Originally published as JCO Early Release 10.1200/JCO.2008.17.7931 on December 8 2008

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Addition of Bevacizumab to Fluorouracil-Based First-Line Treatment of Metastatic Colorectal Cancer: Pooled Analysis of Cohorts of Older Patients From Two Randomized Clinical Trials

Fairooz F. Kabbinavar, Herbert I. Hurwitz, Jing Yi, Somnath Sarkar, Oliver Rosen

From the University of California at Los Angeles, Los Angeles; Genentech Inc, South San Francisco, CA; and Duke University, Durham, NC

Corresponding author: Fairooz F. Kabbinavar, MD, Department of Medicine, Division of Hematology & Oncology, University of California at Los Angeles, 2333D PVUB MC 705907, 10945 Le Conte Ave, Los Angeles, CA 90095-7059; e-mail: fkabbina{at}mednet.ucla.edu

	ABSTRACT

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Purpose Colorectal cancer (CRC) occurs predominantly in older persons. To provide more statistical power to assess risk/benefit in older patients, we examined the clinical benefit of bevacizumab (BV) plus fluorouracil-based chemotherapy in first-line metastatic CRC (mCRC) treatment in patients aged 65 years, using data pooled from two placebo-controlled studies.

Patients and Methods Pooled efficacy data for 439 patients 65 years old randomized to BV plus chemotherapy (n = 218) or placebo plus chemotherapy (n = 221) in study 1 and study 2 were retrospectively analyzed on an intent-to-treat basis for overall survival (OS), progression-free survival (PFS), and objective response. Safety analysis was based on reports of targeted adverse events in treated patients.

Results Median OS with BV plus chemotherapy was 19.3 v 14.3 months with placebo plus chemotherapy (hazard ratio [HR] = 0.70; 95% CI, 0.55 to 0.90; P = .006). Patients treated with BV plus chemotherapy had a median PFS of 9.2 v 6.2 months for placebo plus chemotherapy patients (HR = 0.52; 95% CI, 0.40 to 0.67; P < .0001). The objective response rate was 34.4% with BV plus chemotherapy versus 29.0% with placebo plus chemotherapy (difference not statistically significant). Rates of BV-associated adverse events in the pooled BV plus chemotherapy group were consistent with those reported in the overall populations for the two studies.

Conclusion Analysis of pooled patient cohorts age 65 years from two similar trials in mCRC indicates that adding bevacizumab to fluorouracil-based chemotherapy improved OS and PFS, similar to the benefits in younger patients. Also, the risks of treatment do not seem to exceed those in younger patients with mCRC.

	INTRODUCTION

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Treatment with the antiangiogenic agent bevacizumab (Avastin, rhuMab VEGF; Genentech Inc, South San Francisco, CA)—a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF)—has been investigated in several types of solid tumors. In the United States, bevacizumab has regulatory approval for first- and second-line treatment of metastatic colorectal cancer (mCRC) in combination with fluorouracil-based chemotherapy, and for first-line treatment of metastatic nonsquamous, non–small-cell lung cancer in combination with carboplatin and paclitaxel. Approval for first-line mCRC treatment was based on positive results of a large (N = 813) randomized, double-blind, placebo-controlled phase III trial (Hurwitz et al;¹ henceforth, study 1) that evaluated the addition of bevacizumab to irinotecan/fluorouracil/leucovorin therapy (IFL), and by supporting studies that included a phase II, randomized, placebo-controlled trial (Kabbinavar et al;² henceforth, study 2) that evaluated the addition of bevacizumab to fluorouracil plus leucovorin (FU/LV) in mCRC patients with one or more characteristics (including advanced age) that made them suboptimal candidates for irinotecan-based therapy.^3-7 In the study 1 primary analysis, adding bevacizumab to IFL reduced the hazard of death by 34% relative to IFL alone (hazard ratio [HR] = 0.66; 95% CI, 0.54 to 0.81; P < .0001) and resulted in a statistically significant increase in median overall survival (OS), from 15.6 to 20.3 months. In study 2 (N = 209), adding bevacizumab increased median OS from 12.9 to 16.6 months (HR = 0.79; 95% CI, 0.56 to 1.1; not significant [P = .16]) and median progression-free survival (PFS) from 5.5 to 9.2 months (HR = 0.50; 95% CI, 0.34 to 0.73; P = .0002). In both studies, the bevacizumab-chemotherapy combination was generally well tolerated. Specific adverse events of interest with bevacizumab treatment were subsequently evaluated in a large, prospective, observational cohort study of mCRC patients who received first-line bevacizumab plus chemotherapy,⁸ and the safety and efficacy of bevacizumab in patients 65 years appeared comparable with that of younger patients.⁹

Although approximately two thirds of newly diagnosed mCRC cases are in persons 65 years old,¹⁰ clinicians are sometimes hesitant to aggressively treat cancer in elderly patients, and older patients may also be reluctant to undergo such treatment.^11,12 This tendency is reflected in the under-representation of elderly patients in clinical trials,^13,14 even though pooled analyses of CRC trials before the era of biologicals have indicated that chemotherapy in selected older patients is effective and safe.^15-19

Clinical benefit from bevacizumab treatment was demonstrated for the entire patient population in studies 1 and 2 on the basis of improvements in median PFS (both studies) and median OS (study 1), as well as the risk reduction for disease progression and death, along with the observed safety profile. Given that CRC is mostly a disease of elderly patients, we specifically examined the clinical benefit of adding bevacizumab to FU-based chemotherapy in patients 65 years old. The HRs that demonstrated a benefit of bevacizumab plus chemotherapytherapy compared with chemotherapy alone for OS and PFS from study 1 and 2 were numerically close, and their 95% CIs overlapped.^1,2 Furthermore, the safety profile regarding bevacizumab-associated adverse events was similar for both regimens and was assessed with a similar study design, that is, a randomized, placebo-controlled trial. Thus, we performed a pooled analysis of data for patients in this age cohort in study 1 and study 2, providing more statistical power to assess the risks and benefits in this patient population—an important question in daily oncology practice.

	PATIENTS AND METHODS

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Patients and Study Design
Our primary analysis of outcomes data included patients in either study who were 65 years old. An additional exploratory age subgroup analysis was restricted to patients who were older than 70 years—the only other 5-year increment age cohort of elderly patients for whom the sample size allowed meaningful statistical analysis. To achieve an even distribution of patients by chemotherapy regimen for the study 1 cohort, only patients from the IFL/placebo and IFL/bevacizumab treatment arms were included (a bevacizumab/FU/LV arm was discontinued after an interim analysis demonstrated an acceptable safety profile for the IFL/bevacizumab arm).

Details of the patient eligibility criteria and study designs for study 1 and study 2 were reported previously.^1,2 Both studies enrolled patients with measurable, histologically confirmed metastatic CRC who were not previously treated with chemotherapy or biologic therapy for metastatic disease. Study 1 patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. study 2 patients were required to meet one of four criteria considered to be negative prognostic factors for first-line irinotecan therapy: age 65 years, ECOG performance status 1 or 2, serum albumin 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Both studies required patients to have adequate renal function at study entry. Chronic use of aspirin (> 325 mg/d) or other nonsteroidal anti-inflammatory drugs, the need for full-dose anticoagulant therapy, and known CNS metastases were among the grounds for exclusion in both studies.

Ethics
Institutional review boards of the investigative centers approved the study protocol. The trial was conducted in accordance with the Declaration of Helsinki, US Food and Drug Administration Good Clinical Practices, and local ethical and legal requirements. All patients provided written informed consent for their study participation.

Treatment
The IFL regimen in study 1 comprised irinotecan 125 mg/m² infusion, bolus FU 500 mg/m², and bolus LV 20 mg/m² administration weekly for 4 weeks, with the cycle repeated every 6 weeks. The FU/LV regimen in study 2 comprised weekly LV 500 mg/m² infusion with bolus FU 200 mg/m² for the first 6 weeks of each 8-week cycle. In both studies, bevacizumab 5 mg/kg or placebo was administered intravenously every 2 weeks. Chemotherapy and bevacizumab/placebo were continued as first-line therapy until study completion (96 weeks) or disease progression. In both studies, patients could continue bevacizumab beyond week 96, or beyond initial disease progression, at the investigator's discretion.

Assessments
Investigators assessed tumor response and disease progression by using the Response Evaluation Criteria in Solid Tumors.²⁰ All patients were observed for survival and subsequent disease treatment until death, loss to follow-up, or termination from the study. After baseline evaluation, investigators assessed each patient's tumor status every 6 weeks for the first 24 weeks, then every 12 weeks until therapy ended. Complete and partial responses were confirmed at least 4 weeks later.

Safety was assessed on the basis of adverse event reports, laboratory test results, and vital signs measurements. Adverse events were graded with the Common Toxicity Criteria of the National Cancer Institute (Version 2), in which events are categorized as mild (grade 1), moderate (grade 2), serious (grade 3), or life-threatening (grade 4). In addition to on-study deaths and adverse events leading to study discontinuation, adverse events of particular interest for the present analysis were those previously associated with bevacizumab therapy:²¹ thromboembolic events (any grade); GI perforation (any grade); and bleeding, wound healing abnormality, hypertension, or proteinuria/albuminuria (grade 3 or 4).

Statistical Analyses
Studies 1 and 2 used the same procedures for collecting baseline data and the same definitions for the primary and secondary outcome measures and safety assessments, and both studies were placebo controlled. These features, along with the similar added clinical benefit from bevacizumab with both FU-based chemotherapies, indicated by the similar HRs for OS and PFS and the overlapping 95% CIs of the HRs, provided the rationale for pooling of the studies. Poolability was further investigated by computing the study-by-treatment interaction effect to evaluate any differential effect of treatment between the two studies.

Efficacy analysis was based on all randomly assigned patients (intent-to-treat analysis). The primary outcome measure was OS duration, defined as the time from random allocation to death. PFS, defined as the time from random allocation to disease progression or death from any cause during first-line treatment, was a secondary outcome measurement. Kaplan-Meier methods were used to estimate median OS and PFS durations. Because the patient populations and chemotherapy regimens differed in the two studies, a categoric variable "study" was used to adjust for study-specific differences. The HR for the combined bevacizumab group relative to the combined control group was determined with the stratified Cox model, stratified by study. Durations of OS and PS in the combined bevacizumab group and the combined control were compared by means of a two-sided stratified log-rank test ( = .05). Objective response rates, defined as the rate of complete or partial response determined on two consecutive occasions at least 4 weeks apart during first-line treatment, were compared by means of the Cochran-Mantel-Haenszel test, stratified by study. Objective response and disease progression were determined by an independent review facility's assessments for study 2 and by investigator's assessment according to Response Evaluation Criteria in Solid Tumors for study 1. Incidences of all adverse events, rates of study discontinuation due to adverse events, and rates of on-study death were compared.

Because of possible confounding by an imbalance of the administered treatment regimen (ie, the different chemotherapy regimens used in study 1 and study 2), the two age groups were not formally compared (in the age group younger than 65 years, 93.0% of the patients received IFL, compared with 61.7% in the elderly population). The efficacy within the cohort of age less than 65 in the pooled population was analyzed as well.

	RESULTS

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Of the randomly assigned patient populations in study 1 and study 2, 439 (43%) patients were 65 years old and 276 (27%; 63% of population age 65 years) were > 70 years old. Of these 439 patients, 218 were randomly assigned to BV plus chemotherapy and 221 were randomly assigned to placebo plus chemotherapy. Demographic and baseline disease characteristics of the patient cohorts from the two studies and the pooled cohort are summarized in Table 1. For the pooled cohort, patients in the BV plus chemotherapy and placebo plus chemotherapy groups had similar mean and median ages. The median age in both groups was 72.0 years. Distributions for sex, race/ethnicity, and ECOG performance status were also similar in the two groups. Most patients (> 96%) in each pooled group had an ECOG status of 0 or 1; about half of each group had an ECOG status of 1. Although the age cohort from study 1 had a 5- to 6-month longer mean disease duration before random assignment than did the study 2 cohort, the mean durations in the pooled groups were similar (19.3 months for placebo plus chemotherapy, 19.1 months for BV plus chemotherapy). Median baseline serum albumin and alkaline phosphatase values were essentially identical in the pooled placebo plus chemotherapy and BV plus chemotherapy groups. P values for the treatment-by-study interaction effects for the overall and for the 65-year-old age cohorts were statistically not significant for both end points, indicating no differential effect of treatment by study. However, wide CIs for estimated interaction effects indicated the limited statistical power to detect a clinically meaningful differential effect.

View this table: [in this window] [in a new window]   Table 1. Demographic and Baseline Disease Characteristics of Randomly Assigned Patients 65 Years Old

View this table: [in this window] [in a new window]   Table 2. Overall Survival, Progression-Free Survival, and Objective Response Rate for Patients 65 Years Old Randomly Assigned to Either FU/LV + Placebo or IFL + Placebo or to FU/LV + BV or IFL + BV

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier estimates of overall survival in randomized patients 65 years old in the pooled placebo plus chemotherapy and bevacizumab plus chemotherapy treatment arms. Censored observations are indicated with tick marks. BV, bevacizumab; FU, fluorouracil/leucovorin; b-IFL, bolus irinotecan/fluorouracil/leucovorin.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimates of progression-free survival during first-line therapy in patients 65 years old randomly assigned to the pooled placebo plus chemotherapy and bevacizumab plus chemotherapy treatment arms. Censored observations are indicated with tick marks. BV, bevacizumab; FU/LV, fluorouracil/leucovorin; b-IFL, bolus irinotecan/fluorouracil/leucovorin.

Table 3 summarizes the incidence of selected adverse events during first-line therapy. Rates of on-study deaths from any cause were similar in the BV plus chemotherapy group and the placebo plus chemotherapy group (6.7% v 8.8%, respectively), as were the percentages of death attributed to progressive mCRC (1.4% v 1.8%, respectively). Rates of study discontinuation caused by an adverse event were also similar (14.8% for BV plus chemotherapy, 12.0% for placebo plus chemotherapy), with digestive complaints and various types of cardiovascular events the most common reasons in both groups. The incidence of arterial thromboembolic events of any grade was 7.6% in the BV plus chemotherapy group, compared with 2.8% in the placebo plus chemotherapy group. GI perforation (including events reported as GI abscess, perforation, and fistula of any grade unrelated to surgery) occurred in 2.9% of the BV plus chemotherapy group, compared with 0% of the placebo plus chemotherapy group. The incidence in the bevacizumab-treated patients was higher for each of the GI perforation event types (data not shown). Rates of wound healing abnormalities in pooled patients from study 1 and study 2 have been previously reported,²² and in patients 65 years old or older were 2.4% (5/210 patients) and 0% for the BV plus chemotherapy and placebo plus chemotherapy groups, respectively. Rates of grade 3 to 4 events for bleeding, hypertension, and proteinuria/albuminuria were consistently higher in the BV plus chemotherapy group than in the placebo plus chemotherapy group, but markedly so only for hypertension (13.8% v 1.8% of patients, respectively). Venous thromboembolic events, which were not clearly associated with bevacizumab in previous studies, occurred in 14.8% of the BV plus chemotherapy group and in 17.5% of the placebo plus chemotherapy group; the most potentially serious venous event, pulmonary embolism, occurred in 3.3% of the BV plus chemotherapy group and in 6.5% of the placebo plus chemotherapy group.

View this table: [in this window] [in a new window]   Table 3. Incidence of Selected Adverse Events During First-Line Therapy for Patients 65 Years Old Treated with Either FU/LV + Placebo or IFL + Placebo or with FU/LV + BV or IFL + BV

	DISCUSSION

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This analysis that pooled data from cohorts of older patients from two studies of bevacizumab in mCRC demonstrates that adding bevacizumab to FU-based chemotherapy results in a statistically significant and clinically meaningful prolongation of OS and PFS in patients aged 65 years. Approximately two thirds of the patients were > 70 years old, which is close to the median age of 72 years at diagnosis of CRC according to the SEER database (70% of patients are 65 years),¹⁰ yet the magnitude of the benefit from bevacizumab was similar to that in the overall study populations in the pivotal phase III trial (study 1).¹ In study 1, bevacizumab prolonged median OS by nearly 5 months (20.3 v 15.6 months) and PFS by > 4 months (10.6 v 6.2 months); both differences from the control arm were statistically significant.¹ In the smaller study population of study 2, the difference in OS was not statistically significant, and subgroup analysis suggested that older patients might benefit less from bevacizumab than younger patients. In our pooled analysis of patients 65 years old, in which 40% of patients received FU/LV without irinotecan, improvement caused by the addition of bevacizumab was comparable with that in study 1, with an HR of 0.70 v 0.66 for OS and 0.52 v 0.54 for PFS, and reached significance for OS. Results of the exploratory analysis on the subset of patients > 70 years old (63% of those 65) were similar. This reduction in the risk for disease progression or death in elderly patients is clinically meaningful and is supported by comparable results for median OS and median PFS in the pooled analyses of patients younger than age 65 years. Thus, in this population with mCRC that is more representative with respect to age (ie, closer to the SEER population) than the study population in study 1, a comparable survival was achieved by adding bevacizumab to chemotherapy. Approximately 27% of this patient population was older than 70 years. This proportion of elderly patients is greater than most of the previously reported proportions from other clinical trials.^17-19 Although pooling of data even from two similarly designed studies is sometimes difficult to justify, the effect of adding bevacizumab to chemotherapy does not appear to differ across the two studies or within the subpopulation age 65 years, as demonstrated by the nonsignificant P values.

Rates of adverse events known to be associated with BV in the pooled BV plus chemotherapy group were consistent with those reported in the overall study populations in study 1 and study 2, with no indication that the older patients were at an increased risk for such events. The most frequently reported event grade 3 associated with bevacizumab—hypertension—is common among persons 65 years old, and the rate of grade 3 to 4 hypertension events in the pooled BV plus chemotherapy group (13.8% v 1.8% in the pooled placebo plus chemotherapy group) is cause for careful monitoring but not exclusion from treatment (only one patient in the pooled bevacizumab-treated group discontinued the study because of hypertension). Consistent with a pooled, retrospective analysis of randomized studies of bevacizumab in the treatment of metastatic solid tumors,²³ and as noted in the bevacizumab (Avastin) label,²¹ the incidence of arterial thromboembolic events (7.6%) was approximately 2.5 times greater (1.8 times greater if adjusted for follow-up duration) in the bevacizumab group in this analysis. Notably, this incidence compares with the SEER-Medicare database of medical claims in newly diagnosed stage IV CRC patients between January 1992 and December 2002 who were treated with chemotherapy within 60 days of diagnosis. For comparable definitions of cardiovascular events (ie, including peripheral and visceral arterial ischemia) in patients who received chemotherapy only, we determined an incidence of 8.7% (95% CI, 7.5 to 10.0; data not shown). Cardiovascular events leading to discontinuation from the study were similar in the two pooled groups, and no specific event type predominated. Significant improvements in OS and PFS were demonstrated for the cohort despite this finding.

In summary, retrospective analysis of pooled cohorts of older patients from two similarly designed trials in mCRC indicated that OS and PFS benefits of adding bevacizumab to FU-based chemotherapy in patients aged 65 years are comparable with those of the overall study population and outweigh the risks, which do not appear to be greater than those seen in younger patients with mCRC. These findings suggest that decisions regarding use of bevacizumab-based mCRC therapy should not be contingent on age alone.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Jing Yi, Genentech Inc (C); Somnath Sarkar, Genentech Inc (C); Oliver Rosen, Genentech Inc (C) Consultant or Advisory Role: Herbert I. Hurwitz, Genentech Inc (C), Roche (C) Stock Ownership: Jing Yi, Genentech, Inc; Somnath Sarkar, Genentech Inc; Oliver Rosen, Genentech Inc Honoraria: Herbert I. Hurwitz, Roche Research Funding: Fairooz F. Kabbinavar, Genentech Inc; Herbert I. Hurwitz, Genentech Inc, Roche, Sanofi-aventis Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Fairooz F. Kabbinavar, Herbert I. Hurwitz, Oliver Rosen

Provision of study materials or patients: Fairooz F. Kabbinavar

Collection and assembly of data: Oliver Rosen

Data analysis and interpretation: Fairooz F. Kabbinavar, Herbert I. Hurwitz, Jing Yi, Somnath Sarkar, Oliver Rosen

Manuscript writing: Fairooz F. Kabbinavar, Herbert I. Hurwitz, Jing Yi, Oliver Rosen

Final approval of manuscript: Fairooz F. Kabbinavar, Herbert I. Hurwitz, Jing Yi, Somnath Sarkar, Oliver Rosen

	ACKNOWLEDGMENTS

 
We thank Eric Hedrick, MD, and Robert Mass, MD, Genentech BioOncology, for their critical review of the manuscript, and Wei Dong, MD, PhD, Genentech Epidemiology, for epidemiological support. We also thank Genentech for assistance in preparation of the manuscript.

	NOTES

 
published online ahead of print at www.jco.org on December 8, 2008

Supported by Genentech.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00109070 [ClinicalTrials.gov] and NCT00109226 [ClinicalTrials.gov]

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Submitted April 22, 2008; accepted August 8, 2008.

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