Advancing treatment strategies: Insights from network meta-analysis of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma

Abstract

This study examines the pivotal findings of the network meta-analysis of Zhou et al, which evaluated the efficacy of hepatic arterial infusion chemotherapy and combination therapies for advanced hepatocellular carcinoma (HCC). This meta-analysis suggests that therapeutic combinations have greater efficacy than do standard treatments. The article highlights the key insights that have the potential to shift current clinical practice and enhance outcomes for patients with advanced HCC. Additionally, this article discusses further research that can be conducted to optimize these treatments and achieve personalized care for patients with HCC.

Key Words: Hepatic arterial infusion chemotherapy; Advanced hepatocellular carcinoma; Combination therapy; Network meta-analysis; Treatment efficacy

Core Tip: This study discusses the comprehensive findings of the network meta-analysis of Zhou et al on hepatic arterial infusion chemotherapy (HAIC) and its combination strategies for advanced hepatocellular carcinoma. It highlights the efficacy and comparative benefits of HAIC in improving treatment outcomes and emphasizes its potential as a targeted therapeutic option in clinical practice.

TO THE EDITOR

The study of Zhou et al[1] published in the World Journal of Gastrointestinal Oncology presents a comprehensive network meta-analysis evaluating the efficacy of hepatic arterial infusion chemotherapy (HAIC) and its combination therapies for advanced hepatocellular carcinoma (HCC). HCC often presents in an advanced stage for which treatment options are limited, rendering treatment challenging. HAIC delivers potent anticancer agents directly to the tumor through the hepatic artery. The meta-analysis of Zhou et al[1] compares the effectiveness and safety of HAIC alone and in combination with other treatments. This study contextualizes the findings, explores their clinical implications, and discusses strategies for optimizing therapeutic approaches for managing advanced HCC. Studies such as that of Zuo et al[2] have highlighted the potential of combining HAIC with immune checkpoint inhibitors and antiangiogenic agents such as camrelizumab and apatinib to improve outcomes and survival in patients with advanced HCC. Mei et al[3] introduced the Assessment for Retreatment with HAIC (ARH) score as a tool to guide retreatment decisions on the basis of treatment response and disease progression. Moreover, Wang et al[4] examined the effects of a combination of programmed cell death protein-1 (PD-1) inhibitors, tyrosine kinase inhibitors (TKIs), and HAIC as a first-line treatment of advanced HCC associated with the hepatitis B virus (HBV), and they obtained promising tumor control and survival results. These studies illustrate the ongoing efforts to enhance therapeutic outcomes through innovative combinations and personalized treatment strategies tailored to the clinical profiles of patients with advanced HCC. In summary, the meta-analysis of Zhou et al[1] and recent advancements in combination therapies offer critical insights into the evolving role of HAIC in treating advanced HCC. This study provides clinicians with perspectives on current practices and to guide research and improve outcomes for patients who have received a diagnosis of this challenging condition.

Evolution of HAIC

HAIC was developed as a targeted treatment for HCC that utilizes the liver’s unique vascular anatomy to deliver concentrated chemotherapy drugs directly to tumor sites, reducing systemic exposure and related toxicities[1]. This approach addresses the challenge of the liver’s dual blood supply by enabling selective delivery of therapeutic agents through the hepatic artery, which primarily supplies HCC tumors. Advancements in HAIC have been driven by a deep understanding of HCC’s pathophysiology and the need for localized treatment strategies involving high drug efficacy and small adverse effects. The network meta-analysis of Zhou et al[1] illustrates the comparative effectiveness of HAIC across therapeutic regimens, emphasizing the role of the treatment in improving survival and tumor response rates in patients with advanced HCC. Furthermore, recent studies have explored combination therapies aiming to enhance the efficacy of HAIC. For example, synergistic effects were found when HAIC was combined with immune checkpoint inhibitors such as camrelizumab and targeted therapies such as apatinib; antitumor immune responses were enhanced, and progression-free survival was extended[2]. Mei et al[3] emphasized the importance of personalizing treatment on the basis of a patient’s response and disease progression. HAIC is thus a pivotal advancement in the management of HCC that enables tailored therapeutic approaches, maximizing efficacy and minimizing systemic toxicity. Researchers continue to refine HAIC protocols and explore new combinations to optimize outcomes for patients with advanced HCC.

Comparative effectiveness of HAIC and combination therapies

The network meta-analysis of Zhou et al[1] provides a comprehensive evaluation of HAIC alone and in combination with various therapeutic agents or modalities for advanced HCC. The meta-analysis provides a comparative assessment of outcomes such as tumor response rate, progression-free survival, and overall survival. Additionally, the meta-analysis indicates the efficacy of HAIC in delivering targeted therapy directly to liver tumors, using the liver’s vascular anatomy to achieve high local drug concentrations and to minimize systemic toxicity. Zhou et al[1] employed a frequentist approach to compare the efficacy and safety of HAIC and its combination strategies for treating advanced HCC. This method estimates treatment effects by integrating direct and indirect evidence from multiple studies, enhancing the robustness of the comparative outcomes[1]. Zhou et al[1] used hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals to evaluate overall survival, progression-free survival, the tumor response rate, and adverse events. HRs and ORs provide standardized measures of effect size across studies, enabling comparison of treatments with varying baseline characteristics[1]. Additionally, the P-score, which ranks treatments on the basis of the probability they are the best option, was calculated to provide a detailed interpretation of the relative efficacy of various therapeutic combinations[1]. Use of the P-score enabled the inclusion of studies that did not directly compare all treatments but contributed valuable indirect comparisons. This approach is particularly relevant for HAIC, for which direct head-to-head trials are lacking. Combining direct and indirect evidence addresses gaps in the literature to provide a comprehensive understanding of the benefits and risks associated with various HAIC strategies[1]. This article references studies that have employed similar or complementary statistical methods, emphasizing the importance of robust analysis in advancing treatment strategies for HCC. For example, Zuo et al[2] employed a similar approach to demonstrate the effectiveness of the combination of HAIC, camrelizumab, and apatinib, validating the findings of Zhou et al[1] and highlighting the ability of innovative combination therapies to improve patient outcome. By highlighting the incorporation of detailed statistical methods in the meta-analysis of Zhou et al[1], this article underscores the reliability of network meta-analyses in guiding clinical decisions to advance HCC treatment. The methodological rigor of these studies supports this article’s conclusions and suggests directions for future research and clinical practice[1]. Zhou et al[1] further discussed the synergistic benefits of combining HAIC with therapies such as immune checkpoint inhibitors (camrelizumab) and vascular endothelial growth factor receptor inhibitors (apatinib) that exhibit enhanced antitumor activity and provide long-term disease control in patients with advanced HCC[2,4]. Their findings underscore the focus of research on treating HCC with combination therapies involving HAIC to improve outcomes and patient survival.

Safety and tolerability profiles

Assessing the safety and tolerability of therapeutic regimens is integral to treating HCC. The network meta-analysis of Zhou et al[1] provides insights into the safety of HAIC and its combination therapies for advanced HCC. The meta-analysis highlights safety concerns such as hematological and hepatic toxicities and other treatment-related adverse events[1]. For example, when combined with an immunotherapy agent such as camrelizumab and targeted therapy such as apatinib, HAIC has manageable toxicity if a patient is carefully monitored[2]. Additionally, the retrospective study of Wang et al[4] highlights the balance that must be struck between efficacy and safety, particularly when integrating immune checkpoint inhibitors and TKIs with HAIC to treat advanced HCC associated with HBV. Managing treatment-related adverse effects is essential to optimizing outcomes and ensuring the feasibility of HAIC-based therapies for advanced HCC.

Clinical implications and future directions

The meta-analysis of Zhou et al[1] can inform clinical decision-making and shape research into HCC treatment strategies. Integrating these strategies into clinical practice can enhance outcomes for patients with advanced HCC. For example, combining HAIC with camrelizumab and apatinib may improve the efficacy and tolerability or HAIC[2]. Mei et al[3] emphasized the importance of personalized treatment approaches, suggesting the use of tools such as the ARH score to optimize retreatment decisions and manage adverse events. Future research must identify predictive biomarkers with which patient populations receiving tailored treatments can be identified. Additional research is required to develop combination therapies that minimize toxicity and maximize efficacy[4]. However, acknowledging gaps and challenges in the study of Zhou et al[1] is essential in examining the limitations of evidence regarding the efficacy of HAIC and its combination therapies. One major limitation is the heterogeneity among studies in the network meta-analysis; variations in design, patient populations, and treatment regimens may have affected the generalizability of the findings. The lack of direct comparisons between therapeutic strategies also complicates the interpretation of the results because indirect comparisons can introduce biases that weaken the conclusions[1]. Another limitation is the inadequate representation of certain combination therapies, particularly those involving novel agents such as immune checkpoint inhibitors. Although HAIC combined with PD-1 inhibitors and TKIs has potential, as noted by Wang et al[4], the retrospective nature of the studies and the absence of large-scale randomized controlled trials (RCTs) raise concerns regarding the robustness of the evidence supporting these combinations[1]. Future research must prioritize well-designed RCTs to validate the efficacy and safety of these novel combinations and establish standardized treatment protocols for broader clinical use. However, the literature does not address long-term outcomes or potential late-onset toxicities associated with HAIC and its combination therapies. Studies such as those of Zuo et al[2] and Mei et al[3] provide insights into short-term efficacy and safety, but more comprehensive studies are required to assess long-term survival, quality of life, and posttreatment complications. Future research must also identify and validate predictive biomarkers to enable personalized treatment approaches tailored to each individual patient’s characteristics. Additionally, decision-making tools, such as the ARH score proposed by Mei et al[3], need to be refined and validated in larger cohorts to enhance their clinical utility[1]. Personalized treatment strategies must consider individual patient factors, specifically liver function, tumor burden, and molecular profiles, when evaluating the appropriateness of HAIC and its combination therapies. Using predictive biomarkers in clinical decision-making can help tailor treatment plans to maximize efficacy and minimize adverse effects[1]. Nevertheless, combining HAIC with modalities such as PD-1 inhibitors or TKIs must be approached cautiously until validated by large-scale RCTs. Clinicians must weigh the benefits against the risks, particularly for patients with compromised liver function or comorbidities[1]. Monitoring patients undergoing HAIC-based therapies in terms of their long-term outcomes and potential late-onset toxicities is critical; regular follow-ups and comprehensive assessments are required to manage adverse effects and ensure sustained therapeutic benefits[1]. Ongoing clinical trials can provide additional evidence regarding the effectiveness of HAIC and its combinations and enable refinement of treatment protocols and improvement of outcomes[1]. Addressing these limitations and incorporating these recommendations can help researchers and clinicians effectively harness HAIC’s potential, improving the prognosis for patients with advanced HCC.

CONCLUSION

The network meta-analysis of Zhou et al[1] considerably advances our understanding of HAIC and its combination therapies for treating advanced HCC. Their findings illustrate HAIC’s potency as a localized treatment that delivers high concentrations of chemotherapy agents directly to liver tumors and thereby minimizes systemic side effects[1]. This study summarizes the results of the meta-analysis, emphasizing the comparative efficacy of HAIC alone and in combination with other therapies. Additionally, this article examines HAIC’s history, mechanistic benefits, and safety profiles highlighted in the analysis. The discussion addresses clinical implications, suggesting methods for optimizing treatment strategies and improving patient outcomes for those with advanced HCC. Future research should refine HAIC protocols, explore novel combinations such as HAIC with immunotherapy and targeted agents (e.g., camrelizumab and apatinib), and identify biomarkers that can enable personalization of treatments[2-4]. These efforts can expand therapeutic options for advanced HCC, improving survival rates and patients’ quality of life. In conclusion, the meta-analysis of Zhou et al[1] provides critical insights for future HCC treatment, validating the role of HAIC in managing this challenging disease.