Effect of early adverse events resulting in sorafenib dose adjustments on survival outcomes of advanced hepatocellular c
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ORIGINAL ARTICLE
Effect of early adverse events resulting in sorafenib dose adjustments on survival outcomes of advanced hepatocellular carcinoma patients Warit Ruanglertboon1 · Michael J. Sorich1 · Andrew Rowland1 · Ashley M. Hopkins1 Received: 20 January 2020 / Accepted: 1 May 2020 © Japan Society of Clinical Oncology 2020
Abstract Background Sorafenib is a current first-line treatment option for advanced hepatocellular carcinoma (HCC). This study aimed to evaluate the impact of early adverse events (AEs) requiring sorafenib dose adjustment on survival outcomes of patients with advanced HCC. Methods The study was a secondary analysis of the phase III clinical trial NCT00699374. A landmark Cox proportional hazard analysis was used to evaluate the association between early AEs requiring sorafenib dose adjustment with survival outcomes. The primary outcome was overall survival (OS) with progression-free survival (PFS) as secondary. Results AEs requiring sorafenib dose adjustment within the first 28 days of therapy were significantly associated with OS (HR [95% CI]; dose interruption = 0.9 [0.7–1.2]; dose reduction = 0.6 [0.5–0.9]; discontinuation = 1.7 [0.9–3.4]; P = 0.005). No statistically significant association with PFS was identified (P = 0.148). Conclusion Sorafenib dose interruptions and reduction due to AEs did not compromise the survival outcomes of patient with advanced HCC. Patients who required a sorafenib dose reduction were observed to have more favourable OS compared to those who did not experience an AE which required a dose adjustment. Keywords Sorafenib · Adverse events · Dose adjustment · Prediction · Survival · Response
Introduction Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death [1]. Sorafenib, a tyrosine kinase inhibitor (TKI), is the recommended first-line treatment option for advanced/metastatic HCC with demonstrated improvements in overall survival (OS) and progression-free survival (PFS) compared to previous options [2, 3]. Nevertheless, there is still heterogeneity in survival outcomes and adverse outcomes between patients who receive sorafenib therapy [2–4]. Sorafenib is initiated at a dose of 400 mg twice daily for the treatment of advanced HCC [5]. Within clinical trials Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10147-020-01698-7) contains supplementary material, which is available to authorized users.
approximately 40% of patients treated with sorafenib require a dose interruption and 30% require a dose reduction due to adverse events (AEs). Studies indicate that AEs most commonly occur within the first month of sorafenib therapy, with frequent AEs including hand-foot syndrome and diarrhoea [2, 6–8]. Studies have demonstrated that diarrhoea and handfoot syndrome early after sorafenib initiation were associated with improved survival outcomes [9, 10]. However, studies have not investigated the associations between dose adjustments due to sorafenib-induced AEs and survival outcomes.
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