1. Introduction
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths globally [
1]. For patients with advanced-stage HCC, systemic chemotherapy using molecular targeted agents (MTA) has been the recommended standard treatment [
2,
3]. Sorafenib was approved in 2007 as the first MTA that demonstrated a significant survival benefit in patients with unresectable HCC based on the two Phase III studies [
4,
5]. However, due to its various adverse events (AEs) and limited efficacy, identification of novel MTA compounds has been required. Recently, lenvatinib (Lenvima
®, Eisai Co., Ltd., Tokyo, Japan) was approved as a novel first-line MTA for unresectable HCC in the EU, USA, and Asia, including Japan, China, Korea, and Taiwan, based on the Phase III REFLECT trial [
6].
In order to optimize and maximize the therapeutic effects of pharmacotherapy, especially in the case of anticancer drug treatment, it is essential to appropriately evaluate the patient’s condition before administration, sufficiently manage AEs after initiation, and keep the dose intensity (DI) high. The practicality of relative dose intensity (RDI), calculated as the percentage of the delivered DI divided by the standard DI, has been shown to be an indicator of the treatment intensity of anticancer drugs [
7]. The correlations between RDI and therapeutic efficacy were reported in various types of cancers, including breast cancer [
8], pancreatic ductal adenocarcinoma [
9], renal cell carcinoma [
10], malignant lymphoma [
11], and HCC [
12]. However, since lenvatinib is the first oral MTA that is dosed by the patient’s weight (8 mg once a day for patients weighing <60 kg or 12 mg once a day for those weighing ≥60 kg), RDI may not accurately reflect the actual treatment intensity, as is demonstrated in the following examples.
Case 1: A 170 cm tall patient weighing 60 kg. He started lenvatinib at 12 mg once a day and continued to take 12 mg once a day for the first 20 days. In the next 40 days, lenvatinib was reduced to 8 mg once a day due to AEs.
Case 2: A 170 cm tall patient of 59 kg. He started lenvatinib at 8 mg once a day and continued with 8 mg for 60 days.
Cases 1 and 2 are patients of almost the same weight, and Case 1 was administered with a higher delivered DI compared to Case 2. However, there is a contradiction in the 2M-RDI between Cases 1 and 2. On the other hand, when the delivered DI/body surface area (BSA) ratio at 60 days (2M-DBR) after lenvatinib induction is calculated in the same examples, then:
Therefore, we hypothesized that 2M-DBR might reflect treatment intensity of lenvatinib more accurately than 2M-RDI. This study aimed to evaluate the utility of 2M-DBR by comparing the relationship between 2M-DBR or 2M-RDI and the therapeutic efficacy. We also investigated the clinical factors and biomarkers that were associated with 2M-DBR.
3. Discussion
Lenvatinib was recently approved as a novel first-line tyrosine kinase inhibitor for unresectable HCC based on the Phase III REFLECT trial [
3,
6]. The Phase II study performed before the REFLECT trial revealed positive outcomes with an overall survival (OS) of 18.7 months, ORR of 37%, and DCR of 78% [
13]. The dosage of lenvatinib in the Phase II study was set to 12 mg once a day until the disease progression or the unacceptable toxicity was evident based on the results of the Phase I dose-escalation study in 20 patients [
14,
15]. In the Phase II study, however, many patients required dose reduction (74%) or drug discontinuation (22%) due to AEs. Therefore, based on these results and pharmacokinetic analysis, the Phase III REFLECT trial proceeded with a planned dose of 8 mg once a day in patients weighing <60 kg and 12 mg once a day in those weighing ≥60 kg [
15]. As a result, lenvatinib met its primary endpoint by demonstrating a prolonged effect on OS as confirmed by non-inferiority to sorafenib, and led to a statistically significant improvement for all secondary efficacy endpoints, including PFS, time to progression, and ORR [
6]. Dose reductions and drug discontinuations due to AEs were needed for 37% and 9%, respectively, which decreased compared with those in the Phase II study.
It is well accepted that RDI is a useful indicator for evaluating the feasibility of pharmacotherapy, especially anticancer drug treatment [
7]. The importance of RDI has also been reported in molecular targeted therapy for HCC [
12,
16]. Wang et al. investigated the significance of RDI for the first month (1M-RDI) of regorafenib in patients with HCC, which reported that patients with 1M-RDI ≥50% showed significantly longer OS and PFS than patients with 1M-RDI <50% [
12]. The standard dose of regorafenib for HCC is 160 mg orally once a day, regardless of body weight [
17]. On the other hand, as mentioned earlier, the standard dose of lenvatinib is normally determined by the patient’s weight; therefore, in order to accurately reflect the treatment intensity, another index is required besides the RDI.
In the present study, we demonstrated for the first time that 2M-DBR could reflect the treatment intensity of lenvatinib against HCC more accurately than 2M-RDI. The AUROC of 2M-DBR in predicting the objective response to lenvatinib on CECT at 8–12 weeks after starting treatment was higher than that of 2M-RDI (0.8004 vs. 0.7778). Patients with high 2M-DBR levels achieved significantly better ORR and DCR than those with low 2M-DBR (p < 0.0001 and p = 0.0008). Furthermore, patients with high 2M-DBR experienced significantly longer PFS than those with low 2M-DBR (log-rank test, p < 0.0001), while there was no significant correlation between 2M-RDI levels and PFS. Patients who achieved high 2M-DBR levels had a significantly higher BSA (p = 0.0309), a better baseline liver function (mALBI grade (p = 0.0437)), and a better nutritional status (CONUT score (p = 0.0281) and BTR (p = 0.0222)). In univariate analyses, the baseline BTR level and high 2M-DBR were correlated with longer PFS. Multivariate analysis revealed that high 2M-DBR was the only significant factor associated with longer PFS (p = 0.0127). Taken together, 2M-DBR is an important factor in reflecting treatment intensity and predicting the response to lenvatinib, where the pretreatment liver function and nutritional status are essential for achieving high 2M-DBR levels. Using 2M-DBR will help to develop an appropriate lenvatinib treatment strategy tailored to the patient. From this study, it was shown that lenvatinib achieves a high probability of objective response (CR or PR) and longer PFS if 2M-DBR was 238.9 or higher. Therefore, by calculating the target dose of 60 days (2M-DBR ≥ 238.9) for each patient before the treatment starts, it becomes possible to establish a treatment strategy that balances treatment effects and AE management through an appropriate dosage adjustment after treatment starts.
Hiraoka et al. previously reported that the mALBI grade was the only significant prognostic factor in HCC patients treated with lenvatinib [
18]. Ueshima et al. also recently published the data of 82 HCC patients, which demonstrated that patients with an mALBI grade of 1 had the lowest probability of treatment discontinuation due to AEs (
p < 0.01) [
19]. They also showed that an mALBI grade of 1 was a significant predictor of a high ORR (
p < 0.05) [
19]. In agreement with these reports, we confirmed that the baseline mALBI grade was essential for obtaining high 2M-DBR levels. Interestingly, we also identified, for the first time, that the pretreatment nutritional status, which was measured by the CONUT score and BTR, was essential for achieving high 2M-DBR. The utility of the CONUT score in predicting the patient’s prognosis treated with chemotherapy was reported in various types of gastrointestinal cancers [
20,
21,
22]. Although there was no significant correlation between the CONUT score and PFS in lenvatinib treatment in our study (
p = 0.1505), it may be worth reconsidering in a more extensive cohort study. The impact of BTR as a prognostic factor in patients with HCC or liver cirrhosis was well documented [
23,
24,
25]. Tada et al. recently reported that BCAA therapy improved both OS and disease-specific survival in HCC patients with low BTR levels [
25]. Further studies with the prospective design are required to clarify the utility of BCAA therapy during treatment with lenvatinib.
Our findings provide important clinical implications for the feasibility of 2M-DBR in assessing treatment intensity and predicting the response to lenvatinib against HCC. However, our study has some limitations. First, our study had a retrospective and single-center design with a limited sample size. Therefore, the possibility of selection bias cannot be denied. Second, we could not evaluate whether 2M-DBR has an impact on OS due to the limited sample size and relatively short observation period. Additionally, the optimal cut-off value and the setting period of DBR should be investigated in a large cohort study. Thus, in interpreting our findings, caution should be exercised. Further studies are desired to validate our observations and investigate the relationship between 2M-DBR and the therapeutic efficacy of lenvatinib, including ORR, DCR, PFS, and OS.