Elsevier

European Journal of Cancer

Volume 45, Issue 14, September 2009, Pages 2452-2461
European Journal of Cancer

Current Perspective
Current perspective: Bevacizumab in colorectal cancer – A time for reappraisal?

https://doi.org/10.1016/j.ejca.2009.06.028Get rights and content

Abstract

Bevacizumab was the first anti-angiogenic drug to be licensed in malignant disease, based on the results of a randomised trial in advanced colorectal cancer, in which the addition of bevacizumab to chemotherapy with irinotecan plus fluorouracil/leucovorin (IFL) significantly improved tumour response, progression-free survival (PFS) and overall survival (median 15.6–20.3 months, p < 0.001). A subsequent randomised trial of bevacizumab combined with fluoropyrimidine and oxaliplatin (FOLFOX or CAPOX) confirmed an improvement in PFS, but without a survival benefit, probably due to the limited duration of bevacizumab treatment. However, in the second-line setting a randomised trial of bevacizumab combined with FOLFOX showed a significant improvement in survival, similar to that observed with IFL in the first-line. A benefit from the use of bevacizumab plus chemotherapy beyond progression remains unproven but data from non-randomised trials are encouraging. In contrast, bevacizumab monotherapy has limited efficacy in advanced disease and currently there are no data to support maintenance monotherapy. Bevacizumab is recognised to cause hypertension, arterial and venous thrombosis, intestinal perforation and impairment of wound healing but can be safely used in patients undergoing surgery, particularly when the timing of surgery is controlled. At the 2009 ASCO annual meeting, the first adjuvant study to report its primary end-point, NSABP protocol C-08, failed to demonstrate an improvement in 3-year disease-free survival from the addition of bevacizumab to modified FOLFOX6 for resected stage II/III disease.

Health economics have unfortunately limited the universal use of bevacizumab, but it is hoped that the future identification of predictive biomarkers may enhance the benefits and thereby improve cost-effectiveness.

Section snippets

Rationale for bevacizumab

Bevacizumab is a humanised monoclonal antibody targeting vascular endothelial growth factor (VEGF)-A, one of the family of circulating pro-angiogenic growth factors. The actions of VEGF-A, mediated principally via the VEGF receptors 1 and 2, include the regulation of vascular permeability and neo-vascularisation.1 Angiogenesis is critical to tumour growth and metastatic potential,2 but is also thought to be an early event in tumour development, as the transformation of a pre-malignant tumour to

What are the benefits of adding bevacizumab to chemotherapy for advanced disease?

Bevacizumab was licensed for use in metastatic colorectal cancer (mCRC) in the United States (US) in February 2004 and in Europe in January 2005 after efficacy in the first-line setting was demonstrated by Hurwitz et al. in a phase III randomised, placebo controlled study of 813 patients treated with irinotecan/bolus 5-fluorouracil (5-FU)/leucovorin (IFL) plus bevacizumab or placebo. A statistically significant increase in median overall survival (OS) was reported, corresponding to an absolute

Is there a role for bevacizumab beyond disease progression?

An effort was made to evaluate the strategy of bevacizumab beyond disease progression in the non-randomised, observational BRiTE study. The 1953 patients registered to the study achieved a median survival of 25.1 months (95% confidence interval (CI) 23.4–27.5 months). In the 1445 patients who had documented disease progression, continuation of bevacizumab beyond disease progression was significantly associated with a prolonged survival (HR 0.48; p < 0.001) on multivariate analysis. Median OS was

Bevacizumab and surgery: rationale and efficacy

Selected patients with initially unresectable mCRC may be suitable for secondary resection, usually of liver-only metastases, following down-sizing of the metastases by first-line chemotherapy. The proportion of patients that can be converted from unresectable to resectable disease varies markedly between studies from 0.8% to 15% in phase III studies of unselected mCRC16, 17, 18, 19, 20, 21 to 26.4% to 45% in small phase II studies of patients with liver-only metastases.22, 23, 24, 25 This

What are the potentially adverse effects of bevacizumab and how can they be modified?

The rates of serious bevacizumab-related toxicities, in particular, arterial and venous thromboembolism, bleeding, hypertension, proteinuria, visceral perforation and impaired wound healing, are relatively low when administered in combination with chemotherapy both in the phase III clinical trial setting5, 9, 10 and within large expanded access studies.39, 40 These data are summarised in Table 3. The major overlapping toxicity with the chemotherapy agents used in mCRC is thromboembolism. A

Can EGFR monoclonal antibodies be added to chemotherapy plus bevacizumab?

Given the emerging role for anti-EGFR antibodies in mCRC, panitumumab was evaluated in combination with bevacizumab plus chemotherapy in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study. This four-drug combination resulted in increased diarrhoea, infections and pulmonary emboli, leading to early closure of both dual inhibition arms. Efficacy was also compromised; PFS was significantly lower in the patients receiving dual VEGF/EGFR inhibition and retrospective analysis by KRAS

Biomarkers of efficacy and resistance

The discovery and subsequent confirmation of KRAS mutations as a marker of resistance to EGFR inhibitors was one of several observations that will contribute to the quest for a personalised approach to cancer treatment. As yet, no marker of resistance has been identified for bevacizumab. A retrospective analysis of samples from the phase III study by Hurwitz and colleagues showed that response to bevacizumab is not altered by the presence of KRAS, BRAF or P53 mutations.36 However, it should not

Other anti-angiogenic agents

The VEGF receptor tyrosine kinase inhibitor (TKI), valatanib, was evaluated in a placebo-controlled randomised study, CONFIRM 2. Of interest, the addition of valatanib to second-line FOLFOX4 chemotherapy resulted in a modest prolongation in PFS (5.5 versus 4.1 months, HR 0.83, p = 0.026) but no significant difference in OS (12.1 versus 11.8 months, HR 0.94; p = 0.511).60 An exploratory sub-group analysis demonstrated a significant survival benefit in patients with high LDH, but the efficacy in this

The future of bevacizumab and VEGF inhibition

The future use of bevacizumab in mCRC may be influenced by whether or not predictive biomarkers, to allow selection of patients who will attain the greatest benefit, can be identified. More stringent patient-selection criteria will enhance the cost-effectiveness of the drug and could further refine its role in the metastatic disease setting. Future prospective clinical trials will also determine whether bevacizumab added to conversion chemotherapy improves resection rate and long-term survival

Conclusions

Bevacizumab is the first anti-angiogenic drug to be used in metastatic colorectal cancer, and now has an established role with predictable and generally manageable toxicities. The true overall impact of bevacizumab on survival of patients with this disease has been difficult to quantify, although it seems probable that its use throughout the period of chemotherapy may maximise the benefit. As with many of the new anti-cancer agents, relative cost-effectiveness has been a barrier to the

Conflict of interest statement

Dr. Okines received an honorarium from Roche for a presentation. Professor Cunningham has received research funding from Roche.

Acknowledgement

We acknowledge NHS funding to the NIHR Biomedical Research Centre.

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