PMID- 31449860 OWN - NLM STAT- MEDLINE DCOM- 20210319 LR - 20210319 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 71 IP - 6 DP - 2019 Dec TI - Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients. PG - 1175-1183 LID - S0168-8278(19)30482-9 [pii] LID - 10.1016/j.jhep.2019.08.015 [doi] AB - BACKGROUND & AIMS: Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. It is unknown how physicians' experience has impacted on the management of these AEs and consequently on clinical outcomes. We aimed to assess whether AE 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 3 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. Multivariate time-dependent Cox regression analysis confirmed later period of treatment (2013-2017) 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 has been the standard frontline systemic treatment for hepatocellular carcinoma for over a decade. Its tolerability is limited by different adverse events, which might lead to its permanent discontinuation in a 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 over time, with longer treatment periods and less permanent discontinuation for toxicities. More importantly, these improvements also translated into longer patient survival. Our results have relevant repercussions in clinical practice and in the design of future clinical trials. CI - Copyright (c) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Tovoli, Francesco AU - Tovoli F AD - Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. Electronic address: francesco.tovoli2@unibo.it. FAU - Ielasi, Luca AU - Ielasi L AD - Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. FAU - Casadei-Gardini, Andrea AU - Casadei-Gardini A AD - Department of Medical Oncology, Istituto Scientifico Romagnolo per Lo Studio e Cura Dei Tumori, Meldola, Italy; Department of Oncology and Haematology, University Hospital of Modena, Modena, Italy. FAU - Granito, Alessandro AU - Granito A AD - Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. FAU - Foschi, Francesco Giuseppe AU - Foschi FG AD - Department of Internal Medicine, Degli Infermi Hospital, Faenza, Italy. FAU - Rovesti, Giulia AU - Rovesti G AD - Department of Oncology and Haematology, University Hospital of Modena, Modena, Italy. FAU - Negrini, Giulia AU - Negrini G AD - Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. FAU - Orsi, Giulia AU - Orsi G AD - Department of Oncology and Haematology, University Hospital of Modena, Modena, Italy. FAU - Renzulli, Matteo AU - Renzulli M AD - Unit of Radiology, Department of Diagnostic Medicine and Prevention, Sant'Orsola Hospital, University of Bologna, Bologna, Italy. FAU - Piscaglia, Fabio AU - Piscaglia F AD - Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. LA - eng PT - Journal Article DEP - 20190823 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Antineoplastic Agents) RN - 9ZOQ3TZI87 (Sorafenib) SB - IM MH - Antineoplastic Agents/administration & dosage/adverse effects MH - *Carcinoma, Hepatocellular/drug therapy/mortality/pathology MH - Dose-Response Relationship, Drug MH - *Drug-Related Side Effects and Adverse Reactions/etiology/prevention & control MH - Duration of Therapy MH - Female MH - Humans MH - Italy/epidemiology MH - Learning Curve MH - *Liver Neoplasms/drug therapy/mortality/pathology MH - Male MH - *Medication Therapy Management/statistics & numerical data/trends MH - Middle Aged MH - No-Observed-Adverse-Effect Level MH - Off-Label Use MH - Practice Patterns, Physicians' MH - *Sorafenib/administration & dosage/adverse effects MH - Survival Analysis OTO - NOTNLM OT - Adverse events OT - Hepatocellular carcinoma OT - Learning curve OT - Outcome OT - Prognosis OT - Sorafenib EDAT- 2019/08/27 06:00 MHDA- 2021/03/20 06:00 CRDT- 2019/08/27 06:00 PHST- 2019/04/24 00:00 [received] PHST- 2019/07/10 00:00 [revised] PHST- 2019/08/02 00:00 [accepted] PHST- 2019/08/27 06:00 [pubmed] PHST- 2021/03/20 06:00 [medline] PHST- 2019/08/27 06:00 [entrez] AID - S0168-8278(19)30482-9 [pii] AID - 10.1016/j.jhep.2019.08.015 [doi] PST - ppublish SO - J Hepatol. 2019 Dec;71(6):1175-1183. doi: 10.1016/j.jhep.2019.08.015. Epub 2019 Aug 23.