Abstract
Background/Aim: Lenvatinib is a multiple-tyrosine kinase inhibitor used to treat hepatocellular carcinoma (HCC), and its systematic concentration varies according to liver function. The albumin-bilirubin (ALBI) grade is a novel indicator for predicting liver function in patients with hepatic disease. This study aimed to investigate the relationship between ALBI grade and HCC patients’ lenvatinib treatment duration. Patients and Methods: This is a retrospective cohort study of patients with HCC and Child-Pugh A treated with lenvatinib between April 2018 and December 2019. The baseline liver function was determined using the ALBI grade. The primary outcome was discontinuation owing to adverse events. The risk factors for discontinuation owing to adverse effects were analyzed using logistic regression. Results: This investigation included 48 HCC patients. Patients with ALBI grade 2 had a significantly shorter time of discontinuation due to adverse events than those with grade 1 (p=0.036). However, the time of treatment failure did not differ between the groups. Multiple logistic regression analysis showed that ALBI grade 2 and non-use of antihypertensive drugs were independent factors for discontinuation due to adverse events [odds ratio (OR)=14.1, 95% confidence interval (CI)=1.46-135, p=0.022 and OR=5.48, 95% CI=1.13-23.9, p=0.024, respectively]. Conclusion: The ALBI grades may be useful in predicting adverse events caused by lenvatinib in patients with HCC and Child–Pugh A.
Lenvatinib is an oral multiple-tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor-alpha, c-Kit, and the RET proto-oncogene (1-3). The Phase III REFLECT study showed that lenvatinib could be used as first-line therapy for unresectable hepatocellular carcinoma (HCC) (4). However, in this trial, adverse events, such as hypertension, hand-foot syndrome, hepatotoxicity, fatigue, appetite loss and hypothyroidism were reported (4). It is well known that managing adverse events caused by the TKI is essential to improving therapeutic outcomes in HCC (5). It is important to develop a strategy for predicting severe adverse events that require treatment discontinuation.
Recently, the albumin-bilirubin (ALBI) scoring system was developed to predict liver function in HCC and liver cirrhosis (6). It classifies residual liver function into three grades based on only two variables: serum albumin and bilirubin (7, 8). Therefore, the ALBI score is expected to determine liver function more simply and easily than other methods, such as the Child-Pugh score and the Model for End-Stage Liver Disease (MELD) score. According to a previous study, no significant differences in the incidence of adverse events and the relative dosage intensity (RDI) between the Child-Pugh A and B groups in lenvatinib treatment for unresectable HCC were observed (9). However, a recent study found that patients with Child-Pugh score 5 and ALBI grade 1 had a higher response rate and a lower treatment discontinuation rate due to adverse events of lenvatinib treatment compared to patients with other residual liver function categories (10). The individual efficacy of ALBI grade in evaluating the residual liver function for predicting lenvatinib-related adverse events and treatment duration has not been established. In this study, we investigated the relationship between baseline ALBI grades and the treatment discontinuation rate due to severe adverse events of lenvatinib in patients with unresectable HCC and Child-Pugh A.
Patients and Methods
Patients. Patients with HCC who received lenvatinib treatment at Kobe University Hospital between April 2018 and December 2019 were enrolled in this retrospective analysis. Patients who were untraceable after discharge and had Child-Pugh B and C or discontinued treatment within one day of discharge were excluded from this study. The included patients were divided into two groups based on the ALBI grading method. All procedures in this study were conducted per the institutional and national research committees’ ethical standards, the Helsinki declaration, and its later amendments or comparable ethical standards. This study protocol was approved by the ethical committee of Kobe University Hospital (approval No. B200280).
Data collection. Laboratory data and patient characteristics at the start of lenvatinib therapy were obtained from the electronic medical record. ALBI scores were calculated using serum albumin and bilirubin values as follows: (5). The ALBI grade was determined using the ALBI score as previously reported (5).
Assessment. Adverse events were defined as events that resulted in discontinuation, dosage reduction, or withdrawal, and they were graded using the Common Terminology Criteria for Adverse Events, version 5.0 (11). Positive serum tumor markers were defined as alpha-fetoprotein (AFP) levels greater than 20 ng/ml using the immunoradiometric assay and protein induced by vitamin K absence-II (PIVKA-II) levels greater than 40 mAU/ml using the electrochemiluminescence immunoassay. Treatment discontinuation refers to the transition from initial administration to treatment discontinuation due to adverse events or other factors. The RDI was calculated as the ratio of an actual administered dosage to the initial dosage at 1, 3, 6, 9 and 12 months after the treatment started.
Statistical analysis. All statistical analyses were performed using the EZR software (12). Data are expressed as the number of patients or the median with a range. Fisher’s exact tests were used to estimate the distribution of the categorical data. The medians of continuous values were compared using the Mann-Whitney U-test. The time of treatment discontinuation due to adverse events and the time of treatment failure were estimated using the Kaplan-Meyer method, and their differences were analyzed using the log-rank test. The factors influencing treatment discontinuation due to adverse events were assessed using logistic regression analysis, with independent variables with p-Values of less than 0.2 in the univariate logistic analysis included in the multivariate logistic analysis. The results were expressed as odds ratios (ORs) with a 95% confidence interval (CI). A p-Value less than 0.05 was considered statistically significant.
Results
Patient characteristics. Table I lists the characteristics of the 48 patients who participated in this study, with 13 patients (27%) classified as ALBI grade 1 and the remaining 35 patients (73%) classified as grade 2. The median age of patients with ALBI grade 2 was significantly higher than those with grade 1. In this study, there were no significant differences in body weight or initial dosage between patients with ALBI grade 1 and 2. The median albumin, total bilirubin, and prothrombin time were also comparable between the two groups. Positive PIVKA-II rates were significantly higher in the ALBI grade 2 group than in the grade 1 group, whereas positive AFP rates were comparable.
Patient characteristics.
Time of treatment discontinuation in each ALBI grade. Figure 1 shows the time-to-event analysis for each ALBI grade. The time of treatment discontinuation due to severe adverse events was significantly shorter in patients with ALBI grade 2 than in those with grade 1 (p=0.036). The time of treatment discontinuation for any reason did not significantly differ between the two groups (p=0.46). The median treatment duration in the ALBI grade 1 group was 299 days and 173 days in the grade 2 group. The treatment discontinuation rates in each ALBI grade are shown in Figure 1B. Lenvatinib was discontinued for any reason in seven (53.8%) of ALBI grade 1 patients and 22 (62.9%) of ALBI grade 2 patients.
Time to treatment discontinuation. Time to treatment discontinuation due to adverse events (AEs) (A) and time to treatment discontinuation due to any reason (B), as estimated using the Kaplan-Meier method. The p-Value in the ALBI grade 1 (solid line) vs. grade 2 (dashed line) groups was calculated using the log-rank test. PD: Progressive disease.
Relative dosage intensity. The RDI of lenvatinib at each treatment time is shown in Table II. RDI decreased with treatment time in both groups. There were no differences in the median RDI between the two groups at any treatment time.
Relative dose intensity (RDI) in each albumin-bilirubin (ALBI) grade.
Adverse events in each ALBI grade. Table III shows the breakdown of adverse events by ALBI grade. Two types of adverse events were observed in one patient of ALBI grade 1 and 16 patients of grade 2. Both patients experienced fatigue and anorexia. Patients with ALBI grade 2 had hyperammonemia and hepatic encephalopathy during lenvatinib treatment, whereas those with ALBI grade 1 did not. There were 23 patients in the ALBI grade 1 group and 64 in the ALBI grade 2 group who experienced adverse events that caused dosage reduction or withdrawal, respectively. In both groups, fatigue was the most frequent adverse event that caused dose reduction or withdrawal.
The adverse events in each albumin-bilirubin (ALBI) grade.
Factors influencing treatment discontinuation due to adverse events. Table IV shows the results of univariate and multivariate logistic regression analysis. Univariate analysis revealed that ALBI grade 2, prior surgery, and non-use of antihypertensive drugs were potential risk factors for treatment discontinuation due to adverse events (p<0.2). Multivariate analysis showed that ALBI grade 2 (p=0.022) and non-use of antihypertensive drugs (p=0.024) were significantly associated with treatment discontinuation due to adverse events.
Logistic regression analysis for defining the factors of treatment discontinuation of lenvatinib.
Discussion
Our study found a relationship between ALBI grade and treatment discontinuation due to adverse events caused by lenvatinib in patients with unresectable HCC. Furthermore, ALBI grade 2 and non-use of antihypertensive drugs were independent risk factors for discontinuation due to adverse events. These findings suggest that evaluating liver function by ALBI grade has the potential to predict treatment discontinuation due to severe adverse events in lenvatinib treatment.
The previous study found that the frequency of adverse events in lenvatinib treatment was higher in Child-Pugh B than in Child-Pugh A patients (13). However, their groups had no significant differences in the incidence of severe adverse events or treatment discontinuation. Patients with Child-Pugh A had higher RDI and therapeutic efficacy, including radiological objective response and overall survival, than those with Child-Pugh B (13). A better baseline Child-Pugh score resulted in improved therapeutic efficacy and safety in lenvatinib treatment for Child-Pugh A patients according to the Phase 3 REFLECT study (14).
This study divided patients with Child-Pugh A into ALBI grades 1 and 2. The time to treatment discontinuation due to adverse events was significantly shorter in patients with ALBI grade 2 than in those with ALBI grade 1. However, there was no significant difference in time of treatment discontinuation due to any reason between their groups. According to a multicenter retrospective study, patients with ALBI grade 1 had a significantly lower incidence of all grades of anorexia and fatigue than patients with ALBI grades 2 and 3 (15). In Child-Pugh A, patients with ALBI grade 1 had a significantly lower rate of drug discontinuation due to adverse events than those with ALBI grade 2 (9). Another multicenter retrospective study reported that advanced age, ALBI grade 2, severe fatigue, and severe anorexia were risk factors for lenvatinib treatment discontinuation (16), supporting our results. These findings suggest that the ALBI grade may be appropriate for predicting severe adverse events requiring treatment discontinuation. In contrast, the Child-Pugh classification may be able to predict mild to moderate adverse events caused by lenvatinib, which supports the findings of our study.
ALBI score after lenvatinib administration was more likely to worsen in older patients (17). Additionally, the ALBI score one month after lenvatinib treatment initiation was significantly worsen from baseline in the imaging non-responders, although the difference was not significant in the responders (18). In our study, the time of treatment discontinuation due to PD did not significantly differ between ALBI grades 1 and 2. Therefore, the ALBI grade at the start of lenvatinib treatment was associated with the treatment discontinuation due to adverse events, and the change in ALBI score might be used as a predictor of treatment response.
Previous studies showed that the dose intensity of lenvatinib treatment during the first 8 weeks was associated with progression-free survival and overall survival in patients with HCC (19) and thyroid cancer (20). Furthermore, it has been reported that patients with a higher RDI had a better ALBI grade than those with a lower RDI, whereas the incidence of adverse events was unrelated to RDI (19, 21). Our findings showed that ALBI grade was associated with adverse events caused by lenvatinib but not with the RDI of lenvatinib treatment. The RDI generally corresponded to the incidence of moderate adverse events with dosage reduction during the therapeutic period. The ALBI grade, which may be useful for predicting severe adverse events caused by lenvatinib, may be unrelated to RDI. A more detailed analysis of the relationship between ALBI grade and RDI is required.
A recent study showed that the plasma lenvatinib concentration before the oral intake in patients with thyroid cancer was not associated with lenvatinib-related adverse events, such as hypertension, proteinuria, hand-foot syndrome and diarrhea. However, the incidences of biochemical abnormalities were significantly higher in the high-concentration group (22). There is no consensus on the pharmacokinetic relevance of lenvatinib to the incidence of adverse events. Pharmacokinetic parameters, such as the area under the concentration-time curve (AUC) up to 24 h and the maximum concentration at steady state of lenvatinib, were not significantly different between in patients with Child-Pugh A and B (23). Another study found that lenvatinib AUC was comparable in healthy volunteers and patients with mild to moderate hepatic impairment (24). However, because lenvatinib has an extremely high protein binding ratio of 98%-99% (25), its plasma unbound fraction should be higher in patients with ALBI grade 2 or higher, and unbound lenvatinib concentrations should be high regardless of unchanged plasma total concentration. Higher unbound lenvatinib concentrations may contribute to a higher treatment discontinuation rate due to severe adverse events caused by lenvatinib.
Multivariate analysis revealed that patients who did not use antihypertensive drugs had significantly more treatment discontinuations due to adverse events. The most common adverse event reported in the Phase III REFLECT study was hypertension (4). However, treatment discontinuation due to hypertension was not observed in our study. Since the patients’ blood pressure levels at the time of treatment discontinuation could not be determined, it was unclear whether the antihypertensive effect directly prevented treatment discontinuation due to adverse events. In this study, the most common cause of discontinuation was fatigue. Because proteinuria and hypertension were observed as reasons for dosage reduction or withdrawal during the lenvatinib treatment period, hypertension may account for a portion of the fatigue incidence. Antihypertensive drugs may help reduce lenvatinib treatment discontinuation by preventing hypertension, fatigue, and other adverse events.
This study had several limitations. It was a single-institution retrospective study with a small sample size. We did not measure plasma lenvatinib concentrations, so we could not emphasize the pharmacokinetics relevant to ALBI grade and adverse events caused by lenvatinib.
Conclusion
This study revealed that the ALBI grade was associated with treatment discontinuation due to adverse events but did not affect the time of treatment failure in patients with unresectable HCC. Non-use of antihypertensive drugs, as well as ALBI grade 2, were indicated as independent risk factors for discontinuation due to adverse events. Enhanced supportive therapy or dosage reduction based on ALBI grade at the start of lenvatinib treatment may result in treatment duration extension and overall survival. Further studies are needed to investigate the association between the ALBI grade and treatment response, as well as pharmacokinetics of lenvatinib.
Acknowledgements
The Authors thank Enago (www.enago.jp) for English language editing.
Footnotes
Authors’ Contributions
D.E. and Y.M. contributed to data acquisition; D.E. and Y.M. performed data analysis; K.Y., T.O. and I.Y. provided supervision and methodology; K.Y., T.O. and I.Y. conceived and designed the study; D.E., K.Y. and I.Y. contributed by writing and drafting; all authors take responsibility for the accuracy and integrity of the manuscript and data and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received October 8, 2022.
- Revision received October 28, 2022.
- Accepted October 31, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
