title: Improved survival with bevacizumab in advanced cervical cancer.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer.
  
  
  METHODS
  Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important.
  
  
  RESULTS
  Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).
  
  
  CONCLUSIONS
  The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).
authors.affiliation: From the University of California, Irvine, Medical Center, Orange (K.S.T.); Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo (M.W.S., H.H.); Mayo Clinic, Rochester, MN (H.J.L.); Massachusetts General Hospital, Boston (R.T.P.); M.D. Anderson Cancer Center, Houston (L.M.R.); University of Oklahoma, Oklahoma City (L.M.L.); Vall d'Hebron University Hospital, Barcelona (A.O.); University of Cincinnati College of Medicine-Women's Cancer Center at Kettering, Kettering, OH (T.J.R.); Memorial Sloan-Kettering Cancer Center, New York (M.M.L.); Indiana University School of Medicine, Indianapolis (H.E.M.); and the University of Arizona Cancer Center and Creighton University at St. Joseph's Hospital and Medical Center, Phoenix (B.J.M.).
authors.forename: Krishnansu S
authors.initials: KS
authors.lastname: Tewari
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sill
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Long
authors.forename: Richard T
authors.initials: RT
authors.lastname: Penson
authors.forename: Helen
authors.initials: H
authors.lastname: Huang
authors.forename: Lois M
authors.initials: LM
authors.lastname: Ramondetta
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Landrum
authors.forename: Ana
authors.initials: A
authors.lastname: Oaknin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Reid
authors.forename: Mario M
authors.initials: MM
authors.lastname: Leitao
authors.forename: Helen E
authors.initials: HE
authors.lastname: Michael
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Monk
mesh_terms: 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; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage; D011788:Quality of Life; D016019:Survival Analysis; D019772:Topotecan / Q000008:administration & dosage; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000401:mortality
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D019772:Topotecan; D017239:Paclitaxel; D002945:Cisplatin