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Letters to the Editor

The Authors’ Reply

Invernizzi, Federica MD1; Iavarone, Massimo MD, PhD1

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doi: 10.1097/TP.0000000000003229
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We have read with interest the comments of Mancuso1 on our recently published study on sorafenib treatment of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT).2 We would only clarify 2 points for better understanding the results we obtained and our conclusions. First, the 2 severe adverse events occurred in the study population have been already reported in a previous article by Perricone et al,3 as we have stated in our article and therefore have been already counted for in the meta-analysis,4 occurring at the beginning of the experience in the management of the combination of sorafenib with mammalian target of rapamycin inhibitors (mTORi). We reported the largest series of patients treated with sorafenib and mTORi for HCC recurrence after LT, with no evidence of increase rate of adverse events in those patients treated by combination of sorafenib + mTORi compared with those treated with sorafenib and other immunosuppressive drugs, mainly cyclosporine and tacrolimus. We do believe that with an adequate follow-up and proactive attitude by means of periodically dosing mTORi blood levels and immunosuppressive drugs modifications accordingly, this combination therapy is safe and manageable. We have recently confirmed safety of combining an mTORi with regorafenib, another multikinase inhibitor as sorafenib, in the setting of liver transplanted patients.5

We agree with Mancuso1 that would be unethical to perform a prospective trial comparing sorafenib to placebo for HCC recurrence after LT, while a prospective study on HCC management after LT would be desirable and eventually feasible: however, the effort to enroll an adequate number of patients to compare sorafenib versus sorafenib + mTORi looks titanic. The data we have might be enough in terms of safety, while as long as for efficacy, the data we have can only suggest an activity of mTORi, or at least a positive role in the reduction of calcineurine inhibitor need, whose procancerogenic role is more robust.6-9

To conclude, we agree with Mancuso1 that further studies are needed to evaluate the optimal management of HCC recurrence after LT, in the face of the arrival of new drugs for HCC treatment to be tested in this population, generally excluded from randomized-controlled trial, thus calling for an international coordination effort among transplant centers.


1. Mancuso A. Sorafenib for hepatocellular carcinoma recurrence after liver transplant. Transplantation. 2020In press
2. Invernizzi F, Iavarone M, Zavaglia C, et al. Experience with early sorafenib treatment with mTOR inhibitors in hepatocellular carcinoma recurring after liver transplantation. Transplantation. 2019; 104:568–574
3. Perricone G, Mancuso A, Belli LS, et al. Sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation: does mTOR inhibitors association augment toxicity? Eur J Gastroenterol Hepatol. 2014; 26:577–578
4. Mancuso A, Mazzola A, Cabibbo G, et al. Survival of patients treated with sorafenib for hepatocellular carcinoma recurrence after liver transplant: a systematic review and meta-analysis. Dig Liver Dis. 2015; 47:324–330
5. Iavarone M, Invernizzi F, Czauderna C, et al. Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation. Am J Transplant. 2019; 19:3176–3184
6. Gomez-Martin C, Bustamante J, Castroagudin JF, et al. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl. 2012; 18:45–52
7. Piguet AC, Saar B, Hlushchuk R, et al. Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma. Mol Cancer Ther. 2011; 10:1007–1017
8. Wang Z, Zhou J, Fan J, et al. Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res. 2008; 14:5124–5130
9. Liang W, Wang D, Ling X, et al. Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl. 2012; 18:62–69
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