No adjuvant Chemo Visceral site Hormonal Receptors Negative Prior taxanes Prior Anthra 0.00013 0.18 0.03 0.56 0.009 0.66 0.96 0.45 0.019 0.91 Cuppone et al. Journal of Experimental & Clinical Cancer Research 2011, 30:54 http://www.jeccr.com/content/30/1/54 Page 6 of 9 Table 4 Meta-regression Analysis Outcome PFS OS > 3 sites 0.032 0.99 Anthra (A): anthracyclines PFS: progression free survival; OS: overall survival. cancer after adjuvant anthracyclines based chemother- apy, the HR in terms fir the time to progression is 0.70 [28]. In the phase III trial evaluating the addition of capecitabine to docetaxel in the same setting of patients, the HR for time to disease progression is 0.65 [29]. Taking into account the different approaches to treat- ment such as chemotherapy combination versus single agent therapy for first line treatment of metastatic patients with breast cancer, the HR for taxanes based combinations compared with control arm was 0.92 for PFS [30]. Also with regard to the events of severe toxici- ties that are observed in studies that explore the benefits determined by the polychemotherapy compared to sin- gle drug therapy, are well comparable with the increase in hypertension that occurs in patients treated with bevacizumab. With regard to the concerns regarding the interpreta- tion of those trials providing a significant (sometimes small) benefit in intermediate end-points (such as PFS) without any advantage in late-outcomes (such as OS), a recent original work has been published, trying to weight the impact of the post-progression survival (SPP, as the difference between OS and PFS) [31]. To this purpose, simulation methods have been used to generate clinical 2-arms studies with a median PFS of 6 and 9 months, respectively. The authors indicated that OS represents a reasonable primary endpoint when the SPP is short, while when the SPP is long, that dilutes the variability of the OS, which may consequently loose the eventual sta- tistical significance. This particular effect is especially true for those diseases where the SPP is longer than 1 year. In a context of effective treatments, such as advanced breast cancer, when a clinical trial shows a sig- nificant PFS benefit, the absence of a statistically advan- tage for OS does not necessarily imply the absence of a late-survival improvement [31]. Two meta-analysis analyzed the effect of the addition of Bevacizumab to chemotherapy in metastatic breast cancer [32,33] in over 3,000 patients in three rando- mized trials. showing a statistically significant increase in PFS, resulting in a reduced risk of progression of about 30%. In the meta-analysis conducted by Valachis et al, improved PFS was statistically significant only in the subgroup of patients receiving taxanes (or anthracy- clines in a part of the study RIBBON-1) in combination with Bevacizumab [33], this advantage not seem to get Predictor p-value in combination with capecitabine, although the latter are grouped in heterogeneous populations with regard to the treatment line. In the meta-analysis conducted by Lee et al, with populations more correctly grouped by line of treatment rather than medication, the benefit of the addition of Bevacizumab in PFS is restricted to first- line treatment [32]. Moreover, this analysis shows a marginal but statistically significant benefit in overall survival in first line. At the last ESMO meeting, a meta-analysis of 530 elderly patients (older than 65 years) enrolled in the randomized trials ECOG 2100, AVADO and RIBBON-1, was presented [34]. Although that represent a subgroup analysis, even in these featured advanced breast cancer patients’ sample, bevacizumab in combination with che- motherapy was associated with significantly improved PFS versus chemotherapy alone (HR 0.67, p = 0.0030). Hypertension was more frequent with the addition of bevacizumab, as expected; besides, no differences according to age were found. Another relevant issue that emerges from our analysis is that the prior exposure to treatments containing taxanes does not affect the efficacy of bevacizumab (Table 4). Indeed, the meta-regression analysis for either PFS or OS clearly indicates that no significant correlation exists between the efficacy of bevacizumab and taxanes pre- treatment (p = 0.96 and p = 0.45, respectively). This find- ing is consistent with the ECOG-2100 and AVADO pre- vious release [14,15], and with the recently presented meta-analysis of patients from studies ECOG-2100, AVADO and RIBBON-1, previously treated with taxanes (paclitaxel, docetaxel or paclitaxel protein-bound) [35]. This analysis included only 311 patients from the group of patients treated with taxanes of the RIBBON-1 and AVADO who received bevacizumab 15 mg/kg. The addi- tion of bevacizumab led to an improvement in PFS from 6.2 to 10.6 months (HR 0.50, 95% CI 0.36-0.69). In line with the data of the single trials and our analysis, the authors conclude that patients pretreated with taxanes are good candidates for retreatment with bevacizumab and taxane [35]. With regard to serious adverse events, the main signif- icant toxicity against the addition of bevacizumab was hypertension (Table 3); this represents a common find- ing in all disease setting when this monoclonal antibody is adopted. Our analysis shows that a weighted average