Patients. Eligible patients had histologically confirmed metastatic colorectal carcinoma, with bidimensionally measurable disease.
Other inclusion criteria included an age of at least 18 years, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, a life expectancy of more than three months, and written informed consent. Adequate hematologic, hepatic, and renal function (including urinary excretion of no more than 500 mg of protein per day) was also required.
Exclusion criteria included prior chemotherapy or biologic therapy for metastatic disease (adjuvant or radiosensitizing use of fluoropyrimidines with or without leucovorin or levamisole more than 12 months before study entry was permitted), receipt of radiotherapy within 14 days before the initiation of study treatment, major surgery within 28 days before the initiation of study treatment, clinically significant cardiovascular disease, clinically detectable ascites, pregnancy or lactation, regular use of aspirin (more than 325 mg per day) or other nonsteroidal antiinflammatory agents, preexisting bleeding diatheses or coagulopathy or the need for full-dose anticoagulation, and known central nervous system metastases.
The protocol was approved by the institutional review boards of all participating institutions and carried out in accordance with the Declaration of Helsinki, current Food and Drug Administration Good Clinical Practices, and local ethical and legal requirements.
Eligible patients were assigned to treatment with the use of a dynamic randomization algorithm that was designed to achieve overall balance between groups; randomization was stratified according to study center, baseline ECOG performance status (0 vs. 1), site of primary disease (colon vs. rectum), and number of metastatic sites (one vs. more than one). Initially, patients were randomly assigned in a 1:1:1 ratio to receive IFL plus placebo, IFL plus bevacizumab, or fluorouracil and leucovorin plus bevacizumab (Table 1), each of which was to continue until disease progression or unacceptable adverse effects occurred or for a maximum of 96 weeks.
An interim analysis was scheduled to be performed after 300 patients underwent randomization, at which time an unblinded, independent data-monitoring committee was to assess the safety of IFL plus bevacizumab, on the basis of all the available safety information, including the number of deaths in each group, but in the absence of information related to tumor response. If the data-monitoring committee found no untoward adverse events attributable to the addition of bevacizumab to IFL, the enrollment of patients in the group assigned to receive fluorouracil and leucovorin plus bevacizumab was to be discontinued, and additional patients would be randomly assigned in a 1:1 ratio to receive either IFL plus placebo or IFL plus bevacizumab.
However, if the data-monitoring committee concluded that the safety profile of IFL plus bevacizumab was unacceptable, assignment to that treatment was to be discontinued, and patients would instead be randomly assigned in a 1:1 ratio to receive either the combination of fluorouracil and leucovorin plus bevacizumab or IFL plus placebo.
Tumor responses and progression were determined with the use of the Response Evaluation Criteria in Solid Tumors. At the time of disease progression, the treatment assignment was revealed and patients could be offered second-line treatment. Such patients in the group assigned to bevacizumab-containing treatment had the option to continue bevacizumab during this second-line treatment. No crossovers were allowed in the group given IFL plus placebo. Patients assigned to a treatment containing bevacizumab who had no signs of progressive disease at the end of the 96-week study period could continue to receive bevacizumab in a separate extension study. Patients in a group receiving bevacizumab who had a confirmed complete response or unacceptable adverse effects from chemotherapy could discontinue chemotherapy and receive bevacizumab alone.
Bevacizumab (or placebo) was administered concomitantly with chemotherapy. Doses of bevacizumab and chemotherapy were recalculated if a patient’s weight changed by at least 10 percent during the study. Standard intracycle and intercycle dose modifications of irinotecan and fluorouracil (according to the package insert) were permitted in patients with treatment-related adverse events. The doses of leucovorin and bevacizumab were not altered.
In the analysis of survival and subsequent treatment, all patients were followed until death, loss to follow-up, or termination of the study.
After the baseline evaluation, tumor status was assessed every 6 weeks for the first 24 weeks of the study and then every 12 weeks for the remainder of therapy. All complete and partial responses required confirmation at least four weeks after they were first noted.
Safety was assessed on the basis of reports of adverse events, laboratory-test results, and vital-sign measurements. Adverse events were categorized according to the Common Toxicity Criteria of the National Cancer Institute, version 2, in which a grade of 1 indicates mild adverse events, a grade of 2 moderate adverse events, a grade of 3 serious adverse events, and a grade of 4 life-threatening adverse events. Prespecified safety measures included the incidence of all adverse events, all serious adverse events, and adverse events that have been associated with bevacizumab – hypertension, thrombosis, bleeding of grade 3 or 4, and proteinuria – as well as diarrhea of grade 3 or 4, and changes from baseline in various laboratory values and vital signs.
To monitor the safety of the regimen of IFL plus placebo and of IFL plus bevacizumab, the incidence of death, serious adverse events, diarrhea of grade 3 or 4, bleeding of grade 3 or 4 from any source, and thrombosis was monitored during the study in an unblinded fashion by the data-safety monitoring committee until the completion of recruitment or the time of the interim analysis of efficacy, whichever came first.
The primary outcome measure was the duration of overall survival; survival was measured without regard to subsequent treatments. There was no crossover between groups, however. Secondary outcome measures were progression-free survival, objective response rates (complete and partial responses), the duration of responses, and the quality of life.
For patients who were alive at the time of analysis, data on survival were censored at the time of the last contact. Progression-free survival was defined as the time from randomization to progression or death during the study, with death during the study defined as any death that occurred within 30 days after the last dose of bevacizumab or chemotherapy. For patients without disease progression at the time of the final analysis, data on progression-free survival were censored at the last assessment of tumor status or on day 0 if no further assessment was performed after baseline. Patients without adequate follow-up data were categorized as having no response.
To detect a hazard ratio of 0.75 for death in the group given IFL plus bevacizumab as compared with the control group, approximately 385 deaths were required. All calculations were performed with the log-rank test and involved two-sided P values, with an alpha value of 0.05, a statistical power of 80 percent, and one interim analysis of efficacy.
Interim analyses were conducted in an unblinded fashion by an independent data-monitoring committee. An interim analysis of safety was conducted after the random assignment of approximately 100 patients to each group. A second interim analysis of safety and efficacy was performed after 193 deaths had occurred (half the number of required events). According to the protocol, these interim efficacy analyses were governed by a formal group sequential stopping rule based on an O’Brien–Fleming spending function.
Efficacy analyses were performed according to the intention-to-treat principle. Safety analyses included all patients who received at least one dose of study medication.
The study was designed by Genentech in collaboration with the investigators. Genentech collected and analyzed the data; all authors had access to the primary data. The decision to publish the paper was made by all the investigators. The article was written by Dr. Hurwitz.