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Patient profiles suitable for long-term lenvatinib treatment for unresectable hepatocellular carcinoma (uHCC) are yet to be fully understood. This post-hoc analysis aimed to identify such patient characteristics and explore the impact of treatment duration and relative dose intensity (RDI) on treatment outcomes. The data were obtained from 703 patients in a multicenter, prospective cohort study in Japan. Lenvatinib-naïve patients with uHCC were enrolled between July 2018 and January 2019 and were followed up for 12 months. Moreover, patients were dichotomized using the median treatment duration into the longer- (≥177 days; n = 352) or shorter-treatment (<177 days; n = 351) groups. The longer-treatment group often had better performance status, lower Child-Pugh score and better modified albumin-bilirubin grade than the shorter treatment group (p<0.05 for all). The objective response rate (47.6% vs. 28.2%; p<0.001) and disease control rate (92.4% vs. 60.2%; p<0.001) were both significantly higher in the longer-treatment groups than in the shorter-treatment groups. The proportion of patients with any adverse drug reactions was generally similar between the two treatment groups. Within the longer-treatment group, the disease control rate was high regardless of dose modification (i.e., RDI <100% vs. ≥100% during the initial 177 days) (91.2% vs. 98.0%). In conclusion, patients with longer treatment tended to have better overall conditions. Lenvatinib dose modifications at the physician's discretion, considering the balance between effectiveness and safety, may contribute to the long-term treatment., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Tatsuya Yamashita has received travel grants and honoraria for speaking or participation at meetings from Chugai Pharma, Eli Lilly Japan, and Eisai. Natsumi Suzuki, Katsuaki Motoyoshi, and Wanjun Zhu are employees of Eisai Co., Ltd. Junji Furuse received research grants from Astellas, Astra Zeneca, Incyte Biosciences Japan, Eisai, MSD, Ono Pharmaceutical, Sanofi, J-Pharma, Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, Delta-Fly-Pharma, Chugai Pharma. He has received travel grants and honoraria for speaking or participation at meetings from Ono Pharmaceutical, Chugai Pharma, Incyte Biosciences Japan, Eisai, Eli Lilly Japan, Astra Zeneca, Yakult Honsha, Servier Japan, MSD, Novartis Pharma, Takeda, Bayer, Taiho Pharmaceutical, EA Pharma, Teijin pharma, Daiichi Sankyo, Terumo, Fuji film, Astellas, Onco Therapy Science, Delta-Fly-Pharma, Merck Bio, Incyte Biosciences Japan, J-Pharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Yamashita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Lenvatinib was approved for use in unresectable hepatocellular carcinoma (uHCC) in Japan in 2018. Patients with diverse clinical characteristics receive lenvatinib treatment in clinical practice. Thus, it is crucial to evaluate the safety and effectiveness of lenvatinib in real-world clinical settings., Objective: This study aimed to evaluate the real-world safety and effectiveness of lenvatinib for uHCC in clinical practice in Japan., Patients and Methods: Between July 2018 and January 2019, patients with uHCC who were administered lenvatinib for the first time were enrolled in this prospective, multicenter, observational post-marketing study (NCT03663114). Patients were orally administered lenvatinib and followed up for 12 months. For safety, adverse drug reactions (ADRs) were evaluated. For effectiveness, the objective response rate (ORR) was calculated to evaluate tumor response. Overall survival (OS) was estimated using the Kaplan-Meier method., Results: Data of 703 patients (median age, 73 years; 80.2% males) were analyzed. The median (range) treatment duration was 25.3 (0.3-68.9) weeks. The mean ± standard deviation initial dose was 7.37 ± 1.65 mg in patients with body weight < 60 kg and 10.43 ± 2.49 mg in those with body weight ≥ 60 kg. ADRs (any grade) were reported in 84.9% of the patients, with Grade ≥ 3 ADRs reported in 42.5% of the patients. The most common ADRs (> 10%) were decreased appetite, fatigue, hypertension, proteinuria, palmar-plantar erythrodysesthesia, hypothyroidism, and diarrhea. The median OS of the 703 patients was 498.0 days. In 494 patients assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the ORR was 39.5% (95% confidence interval: 35.1-43.9%). Patients with better liver or renal function at baseline achieved significantly higher ORR than those with worse liver or renal function., Conclusions: In patients with uHCC in real-world clinical practice in Japan, treatment with lenvatinib was generally well tolerated, and no new safety concerns were identified. The ORR and median OS were similar to or better than the results of the Japanese subset of the global Phase III REFLECT trial. Our results demonstrated that clinically meaningful treatment responses were achieved with lenvatinib in real-world clinical practice., (© 2023. The Author(s).)

Objective: Edoxaban is sometimes given at reduced doses when used concomitantly with physical prophylaxis to prevent symptomatic venous thromboembolism (VTE) after total hip arthroplasty (THA). This study aimed to evaluate the safety of reduced doses of edoxaban administered independent of the dose-reduction criteria and their effects on D-dimer levels after THA in Japanese patients., Materials and Methods: This study enrolled 22 patients who received edoxaban 30 mg/day and 45 patients who received edoxaban 15 mg/day with dose adjustment as a standard-dose group, and 110 patients who received edoxaban 15 mg/day without dose adjustment as a low-dose group. The incidence of bleeding events was then compared between groups with patients wearing elastic stockings. Multivariate regression analysis was also performed to examine the effect of edoxaban administration on D-dimer levels after THA., Results: The incidence of bleeding events after THA did not differ significantly between groups. In the multivariate model, dose reduction of edoxaban did not correlate with D-dimer levels on postoperative days 7 and 14, but higher D-dimer levels at postoperative days 7 and 14 correlated significantly with longer duration of surgery (odds ratio (OR) 1.66, 95% confidence interval (CI) 1.20 - 2.29, p = 0.002; OR 1.63, 95% CI 1.17 - 2.29, p = 0.004, respectively)., Conclusion: These results suggest that information on the duration of surgery may be useful in the pharmaceutical management in edoxaban drug prophylaxis combined with physical prophylaxis after THA in Japanese patients.