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

Scappaticci 2007

ATE

• angina pectoris, arterial thrombosis, cerebral infarct, cerebral ischemia, cerebrovascular accident, myocardial infarction, and myocardial ischemia.

ExclusionsWithin 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

Scappaticci 2007

Patients

• 1745 patients– Colorectal cancer 69%– Breast cancer 25%– Non small cell lung 6%

– Fluoropyrimidine based therapy 94%

– Bevacizumab• 5 mg/kg/week 31%• 2.5 mg/kg/week 69%

Scappaticci 2007

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%

Scappaticci 2007

Time to First ATE

Scappaticci 2007

Risk Factors

• Evaluated:– Exposure to bevacizumab– Age >65 years– Hypertension at baseline– History of ATE– History of atherosclerosis– History of myocardial infarction

Scappaticci 2007

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

Scappaticci 2007

Risk Factors

Scappaticci 2007

Elderly Patients and the Risk ofArterial 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

Scappaticci 2007

Elderly Patients and the Risk ofArterial 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

Scappaticci 2007

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)

*not mutually exclusiveScappaticci 2007

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)

*not mutually exclusiveScappaticci 2007

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)

*not mutually exclusiveScappaticci 2007

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)

*not mutually exclusiveScappaticci 2007

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

Scappaticci 2007

Risk-Benefit

Scappaticci 2007

Lung CancerPaclitaxel/Carboplatin +/- bevacizumab

Ramalingam 2008

Lung CancerPaclitaxel/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

BevacizumabLong 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