Most guidelines on treatment for advanced colorectal cancer recommend chemotherapy in combination with a biological agent in the first line and second line, but the optimum duration of treatment with these agents remains unclear.
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It is suggested that prolonged duration of anti-VEGF treatment is needed to optimise the efficacy of monoclonal antibodies. The phase 3 NO16966 trial, which investigated the addition of bevacizumab to oxaliplatin-based first-line treatment, provided indirect evidence that continuing bevacizumab until tumour progression improved outcome more than stopping treatment prematurely. Data from two adjuvant trials of bevacizumab also showed that delay in tumour recurrence was only apparent as long as anti-VEGF treatment was administered. Two non-randomised observational cohort studies showed a correlation between the use of bevacizumab beyond progression and improvement in overall survival in advanced colorectal cancer. In view of these findings, a prospective, randomised trial has examined the optimum duration of bevacizumab in metastatic colorectal cancer and the findings published in The Lancet Oncology.
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The open-label, phase III study involved patients (aged ?18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy. They were randomised in a 1:1 ratio to second-line chemotherapy with (n= 409) or without (= 411) bevacizumab 2.5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks, IV). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). The primary endpoint was overall survival, analysed by intention to treat.
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The median follow-up was 11.1 months in the bevacizumab plus chemotherapy group and 9.6 months in the chemotherapy alone group. The following findings were reported:
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??Median overall survival was 11.2 months for bevacizumab plus chemotherapy and 9.8 months for chemotherapy alone (hazard ratio 0.81, 95% CI, 0.69 to 0.94; p=0?0062).
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??Grade 3 to 5 bleeding or haemorrhage (8 [2%] vs. 1 [<1%]), gastrointestinal perforation (7 [2%] vs. 3 [<1%]), and venous thromboembolisms (19 [5%] vs. 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group.
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??The most frequently reported grade 3 to 5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs. 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs. 34 [8%], respectively), and asthenia (23 [6%] vs. 17 [4%], respectively).
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??Treatment-related deaths were reported for 4 patients in the bevacizumab plus chemotherapy group and 3 in the chemotherapy alone group.
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The researchers conclude from these findings that maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression is linked to a small survival advantage in patients with metastatic colorectal cancer.
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A Comment article discusses if the use of bevacizumab beyond progression can now be considered the new standard of care in metastatic colorectal cancer, noting that previous advocates of this idea will feel validated, whilst others might voice disappointment in the marginal 1?4 months difference in median survival from a pharmacoeconomic perspective. The identification of a subgroup of patients who derive more sustained improvements in outcome from using prolonged VEGF inhibition would be important though the search for predictive biomarkers of anti-VEGF treatment has been largely elusive. The authors concludes that the results of the trial provide new insights into tumour biology and acquired resistance to anticancer treatment which will hopefully open the way for future innovative and optimised treatment strategies for patients with colorectal cancer and other malignancies.
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