Eligibility criteria included patients with persistent or recurrent squamous cell carcinoma of the cervix (including adenosquamous tumors) that was measurable by Response Evaluation Criteria in Solid Tumors;14
one or two prior cytotoxic regimens, not including prior cisplatin-based chemotherapy concomitantly administered with primary pelvic radiation; GOG performance status (PS) of 0 or 1, with PS level 2 allowed in patients having received only one prior cytotoxic regimen; and adequate hematologic (absolute neutrophil count ≥ 1,500/μL and platelets ≥ 100,000/μL), renal (serum creatinine ≤ 1.5× the institutional upper limit of normal [ULN]; if higher, then creatinine clearance > 60 mL/min was required), hepatic (serum bilirubin ≤ 1.5× ULN, and both AST and alkaline phosphatase ≤ 2.5× ULN), and coagulation (prothrombin time such that international normalized ratio is ≤ 1.5 or between 2.0 and 3.0 for patients on stable doses of therapeutic anticoagulants and partial thromboplastin time < 1.2× control) laboratory values. Documentation of tumor type was confirmed by central review by the GOG Pathology Committee.
Patients with nonsquamous tumors (eg, adenocarcinomas), other malignancies evident within 5 years, prior noncytotoxic therapy for management of recurrent or persistent cervical cancer, nonhealing wounds, infection requiring antibiotics, active bleeding, coagulopathy, or CNS disease (primary brain tumor history, brain metastases, uncontrolled seizure disorder, or cerebrovascular accident within 6 months) were ineligible. Patients were also excluded for significant cardiovascular disease (uncontrolled hypertension, myocardial infarction or angina within 6 months, New York Heart Association ≥ grade 2 congestive heart failure, or cardiac arrhythmia requiring medication), modified Fontaine ≥ grade 2 peripheral vascular disease or claudication within 6 months, ≥ 1.0 g of proteinuria per 24 hours, pregnancy or nursing, prior therapy with bevacizumab, or major surgical procedures within 28 days or anticipated while on study.15
The study received local institutional review board approval at participating institutions, and all patients gave informed consent according to institutional and federal guidelines before enrollment.
Enrolled patients were to receive bevacizumab 15 mg/kg intravenously every 21 days with no dose modification except in cases when there was at least a 10% change in body weight. This dose and schedule of bevacizumab were selected because of the average 21-day half-life of the drug when administered systemically, the dose density similar to that used in active phase II trials in other disease sites, and the potential for combining bevacizumab with standard primary cytotoxic therapy regimens in future phase III trials for patients with cervical cancer.13
Toxicity was monitored with history, physical examination, and laboratory assessment before each treatment cycle, with adverse events defined and graded according to National Cancer Institute Common Toxicity Criteria version 2.0.16
Bevacizumab was to be held for grade 3 nonhematologic toxicity for a maximum of 3 weeks to allow resolution to grade 1 or less. Treatment was discontinued for any grade 4 nonhematologic toxicity.
Activity of bevacizumab was assessed according to Response Evaluation Criteria in Solid Tumors either by palpation before each cycle for peripheral lesions or by computed tomography or magnetic resonance imaging at baseline and before every other cycle for the last 29 patients after amending the protocol (the first 17 eligible and assessable patients were evaluated before cycles 5, 7, 9, and so on, skipping the evaluation before cycle 3) for the measurement of target lesions, the classification of clinical response, and the determination of disease progression.14
Therapy was discontinued for disease progression, unacceptable toxicity, receipt of other anticancer therapy, or voluntary withdrawal.
The level of activity that would be considered interesting for future phase III studies was determined from an evaluation of historical control data involving six GOG trials performed in similar patients to those enrolled onto the current study ().17–22
Because cytostatic agents are often better tolerated than cytotoxic agents, the purpose of the protocol was to screen agents for any activity greater than a limit that is considered clinically uninteresting. This limit was established with the help of previously reported studies. The historical phase II trials included the use of some agents such as cisplatin, topotecan, and gemcitabine, which have been studied in GOG phase III trials in recurrent cervical cancer, as well as other agents with minimal to modest activity such as isotretinoin plus interferon alfa, altretamine, and etoposide.17–22
The latter agents were selected for comparison and used to help establish that 10% PFS at 6 months was uninteresting.
Table 1. Historical Database Used to Help Assess the Activity of Bevacizumab in GOG Protocol 227-C Among Women With Recurrent Cervical Cancer After Experiencing Treatment Failure With One or Two Cytotoxic Regimens (not including chemotherapy with primary radiation) (more ...)
Bevacizumab was to be considered interesting if eight or more patients survived (progression free) for ≥ 6 months, assuming an accrual of 46 to 51 patients. Specifically, using a two-stage design, the targeted sample size for the first stage of accrual was 22 eligible and assessable patients but was permitted to range from 19 to 26 patients for administrative reasons. If there were more than two of 19 to 25 patients or more than three of 26 patients alive and progression free for at least 6 months and medical judgment indicated, accrual to the second stage of the trial was to be initiated. Otherwise, the treatment regimen was to be classified as clinically uninteresting without any additional accrual. If the study advanced to the second stage, then an overall sample size of 47 eligible and assessable patients was targeted but was permitted to range from 44 to 51 patients. If there were no more than six of 44 to 45 patients or no more than seven of 46 to 51 patients who were alive and progression free after 6 months, then the regimen was to be considered clinically uninteresting. For a true probability of being alive and progression free after 6 months of 25%, the average probability of correctly classifying the treatment as active was 90%; whereas for a true probability of 10%, the average probability of designating the treatment as active (a false-positive misclassification) was 10%, and the average probability of stopping after completing the first stage of accrual was 64%.23
The distribution of PFS and OS for patients on this study was described using Kaplan-Meier plots and median estimates. Prognostic factors were evaluated with Cox proportional hazards models using end points for PFS and OS. The factors assessed included age (in years), exposure to prior radiation therapy, one versus two prior chemotherapy regimens, African American versus other race, performance status of 0 or worse, and location of target tumor within or outside the zone of prior radiation. We also examined prior cisplatin use as a sensitizer to radiation; because the amount of missing data in this analysis was high (15 observations, corresponding to approximately 33% of the patients), this analysis was conducted separately. All of the analyses, regardless of the level of missing data, were considered exploratory, and given the small sample size and the number of relationships examined, all results were considered hypothesis generating rather than hypothesis testing. The reported P
values were considered indicators of possible association but were not meant to be interpreted as statistically significant in the traditional sense.