Time is a crucial factor for the use of oncological treatment for post-transplantation recurrence of hepatocellular carcinoma
Authors: Guilherme Felga, Paolo Rogério Salvalaggio, Marcelo Bruno de Rezende, Marcio Dias de Almeida
Journal: Journal of Hepatology (2013)

Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: A case-control studyJournal of HepatologyVol. 59Issue 1PreviewThe efficacy of sorafenib in the post-liver transplantation (LT) setting has been scarcely studied. The aim of this study was to evaluate the efficacy of sorafenib, compared to best supportive care (BSC), in two cohorts of patients which presented with hepatocellular carcinoma (HCC) recurrence after LT. Full-Text PDF Reply to: "Time is a crucial factor for the use of oncological treatment for post-transplantation recurrence of hepatocellular carcinoma"Journal of HepatologyVol. 60Issue 1PreviewWe thank Dr. Felga and colleagues for their comments on our article demonstrating the efficacy of sorafenib treatment in case of recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) [1]. In their experience with 20 of such patients in Brazil they observed that time-to-recurrence (TTR) after LT might be influenced by adverse baseline tumor biology – i.e., G3 tumors and presence of macrovascular invasion – and tumor load, suggesting that early recurrences within 1 year after LT were characterized by a worse prognosis, while patients with later recurrences were more prone to receive some form of HCC treatment and had a higher median survival. Full-Text PDF Open Access We have read with great interest the work of Sposito et al., in which they demonstrated a survival benefit for patients who use sorafenib for recurrent hepatocellular carcinoma after liver transplantation [[1]Sposito C. Mariani L. Germini A. Reyes M.F. Bongini M. Grossi G.G. et al.Comparative efficacy of sorafenib vs. best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study.J Hepatol. 2013; 59: 59-66Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar]. As pointed out by the authors and in the elegant editorial by Toso et al., there is an absence of solid data to guide evidence-based practice for the practitioner managing patients with this complication of the disease [1Sposito C. Mariani L. Germini A. Reyes M.F. Bongini M. Grossi G.G. et al.Comparative efficacy of sorafenib vs. best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study.J Hepatol. 2013; 59: 59-66Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 2Toso C. Mentha G. Majno P. Integrating sorafenib into an algorithm for the management of post-transplant hepatocellular carcinoma recurrence.J Hepatol. 2013; 59: 3-5Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. Moreover, due to the infrequent nature of the problem, it might be difficult to conduct well-powered randomized control trials in this setting. Another possibility is that patients with early recurrence may not only have a higher baseline tumor load, but also more aggressive biology. This assumption is strengthened by the observation that patients with early recurrence of hepatocellular carcinoma have larger lesions and more undifferentiated tumors than those with later recurrence [3Roayaie S. Schwartz J.D. Sung M.W. Emre S.H. Miller C.M. Gondolesi G.E. et al.Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis.Liver Transpl. 2004; 10: 534-540Crossref PubMed Scopus (382) Google Scholar, 4Schlitt H.J. Neipp M. Weimann A. Oldhafer K.J. Schmoll E. Boeker K. et al.Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation.J Clin Oncol. 1999; 17: 324-331PubMed Google Scholar]. Other authors have also suggested that a longer time from transplant to recurrence might have an impact on prognosis [5Taketomi A. Fukuhara T. Morita K. Kayashima H. Ninomiya M. Yamashita Y. et al.Improved results of a surgical resection forthe recurrence of hepatocellular carcinoma after living donor liver transplantation.Ann Surg Oncol. 2010; 17: 2283-2289Crossref PubMed Scopus (68) Google Scholar, 6Kornberg A. Kupper B. Tannapfel A. Katenkamp K. Thrum K. Habrecht O. et al.Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables.Eur J Surg Oncol. 2010; 36: 275-280Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 7Shin W.Y. Suh K.S. Lee H.W. Kim J. Kim T. Yi N.J. et al.Prognostic factors affecting survival after recurrence in adult living donor liver transplantation for hepatocellular carcinoma.Liver Transpl. 2010; 16: 678-684Crossref PubMed Scopus (65) Google Scholar]. To test this hypothesis, our group has performed a retrospective analysis of patients who underwent liver transplantation at our institution between May 2005 and March 2013. In this cohort of 919 consecutive patients, 257 presented with hepatocellular carcinoma on their liver explants, and 20 patients developed post-operative recurrence during an average follow-up of 24.3 ± 20.2 months. Twelve patients (60%) had early post-transplant recurrence (within the first year of transplantation), and 8 patients (40%) had late post-transplant recurrence (after the first year of transplantation). Patients with recurrence of the tumor after the first year after liver transplantation have shown a very distinct profile compared to those with earlier recurrence. The frequencies of low grade tumors (7 patients with late recurrence vs. 1 patient with early recurrence, p = 0.000), and microvascular invasion (1 patient with late recurrence vs. 10 patients with late recurrence, p = 0.005) were significantly different when time to recurrence was considered. We also observed a trend towards a higher frequency of macrovascular invasion in the group with early recurrence (0 patients with late recurrence vs. 5 patients with early recurrence, p = 0.055). The group with late recurrence had similar immunosuppression (tacrolimus based) and was much more likely to receive some form of oncological treatment (OR 35.0; CI 95%: 2.6–465.3, p = 0.007) than those with early recurrences. In this circumstance sorafenib was the mainstay of therapy, either alone (6 cases) or in association with sirolimus (3 cases). In the same fashion as in Sposito et al., patients who received oncological treatment survived longer (452.0 ± 353.7 days vs. 93.8 ± 59.8 days, p = 0.004) than those who received the best supportive care. The work of Sposito et al. represents a major contribution in clarifying the role of sorafenib for hepatocellular carcinoma post-transplant recurrence. The article has shown compelling evidence of its efficacy, and above all, safety. Although all factors have been controlled and the use of sorafenib was the only factor influencing survival, we now add that time from transplantation to recurrence also impacts on the prescription of sorafenib. Longer periods between transplantation and recurrence may allow patients to recover from transplantation, to improve their performance status, and, most importantly, to reduce their baseline immunosuppression, which is suggested as first-line treatment in the algorithm proposed by Toso et al. [[2]Toso C. Mentha G. Majno P. Integrating sorafenib into an algorithm for the management of post-transplant hepatocellular carcinoma recurrence.J Hepatol. 2013; 59: 3-5Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. Furthermore, recurrence in the early post-operative setting possibly represents a distinct clinical entity from later recurrence. In the setting of early recurrence, a highly aggressive behavior of the tumor allows little, if any, therapeutic endeavors to control disease progression. All of the authors are supported by the Sistema Integrado de Transplantes, Hospital Israelita Albert Einstein, and Ministério da Saúde (PROADI-SUS). The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.