Sorafenib: Experience and Better Manage­ment of Side Effects Improve Overall Survival in Hepatocellular Carcinoma Patients: A Real-Life Retrospective Analysis

Abstract

<b><i>Background:</i></b> Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). The management of its side effects is improving. This study aimed to assess, in real life, if this translates into a better prognosis. <b><i>Methods:</i></b> This was a retrospective study of advanced HCC patients treated with sorafenib between 2007 and 2017. <b><i>Results:</i></b> 188 advanced HCC patients received > 4 weeks of sorafenib. Median treatment duration was 5.4 months and median overall survival (mOS) 10 months (95% confidence interval 15–27). Sorafenib was initiated in 65 patients in 2007–2012 and 123 in 2013–2017. Both groups were comparable except for Barcelona Clinic liver cancer class. Tumor progression, disease control (DC) rate, and incidence of toxicity were similar in the 2 periods, but the duration of treatment (4.3 vs. 5.9 months; <i>p</i> < 0.01) and mOS (8 vs. 12 months; <i>p</i> < 0.002) differed. Among progressive disease patients, mOS was similar (7 months) but for those who had DC at 8 weeks, mOS was longer in the recent period (13 vs. 27 months; <i>p</i> < 0.0001). In the univariate analysis of OS, the period of treatment had a prognostic value. <b><i>Conclusion:</i></b> When comparing 2 periods of treatment in advanced HCC patients under sorafenib, duration of treatment and mOS were higher in the recent period. While mOS did not differ for patients who progressed, it was 2-fold higher in the recent period for those who had tumor control. Improvements in the use of sorafenib seem to be associated with better outcomes limited to patients with DC.

Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients

“…So far there had been no direct demonstration of an improvement in the OS of patients treated with sorafenib over time. In the aforementioned study by Raoul et al [10], the OS was in fact significantly higher in the last five years (12 vs 8 months) in the univariate analysis, but it was not possible to confirm this result also in a multivariate regression. Even indirect evidence about the critical aspect of OS is minimal, deriving mainly from information collected in the REFLECT trial.…”

“…While treatment beyond radiological progression was allowed in the first trial, progression automatically resulted in permanent treatment discontinuation as of protocol rules in the latter [2,9]. Only very recently, Raoul and colleagues [10] reported similar results in a retrospective monocenter study. Their report of an increase in treatment duration from 4.3 months in 2008-2012 vs 5.9 months in 2013-2017 is strikingly similar to our results.…”

“…Our study provides a validation of these initial results through a large multicenter collaboration. DISCUSSION:" In the aforementioned study by Raoul et al [10], the OS was in fact significantly higher in the last five years (12 vs 8 months) in the univariate analysis, but it was not possible to confirm this result also in a multivariate regression. "…”

“…However, the reasons for this phenomenon have not been fully elucidated. A very recent monocentric study [10] suggested that the experience in managing sorafenib AEs has improved overtime, but rigorous multicentric studies taking into account also timedependent variables, addressing the possible confounding factor of second-line treatments, and providing a confirmation of the survival benefit through multivariable regressions models are still lacking.…”

“…We further quoted this paper in the Introduction. This paper is now being referenced in the following sentences INTRODUCTION: "A very recent monocentric study [10] suggested that the experience in managing sorafenib AEs has improved overtime, but rigorous multicentric studies taking into account also time-dependent variables, addressing the possible confounding factor of second-line treatments, and providing a confirmation of the survival benefit through multivariable regressions models are still lacking" DISCUSSION: "Only very recently, Raoul and colleagues [10] reported similar results in a retrospective monocenter study. Their report of an increase in treatment duration from 4.3 months in 2008-2012 vs 5.9 months in 2013-2017 is strikingly similar to our results.…”