Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free ...survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.
Background
Fibroblast growth factor receptor 2
(
FGFR2
) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and ...the exact frequency of
FGFR2
rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of
FGFR2
rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of
FGFR2
rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics.
Methods
Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of
FGFR2
rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients.
Results
A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as
FGFR2
-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as
FGFR2
rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years;
p
= 0.018) and HCV Ab- and/or HBs Ag-positivity (
p
= 0.037) were significantly associated with the presence of
FGFR2
rearrangement (logistic regression).
Conclusions
FGFR2
rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.
Transarterial chemoembolization (TACE) has been standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, all intermediate-stage HCC patients did not benefit from TACE ...treatment because intermediate-stage HCC encompasses a wide variety of HCCs. Owing to remarkable progress in systemic therapy, including molecular-targeted therapy for advanced-stage HCC, the standard treatment of HCC has recently shifted to systemic therapy. However, it remains controversial as to which treatment should be initially performed for intermediate-stage HCC. In addition, although curative treatment can be considered when the tumor shrinks, the timing of conversion therapy remains uncertain. This review summarizes the advances of HCC treatment and discusses treatment strategies for intermediate-stage HCC.
Background
The once-daily, all oral, RBV-free, pangenotypic direct-acting anti-viral regimen consisting of co-formulated NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (G/P), ...demonstrated high rates of sustained virologic response (SVR) in phase 2 and 3 studies outside Japan.
Methods
CERTAIN-1 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in Japanese patients with chronic HCV GT1 infection. Patients without cirrhosis received 8 weeks of G/P or 12 weeks of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r, 25/150/100 mg); patients with cirrhosis received G/P for 12 weeks. The primary efficacy endpoint was non-inferiority of G/P compared to OBV/PTV/r by assessing SVR at post-treatment week 12 (SVR12) among non-cirrhotic patients without the NS5A Y93H polymorphism.
Results
SVR12 was achieved by 128/129 (99.2%; one patient lost to follow-up) non-cirrhotic patients in the 8-week G/P Arm (including 23/23 patients with the NS5A Y93H polymorphism) and 52/52 (100%) patients in the 12-week OBV/PTV/r Arm. No patients from the G/P Arm prematurely discontinued the study drug or experienced a treatment-emergent serious adverse event (TESAE). Three patients from the OBV/PTV/r Arm experienced five TESAEs and one of these patients discontinued the study drug due to TESAEs. All 38 (100%) patients with compensated cirrhosis achieved SVR12; in this group, no TESAEs were reported and one patient discontinued treatment due to an AE.
Conclusions
CERTAIN-1 study results demonstrate high efficacy and favorable tolerability of G/P in GT1-infected Japanese patients including those with the NS5A Y93H polymorphism, with no virologic failures observed.
Objective The therapeutic effect of pemafibrate on metabolic dysfunction-associated fatty liver disease (MAFLD) remains unknown. This retrospective, single-arm study investigated the efficacy and ...safety of pemafibrate in MAFLD patients with hypertriglyceridemia. Methods A total of 10 patients who received pemafibrate (oral, 0.1 mg, twice a day) at Gunma Saiseikai Maebashi Hospital between September 2018 and September 2019 were included. All patients underwent a liver biopsy, and the disease grade and stage were pathologically assessed based on the FLIP algorithm. Results The median age was 66.0 (53.8-74.8) years old, and 5 patients (50.0%) were men. All patients were diagnosed with non-alcoholic steatohepatitis (NASH). The fasting and non-fasting triglyceride (TG) levels were 175 (149-247) mg/dL and 228 (169-335) mg/dL, respectively. The AST and ALT values at 6 months were significantly lower than at baseline AST: 28.0 (22.0-33.8) U/L vs. 43.5 (24.0-55.0) U/L, p=0.008, ALT: 23.0 (14.8-26.5) U/L vs. 51.5 (23.0-65.3) U/L, p=0.005, respectively, especially in NASH patients with significant activity and advanced fibrosis (p=0.040 and 0.014, respectively). Fasting TG levels were significantly lower and HDL-C levels significantly higher at 6 months than at baseline (p=0.005 and 0.032, respectively). At six months, FIB-4, the aspartate aminotransferase-to-platelet ratio index, and the macrophage galactose-specific lectin-2 binding protein glycosylation isomer level were significantly improved compared with baseline (p=0.041, 0.005 and 0.005, respectively). Treatment-related adverse events were not observed. Conclusion Pemafibrate treatment may be safe and effective for MAFLD patients with hypertriglyceridemia.
Background
Identification of positive biomarkers for the effects of nivolumab on patients with advanced gastric cancer (AGC) is significant. The Gustave Roussy Immune Score (GRIm-s) is associated ...with therapeutic resistance of immune checkpoint inhibitors (ICIs) in other cancers. This multicenter, retrospective study was designed to analyze the association of GRIm-s with therapeutic sensitivity of nivolumab in patients with AGC.
Methods
We reviewed 58 patients with AGC treated with nivolumab from October 2017 to November 2018 at five participating institutions. We performed blood tests before the start of nivolumab and after administration of two courses. We evaluated the correlation between the best overall response and GRIm-s. Additionally, we focused on the changes in GRIm-s before the start of nivolumab and after administration of two courses.
Results
Of the 58 patients, 21 (36.2%) were classified into the disease control (DC) group and 37 (63.8%) into the progressive disease (PD) group. GRIm-s before nivolumab treatment did not correlate with the best therapeutic response (
p
= 0.086). However, GRIm-s after two courses of nivolumab showed that significantly more PD cases were in the high-risk group (
p
< 0.0001). After two courses of nivolumab, overall survival was significantly worse in the high-risk group (
p
< 0.0001). For progression-free survival, the high-risk group had a significantly worse prognosis both before (
p
= 0.04) and after two courses of nivolumab treatment (
p
< 0.0001).
Conclusions
GRIm-s after two courses of nivolumab and its changes compared to pretreatment values proved beneficial in predicting nivolumab sensitivity.
A 60-year-old man presented with postoperative recurrence of intrahepatic cholangiocarcinoma with right portal vein tumor thrombosis (PVTT). After failure of standard chemotherapy, a liver biopsy ...showed that his microsatellite instability (MSI) status was high. Treatment with the immune checkpoint inhibitor (ICI) pembrolizumab was commenced, which resulted in a partial response and resolution of the PVTT. There were no significant immune-related adverse events. According to recently published reports, the frequency of MSI-high biliary tract cancer (BTC) is about 0-2.1%, which is extremely rare. However, ICIs may be effective in patients with MSI-high BTC, such as the present patient.
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.
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.
Background
The albumin–bilirubin (ALBI) score and the modified ALBI (mALBI) grade are known useful prognostic factors for patients with hepatocellular carcinoma (HCC) treated with lenvatinib ...(LEN-HCC). However, the ALBI score requires complicated logarithmic calculations. Therefore, we attempted to create a simplified score.
Methods
We developed the albumin simplified (ALBS) grade that corresponded to mALBI using the data of 5985 newly developed HCC and examined the usefulness of this grading system for the prediction of the prognosis of 678 patients with LEN-HCC.
Results
The analysis using Cox proportional hazard models revealed that the overall survival of patients with LEN-HCC was not correlated with the total bilirubin but albumin (Alb), which means that the prediction with Alb alone was logical. The ALBS grade cutoffs that corresponded to mALBI grade 1, 2a, 2b, and 3 were Alb ≧ 4.0 g/dL, 4.0 g/dL > Alb ≧3.5 g/dL, 3.5 g/dL > Alb≧2.8 g/dL, and Alb < 2.8 g/dL, respectively. The stratification ability of the ALBS grade for LEN-HCC was good. The Akaike information criterion (AIC) and c-index were comparable with those of mALBI (AIC 4096.3 vs. 4090.7, c-index 0.765 vs. 0.778). The prognosis of LEN-HCC was stratified by the ALBS grade at 1 month after starting LEN, and patients with ALBS grade 1/2a demonstrated better survival than patients with ALBS grade 2b/3 regardless of the ALBS grade before treatment.
Conclusion
The ALBS grade is easy to calculate and is useful for the prediction of the prognosis of LEN-HCC.
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