25 There is still is a great deal to learn before integrating sorafenib into the broader medical practice. For one, the registrational studies with sorafenib have focused on patients with Child-Pugh A cirrhosis. Small series have evaluated sorafenib Ibrutinib in vivo safety and efficacy in patients with Child-Pugh B cirrhosis, and have generally found the drug tolerable in this patient population. Efficacy is hard to assess as these are single-arm studies without a control arm.29, 30 One could rationalize that because sorafenib

has proven anticancer activity in Child-Pugh A patients it would have the same activity in patients with less compensated liver disease so in the absence of a clinical trial, patients in stable condition and adequate performance status could be offered treatment with close monitoring. The unknown variable being, that even if their cancer was controlled with sorafenib, will it impact their overall survival given the extent of liver dysfunction. In general, Child-Pugh B patients treated with sorafenib do not live as long as patients with Child-Pugh A, but that could very well reflect the natural history Silmitasertib of their liver disease rather than a difference in anticancer activity of sorafenib. This is magnified for patients with Child-Pugh C liver disease as well in which treatment is unlike to be of any benefit. The answer as to how, if at all, to use sorafenib in other clinical stages remains to be answered.

Randomized studies aiming at assessing sorafenib after curative resection or RFA (STORM study, NCT00692770) or in combination with TACE (SPACE study, MCT00855218) are ongoing. These randomized studies are aimed at improving survival with sorafenib in the adjuvant setting. To date, there has been no significant safety signal for its use in these settings. The role of sorafenib in liver transplantation needs to be addressed as well in the context of clinical studies. In this case, one could envision use prior to transplant (neoadjuvant setting) in an attempt to control tumor burden BCKDHA and keep patients within Milan criteria and thus on the transplant list. As discussed,

sorafenib does not typically induce tumor shrinkage, but for patients with long wait times, its use may provide them a way of not exceeding Milan criteria and remaining on the list. Conceivably, this would be used in conjunction with locally ablative therapies. Theoretical concerns in this case include potential complications at the time of transplant. The exact timing of liver transplant is typically not known, which means a patient could be taking the drug a few hours prior to transplantation. Although the half-life of sorafenib is relatively short, any lingering effects on the vasculature are not known and safety of the graft must be ensured. In another scenario, after transplant, pathologic review of the explanted liver often differs from the noninvasive assessment done pre-operatively.