Introduction
Lenvatinib (LEN) is a multitarget tyrosine kinase inhibitor that can target vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, rearranged during transfection (RET), and stem cell factor receptor (KIT). Moreover, LEN also inhibits the formation of vessel-like luminal structures of vascular endothelial cells induced by VEGF and FGF. The recommended dose of LEN is usually 12 mg/day for those weighing ≥60 kg and 8 mg/day for those weighing <60 kg, administered orally once a day.
LEN is a standard therapeutic agent for hepatocellular carcinoma, but the high incidence of adverse events (AEs) is a problematic aspect of LEN treatment (1–4), since these AEs may necessitate treatment discontinuation. Rash and diarrhea are common side effects of tyrosine kinase inhibitor (TKI) therapy administered to patients with non-small cell lung cancer (5). The most common any-grade AEs of LEN are hypertension (42%), diarrhoea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%) (2). Iwamoto reported that the incidence rates of any grade and grade ≥3 AEs were 82.1 and 49.6%. Fatigue is the most important AE because it can result in dose reduction and discontinuation (4).
Although the LEN dose can be tapered in cases with severe AEs, the lowest dose is 4 mg/day. Therefore, in clinical practice, if the dose is to be further reduced for treatment continuation, modified administration methods such as taking the drug for 5 days with 2-day intervals (weekends off) may have to be applied. Iwamoto et al reported the tolerability and therapeutic effects of weekends off administration (4), and in their study, of the 30 patients who received weekends off LEN, 66.7% had tolerable AEs. Thus, weekends off administration significantly prolongs the administration period and survival (4). In actual clinical practice, other modified administration methods such as administration every other day may also be performed depending on the patient's condition. However, the benefit of administration every other day has not been reported. Therefore, analyses of LEN dosage and reasons for discontinuation due to AEs and clarifying the usefulness of these administration methods will facilitate AE management in the future.
The purpose of this study is to clarify the therapeutic efficacy and tolerability of LEN administered with a modified dosing method such as alternate day dosing due to AEs.
Discussion
This study clarified the therapeutic effects and tolerability of AEs with modified LEN administration methods such as alternate day administration. Modification of the administration method ensured fewer AE-related treatment discontinuations. However, weekends off dosing showed in a longer treatment duration than standard dosing, whereas alternate day dosing showed no difference from standard dosing.
In the REFLECT study, fatigue and anorexia frequently occurred from the beginning of administration (2). Among AEs leading to discontinuation of LEN, Iwamoto et al reported that fatigue was the most important because it led to dose reduction and discontinuation (4). Moreover, Katsuragawa et al reported that in patients taking LEN for hepatocellular carcinoma, fatigue and anorexia are often responsible for discontinuation of administration (9). Similar to these reports, the present study showed that fatigue and anorexia were the most common AEs that led to discontinuation. The number of discontinuations due to AEs in the modified LEN group was lower (1 of 18) than that in the standard LEN group (16 of 48), suggesting that AE-related discontinuations can be prevented by devising an appropriate administration method. Modified LEN had more discontinuations due to PD than standard LEN. This may be caused by the increased PD discontinuations due to reduced discontinuations because of the side effects with modified LEN.
In our analyses of the AEs leading to treatment discontinuation and the doses at the time of discontinuation, one patient in the modified LEN group discontinued treatment due to AEs despite receiving 4 mg every other day. In contrast, 10 of the 16 patients (62.5%) in the standard LEN group who discontinued treatment due to AEs were administered 4 mg/day. Thus, in the standard LEN group, if treatment continuation was difficult due to AEs at a dose of 4 mg/day, treatment could be continued by modifying the dosing method, e.g., by administering 4 mg every other day. In the standard LEN group, the remaining six of the 16 patients (37.5%) who discontinued treatment due to LEN were receiving treatment at 8 mg or 12 mg. Thus, it is conceivable that treatment could be continued by further dose reduction or drug interruption. This finding highlights the importance of AE management, including prompt dose reduction and changes in the administration method. However, in terms of treatment duration, alternate day dosing resulted in fewer treatment withdrawals due to AEs than standard dosing, but the treatment duration remained the same. However, weekends off dosing resulted in a significantly longer treatment duration than standard dosing, indicating that alternate day administration was insufficient in terms of efficacy. Iwamoto et al reported that the weekend administration method significantly extends the administration period and survival rate (4).
In our assessments of the RDI of LEN during the treatment period, the RDI in the alternate day dosing group was lower than that in standard administration group. However, no difference in RDI was observed between standard dosing and weekends off dosing. To derive the optimal therapeutic benefit of LEN in anticancer drug therapy, adequately manage of AEs during LEN therapy and maintain RDI is important (10). In addition, a higher RDI is associated with better overall survival and progression-free survival as factors affecting the continuation of LEN treatment (11–14). In this study, there was no difference in treatment duration between alternate-day administration and standard administration, suggesting that the RDI results indicate that the therapeutic effect is low if the RDI is below a certain level. Based on these findings, we consider that if the RDI is too low, the treatment duration cannot be prolonged. However, for sorafenib, a multikinase inhibitor similar to LEN, the presence of HFS or diarrhoea may be relevant factors predicting longer overall survival in patients with advanced hepatocellular carcinoma (15–17). Therefore, early identification and control of these reactions are important for continued sorafenib therapy (15–17). Specifically, we considered that even if the RDI is high, if treatment is discontinued because of AEs, it will lead to a shortened duration of treatment and may affect survival.
To facilitate the management of AEs in patients receiving LEN for liver cancer, we would like to emphasise some aspects of the study: First, the dose of LEN was tapered due to AEs, but the lowest dose was maintained at 4 mg. Therefore, in the clinical setting, patients should be explained that AEs can be tolerated and treatment can be continued by devising a modified dosing method such as weekends off dosing. Second, Ogushi et al reported that Child-Pugh B patients require dose reduction due to grade 2 AEs and show less tolerability to these AEs than Child-Pugh A patients (3). Therefore, special care should be taken in the management of Child-Pugh B patients.
The study limitations included the relatively short observation period, the limited sample, and the retrospective, single-centre nature of the study. Because of the small sample size, this study may not have had sufficient statistical power to yield accurate estimates. In some cases, we were unable to capture information on tumour size, so we were unable to analyse treatment response (PD, stable disease, partial response). Future studies should aim to address this limitation. Moreover, we recommend calculating the effective RDI when determining the administration method. Although overall survival (OS) was not examined in this study, it would be desirable to clarify the relationship between reasons for treatment discontinuation and OS.
In the future, to demonstrate the therapeutic effects of LEN, adequate management of AEs by appropriately modifying the timing and duration of treatment will be an important consideration. Among the management approaches, devising an administration method to prevent treatment discontinuation owing to AEs is considered useful.