Study Oversight

The study was sponsored by the National Cancer Institute, which provided bevacizumab without charge. All the authors wrote the manuscript and take responsibility for the accuracy and completeness of the reported data and for the fidelity of the study to the protocol, which is available with the full text of this article at NEJM.org.

Patients

Patients with metastatic, persistent, or recurrent cervical carcinoma were eligible for the study. Patients with recurrent disease were excluded if they were candidates for curative therapy by means of pelvic exenteration. All cancers were confirmed by a central pathology laboratory. A GOG performance status score of 0 or 1 (on a scale of 0 to 4, with 0 indicating that the person is fully active and 1 indicating that the person is restricted in physically strenuous activities but ambulatory) was required, and patients had to have adequate renal, hepatic, and bone marrow function. All patients were required to have measurable disease. Patients treated with chemotherapy for recurrence and those with nonhealing wounds, active bleeding conditions, or inadequately anticoagulated thromboembolism were ineligible. All patients provided written informed consent before enrollment.

Study Design and Treatment

Patients were randomly assigned to one of four intravenous regimens that were repeated at 21-day intervals. Control treatment 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 on day 1). The nonplatinum combination chemotherapy consisted of 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). Each of these regimens was studied with and without bevacizumab (at a dose of 15 mg per kilogram of body weight on day 1). Treatment was discontinued at the onset of disease progression or the development of unacceptable toxic effects, or if the patient had a complete response.

Assessments

Disease was assessed by means of physical examination and chest radiography, as well as by means of computed tomography or magnetic resonance imaging of the abdomen and pelvis within 28 days before the study treatment was initiated. In patients without disease progression, imaging was repeated every other cycle. Tumor measurements according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1, were made within 1 week before the next planned cycle.21 After discontinuation of treatment, disease was assessed every 3 months for 2 years, followed by assessment every 6 months for 3 years until disease progression was documented.

Three validated, sensitive instruments were used to measure health-related quality of life. The Trial Outcome Index of the Functional Assessment of Cancer Therapy (FACT)–Cervix (FACT-Cx-TOI) survey was used to assess physical and functional well-being (on a scale from 0 to 4, with higher scores indicating worsening well-being). Pain was measured with the use of the Brief Pain Inventory (BPI) (on a scale from 0 to 10, with higher scores indicating more severe pain). Neurotoxicity was measured with the use of the neurotoxicity subscale short form (FACT/GOG-NTX) (on a scale from 0 to 4, with higher scores indicating increased neurotoxicity).22 Baseline assessments were completed before randomization, before cycles 2 and 5, and 6 and 9 months after cycle 1.

Safety, as assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, was monitored during each cycle.23,24 Myeloid growth factor was permitted only for hospitalized patients with grade 3 or higher febrile neutropenia (absolute neutrophil count, <1000 per cubic millimeter and a single temperature measurement higher than 38.3°C [101.0°F] or a sustained temperature of 38.0°C [100.4°F] or higher for more than 1 hour). Subsequent prophylaxis was allowed if febrile neutropenia occurred despite one dose level reduction (see the protocol and Tables S2 through S7 in the Supplementary Appendix, available at NEJM.org). The bevacizumab dose was modified only if the patient's weight changed by more than 10%. If chemotherapy was withheld because of a low absolute neutrophil count or thrombocytopenia, bevacizumab was also withheld. Bevacizumab could be delayed or discontinued depending on the occurrence, duration, and severity of uncontrolled hypertension (systolic blood pressure >150 mm Hg or diastolic blood pressure >100 mm Hg), proteinuria (urine protein-to-creatinine ratio ≥3.5), arterial thrombosis, venous thrombosis, coagulopathy, or intestinal obstruction or disruption.

Statistical Analysis

The statistical analysis plan is available with the protocol at NEJM.org. Assuming an absence of interaction between experimental agents, we used a 2-by-2 factorial design to investigate the effect of anti-VEGF therapy (bevacizumab) and a regimen of nonplatinum combination chemotherapy (topotecan–paclitaxel).25 The study was based on the intention-to-treat principle. Patients were prospectively stratified according to GOG performance status, prior use or nonuse of radiosensitizing platinum, and disease status (recurrence or persistence of disease vs. advanced primary disease).

The primary end points were overall survival and the frequency and severity of adverse events associated with each regimen. Progression-free survival and the response rate were secondary end points. Differences in overall survival and progression-free survival according to intervention level were assessed primarily by means of the log-rank test, stratified according to clinical prognostic markers and the level of the other intervention.26 Hazard ratios were estimated with the use of a Cox proportional-hazards model.27

We calculated that we would need to enroll approximately 450 patients, with approximately 346 deaths expected, to provide the study with 90% power to detect a reduction in the risk of death of at least 30% with either experimental treatment, with the one-sided type I error rate limited to 2.5% for each regimen (overall error rate, 5%). An interim analysis, scheduled to be conducted after 173 patients had died, allowed for elimination of one of the experimental treatments or discontinuation of the study for futility or for reporting treatment activity early in the event of dramatic improvement in survival.28,29 Since the study was designed with futility rules, one-sided tests were specified for the alternative hypotheses, critical regions, and P values.

Adverse events were reported until 30 days after the last dose of study treatment had been administered and were summarized for patients who received any therapy and for whom adverse event information was submitted. Changes in health-related quality of life were evaluated with the use of a mixed model for analysis of repeated measures.30