Reply to: “Time is a crucial factor for the use of oncological treatment for post-transplantation recurrence of hepatocellular carcinoma”
Authors: Carlo Sposito, Vincenzo Mazzaferro
Journal: Journal of Hepatology (2013)

Time is a crucial factor for the use of oncological treatment for post-transplantation recurrence of hepatocellular carcinomaJournal of HepatologyVol. 60Issue 1PreviewWe 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]. 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 [1,2]. Moreover, due to the infrequent nature of the problem, it might be difficult to conduct well-powered randomized control trials in this setting. Full-Text PDF Open AccessComparative 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 We 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]Sposito C. Mariani L. Germini A. Flores R.M. Bongini M. Grossi G. et al.Comparative efficacy of sorafenib versus 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]. 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. Indeed, we thank for the opportunity to add to our previous report a few comments on the supposed differences among early vs. late recurrences after LT. Differently from Dr. Felga et al., we did not find that HCC factors such as tumor load (within/beyond Milan criteria at radiology and pathology), presence of microvascular invasion (mVI) and presence of microsatellites were correlated with TTR (with p = 0.217, 0.510, 0.128, and 0.510 respectively at the Pearson Chi-square test). Only a higher number of nodules per se – evaluated as a continuous variable at pre-LT radiology and at histology – appeared to be associated with an earlier recurrence (p = 0.019 and 0.036 respectively at the Kruskal-Wallis test). Therefore, even if the aforementioned HCC characteristics are associated with the probability of tumor recurrence after LT [[2]Mazzaferro V. Llovet J.M. Miceli R. Bhoori S. Schiavo M. Mariani L. et al.Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.Lancet Oncol. 2009; 10: 35-43Abstract Full Text Full Text PDF PubMed Scopus (1452) Google Scholar], they are apparently poor predictors of the TTR after LT. Although TTR is not predictable, timing and pattern of the observed recurrences may happen to be correlated. In our series, patients with early recurrence suffered that in multiple organs more frequently than patients with a later recurrence (63.6% vs. 28.6%, p = 0.43). This resulted in a reduced eligibility to curative treatments – such as surgical resection or radiofrequency ablation – that were applied only in 18.2% of those with early recurrence vs. 75% of late recurring patients (p = 0.001), since also the median time to untreatable progression/presentation was significantly different among groups [0.5 months (0.5–54.8) vs. 11.1 months (0.5–77.4), p = 0.131 respectively]. As brilliantly stated by Toso et al. [[3]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], early recurrences may be linked to remaining extrahepatic HCCs deposits left at the time of LT, or result from the post-transplant engraftment of aggressive circulating HCC clones. Such a tumor aggressiveness, that influences treatment applicability and patients outcome, has been previously demonstrated by different authors [4Roayaie 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, 5Toso C. Cader S. Mentha-Dugerdil A. Meeberg G. Majno P. Morard I. et al.Factors predicting survival after post-transplant hepatocellular carcinoma recurrence.J Hepatobiliary Pancreat Sci. 2013; 20: 342-347Crossref PubMed Scopus (44) Google Scholar] and confirmed herein by Felga et al. In our recent paper, we observed that the more indolent course of late HCC recurrences, occurring more than 2 years after LT, is associated with a reduction in the risk of death of more than 70% if compared to early recurrent patients. Noteworthy, the median TTR of those 5 patients of our series remaining alive and cured after surgical resection of their recurring HCC approached 5 years (58.7 months). In these patients HCC recurrence is probably the result of the reactivation of a few dormant HCC cells, engrafted at the time of LT: in such circumstances a prompt surgical removal may be associated with some chance of cure. Conversely, when facing early recurrences after LT, an aggressive surgical treatment may be useless and even harmful considering the high risk of further growth of occult disease. As suggested [[3]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], the first step in the treatment of an early intrahepatic recurrence may be a loco-regional treatment, used as a test of time in order to observe potential progression in other sites. In the instance of an early recurrence emerging in multiple organs, or when facing an untreatable progression, we recommend the use of sorafenib at the onset of recurrence, considering its safety and possible benefit in survival [1Sposito C. Mariani L. Germini A. Flores R.M. Bongini M. Grossi G. et al.Comparative efficacy of sorafenib versus 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, 6Waghray A. Balci B. El-Gazzaz G. Kim R. Pelley R. Narayanan M.K. et al.Safety and efficacy of sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation.Clin Transplant. 2013; 27: 555-561Crossref PubMed Scopus (39) Google Scholar]. The authors have received lecture fees from Bayer Healthcare for training courses with educational purposes on hepatocellular carcinoma.