Bevacizumab is approved for use in first- or second-line treatment of metastatic colorectal cancer (mCRC) in combination with an infusional 5-flurouracil regimen. To analyze the risk factors for, and the timing of specific bevacizumab-targeted adverse events in the post-approval period, the Bevacizumab Regimens Investigation of Treatment Effects (BRiTE) observational study was conducted.
Findings of this US-based, prospective, observational cohort study of previously untreated mCRC patients receiving first-line bevacizumab-containing regimens between February 2004 and July 2005 was recently published by Kozloff and colleagues. The intent of this study was to reflect usual clinical practice, therefore no compensation for patients or physicians or drug was provided. Patients with previously untreated mCRC who were receiving a bevacizumab-containing regimen first-line were eligible to participate. There were no exclusion criteria.
Quarterly follow-up data included:
- Change in cancer status (response, progression or death) or treatment regimen
- Information on pre-specified bevacizumab-related adverse events (AEs)
- Gastrointestinal perforation
- MI, CVA, TIA, unstable angina
- Grades 3-4 bleeding
- Post-operative wound healing or bleeding complications
- Any new or modified antihypertensive, anticoagulant or antiplatelet therapy
- Major surgery
Targeted pre-specified adverse events (AEs) attributed to bevacizumab were reported by the investigator up to 90 days following discontinuation of bevacizumab. To minimize underreporting, clinical research forms were completed quarterly requiring a “yes” or “no” response regarding the occurrence of any pre-specified bevacizumab-related AEs.
The BRiTE study enrolled 1,953 patients from 49 U.S. states including 239 community and 9 academic sites. Baseline patient characteristics and on-study treatment duration:
|
Characteristic |
BRiTE N = 1,953 |
|
Median age (yrs) |
63.6 |
|
Race/Ethnicity % |
Predominantly white 81.4 |
|
Male/female % |
55.7/44.3 |
|
Site of primary tumor (if known) %
Colon
Rectum |
79.4
20.4 |
|
ECOG performance status |
85.1% (ECOG 0-1), 7% (ECOG 2+), 7.9% (unknown) |
|
Mean albumin g/dL |
3.8g/dL |
|
Mean alkaline phosphatase U/l |
101 U/l |
|
Prior adjuvant therapy |
Chemotherapy (36.4%), Radiotherapy (13.4%) |
|
Sites of metastatic disease at study entry %
· Primary local/regional
· Primary hepatic
· Lung
· Other |
29.6
58.5
18.8
14.1 |
|
Medical History %
· Diabetes requiring medication
· Hypertension requiring medication
· Arterial disease history
· Diverticulosis
· Peptic ulcer disease
· Use of ASA or NSAIDs
· Receiving anticoagulation |
12.4
42.7
18.0
5.9
2.9
1.7
22.6 |
|
Duration of treatment during BRiTE
· Median duration of 1st line bevacizumab, mos.
· Median duration of total bevacizumab use, mos.
· Median duration of 1st line chemotherapy/EGFRI use, mos.
· Median duration of total chemotherapy/EGFRI use, mos. |
5.4
7.2
5.7
11.1 |
Bevacizumab dose was 5mg/kg every 2 weeks. First-line chemotherapy regimens:
- 56% flurouracil (5-FU)/leucovorin (LV) and oxaliplatin (FOLFOX)
- 14% irinotecan, 5-FU/LV followed by infusional 5-FU (FOLFIRI)
- 10% irinotecan, 5-FU/LV (IFL)
- 7% bolus 5-FU/LV
- 5% capecitabine, oxaliplatin
- 3% infusional 5-FU/LV
- 2% bolus 5-FU and oxaliplatin
- 1% capecitabine
- 0.6% irinotecan
- 0.4% capecitabine and irinotecan
- 0.1% irinotecan and oxaliplatin
Safety data revealed that the all-cause 60-day mortality rate was 2.1% with at least 70% of events occurring within 9 months of starting bevacizumab.
|
Bevacizumab-Related AE |
Overall n (%) of Patients With Event |
Median Time to Event, (mos.) |
|
GI Perforation |
37 (1.9) |
3.4 |
|
Arterial Thrombotic Event |
40 (2.0) |
5.1 |
|
Grade 3-4 Bleeding |
43 (2.2) |
15.0 |
|
Post-Op Wound Healing Complications |
23/521 (521 is the # pts with surgery within 90 days of last bevacizumab dose |
|
Results
Results of the study revealed that the median progression-free survival (PFS) and overall survival (OS) were 9.9 months (95% confidence interval [CI], 9.5-10.3) and 22.9 months respectively. The authors concluded that the median PFS and OS durations and safety profile of bevacizumab in BRiTE are similar to those in randomized clinical trials (RCT) of bevacizumab plus chemotherapy in first-line mCRC patients therefore complementing and expanding on RCT data of bevacizumab-treated patients including the elderly.
Reference
Kozloff M, Yood MU, Berlin J, et al. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: The BRiTE Observational Cohort Study. The Oncologist. 2009;14:862-870. Link to abstract: http://theoncologist.alphamedpress.org/cgi/content/abstract/theoncologist.2009-0071v1