Inducing tolerability of adverse events increases sorafenib exposure and optimizes patient's outcome in advanced hepatocellular carcinoma. (20th January 2016) - Ponziani, Francesca Romana
Abstract: Background & Aims: Various grades of adverse events are associated with sorafenib and have recently been considered as a surrogate of response in patients with advanced hepatocellular carcinoma. The aim of this prospective study was to measure the efficacy of a sorafenib dose reduction regimen, adjusted on patient's tolerability, and aimed at increasing the exposure to the drug. Methods: A total of 73/140 patients with advanced hepatocellular carcinoma receiving sorafenib developed relevant adverse events (grade ≥2) and were managed with a tolerable‐adverse‐event‐protocol consisting of a drug stepwise dose reduction adjusted on patient's tolerability. The remaining 67 patients with toxicity grade 0–1 (minor adverse event group) were managed conventionally with just symptomatic treatment. Results: Median follow‐up was 7 months. By adopting the tolerable‐adverse‐event‐protocol, 48% of patients meant to transiently or definitively interrupt the drug were kept on treatment. Macrovascular invasion with/out extra‐hepatic spread (HR = 1.9, 95% CI: 1.3–2.8; P = 0.001) and sorafenib exposure <2 months (HR = 4, 95% CI: 2.5–6.4; P < 0.0001) were independently related to a worse survival. Overall disease control rate, time to progression and survival were: 63.5%, 6 and 9.1 months respectively. The tolerable‐adverse‐event‐protocol group experienced a more favourable outcome with respect to the minor adverse event group as for disease control rate (78% vs. 48%: P < 0.0001), time to progression (9.5 vs. 3 months; HR = 0.3, 95% CI: 0.2–0.5, P < 0.0001) and survival (12.5 vs. 5.7 months; HR = 0.4, 95% CI: 0.3–0.6; P < 0.0001). Conclusions: In patients with advanced hepatocellular carcinoma, sorafenib dose adjustments based on inducing tolerability of relevant adverse events prolong drug exposure and maximize survival.