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

BACKGROUND &AIMS: Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. The impact of the physicians experience on the management of these AEs and the relative implications on clinical outcomes are unknown. We verified if the AEs management changed over time and if these modifications impacted on treatment duration and overall survival (OS).

METHODS: We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in three tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008-2012; n=154), and Group B (2013-2017, n=184). Baseline and follow up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy.

RESULTS: Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs 568 mg/day, p<0.001) due to more frequent dose modifications. However, treatment duration was longer (5.8 vs 4.1 months, p=0.021) with a trend toward a higher cumulative dose in Group B. Notably, the OS was also higher (12.0 vs 11.0 months, p=0.003) with a sharp increase in the 2-year survival rate (28.1 vs 18.4%, p=0.003) in Group B. The multivariate time-dependent Cox regression confirmed later period of treatment as an independent predictor of survival (HR 0.728, 95%CI 0.581-0.937, p=0.013). Unconsidered confounders were unlikely to affect these results at the sensitivity analysis.

CONCLUSIONS: experience in the management of sorafenib-related AEs prolongs treatment duration and survival. This factor should be considered in the design of future randomised clinical trials including a sorafenib treatment arm, as an underestimate of sample size may derive.

LAY SUMMARY: Sorafenib is the standard frontline systemic treatment for hepatocellular carcinoma since over a decade. Its tolerability is limited by different adverse events which might lead to its permanent discontinuation in sizeable proportion of patients. After a careful analysis of potential confounders, we demonstrated that the physicians' experience in managing adverse events related to sorafenib has improved overtime, with longer treatment periods and less permanent discontinuation for toxicities. More importantly, these improvements also translated into a longer survival of the patients. Our results have relevant repercussions in clinical practice and in the design of future clinical trials.