Journal of Clinical Oncology, Vol 21, Issue 1
(January), 2003: 60-65
© 2003 American Society for Clinical Oncology
Phase II, Randomized Trial Comparing Bevacizumab Plus Fluorouracil (FU)/Leucovorin (LV) With FU/LV Alone in Patients With Metastatic Colorectal Cancer
Fairooz Kabbinavar,
Herbert I. Hurwitz,
Louis Fehrenbacher,
Neal J. Meropol,
William F. Novotny,
Grazyna Lieberman,
Susan Griffing,
Emily Bergsland
From the Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, Hematology/Oncology Clinic, Kaiser Permanente, Vallejo, Genentech Inc, South San Francisco, and Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA; Division of Hematology and Oncology, Duke University, Durham, NC; and Divisions of Medical Science and Population Science, Fox Chase Cancer Center, Philadelphia, PA.
Address reprint requests to Fairooz Kabbinavar, MD, UCLA School of Medicine, Division of Hematology/Oncology, 10945 Le Conte Ave, Ste 2338J, Los Angeles, CA 90095; email: fkabbina{at}mednet.ucla.edu.
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ABSTRACT
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Purpose: This phase II trial investigated the safety and efficacy of two doses of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, plus fluorouracil (FU)/leucovorin (LV) versus FU/LV alone in patients with metastatic colorectal cancer.
Patients and Methods: One hundred four previously untreated patients with measurable metastatic colorectal cancer were randomly assigned to one of the following three treatment groups: 36 to FU (500 mg/m2)/LV (500 mg/m2) alone, 35 to FU/LV + low-dose bevacizumab (5 mg/kg every 2 weeks), and 33 to FU/LV + high-dose bevacizumab (10 mg/kg every 2 weeks). FU/LV was given weekly for the first 6 weeks of each 8-week cycle.
Results: Compared with the FU/LV control arm, treatment with bevacizumab (at both dose levels) plus FU/LV resulted in higher response rates (control arm, 17%, 95% confidence interval [CI], 7% to 34%; low-dose arm, 40%, 95% CI, 24% to 58%; high-dose arm, 24%, 95% CI, 12% to 43%), longer median time to disease progression (control arm, 5.2 months, 95% CI, 3.5 to 5.6 months; low-dose arm, 9.0 months, 95% CI, 5.8 to 10.9 months; high-dose arm, 7.2 months, 95% CI, 3.8 to 9.2 months), and longer median survival (control arm, 13.8 months; 95% CI, 9.1 to 23.0 months; low-dose arm, 21.5 months, 95% CI, 17.3 to undetermined; high-dose arm, 16.1 months; 95% CI, 11.0 to 20.7 months). After cross-over, two of 22 patients had a partial response to bevacizumab alone. Thrombosis was the most significant adverse event and was fatal in one patient. Hypertension, proteinuria, and epistaxis were other potential safety concerns.
Conclusion: The encouraging results of this randomized trial support further study of bevacizumab 5 mg/kg plus chemotherapy as first-line therapy for metastatic colorectal cancer.
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INTRODUCTION
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ONE NOVEL approach to the treatment of solid cancers involves therapeutic agents that inhibit vascularization of growing tumors. The evidence linking tumor growth and metastases with angiogenesis is compelling.1 In colorectal and breast cancers, the density of microvessels in histologic specimens is correlated with disease recurrence, metastases, and survival.2–10
Of the identified angiogenic factors, vascular endothelial growth factor (VEGF) is the most potent and specific and has been identified as a crucial regulator of both normal and pathologic angiogenesis, with increased expression being observed in many human tumor types.11 In colorectal cancer, increased VEGF expression correlates with invasiveness, vascular density, metastasis, recurrence, and prognosis.12–16 Furthermore, intense expression of VEGF mRNA is detected in human liver metastases from primary colon or rectal carcinomas, and expression of two VEGF receptors, Flt-1 and KDR, was upregulated in liver metastases compared with adjacent nontumorous liver.14
In mouse models, administration of anti-VEGF monoclonal antibodies that inhibit VEGF blocks the growth of human tumor xenografts and dramatically reduces the size and number of liver tumors in a mouse xenograft model of human colon cancer metastasis.11,14 In addition, the combination of anti-VEGF antibody and chemotherapy in nude mice injected with human cancer xenografts has an increased antitumor effect compared with antibody or chemotherapy treatment alone.17
Bevacizumab (Avastin, Genentech, South San Francisco, CA), a recombinant humanized monoclonal antibody to VEGF, is currently being investigated in a number of tumor types, including non–small-cell lung, breast, prostate, renal cell, and colorectal cancers. In phase I trials, bevacizumab was generally well tolerated and did not demonstrate dose-limiting toxicity or interactions with commonly used chemotherapy regimens.18,19 The goal of this trial was to investigate the safety, efficacy, and pharmacokinetics of bevacizumab plus fluorouracil (FU)/leucovorin (LV) as first-line therapy for metastatic colorectal cancer.
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PATIENTS AND METHODS
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Patient Eligibility
Patients with histologically confirmed colorectal carcinoma and evidence of bi-dimensionally measurable disease with metastases more than 1 cm2, and patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life expectancy of more than 3 months were eligible. Patients had to be at least 18 years of age.
Exclusion criteria included prior chemotherapy (other than adjuvant fluoropyrimidines in combination with FU/LV and/or levamisole > 12 months before day 0) and radiotherapy or major surgery within 28 days before day 0. Patients with serious nonhealing wounds, ulcers, or bone fractures or with clinically significant cardiovascular or peripheral vascular disease were excluded, as were those who had undergone a major surgical procedure within 28 days before day 0. Recent or current use of oral and parenteral anticoagulants (except for the maintenance of central lines) or aspirin was not allowed. Adequate hematologic, hepatic, and renal function was required. Pregnant or lactating women were excluded.
Written informed consent was required. This study was approved by the institutional review boards of all participating centers and was conducted in accordance with the guidelines established by the United States Department of Health and Human Services.
Study Design and Treatments
Eligible patients were randomly assigned to one of the following three treatment arms: one control arm (FU/LV alone) and two bevacizumab plus FU/LV arms. All patients received FU/LV weekly for the first 6 weeks of an 8-week cycle according to the Roswell Park regimen20 (LV, 500 mg/m2, by 2-hour intravenous [IV] infusion, once weekly for 6 weeks per cycle; FU, 500 mg/m2 by IV bolus [slow push] 1 hour after initiation of the LV infusion). Patients continued FU/LV in subsequent cycles until disease progression or for a total of six cycles, whichever occurred first. In addition to FU/LV, patients in the two experimental arms received bevacizumab (5 or 10 mg/kg) as a continuous 90-minute IV infusion every 2 weeks until disease progression or for up to 48 weeks, whichever occurred first. Bevacizumab infusion times could be shortened if the patient tolerated the infusion well (initially to 60 minutes and then to 30 minutes). Bevacizumab administration always followed chemotherapy administration.
Patients in the control arm who experienced disease progression were given the option of receiving monotherapy with 10 mg/kg bevacizumab every 2 weeks. These cross-over patients underwent tumor assessments per protocol for the remainder of the treatment period or until disease progression after a minimum of four doses of bevacizumab.
Patients randomly assigned to receive bevacizumab who demonstrated a complete or partial response or stable disease at the end of the treatment period were eligible to receive additional bevacizumab in an open-label extension study if their disease progressed within 6 months after their last bevacizumab dose in this study.
Study Parameters
Screening and baseline evaluations included assessments of ECOG performance status, laboratory tests (hematology, chemistry, electrolytes, urinalysis, and international normalization ratio of prothrombin time/activated partial thromboplastin time), and physical examinations. Baseline tumor assessments, with prospective identification of index lesions to be followed over the course of the study, included a chest x-ray, abdominal and pelvis computed tomography scans, and serum carcinoembryonic antigen (CEA) measurement.
During the treatment, tumor status was assessed at the completion of each 8-week cycle. Assessments continued every 8 weeks during the posttreatment period. The ECOG Tumor Response Criteria were used to evaluate responses and determine disease progression.21 The primary analyses of disease status were based on blinded assessments of an independent review facility. Responses were confirmed  4 weeks after initial documentation.
Safety evaluations included physical examinations, laboratory tests (hematology, chemistry and electrolytes, and urinalysis), and ECOG performance status. Vital signs were monitored before, during, and after bevacizumab infusions (before chemotherapy for patients in the control arm). Patients were questioned regarding concomitant medication use, adverse events, and changes in menstrual cycles (if applicable). Patients who discontinued or completed the study were followed for survival information every 2 months until death or loss to follow-up.
Statistical Considerations
The primary efficacy end points for this study were time to disease progression and best (confirmed) tumor response rate (complete or partial response). Secondary efficacy end points included overall survival and duration of response. To increase the power for detecting a treatment effect, a retrospective efficacy analysis was conducted using data pooled from both bevacizumab arms.
Time to disease progression, duration of response, and survival were evaluated using survival analysis techniques. The Kaplan-Meier method, log-rank test, and Cox proportional hazards model were used. A two-sided  2 test was used to compare tumor response in each bevacizumab arm with the control arm.
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RESULTS
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Patient Characteristics
Table 1 shows that there were imbalances in demographic and baseline characteristics across the three treatment arms that could have affected clinical outcome; the largest were in the proportion of men, the distribution of ECOG performance status, the proportion of patients with liver/lung metastases, and the proportion of patients with low serum albumin at baseline. There was a trend toward less surgery in the bevacizumab arms. Duration of cancer was balanced across treatment arms.
Patient Disposition
A total of 104 patients were randomly assigned to three treatment arms at 36 sites between June 29, 1998, and November 3, 1998 (Table 2). The median number of received doses and the cumulative dose of chemotherapy were highest in the 5-mg/kg arm. Of the 67 patients who were randomly assigned to one of the bevacizumab arms and received at least one dose of bevacizumab, 47 patients (70%) did not miss any bevacizumab infusions and 16 patients (24%) missed only one or two infusions. Of the 102 treated patients, 43 (42%) did not miss any chemotherapy infusions and 45 (44%) missed only one or two infusions. The distribution of missed chemotherapy infusions did not differ across treatment arms.
Efficacy Results
Time to progression.
Estimates of time to progression and associated hazards ratios are listed in Table 3. A multivariate Cox model was fit by including variables first found to be associated with time to progression in a univariate model. Variables that were not significantly associated with time to progression were dropped. After adjustment for baseline albumin, additional variables were not significantly associated with time to progression in a multivariate model. After controlling for the effect of albumin on time to progression, there was a 61% reduction in the hazard of progressing in the 5-mg/kg arm (P = .002) and a 46% reduction in the 10-mg/kg arm (P = .052) compared with the control arm. When the data for bevacizumab-treated patients were pooled, there was a 55% reduction in the hazard of progressing compared with the control arm (P = .003).
Response rate.
Estimates of response rate with 95% confidence intervals are listed in Table 4.
Survival.
Median survival was 13.8 months (range, 0.6 to 27.5+ months) in the control arm, 21.5 months (range, 1.2 to 28.2+ months) in the bevacizumab 5-mg/kg arm, and 16.1 months (range, 0.9 to 27.1+ months) in the bevacizumab 10-mg/kg arm. At the 18-month time point, 37% of patients in the 5-mg/kg arm were alive. Even though survival time was censored for 46% of the patients in the 5-mg/kg arm, follow-up exceeded the median survival time of 21.5 months in these patients. The hazard of death was reduced by 37% in the 5-mg/kg arm compared with the control arm; it was approximately the same for the 10-mg/kg arm (hazard ratio, 1.17), the pooled bevacizumab-treated population (hazard ratio, 0.86), and the control arm (hazard ratio, 1.0; Cox proportional hazard regression analysis).
Carcinoembryonic antigen.
Of the 94 patients who had CEA measurements evaluated before treatment and at least once during treatment, 15 patients had baseline CEA levels of less than 3 ng/mL (the upper limit of the normal range for this test). Of the remaining 79 patients, only one (1.9%) of 53 patients who received bevacizumab experienced an increase of 50% in CEA compared with four (15%) of 26 control patients. Conversely, 13 (50%) of 26, 20 (74%) of 27, and 18 (69%) of 26 patients in the control, 5-mg/kg bevacizumab, and 10-mg/kg bevacizumab arms, respectively, experienced CEA decreases of 50%.
Cross-over patients.
Twenty-two patients (61%) in the control arm received single-agent bevacizumab at 10 mg/kg as cross-over therapy. For these 22 patients, the median duration of bevacizumab therapy was 2 months, with follow-up ranging from 1 day to 7 months. Two cross-over patients experienced a partial response, and seven patients had stable disease. The median time to progression for cross-over patients was 2 months, with follow-up ranging from 1 day to 5 months.
Safety Results
Adverse events.
Fifty deaths (48%) were reported on study. Three patients died from a cause other than disease progression: mucositis/diarrhea/neutropenia (control arm), respiratory distress (5-mg/kg arm), and pulmonary embolism (10-mg/kg arm). More patients in the bevacizumab arms experienced at least one National Cancer Institute common toxicity criteria (version 1) grade 3 or 4 adverse event. The increase in incidence of grade 3 and 4 events seen in the bevacizumab arms compared with the control arm was statistically significant (P = .042; two-tailed Fisher’s exact test) but may be a result of patients in these arms being on study longer (hazard ratio for bevacizumab v control = 1.15; P = .61). Table 5 lists adverse events of particular interest.
The incidence and severity of adverse events known to be associated with FU/LV (diarrhea, leukopenia, and stomatitis) was as expected when bevacizumab was added to the regimen. Bevacizumab therapy was associated with fever, headache, rash, epistaxis, and chills; these events were generally mild to moderate in severity. Bleeding, hypertension, and thrombosis have been observed in other clinical trials of bevacizumab and occurred at an increased incidence in the bevacizumab arms in this trial.
The most common type of bleeding in this study was transient epistaxis (lasting < 5 minutes), reported in 11% of control patients, 46% of 5-mg/kg patients, and 53% of 10-mg/kg patients. Three patients in the 10-mg/kg arm had a grade 3 or 4 gastrointestinal hemorrhage; the relationship to therapy was unclear.
The following is a list of all reported venous and arterial thrombotic adverse events:
- Control arm (before crossover; three events): retinal vein thrombosis (grade 4), cerebral ischemia (grade 1), and phlebitis (grade 1).
- 5-mg/kg arm (nine events): venous sclerosis (grade 2), port-a-cath thrombosis (grade 1), deep venous thrombosis (grade 3), deep venous thrombosis (grade 4), pulmonary embolus (grade 4), deep venous thrombosis (grade 3), superior mesenteric thrombosis (grade 3), deep venous thrombosis (grade 2), and left axillary/subclavian vein occlusion (grade 2).
- 10-mg/kg arm (four events): right arm phlebitis (grade 2), cerebral vascular accident (grade 3), pulmonary embolism (grade 5), and transient ischemic attack (grade 2).
- The number of patients with any adverse event of hypertension was as follows (with number of patients having a grade 3 or 4 given in parentheses): control arm, one patient (n = 0); cross-over group, five patients (n = 3); 5-mg/kg arm, four patients (n = 3); and 10-mg/kg arm, nine patients (n = 8).
- Of the 19 patients reported to have an adverse event of hypertension, nine had a preexisting history of hypertension. Sixteen of the 19 patients required oral antihypertensive therapy. One patient discontinued bevacizumab because of angina and hypertension.
- A total of 13 patients (12%) discontinued the study as the result of an adverse event related to either treatment or disease progression: two patients in the control arm, one cross-over patient, four patients in the 5-mg/kg arm, and six patients in the 10-mg/kg arm.
Laboratory results.
An excess of proteinuria was observed among patients treated with bevacizumab, as determined by routine dipstick analysis. Eight patients in the 5-mg/kg arm and nine patients in the 10-mg/kg arm either developed proteinuria or experienced worsening proteinuria while on study (compared with four patients in the control arm). No patient developed nephrotic syndrome.
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DISCUSSION
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This relatively small, randomized, phase II trial compared the safety and efficacy of bevacizumab (at two dose levels) plus FU/LV versus FU/LV alone as first-line therapy for metastatic colorectal cancer. The control regimen used of FU/LV has been one of the standard chemotherapy regimens in the first-line metastatic setting.
There were imbalances in randomization, especially sex, ECOG performance status, and baseline serum albumin, that might have affected the results. More women were randomly assigned to the bevacizumab arms compared with the control arm, and the survival rate for women with colorectal cancer is higher than that for men.22–24 More patients in the 10-mg/kg arm had poor baseline performance status compared with the control arm, and more patients had low baseline albumin (related to performance status) in both bevacizumab arms compared with the control arm. Studies have shown that poor performance status and low albumin are associated with earlier mortality in patients with colorectal cancer.25 The results of univariate analyses supported the conclusion that low-baseline albumin in this study is correlated with both earlier disease progression and earlier mortality.
Administration of bevacizumab at 5 mg/kg and 10 mg/kg every 2 weeks resulted in increases of 3.8 months (from 5.2 to 9.0 months; P = .005) and 2.0 months (from 5.2 to 7.2 months; P = .217), respectively, in the estimated median time to progression compared with FU/LV alone, based on blinded assessment by the independent review facility. A statistically significant increase in response rate was demonstrated for the 5-mg/kg arm compared with the control arm (40% v 17%, respectively; P = .029); the difference in response rate between the 10-mg/kg arm and the control arm was not statistically significant (24% v 17%, respectively; P = .434). Median survival was 21.5 months for the 5-mg/kg arm and 16.1 months for the 10-mg/kg arm, compared with 13.8 months for the control arm (P = .137 for the 5 mg/kg v control comparison and P = .582 for the 10 mg/kg v control comparison). A higher estimate of median survival was achieved with addition of bevacizumab therapy despite the fact that 22 patients in the control arm crossed over to receive bevacizumab. Two of 22 control patients who received single-agent bevacizumab as cross-over therapy showed a partial response.
The reason why the lower dose of bevacizumab seemed to be more effective than the higher dose in this study is unclear, although there are at least three possible explanations. First, this was a relatively small study, and the differences between treatment arms may be a result of chance. Second, it is possible that imbalances in randomization resulted in more patients with poor prognostic factors in the high-dose arm. Third, it is possible that the lower dose is more effective than the higher dose. Studies have shown that the ability to reduce intratumor pressure and improve delivery of chemotherapy can result in greater efficacy than the ability to cause vascular collapse inside the tumor.26,27 It is possible that the 5-mg/kg dose resulted in improved delivery of chemotherapy as well as an antitumor effect, whereas the 10-mg/kg dose resulted in vascular collapse, limiting delivery of chemotherapy. A trial in non–small-cell lung cancer using different doses of bevacizumab than those used here does not provide any data to clarify this issue because the higher bevacizumab dose used in that trial (15 mg/kg) seemed to be more effective than a 7.5-mg/kg dose.28
A number of safety concerns were identified, although bevacizumab was generally well tolerated. The most clinically significant of these was thrombosis. Despite being a known complication of cancer therapy,29 thrombosis occurred more frequently with bevacizumab than with chemotherapy alone, was fatal in one patient, and resulted in bevacizumab discontinuation in three additional patients. An upcoming clinical trial will evaluate whether bevacizumab can be safely combined with low-dose warfarin to manage this issue. Other potential concerns included proteinuria, hypertension, epistaxis, headache, fever, and rash. Most of these events were either manageable (proteinuria and hypertension) or clinically insignificant (epistaxis, headache, fever, and rash).
These preliminary results suggest that bevacizumab, in combination with FU/LV, increases response rate, prolongs time to progression, and prolongs survival compared with FU/LV alone in patients with metastatic colorectal cancer. Although there were imbalances in the random assignment of patients, correction for these imbalances seemed to strengthen the bevacizumab treatment effect. These data support further evaluation of the efficacy and safety of bevacizumab in metastatic colorectal cancer.
Two phase III trials are ongoing. One trial will compare FU/LV/irinotecan (CPT-11) with either FU/LV/CPT-11/bevacizumab or FU/LV/bevacizumab in the first-line setting, followed by CPT-11 in the second-line setting. This design is based on data demonstrating that combining CPT-11 with FU/LV results in a statistically significant increase in survival (increases of 2.2 and 3.3 months), time to progression, and response rate compared with FU/LV alone30,31 and on its subsequent emergence as a new therapy for metastatic colorectal cancer. The second trial will compare FU/LV with FU/LV/bevacizumab in patients who are not optimal candidates for first-line CPT-11. An additional ECOG-sponsored trial (E3200) will study single-agent bevacizumab and bevacizumab plus FU/LV/oxaliplatin in patients who have progressed after previous chemotherapy with FU/LV/CPT-11.
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NOTES
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Supported by Genentech, Inc, South San Francisco, CA.
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Submitted October 11, 2001;
accepted September 10, 2002.
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TOP
ABSTRACT
INTRODUCTION
