Both analyses show that whereas the use of sorafenib was associated with an increased risk of bleeding in HCC, this was primarily for lower-grade events and similar in magnitude to the risk encountered in RCC. Although the nature of these low-grade events for the most part were not characterized, they were defined as grade 1 or 2, meaning that by Common Terminology Criteria for Adverse Events (CTCAE) definition they did not require transfusion or endoscopic intervention. We also set out to describe the heterogeneity with regard

to the eligibility criteria employed across HCC trials for study entry, as these are reflective of EGFR activation baseline risk and are nonstandardized in HCC compared to other solid tumors. A major drawback of this analysis is the fact that only four of the HCC studies contained a control arm. When we confined our analysis to randomized studies—all of which involved sorafenib—there GS-1101 in vivo was a significant (P = 0.04) increase in the odds of bleeding events of (OR 1.73; 95% CI 1.02, 2.94) associated with sorafenib compared to control, although this increased risk appeared to be confined to lower-grade events. To ascertain whether this

was a disease-specific effect we also analyzed the hemorrhagic risk in studies evaluating sorafenib in RCC and found the risk to be similarly increased (OR 1.92; 95% CI 1.30, 2.85), suggesting that this is not necessarily greater in HCC patients beyond the effect of the drug itself. Given that the majority of studies evaluating an antiangiogenic agent in HCC are single-arm, nonrandomized phase 2 trials it is very difficult to estimate the overall bleeding risk in these studies, especially given the heterogeneity of treatments administered. To address this, at least partially, we performed a comparative analysis with a group of single-arm phase 2 studies that did not include therapy considered antiangiogenic. We acknowledge the limitations of this approach, and certainly one cannot draw conclusions on causal effects from these uncontrolled studies evaluating heterogeneous agents. Because our outcome is one CYTH4 of safety, however, we felt that the phase II single-arm studies could provide valid additional data. The results were instructive

in that patients with HCC taking part in these studies appeared to have a significantly increased risk of all-grade bleeding compared to non-antiangiogenic therapy. It must be emphasized, however, that sorafenib is the only approved agent for HCC. From a biological standpoint, although we do not know whether the benefit of sorafenib is predominantly related to its signal transduction inhibition versus its antiangiogenic properties, it seems likely—by association rather than direct proof—that the hemorrhagic risk is related to its anti-VEGF effect.9, 10 It is known that VEGF has an important role in the maintenance of architectural integrity within the endothelial cells of the microvasculature, inhibition of which may induce the increased risk of bleeding.