Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events

Abstract

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

Clinical Significance of Adverse Events for Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study

“…Further, according to analyzed PROSASH model, MST in the risk group 1 was significant longer than other the groups (Appendix A: Figure A3). Moreover, previous studies have reported that ALBI grade 2, fatigue grade ≥ 3, and appetite loss ≥ 2 were predictive factors for therapeutic effect or OS in patients treated by MTAs, including LEN [18,[39][40][41]. OS in the group that did not require DLSAE was significantly longer than that of the group that did require DLSAE, indicating that our results were consistent with previous findings [18,37,[39][40][41].…”

“…Moreover, previous studies have reported that ALBI grade 2, fatigue grade ≥ 3, and appetite loss ≥ 2 were predictive factors for therapeutic effect or OS in patients treated by MTAs, including LEN [18,[39][40][41]. OS in the group that did not require DLSAE was significantly longer than that of the group that did require DLSAE, indicating that our results were consistent with previous findings [18,37,[39][40][41]. Furthermore, Yang et al previously reported that discontinuation of anti-VEGF therapy promoted metastasis through a liver revascularization mechanism [19].…”

“…Thus, development of fatigue grade ≥3 is also thought to be a critical AE in LEN treatment. We recently reported a useful protocol for LEN involving a 5 days-on/ 2 days-off administration schedule (the weekends-off protocol) [18]. The weekends-off protocol for LEN significantly contributed to improvements in the therapeutic response and tolerance of AEs induced by LEN, thereby prolonging the administration period of LEN and the OS of patients treated with LEN.…”

“…LEN targets vascular endothelial growth factor (VEGF) receptors 1-3 (VEGFR1-3) and fibroblast growth factor (FGF) receptors 1-4 (FGFR1-4) [ 16 , 17 ], which strongly inhibit tumor angiogenesis. However, recent studies revealed that antiangiogenic drugs, such as LEN, not only inhibited tumor angiogenesis but also inhibited the vascular structure of other healthy organs, such as the thyroid, adrenal grands, and others [ 18 , 19 ].…”

Lenvatinib for Hepatocellular Carcinoma: A Literature Review

“…However, this decreases the efficacy of lenvatinib and possibly causes tumor regrowth. The weekend-off protocol, which was defined as a scheduled protocol with administration for a period of five days on and two days off, was the one of the methods for improving tolerability and sustaining efficacy [41]. Although no medical agents relieving these symptoms have been established, one study showed that lenvatinib-related fatigue was associated with carnitine insufficiency [42].…”