Multicenter retrospective study of initial treatment outcome and feasibility of initiating dose reduction of cabozantinib in unresectable hepatocellular carcinoma.

AIM: Cabozantinib (CAB), a multiple kinase inhibitor, has been approved for use in patients with previously treated unresectable hepatocellular carcinoma (uHCC). However, real-world clinical data are lacking, particularly clinical data regarding dose modifications of CAB. We analyzed the clinical outcomes of CAB in uHCC and compared treatment outcomes between the full- and reduced-dose groups. METHODS: This multicenter, observational study included patients with uHCC who were treated with CAB from March 2021 to April 2022. Patient characteristics, efficacy, and safety were compared between the full- and reduced-dose groups. RESULTS: Twenty-six patients from eight institutes were analyzed. Cabozantinib was administered as a third-line or later treatment in 25 (96.2%) patients and postimmunotherapy in 21 (80.5%) patients. There were 15 patients in the full-dose group (60 mg CAB) and 11 in the reduced-dose group (40 or 20 mg CAB). The objective response rate (ORR) and disease control rate (DCR) were not significantly different between the two groups. The ORR was 6.7% for the full-dose group and 9.1% for the reduced-dose group, and the DCR was 53.4% and 81.8%, respectively. Progression-free survival analysis showed no significant differences between the two groups. The incidence of decreased appetite, fatigue, and diarrhea, and the rate of discontinuation and dose reduction, was significantly higher in the full-dose group. CONCLUSIONS: Our study suggests that the efficacy and safety of CAB in real-world clinical practice are comparable to those of the phase III trial (CELESTIAL), and that dose reduction of CAB may be a safer treatment option.

Sequential therapy including regorafenib for unresectable hepatocellular carcinoma: Effect of early relative changes in hepatic functional reserve after regorafenib administration on prognosis.

AIM: Regorafenib is a second-line treatment for unresectable hepatocellular carcinoma after sorafenib-refractory treatment. This study examined the effects of regorafenib administration on hepatic functional reserve and the treatment course after regorafenib discontinuation. METHODS: This retrospective, multicenter study involved 51 patients treated with regorafenib after sorafenib-refractory treatment for u-HCC at seven institutions before March 2021. RESULTS: Fourteen, 13, and 24 patients were classified based on modified albumin-bilirubin (mALBI) grade 1, 2a, and 2b, respectively. The median survival time and progression-free survival were 16.7 and 3.3 months, respectively. Only mALBI grade 2b or 3 was significantly associated with survival rate (hazard ratio, 2.13; 95% confidence interval, 1.01-4.49; p = 0.047). A comparison of median ALBI scores at the initiation of regorafenib (-2.35) with those at 4 weeks (-1.93) revealed a significant relative change (p = 0.0001). After 4 weeks, grade 1 or 2a persisted in 15 patients (Group 1); grade 1 or 2a deteriorated to 2b in 12 patients (Group 2); grade 2b or 3 before regorafenib administration was present in 22 patients (Group 3); and MST was 33.3, 12.8, and 11.3 months in the three groups, respectively (p = 0.05). Patients treated with lenvatinib (LEN) (n = 27, MST = 23.4 months) after regorafenib had a significantly longer survival time from regorafenib initiation than those not treated with LEN (n = 24, 11.8 months; p = 0.043). CONCLUSIONS: Hepatic functional reserve significantly declined after regorafenib administration. During regorafenib treatment, favorable hepatic functional reserve before administration and maintenance of favorable hepatic reserve after administration lead to prolonged prognosis.

Comparison of therapeutic outcomes of sorafenib and lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis.

AIM: The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. METHODS: This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). RESULTS: The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p < 0.01; progression-free survival: 10 months [LEN] vs. 5.1 months [SOR], p < 0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival (4.3  vs. 2.8 months, p = 0.0047). Multivariate analysis demonstrated that the CP score (p < 0.01) and alpha-fetoprotein level (p < 0.01) were independent prognostic factors. CONCLUSIONS: Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.

Initial treatment efficacy and safety of durvalumab plus tremelimumab combination therapy in unresectable hepatocellular carcinoma in clinical practice.

Background and Aims: We aimed to evaluate the efficacy and safety of durvalumab plus tremelimumab (Dur + Tre) combination therapy in patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice. Methods: We retrospectively evaluated 37 patients with uHCC from our institutions between April 2023 and January 2024. Patients were divided into first- and later-line groups for analysis of antitumor efficacy, adverse events (AEs), and transition rate to second-line treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST). Results: The disease control rate (DCR) for the first-line group was 80.9%, which was significantly higher than that for the later-line group (50%). The incidence of immune-related AEs (irAEs) was 24.3%, with grade 3 or higher irAEs including increased transaminase (8.1%), diarrhea (8.1%), and adrenal insufficiency (2.7%). The rates of drug withdrawal and discontinuation owing to AEs were 23.8% and 19%, respectively, in the first-line treatment and 31.2% and 12.5%, respectively, in the later-line treatment, with no significant difference. Analysis of changes in liver reserve using the albumin-bilirubin (ALBI) score showed no obvious loss of liver reserve for up to 12 weeks. The transition rate from first- to second-line therapy after progressive disease (PD) was as high as 94.7%. Conclusion: The efficacy and safety of Dur + Tre in clinical practice were comparable to those reported in a recent phase III trial. The first-line Dur + Tre therapy had a higher DCR than that of the later lines, and the transition rate to second-line therapy was considerably high, suggesting that Dur + Tre therapy would be more beneficial in first-line treatment.

Cytological Study of Grade 3 Endometrioid Adenocarcinoma of Endometrial Origin: Cytoarchitecture and Features of Cell Clusters Assessed With Endometrial Brushing Cytology--Focusing on a comparison with endometrioid adenocarcinoma Grade 1, 2.

OBJECTIVES: Aim of study was to clarify the cytological characteristics of grade 3 endometrioid adenocarcinoma of endometrial origin (G3 EA) by endometrial brushing cytology. METHODS: The subjects were 11 patients in whom G3 EA was diagnosed by review of preoperative cytological specimens obtained at our hospital and related institutions between 2000 and 2010. These patients were investigated with respect to the preoperative cytological diagnosis, background changes, cell cluster patterns, and individual cellular findings. Background changes were classified as inflammatory or tumorous, while cell clusters were classified as overlapping cell cluster, sheet-like cell cluster, clump of high dense gland, papillary, or other cell cluster. Cellular findings were investigated by comparing the incidence of squamous and clear cell metaplasia, the nuclear rounding rate, and the nuclear area with the findings in a control group (35 patients with G1-2 EA). RESULTS: Background changes were classified as inflammatory in 63.6% and necrotic in 36.4%. The cell clusters were classified as overlapping cell cluster in 44.8%, cell cluster in 21.7%, clump of high dense gland in 10.0%, papillary in 4.0%, and other cell cluster in 19.5%. The incidence of squamous and clear cell metaplasia was 27.2% and 18.1%, respectively. The mean nuclear rounding rate was 0.97, and the mean nuclear area was 55.98 µm2. CONCLUSION: Investigation of the cytoarchitecture of G3 EA with endometrial brushing cytology revealed overlapping cell cluster and tumor cells of a relatively uniform size. These findings suggest that it is necessary to recognize that there are differences between the cytological findings of G3 EA and the usual features of G1-2 EA.