Branched‐chain amino acid to tyrosine ratio is an essential pre‐treatment factor for maintaining sufficient treatment intensity of lenvatinib in patients with hepatocellular carcinoma

Eso, Yuji; Nakano, Soichiro; Mishima, Masako; Arasawa, Soichi; Iguchi, Eriko; Takeda, Haruhiko; Takai, Atsushi; Takahashi, Ken; Seno, Hiroshi

doi:10.1002/jhbp.821

Cited by 6 publications

(6 citation statements)

References 19 publications

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“…In this study, the BTR before the start of treatment was extracted as an independent factor for treatment duration. This is similar to the report by Eso et al 11 The BTR is an index of abnormal protein/amino acid metabolism in chronic liver disease as well as the Fisher ratio (branched chain amino acids/aromatic amino acids). In cases of liver cirrhosis, branched-chain amino acids are used as an energy source and for ammonia metabolism; thus, they decrease in the blood.…”

Section: Discussionsupporting

confidence: 91%

Analysis of adverse events leading to dose reduction/interruption of lenvatinib treatment in patients with Child-Pugh B unresectable hepatocellular carcinoma

Kimura

Asano

Usami

et al. 2022

J Oncol Pharm Pract

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Introduction We aimed to compare the safety of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma (HCC) in patients with Child-Pugh A (CP-A) and Child-Pugh B (CP-B) and to determine the adverse events (AEs) that cause dose reduction/interruption of treatment in patients with CP-B. Methods Sixty-six patients with lenvatinib as a first-line treatment for HCC at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and January 2022 were retrospectively evaluated. We analyzed the treatment duration, AEs, and reasons for dose reduction/interruption associated with lenvatinib treatment in patients with CP-A and CP-B HCC. Results The CP-B group had significantly more cases of grade ≥ 2 fatigue and anorexia than the CP-A group ( p = 0.045 and p = 0.042, respectively). Regarding AEs that caused dose reduction/interruption of treatment, the CP-A group had significantly more cases of proteinuria than the CP-B group ( p = 0.015), whereas the CP-B group had significantly more cases of hand-foot syndrome (HFS) than the CP-A group ( p = 0.013). Conclusion Patients with CP-B have greater difficulty than patients with CP-A in continuing treatment with repeated dose reductions/interruption of treatment due to intolerable grade ≥ 2 AEs (fatigue and anorexia). HFS is more likely to cause dose reduction/interruption of treatment in CP-B than in CP-A unresectable HCC.

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Section: Discussionsupporting

confidence: 91%

Analysis of adverse events leading to dose reduction/interruption of lenvatinib treatment in patients with Child-Pugh B unresectable hepatocellular carcinoma

Kimura

Asano

Usami

et al. 2022

J Oncol Pharm Pract

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“…Takahashi et al previously reported that patients with RDI ≥75% during the initial 8 weeks of lenvatinib treatment experienced a higher response rate and longer PFS than those with RDI <75% 17 . We have also reported that the dose intensity of lenvatinib during the first 60 days of treatment strongly correlated with ORR and was a significant factor that contributed to prolonged PFS 5,6 . In other words, if patients do not tolerate lenvatinib therapy, they are consequently not expected to achieve sufficient dose intensity and therefore unlikely to benefit from it.…”

Section: Discussionmentioning

confidence: 60%

“…3 Several studies have demonstrated that lenvatinib has comparable therapeutic efficacy in real-world clinical practice, as observed in the REFLECT trial. [4][5][6] Importantly, these data support a strong correlation between the relative dose intensity (RDI), which is defined as administered dose in a systemic therapy divided by the planned dose, and therapeutic efficacy of lenvatinib. However, sufficient RDI of lenvatinib is not achieved in a significant number of treated patients due to associated adverse events (AEs).…”

Section: Introductionmentioning

confidence: 68%

“…17 We have also reported that the dose intensity of lenvatinib during the first 60 days of treatment strongly correlated with ORR and was a significant factor that contributed to prolonged PFS. 5,6 In other words, if patients do not tolerate lenvatinib therapy, they are consequently not expected to achieve sufficient dose intensity and therefore unlikely to benefit from it. In addition, combination therapy with two monoclonal antibodies, atezolizumab and bevacizumab, was approved in 2020 as a novel first-line treatment.…”

Section: Discussionmentioning

confidence: 99%

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Mac‐2 binding protein glycosylation isomer predicts tolerability and clinical outcome of lenvatinib therapy for hepatocellular carcinoma

Eso

Nakano

Mishima

et al. 2021

J Hepato Biliary Pancreat

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Background Many patients with hepatocellular carcinoma present with impaired hepatic function, which often requires interruption or withdrawal of lenvatinib due to associated adverse events. We aimed to identify pre‐treatment predictors of tolerability and clinical outcome of lenvatinib therapy. Methods Eighty patients who received lenvatinib at our institution between 2018 and 2020 were included in this study. We assessed essential factors associated with prolonged progression‐free survival (PFS), using Cox proportional hazards model. We also investigated the correlation between the factor identified as contributing most to PFS and the relative dose intensity (RDI), response rate, and duration of treatment with lenvatinib. Results Pre‐treatment level of Mac‐2‐binding protein glycosylation isomer (M2BPGi) showed significant association with PFS (hazard ratio = 0.52, P = .0358). Low M2BPGi levels (<1.5) correlated significantly with longer PFS than higher levels (P = .0003). Patients with M2BPGi <1.5 achieved significantly higher RDI, objective response rate, and disease control rate, and maintained lenvatinib treatment for longer than those with baseline values ≥1.5. Patients with M2BPGi ≥1.5 had a higher incidence of adverse events such as fatigue and anorexia. Conclusions Baseline M2BPGi levels may predict the tolerability and treatment response to lenvatinib. Patients with high M2BPGi levels may less likely to benefit from lenvatinib therapy.

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“…The BTR was a prognostic indicator for early HCC and a predictive indicator for intrahepatic recurrence and survival based on 50 HCC patients at stage I/II. 36 Yuji et al 37 found that the BTR was an essential pretreatment indicator on maintaining the efficacy of lenvatinib in patients with HCC. Hiraoka et al 38 concluded a low BTR (≤4.4) may be an available prognostic indicator in early HCC patients.…”

Section: Discussionmentioning

confidence: 99%

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Zheng

Yang

et al. 2022

ACS Omega

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Background: The study aimed to find out the alterations in serum amino acid (AA) profiles and to detect their relationship with carcinoma formation. Methods: Targeted metabolomics based on ultraperformance liquid chromatography triple quadrupole mass spectrometry to quantitatively analyze serum AA levels in 136 hepatitis B (CHB) patients and 93 hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. Results: It was shown that decreased serum levels of leucine, lysine, threonine, tryptophan, valine, serotonin, and taurine were observed in more HCC patients than CHB patients, but the serum phenylalanine level was increased. Serum valine and serotonin were lower in Class C than Class A and Class B in HCC patients. Accompanied with the higher score of Model for End-Stage Liver Disease, serum phenylalanine was increased not only in CHB patients but also in HCC patients. The serum level of phenylalanine increased in the decompensated stage more than in the compensated stage, while serum leucine and serotonin significantly decreased. Serum serotonin still had significant differences between CHB and HCC both in the HBV desoxyribonucleic acid (HBV-DNA) negative group and in the HBV-DNA positive group. Furthermore, it was shown that the tryptophan ratio, branched-chain amino acids (BCAA)/aromatic amino acids ratio, BCAAs/tyrosine ratio, Fischer’s ratio, and serotonin-to-tryptophan ratio significantly decreased, while the tyrosine ratio and the kynurenine-to-tryptophan ratio increased in HCC patients more than those in CHB. Conclusions: A distinct metabolite signature of some specific serum amino acids was found between CHB and HCC patients, which may help predict the development of HCC at an early stage.

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Branched‐chain amino acid to tyrosine ratio is an essential pre‐treatment factor for maintaining sufficient treatment intensity of lenvatinib in patients with hepatocellular carcinoma

Cited by 6 publications

References 19 publications

Analysis of adverse events leading to dose reduction/interruption of lenvatinib treatment in patients with Child-Pugh B unresectable hepatocellular carcinoma

Analysis of adverse events leading to dose reduction/interruption of lenvatinib treatment in patients with Child-Pugh B unresectable hepatocellular carcinoma

Mac‐2 binding protein glycosylation isomer predicts tolerability and clinical outcome of lenvatinib therapy for hepatocellular carcinoma

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

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