Editor’s Note: The combination of atezolizumab and bevacizumab (“T+A”) has emerged as the first-line standard treatment for unresectable hepatocellular carcinoma (uHCC) and is widely used in clinical practice. However, the question remains: does discontinuation due to treatment tolerability affect patient survival outcomes? What are the clinical and pathological characteristics of patients undergoing surgery conversion with “T+A”? Antibiotic use is common in clinical settings, but does it affect the efficacy of “T+A”? This article summarizes three recent real-world studies from Japan that address these treatment-related questions, providing insights for clinicians in optimizing “T+A” therapy strategies.
01
Managing Toxic Side Effects of “T+A”: A Strategy Beyond Abrupt Discontinuation
While “T+A” has become the first-line standard treatment for uHCC, a small number of patients experience drug-related adverse events during clinical trials and practice, leading to discontinuation, interruption, or dose reduction. These treatment modifications may impact patient survival outcomes.
A retrospective analysis conducted by Tokunaga et al. [1] investigated the influence of treatment modifications on the prognosis of uHCC patients receiving “T+A”. These modifications included interruptions or discontinuations of atezolizumab and bevacizumab, as well as individual reduction, interruption, or discontinuation of bevacizumab. The study included 100 uHCC patients from five Japanese hospitals. As shown in the table below, 29 patients underwent no treatment adjustments, 46 patients did not undergo atezolizumab or bevacizumab discontinuation adjustments, 20 patients had “T+A” discontinuation adjustments, and 5 patients had both “T+A” discontinuation and other treatment adjustments.
After a median follow-up of 9.4 months, it was observed that patients who did not undergo “T+A” discontinuation adjustments (n=46) were associated with favorable overall survival (median OS not reached; HR 0.23, 95% CI: 0.075–0.68, P=0.0080) and prolonged time to disease progression (median TTP=10.00 months; HR 0.45, 95% CI: 0.24–0.87, P=0.0160).
In contrast, patients with “T+A” discontinuation adjustments (n=20) were associated with poorer OS (median OS=9.63 months; HR 2.72, 95% CI: 1.05–7.07, P=0.040) and shorter TTP (median TTP=2.53 months, HR 2.78, 95% CI: 1.40–5.51, P=0.0040).
Patients with liver function changes classified as modified albumin-bilirubin grade 2b (mALBI 2b) (n=43, 30.2%) or those experiencing immune-related adverse events (irAE) (n=31, 35.5%) had a higher rate of “T+A” discontinuation compared to those with mALBI grade 1 (10.2%) and without irAE (13.0%). Patients with objective response (n=48) had a higher frequency of irAE occurrence (n=21) compared to patients without objective response (n=10) (P=0.027).
This study suggests that among patients with unresectable hepatocellular carcinoma (uHCC) receiving “T+A” therapy, the absence of “T+A” discontinuation adjustments is associated with better overall survival, time to progression, and tumor response. On the contrary, patients who discontinued “T+A” had worse prognosis. Therefore, avoiding discontinuation of “T+A” appears to be the optimal strategy to improve the outcomes of patients undergoing this treatment. The study also identified factors associated with higher discontinuation rates (mALBI 2b grade, presence of irAE), emphasizing the importance of monitoring and managing adverse events in such populations. Efforts should be made to ensure patients can tolerate the treatment, and dose adjustments if necessary may contribute to maximizing patient outcomes.
02
Positive Signals for “T+A” Conversion Therapy: Identifying Predictive Factors
Numerous studies have explored the efficacy and safety of “T+A” for conversion therapy in unresectable hepatocellular carcinoma (uHCC), demonstrating promising conversion rates. Establishing predictive factors for conversion therapy can aid in identifying patients who will benefit most. Previous reports have linked neutrophil-to-lymphocyte ratio (NLR), albumin-bilirubin grade (ALBI), neo-Glasgow Prognostic Score, and Prognostic Nutritional Index to the efficacy and overall survival (OS) of “T+A”. However, there is limited research on predictive factors specifically for “T+A” conversion therapy.
A retrospective study conducted by Shimose et al. [2] included 156 Child Pugh A grade uHCC patients undergoing “T+A” therapy. Decision tree analysis was employed to investigate the landscape of objective responses, evaluating progression-free survival (PFS), recurrence-free survival, and overall survival. Baseline characteristics of the enrolled patients are presented in the table below, with the majority having tumors ≥5 cm (110/156), and 39.1% (61/156) receiving second-line or subsequent treatments. The study cohort demonstrated a median PFS of 6.1 months, an impressive OS of 18.0 months, an objective response rate (ORR) of 32%, and a disease control rate (DCR) of 84%.
Decision tree analysis revealed that neutrophil-to-lymphocyte ratio (NLR) <3, modified albumin-bilirubin grade (m-ALBI) 1 or 2a, and age <75 were sequential splitting variables for objective response. In multifactorial analysis, NLR <3 and m-ALBI 1 or 2a were identified as predictive factors for objective response.
Following significant response to “T+A” therapy, a total of 17 patients successfully qualified for conversion therapy. After conversion therapy, the recurrence-free survival (RFS) rate in the surgical resection or radiofrequency ablation (RFA) group was significantly higher compared to transcatheter arterial chemoembolization (TACE) and “T+A” discontinuation (Surgery/RFA vs. TACE: not reached vs. 5.3 months, P=0.008; Surgery vs. “T+A” discontinuation: not reached vs. 3.9 months, P=0.048).
The results of this study indicate that NLR <3 and m-ALBI grade 1 or 2a are crucial predictive factors for both the relief of “T+A” therapy and successful conversion therapy. These factors contribute to better drug-free and tumor-free survival in patients with unresectable hepatocellular carcinoma (uHCC), effectively extending patient recurrence-free survival (RFS). This helps clinicians identify patients who are more likely to qualify for conversion therapy from “T+A” treatment and further improve patient survival through local treatments such as surgery or RFA.
03
Consideration of Antibiotic Treatment History Prior to “T+A” Therapy
Antibiotics can impact the integrity of the gut microbiota, leading to a decrease in microbial diversity. Previous studies have suggested that the use of antibiotics before or during immune checkpoint inhibitor (ICI) therapy may modulate the gut microbiota, potentially resulting in resistance of some tumors to ICI. However, there is a lack of research on the correlation between ICI treatment response and antibiotics in hepatocellular carcinoma (HCC) patients.
In a retrospective analysis by Maesaka et al.[3], 105 patients with primary liver cancer receiving “T+A” therapy were studied, sourced from a prospective registry of a multicenter cohort. Among them, 19 patients had a history of antibiotic treatment (ATB+), while 86 patients had no history of antibiotic treatment (ATB-). Except for baseline C-reactive protein (CRP), which showed some differences, there were no significant differences in other baseline characteristics between the two groups.
There were no significant differences between ORR assessed against RECIST v1.1 in the ATB- and ATB+ groups (30.1% vs. 11.1%; P=0.143), and ORR as assessed by mRECIST (44.6% vs. 27.8%; P=0.190). DCR assessed against RECIST v1.1 (74.7% vs. 44.4%; P=0.012), and DCR as assessed by mRECIST (78.3% vs. 50.0%; P=0.020) showed that the DCR of ATB- group was higher than that of ATB+ group.
A history of prior antibiotic use was independently associated with radiological progression of disease at the first treatment assessment. According to RECIST v1.1 (9.1 vs. 3.0 months; P=0.049) and mRECIST (9.1 vs. 3.0 months; P=0.036) assessments of progression-free survival (PFS), the ATB- group exhibited significantly longer PFS compared to the ATB+ group. Additionally, overall survival (OS) in the ATB- group was also significantly longer than in the ATB+ group (not reached vs. 11.4 months; P=0.015).
Single-factor analysis indicated that age, tumor invasion of major vessels, neutrophil-to-lymphocyte ratio (NLR), and antibiotic use (ATB) were associated with disease progression (PD). However, multi-factorial analysis revealed that only antibiotic use (ATB) was correlated with disease progression. Additionally, multi-factorial analysis did not identify ATB as an independent predictive factor for OS.
This study represents the first report on the impact of antibiotics on the efficacy of “T+A” therapy in liver cancer. Patients who had received antibiotic treatment exhibited significantly shorter progression-free survival (PFS) and overall survival (OS) compared to those who had not received antibiotic treatment, suggesting a potential association between antibiotics and reduced effectiveness of “T+A” therapy. However, in multi-factorial analysis, the history of antibiotic treatment was not identified as an adverse predictive factor for survival outcomes. It is crucial to emphasize that the sample size in this study is relatively small, especially in the antibiotic use group with only 19 cases. Background factors related to antibiotic treatment in both groups might influence the result analysis. Future research should involve larger real-world studies or clinical randomized controlled trials to validate these findings.
References:
[1] Tokunaga T, Tateyama M, Kondo Y, et al. Therapeutic Modifications without Discontinuation of Atezolizumab Plus Bevacizumab Therapy Are Associated with Favorable Overall Survival and Time to Progression in Patients with Unresectable Hepatocellular Carcinoma. Cancers (Basel). 2023;15(5):1568. Published 2023 Mar 2. doi:10.3390/cancers15051568
[2] Shimose S, Iwamoto H, Shirono T, et al. The impact of curative conversion therapy aimed at a cancer-free state in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Cancer Med. 2023;12(11):12325-12335. doi:10.1002/cam4.5931
[3] Maesaka K, Sakamori R, Yamada R, et al. Pretreatment with antibiotics is associated with reduced therapeutic response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma. PLoS One. 2023;18(2):e0281459. Published 2023 Feb 7. doi:10.1371/journal.pone.0281459
TAG: review; hepatocellular carcinoma
