/59)
15.7
(14/89)
Both
(6.5)
2.2
(1/46)
17.9
(12/67)
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*not mutually exclusive
ATE Incidence by Risk
Group
% of ATE
Baseline risk factor
(% of population)
Control
(n/N)
BV
(n/N)
All patients
(100)
1.7
(13/782)
3.8
(37/963)
None
(63)
1.0
(5/490)
1.8
(11/602)
Age >65 years*
(35)
2.5
(7/279)
7.1
(24/339)
History of ATEs*
(8.5)
3.4
(2/59)
15.7
(14/89)
Both
(6.5)
2.2
(1/46)
17.9
(12/67)
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*not mutually exclusive
ATE Incidence by Risk
Group
% of ATE
Baseline risk factor
(% of population)
Control
(n/N)
BV
(n/N)
All patients
(100)
1.7
(13/782)
3.8
(37/963)
None
(63)
1.0
(5/490)
1.8
(11/602)
Age >65 years*
(35)
2.5
(7/279)
7.1
(24/339)
History of ATEs*
(8.5)
3.4
(2/59)
15.7
(14/89)
Both
(6.5)
2.2
(1/46)
17.9
(12/67)
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*not mutually exclusive
ATE Incidence by Risk
Group
% of ATE
Baseline risk factor
(% of population)
Control
(n/N)
BV
(n/N)
All patients
(100)
1.7
(13/782)
3.8
(37/963)
None
(63)
1.0
(5/490)
1.8
(11/602)
Age >65 years*
(35)
2.5
(7/279)
7.1
(24/339)
History of ATEs*
(8.5)
3.4
(2/59)
15.7
(14/89)
Both
(6.5)
2.2
(1/46)
17.9
(12/67)
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*not mutually exclusive
Aspirin Use
• More common patients with history of ATE
• Aspirin use associated with increased risk
of bleeding in both groups
• No difference between bevacizumab and
control
• Data not adequate to comment on
prophylaxis
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Risk-Benefit
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Lung Cancer
Paclitaxel/Carboplatin +/- bevacizumab
Ramalingam 2008
Lung Cancer
Paclitaxel/Carboplatin +/- bevacizumab
• Elderly patients had higher incidence of grade 3 to 5
neutropenia, bleeding, and proteinuria with PCB
compared with younger patients.
Conclusion
In elderly NSCLC patients, PCB was associated with a
higher degree of toxicity, but no obvious improvement in
survival compared with PC. Data from this unplanned,
retrospective analysis justify prospective evaluation of
the therapeutic index of PCB regimen in elderly patients.
Ramalingam 2008
Bevacizumab
Long Term: BRITE
Observational Cohort
Safety Events
Duration of exposure
<12 months; N=1396
>12 months; N=557
%
%
Perforation
2.2
0.3
ATE
2.1
0.7
Gr 3-4 bleeding
2.6
0.7
New or increased HT
17.3
27.5
Median followup 20.8 months
ASCO 2008
Safety and effectiveness of bevacizumab (BV) and chemotherapy
(CT) in elderly patients (pts) with metastatic colorectal cancer
(mCRC): Results from the BRiTE Prospective Cohort Study
GI ASCO 2008
Initial safety report of NSABP C-08, a randomized phase III study
of modified 5-fluorouracil /leucovorin and oxaliplatin (mFOLFOX6)
with or without bevacizumab in the adjuvant treatment of patients
with stage II/III colon cancer.
ASCO 2008
Questions
• Is this risk applicable to general elderly
population?
• What should be recommended to patients
with increased comorbidity?
• What should be recommended to patients
with more recent ATE?
• Were there functional consequences of
ATE which affect QOL?/
Conclusion
• Bevacizumab is an important component
of therapy in various solid tumors
• Vascular complications of therapy is a well
recognized entity
• Patient selection is critical to ensure safety
with this palliative treatment