Cuppone et al. Journal of Experimental & Clinical Cancer Research 2011, 30:54 http://www.jeccr.com/content/30/1/54 Page 3 of 9 of patients needed to treat (or to harm one in case of toxi- city) for one single beneficial patient was determined (NNT or NNH: 1/[(Absolute Benefit)/100]) [25]. Results were depicted in all figures as conventional meta-analysis forest plots. In order to find possible correlations between outcome effect and negative prognostic factors (selected among trials’ reported factors: > 3 sites, no adjuvant CT, visceral site, hormonal receptors negative (RN), prior tax- anes, T or anthracyclines, A) a meta-regression approach was adopted (i.e. regression of the selected predictor on the Log HR/RR of the corresponding outcome). Calcula- tions were accomplished using the Comprehensive Meta- Analysis Software, version v. 2.0 (CMA, Biostat, Engle- wood, NJ, USA). Results Selected trials Five trials (3,841 patients) were identified (Figure 1) [13,14,16,26,27], all included in the meta-analysis, and evaluable for PFS (primary outcome). The patients’ sam- ple for each trial ranged from 462 to 736 patients (Table 1). One trial was conducted with a double comparison [16]. Trials characteristics are listed in Table 1; 2 RCTs evaluated the addition of Bevacizumab as second line treatment [26,27], and one of these included patients who received 2 or more regimens of chemotherapy for metastatic disease [27]. One trial (462 patients) did not report survival data [27], so 4 RCTs were evaluable for OS (3,379 patients). With regard to secondary outcomes, all RCTs were evaluable for ORR, HTN, Bleeding, Pro- teinuria and Thrombosis; 4 RCTs (3,379 patients) were evaluable for Neurotoxicity, Febrile Neutropenia, Gas- tro-intestinal perforation [13,14,16,26]. With regard to the meta-regression analysis, 2 trials did not report data of two previous adjuvant chemotherapy [27], 1 trial did not refer to overall visceral disease rate [14], 1 to nega- tive hormonal receptors [27], and 1 did not report data for previous treatment either with taxanes and anthracy- clines [26]. Combined Analysis With regard to the primary outcomes, the addition of Bevacizumab to chemotherapy increased PFS in patients untreated for advanced disease (HR 0.68, 95% CI 0.56, 0.81, p = 0.0001), with an absolute benefit of 8.4%, cor- responding to 12 patients to be treated for one to bene- fit, although with significant heterogeneity (p = 0.0001) (Table 2) (Figure 2) . A significant interaction according to treatment lines for PFS was found (p = 0.027), given the non significant difference between the 2 arms in sec- ond line setting (HR 0.86, 95% CI 0.69, 1.07, p = 0.19). No significant differences were found in OS in favor of 5 RCTs included in the meta-analysis (3,841 pts) Primary Outcomes Secondary Outcomes 5 RCTs evaluable for PFS (3,841 pts) Data not available for 1 RCT (462pts) 5 RCTs evaluable for ORR, HTN, Bleeding, Proteinuria, Thrombosis (3,841 pts) Data not available for 1 RCT (462 pts) 4 RCTs evaluable for OS (3,379 pts) 4 RCTs evaluable for Neuro, FN, GI Perforation (3,379 pts) Figure 1 Outline of the search - Flow diagram. RCTs: randomized clinical trials; pts: patients; PFS: progression free survival; OS: overall survival; ORR: overall response rate; HTN: hypertension; neuro: neurotixicity; FN: febrile neutropenia; GI: gastro-intestinal.