Aim
Lenvatinib (LEN) has recently become available as a first‐line tyrosine‐kinase inhibitor (TKI) for unresectable hepatocellular carcinoma (u‐HCC). In patients who showed intolerability or failure ...in other TKI treatments, alternative treatment options are needed. This retrospective study evaluated the therapeutic potential of LEN in clinical practice.
Methods
We enrolled 57 u‐HCC patients treated with LEN from March to June 2018. Lenvatinib was given orally to patients weighing <60 kg at 8 mg/day and at 12 mg/day to those ≥60 kg. Following the exclusion of patients whose initial LEN dose was reduced, 49 patients were evaluated in regard to their characteristics and early therapeutic response using modified Response Evaluation Criteria in Solid Tumors for findings of follow‐up computed tomography (CT)/magnetic resonance imaging (MRI) examinations at 4 weeks after introducing LEN.
Results
The average patient age was 72.4 ± 9.3 years and 38 (77.6%) were men. The LEN dose was 8 and 12 mg in 32 and 17 patients, respectively. Twenty‐nine (59.2%) had history of treatment with sorafenib and six of them (20.7%) with regorafenib. Of the 49 patients, 27 were evaluated using findings obtained by enhanced CT/MRI at 4 weeks after introducing LEN. Partial response was shown in 11, stable disease in 12, and progressive disease in four (overall response rate ORR, 40.7%; disease control rate DCR, 85.2%). The ORR and DCR of TKI‐naïve patients (n = 8) were 50.0% and 87.5%, respectively, whereas those of TKI‐experienced patients (n = 19) were 36.8% and 84.2%, respectively (P = 0.675 and P = 1.00, respectively).
Conclusion
Early therapeutic response to LEN was favorable. This new TKI could have therapeutic potential both in patients with and without past TKI treatments.
Abstract
It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present ...study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child–Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.
Background/Aim
Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u‐HCC) classified as beyond the up‐to‐7 criteria (UT‐7 ...out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u‐HCC patients classified as UT‐7 out/multiple.
Material/Methods
From September 2020 to September 2021, 95 u‐HCC Japanese patients classified as UT‐7 out/multiple/Child‐Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child‐Pugh 5:6 = 68:27, TNM stage II:III = 17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST).
Results
Atez/Bev was given as first‐line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0 months). Child‐Pugh A/modified Albumin‐bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any‐grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%).
Conclusion
Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition.
Background/Aim
Presently, there are no therapeutic options for unresectable hepatocellular carcinoma (u‐HCC) patients who are intolerant to sorafenib or regorafenib failure. There have been no ...reports with detailed clinical findings of lenvatinib (LEN), a newly developed first‐line tyrosine kinase inhibitor (TKI), obtained in real‐world practice. We aimed to elucidate the therapeutic efficacy of LEN.
Materials/Methods
From March to August 2018, 105 u‐HCC patients were treated with LEN. Following exclusion of those who started with a reduced LEN dose and/or had a short observation period (<2 weeks), 77 patients (72.0 ± 8.9 years, 59 males, 8 mg/12 mg = 49/28, Liver Cancer Study Group of Japan 6th LCSGJ‐TNM stage II/III/IVa/IVb = 8/28/4/37, and American Joint Committee on Cancer/Union for International Cancer Control 8th AJCC/UICC‐TNM stage IB:II:IIIA:IIIB:IVA:IVB = 2:27:6:5:9:28) were divided into two groups (TKI naïve n = 33 and TKI experienced n = 44, including 11 with regorafenib history). Therapeutic response was evaluated using mRECIST. Clinical data were retrospectively evaluated.
Results
There were significant differences in age (74.6 ± 11.2 vs 70.0 ± 5.9 years, P = 0.040), LCSGJ‐TNM (II:III:IVa:IVb = 8:12:1:12 vs 0:16:3:25, P = 0.006), and AJCC/UICC‐TNM (IB:II:IIIA:IIIB:IVA:IVB = 2:17:1:1:4:8 vs 0:10:5:4:5:20, P = 0.028), while hepatic reserve function, adverse event (AE) profiles, and progression‐free survival (89.7%/80.4% vs 90.5%/80.1%, P = 0.499) and overall survival (96.7%/96.7% vs 100%/92.3%, P = 0.769) after 4 and 12 weeks were not significantly different between the TKI‐naïve and TKI‐experienced groups. Overall response rate and disease control rate at 4 weeks (n = 52) were 38.5% and 80.8%, respectively, and 32.4% and 70.3%, respectively, at 12 weeks (n = 37). A significant decline in log10 AFP from the baseline to 4 weeks after introducing LEN was observed in patients with PR and SD (2.047 ± 1.148 vs 1.796 ± 1.179, P < 0.001).
Conclusion
Regardless of past TKI therapy, therapeutic response and AEs after introducing LEN were similar. LEN may be an important treatment for the present unmet need regarding TKI treatment against u‐HCC.
Presently, there are no therapeutic options for unresectable hepatocellular carcinoma (u‐HCC) patients who are intolerant to sorafenib or regorafenib failure, and there have been no reports with detailed clinical findings of lenvatinib (LEN), a newly developed first‐line tyrosine kinase inhibitor (TKI), obtained in real‐world practice. Regardless of past TKI therapy, therapeutic response and adverse events after introducing LEN were similar. LEN may be an important treatment for the present unmet need regarding TKI treatment for u‐HCC.
We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined ...the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2-22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥ 0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495-2.452), Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.429), and α-fetoprotein ≥ 400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p < 0.001). Median progression-free survival was 7.5 (95% CI, 6.7-8.1) months. Multivariate analysis showed that age, CAR ≥ 0.108 (HR, 1.644; 95% CI, 1.324-2.043), and non-hepatitis B, non-hepatitis C etiology (HR, 0.726) were independently associated with progression-free survival. Cumulative progression-free survival differed significantly between patients with low versus high CAR (p < 0.001). CAR values were significantly higher as Japan Integrated Staging score increased (p < 0.001). In conclusion, CAR can predict outcomes in patients with unresectable HCC treated with lenvatinib.
Background/aim
We assessed suitable factors indicating newly developed lenvatinib (LEN) treatment for unresectable hepatocellular carcinoma (u‐HCC) by investigating real‐world clinical features of ...patients.
Materials/methods
One hundred fifty two u‐HCC patients, who receive LEN treatment from March to December 2018, were enrolled. (Child‐Pugh score CPS 5/6/7/8 = 76/61/13/2, modified albumin‐bilirubin grade mALBI 1/2a/2b/3 = 53/35/60/4). Clinical features were evaluated retrospectively.
Results
Overall‐response rate (ORR)/disease control rate (DCR) at 1 month after starting LEN were 38.7%/86.0%, respectively. Estimated median time to progression (TTP) was 7.0 months, while median survival time was not reached within the observation period. CPS (≥7) and past history of tyrosine‐kinase inhibitor (TKI) were not significant prognostic factors. mALBI ≥2b was an only significant prognostic factor (HR 4.632, 95%CI 1.649‐13.02, P = 0.004) in Cox‐hazard multivariate analysis. In patients with Child‐Pugh A, c‐index/Akaike's information criterion (AIC) of prognostic predictive value of mALBI were superior to CPS (0.682/135.6 vs 0.652/138.7), while those of stopping LEN also showed that mALBI was better (0.575/447.3 vs 0.562/447.8). Additional analysis of patients with good mALBI (1/2a) revealed that time to stopping LEN was significantly shorter in those with the adverse event (AE) of appetite loss (any grade) than those without (P = 0.006) and body mass index (BMI) was also lower in patients with that AE (20.3 ± 3.0 vs 23.6 ± 4.0kg/m2, P < 0.001), while patients with a hand‐foot skin reaction (any grade) showed good ORR/DCR (59.1%/86.4%) and longer TTP as compared to patients without (P = 0.007).
Conclusion
Good hepatic function (mALBI 1/2a) is the best indication for LEN, while potential appetite loss in association with low BMI should be kept in mind in such cases.
Child‐Pugh score was not enough for evaluation of hepatic function in unresectable patients treated with lenvatinib. Good hepatic function (modified Albumin‐bilirubin grade 1/2a) is the best indication for lenvatinib. When lenvatinib is given to patients with lower BMI (<21.0 kg/m2), close attention is needed for decline of appetite, while a dose adjustment may be required soon in accordance with the condition in order to avoid a long period of interruption or stopping the drug, which can reduce therapeutic efficacy.
Background/Aim
Atezolizumab plus bevacizumab (Atez/Bev) treatment is recommended for unresechepatocellular carcinoma (u‐HCC) patients classified as Child‐Pugh A (CP‐A). This study aimed to elucidate ...the prognosis of patients treated with Atez/Bev, especially CP‐A and ‐B cases.
Materials/methods
From September 2020 to March 2022, 457 u‐HCC patients treated with Atez/Bev were enrolled (median age 74 years, male:female = 368:89, CP‐A:CP‐B = 427:30, Child‐Pugh score CPS 5:6:7:8:9 = 271:156:21:8:1). Therapeutic response was evaluated using RECIST ver.1.1. Clinical features and prognosis were retrospectively evaluated.
Results
There were no significant differences between CP‐A and ‐B patients in regard to best response (CR:PR:SD:PD = 16:91:194:81 vs. 0:7:13:8, p = 0.739; objective response rate/disease control rate = 28.0%/78.8% vs. 25.0%/71.4%). Analysis performed using inverse probability weighting adjustments of clinical factors other than those related to hepatic reserve function with a p value < 0.10 for comparisons between patients with CP‐A and ‐B showed that the progression‐free survival (PFS) rate for CP‐A cases was better (6‐/12‐/18‐month: 58.2%/36.1%/27.8% vs. 49.6%/8.7%/non‐estimable NE, p < 0.001), as was overall survival (OS) rate (6‐/12‐/18‐month: 89.9%/71.7%/51.4% versus 63.6%/18.4%/NE; p < 0.001). Median PFS (mPFS) and median OS (mOS) for the CPS‐5 were 9.5 months/NE, and 5.1/14.0 months for the CPS‐6 (both p < 0.001). Furthermore, for modified albumin‐bilirubin grade (mALBI)‐1/2a/2b, mPFS was 9.4/8.5/5.3 months (p < 0.001) and mOS was NE/17.8/13.4 months (p < 0.001).
Conclusion
Better hepatic function, such as mALBI grade 1 or 2a are thought to indicate a better condition for obtaining sufficient prognosis with Atez/Bev treatment for u‐HCC patients, whereas for CP‐B patients, who mainly shown an mALBI grade of 2b or 3, Atez/Bev might have less therapeutic efficacy.
Aim
This study aimed to investigate the utility of C-reactive protein (CRP) and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score in hepatocellular carcinoma (HCC) patients receiving ...atezolizumab and bevacizumab (Atez/Bev).
Methods
This retrospective cohort study included a total of 297 patients receiving Atez/Bev from September 2020 to November 2021 at 21 different institutions and hospital groups in Japan. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point.
Results
The patients were assigned CRAFITY scores of 0 points (
n
= 147 49.5%), 1 point (
n
= 111 37.4%), and 2 points (
n
= 39 13.1%). AFP ≥ 100 ng/mL and CRP ≥ 1.0 mg/dL were significantly associated with progression-free survival (PFS) and overall survival (OS). The median PFS in the CRAFITY score 0, 1, and 2 groups was 11.8 months (95% confidence interval CI 6.4-not applicable NA), 6.5 months (95% CI 4.6–8.0), and 3.2 months (95% CI 1.9–5.0), respectively (
p
< 0.001). The median OS in patients with CRAFITY score 0, 1 and 2 was not reached, 14.3 months (95% CI 10.5-NA), and 11.6 months (95% CI 4.9-NA), respectively. The percentage of patients with grade ≥ 3 liver injury, any grade of decreased appetite, any grade of proteinuria, any grade of fever, and any grade of fatigue was lowest in patients with a CRAFITY score of 0, followed by patients with CRAFITY scores of 1 and 2.
Conclusions
The CRAFITY score is simple and could be useful for predicting therapeutic outcomes and treatment-related adverse events.
Aim
Lenvatinib has become available as first‐line therapy for patients with unresectable hepatocellular carcinoma (HCC). However, the safety and efficacy of lenvatinib in elderly patients with HCC ...has not been sufficiently investigated. We compared the frequency of adverse events and prognosis between elderly and non‐elderly patients with HCC who received lenvatinib.
Methods
A total of 100 patients with HCC who received lenvatinib were selected using propensity score matching: 50 patients were elderly (age ≥75 years) and 50 patients were non‐elderly.
Results
In the elderly group, >20% of patients experienced fatigue (36.0%), decreased appetite (26.0%), hypothyroidism (24.0%), proteinuria (22.0%), palmar‐plantar erythrodysesthesia (22.0%), and hypertension (20.0%) of any grade as treatment‐related adverse events. In addition, >10% of patients experienced grade ≥3 treatment‐related fatigue (12.0%). In the non‐elderly group, >20% of patients experienced palmar‐plantar erythrodysesthesia (42.0%), fatigue (28.0%), decreased appetite (22.0%), and diarrhea (20.0%) of any grade as treatment‐related adverse events. In addition, >10% of patients experienced grade ≥3 treatment‐related proteinuria (10.0%). There were no significant differences between the elderly and non‐elderly groups in the frequency of adverse events. Regarding overall and progression‐free survival, there were no significant differences between the elderly and non‐elderly groups (hazard ratio 0.972, 95% confidence interval 0.374–2.529; and hazard ratio 1.362, 95% confidence interval 0.687–2.700, respectively). Palmar‐plantar erythrodysesthesia (hazard ratio 0.117, 95% confidence interval 0.015–0.916) was independently associated with overall survival in a multivariate analysis.
Conclusions
Lenvatinib can be used safely and efficaciously regardless of age in patients with HCC.
Background
This retrospective, multicenter study evaluated the effect of pemafibrate treatment on liver function and fibrosis by liver function tests (LFTs) and various fibrotic biomarkers including ...FibroScan in non-alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia.
Methods
A total of 138 NAFLD patients treated with pemafibrate at three hospitals between September 2018 and April 2021 were included. To evaluate the effect of pemafibrate treatment, FibroScan-aspartate aminotransferase (FAST) score, a novel index of steatohepatitis that can be calculated based on the aspartate aminotransferase (AST) value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) was used.
Results
Serum TG levels were significantly decreased 4 weeks after pemafibrate treatment (
p
= 0.003). The levels of AST (
p
= 0.038), alanine aminotransferase (ALT) (
p
= 0.003), and gamma-glutamyl transferase (GGT) (
p
= 0.047) also significantly diminished 12 weeks after pemafibrate administration compared to before administration (
p
< 0.05). However, serum HDL-cholesterol (
p
= 0.193), LDL-cholesterol (
p
= 0.967), and eGFR (
p
= 0.909) levels were not significantly altered 12 weeks after pemafibrate administration. In addition, the fibrosis biomarkers’ Type IV collagen (
p
= 0.753) and FIB-4 index (
p
= 0.333) did not significantly differ, while Autotaxin (
p
= 0.006) and the AST-to-platelet ratio index (APRI) (
p
= 0.003) significantly decreased 48 weeks after pemafibrate administration. No significant reductions in LSM (
p
= 0.959) and CAP (
p
= 0.266) were detected using FibroScan 48 weeks after pemafibrate administration. FAST score was significantly improved (
p
= 0.0475).
Conclusion
Pemafibrate improved LFTs, including fibrotic biomarkers and FAST score, due to the hepatic anti-inflammatory effect, suggesting that pemafibrate may prevent disease progression in NAFLD patients with hypertriglyceridemia.
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