Post-treatment adverse events ranking in targeted immunotherapy for hepatocellular carcinoma: a network meta-analysis based on risk probability assessment

<h2>Abstract</h2><h3>Background</h3> The adoption of targeted and immunotherapeutic drugs in the management of hepatocellular carcinoma (HCC) signifies a pivotal modern therapeutic approach. Nevertheless, a conspicuous gap exists in exhaustive research regarding the adverse effects of these medications in relation to their efficacy and influence on survival outcomes. This systematic review and network meta-analysis aim to assess the diverse frequencies and severities of specific adverse reactions induced by different targeted and immunotherapy interventions. <h3>Methods</h3> Clinical studies on targeted therapies and immunotherapeutic approaches in hepatocellular carcinoma (HCC) patients were selected from reputable databases including PubMed, Embase, Web of Science, and the Cochrane Library, covering the period from 2008 to 2023. These chosen studies encompassed a variety of treatment regimens. Data processing and evaluation adhered to PRISMA guidelines, utilizing a random-effects model for data synthesis. As all included studies were randomized controlled trials (RCTs), bias assessment followed the Cochrane Risk of Bias Assessment Tool and was assessed using Revman 5.3 software. The Relative Risk (RR) was selected as the effect measure over Odds Ratio (OR) to enable a risk probability analysis that better suited the characteristics of the research findings. To ensure model convergence, researchers generated trajectory plots, density plots, and Brooks-Gelman-Rubin diagnostic plots, and calculated the Potential Scale Reduction Factor (PSRF). Heterogeneity was evaluated by determining the I2 for both direct and indirect comparisons within the network model. <h3>Findings</h3> A meticulous review of pertinent literature was conducted, identifying 13 Randomized Controlled Trials (RCTs) covering 13 treatment protocols for hepatocellular carcinoma (HCC), including first-line and select second-line therapies. This study encompassed a total of 10,760 patients. Initially, adverse events within the same category were consolidated, followed by the sequential construction of a network model to evaluate the risk probabilities associated with various adverse events of different targeted immunotherapy regimens and establish priority rankings. The primary outcomes of the systematic evaluation included 38 types of adverse reactions, graded for severity based on the National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). Additionally, statistical analysis was conducted on adverse events related to 28 immune checkpoint inhibitors, with each analyzed comprehensively to assess the risk probability of the corresponding drugs. <h3>Interpretation</h3> Cabozantinib, camrelizumab, and their combination therapy for hepatocellular carcinoma (HCC) are linked to an elevated occurrence of prevalent adverse reactions. These reactions encompass elevated aminotransferase levels, fatigue, diarrhea, reduced appetite, nausea, thyroid dysfunction, hypertension, rash, palmar-plantar erythrodysaesthesia syndrome, and alopecia. In contrast, durvalumab, lenvatinib, and their combined therapy are less prone to induce common adverse effects.