Postoperative immune checkpoint inhibitors plus anti-angiogenesis for hepatitis B virus-associated hepatocellular carcinoma: Analyzing the evidence and future prospects

Abstract

A recent study by Lu et al examined the potential benefits of postoperative combined therapy (PCT) using anti-programmed cell death protein-1/PD-ligand-1 and anti-vascular endothelial growth factor agents for patients with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC). At the same time, the findings offer important insights; however, several methodological and statistical limitations should be noted. These limitations include selection bias from the study’s retrospective design, variability in treatment regimens, a small sample size, and inadequate monitoring of hepatitis B virus (HBV) reactivation. The study’s conclusions about PCT efficacy warrant cautious interpretation due to unresolved biases. Prospective trials with biomarker stratification are critical to confirm these preliminary findings. These findings underscore the need for prospective, biomarker-driven trials to validate the efficacy of PCT. Future research should prioritize standardized regimens, HBV reactivation monitoring, and global collaborations to optimize therapeutic strategies for HBV-HCC.

Key Words: Adverse events; Biomarkers; Bias; Confounders; Hepatitis B virus; Hepatocellular carcinoma; Postoperative combined therapy; Immunotherapy; Follow-up

Core Tip: A recent study by Lu et al examined postoperative combined therapy (PCT) for hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC). While the findings provide important insights, it is essential to acknowledge several significant limitations. These include the potential for selection bias, a small sample size, and an insufficient focus on monitoring hepatitis B virus reactivation in detail. Future research should prioritize prospective, randomized controlled trials and adopt biomarker-driven approaches to advance the knowledge of the efficacy and safety of PCT. Moreover, extending follow-up periods and fostering global collaboration could enhance treatment outcomes and more effective patient care strategies in managing HBV-HCC.

TO THE EDITOR

We read with great interest the recent article by Lu et al[1] reporting on the value of postoperative combined therapy (PCT) with anti-programmed cell death protein-1 (PD-1)/PD-ligand-1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) agents in patients with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC). The most effective approach for managing chronic hepatitis B involves achieving seroclearance of hepatitis B surface antigen (HbsAg). This is considered the ideal goal of antiviral treatment[2]. Attaining HBsAg seroclearance significantly lowers the risk of hepatocellular carcinoma (HCC) and slows disease progression. As a result, it is frequently referred to as a “functional cure”[2]. Although the study provides valuable insight, certain aspects warrant further discussion.

Methodological limitations

Retrospective design and selection bias: The study’s retrospective design presents notable selection bias, as the decision to administer PCT was likely influenced by individual patient factors, including liver function, comorbidities, and physician preferences. These variables were not entirely accounted for in the analysis, introducing the potential for confounding by indication. For instance, patients with better baseline liver function or fewer comorbidities might have had a higher chance of receiving PCT, which could skew the results in favor of the treatment group. We need a well-designed, prospective, randomized controlled trial approach to mitigate selection bias and establish balanced groups in future research. We propose that the authors conduct sensitivity analyses to evaluate the robustness of the findings in this case of retrospective studies[3]. Alongside advanced statistical techniques such as instrumental variable analysis, it is essential to handle unmeasured confounding.

Heterogeneity in treatment regimens: The study included a range of anti-PD-1/PD-L1 and anti-VEGFR agents, each with distinct mechanisms of action, pharmacokinetic properties, and safety profiles. This heterogeneity could have influenced the outcomes, as the efficacy and toxicity levels of these agents can differ significantly. The authors did not perform subgroup analyses based on specific drug combinations, limiting the findings’ interpretability. Future studies should standardize treatment regimens or conduct stratified analyses based on specific drug combinations to more effectively discern the distinct effects of individual agents[3,4].

Sample size and statistical power: With only 150 patients enrolled, of which 30 received PCT, the study’s limited sample size may have compromised its statistical power. This may have made it challenging to identify significant differences in survival outcomes, particularly given the complexities surrounding HBV-HCC and the heterogeneity in responses to immunotherapy. Future investigations should include a large sample of patients and/or multicenter studies to improve the validity of findings and assess the broader applicability of PCT across diverse populations.

Lack of detailed hepatitis B virus reactivation monitoring: Hepatitis B virus (HBV) reactivation (HBVr) is a significant concern for patients with HBV-HCC who receive immunotherapy[5]. Although the authors briefly mentioned HBVr, they did not present comprehensive data on HBV DNA levels, HBsAg status, or the timing of reactivation during treatment. This lack of detail is noteworthy, as HBVr can have substantial implications for liver function and oncological outcomes. Future research should prioritize regularly monitoring HBV DNA and HBsAg levels, ensuring meticulous reporting of HBVr events and their influence on recurrence-free survival (RFS) and overall survival (OS)[6]. Additionally, it is essential to consider prophylactic antiviral therapy for all patients and assess its impact on HBV recurrence and treatment outcomes.

Lack of control for postoperative management differences: The authors did not adequately account for differences in postoperative management, such as supportive care, dietary adjustments, and concurrent medications, which may significantly affect patient outcomes[7]. Standardized postoperative management protocols are crucial for reducing potential confounding effects in future studies.

Statistical analysis limitations

Inadequate handling of confounders: Although the authors utilized propensity score matching and inverse probability treatment weighting to adjust for confounding variables, several critical factors were insufficiently addressed. Notably, baseline liver function metrics, liver function reserve indicated by the MELD score, and baseline alpha-fetoprotein levels were not adequately considered[8,9]. Moreover, the authors did not account for differences in patient adherence to antiviral therapy, which can significantly impact HBV replication and the recurrence of HCC. Additionally, the potential impact of adjuvant transcatheter arterial chemoembolization (TACE), known for its role in reducing recurrence rates in HCC associated with HBV, was not explored in depth[10]. Future analyses should aim for a more comprehensive adjustment for these confounders. It is also advisable to perform sensitivity analyses to address missing data and include additional confounders in multivariable models.

Subgroup analysis limitations: The subgroup analyses were limited by a small sample size, resulting in insufficient power to detect significant interaction effects. This undermines the capacity to identify specific patient subgroups that may derive greater benefits from PCT. Furthermore, the authors did not investigate possible interactions between treatment and critical prognostic factors such as tumor size, vascular invasion, and satellite nodules. Future research should pre-specify subgroup analyses grounded in clinically relevant factors and ensure sufficient power to capture interaction effects[11]. Using Bayesian methods may improve the interpretability of subgroup analyses, particularly in studies with limited sample sizes[3]. Additionally, machine learning techniques could pinpoint patient subgroups most likely to benefit from PCT.

Survival analysis and interpretation of non-significant results: The results from Kaplan-Meier curves and Cox regression analyses demonstrated no statistically significant improvement in RFS or OS associated with PCT. However, the discussion failed to adequately address the clinical implications of these findings. We recommend that the authors consider alternative statistical methodologies, such as time-dependent Cox models, to assess the effects of PCT over various time intervals[12].

Insufficient discussion on the impact of adverse events: Although the study reported adverse events (AEs), it lacks a detailed analysis of how these events may have influenced patient adherence, treatment discontinuation, or survival outcomes. A detailed subgroup analysis focusing on the impact of AEs on treatment outcomes would provide a more comprehensive safety assessment and contribute valuable insights for future investigations[13].

Results and discussion limitations

Overinterpretation of non-significant findings: The authors noted improved RFS rates in the PCT group at 6 and 12 months after adjusting for confounders. However, these differences did not reach statistical significance in the primary analysis. Emphasizing these non-significant findings may lead to hasty conclusions regarding the effectiveness of PCT. The authors should approach the interpretation of non-significant results with caution. They should indicate that the observed trends require validation through larger, prospective studies. The discussion should prioritize the findings’ clinical implications rather than emphasizing non-significant results.

Lack of mechanistic insights: The discussion section did not thoroughly explore PCT may delay recurrence in HBV-HCC. Notably, aspects such as the potential role of immune microenvironment reprogramming and vascular normalization in mitigating intrahepatic micrometastases are not examined in detail. Future research should integrate translational elements, including immunohistochemistry and flow cytometry, to better understand the mechanisms behind the observed clinical outcomes[14,15]. Additionally, the discussion should delve into the potential influence of immune cell infiltration, cytokine profiles, and angiogenesis in mediating PCT’s effects.

Inadequate discussion of AEs: The study reports a significant incidence of hypertension and hepatic impairment in the PCT group; however, the discussion did not sufficiently address the clinical implications of these AEs. The effects of hepatic impairment on treatment discontinuation and its potential association with recurrence also warrant further examination. Future studies should provide in-depth analyses of AEs, considering their impact on treatment adherence, quality of life, and long-term outcomes[16]. Incorporating patient-reported outcomes would facilitate a more comprehensive evaluation of treatment tolerability. Furthermore, the discussion should include strategies for managing AEs, such as dose adjustments and supportive care measures.

Unaddressed biases

Attrition bias: The study excluded patients who were lost to follow-up, which raises concerns about attrition bias, especially if those patients had outcomes that differed from those of the patients who remained in the study[17]. The authors did not conduct sensitivity analyses to evaluate how missing data might affect the results. Future research should focus on strategies to reduce the loss of follow-up, such as sending regular reminders to patients and utilizing telemedicine for follow-up visits. Implementing sensitivity analyses, including multiple imputation methods, will also be important for assessing the impact of missing data[18,19]. Additionally, the study should provide reasons for patient attrition and compare the baseline characteristics of those lost to follow-up with those who continued in the study.

Observer, reporting, and immortal time bias: Due to the study’s retrospective nature, data collection relied on existing medical records, which may introduce observer bias in reporting recurrence instances and AEs[20]. To improve the reliability of the data, prospective validation with independent adjudication committees is advisable. Patients who survived long enough to receive treatment may have had an inherent survival advantage, which could lead to an overestimation of treatment efficacy[21]. The study did not appropriately account for this potential bias in its design. Future analyses should consider time-dependent exposure modeling to address the immortal time bias issue effectively.

Future directions

Biomarker-driven approaches: Future research should focus on the importance of biomarkers in predicting patient responses to PCT, including PD-L1 expression, tumor mutational burden, and circulating tumor DNA[22]. Identifying patients likely to benefit from this treatment could improve therapeutic strategies. Additionally, the influence of immune-related gene expression profiles and tumor-infiltrating lymphocytes on PCT effectiveness warrants further exploration. It is essential for forthcoming studies to integrate comprehensive biomarker analyses to pinpoint predictive and prognostic markers for PCT. Combining multi-omics data, encompassing genomics, transcriptomics, and proteomics, enables a better understanding of the mechanisms driving treatment responses[23].

Combination with novel therapies: Investigating the combined effect of immunotherapy and anti-angiogenic agents with emerging therapies, such as oncolytic viruses and cancer vaccines, is vital for improving the efficacy of postoperative adjuvant therapy in patients with HBV-HCC[24]. Moreover, examining the role of targeted therapies, including tyrosine kinase inhibitors and mTOR inhibitors, in conjunction with PCT should be prioritized. Future studies should evaluate the safety and efficacy of these innovative combination therapies in patients with HBV-HCC. Initial preclinical studies can help identify potential synergistic drug combinations, which should then progress to early-phase clinical trials to evaluate their safety and preliminary effectiveness.

Global collaboration: Given the significant prevalence of HBV-HCC in Asia, international collaborations are vital for ensuring the generalizability of research findings. Such partnerships would facilitate the recruitment of larger patient cohorts and support investigations into regional variations in treatment outcomes. Establish international consortia to conduct large-scale, multicenter studies on PCT in HBV-HCC[25]. Collaboration among researchers from various geographic areas will enhance the applicability of the findings across different patient populations.

Longer follow-up duration: Current studies report a median follow-up duration of 17.4 months, which may not adequately capture long-term recurrence and survival trends. Extending the follow-up period is essential for a more thorough evaluation of treatment efficacy.

Comparative effectiveness studies: Future investigations should compare PCT with other adjuvant therapies, such as TACE and targeted therapy, to identify the optimal postoperative strategy for patients with HBV-HCC.

Investigation into the mechanisms of hepatic impairment: While the study suggests a link between hepatic impairment and recurrence, it does not examine the underlying mechanisms. Subsequent research should investigate the pathophysiological foundations of hepatic impairment during PCT and its effects on long-term outcomes.

CONCLUSION

We commend the authors and their contributions, offering valuable insights into adjuvant therapy for HBV-HCC. However, methodological limitations, such as retrospective design and unaddressed confounders, necessitate cautious interpretation. Our analysis highlights the urgent need for prospective trials integrating biomarker-driven approaches (e.g., PD-L1 expression, ctDNA) and standardized PCT regimens. Clinically, these advancements could reduce the risk of recurrence and improve survival outcomes. Future studies the mechanisms of hepatic impairment and focus on understanding these mechanisms, as well as addressing global disparities in HBV-HCC management to ensure equitable therapeutic progress. By addressing these gaps, we can better understand the efficacy and safety of PCT in this patient demographic, ultimately optimizing treatment strategies to improve patient outcomes.