Cuppone et al. Journal of Experimental & Clinical Cancer Research 2011, 30:54 http://www.jeccr.com/content/30/1/54 Page 7 of 9 of 4.5% difference between the control arm and patients undergoing bevacizumab was found, corresponding to 22 patients to be treated for one harmed (Table 3). These data are in line with those recently reported in two further cumulative analyses on the individual patients’ basis, where hypertension seems to occur with different rates according to the chemotherapeutic beva- cizumab is combined with [34,35]. Indeed, the initial 14- 17% rate reported in the ECOG-2100 trial should be carefully evaluated, given the adoption of paclitaxel on a weekly basis (with its steroid pre-medication) could have biased the specific toxicity rate. The other signifi- cant toxicities seem to occur rarely, and in particular those toxicities supposed to be bevacizumab-related (i.e. proteinuria, bleeding) require 175-250 patients to be treated for one to be harmed. From a very practical per- spective, in order to weight the relative severities of positive and negative events, breast cancer patients receiving bevacizumab in addition to chemotherapy have ‘likelihood to be helped and harmed’ (LHH) of 2- 20 [36]; that means that patients receiving bevacizumab are from 2 to 20 times more likely to be helped than armed. Recently, other anti-angiogenesis drugs have been stu- died in randomized trials for locally advanced or meta- static breast cancer [37-39]. In the SOLTI-0701 study, patients randomized to the combination of sorafenib and capecitabine showed a median PFS of 6.4 months, com- pared to the 4.1 months achieved by the patients who received capecitabine alone (HR 0.58, p = 0.0006) [38], although with a higher incidence of serious adverse events (hand-foot syndrome 45% versus 13%). A further rando- mized phase II study evaluated the efficacy and toxicity of sorafenib in addition to paclitaxel compared to paclitaxel plus placebo in patients untreated for metastatic disease, demonstrating a statistically significant improvement in PFS, TTP and responses [39]. Also for the first line treat- ment, the first analysis of a 3-arm randomized trial com- paring paclitaxel plus placebo or bevacizumab or motesanib (small molecule inhibitor of VEGF tyrosine kinase) has been recently presented, with a median follow up of 10 months [40]. No significant differences in the pri- mary objective of the study (the response rate), were found between the three arms, at the expense of a higher grade 3 and 4 incidence of neutropenia, hepato-biliary and gastrointestinal toxicity for patients receiving motesanib. For the second line setting of HER-2 negative patients, a recent trial randomizing patients between capecitabine and sunitinib, did not show any PFS superiority of the tyr- osine kinase over capecitabine [37]. More concerning data with regard to the overall safety profile of bevacizumab have been recently released [41,42]: in the context of a literature based meta-analysis evaluating the addition of bevacizumab to chemotherapy or biologics accruing data of more than 10,000 patients regardless of the cancer type, the rate of treatment- related mortality was significantly higher in the experi- mental arm [41,43]. Deaths seem to be associated with hemorrhage, neutropenia and gastrointestinal perfora- tion, with a significant interaction according to the che- motherapeutics combined (against the use of platinum or taxanes). With specific regard to breast cancer, a further meta-analysis recently showed a statistically sig- nificant higher risk of heart failure with bevacizumab [41]; both meta-analyses report no interaction according to the bevacizumab dose as a common finding. Although all these data require an individual patient data analysis for the competitive death risk evaluation, in order to clearly correlate the adverse events together, and even taking into account the heterogeneity across all studies and settings, many concerns still remain for the wide adoption of this agents [43,44]. Conclusions Our data in context with the other exploring the safety- efficacy balance of the addition of bevacizumab to che- motherapy for advanced breast cancer do strengthen the need of a deep analysis of the correlation between adverse events and deaths on one side, and the maximi- zation of the efficacy by restricting the drug to those patients who will really benefit. The latest approach is far to be understood, although positive hints with regard to polymorphisms analyses are encouraging. Bevacizu- mab, from a clinical practice standpoint, slightly increases the efficacy of chemotherapy in HER-2 nega- tive advanced breast cancer, although a close follow-up monitoring for adverse events must be adopted. Acknowledgements & Funding Supported by a grant of the National Ministry of Health and the Italian Association for Cancer Research (AIRC). Previous Presentation Presented at the 46th ASCO (American Society of Medical Oncology) annual meeting, Chicago, Illinois (US), June 4th-8th, 2010. Author details 1Department of Medical Oncology, Regina Elena National Cancer Institute, Roma, Italy. 2Medical Oncology, University of Verona, Italy. 3Department of Medical Oncology, University Hospital of Udine, Udine, Italy. 4Biostatistics/ Scientific Direction, Regina Elena National Cancer Institute, Roma, Italy. 5Institut Multidisciplinaire d’Oncologie, Clinique de Genolier, Genolier, Switzerland. Authors’ contributions FCu, EB, VV, PC, MM and SG conceived the analysis, and supervised the calculations; FCu, EB, IS, and DG performed the calculations in a blinded fashion; VV, FB, AF, PC, MM, CN, MR, PP, and GF participated in the trials recruitment and selection process; FCu, EB, VV, FP, AF and MM drafted and revised the manuscript; EB, PC, MM, MA, DG and FC did coordinate the overall study process and did provide the funding. All authors read and approved the final manuscript.