Dexamethasone and N-acetylcysteine for the prevention of post-embolization syndrome following transarterial chemoembolization in hepatocellular carcinoma: a systematic review and network meta-analysis

Introduction

Hepatocellular carcinoma (HCC) is a major global public health concern. It accounts for 75–85% of primary liver cancer cases and is the fourth leading cause of cancer-related death worldwide (1). For patients with HCC classified as stage B according to the Barcelona Clinic Liver Cancer staging system, conventional transarterial chemoembolization (cTACE) has been established as the standard treatment, significantly improving patient survival (2). The technical principle of cTACE involves injecting a mixture of chemotherapeutic agents (such as doxorubicin and mitomycin) and embolic materials (such as lipiodol and gelatin sponge particles) into the tumor’s feeding arteries, thereby achieving localized chemotherapy and inducing tumor ischemic necrosis.

Despite the proven efficacy of cTACE, post-embolization syndrome (PES) remains the most common and clinically significant complication, markedly increasing patient discomfort and prolonging hospital stays (3). PES is a multifactorial clinical condition primarily characterized by fever, abdominal pain, nausea, and vomiting. The exact pathophysiology of PES remains unclear; however, it is generally understood to result from the combined effects of multiple mechanisms, including inflammatory response, chemotherapeutic toxicity, and ischemia–reperfusion injury. The inflammatory response occurs as ischemic tumor and normal liver cells undergo necrosis after embolization, releasing inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha, which trigger systemic inflammation. Chemotherapeutic toxicity arises when a portion of locally infused agents enters the systemic circulation, exerting direct toxic effects. Additionally, during the reperfusion process of ischemic liver tissue, a large amount of oxygen radicals is generated, causing hepatocellular injury (4,5).

Given that the pathogenesis of PES involves inflammation and oxidative stress, corticosteroids and antioxidants are considered potential preventive options. Dexamethasone (DEXA) has been shown to be effective for the prophylaxis of PES during TACE in previous studies due to its potent anti-inflammatory and immunosuppressive properties (6-10). N-acetylcysteine (NAC), a glutathione precursor and hepatoprotective antioxidant, has also been demonstrated to reduce the incidence of PES (11). It exerts cytoprotective effects by replenishing glutathione stores and scavenging oxygen free radicals. In animal models, NAC has further been shown to ameliorate hepatic ischemia–reperfusion injury (12,13).

Since DEXA and NAC prevent PES through different mechanisms, their combination may exert synergistic effects, particularly in preventing more severe complications such as liver dysfunction. The study by Simasingha et al. (3) addressed this knowledge gap and demonstrated the effectiveness of the combined use of DEXA and NAC (NAC + DEXA) in preventing PES. Although several randomized controlled trials (RCTs) and retrospective studies have evaluated the effects of DEXA and NAC in the prevention of PES, only the study by Koonsiripaiboon et al. (14) directly compared the efficacy of the two agents. However, direct comparative evidence on the use of DEXA and NAC, either alone or in combination, remains limited.

To address this limitation, we conducted a systematic review and Bayesian network meta-analysis of RCTs to assess the relative efficacy and safety of DEXA, NAC, and their combination in preventing PES after TACE among patients with HCC, providing further evidence to guide clinical decision-making. We present this article in accordance with the PRISMA-NMA reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2815/rc).

Methods

Search strategy

The study protocol was registered in PROSPERO (ID: CRD420251248347). PubMed, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched for studies published up to November 12, 2025, without language restrictions. The following keywords were used: (“Dexamethasone” OR “N-acetylcysteine” OR “DEXA” OR “Dex” OR “NAC”) AND (“embolization” OR “chemoembolization”). Additionally, reference lists of relevant articles, systematic reviews, and meta-analyses were manually screened to identify potential studies that might have been missed in the database search.

Inclusion and exclusion criteria

Two reviewers independently assessed the retrieved articles to determine whether they met the following inclusion criteria: studies involving adult patients with HCC undergoing TACE; prophylactic administration of at least one of DEXA or NAC for the prevention of PES; RCTs; and reporting at least one outcome in quantitative form. Conversely, studies were excluded if they contained incomplete or irrelevant data; were in vitro or animal studies; were non-RCTs; were duplicate publications; or were not original research articles (e.g., protocols, letters, case reports, reviews, comments, or meta-analyses). Any discrepancies in article eligibility between the two reviewers were resolved through discussion with a third author until consensus was achieved.

Data extraction

Two reviewers independently screened eligible studies and extracted data using NoteExpress software (version 4.2.0). Disagreements were resolved by consultation with a third reviewer. Extracted data included general study characteristics (first author, sample size, publication year, and country) and participant characteristics (age, sex, interventions, and outcome measures). In addition to the incidence of PES, data on specific symptoms—particularly pain, fever, nausea, and vomiting—as well as metabolic indicators were collected for quantitative analysis.

Quality assessment

Two independent reviewers evaluated the methodological quality of the included clinical studies using the Cochrane Risk of Bias Assessment Tool, which comprehensively examines seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other potential sources of bias. The results were visualized using Review Manager software (version 5.3; The Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen).

Statistical analysis

The Bayesian random-effects network meta-analysis was performed using R software (version 4.5.2) with the “gemtc” package (based on JAGS) employing Markov Chain Monte Carlo (MCMC) simulation. We used the default prior distributions implemented in the “gemtc” package. For the between-study heterogeneity, a uniform prior was employed: τ ~ Uniform(0, 2.5). For the relative treatment effects, a normal prior was used: δ ~ N(0, 37.5²). To handle sparse data and zero events, we used an arm-based binomial likelihood model, which naturally accommodates zero events without requiring continuity corrections. Four MCMC chains were run for 20,000 iterations with a thinning interval of 10 and 5,000 burn-ins. Model convergence was assessed using the Potential Scale Reduction Factor (PSRF), with a value of 1 indicating convergence. Trace plots were visually inspected to evaluate chain mixing and stability, and autocorrelation plots were examined to assess sampling efficiency. Effective sample sizes (ESS) were computed for all parameters, with ESS >1,000 considered sufficient to ensure precision of the posterior estimates. If the PSRF exceeded 1.1 or the ESS was <1,000 for any parameter, the number of iterations and model parameters was adjusted to improve convergence. In networks containing closed loops, consistency between direct and indirect comparisons was evaluated using the node-splitting method implemented via the “mtc.nodesplit” function. Heterogeneity was assessed by reporting the posterior distribution of τ with its 95% credible interval (CrI) for each outcome risk ratios (RRs) and their 95% CrIs were estimated as effect size measures. The surface under the cumulative ranking curve (SUCRA) was used to rank the relative efficacy of each treatment, with lower SUCRA values indicating a higher likelihood of adverse outcomes. To explore whether the administration regimen influenced the prophylactic effect of DEXA, we performed subgroup analyses for outcomes with sufficient data (fever, nausea, pain, vomiting) using the “meta” package, a continuity correction of 0.5 was applied to studies with zero events. Results are presented as RRs with 95% confidence intervals (CIs). Finally, because of the limited number of studies on each outcome, Egger’s test for funnel plot asymmetry was not performed, as it has low power when fewer than 10 studies were available (15). Instead, we visually assessed the potential small-study effects using funnel plots for each outcome.

Certainty of evidence assessment

The confidence in the network meta-analysis findings was assessed using the Confidence in Network Meta-Analysis (CINeMA) framework (16). Six domains were evaluated for each comparison: within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence. Each domain was rated as “no concerns”, “some concerns”, or “major concerns”, and these judgments were summarized into an overall confidence rating (“high”, “moderate”, “low”, or “very low") for each treatment effect.

Sensitivity analysis

We conducted two sensitivity analyses to assess the robustness of the results. First, we repeated the network meta‑analysis restricted to double-blind RCTs. Second, we excluded studies with the smallest sample sizes to evaluate their impact on the overall estimates.

Results

Literature screening and participant characteristics

A total of 733 records were identified from databases, registers, and manual search of references, and 8 RCTs were ultimately included after removing duplicates and applying the predefined inclusion and exclusion criteria. The flowchart of the literature screening process is shown in Figure 1. The included studies were published between 2005 and 2025. All studies were conducted in Asian countries, including four in Thailand, two in China, one in South Korea, and one in Japan. The eight RCTs collectively enrolled 667 patients: 227 received DEXA, 85 received NAC, 50 received the combination of DEXA and NAC (NAC + DEXA), and 305 received placebo. Five studies reported the overall incidence of PES, six studies reported the incidence of specific symptoms (pain, fever, nausea, and vomiting), and three studies reported the incidence of post-TACE liver decompensation. The main characteristics of the included studies are summarized in Table 1.

Figure 1 PRISMA flow diagram illustrating the study selection process.

Literature quality assessment

Except for the study by Siramolpiwat et al. [2019] (11), which was an open-label trial, all other studies were randomized, double-blind, controlled trials. However, the authors of the Siramolpiwat et al. [2019] study emphasized that patients in the placebo group also received 5% dextrose until 48 h after TACE, and all outcome measures were objective, which could minimize the potential bias associated with an open-label design. Therefore, the domains for blinding of participants and outcome assessment were rated as having an “unclear risk” of bias. Three studies (7,8,10) did not report the incidence of PES but instead used the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 to evaluate symptoms, including fever, pain, and nausea/vomiting, as the study endpoints. Accordingly, selective outcome reporting in these studies was judged as “unclear risk”. Additionally, because the types of embolization techniques and chemotherapy regimens were relatively limited across all studies, which may have reduced external validity, the domain of “other potential sources of bias” for all eight studies was also rated as “unclear risk”. Overall, the eight included RCTs were considered to be of high methodological quality. The risk of bias graph and summary are presented in Figures 2,3.

Figure 2 Summary of the risk of bias for the included studies.

Figure 3 Overall risk of bias graph for the included studies.

Network model

All treatment arms from the included trials were incorporated into the network model to test the feasibility of the network meta-analysis. The Brooks-Gelman-Rubin diagnostic plots confirmed that the network models exhibited excellent convergence and were valid for analysis. All PSRF values were below 1.1, indicating satisfactory convergence. The trace plots demonstrate the good mixing and stability of the four chains. Autocorrelation plots showed some residual correlation at higher lags, although this was expected given the MCMC sampling. The large ESS (>1,000 for all parameters) confirm that the chains have explored the posterior distribution efficiently and that the estimates are precise. The detailed diagnostic outputs are provided in Appendix 1.

Outcomes

Incidence of PES and specific symptoms

A total of five studies involving 448 patients and four treatment arms contributed data on the incidence of PES (Figure 4A). Compared with placebo, only the NAC + DEXA combination was significantly more effective in preventing PES (RR =0.11; 95% CrI: 0.018–0.69; Figure 4B) and ranked highest among all interventions (SUCRA, 96.1%; Figure 4C). Although the NAC + DEXA regimen showed a trend toward superiority compared with DEXA or NAC monotherapy, the difference did not reach statistical significance. Six studies involving 500 patients and three treatment arms (NAC + DEXA, DEXA, and placebo) were included in the network analysis for fever (Figure 5A). Consistent with the PES results, prophylactic combination therapy with DEXA and NAC was significantly more effective than placebo in reducing fever (RR =0.065; 95% CrI: 0.0095–0.36; Figure 5B). SUCRA analysis indicated that NAC + DEXA ranked first for fever (Figure 5C). For nausea, the same six studies were included in the network analysis (Figure 6A). The combination therapy was significantly more effective than placebo in reducing nausea (RR =0.022; 95% CrI: 0.00076–0.17; Figure 6B), and NAC + DEXA ranked first (Figure 6C). For pain, the same six studies were included in the network analysis (Figure 7A). The combination therapy significantly reduced pain compared with placebo (RR =0.037; 95% CrI: 0.0015–0.22; Figure 7B), with NAC + DEXA ranking first (Figure 7C). For vomiting, four studies were included in the network analysis (Figure 8A). The combination therapy was significantly more effective than placebo in reducing vomiting (RR =0.067; 95% CrI: 0.005–0.56; Figure 8B), and NAC + DEXA ranked first (Figure 8C). Of note, the extremely small point estimates reflect very low event rates in the combination therapy arms, and the wide CrIs reflect imprecision due to data sparsity. Furthermore, the NAC + DEXA group showed favorable trends in all symptoms compared with the DEXA monotherapy group. SUCRA analysis indicated that NAC + DEXA ranked first across all symptom domains, suggesting the highest probability of being the most effective prophylactic regimen for symptom control. Appendix 2 provides a league table of all outcomes. Subgroup analyses revealed no statistically significant differences in treatment effect by administration regimen (multi-day vs. single-day) or by route (oral vs. intravenous) for any outcome. Detailed forest plots for each outcome are presented in Appendix 3.

Figure 4 Network meta-analysis results for PES. (A) Network diagram of PES; (B) forest plot comparing PES outcomes with placebo or NAC + DEXA; (C) SUCRA probabilities of different treatments for PES. SUCRA is a probabilistic ranking metric derived from the posterior distributions and does not directly convey the magnitude of treatment effects or the statistical significance of pairwise comparisons. CrI, credible interval; DEXA, dexamethasone; NAC, N-acetylcysteine; NAC + DEXA, combination of dexamethasone and N-acetylcysteine; PES, post-embolization syndrome; SUCRA, surface under the cumulative ranking curve.

Figure 5 Network meta-analysis results for fever. (A) Network diagram of fever; (B) forest plot comparing fever outcomes with placebo or NAC + DEXA; (C) SUCRA probabilities of different treatments for fever. See footnote in Figure 4 for detailed explanation of SUCRA interpretation. CrI, credible interval; DEXA, dexamethasone; NAC, N-acetylcysteine; NAC + DEXA, combination of dexamethasone and N-acetylcysteine; SUCRA, surface under the cumulative ranking curve.

Figure 6 Network meta-analysis results for nausea. (A) Network diagram of nausea; (B) forest plot comparing nausea outcomes with placebo or NAC + DEXA; (C) SUCRA probabilities of different treatments for nausea. See footnote in Figure 4 for detailed explanation of SUCRA interpretation. CrI, credible interval; DEXA, dexamethasone; NAC, N-acetylcysteine; NAC + DEXA, combination of dexamethasone and N-acetylcysteine; SUCRA, surface under the cumulative ranking curve.

Figure 7 Network meta-analysis results for pain. (A) Network diagram of pain; (B) forest plot comparing pain outcomes with placebo or NAC + DEXA; (C) SUCRA probabilities of different treatments for pain. See footnote in Figure 4 for detailed explanation of SUCRA interpretation. CrI, credible interval; DEXA, dexamethasone; NAC, N-acetylcysteine; NAC + DEXA, combination of dexamethasone and N-acetylcysteine; SUCRA, surface under the cumulative ranking curve.

Figure 8 Network meta-analysis results for vomiting. (A) Network diagram of vomiting; (B) forest plot comparing vomiting outcomes with placebo or NAC + DEXA; (C) SUCRA probabilities of different treatments for vomiting. See footnote in Figure 4 for detailed explanation of SUCRA interpretation. CrI, credible interval; DEXA, dexamethasone; NAC, N-acetylcysteine; NAC + DEXA, combination of dexamethasone and N-acetylcysteine; SUCRA, surface under the cumulative ranking curve.

Adverse events

Metabolic adverse events were the most common and were most frequently reported in the DEXA group. In the study by Sainamthip et al. [2021], the incidence of grade ≥3 hyperglycemia was higher in the DEXA group than in the placebo group, although the difference was not statistically significant (22.4% vs. 15.7%; P=0.74). In the study by Koonsiripaiboon et al. [2025], five patients in the DEXA group developed grade 3 hyperglycemia. Similarly, in the study by Simasingha et al. [2023], three patients experienced grade 3 hyperglycemia, but the incidence did not differ significantly between the NAC + DEXA and placebo groups (34% vs. 32%; P=0.83). Regarding hepatic function, only one patient in the DEXA group developed grade ≥3 transient hyperbilirubinemia in the study by Sainamthip et al. [2021]. Additional potential risks associated with DEXA were reported in the study by Ogasawara et al. [2018], where ascites (28.8% vs. 16.7%; P=0.11), pleural effusion (15.3% vs. 10.0%; P=0.39), and hypertension (30.5% vs. 20.0%; P=0.19) occurred more frequently in the DEXA group than in the placebo group, though without statistical significance. One case each of grade 3 hepatic infection and grade 3 heart failure was also observed in the DEXA group. In the study by Yang et al. [2017], one patient in the DEXA group developed grade 3 lipiodol pulmonary embolism after chemoembolization but recovered with conservative management.

In the study by Siramolpiwat et al. [2019], four patients in the NAC group experienced mild allergic skin reactions during infusion. All reactions resolved spontaneously after discontinuation of the infusion, and all patients successfully completed treatment after readministration. No serious adverse events related to NAC were reported in any of the included studies.

Publication bias

Funnel plots for all outcomes were constructed and visually inspected (Appendix 4). For most outcomes (PES, pain, nausea, vomiting), visual inspection revealed no apparent asymmetry, suggesting no evidence of publication bias. However, for fever, the funnel plot showed a mild asymmetry, with one small study located in the lower right quadrant and a predominance of larger studies on the right side. This asymmetry may indicate possible small-study effects. However, given the limited number of studies (n=6), definitive conclusions could not be drawn.

Heterogeneity and inconsistency assessment (Appendix 5)

The posterior medians of the between-study heterogeneity (τ) and their 95% CrIs for each outcome are presented in Table S7. Heterogeneity was moderate for most outcomes, with τ values ranging from 0.34 to 0.48, although CrIs were wide, reflecting the limited number of included trials. Because the network plot of PES contained a closed loop, a consistency test was conducted. The node-splitting analysis revealed no significant differences between direct and indirect comparisons (Figure S24).

Certainty of evidence (Appendix 6)

The CINeMA assessment indicated moderate certainty for the comparison of NAC + DEXA versus placebo, reflecting concerns regarding within-study bias and imprecision. For comparisons of all other comparisons, the certainty of evidence was low, primarily due to major concerns regarding indirectness, imprecision, or heterogeneity. The detailed ratings for each comparison are presented in Table S8.

Sensitivity analyses (Appendix 7)

After excluding non-blinded trials (Table S9) and the smallest trial (Table S10), the results were generally consistent with the primary analysis, supporting the robustness of the main conclusions. After excluding one non-blinded trial, NAC + DEXA versus placebo remained statistically significant (RR =0.11; 95% CrI: 0.011–0.99) for PES. Other outcomes were based entirely on double-blind trials and were therefore unchanged from the primary analysis. After excluding the trial with the smallest sample size, the NAC + DEXA versus placebo comparison remained significant for PES (RR =0.11; 95% CrI: 0.010–0.95). Two comparisons that were statistically significant in the primary analysis became non-significant: DEXA versus placebo for nausea and DEXA versus NAC + DEXA for vomiting. These changes are expected owing to the reduced sample size and consequent loss of precision and do not alter the overall interpretation, as the direction of the effects remains consistent.

Discussion

The reported incidence of PES varies widely, ranging from 45% to 90%, which may be attributed to differences in tumor burden, chemotherapeutic dosage, hepatic functional status, and diagnostic criteria across studies (17,18). This variability underscores the clinical need for effective prophylactic strategies. This network meta-analysis evaluated the efficacy of DEXA and NAC, administered either alone or in combination, for the prevention of PES following TACE, based on evidence from eight RCTs. The pooled analysis demonstrated that the combination of DEXA and NAC was significantly more effective than placebo in reducing the incidence of PES. Compared to DEXA or NAC monotherapy, combination therapy showed favorable trends, although these differences were not statistically significant. Moreover, the beneficial effects of the combination therapy on specific symptoms—fever, abdominal pain, nausea, and vomiting—were consistent with the primary findings.

The superior therapeutic efficacy of the combined regimen compared with placebo may be explained by the complementary mechanisms of action of DEXA and NAC. DEXA exerts potent anti-inflammatory and central antiemetic effects, whereas NAC primarily acts as an antioxidant, replenishing endogenous glutathione, improving hepatic microcirculation, and attenuating inflammation. Together, these mechanisms provide a comprehensive protective effect, targeting both upstream oxidative stress and downstream inflammatory cascades (19).

Liver decompensation is among the most severe complications of TACE and is associated with substantial morbidity and mortality. It is characterized by an elevated Child-Pugh score, increased serum bilirubin, and the development of new ascites or hepatic encephalopathy within two weeks after TACE. The study by Siramolpiwat et al. [2019] reported that the occurrence of PES was a predictive factor for post-TACE liver dysfunction; however, NAC alone did not prevent this complication. In contrast, the study by Simasingha et al. [2023] found that the incidence of post-TACE liver decompensation was lower in the combination therapy group, with decompensation occurring only in the placebo group (14% vs. 0%; P=0.006). However, as this finding was derived from a single randomized trial instead of a pooled endpoint of the present network meta-analysis, it should be considered hypothesis-generating and exploratory, warranting confirmation in prospective studies specifically designed to assess hepatic outcomes.

The included studies also employed the albumin-bilirubin (ALBI) grading system to compare liver function between groups. In the study by Sainamthip et al. [2021], a higher proportion of patients in the DEXA group had grade 1 ALBI scores compared with the placebo group, although the difference was not statistically significant (40.8% vs. 21.6%; P=0.11). In the study by Simasingha et al. [2023], univariate analysis revealed that an increase in the ALBI score of more than 0.5 was associated with the development of both PES and liver decompensation. In multivariate analysis, a dynamic change in ALBI score greater than 0.5 point was the only independent indicator predictive of liver decompensation [odds ratio (OR) =42.77; 95% CI: 1.01–1810; P=0.049]. Previous studies have demonstrated that patients with grade 1 ALBI scores exhibit superior overall survival compared with those in higher grades (20). The ALBI score can also serve as a useful predictor of liver decompensation and liver failure (21). Moreover, a retrospective study reported that serum albumin (ALB), but not the Child-Pugh score, was an independent predictor of PES following TACE (22). Therefore, elevation of the ALBI score is considered a promising noninvasive tool for predicting liver dysfunction after TACE—potentially offering earlier detection than the Child-Pugh classification. Further research should focus on using dynamic changes in ALBI scores or exploring additional biomarkers, such as baseline or serial inflammatory cytokine levels (e.g., IL-6), to enable early prediction of liver decompensation and promote individualized preventive strategies.

Given that contemporary supportive care for patients undergoing TACE often includes antiemetics and analgesics, combining DEXA and NAC with these standard medications warrants consideration for multimodal prophylaxis, which may offer synergistic benefits. Parecoxib sodium, a selective COX-2 inhibitor, provides effective analgesia and reduces opioid requirements after TACE (23). For NSAIDs/COX-2 inhibitors, preclinical evidence suggests that NAC may enhance the anti-inflammatory effects by potentiating the suppression of prostaglandin production. This raises the possibility that combining NAC with NSAIDs/COX-2 inhibitors could achieve better symptom control or allow lower doses of NSAIDs, potentially reducing gastrointestinal and renal toxicity. The combination of DEXA with palonosetron (a 5-HT3 receptor antagonist) can also effectively reduce PES incidence (24,25). DEXA exerts antiemetic effects through multiple pathways, including anti-inflammatory actions, direct effects on the nucleus tractus solitarius, and interactions with the serotonin and tachykinin receptor systems. These mechanisms complement those of 5-HT3 receptor antagonists, which selectively block the peripheral and central 5-HT3 receptors. NK1 receptor antagonists (e.g., aprepitant) are widely used to treat chemotherapy-induced nausea and vomiting, with the recent validation of triple regimens combining NK1 antagonists, 5-HT3 antagonists, and DEXA (26). The mechanism also lies in the complementary blockade of multiple emetic pathways: NK1 antagonists inhibit substance P, 5-HT3 antagonists block serotonin signaling, and DEXA exerts broad anti-inflammatory and central effects. However, drug-related toxicities associated with combination therapies may increase hepatic metabolic burden or gastrointestinal bleeding (27); therefore, further evidence is required to establish their tolerability. Existing studies have demonstrated that the adverse effects of DEXA and NAC are generally mild and manageable. Notably, the study by Simasingha et al. [2023] reported no serious adverse events in the NAC + DEXA group. Nevertheless, during clinical use, it remains essential to closely monitor blood glucose levels and observe for signs of fluid retention, such as ascites and hypertension. For patients with diabetes, heart failure, active infection, or severe hepatic dysfunction, the potential benefits and risks of therapy should be carefully evaluated. Although adverse effects of NAC are typically mild, clinicians should remain vigilant for infusion-related allergic reactions.

The potential influence of DEXA on the tumor immune microenvironment, which may theoretically suppress the anti-tumor immune response triggered by TACE, has also attracted academic attention. Preclinical studies have demonstrated that corticosteroids can upregulate co-inhibitory molecules, such as PD-1 and LAG-3 on immune cells, potentially compromising the efficacy of immune checkpoint inhibitors (28). Clinical evidence from a multi-tumor cohort study indicates that corticosteroid use within 30 days before or during immune checkpoint inhibitor therapy is associated with significantly lower objective response rates, with this negative effect being dose-dependent (29). Delayed steroid initiation has also been associated with an improved response to the PD-1/CTLA-4 blockade, whereas higher peak doses are correlated with worse survival outcomes (30). In the study by Ogasawara et al. [2018], tumor response was assessed at 4 and 12 weeks after TACE using both RECIST and mRECIST criteria. Compared with placebo, DEXA did not promote tumor necrosis, invasion, or metastasis. However, the oncologic implications of corticosteroid use beyond this period remain uncertain. A retrospective cohort study in patients with autoimmune hepatitis-related cirrhosis has indicated that prolonged corticosteroid exposure was independently associated with a significantly higher incidence of HCC. Potential mechanisms include glucocorticoid-induced impairment of CD8⁺ T cell-mediated immune surveillance, activation of oncogenic pathways such as PI3K/Akt and Wnt/β-catenin, and promotion of metabolic dysregulation and hepatic fibrosis (31). Although this study was conducted in a different patient population, prolonged corticosteroid exposure may contribute to hepatocarcinogenesis. These findings underscore the importance of weighing the short-term benefits of PES prevention against the theoretical long-term risks, particularly in patients with preserved liver function who may be candidates for future immunotherapy. Further studies with extended follow-up are warranted to clarify the long-term effects of DEXA on tumor progression following TACE.

This network meta-analysis comprehensively synthesized the available evidence on the efficacy of DEXA and NAC, alone or in combination, for preventing PES after TACE. The findings indicate that combination therapy significantly reduces the incidence of PES and alleviates associated symptoms, including nausea, vomiting, fever, and pain, compared with placebo. Combination therapy also showed favorable trends compared with DEXA or NAC monotherapy. These results provide valuable clinical evidence to guide post-TACE patient management and may support the use of DEXA plus NAC as an effective prophylactic strategy when considered in the context of individual patient characteristics.

However, there are several limitations in this meta-analysis. First, all included studies were conducted in Asian populations, with limited diversity in patient backgrounds, embolization techniques, and chemotherapy regimens—most commonly using conventional cTACE with mitomycin or doxorubicin. Consequently, the findings of these Asian studies may have limited external validity and may not be fully generalizable to Western populations. In Asia, hepatitis B virus (HBV) infection is the predominant cause of HCC, whereas in Western countries, HCC is primarily related to metabolic etiologies of cirrhosis. Therefore, a considerable proportion of Western patients with type 2 diabetes or hypertension may not be suitable candidates for high-dose DEXA prophylaxis (32). In addition, drug-eluting bead (DEB)-TACE is an effective and safe treatment for patients with impaired liver function and is more commonly used in Western countries than cTACE (33). Therefore, further studies are warranted to evaluate the preventive efficacy of DEXA and/or NAC in Western populations. Second, substantial heterogeneity was observed in the endpoints related to PES, pain, and nausea. This heterogeneity may have resulted from variations in the definition of PES, as well as differences in DEXA or NAC dosage and treatment duration across studies. There are no standardized diagnostic criteria for PES, the Southwest Oncology Group (SWOG) toxicity code is commonly applied, defining PES as a cumulative score of the aforementioned symptoms greater than 2 (6,14). Some studies adopt a narrower definition, describing PES as fever ≥38.5 ℃ accompanied by an alanine aminotransferase (ALT) elevation exceeding threefold the baseline level (3,11). The studies by Sainamthip et al. [2021] and Yang et al. [2017] administered single doses of DEXA at low (8 mg) and moderate (12 mg) levels, respectively. In contrast, Ogasawara et al. [2018] employed a three-day cumulative regimen totaling 36 mg, which increased the complete remission rate of fever, nausea, and vomiting to 47.5% compared with single-dose administration. This finding suggests a potential dose-response relationship between DEXA dose and prophylactic efficacy; however, the small number of included trials limits formal meta-regression, definitive conclusions cannot be drawn from exploratory dose-response analyses [Table S11 (Appendix 8)]. Although no significant subgroup differences were found by DEXA regimen or route, the limited studies per subgroup still require cautious interpretation. For NAC, although a prolonged infusion (72 hours) may provide sustained antioxidant effects, shorter protocols can enhance patient adherence and reduce costs. Therefore, future head-to-head trials comparing different DEXA or NAC regimens are warranted to establish the optimal timing, duration, and dose for PES prevention. Third, most studies focused on short-term symptom control (ranging from 48 hours to one week), whereas few included long-term imaging or survival follow-up. Although Ogasawara et al. [2018] reported no difference in tumor response within 12 weeks, it was acknowledged that longer follow-up is required to confirm this observation. As discussed above, the potential oncologic implications of corticosteroid use beyond 12 weeks, particularly in the context of immunotherapy, remain an important area for future investigation. Fourth, the small number of studies per outcome was insufficient for formal statistical testing of publication bias. Although funnel plots showed no evident asymmetry for most outcomes, the possibility of small-study effects cannot be excluded given the limited sample size. Future meta-analyses with a larger evidence base are needed to investigate the possibility of publication bias.

Conclusions

This network meta-analysis demonstrated that the combination of DEXA and NAC is an effective prophylactic strategy for preventing PES in patients with HCC undergoing TACE. Compared with placebo, combination therapy significantly reduced PES incidence and consistently alleviated key symptoms, including fever, abdominal pain, nausea, and vomiting, with a manageable safety profile. Compared with DEXA or NAC monotherapy, the combination showed favorable trends for the primary outcome, although these differences did not reach statistical significance. However, as the current evidence is primarily derived from small-scale studies, future research should aim to validate these findings in larger and more diverse populations, optimize treatment duration and dosing regimens, identify predictive biomarkers, and assess long-term clinical outcomes to support personalized preventive strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-NMA reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2815/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2815/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2815/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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