1. Vascular issues associated with bevacizumab Stuart M. Lichtman, MD, FACP 65+ Clinical Geriatric Program Associate Attending Memorial Sloan-Kettering Cancer Center New York

2. 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

3. 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

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

5. 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)

6. ATE Scappaticci 2007

7. Patients 1745 patients –Colorectal cancer 69% –Breast cancer25% –Non small cell lung 6% –Fluoropyrimidine based therapy94% –Bevacizumab 5 mg/kg/week31% 2.5 mg/kg/week69% Scappaticci 2007

8. 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

9. Time to First ATE Scappaticci 2007

10. Risk Factors Evaluated: –Exposure to bevacizumab –Age >65 years –Hypertension at baseline –History of ATE –History of atherosclerosis –History of myocardial infarction Scappaticci 2007

11. 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

12. Risk Factors Scappaticci 2007

13. Elderly Patients and the Risk of Arterial Thromboembolic Events (ATEs) Percent Chemotherapy Alone (n=782) bevacizumab + Chemotherapy (n=963) ATEs (overall)*1.73.8 <65 years1.42.1  65 years 2.57.1 Scappaticci 2007

14. Elderly Patients and the Risk of Arterial Thromboembolic Events (ATEs) Percent Chemotherapy Alone (n=782) bevacizumab + Chemotherapy (n=963) ATEs (overall)*1.73.8 <65 years1.42.1  65 years 2.57.1 Scappaticci 2007

15. 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 exclusive Scappaticci 2007

16. 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 exclusive Scappaticci 2007

17. 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 exclusive Scappaticci 2007

18. 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 exclusive Scappaticci 2007

19. 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

20. Risk-Benefit Scappaticci 2007

21. Lung Cancer Paclitaxel/Carboplatin +/- bevacizumab Ramalingam 2008

22. 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

23. Bevacizumab Long Term: BRITE Observational Cohort Safety EventsDuration of exposure <12 months; N=1396>12 months; N=557 % Perforation2.20.3 ATE2.10.7 Gr 3-4 bleeding2.60.7 New or increased HT17.327.5 Median followup 20.8 months ASCO 2008

24. 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

25. 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

26. 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?/

27. 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