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

Abstract

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.

Hypothyroidism Is a Predictive Factor for Better Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Undergoing Lenvatinib Therapy

“…The association of lenvatinib-induced hypothyroidism with clinical outcomes is controversial. Koizumi et al reported similar results [ 21 ] to ours, whereas Ohki et al, related this AE to poor survival [ 20 ]. Several studies analyzed the impact of therapy-induced hypothyroidism on prognosis.…”

“…However, information on the association of AE occurrence with prognosis in lenvatinib therapy for HCC is limited. Ohki et al reported that lenvatinib-induced hypothyroidism of Grade ≥2 was an independent predictor of poorer PFS [ 20 ], whereas Koizumi et al, found that thyroid dysfunction was associated with better PFS [ 21 ]. Therefore, the impact of thyroid-related AE on prognosis is controversial.…”

Lenvatinib for Hepatocellular Carcinoma: A Literature Review

“…Many real-world studies have reported the short-term therapeutic response of lenvatinib, resulting in an ORR of 29.9-53.5%, as assessed by mRECIST [17][18][19][20][21][22][23][24], and 14-25%, as assessed by RECIST ver.1.1 [19,22,25,26]. These findings seemed to be in agreement with the results of phase 2 and 3 studies (Table 1).…”

“…We reported that BCLC intermediate stage was a significant predictive factor that was associated with the ORR in a multivariate analysis [18], which agreed with the results regarding the ORRs in the analysis of a Japanese subpopulation in the REFLECT trial [27]. A high ORR was found in patients with a good PS [21], Child-Pugh class A [21], and Child-Pugh score 5 (CP-5A) [23]. Some of the researchers also reported that the high relative dose intensity (RDI) at four weeks (30 days) [23,28,29] or eight weeks (60 days) [19,21,30,31] was relevant to therapeutic response of lenvatinib, including the PFS and OS ( Table 2).…”

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

“…Another study reported that approximately 30% of patients had grade 3 or 4 AEs while undergoing treatment with LEN. They additionally reported that thyroid dysfunction and appetite loss during the administration of LEN were independent factors associated with shorter progression-free survival (PFS) [20]. We therefore considered that DLSAE was associated with poor prognosis in patients with HCC treated by LEN.…”