Abstract
Objective
Hepatic encephalopathy (HE) is a serious adverse event associated with lenvatinib (LEN) that requires discontinuation of the medication. We investigated the risk factors for HE in patients with hepatocellular carcinoma (HCC) who received LEN. We also explored the usefulness of rifaximin in preventing HE and LEN.
Methods
We enrolled 216 patients with HCC who had undergone LEN. The incidence of HE was evaluated [observational period 171 (1-2,079) days]. LEN dosage was assessed using the relative dose intensity (RDI). A decision-tree algorithm was constructed to reveal the profiles associated with HE.
Results
The incidence rate of HE was 8.8%. There were no significant differences in the age, sex, body mass index, or tumor stage between the HE and non-HE groups. A splenorenal shunt (≥8 mm in diameter) was identified as an independent risk factor for HE (hazard ratio 7.653, 95% confidence interval 2.489-23.535, p＜0.001). A decision-tree analysis revealed that, in patients with splenorenal shunt and ALBI grade 2, HE occurred in 66.6% of patients with no refaxmin. In contrast, 16.6% developed HE in patients treated with rifaximin. Furthermore, the prevalence of RDI ＞70% was 20.0% and 66.7% in patients who did not receive rifaximin and rifaximin, respectively.
Conclusion
Splenorenal shunt placement is an independent risk factor for HE in patients with HCC receiving LEN. Furthermore, rifaximin prevented HE and contributed to a sufficient dose of LEN in patients with HCC, splenorenal shunts, and ALBI grade 2. Thus, rifaximin may be beneficial for the management of patients with HCC receiving LEN, especially those with HCC with splenorenal shunt and hepatic dysfunction.
Keywords: lenvatinib, hepatic encephalopathy, rifaximin, splenorenal shunt, portosystemic shunt, liver dysfunction
Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide (1). Recent progress in HCC treatment has significantly improved patient outcomes. Lenvatinib (LEN), a multi-target tyrosine kinase inhibitor, effectively inhibits tumor angiogenesis and HCC growth (2,3). Various studies have demonstrated its efficacy in improving overall survival rates in patients with unresectable HCC (4-6). In the Clinical Practice Guidelines for Hepatocellular Carcinoma 2021 compiled by the Japan Society of Hepatology, LEN is recommended as second-line systemic therapy after progression to immune checkpoint inhibitors or as first-line systemic therapy for patients with no indication for immune checkpoint inhibitors (7).
In patients with HCC receiving LEN, the effective management of adverse events (AEs) is crucial to ensure patient safety and treatment efficacy. Common AEs associated with LEN include hypertension, fatigue, and loss (8). Hepatic encephalopathy (HE), while not a common AE, is a serious one that requires temporary cessation or discontinuation of LEN (9). A possible mechanism is that LEN inhibits vascular endothelial growth factor receptors and reduces nitric oxide production from sinusoidal endothelial cells, leading to contraction of hepatic stellate cells and a subsequent increase in portal pressure (10,11). The efficacy of LEN in treating HCC significantly decreases when the relative dose intensity (RDI) falls below 70% (12). Therefore, it is important to investigate the risk factors of HE in patients with HCC receiving LEN. Previous studies have demonstrated that blood ammonia levels, baseline hepatic liver functional reserve, and portosystemic shunt are risk factors for HE during LEN treatment (9,13). However, none of the studies have compared these risk factors, and the most impactful risk factor for HE in patients with HCC receiving LEN remains unclear.
Rifaximin is a minimally absorbed oral antimicrobial agent that reduces the risk of HE recurrence and the need for hospitalization (14-19). In phase II/III clinical trials conducted in Japan, rifaximin has been reported to improve HE through alteration of gut microbiota components associated with neuropsychological functions in patients with liver cirrhosis (20,21). Rifaximin was also reported to alleviate HE by ameliorating leaky gut in patients with decompensated liver cirrhosis (22). Rifaximin is strongly recommended as a useful treatment for HE with 100% agreement and a high evidence level in Evidence-based clinical practice guidelines for Liver Cirrhosis 2020 compiled by the Japan Society of Hepatology (23,24). Furthermore, several meta-analyses have recently reported that rifaximin is effective for not only the improvement of HE but also the primary prevention of HE in patients with liver cirrhosis (25,26). However, whether or not rifaximin is effective in the prevention of HE in patients with HCC receiving LEN remains unclear.
The present study investigated the independent and most impactful risk factors for HE in patients with HCC receiving LEN. In addition, we explored the usefulness of rifaximin for the prevention of HE and the continuous administration of a sufficient dose of LEN in patients with HCC receiving LEN.
Materials and Methods
Study design and ethics
This retrospective observational cohort study aimed to examine the factors associated with the incidence of HE in patients with unresectable HCC who received LEN. This protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board of Kurume University School of Medicine (No. 22293). All experiments were performed in accordance with the relevant guidelines and regulations. We used an opt-out approach to obtain informed consent from patients, and personal information was protected during data collection.
Study population
This 2-center retrospective cohort included 241 patients who underwent LEN at multiple centers between March 2018 and September 2024 [observational period 171 (1-2,079) days]. The cut-off date for this analysis was February 29, 2024. The exclusion criteria were as follows: 1) Child-Pugh class B or C; 2) incomplete evaluation of clinical data and efficacy; and 3) short-term administration of LEN before transarterial chemoembolization or hepatic arterial infusion chemotherapy. We excluded 25 patients from the study, and the remaining 216 patients were analyzed (Supplementary material 1). None of the study participants had a history of HE.
Data collection
Baseline data were collected at the initiation of the LEN treatment. The following information was obtained using a self-report questionnaire: age, sex, performance status, and amount of alcohol consumption. The use of rifaximin, lactulose, or branched-chain amino acid-related agents was collected from medical records. Blood samples were collected after an overnight fast. The following laboratory tests were performed: hepatitis B surface antigen, hepatitis C virus antibody, albumin, total bilirubin, and alpha-fetoprotein. The albumin-bilirubin (ALBI) score was calculated and classified as grades 1 to 3, as previously described (27).
The diagnosis and staging of HCC
HCC was diagnosed by a combination of the following serum markers and imaging modalities: α-fetoprotein and des-γ-carboxy prothrombin, and imaging procedures that included ultrasonography, computed tomography, and magnetic resonance imaging. HCC was classified using the Barcelona Clinic Liver Cancer (BCLC) staging system (28).
Lenvatinib treatment protocol and follow-up
LEN was orally administered at 12 mg/day in patients with a body weight ≥60 kg or 8 mg/day in patients with a body weight ＜60 kg, according to the manufacturer's instructions. However, the initial dose was adjusted at the discretion of the attending physician. The LEN dose was reduced or the treatment was interrupted in patients who developed grade ≥3 severe AEs. After the initial administration of LEN, outpatient visits were scheduled approximately once per month.
Calculation of RDI and definition of 4-week RDI ≥70%
We calculated as the actual dose divided by the standard dose. The 4-week RDI was calculated as the cumulative dose within the initial 4 weeks of LEN treatment, divided by the standard dose. A 4-week RDI ≥70% was used in the present study because it has been reported that a 4-week RDI of ≥70% indicates tolerability to AE (12,29).
Treatment with rifaximin
Before the initiation of LEN, patients with hyperammonemia (≥80 μg/dL) were treated with oral rifaximin (RifximaⓇ tablet; ASKA Pharmaceutical, Tokyo, Japan) at a dose of 1,200 mg/day. Rifaximin administration was not a protocol-defined intervention. Rifaximin was prescribed to patients with hyperammonemia based on its approved indications under the National Health Insurance System.
Furthermore, some patients developed HE during lenvatinib therapy, and rifaximin was administered. However, for the purpose of this study, such cases were not classified as involving “rifaximin administration,” as this constitutes treatment after HE.
Changes in blood ammonia levels
Blood ammonia levels were evaluated before and at each visit after LEN initiation. Changes in blood ammonia levels were calculated based on the highest levels versus the baseline levels.
Definition of splenorenal shunt
The presence of a splenorenal shunt was identified based on contrast-enhanced computed tomography or magnetic resonance imaging performed prior to lenvatinib initiation. A shunt was defined as a collateral vessel connecting the splenic vein with the left renal vein, with a diameter ≥8 mm, which has been reported as a risk factor for hepatic encephalopathy (30).
The diagnosis of HE
HE was evaluated at each visit after LEN initiation. It was diagnosed according to the presence of asterixis and/or mental symptoms from disorientation through coma, based on the International Society for Hepatic Encephalopathy and Nitrogen Metabolism criteria (31).
Statistical analyses
Continuous variables were expressed as medians, ranges, or numbers. Categorical variables are expressed as frequencies and percentages. Differences between the two groups were analyzed using Wilcoxon's rank-sum test for continuous variables and Fisher's exact test for categorical variables. A Kaplan-Meier analysis was performed to estimate the cumulative incidence-free rate of HE. The difference between patients with and without a splenorenal shunt was evaluated using the log-rank test. A Cox regression analysis was used to identify independent variables associated with HE. Statistical significance was set at p＜0.05, as described previously.
A decision tree algorithm was constructed to reveal the profiles associated with HE as previously described (32). The initial classification was the factor that was most affected by HE. The patients were classified according to the category or cutoff values indicated for each variable. The cutoff value was determined using a decision tree analysis, which yielded the best split of variables. Variables were selected based on the age, sex, body mass index (BMI), performance status, BCLC stage, ALBI grade, splenorenal shunt, ammonia levels, and use of rifaximin, lactulose, and branched-chain amino acid-related agents.
Results
Patients' characteristics
The incidence of HE was 8.8% (19/216) (Table 1). The median observation period was 41 days in the HE group, which was significantly shorter than that in the non-HE group. There were no significant differences in the age, sex, or BMI between the HE and non-HE groups. The prevalence of performance status 2 was significantly higher in the HE group than that in the non-HE group. No significant differences were observed in the etiology of HCC, BCLC stage, presence of macrovascular invasion, presence of extrahepatic spread of HCC, or serum alpha-fetoprotein level.
Table 1.
Patients’ Characteristics.
| Factor | All patients | Hepatic encephalopathy | Non-hepatic encephalopathy | p |
|---|---|---|---|---|
| Number | 216 | 8.8% (19/216) | 91.2% (197/216) | |
| Observational period (days) | 171 (1-2,079) | 41 (1-673) | 175 (7-2,079) | 0.005 |
| Age (years) | 73 (42-90) | 73 (62-86) | 73 (42-90) | 0.426 |
| Sex (female/male) | 18.1%/81.9% (39/177) | 15.8%/84.2% (3/16) | 18.3%/81.7% (36/161) | 0.788 |
| BMI | 22.6 (15.0-38.9) | 22.3 (17.7-32.4) | 22.6 (15.0-38.9) | 0.782 |
| Performance status (0 or 1/2) | 90.7%/9.3% (196/20) | 73.7%/26.3% (14/5) | 92.4%/7.6 (182/15) | 0.007 |
| Etiology of HCC (viral/alcohol/non-viral) | 61.5%/17.6%/20.8% (133/38/45) | 68.4%/15.8%/15.8% (13/3/3) | 61.0%/17.7%/21.3% (120/35/42) | 0.797 |
| BCLC stage (A/B/C) | 1.8%/52.7%/45.5% (4/114/98) | 0.0%/47.4%/53.6% (0/9/10) | 2.0%/53.3%/44.7% (4/105/88) | 0.689 |
| Macrovascular invasion of HCC (yes/no) | 12.0%/88.0% (26/190) | 15.8%/84.2% (3/16) | 11.7%/88.3% (23/174) | 0.596 |
| Extrahepatic spread (yes/no) | 32.8%/67.2% (71/145) | 56.8%/43.2% (7/12) | 32.5%/67.5% (64/133) | 0.699 |
| AFP (ng/mL) | 34.0 (1.0-268,112) | 157 (2.9-96,460) | 25.5 (1.0-268,112) | 0.256 |
| Lenvatinib treatment line (first/later) | 68.0%/32.0% (147/69) | 73.7%/26.3% (14/5) | 67.5%/32.5% (133/64) | 0.582 |
| ALBI score | -2.49 (-3.61- -1.72) | -2.25 (-3.02- -1.74) | -2.50 (-3.60- -1.72) | 0.006 |
| ALBI grade (1/2) | 43.1%/56.9% (93/123) | 15.8%/84.2% (3/16) | 45.7%/54.3% (90/107) | 0.012 |
| Splenorenal shunt (yes/no) | 12.0%/88.0% (26/190) | 57.9%/42.1% (11/8) | 7.6%/92.4% (15/182) | <0.001 |
| Ammonia (µg/dL) | 38 (13-153) | 50 (18-153) | 28 (13-130) | 0.182 |
| Rifaximin (yes/no) | 5.6%/94.4% (12/204) | 5.2%/94.8% (1/18) | 5.6%/94.4% (11/186) | 0.953 |
| Lactulose (yes/no) | 7.8%/92.2% (17/199) | 36.8%/63.2% (7/12) | 5.1%/94.9% (10/187) | <0.001 |
| BCAA (yes/no) | 34.7%/65.3% (75/141) | 63.2%/36.8% (12/7) | 32.0%/68.0% (63/138) | 0.006 |
BMI: body mass index, HCC: hepatocellular carcinoma, BCLC: barcelona clinic liver cancer, ALBI: albumin-bilirubin score, AFP: α-fetoprotein, BCAA: branched chain amino acid
A higher prevalence of ALBI grade 2 was observed in the HE group than in the non-HE group. Although there was no significant difference in blood ammonia levels between the two groups, the prevalence of splenorenal shunts was significantly higher in the HE group than in the non-HE group. There was no significant difference in the prevalence of rifaximin treatment between the two groups. A higher prevalence of patients treated with lactulose and branched-chain amino acids was observed in the HE group than in the non-HE group.
Changes in blood ammonia levels in patients with HCC receiving LEN
Blood ammonia levels were significantly increased after the initiation of LEN treatment in all patients (Fig. 1). The increase in blood ammonia level was significantly higher in patients with splenorenal shunts than in those without splenorenal shunts (Fig. 1).
Figure 1.
Changes in blood ammonia levels after LEN treatment.
Incidence HE in patients with HCC receiving LEN
The incidence of HE was 8.8% in all patients with HCC who received LEN. The incidence of HE was significantly higher in patients with splenorenal shunts than in those without splenorenal shunts (Fig. 2A).
Figure 2.
The incidence of HE after LEN treatment.
The Kaplan-Meier curve shows the cumulative incidence-free rate of HE over time. The cumulative incidence-free rate gradually declined during the observation period (Fig. 2B). Furthermore, a Kaplan-Meier analysis revealed that patients in the splenorenal shunt group had a significantly lower HE-free rate, which decreased sharply to approximately 60% within the first 100 days (Fig. 2C). In contrast, patients with no splenorenal shunt maintained a significantly higher HE-free rate than those with a shunt, remaining above 90% over the observation period.
Independent risk factors for HE in patients with HCC receiving LEN
In the univariate analysis, the following five factors were significantly associated with the incidence of HE: performance status, ALBI grade, splenorenal shunt, lactulose, and branched-chain amino acid. Using these five factors, we performed a multivariate analysis of the incidence of HE. Performance status was an independent risk factor for HE (Table 2). In addition, a splenorenal shunt was identified as an independent risk factor for HE in patients with HCC receiving LEN.
Table 2.
Univariate and Multivariate Analyses Associated with HE in Patients with HCC Receiving LEN.
| Variable | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|
| HE (yes/no) | p value | Hazard ratio | 95% CI | p value | |
| Age | |||||
| <70 years old | (7.1%/92.9%) | 0.493 | |||
| ≥70 years old | (9.9%/90.1%) | ||||
| Sex | |||||
| Male | (9.0%/91.0%) | 0.787 | |||
| Female | (7.7%/92.3%) | ||||
| Performance status | |||||
| 0 | (7.1%/92.9%) | 0.007 | 4.148 | 1.340-12.326 | 0.011 |
| 1 or 2 | (25.0%/75.0%) | ||||
| Etiology of HCC | |||||
| Viral | (9.7%/90.3%) | 0.797 | |||
| Alcohol | (7.9%/92.1%) | ||||
| Non-viral | (6.7%/93.3%) | ||||
| ALBI grade | 0.012 | 1.848 | 0.470-7.270 | 0.379 | |
| 1 | (3.2%/96.8%) | ||||
| 2 | (13.0%/87.0%) | ||||
| BCLC stage | |||||
| A | (0.0%/100.0%) | 0.689 | |||
| B | (7.8%/92.2%) | ||||
| C | (10.2%/90.2%) | ||||
| Hyperammonemia | |||||
| Yes | (13.0%/87.0%) | 0.447 | |||
| No | (8.3%/91.7%) | ||||
| Splenorenal shunt | |||||
| Yes | (42.3%/57.7%) | <0.001 | 7.653 | 2.489-23.535 | <0.001 |
| No | (4.2%/95.8%) | ||||
| Lactulose | |||||
| Yes | (41.2%/58.8%) | <0.001 | 1.196 | 0.367-3.891 | 0.766 |
| No | (6.0%/94.0%) | ||||
| BCAA | |||||
| Yes | (16.0%/84.0%) | 0.006 | 1.517 | 0.533-4.322 | 0.434 |
| No | (5.0%/95.0%) | ||||
| Rifaximin | |||||
| Yes | (8.3%/91.7%) | 0.953 | |||
| No | (8.8%/91.2%) | ||||
| AFP | |||||
| <400 ng/mL | (8.5%/91.5%) | 0.810 | |||
| ≥400 ng/mL | (9.6%/90.4%) | ||||
HE: hepatic encephalopathy, ALBI: albumin-bilirubin score, BCLC: barcelona clinic liver cancer, AFP: α-fetoprotein, BCAA: branched chain amino acid
Decision-tree analyses for the incidence of HE in patients with HCC receiving LEN
We investigated the profiles associated with HE in patients with HCC who received LEN (Fig. 3). The initial classification was a splenorenal shunt. Among patients without a shunt, 4.2% developed HE. However, 42.3% of patients with splenorenal shunts developed HE. Of these patients, the second classifier was the ALBI grade. None of the ALBI grade 1 patients developed HE. However, 52.3% of patients with a splenorenal shunt and ALBI grade 2 developed HE. Among these, the third classifier was rifaximin. In patients who did not receive rifaximin, 66.6% developed HE. However, 16.6% of patients treated with rifaximin developed HE (Fig. 3).
Figure 3.
Profiles of the incidence of HE after LEN treatment.
Difference in the prevalence of patients with a 4-week RDI of LEN >70% between rifaximin and no rifaximin treatment among HCC patients with splenorenal shunt and ALBI grade 2
The prevalence of patients with a 4-week RDI of LEN ＞70% was 20.0% among patients with splenorenal shunt, ALBI grade 2, and no rifaximin treatment (Fig. 4). In contrast, the prevalence was 66.7% in patients who received rifaximin treatment. The prevalence of patients with a 4-week RDI of LEN ＞70% was significantly higher in those treated with rifaximin than in those without rifaximin treatment (Fig. 4).
Figure 4.
The impact of rifaximin on the relative dose intensity of LEN >70% in patients with HCC splenorenal shunt and ALBI grade 2.
Discussion
We demonstrated that splenorenal shunt was an independent risk factor and the most influential classifier for HE in patients with HCC receiving LEN. We further revealed that rifaximin was associated with a reduced incidence of HE and an increased prevalence of 4-week RDI of LEN ＞70% in patients with HCC with splenorenal shunt and ALBI grade 2.
In this study, the incidence of HE was 8.8% in patients with HCC who received LEN. In a randomized phase 3 non-inferiority trial of LEN (REFLECT study), the incidence of HE was 3.8% (2). In a real-world study with 240 patients with HCC receiving LEN, the incidence of HE was reported to be 11.3% (33). Thus, the incidence of HE in our study showed good agreement with previous reports, indicating that our patients had a general characteristic of HCC receiving LEN.
Our study identified a splenenal shunt as an independent risk factor for HE in patients with HCC receiving LEN. We also revealed that the splenorenal shunt, but not liver dysfunction, was the most influential classifier for HE in a decision tree analysis. Kuwahara et al. and Namba et al. previously reported cases of HCC in which occlusion of the portosystemic shunt before LEN treatment effectively suppressed the development of HE (34,35). Fujiwara et al. recently examined factors that exacerbate portal hypertension-related complications in patients with HCC receiving systemic therapy (13). They found that a portosystemic shunt diameter ≥6.8 mm was a predictor of HE. As a possible explanation for the incidence of HE during LEN treatment, LEN is a potent inhibitor of vascular endothelial growth factor receptors 1-3 (2). Inhibition of vascular endothelial growth factor receptors reduces nitric oxide production from sinusoidal endothelial cells, leading to contraction of hepatic stellate cells and subsequent increase in hepatic sinusoidal pressure and portal pressure (10,11). Taken together, these findings suggest that LEN may cause HE through an increase in portal pressure; therefore, attention should be paid to splenorenal shunt and portal hypertension management of LEN treatment in patients with HCC.
A decision-tree analysis revealed that rifaximin was associated with a lower incidence of HE in HCC patients with splenorenal shunts and ALBI grade 2 receiving LEN than in others. Besides the portal-systemic shunt, a leaky gut is another important pathogenesis of HE (36), and gut permeability is increased in patients with advanced liver cirrhosis (37). Fujimoto et al. reported that an increase in gut permeability was associated with adverse events, including HE, in patients with HCC receiving LEN (38). In contrast, rifaximin is also known as a ligand of the pregnane X receptor (39) and has been reported to improve gut permeability through the suppression of inflammation in several animal studies (40-42). Furthermore, in patients with decompensated liver cirrhosis, Kaji et al. reported that rifaximin alleviated HE and endotoxemia with improvement in intestinal hyperpermeability (22). Taken together, these findings suggest that rifaximin may suppress the incidence of HE by improving leaky gut in patients with HCC receiving LEN. We also found that rifaximin was associated with an increased prevalence of 4-week RDI of LEN ＞70% in patients with HCC splenorenal shunt and ALBI grade 2. A 4-week RDI of LEN ＞70% is a crucial factor for an improved treatment response and lengthened overall survival (12,43,44). Thus, rifaximin may be beneficial for the management of patients with HCC with splenorenal shunt and ALBI grade 2 receiving LEN.
Several limitations associated with the present study warrant mention. First, it was a retrospective observational study with a small sample size. Second, this study was conducted at two institutions in Japan. Thus, the results of our study should be validated by an international randomized controlled study with a large sample size.
In conclusion, we found that a splenorenal shunt was an independent risk factor and the most important factor for HE in patients with unresectable HCC receiving LEN. We further revealed that rifaximin was associated with a reduced onset of HE and the continuous administration of a sufficient dose of LEN in patients with unresectable HCC. Thus, rifaximin may be beneficial for the management of patients with unresectable HCC receiving LEN in patients with splenorenal shunts and decreased hepatic reserve capacity.
Author’s disclosure of potential Conflicts of Interest (COI).
Shigeo Shimose received lecture fees from AstraZeneca, Eisai, and Chugai Pharmaceutical. Hideki Iwamoto received lecture fees from Chugai Pharmaceutical and Eizai and research funding from Eizai. Takumi Kawaguchi received lecture fees from ASKA Pharmaceutical; Taisho Pharmaceutical; Kowa; AbbVie; Eisai; EA Pharma; Nippon Boehringer Ingelheim; Sumitomo Pharma; Novo Nordisk Pharma; Otsuka Pharmaceutical; and Janssen Pharmaceutical. The other authors have no conflicts of interest to declare.
Supplementary Material
This flowchart illustrates the selection process for 241 patients with hepatocellular carcinoma who received lenvatinib treatment. Following the exclusion of 25 patients based on specific criteria, a final cohort of 216 patients was established for the study analysis. Abbreviations: HCC, hepatocellular carcinoma; LEN, lenvatinib; TACE, transarterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy.
Funding Statement
his work was supported by AMED under JP24fk0210149 and by JSPS KAKENHI Grant Number JP24K11119. The funding source had no role in the design, practice, or analysis of this study.
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Associated Data
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Supplementary Materials
This flowchart illustrates the selection process for 241 patients with hepatocellular carcinoma who received lenvatinib treatment. Following the exclusion of 25 patients based on specific criteria, a final cohort of 216 patients was established for the study analysis. Abbreviations: HCC, hepatocellular carcinoma; LEN, lenvatinib; TACE, transarterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy.