Hepatocellular Carcinoma Treatment Outcomes: The Influence Of Butyrate Producers
Overview
In a retrospective multi-center study involving 747 patients with advanced hepatocellular carcinoma (HCC) treated with a combination therapy of atezolizumab and bevacizumab, the influence of butyric acid-producing enterobacteria on treatment outcomes was investigated. Previous research has established a link between the gut microbiome and the response to checkpoint inhibitors in cancer patients, with reports indicating that oral administration of such bacteria can enhance the efficacy of these inhibitors. However, this study sought to explore this relationship specifically in patients with HCC.
The study divided patients into two groups: one consisting of 99 patients who ingested drugs containing butyric acid-producing enterobacteria (the butyric acid group), and the other comprising the remaining patients (the control group). The study evaluated tumor response, survival rates, and adverse effects in both groups.
The results indicated that the butyric acid group demonstrated slightly higher objective response and disease control rates (29.7% and 77.8%, respectively) compared to the control group (26.4% and 72.7%, respectively). However, these differences were not statistically significant (p=0.543 and p=0.222, respectively). Median survival time also showed no significant difference between the two groups (20.0 months in the butyric acid group vs. 21.4 months in the control group; p=0.789), even after adjusting for patient backgrounds using propensity scores (p=0.714).
It’s worth noting that the administration of butyrate-producing bacteria did not result in adverse effects. However, certain adverse effects were more common in the butyric acid group, including proteinuria (41.4% vs. 30.9%; p=0.041), fever (17.2% vs. 10.2%, p=0.036), and diarrhea (15.2% vs. 6.2%; p=0.001).
In conclusion, the study did not find evidence that butyrate-producing bacteria enhanced the efficacy of atezolizumab–bevacizumab combination therapy in patients with HCC. While there were slightly improved response rates in the butyric acid group, these differences were not statistically significant, and overall survival rates were similar between the two groups. Additionally, some adverse effects were more common in the group receiving butyrate-producing bacteria.
Introduction
Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths globally, often detected at advanced stages. Emerging treatments like the combination of immunotherapy using atezolizumab and bevacizumab have shown promise, becoming a recommended first-line therapy for advanced HCC in many treatment guidelines. Notably, the gut microbiome has been linked to the prognosis of various cancers, with beneficial effects observed when cancer patients are supplemented with butyrate-producing bacteria.
Previous research, such as Dizman et al.’s study, demonstrated that CBM588, containing butyric acid-producing bacteria, prolonged progression-free survival in patients with metastatic renal cell carcinoma treated with checkpoint inhibitors (CPIs) like nivolumab and ipilimumab. However, the specific relationship between enterobacteria and the outcomes of chemotherapy, including CPIs, in patients with HCC remains unclear.
To address this gap, the present study aimed to investigate the impact of butyric acid-producing enterobacteria on patients with advanced hepatocellular carcinoma receiving treatment with atezolizumab and bevacizumab.
Method
This study involved 747 patients with advanced hepatocellular carcinoma (HCC) who received treatment with atezolizumab and bevacizumab at 25 different hospitals in Japan. The enrolment period spanned from November 2020 to January 2023, and the study’s final observation date was in January 2023. To participate in the study, all patients provided their consent for the review of their clinical records. The study protocol adhered to the principles of the Declaration of Helsinki and received approval from the Institutional Ethics Committee of Ehime Prefectural Central Hospital, along with approval from each participating institution.
Patients in the study received intravenous treatment, consisting of 1200mg of atezolizumab and 15mg per kilogram of body weight of bevacizumab, administered once every three weeks, following the manufacturer’s guidelines. Treatment could be discontinued in cases of tumor progression or if patients experienced unacceptable adverse effects (AEs), as assessed by their physicians based on individual patient factors like age and overall health status. Management of AEs involved measures such as interrupting treatment or adjusting the dose according to supplier instructions.
Patients who concurrently consumed medications containing butyric acid-producing enterobacteria (specifically MIYA-BM by MIYARISAN Pharmaceutical CO., LTD. or BIO-THREE by TOA Pharmaceuticals CO., LTD.) during their treatment were categorized as the butyric acid group, while those who did not constituted the control group. Tumor response assessments were performed through computed tomography or magnetic resonance imaging scans, conducted every 2-3 months, and evaluated following the Response Evaluation Criteria in Solid Tumors version 1.1.
Statistical Analysis
The study’s baseline characteristics were presented using median values and ranges. Continuous variables were compared using the Wilcoxon rank-sum test, while categorical values were analyzed using the chi-squared test. Prognosis was assessed through the Kaplan-Meier method and the log-rank test.
To ensure balanced comparisons, propensity score matching was carried out for various factors, including age, sex, albumin-bilirubin (ALBI) score, Barcelona Clinic Liver Cancer (BCLC) stage, the cause of HCC, and the first-line treatment group, which served as matching variables. The matching process employed a caliper of 0.3, and a 1×2 matching approach was utilized.
All significance tests were conducted as two-sided tests, and p-values below 0.05 were considered statistically significant. The statistical analyses were conducted using the JMP software (version 16.0; SAS Institute Japan Ltd., Tokyo, Japan), except for the survival analysis, for which EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), was employed.
Result
Among the 747 hepatocellular carcinoma (HCC) patients treated with atezolizumab and bevacizumab, 99 individuals chose to consume medications containing butyric acid-producing enterobacteria, forming the butyric acid group. The majority of these patients (84.8%) opted for MIYA-BM, often based on previous prescriptions with unclear reasons, potentially related to conditions like irritable bowel syndrome. Notably, 13 patients (13.1%) in this group experienced chemotherapy-related diarrhea.
The median age of patients in both the butyric acid and control groups was 74 years. The cause of HCC was nonviral in 45.5% of the butyric acid group and 50.9% of the control group. Furthermore, 58.6% of patients in the butyric acid group received atezolizumab and bevacizumab as their first-line systemic therapies, which was significantly lower compared to the control group (68.7%; p=0.046). The ALBI score in the butyric acid group was notably higher than that in the control group (-2.23 vs. -2.43; p=0.001). However, no significant differences were observed in other variables between the two groups.
Although the objective response rate and disease control rate were higher in the butyric acid group (29.7% and 77.8%, respectively) compared to the control group (26.4% and 72.7%, respectively), these differences did not reach statistical significance (p=0.543 and p=0.222, respectively). Similarly, there was no statistically significant difference in median survival times between the butyric acid group (20.0 months) and the control group (21.4 months; p=0.789).
To minimize the influence of background factors, propensity score matching was conducted for age, sex, ALBI score, BCLC stage, cause of hepatocellular carcinoma, and the first-line treatment group, revealing no significant differences in median survival times between the two groups (p=0.714). Even when considering only first-line treatment patients, no significant differences in overall survival were observed (p=0.394).
The most common adverse event (AE) was proteinuria, followed by fatigue, with similar patterns of AEs in both the butyric acid and control groups. However, the butyric acid group experienced a higher frequency of proteinuria (41.4% vs. 30.9%; p=0.041), fever (17.2% vs. 10.2%; p=0.036), and diarrhea (15.2% vs. 6.2%; p=0.001) compared to the control group. Importantly, there were no unexpected AEs observed in either group.
Conclusion
The study aimed to explore the impact of butyrate-producing enterobacteria on the prognosis of patients with hepatocellular carcinoma (HCC) undergoing atezolizumab and bevacizumab combination therapy. Contrary to findings in patients with non-small cell lung cancer or metastatic renal cancer treated with checkpoint inhibitors (CPIs), this study did not uncover any benefits associated with butyrate-producing bacteria for HCC patients. The tumor response and overall survival rates remained similar between the butyric acid and control groups, even after adjusting for patient backgrounds using propensity matching.
Several factors might explain the absence of beneficial effects. Firstly, the combination therapy in this study involves atezolizumab and bevacizumab, with the latter being an anti-vascular endothelial growth factor (VEGF) antibody. Certain Bifidobacterium species have shown resistance to VEGF inhibition, which could affect the efficacy of butyrate-producing bacteria. Secondly, patients in the butyric acid group may have experienced physical deconditioning that weakened the impact of the combination therapy. Although differences in adverse events (AEs), such as diarrhea, were noted between the groups, the reasons for patients choosing these drugs were not clear. This physical deconditioning may have contributed to increased AEs in the butyric acid group.
Another factor to consider is the unrestricted consumption of bacteria-fortified foods, like yogurt and supplements, which could influence microbiome composition. This practice, allowed in the control group, might have minimized differences between the two groups. Additionally, the regular consumption of fermented foods like Natto and Miso in Japan, which are bifidogenic, could further diminish these differences.
The retrospective nature of the study represents a significant limitation. Furthermore, the effects of butyrate-producing enterobacteria might vary depending on the dosing period, but the majority of patients in the butyric acid group took the drug for over a month, rendering the impact of a few patients negligible. Although antibiotics can alter the gut microbiome and have been shown to affect the efficacy of combination therapy, this study did not observe any effects from antibiotics or proton pump inhibitors.
In conclusion, this study did not find evidence supporting the beneficial effects of butyric acid-producing enterobacteria in HCC patients treated with atezolizumab and bevacizumab combination therapy. However, considering the development of combination therapy involving CPIs like durvalumab and tremelimumab for HCC treatment, the potential utility of butyrate-producing enterobacteria remains an area for further exploration, necessitating prospective studies for validation.
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