There is great interest in the role of neoadjuvant therapies in patients with hepatocellular carcinoma (HCC) awaiting liver transplantation. The recent study by Vitale et al.1 in HEPATOLOGY considers the role of sorafenib in this setting, and this approach is highlighted in the review of sorafenib by Finn.2 Sorafenib inhibits multiple pathways implicated in HCC pathogenesis, most notably vascular endothelial growth factor (VEGF)–stimulated angiogenesis through inhibition of the receptor tyrosine kinase activity of VEGF receptors.
Although this study addresses an important and highly relevant clinical question, there are developing concerns regarding the use of anti-VEGF therapies in this setting. It is recognized that despite effective blockade of angiogenesis, there is inevitable tumor progression (reviewed by Bergers and Hanahan3). There is now emerging evidence from preclinical mouse models that anti-VEGF therapy in the form of receptor tyrosine kinase inhibition promotes invasion and increases the metastatic potential of tumors.4, 5 In the study by Pàez-Ribes et al.,4 treatment with sunitinib (a multiple-receptor tyrosine kinase inhibitor similar to sorafenib) for as little as 1 week increased invasiveness and metastases in models of pancreatic neuroendocrine tumors and glioblastoma. In models of both breast cancer and malignant melanoma, when mice were pretreated with either sorafenib or sunitinib, both agents promoted metastases and shortened survival.5 It is important to note that the authors also found more rapid development of metastases in models in which anti-VEGF therapy was given as adjuvant therapy. The mechanisms driving tumor progression in this environment are not well understood but may rely on the generation of tumor hypoxia, the expression of alternative growth factors, and/or the induction of an epithelial-to-mesenchymal transition.3
These preclinical data argue that neoadjuvant treatment with sorafenib, rather than slowing disease progression, may increase tumor invasiveness and metastatic potential during therapy and the recurrence of HCC after liver transplantation. The study by Vitale et al.1 is based on the assumption that the hazard ratio of disease progression with sorafenib treatment is known. However, because the clinical studies of sorafenib6, 7 address the use of this drug in patients with advanced disease, this may not be representative of the efficacy of sorafenib in the population with HCC being considered for liver transplantation. It would be interesting to know to what extent increased HCC recurrence and consequent decreases in survival rates after transplantation would influence overall outcomes in this model.
Although a study of sorafenib as neoadjuvant therapy for patients with HCC is appropriate,1, 2 it is imperative that such a study be adequately designed to assess disease progression while patients are receiving sorafenib treatment, the tumor phenotype in the explant, and the overall outcomes of patients receiving this therapy.