Abstract

Background: Fluoropyrimidine-based chemotherapy is considered standard treatment of advanced colorectal cancer. Recent studies indicate benefit to the addition of bevacizumab, a recombinant monoclonal antibody targeting vascular endothelial growth factor.

Methods: Medline, EMBASE, Cochrane Library, and conference proceedings were searched to identify randomized trials in advanced colorectal cancer comparing chemotherapy plus bevacizumab with chemotherapy alone. A meta-analysis of published data was carried out.

Results: Five trials comparing chemotherapy plus bevacizumab with chemotherapy alone as first- or second-line treatment were identified. Our meta-analysis indicates an advantage in favor of the addition of bevacizumab to chemotherapy in terms of overall survival (OS) [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.69–0.90; P = 0.0005], progression-free survival (PFS) (HR 0.63; 95% CI 0.49–0.81, P = 0.0004), and response rate (RR 1.50; 95% CI 1.06–2.10, P = 0.02). The most commonly observed adverse effects related to bevacizumab included hypertension, proteinuria, bleeding, and thrombosis. Gastrointestinal perforation and poor wound healing were also observed; however, their incidence was rare.

Conclusions: For patients with advanced colorectal cancer receiving first- or second-line fluoropyrimidine-based chemotherapy, the addition of bevacizumab improves PFS and OS at the expense of increased incidence of toxicity. The magnitude of benefit may differ based on the chemotherapy regimen with which bevacizumab is partnered.

background

Colorectal cancer is the fourth most common cancer site in both sexes combined, representing approximately 13% of all new cancer cases in Canada in 2007 [1]. Colorectal cancer is the second leading cause of cancer death in both sexes combined, representing 12% of all cancer deaths [1], despite the fact that mortality rates have been declining in both men and women at a rate of 1.3% and 1.7% per year, respectively [1]. For males, colorectal cancer ranks second as the leading cause of cancer death, following lung cancer. For females, colorectal cancer ranks third as the leading cause of cancer death, following breast and lung cancer [1]. For that reason, there is great interest in improving the treatment results for this group of patients.

Currently, the standard first-line treatment of metastatic colorectal cancer in Canada is either a combination of infusional 5-fluorouracil (5-FU), folinic acid (FA; also known as leucovorin calcium), and irinotecan (CPT-11), known as FOLFIRI [2], or a combination of infusional 5-FU, FA, and oxaliplatin (L-OHP) (FOLFOX). An alternative to combination FOLFIRI or FOLFOX4 is sequential monotherapy with a first-line thymidylate synthase inhibitor (such as 5-FU/FA or capecitabine [3]) followed by second-line irinotecan or combination therapy [4].

In recent years, considerable attention has been paid to targeted therapies to improve on the therapeutic ratio of cancer pharmaceuticals. Tumor angiogenesis is associated with invasiveness and the metastatic potential of various cancers. Vascular endothelial growth factor (VEGF), the most potent and specific angiogenic factor identified to date, regulates normal and pathological angiogenesis. The increased expression of VEGF has been correlated with metastasis, recurrence, and poor prognosis in many cancers, including colorectal cancer.

Bevacizumab is a recombinant humanized monoclonal antibody to VEGF. It has shown inhibition of growth in several tumor types in animal models and was well tolerated in phase I trials [5, 6]. Phase II clinical trials have indicated activity of this drug in the metastatic setting for breast, lung, renal, and colorectal cancer [7].

On the basis of emerging phase III trials involving bevacizumab, Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) Gastrointestinal Cancer Disease Site Group (DSG) developed a systematic review with meta-analysis to determine whether the evidence supports the addition of bevacizumab to cytotoxic chemotherapy for patients with locally advanced nonresectable or metastatic colorectal cancer who are considered candidates for systemic therapy.

methods

The present systematic review was originally completed in the context of developing an evidence-based series, including a clinical practice guideline, for Cancer Care Ontario’s PEBC, using the methodology of the practice guidelines development cycle [8]. The evidence was selected and reviewed by two members of the PEBC’s Gastrointestinal Cancer DSG. Consensus on the interpretation of the evidence was reached by the entire DSG membership. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent of its funding source. Evidence-based series produced by the PEBC undergo periodic review and evaluation of the literature, and new evidence is incorporated into the original reports as appropriate. The most recent versions of the reports can be found on the Cancer Care Ontario Web site: www.cancercare.on.ca.

literature search strategy

Entries to Medline (1996 to April 2008), EMBASE (1996 to week 19, 2008), and Cochrane Library (2008, Issue 1) databases and abstracts and presentations published in the proceedings of the annual meetings of the American Society of Clinical Oncology (2002 through 2007) were systematically searched for relevant evidence.

The keywords ‘bevacizumab’ and ‘avastin’ were used in a multipurpose search (.mp.) and combined with search terms for colorectal cancer in Medline, including the Medical subject headings search terms ‘colorectal neoplasms’, ‘colon neoplasms’, and ‘rectal neoplasms’ and associated text words. These results were combined with search terms to identify randomized controlled trials (RCTs) and meta-analyses. Appropriate modifications were made to the search strategy for use in EMBASE. Relevant articles and abstracts were selected and reviewed by two reviewers and the reference lists from these sources were searched for additional trials, as were the reference lists from relevant review articles. Disagreements regarding study inclusion were resolved by consensus.

study selection criteria

Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of RCTs comparing chemotherapy plus bevacizumab with chemotherapy alone in the treatment of adult patients with advanced colorectal cancer. Overall survival (OS), progression-free survival (PFS), and/or objective response rate (ORR) had to be reported. Syntheses of evidence in the form of meta-analyses of RCTs meeting the above criteria were also included.

The following were not considered for inclusion in this report: abstract reports of RCTs presenting preliminary or interim data only, results of RCTs reported in letters or editorials, and papers published in a language other than English, as translation services were not available.

trial quality assessment

Assessment of trial quality was carried out by extracting key methodological characteristics from published trial reports, including declaration of funding source, randomization method, patients’ baseline characteristics, statistical power, follow-up, and type of analysis [e.g. intention to treat (ITT)]. As the published trial reports were used to determine quality, this assessment was limited by the detail of the study methods that were reported by the authors.

synthesizing the evidence

Where possible, the data were pooled to estimate the overall effect of chemotherapy with bevacizumab versus chemotherapy alone on OS, PFS, and ORR. Since hazard ratios (HRs), rather than the number of events at a certain time point, are the preferred statistic for pooling time-to-event outcomes [9], these were extracted directly from the reported trial results for OS and PFS. The variances of the HRs were estimated from the reported confidence intervals (CI) or log-rank P values where available. For ORR, the number of responses was extracted from the trial reports and results were expressed as relative risk ratios. The individual effect sizes were weighted according to the reciprocal of their variance. A random-effects model was used for all summary estimates as it provides the more conservative estimate of effect [10]. The trial results were pooled using Review Manager 4.2.7 [11], which is freely available through the Cochrane Collaboration.

Statistical heterogeneity was calculated using the χ2 test for heterogeneity and the I2 percentage. A probability level for the χ2 statistic ≤ 10% (P ≤ 0.10) or an I2 > 50% were considered indicative of statistical heterogeneity. Results are expressed as HRs with 95% CI.

results

literature search results

Three phase III RCTs [12–14] and two randomized phase II trials [15, 16] comparing chemotherapy with chemotherapy plus bevacizumab met the inclusion criteria for this review. A third treatment arm of one of the phase III RCTs [12] is published separately from the parent trial report [17]. A pooled analysis [18] of individual patient data from three RCTs [12, 15, 16] was also identified.

Four of the included trials were of first-line therapy [12, 14–16], while one trial included only patients previously treated with irinotecan and a fluoropyrimidine for advanced or metastatic disease [13]. Two trials investigated the addition of bevacizumab to 5-FU/FA [15, 16], two to an oxaliplatin-containing regimen [13, 14], and one to an irinotecan-containing regimen [12].

trial characteristics and quality assessment

Selected characteristics of included trials are reported in Table 1. The primary end point was OS in three trials [12, 13, 16], PFS in one trial [14], and time to progression (TTP) and ORR in another trial [15]. Four trials were supported by industry grants [12, 14–16], whereas one was led by a cooperative group [13]. Method of randomization was reported for only three trials and allocation concealment was adequate in all three trials [12, 14, 16]. Patient stratification was by Eastern Cooperative Oncology Group’s (ECOG) performance score (PS), site of primary disease, and number of metastatic sites in two trials [12, 16]; by ECOG PS and prior radiotherapy in one trial [13]; and by region, ECOG PS, liver as a metastatic site, alkaline phosphatase level, and number of metastatic sites in another trial [14]. Three of the trials were double-blinded and placebo-controlled with regard to bevacizumab [12, 14, 16]. One trial reported that primary analyses were carried out by a blinded independent review committee but blinding of patients was not discussed [15]. The fifth trial was open-label [13]. Statistical power to detect a significant difference between groups for primary outcomes was reported in four trials [12, 13, 14, 16]. One trial allowed patients in the control arm to cross over to receive bevacizumab at disease progression [15]; however, all trials used an ITT analysis approach.

Table 1.

Selected characteristics of included randomized controlled trials

Author (reference) Treatment allocation Treatment dose and schedule Selected patient inclusion criteria Statistical power Follow-up Comments 
Hurwitz et al. [12, 17IFL/placebo 5-FU: 500 mg/m2, i.v. bolus; FA: 20 mg/m2, i.v. over 2 h; irinotecan: 125 mg/m2, given first 4 weeks of 6-week cycle Histologically confirmed mCRC; age ≥18 years; ECOG PS 0 or 1; life expectancy >3 months; no prior CT or biologic therapy for metastatic disease 80% power to detect HR of 0.75 for death with 385 deaths, two-sided P values, α = 0.05, one interim analysis of efficacy NR 50% of patients received second-line therapy. 25% of patients received oxaliplatin. Only patients randomized to a BV arm could receive BV as second-line therapy 
IFL/BV BV: 5 mg/kg i.v. every 2 weeks 
5-FU/FA/BVa 5-FU: 500 mg/m2; FA: 500 mg/m2, given first 6 weeks of 8-week cycle; BV: as above 
Giantonio et al. [13FOLFOX4 5-FU: 400 mg/m2 i.v. bolus, then 600 mg/m2 by 22 h infusion, days 1 and 2; FA: 200 mg/m2 i.v. over 2 h, days 1 and 2; oxaliplatin: 85 mg/m2 i.v., day 1; BV: 10 mg/kg i.v., day 1; all agents given every 2 weeks Prior CT with irinotecan and a fluoropyrimidine required. Histologically confirmed advanced or mCRC 95% power to detect 50% difference in overall survival with 13 months follow-up Median 28 months Open-label trial 
FOLFOX4/BV 
BVb 
Saltz et al. [14XELOX/placebo or FOLFOX4/placebo FOLFOX: 5-FU: 400 mg/m2 i.v. bolus, then 600 mg/m2 by 22 h infusion, days 1 and 2; FA: 200 mg/m2 i.v. over 2 h, days 1 and 2; oxaliplatin: 85 mg/m2 i.v., day 1; BV: 5 mg/kg i.v., day 1; all agents given every 2 weeks Histologically confirmed mCRC; age ≥18 years; ECOG PS 0 or 1; no prior systemic therapy for advanced or mCRC; no prior oxaliplatin or bevacizumab 98% power based on HR of 0.75 for PFS in the pooled superiority comparison with 985 events in the ITT population Median 28 months 29% of patients in BV arm and 47% of patients in the placebo arm continued treatment until progression 
XELOX/BV or FOLFOX4/BV XELOX: Capecitabine: 1000 mg/m2 orally, twice daily, days 1–14; oxaliplatin: 130 mg/m2 i.v. day 1; BV: 7.5 mg/kg i.v. day 1; all agents given every 3 weeks 
Kabbinavar et al. [155FU/FA 5-FU: 500 mg/m2, i.v. bolus; FA: 500 mg/m2 i.v. over 2 h, given first 6 weeks of 8-week cycle; BV: 5 or 10 mg/kg i.v., given every 2 weeks Histologically confirmed mCRC with metastases >1 cm2; age ≥18 years; ECOG PS 0 or 1; life expectancy >3 months NR NR Imbalance in men, ECOG PS, patients with liver/lung metastases, low serum albumin at baseline. 61% of patients in the control arm received single-agent BV (10 mg/kg) as crossover therapy 
5FU/FA/BV (5 mg/kg) 
5FU/FA/BV (10 mg/kg) 
Kabbinavar et al. [165-FU/FA/placebo 5-FU: 500 mg/m2, i.v. bolus; FA: 500 mg/m2 i.v. over 2 h, given first 6 weeks of 8-week cycle; BV: 5 mg/kg i.v. every 2 weeks Histologically confirmed mCRC. Not optimal candidates for first-line irinotecan-containing therapy. One of the following characteristics: age ≥65 years, ECOG PS 1 or 2, serum albumin ≤3.5 g/dl, or prior RT to abdomen or pelvis 80% power to detect HR of 0.61 for death with 133 deaths, two-sided P values, α = 0.05, two interim analyses NR Approximately 50% of patients in each arm received subsequent therapies following assigned therapy. Only patients in BV arm could receive BV as a component of second-line treatment 
5-FU/FA/BV 
Author (reference) Treatment allocation Treatment dose and schedule Selected patient inclusion criteria Statistical power Follow-up Comments 
Hurwitz et al. [12, 17IFL/placebo 5-FU: 500 mg/m2, i.v. bolus; FA: 20 mg/m2, i.v. over 2 h; irinotecan: 125 mg/m2, given first 4 weeks of 6-week cycle Histologically confirmed mCRC; age ≥18 years; ECOG PS 0 or 1; life expectancy >3 months; no prior CT or biologic therapy for metastatic disease 80% power to detect HR of 0.75 for death with 385 deaths, two-sided P values, α = 0.05, one interim analysis of efficacy NR 50% of patients received second-line therapy. 25% of patients received oxaliplatin. Only patients randomized to a BV arm could receive BV as second-line therapy 
IFL/BV BV: 5 mg/kg i.v. every 2 weeks 
5-FU/FA/BVa 5-FU: 500 mg/m2; FA: 500 mg/m2, given first 6 weeks of 8-week cycle; BV: as above 
Giantonio et al. [13FOLFOX4 5-FU: 400 mg/m2 i.v. bolus, then 600 mg/m2 by 22 h infusion, days 1 and 2; FA: 200 mg/m2 i.v. over 2 h, days 1 and 2; oxaliplatin: 85 mg/m2 i.v., day 1; BV: 10 mg/kg i.v., day 1; all agents given every 2 weeks Prior CT with irinotecan and a fluoropyrimidine required. Histologically confirmed advanced or mCRC 95% power to detect 50% difference in overall survival with 13 months follow-up Median 28 months Open-label trial 
FOLFOX4/BV 
BVb 
Saltz et al. [14XELOX/placebo or FOLFOX4/placebo FOLFOX: 5-FU: 400 mg/m2 i.v. bolus, then 600 mg/m2 by 22 h infusion, days 1 and 2; FA: 200 mg/m2 i.v. over 2 h, days 1 and 2; oxaliplatin: 85 mg/m2 i.v., day 1; BV: 5 mg/kg i.v., day 1; all agents given every 2 weeks Histologically confirmed mCRC; age ≥18 years; ECOG PS 0 or 1; no prior systemic therapy for advanced or mCRC; no prior oxaliplatin or bevacizumab 98% power based on HR of 0.75 for PFS in the pooled superiority comparison with 985 events in the ITT population Median 28 months 29% of patients in BV arm and 47% of patients in the placebo arm continued treatment until progression 
XELOX/BV or FOLFOX4/BV XELOX: Capecitabine: 1000 mg/m2 orally, twice daily, days 1–14; oxaliplatin: 130 mg/m2 i.v. day 1; BV: 7.5 mg/kg i.v. day 1; all agents given every 3 weeks 
Kabbinavar et al. [155FU/FA 5-FU: 500 mg/m2, i.v. bolus; FA: 500 mg/m2 i.v. over 2 h, given first 6 weeks of 8-week cycle; BV: 5 or 10 mg/kg i.v., given every 2 weeks Histologically confirmed mCRC with metastases >1 cm2; age ≥18 years; ECOG PS 0 or 1; life expectancy >3 months NR NR Imbalance in men, ECOG PS, patients with liver/lung metastases, low serum albumin at baseline. 61% of patients in the control arm received single-agent BV (10 mg/kg) as crossover therapy 
5FU/FA/BV (5 mg/kg) 
5FU/FA/BV (10 mg/kg) 
Kabbinavar et al. [165-FU/FA/placebo 5-FU: 500 mg/m2, i.v. bolus; FA: 500 mg/m2 i.v. over 2 h, given first 6 weeks of 8-week cycle; BV: 5 mg/kg i.v. every 2 weeks Histologically confirmed mCRC. Not optimal candidates for first-line irinotecan-containing therapy. One of the following characteristics: age ≥65 years, ECOG PS 1 or 2, serum albumin ≤3.5 g/dl, or prior RT to abdomen or pelvis 80% power to detect HR of 0.61 for death with 133 deaths, two-sided P values, α = 0.05, two interim analyses NR Approximately 50% of patients in each arm received subsequent therapies following assigned therapy. Only patients in BV arm could receive BV as a component of second-line treatment 
5-FU/FA/BV 
a

Recruitment to 5-FU/FA/BV arm terminated at interim safety analysis after IFL/BV was determined to be safe.

b

Recruitment to BV arm terminated at interim efficacy analysis after survival determined to be inferior.

IFL, bolus 5-fluorouracil/folinic acid/irinotecan; BV, bevacizumab; 5FU, 5-fluorouracil; FA, folinic acid; i.v., intravenous; mCRC, metastatic colorectal cancer; ECOG, Eastern Cooperative Oncology Group; PS, performance status; CT, chemotherapy; HR, hazard ratio; NR, not reported; FOLFOX4, infusional 5-fluorouracil/bolus folinic acid/oxaliplatin; XELOX, capecitabine/oxaliplatin; PFS, progression-free survival; ITT, intention-to-treat; RT, radiotherapy.

Two of the included reports were randomized phase II studies [15, 16]. The results of these studies must be interpreted with caution due to the methodological limitations associated with phase II studies. Both randomized phase II studies included in this review were designed to evaluate the efficacy and safety of bevacizumab with 5-FU/FA compared with 5-FU/FA alone using statistical comparisons between groups; however, these studies had relatively small sample sizes, were imbalanced in baseline prognostic characteristics between treatment groups, and were statistically powered to detect only large differences between groups with regard to primary end points.

outcomes

bevacizumab with 5-FU/irinotecan (IFL)

The placebo-controlled RCT reported by Hurwitz et al. [12] investigated the efficacy and tolerability of bevacizumab in combination with the Saltz regimen of bolus 5-FU/FA and irinotecan (CPT-11) (IFL) compared with IFL alone as first-line treatment of patients with advanced colorectal cancer. The third treatment arm, composed of 5-FU/FA with bevacizumab (without irinotecan), was abandoned after the safety of the addition of bevacizumab to irinotecan was established. Patients with cerebral metastases, significant atherosclerotic disease, proteinuria, or a history of coagulopathy were excluded. The primary end point was OS.

Significant improvements in OS, PFS, and ORR were detected for IFL combined with bevacizumab compared with IFL alone (Table 2). The combination of IFL and bevacizumab was generally well tolerated; however, an increase in grade 3 or 4 toxicity with IFL combined with bevacizumab (85% versus 74%) compared with IFL alone was observed (Table 3). This discrepancy can be attributed to an increase in grade 3 hypertension (10.9% versus 2.3%), which was treated with oral medications. There was no significant difference in bleeding, thrombosis, or proteinuria between the two arms. Gastrointestinal perforation was a rare complication observed in the IFL plus bevacizumab arm.

Table 2.

Efficacy results reported in randomized trials of bevacizumab in advanced colorectal cancer

Author (reference) Treatment allocation Assessable patients OS
 
PFS
 
ORR (%) 
Median (months) 1-year (%) HR, P value Median (months) HR, P value 
Bevacizumab with fluoropyrimidines plus irinotecan 
    Hurwitz et al. [12, 17IFL/placebo 411 15.6 63.4  6.2  34.8 
IFL/BV 402 20.3 74.3 0.66, P < 0.001 10.6 0.54, P < 0.001 44.8; P = 0.004 
5-FU/FA/BV 110 18.3 68a  8.8  40 
Bevacizumab with fluoropyrimidines plus oxaliplatin 
    Giantonio et al. [13] (second-line) FOLFOX4 291 10.8 43  4.7  8.6 
FOLFOX4/BV 286 12.9 56 0.75, P = 0.0011 7.3 0.61, P < 0.0001 22.7; P < 0.0001 
BV 243 10.2 44  2.7  3.3 
    Saltz et al. [14XELOX/FOLFOX4/placebo 701 19.9 72a  8.0  49 
XELOX/FOLFOX4/BV 699 21.3 79a 0.89 (95% CI 0.76–1.03), P = 0.0769 9.4 0.83 (95% CI 0.72–0.95), P = 0.0023 47; P = 0.31 
Bevacizumab with fluoropyrimidines alone 
    Kabbinavar et al. [155-FU/FA 36 13.8 NR  5.2c  17 
5-FU/FA/BV (5 mg/kg) 35 21.5 0.63 9.0c 0.46, P = 0.005c 40 
5-FU/FA/BV (10 mg/kg) 33 16.1 1.17 7.2c 0.66, P = 0.217c 24 
5-FU/FA/BV (pooled) 68 18.0 0.86 7.4c 0.54; P = 0.013c 32 
    Kabbinavar et al. [165-FU/FA/placebo 105 12.9 53a  5.5  15 
5-FU/FA/BV 104 16.6 63a 0.79 (95% CI 0.56–1.10), P = 0.159 9.2 0.50 (95% CI 0.34–0.73), P = 0.0002b 26; P = 0.0552b 
Author (reference) Treatment allocation Assessable patients OS
 
PFS
 
ORR (%) 
Median (months) 1-year (%) HR, P value Median (months) HR, P value 
Bevacizumab with fluoropyrimidines plus irinotecan 
    Hurwitz et al. [12, 17IFL/placebo 411 15.6 63.4  6.2  34.8 
IFL/BV 402 20.3 74.3 0.66, P < 0.001 10.6 0.54, P < 0.001 44.8; P = 0.004 
5-FU/FA/BV 110 18.3 68a  8.8  40 
Bevacizumab with fluoropyrimidines plus oxaliplatin 
    Giantonio et al. [13] (second-line) FOLFOX4 291 10.8 43  4.7  8.6 
FOLFOX4/BV 286 12.9 56 0.75, P = 0.0011 7.3 0.61, P < 0.0001 22.7; P < 0.0001 
BV 243 10.2 44  2.7  3.3 
    Saltz et al. [14XELOX/FOLFOX4/placebo 701 19.9 72a  8.0  49 
XELOX/FOLFOX4/BV 699 21.3 79a 0.89 (95% CI 0.76–1.03), P = 0.0769 9.4 0.83 (95% CI 0.72–0.95), P = 0.0023 47; P = 0.31 
Bevacizumab with fluoropyrimidines alone 
    Kabbinavar et al. [155-FU/FA 36 13.8 NR  5.2c  17 
5-FU/FA/BV (5 mg/kg) 35 21.5 0.63 9.0c 0.46, P = 0.005c 40 
5-FU/FA/BV (10 mg/kg) 33 16.1 1.17 7.2c 0.66, P = 0.217c 24 
5-FU/FA/BV (pooled) 68 18.0 0.86 7.4c 0.54; P = 0.013c 32 
    Kabbinavar et al. [165-FU/FA/placebo 105 12.9 53a  5.5  15 
5-FU/FA/BV 104 16.6 63a 0.79 (95% CI 0.56–1.10), P = 0.159 9.2 0.50 (95% CI 0.34–0.73), P = 0.0002b 26; P = 0.0552b 
a

Estimated from Kaplan–Meier survival curves.

b

P value reported in American Society of Clinical Oncology abstract [19], not in full publication.

c

Time to progression.

OS, overall survival; HR, hazard ratio; PFS, progression-free survival; ORR, objective response rate; IFL, bolus 5-fluorouracil/folinic acid/irinotecan; BV, bevacizumab; 5FU, 5-fluorouracil; FA, folinic acid; FOLFOX4, infusional 5-fluorouracil/bolus folinic acid/oxaliplatin; XELOX, capecitabine/oxaliplatin; CI, confidence interval; NR, not reported.

Table 3.

Adverse events reported in randomized trials of bevacizumab in advanced colorectal cancer

Adverse effect Hurwitz et al. [12Giantonio et al. [13Saltz et al.a [14Kabbinavar et al.a [15Kabbinavar et al.a [16
IFL (n = 397) (%) IFL+BV (n = 393) (%) FOLFOX4 (n = 287) (%) FOLFOX4+BV (n = 285) (%) FOLFOX/XELOX (n = 675) (%) FOLFOX/XELOX+BV (n = 694) (%) 5-FU/FA (n = 35) (%) 5-FU/FA/BV 5 mg/kg (n = 35) (%) 5-FU/FA/BV 10 mg/kg (n = 32) (%) 5-FU/FA (n = 104) (%) 5-FU/FA/BV (n = 100) (%) 
All grade 3 or 4 toxicity 74 85b 61 75b 75 80 54 74 78 71 87 
60-day all-cause mortality – – – 14 
Leukopenia 
    Grade 3 or 4 31 37 – – – – 
Diarrhea 
    Grade 3 or 4 25 32 – – – – 37 29 31 40 39 
Neuropathy 
    Grade 3 or 4 – – 16b – – – – – – – 
Hypertension 
    Any 22b – – – – 11 28 32 
    Grade 3 or 4 11b 6b 25 16 
Thrombosis 
    Any 16 19 – – – – 26 13 18 18 
    Grade 3 or 4 – – 2.5 1c 2c 14 – – 
Hemorrhage 
    Grade 3 or 4 <1 3b 
Proteinuria 
    Any 22 27 – – – – 11 23 28 19 38 
    Grade 3 <1 <1 <1 – – – 
GI perforation 1.5 <1 <1 – – – 
Adverse effect Hurwitz et al. [12Giantonio et al. [13Saltz et al.a [14Kabbinavar et al.a [15Kabbinavar et al.a [16
IFL (n = 397) (%) IFL+BV (n = 393) (%) FOLFOX4 (n = 287) (%) FOLFOX4+BV (n = 285) (%) FOLFOX/XELOX (n = 675) (%) FOLFOX/XELOX+BV (n = 694) (%) 5-FU/FA (n = 35) (%) 5-FU/FA/BV 5 mg/kg (n = 35) (%) 5-FU/FA/BV 10 mg/kg (n = 32) (%) 5-FU/FA (n = 104) (%) 5-FU/FA/BV (n = 100) (%) 
All grade 3 or 4 toxicity 74 85b 61 75b 75 80 54 74 78 71 87 
60-day all-cause mortality – – – 14 
Leukopenia 
    Grade 3 or 4 31 37 – – – – 
Diarrhea 
    Grade 3 or 4 25 32 – – – – 37 29 31 40 39 
Neuropathy 
    Grade 3 or 4 – – 16b – – – – – – – 
Hypertension 
    Any 22b – – – – 11 28 32 
    Grade 3 or 4 11b 6b 25 16 
Thrombosis 
    Any 16 19 – – – – 26 13 18 18 
    Grade 3 or 4 – – 2.5 1c 2c 14 – – 
Hemorrhage 
    Grade 3 or 4 <1 3b 
Proteinuria 
    Any 22 27 – – – – 11 23 28 19 38 
    Grade 3 <1 <1 <1 – – – 
GI perforation 1.5 <1 <1 – – – 
a

Description of statistical significance not published.

b

Data are statistically significant (P < 0.05) compared with control group.

c

Data for arterial thrombosis. Venous thrombosis was 8% in the bevacizumab group compared with 5% in the control group.

IFL, bolus 5-fluorouracil/folinic acid/irinotecan; BV, bevacizumab; FOLFOX4, infusional 5-fluorouracil/bolus folinic acid/oxaliplatin; XELOX, capecitabine/oxaliplatin; 5FU, 5-fluorouracil; FA, folinic acid.

bevacizumab with 5-FU or capecitabine/oxaliplatin (FOLFOX or XELOX)

Two RCTs were identified that investigated the addition of bevacizumab to an oxaliplatin-containing regimen, one as first-line therapy [14] and one in previously treated patients [13]. Results of a previous RCT, N9741, demonstrated the superiority of FOLFOX4 (infusional 5-FU plus oxaliplatin) over IFL in terms of PFS and OS [20].

A phase III RCT by Giantonio et al. [13] was designed to evaluate the efficacy of bevacizumab plus FOLFOX4 compared with FOLFOX4 alone as second-line therapy for patients with metastatic colorectal cancer. Patients were eligible if they had previously received irinotecan with a fluoropyrimidine for advanced disease. The investigators chose to use high-dose bevacizumab in the experimental arm at a dose of 10 mg/kg every 2 weeks. A third trial arm consisted of bevacizumab as a single agent; however, an independent data-monitoring committee closed this arm early due to inferior efficacy. The primary end point was OS.

After a median follow-up of 28 months, a statistically significant improvement in OS and PFS was shown with the addition of bevacizumab to FOLFOX4 (Table 2). There was more frequent grade 3 or 4 toxicity related to the addition of bevacizumab (75% versus 61%; see Table 3). The increase in grade 3 neuropathy was likely a consequence of longer oxaliplatin exposure in the experimental arm. Thrombosis, hemorrhage, and bowel perforation were rare events, seen primarily in patients receiving bevacizumab.

A second trial by Saltz et al. [14] (NO16966) evaluated the addition of bevacizumab to fluoropyrimidines with oxaliplatin as first-line treatment. The NO16966 trial was initiated as an international open-label RCT with the primary objective attempting to confirm the noninferiority of capecitabine with oxaliplatin (XELOX) versus FOLFOX4. In 2004, with the regulatory approval of bevacizumab in advanced colorectal cancer, the protocol was amended to include a second double-blinded randomization to bevacizumab or placebo. Fourteen hundred patients were recruited to the amended protocol. The results have been reported both in terms of XELOX versus FOLFOX [21] and in terms of bevacizumab versus placebo [14]. The primary end point for the latter analysis was improvement in PFS with bevacizumab over placebo.

Despite similar response rates, there was a statistically significant improvement in PFS favoring bevacizumab over placebo (Table 2). OS was prolonged in the bevacizumab arm, but this difference was not statistically significant.

The investigators noted that fewer patients in the bevacizumab arm were treated until progression compared with the placebo arm [14]. Thirty percent of patients discontinued treatment due to adverse events in the experimental arm compared with only 21% in the control arm. The majority of these discontinuations were due to events classically associated with chemotherapy rather than bevacizumab, such as neurotoxicity, gastrointestinal toxicity, and myelosuppression. As with previous bevacizumab trials in colorectal cancer, the incidence of thrombosis, bowel perforation, and thrombosis was rare (Table 3). There was no significant difference in 60-day mortality between the bevacizumab arm and the placebo arm. The relatively modest improvements in PFS and OS associated with bevacizumab may be explained by the inability to continue treatment until progression in the majority of patients and has led to the hypothesis that continuing bevacizumab alone until disease progression may be necessary.

bevacizumab with 5-FU/FA alone

Two randomized phase II trials by Kabbinavar et al. [15, 16] have investigated the efficacy and safety of bevacizumab in addition to 5-FU/FA versus 5-FU/FA alone in patients previously untreated for advanced colorectal cancer. In both trials, 5-FU/FA was given using the Roswell Park regimen (bolus infusions weekly for 6 of 8 weeks), while bevacizumab was given every 2 weeks.

In the first trial, 104 patients were randomly assigned to receive 5-FU/FA combined with 10 mg/kg bevacizumab, 5-FU/FA combined with 5 mg/kg bevacizumab, or 5-FU/FA alone [15]. Patients in the 5-FU/FA arm were allowed to receive bevacizumab alone after disease progression but were analyzed in the group to which they were randomly assigned. The primary end points of the trial were TTP and tumor response rate.

Compared with 5-FU/FA alone, 5-FU/FA plus bevacizumab at both dose levels was associated with significant improvements in median TTP and ORR (Table 2). There was no significant improvement in median survival; however, this trial had limited statistical power. Partial response was seen in 2 out of 22 patients who crossed over to receive bevacizumab after progression. Grade 3 or 4 toxicity occurred more frequently in both bevacizumab arms compared with the 5-FU/FA arm (Table 3) [15]. Bleeding, hypertension, and thrombosis were observed at greater frequency in the bevacizumab arms in this trial compared with control.

The second trial was a randomized placebo-controlled phase II trial of 209 patients thought to be unsuitable for first-line irinotecan [16]. The mean age was 71 years in both arms. Results for the primary end point of OS showed no significant benefit for bevacizumab over control; however, a significant improvement in PFS was observed for patients receiving 5-FU/FA combined with bevacizumab compared with those receiving 5-FU/FA with placebo (Table 2). While ORR was higher in patients who received bevacizumab, the difference between groups was marginally nonsignificant. Although more grade 3 and 4 toxic effects were seen in the 5-FU/FA/bevacizumab arm, the 60-day mortality was higher in the 5-FU/FA-alone arm (Table 3). Sixteen percent of the 5-FU/FA/bevacizumab group suffered grade 3 hypertension compared with 2.9% of the 5-FU/FA-alone group [16]. Gastrointestinal perforation occurred in two patients receiving bevacizumab.

meta-analyses

A meta-analysis of published data from four RCTs that reported mortality HRs and sufficient data to calculate variance estimates was conducted [12–14, 16]. Insufficient data were reported in the publication of the smaller randomized phase II trial by Kabbinavar et al. [15] to be included in the meta-analysis. The meta-analysis indicated a significant reduction in mortality for patients receiving bevacizumab, with an HR of 0.79 (95% CI 0.69–0.90; P = 0.0005) compared with patients who received fluoropyrimidine-based chemotherapy alone (Figure 1). No significant statistical heterogeneity was detected between studies (P = 0.14). A sensitivity analysis of only the first-line therapy trials [12, 14, 16] demonstrated a similar benefit for the addition of bevacizumab to chemotherapy, with a mortality HR of 0.79 (95% CI 0.65–0.96; P = 0.02).

Figure 1.

Meta-analysis of mortality hazard ratios in randomized trials of chemotherapy plus bevacizumab versus chemotherapy alone in patients with advanced colorectal cancer. CI, confidence interval.

Figure 1.

Meta-analysis of mortality hazard ratios in randomized trials of chemotherapy plus bevacizumab versus chemotherapy alone in patients with advanced colorectal cancer. CI, confidence interval.

The meta-analysis of PFS data for the same four RCTs [12–14, 16] indicates an advantage in favor of the addition of bevacizumab, with an HR of progression or death of 0.63 (95% CI 0.49–0.81) (Figure 2). For the PFS analysis, significant statistical heterogeneity was detected between study results (P = 0.003).

Figure 2.

Meta-analysis of hazard ratios for death or progression in randomized trials of chemotherapy plus bevacizumab versus chemotherapy alone in patients with advanced colorectal cancer. CI, confidence interval.

Figure 2.

Meta-analysis of hazard ratios for death or progression in randomized trials of chemotherapy plus bevacizumab versus chemotherapy alone in patients with advanced colorectal cancer. CI, confidence interval.

Objective response data from all five RCTs were pooled in a meta-analysis (Figure 3). In this analysis, a relative risk (RR) > 1 favors bevacizumab over control. Results indicate an improvement in the likelihood of response with the addition of bevacizumab (RR for response 1.50, 95% CI 1.06–2.10; P = 0.02) when considering first- and second-line therapy trials together. Again, statistical heterogeneity between study results was observed in this analysis (P < 0.00001). It is noteworthy that the largest trial showed no difference in response rate, despite showing a statistically significant improvement in PFS [14].

Figure 3.

Meta-analysis of risk ratios for objective response in randomized trials of chemotherapy plus bevacizumab versus chemotherapy alone in patients with advanced colorectal cancer. CI, confidence interval.

Figure 3.

Meta-analysis of risk ratios for objective response in randomized trials of chemotherapy plus bevacizumab versus chemotherapy alone in patients with advanced colorectal cancer. CI, confidence interval.

Kabbinavar et al. [18] have published a pooled analysis of individual patient data from the three RCTs investigating the addition of bevacizumab to 5-FU/FA compared with 5-FU/FA-based chemotherapy alone. For the trial of Hurwitz et al. [12], patients who received IFL plus placebo were included in the chemotherapy-alone control group, whereas the two bevacizumab-containing arms were included in the experimental arm. The results indicated a significant benefit in medial survival (17.9 versus 14.6 months), mortality HR [0.742 (95% CI 0.59–0.93)], median PFS (8.77 versus 5.55 months), progression HR [0.63 (95% CI 0.5–0.78)], and ORR (34.1% versus 24.5%, P = 0.019) for patients who received 5-FU/FA-based chemotherapy plus bevacizumab compared with patients who received 5-FU/FA-based therapy alone.

discussion

Two phase III RCTs have demonstrated improved survival in patients with advanced colorectal cancer when bevacizumab was added to standard 5-FU-based chemotherapy regimens, which incorporate irinotecan (IFL) and oxaliplatin (FOLFOX4) [12, 13]. A third RCT involving two oxaliplatin-based regimens did not demonstrate improved survival with the addition of bevacizumab; however, PFS was significantly improved in the bevacizumab-containing arms of all three studies [14]. Survival and response rates were similarly improved in randomized phase II trials comparing 5-FU/FA combined with bevacizumab with 5-FU/FA alone in advanced colorectal cancer [15, 16]. A meta-analysis of mortality HRs reported in four of the RCTs demonstrated a significant survival benefit for patients receiving bevacizumab. Survival benefit has been shown when bevacizumab is added to 5-FU regimens given by bolus injection (IFL) and by continuous infusion (FOLFOX). Bevacizumab in combination with 5-FU-based chemotherapy has been shown to be effective in both first- and second-line treatment of advanced colorectal cancer.

Despite the fact that bevacizumab has not been shown to add benefit to all available 5-FU-based combination therapies in an RCT (e.g. FOLFIRI), it is reasonable to believe that bevacizumab in combination with any fluoropyrimidine-based chemotherapy is more effective than any fluoropyrimidine-based chemotherapy alone. This conclusion is supported by two large observational registry trials in first-line metastatic colorectal cancer—the BRiTE trial in the United States [22] and the First Bevacizumab Expanded Access Trial (BEAT) conducted in Europe and Canada [23]. These trials were designed to evaluate safety events of bevacizumab used in combination with a variety of chemotherapy regimens in a broad community-based population of patients with metastatic colorectal cancer. Nearly 4000 patients have been enrolled in these two studies to date. These observational data indicate that bevacizumab in combination with a variety of fluoropyrimidine-based chemotherapy regimens is safe, with efficacy similar to that seen in prospective randomized clinical trials.

The Food and Drug Administration and other regulatory agencies approved bevacizumab in 2004, leading to sequential studies where the first cohort compared two or more chemotherapy regimens without bevacizumab and the second cohort evaluated the same regimens with bevacizumab. Although patients were not randomly assigned to receive or not receive bevacizumab, three sets of sequential randomized trials provide supporting evidence for the safety and efficacy of the use of bevacizumab with a variety of chemotherapy regimens in the treatment of advanced colorectal cancer [24–27] (Table 4). Historical comparisons between the Bowel Oncology with Cetuximab Antibody (BOND) trial [24] (cetuximab plus irinotecan compared with cetuximab alone in irinotecan-refractory patients) and the BOND-2 trial [25], which added bevacizumab to both arms, indicated improved ORR and TTP with the addition of bevacizumab both to cetuximab alone and to the combination of cetuximab and irinotecan. The TREE-1 study randomized patients to receive oxaliplatin with infusional 5-FU (FOLFOX), bolus 5-FU (bFOL), or oral 5-FU (CapeOx), and the TREE-2 study added bevacizumab to all three study arms [26]. The addition of bevacizumab in the TREE-2 study caused more grade 3 or 4 hypertension, wound healing, and bowel perforation in each arm; however, there appeared to be significant improvements in ORR, TTP, and OS for all three treatment arms. Similarly, historical comparison of two cohorts of the BICC-C trial indicated that all measures of efficacy were improved with the addition of bevacizumab to both modified IFL and FOLFIRI [27].

Table 4.

Sequential randomized trials where bevacizumab has been added to all arms of the second cohort

Author (reference) Treatment allocation Assessable patients Median survival (months) Median TTP (months) ORR (%) 
Cunningham et al. [24
    BOND Cetux/CPT-11 218 8.6 4.1 23 
Cetux 111 6.9 1.5 11 
Saltz et al. [25
    BOND-2 Cetux/CPT-11/BV 43 14.5 7.3 37 
Cetux/BV 40 11.4 4.9 20 
Hochster et al. [26
    TREE-1 FOLFOX 49 19.2a 8.7 41 
bFOL 50 17.9 6.9 20 
CapeOx 48 17.2 5.9 27 
    TREE-2 FOLFOX/BV 71 26.1a 9.9 52 
bFOL/BV 70 20.4 8.3 39 
CapeOx/BV 72 24.6 10.3 46 
Fuchs et al. [27, 28
    BICC-C P1 FOLFIRI 144 23.1 7.6 47 
mIFL 141 17.6 5.9 43 
CapeIri 145 18.9 5.8 39 
    BICC-C P2 FOLFIRI/BV 57 28.0b 11.2 58 
mIFL/BV 60 19.2 8.3 53 
Author (reference) Treatment allocation Assessable patients Median survival (months) Median TTP (months) ORR (%) 
Cunningham et al. [24
    BOND Cetux/CPT-11 218 8.6 4.1 23 
Cetux 111 6.9 1.5 11 
Saltz et al. [25
    BOND-2 Cetux/CPT-11/BV 43 14.5 7.3 37 
Cetux/BV 40 11.4 4.9 20 
Hochster et al. [26
    TREE-1 FOLFOX 49 19.2a 8.7 41 
bFOL 50 17.9 6.9 20 
CapeOx 48 17.2 5.9 27 
    TREE-2 FOLFOX/BV 71 26.1a 9.9 52 
bFOL/BV 70 20.4 8.3 39 
CapeOx/BV 72 24.6 10.3 46 
Fuchs et al. [27, 28
    BICC-C P1 FOLFIRI 144 23.1 7.6 47 
mIFL 141 17.6 5.9 43 
CapeIri 145 18.9 5.8 39 
    BICC-C P2 FOLFIRI/BV 57 28.0b 11.2 58 
mIFL/BV 60 19.2 8.3 53 
a

Median overall survival for all three arms combined was 18.2 months in TREE-1 and 24.4 months in TREE-2.

b

Median survival for FOLFIRI plus bevacizumab arm reported in updated results published in a letter to the editor [28].

TTP, time to progression; ORR, objective response rate; BOND, Bowel Oncology with Cetuximab Antibody; Cetux, cetuximab; CPT-11, irinotecan; BV, bevacizumab; FOLFOX, infusional 5-fluorouracil/oxaliplatin; bFOL, bolus 5-fluorouracil/oxaliplatin; CapeOx, capecitabine/oxaliplatin; FOLFIRI, infusional 5-fluorouracil/irinotecan; mIFL, modified bolus 5-fluorouracil/irinotecan; CapeIri, capecitabine/irinotecan.

Although the meta-analysis of available comparisons of chemotherapy versus chemotherapy with bevacizumab indicates a survival advantage with the addition of bevacizumab, the magnitude of benefit is not consistent across trials. The magnitude of incremental benefit with bevacizumab may change based on the cytotoxic chemotherapeutic regimen with which it is partnered. There is insufficient evidence at present to recommend which chemotherapy regimen is optimal in combination with bevacizumab.

Achievement of OS and PFS benefit with the addition of bevacizumab to chemotherapy is at the cost of a significant increase in toxicity. Commonly observed adverse effects in clinical trials with bevacizumab included bleeding, thrombosis, hypertension, and proteinuria. Hypertension observed in clinical trials has been manageable with oral antihypertensives; however, frequent monitoring of blood pressure is necessary. Reported and ongoing phase III trials have excluded patients with cerebral metastases, advanced atherosclerotic disease, or proteinuria; therefore, those conditions should be considered contraindications to the use of bevacizumab. Gastrointestinal perforation and poor wound healing are consistently seen in association with bevacizumab across clinical trials; however, their incidence is rare [29].

There is no evidence to support the use of bevacizumab as monotherapy in advanced colorectal cancer [13]. In addition, the combination of 5-FU and bevacizumab has failed to show significant efficacy in patients with advanced colorectal cancer that progressed on both irinotecan-containing and oxaliplatin-containing regimens [30]. Thus, bevacizumab should not be seen as an alternative in the third-line setting of systemic treatment of advanced colorectal cancer.

All patients in the aforementioned clinical trials were bevacizumab-naïve at the initiation of the trial. There is no available evidence to answer the question of whether bevacizumab, when used as a part of first-line therapy, should be continued upon progression as part of a second-line regimen. Further randomized clinical trials are required to answer this question.

conclusions

For patients with advanced colorectal cancer receiving fluoropyrimidine-based chemotherapy as first-line therapy, the addition of bevacizumab improves OS. The addition of bevacizumab to fluoropyrimidine-based chemotherapy also improves survival for patients with advanced colorectal cancer receiving second-line therapy if they did not receive bevacizumab as part of their initial treatment.

Data from available randomized clinical trials have demonstrated a survival benefit with the addition of bevacizumab to several fluoropyrimidine-based regimens, including regimens of 5-FU/FA, 5-FU with irinotecan (IFL), 5-FU with oxaliplatin (FOLFOX4), and capecitabine with oxaliplatin (XELOX). Regimens using 5-FU given by bolus, infusional, and oral means have been represented in those studies. Survival benefit has been shown with the addition of bevacizumab to both first- and second-line chemotherapy. It is reasonable to conclude that bevacizumab in combination with any fluoropyrimidine-based chemotherapy is more effective than fluoropyrimidine-based chemotherapy alone.

The role of continuing bevacizumab after disease progression on a bevacizumab-containing regimen is not clear due to the absence of evidence. Therefore, the continuation of bevacizumab in patients who have progressed on that therapy cannot currently be recommended outside of clinical trials.

Improvements in PFS and OS with bevacizumab come at the expense of greater toxicity. Bevacizumab should not be administered to patients with cerebral metastases, uncontrollable hypertension, severe proteinuria, advanced atherosclerotic disease, bleeding diatheses, or to those with nonhealing wounds or recent surgery or trauma (i.e. within the previous 28 days).

funding

The Cancer Care Ontario's Program in Evidence-Based Care is sponsored by Cancer Care Ontario and the Ministry of Health and Long-Term Care.

disclosure

JM has attended an advisory board for Roche and has received honoraria from Roche for two presentations at grand rounds. SW has received honoraria from Roche.

Please see the Cancer Care Ontario's Program in Evidence-Based Care Web site (http://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/gastro-ebs/gastro-dsg/) for a complete list of current Gastrointestinal Cancer Disease Site Group members.

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