Recent data indicate a survival benefit of VA or combinational CTx+VA-therapy in advanced or metastatic cancer patients [43, 84, 85]. depending on patients condition, tumor and immunological parameters . In addition, intravenous and intratumoral applications of VA have been reported both being described as safe applications [66, 83]. Clinical end result may depend around the composition of VA extracts, dose and length of application [45, 62]. Recent data show a survival benefit of VA Itga2 or combinational CTx+VA-therapy in advanced or metastatic malignancy patients GSK-269984A [43, 84, 85]. In contrary, a prospective randomized phase II study of Bar-Sela and colleagues applying VA Iscador extracts in patients with NSCLC inaddition to platinum-based chemotherapy did not reveal survival improvement . It has to be remarked, that survival was only the secondary endpoint of the Bar-Sela study and only half the patient number (n = 72) compared to our study has been enrolled. Even though Bar-Sela and colleagues did not find survival differences between treatment groups they observed a statistically significant increased CTx dose reduction (44%) in the control group (CTx only) compared to the add-on VA group (13%, p = 0.005) and the authors conclude that decreasing CTx dose reduction due to add-on VA may improve survival of these patients. In contrast, a meta analysis performed by Ostermann and collegues GSK-269984A in 2009 2009  analyzing 41 eligible controlled clinical studies until 2008 around the clinical impact of adjuvant VA suggested its association with better survival of cancer patients (overall hazard ratio = 0.59 (CI: 0.53 to 0.66, p 0.0001). A Cochrane statement published in 2008 on VA therapy in oncology including randomized controlled trials analysed among other outcomes 13 eligible trials on survival in adults with any malignancy type. Seven trials reported no, six trials reported a survival benefit. The authors concluded that VA experienced generally no consistent impact on disease free surival or overall survival. However, for lung malignancy, the authors added that the GSK-269984A evidence for non-superiority of VA is limited to moderate as only two trials were GSK-269984A eligible. One trial included patients with inoperable lung malignancy and one trial patients after surgery, both not with stage IV NSCLC. Even though the evidence of VAs impact on survival is discussed controversially [25C27], Ostermann and collegues summarized in their meta-analysis in 2009 2009 that em one can not ignore the fact that studies with positive effects of VA-E on survival of cancer patients are accumulating /em . The results of our study fit into this statement and may, among other studies, be the basis for any prospective randomized controlled trial with combined CTx and VA in metastasized NSCLC. Unwanted biases may have been launched into the analysis, e.g. the assignment of treatment with add-on VA was performed in a non-randomized, non-controlled and un-blinded fashion and physicians could have unintentionally selected patients with better prognoses for VA therapy. Furthermore, it has been stated, that patients with a healthier lifestyle may be more open for additional integrative treatments and could have selected add-on VA therapy. As sound lifestyle data were not available, this aspect cannot be ruled out so far. Due to its specific moderate to moderate local reactions such as erythema and flu-like symptoms it is difficult to apply VA in blinded studies which in most cases results in a lower grading in meta-analyses or reviews . Further limitations of the present study may be its observational nature. Therefore, our findings and conclusions have to be dealt with with caution and should be interpreted in light of existing randomized, controlled trials. As suggested earlier, evidence for best treatment for patients em should generally not be chosen based only on evidence from observational studies or single randomised clinical trials /em . Even a circular model of evidence evaluation has been suggested by Walach and collegues, in.