Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis

Alessandro Rizzo; Margherita Nannini; Marco Novelli; Angela Dalia Ricci; Valerio Di Scioscio; Maria Abbondanza Pantaleo

doi:10.1177/1758835920936932

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis

Ther Adv Med Oncol. 2020 Jul 7:12:1758835920936932. doi: 10.1177/1758835920936932. eCollection 2020.

Authors

Alessandro Rizzo¹, Margherita Nannini², Marco Novelli³, Angela Dalia Ricci¹, Valerio Di Scioscio³, Maria Abbondanza Pantaleo¹

Affiliations

¹ Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
² Medical Oncology Unit, Sant'Orsola-Malpighi University Hospital, via Massarenti 9, Bologna, 40138, Italy.
³ Department of Statistical Sciences, University of Bologna, Bologna, Italy.

Abstract

Background: Regorafenib (REG) is an oral multikinase inhibitor used in colorectal cancer, gastrointestinal stromal tumour and hepatocellular carcinoma. Several adverse events (AEs) are commonly reported during REG administration, and strategies for managing AEs in everyday clinical practice include supportive care, dose modifications and, when necessary, treatment withdrawal. We performed a systematic review and meta-analysis to assess the schedule treatment modifications of REG associated with AEs across randomized controlled clinical trials (RCTs).

Methods: Eligible studies included RCTs assessing standard dose REG versus placebo. Outcomes of interest included: AE-related permanent discontinuation, dose interruptions and dose reductions.

Results: We retrieved all the relevant RCTs through PubMed/Med, Cochrane library and EMBASE: 7 eligible studies involving a total of 2099 patients (Regorafenib: 1362; placebo: 737) were included in our analysis. The use of REG was associated with higher incidence and risk of all outcomes of interest when compared with placebo. The incidences of permanent discontinuation, dose interruptions and dose reductions in patients receiving REG were 9.7%, 57.2% and 47%, respectively, versus 3.3%, 16.7% and 7.7% of placebo group; compared with placebo, the summary relative risks (RRs) of permanent discontinuation, dose interruptions and dose reductions in REG arm were 2.80 (95% CI 1.85-4.22), 3.21 (95% CI 2.59-3.99) and 6.02 (95% CI 3.28-11.03), respectively.

Conclusions: Treatment with REG at the standard dose of 160 mg is associated with a significant increase in AE-related permanent discontinuation, dose interruptions and dose reductions. Prompt identification and management of AEs seem mandatory to obtain maximal benefit from REG treatment. In the current landscape, dose personalization of REG may have the potential to improve quality of life, minimize treatment discontinuation and maximize patient outcomes.

Keywords: GIST; colorectal cancer; gastrointestinal stromal tumours; meta-analysis; regorafenib.