Impact of Relative Dose Intensity of Early-phase Lenvatinib Treatment on Therapeutic Response in Hepatocellular Carcinoma

Takahashi, Aya; Moriguchi, Michihisa; Seko, Yuya; Ishikawa, Hiroki; Takaharu, Yo; Kimura, Hiroyuki; Fujii, Hideki; Shima, Toshihide; Mitsumoto, Yasuhide; Ishiba, Hiroshi; Takashima, Hidetaka; Nagao, Yasuyuki; Jo, Masayasu; Arai, Masahiro; Hara, Tasuku; Okajima, Akira; Muramatsu, Akira; Morita, Atsuhiro; Yoshinami, Naomi; Nakajima, Tomoki; Mitsuyoshi, Hironori; Umemura, Atsushi; Nishikawa, Taichiro; Yamaguchi, Kanji; Itoh, Yoshito

doi:10.21873/anticanres.13710

Cited by 57 publications

(71 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RDI was found to be significantly related to complete or partial response. Recently, the therapeutic effects of LEN at particular dosages have been reported [23,24]. Those works concluded that achieving a sufficient RDI was crucial to therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of Adverse Events on the Progression-Free Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study

Ohki

Sato

Kondo

et al. 2020

Drugs - Real World Outcomes

View full text Add to dashboard Cite

Background and Objective Experience of the use of lenvatinib (LEN) in the clinical setting remains limited. We conducted this study to elucidate the factors associated with progression-free survival (PFS) in patients with advanced HCC treated with LEN. Methods In this multicenter retrospective study, we analyzed data on patient characteristics, treatment outcomes, and adverse events (AEs) for 77 patients with advanced hepatocellular carcinoma (HCC). We also analyzed PFS and factors that influence PFS. Results The response rate to LEN was 29.9% and the disease control rate was 77.9%. Patients who achieved relative dose intensities of more than 70% had better outcomes (response rate 45.2% vs. 11.4%, P < 0.01). Appetite loss, fatigue, diarrhea, hypertension, and thyroid dysfunction were the most frequent AEs. Twenty-three patients (29.9%) had grade 3 or 4 AEs. Fifty-two patients (67.5%) required a dose reduction and 47 (61.0%) stopped taking the drug due to AEs. The PFS rates at 3, 6, and 12 months were 81.2%, 49.8%, and 34.8%, respectively. The median PFS was 5.6 months. Multivariate analysis showed that thyroid dysfunction of grade ≥ 2 (hazard ratio [HR] 4.57, 95% confidence interval [CI] 2.05-10.2, P < 0.01), appetite loss (HR 3.58, 95% CI 1.72-7.52, P < 0.01), and tumor diameter ≥ 40 mm (HR: 2.27, 95% CI 1.17-4.40, P = 0.015) were independent factors associated with poor PFS. On the other hand, Child-Pugh class 5A (HR 0.41, 95% CI 0.19-0.90, P = 0.027) and complete or partial response (HR 0.40, 95% CI 0.17-0.95, P = 0.039) were independent factors associated with better PFS. Conclusions Thyroid dysfunction and appetite loss after the administration of LEN were independent factors associated with shorter PFS, so these AEs should be carefully managed after administering LEN. Key PointsSince being introduced recently, lenvatinib (LEN) has been used for unresectable advanced hepatocellular carcinoma (HCC) in the clinical setting.We found that thyroid dysfunction and appetite loss after the administration of LEN were independent factors associated with shorter progression-free survival.Relative dose intensity (RDI) was also found to be an important influence on the effect of LEN.

show abstract

Section: Discussionmentioning

confidence: 99%

“…If an AE occurred, the dose was reduced or the treatment was temporarily interrupted until the symptoms improved to grade 1 or 2, based on the guidelines from Eisai Co., Ltd. The relative dose intensity (RDI) was calculated by dividing the actual dose by the ideal dose for the first 30 days of treatment [23,24].…”

Section: Protocolmentioning

confidence: 99%

Impact of Adverse Events on the Progression-Free Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study

Ohki

Sato

Kondo

et al. 2020

Drugs - Real World Outcomes

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Discussionmentioning

confidence: 99%

Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma

Eso

Nakano

Mishima

et al. 2019

Cancers

View full text Add to dashboard Cite

Lenvatinib was recently approved as a novel first-line molecular targeted agent (MTA) for treating hepatocellular carcinoma (HCC). The importance of relative dose intensity (RDI) has been shown in the treatment of various types of cancers. However, RDI may not accurately reflect the treatment intensity of lenvatinib, as it is the first oral MTA where the dose is based on the patient's weight. We aimed to evaluate the utility of 2M-DBR (the delivered dose intensity/body surface area ratio at 60 days) by comparing the relationship between 2M-DBR, 2M-RDI (RDI at 60 days), and the therapeutic response. The therapeutic response to lenvatinib was evaluated in 45 patients who underwent computed tomography 8-12 weeks after treatment initiation. We also investigated the clinical factors associated with high 2M-DBR. The area under the receiver operating characteristic of 2M-DBR that predicts the response to lenvatinib was higher than that of 2M-RDI (0.8004 vs. 0.7778). Patients with high 2M-DBR achieved significantly better objective responses and disease control rates than those with low 2M-DBR (p < 0.0001 and 0.0008). Patients with high 2M-DBR experienced significantly longer progression-free survival (PFS) than those with low 2M-DBR (p = 0.0001), while there was no significant correlation between 2M-RDI levels and PFS (p = 0.2198). Patients who achieved higher levels of 2M-DBR had a significantly better modified ALBI grade (p = 0.0437), better CONUT score (p = 0.0222), and higher BTR (p = 0.0281). Multivariate analysis revealed that high 2M-DBR was the only significant factor associated with longer PFS. In conclusion, 2M-DBR could be an important factor that reflects treatment intensity and useful for predicting the response to lenvatinib against HCC, instead of 2M-RDI.Cancers 2020, 12, 49 2 of 12 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...

show abstract

“…Recently, a post-hoc analysis of the REFLECT trial reported that the objective response based on the mRECIST was an independent predictor of OS [14]. In addition, we previously reported that 95.5% of responders achieved an objective response at the first evaluation after LEN initiation [15]. Therefore, we hypothesized that ETS may also reflect the treatment outcome of patients with HCC.…”

Section: Introductionmentioning

confidence: 95%

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

Takahashi

Moriguchi

Seko

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions’ longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child–Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.

show abstract

Impact of Relative Dose Intensity of Early-phase Lenvatinib Treatment on Therapeutic Response in Hepatocellular Carcinoma

Cited by 57 publications

References 27 publications

Impact of Adverse Events on the Progression-Free Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study

Impact of Adverse Events on the Progression-Free Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study

Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

Contact Info

Product

Resources

About