Several randomised trials have tested bevacizumab in diverse combinations of oxaliplatin, irinotecan, 5-FU or capecitabine. By analysing these data, it is possible to observe high heterogeneity amongst studies. There are two hypotheses to explain these differences: firstly, the fact that trials being as divergent in their results as in their designs (number of patients, selection criteria, bevacizumab dose) could influence the data and consequently introduce bias. The second explanation is a possible interaction of cytotoxic agents with VEGF-inhibitors like bevacizumab.
Evidence to support this second hypothesis is evident in the subgroup analyses of this study. Irinotecan based-regimens appear to be the most advantageous with regards to OS. The first study to evaluate this combination, AVF2107 , enrolled 813 patients in a double-blind, randomised phase III study involving IFL regimen, and revealed a clear advantage on OS (4.7 months) as well as PFS with the addition of bevacizumab at 5 mg/kg. However, other subsequent study failed to demonstrate the same response pattern. The recent single-centre randomised trial by Stathopoulos et al  with 222 patients, compared the combination of bevacizumab at 7.5 mg/kg to a bolus regimen of irinotecan and fluorouracil, both every 21 days. Though the limitations of this trial should not be taken aside (single-centre, unblinded, and a particular irinotecan-based regimen), OS and ORR were not advantageous in the regimen. It is also important to consider that current studies indicate infusional 5-FU regimens like FOLFIRI to be more beneficial than IFL. The protocol amendment from BICC-C, a trial originally planned to compare distinct irinotecan-based therapies, randomised 117 patients to FOLFIRI plus bevacizumab, 5 mg/kg every 2 weeks, or IFL plus bevacizumab, 7.5 mg/kg every 3 weeks . Updated analyses described a significant superiority on OS (28 months v 19.8 months; P = 0.037) for the infusional treatment, versus bolus regimen, at the cost of increased grade 3/4 hypertension (12.5% v 1.7%). Whether the presence of bevacizumab is an advantage to this combination and what should be the extent of such benefit are still uncertain issues.
Regarding oxaliplatin-based therapies, results are even more contradictory. In the first-line setting, there is only increased PFS supported by the single-study NO16966 , in the XELOX subgroup. The same marginal benefit in PFS without impact in OS from oxaliplatin association seems to extend to other trials involving VEGF-inhibitors. Two recent studies associating PTK/ZK, an oral antibody, to FOLFOX in first-  and second-line therapies , and one trial with the addition of the multikinase inhibitor cediranib to FOLFOX or XELOX , presented a similar pattern of results. This evidence could reinforce the impression that oxaliplatin might not be an ideal partner for such target inhibitors. Nonetheless, there are studies indicating otherwise. The E3200 trial  evaluated the addition of bevacizumab, with a higher dose of 10 mg/kg, to the FOLFOX4 scheme. Amongst 829 patients enrolled for second-line treatment, this study demonstrated statistically significant gain on OS (10.8 v 12.9 months; P = 0.0011) as well as ORR (8.6% v 22.7%). Thus, data available are insufficient to reach a conclusion about whether the addition of bevacizumab to an oxaliplatin-based regimen, especially with FOLFOX, could be beneficial in chemotherapy-naive patients.
Furthermore, when combined only with 5-FU, bevacizumab demonstrated the highest benefit in PFS, despite the absence of significant results for OS, in the subgroup meta-analysis previously presented. In contrast to the other agent subsets, no heterogeneity was observed. This effect over PFS without impact on survival could be explained by the selected population, restricted to the elderly, usually unfit for other combination therapies.
The addition of bevacizumab to palliative chemotherapy in advanced colorectal cancer is a paradigm left unsolved. The overall benefit of such combination was already attested in three global meta-analyses previously published. The two first major systematic reviews assessed five trials either in first- or second-line settings [32, 33]. A comparison performed by Welch and colleagues in 2010  demonstrated significant reduction in mortality (HR = 0.79; 95% CI: 0.69-0.90; P = 0.0005), as well as progression (HR = 0.63; 95% CI: 0.49-0.81; P = 0.0004), reass!uring the former findings from the first published meta-analysis, by Cao and colleagues . With the advent of one new randomised trial, a subsequent global review was repeated by Galfrascoli et al , maintaining global benefit observed in OS and PFS.
The delicate point of discussion from all those former systematic reviews is that this advantage is not uniform. Individual results are contradictory when assessed in particular, since the regimens of comparison are distinct. Most trials have failed to prove statistical benefit for survival, in light of the incremental cost and toxicity. Considering that those differences should not be underestimated, the main focus of this current meta-analysis was the separate comparison of backbone chemotherapies, according to cytotoxic elements involved and pattern of 5-FU administration.
Although the present study did not show higher fatal adverse events, a recent meta-analysis involving 16 clinical trials with bevacizumab for solid tumours described a significant increase in treatment-related mortality rate (2.5% v 1.7%; P = 0.01), particularly in association to taxanes and platinum agents (RR = 3.49; 95% CI: 1.82-6.66; incidence, 3.3% vs 1.0%) .
These divergent results led to distinctly different practices throughout health systems: whereas bevacizumab is approved for management of metastatic colorectal neoplasm by the FDA and European Medicines Agency (EMA), guidance recently published from the United Kingdom's National Institute for Health and Clinical Excellence (NICE) according to data and cost analyses, indicates a refusal to approve the use of such medication.
All studies currently available, including the overall results of this meta-analysis, lead to the conclusion that bevacizumab is an effective agent for first-line treatment for metastatic colorectal cancer. Nevertheless, its effectiveness is observed in limited subsets as bolus fluorouracil, capecitabine-regimens, and in combination with irinotecan. Further studies involving infusional chemotherapy and oxaliplatin combinations are required to better characterize the pharmacological interference from companion agents.