Experience With Early Sorafenib Treatment With mTOR Inhibitors in Hepatocellular Carcinoma Recurring After Liver Transplantation

Abstract

Background: Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence. Methods: All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (01/2008-06/2018). Baseline and on-treatment data were collected. Results: Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor (mTORi), 54% HCCtreated at baseline) were enrolled. During 7.3 (0.3-88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3-4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% Confidence Interval [CI] 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18 months (95%CI 8-27); 5-year OS was 18% (95%CI 4-32%). Baseline predictors of OS were SOR+mTORi (HR 0.4, 95%CI 0.2-0.9, p=0.04), previous curative treatments (HR 0.3, 95%CI 0.2-0.7, p=0.003) and alpha-fetoprotein>100ng/ml (HR 2.5, 95%CI 1.1-5.0, p=0.02). At multivariate analysis, HCC curative treatment was the only independent predictor (HR 0.4, 95%CI 0.2-1.0, p=0.04). Conclusions: Early and combined treatment with sorafenib and mTORi resulted in a favourable safety profile, while its effectiveness should be confirmed by meta-analysis of previous studies or by larger studies. Curative treatment for HCC resulted the only independent predictor of OS.

Non-cirrhotic hepatocellular carcinoma in chronic viral hepatitis: Current insights and advancements

“…GEMOX showed complete response in fibrolamellar HCC. Combination therapy such as use of Sorafenib and mammalian target of rapamycin inhibitors[ 115 ] has been attempted with one year survival of 82% and five year survival of 33%[ 116 ]. New immunotherapy protocols such as atezolizumab-bevacizumab combination has not been studied in NCHCC, however future trials can be expected with these agents in NCHCC[ 117 ].…”

Liver transplantation as therapy for hepatocellular carcinoma

“…An earlier diagnosis of recurrence could help improve outcomes as several case series have shown improved survival in patients who underwent resection for localized recurrence compared to patients with multifocal recurrence . Early use of sorafenib and other mTOR inhibitors may also be options as well as resection or LRT, though more data are needed . In a metaanalysis of 1021 LT recipients with HCC recurrence, the median survival after diagnosis of recurrence was 13 months.…”

“…23,32,33 Early use of sorafenib and other mTOR inhibitors may also be options as well as resection or LRT, though more data are needed. 34 In a metaanalysis of 1021 LT recipients with HCC recurrence, the median survival after diagnosis of recurrence was 13 months. A variety of treatments were used including surgical resection, systemic therapy with sorafenib, LRT, and the best supportive care.…”

High trough levels of everolimus combined to sorafenib improve patients survival after hepatocellular carcinoma recurrence in liver transplant recipients

“…In the multivariable Cox proportional hazard analysis, the combination therapy (SOR plus EVL) was an independent predictive factor for better survival (RR: 0.320, 95% CI 0.014-0.660). Invernizzi et al reported similar results that the combination therapy (SOR plus EVL) is associated with better OS (MST: 18 months, 95% CI 8-27) after analyzing data of 37/50 patients treated with SOR in combination to EVL [25].…”

“…Theoretically, such systemic therapies could be a favorable approach and their combination (SOR plus mTORi) might have some synergetic effect for this systematic disease. However, there were few reports about the efficacy and safety of the combination therapy for recurrent HCC after LT [25][26][27]. The aim of this study was to evaluate the predictive factors of survival after HCC recurrence and to evaluate the efficacy and safety of the combination therapy (SOR plus EVL) as a treatment for HCC recurrence after LT.…”