A phase 3 trial of bevacizumab in ovarian cancer.
BACKGROUND
Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease.


METHODS
We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival.


RESULTS
A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months.


CONCLUSIONS
Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).
St. James's Institute of Oncology, St. James's University Hospital, Leeds, United Kingdom.
Timothy J
TJ
Perren
Ann Marie
AM
Swart
Jacobus
J
Pfisterer
Jonathan A
JA
Ledermann
Eric
E
Pujade-Lauraine
Gunnar
G
Kristensen
Mark S
MS
Carey
Philip
P
Beale
Andrés
A
Cervantes
Christian
C
Kurzeder
Andreas
A
du Bois
Jalid
J
Sehouli
Rainer
R
Kimmig
Anne
A
Stähle
Fiona
F
Collinson
Sharadah
S
Essapen
Charlie
C
Gourley
Alain
A
Lortholary
Frédéric
F
Selle
Mansoor R
MR
Mirza
Arto
A
Leminen
Marie
M
Plante
Dan
D
Stark
Wendi
W
Qian
Mahesh K B
MK
Parmar
Amit M
AM
Oza
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D016190:Carboplatin / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage; D011788:Quality of Life; D016019:Survival Analysis
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel