title: Inducing tolerability of adverse events increases sorafenib exposure and optimizes patient's outcome in advanced hepatocellular carcinoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  In patients with advanced hepatocellular carcinoma, sorafenib dose adjustments based on inducing tolerability of relevant adverse events prolong drug exposure and maximize survival.
authors.affiliation: Surgery, Hepatology and Hepato-Oncology Group, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Ponziani
authors.affiliation: Surgery, Hepatology and Hepato-Oncology Group, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Sherrie
authors.initials: S
authors.lastname: Bhoori
authors.affiliation: Surgery, Hepatology and Hepato-Oncology Group, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Germini
authors.affiliation: Surgery, Hepatology and Hepato-Oncology Group, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bongini
authors.affiliation: Surgery, Hepatology and Hepato-Oncology Group, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Flores
authors.affiliation: Surgery, Hepatology and Hepato-Oncology Group, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sposito
authors.affiliation: Surgery, Hepatology and Hepato-Oncology Group, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Facciorusso
authors.affiliation: Internal Medicine and Gastroenterology, Catholic University, Gemelli Hospital, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gasbarrini
authors.affiliation: Surgery, Hepatology and Hepato-Oncology Group, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007558:Italy; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D000077157:Sorafenib; D013997:Time Factors; D028761:Withholding Treatment; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: adverse events; hepatocellular carcinoma; sorafenib; tolerable adverse event protocol; toxicity; tumour response