Title: A Network Meta-analysis of Different Interventional Treatment Strategies for
Unresectable Hepatocellular Carcinoma
Version: 2 Date: 04 Apr 2025
Reviewer's report:
This network meta-analysis (NMA) evaluates the efficacy and safety of interventional therapies
for unresectable hepatocellular carcinoma (uHCC), comparing transarterial chemoembolization
(TACE), hepatic arterial infusion chemotherapy (HAIC), and their combinations with local
ablative therapies. The authors included 30 studies (15 RCTs, 15 propensity score-matched
cohorts) and found that **TACE combined with microwave ablation (MWA)** achieved
the highest disease control rate (DCR), while **TACE combined with high-intensity focused
ultrasound (HIFU)** showed superior 1- and 2-year survival rates. Importantly, combination
therapies did not increase serious adverse events compared to monotherapies. The study
addresses a clinically significant gap in uHCC management and employs robust methodology,
including PRISMA adherence, Bayesian NMA, and risk-of-bias assessments. However,
limitations include heterogeneity from observational studies, imprecise effect estimates, and
limited HAIC data.
Major Comments
1. The inclusion of propensity score-matched (PSM) observational studies introduces potential
residual confounding, despite statistical adjustments. While the authors acknowledge this
limitation, the impact of combining RCTs and PSM studies on heterogeneity and validity
is underdiscussed. Sensitivity analyses excluding observational studies would strengthen the
findings.
2. Imprecision in Effect Estimates
- Key results, such as the 1-year survival benefit of TACE+HIFU (OR: 8.04; 95% CI: 1.54–
126.53), have extremely wide confidence intervals, indicating substantial uncertainty. The
clinical relevance of such estimates is questionable and should be interpreted cautiously.
3. Limited Data on HAIC
- Only one RCT compared HAIC to TACE, limiting the reliability of conclusions about
HAIC’s efficacy. The authors should explicitly state that HAIC-related findings are hypothesis-
generating and require validation in larger trials.
4. Safety Outcomes Interpretation
- The conclusion that combination therapies “did not increase serious adverse events” is
misleading. The analysis found no *statistically significant differences*, but this does not equate
to equivalence. A discussion of absolute risk differences and power limitations is needed.
5. Language Restriction and Publication Bias
- Restricting the search to English-language studies may exclude relevant data, particularly from
Asian regions where uHCC is prevalent. The funnel plots (Supplementary Figure S2) suggest
low publication bias, but with only 30 studies, the power to detect bias is limited. Expanding the
search to non-English databases (e.g., CNKI, Japana Centra Revuo Medicina) would improve
comprehensiveness.
Minor Comments
1. The statistical model (consistency vs. inconsistency) is not fully detailed. Clarify how closed-
loop inconsistencies were handled and whether node-splitting was performed.
2. While SUCRA rankings are useful, their clinical significance should be emphasized. For
example, a 90.6% SUCRA for TACE+MWA does not quantify the magnitude of benefit over
other therapies.
3. Abbreviations and Formatting
- Some abbreviations (e.g., RECIST, CTCAE) are undefined at first use. Standardize decimal
places (e.g., “0.040” vs. “0.04”) and ensure consistent formatting in tables (e.g., “ND” usage).
4. Figure and Table Accessibility
- Figures 1–4 are referenced but not visible in the manuscript. Ensure high-resolution images
are provided, and label network nodes in Figure 2 with sample sizes to aid interpretation.
5. Discussion of HAIC Guidelines
- The manuscript notes that HAIC is omitted from Western guidelines but included in Asian
ones. Expand this discussion to explore regional practice variations and potential reasons (e.g.,
differences in drug regimens, patient selection).
6. Reference to Novel Therapies
- References to immunotherapies (e.g., nivolumab) and targeted therapies (e.g., cabozantinib)
are cursory. Briefly contextualize how combination interventional therapies compare to systemic
options in current treatment algorithms.
Title: A Network Meta-analysis of Different Interventional Treatment Strategies for
Unresectable Hepatocellular Carcinoma
Version: 2 Date: 04 Apr 2025
Reviewer's report:
This network meta-analysis (NMA) evaluates the efficacy and safety of interventional therapies
for unresectable hepatocellular carcinoma (uHCC), comparing transarterial chemoembolization
(TACE), hepatic arterial infusion chemotherapy (HAIC), and their combinations with local
ablative therapies. The authors included 30 studies (15 RCTs, 15 propensity score-matched
cohorts) and found that **TACE combined with microwave ablation (MWA)** achieved
the highest disease control rate (DCR), while **TACE combined with high-intensity focused
ultrasound (HIFU)** showed superior 1- and 2-year survival rates. Importantly, combination
therapies did not increase serious adverse events compared to monotherapies. The study
addresses a clinically significant gap in uHCC management and employs robust methodology,
including PRISMA adherence, Bayesian NMA, and risk-of-bias assessments. However,
limitations include heterogeneity from observational studies, imprecise effect estimates, and
limited HAIC data.
Major Comments
1. The inclusion of propensity score-matched (PSM) observational studies introduces potential
residual confounding, despite statistical adjustments. While the authors acknowledge this
limitation, the impact of combining RCTs and PSM studies on heterogeneity and validity
is underdiscussed. Sensitivity analyses excluding observational studies would strengthen the
findings.
2. Imprecision in Effect Estimates
- Key results, such as the 1-year survival benefit of TACE+HIFU (OR: 8.04; 95% CI: 1.54–
126.53), have extremely wide confidence intervals, indicating substantial uncertainty. The
clinical relevance of such estimates is questionable and should be interpreted cautiously.
3. Limited Data on HAIC
- Only one RCT compared HAIC to TACE, limiting the reliability of conclusions about
HAIC’s efficacy. The authors should explicitly state that HAIC-related findings are hypothesis-
generating and require validation in larger trials.
4. Safety Outcomes Interpretation
- The conclusion that combination therapies “did not increase serious adverse events” is
misleading. The analysis found no *statistically significant differences*, but this does not equate
to equivalence. A discussion of absolute risk differences and power limitations is needed.
5. Language Restriction and Publication Bias
- Restricting the search to English-language studies may exclude relevant data, particularly from
Asian regions where uHCC is prevalent. The funnel plots (Supplementary Figure S2) suggest
low publication bias, but with only 30 studies, the power to detect bias is limited. Expanding the
search to non-English databases (e.g., CNKI, Japana Centra Revuo Medicina) would improve
comprehensiveness.
Minor Comments
1. The statistical model (consistency vs. inconsistency) is not fully detailed. Clarify how closed-
loop inconsistencies were handled and whether node-splitting was performed.
2. While SUCRA rankings are useful, their clinical significance should be emphasized. For
example, a 90.6% SUCRA for TACE+MWA does not quantify the magnitude of benefit over
other therapies.
3. Abbreviations and Formatting
- Some abbreviations (e.g., RECIST, CTCAE) are undefined at first use. Standardize decimal
places (e.g., “0.040” vs. “0.04”) and ensure consistent formatting in tables (e.g., “ND” usage).
4. Figure and Table Accessibility
- Figures 1–4 are referenced but not visible in the manuscript. Ensure high-resolution images
are provided, and label network nodes in Figure 2 with sample sizes to aid interpretation.
5. Discussion of HAIC Guidelines
- The manuscript notes that HAIC is omitted from Western guidelines but included in Asian
ones. Expand this discussion to explore regional practice variations and potential reasons (e.g.,
differences in drug regimens, patient selection).
6. Reference to Novel Therapies
- References to immunotherapies (e.g., nivolumab) and targeted therapies (e.g., cabozantinib)
are cursory. Briefly contextualize how combination interventional therapies compare to systemic
options in current treatment algorithms.
Please review this paper.
user
Title: A Network Meta-analysis of Different Interventional Treatment Strategies for
Unresectable Hepatocellular Carcinoma
Version: 2 Date: 04 Apr 2025
Reviewer's report:
This network meta-analysis (NMA) evaluates the efficacy and safety of interventional therapies
for unresectable hepatocellular carcinoma (uHCC), comparing transarterial chemoembolization
(TACE), hepatic arterial infusion chemotherapy (HAIC), and their combinations with local
ablative therapies. The authors included 30 studies (15 RCTs, 15 propensity score-matched
cohorts) and found that **TACE combined with microwave ablation (MWA)** achieved
the highest disease control rate (DCR), while **TACE combined with high-intensity focused
ultrasound (HIFU)** showed superior 1- and 2-year survival rates. Importantly, combination
therapies did not increase serious adverse events compared to monotherapies. The study
addresses a clinically significant gap in uHCC management and employs robust methodology,
including PRISMA adherence, Bayesian NMA, and risk-of-bias assessments. However,
limitations include heterogeneity from observational studies, imprecise effect estimates, and
limited HAIC data.
Major Comments
1. The inclusion of propensity score-matched (PSM) observational studies introduces potential
residual confounding, despite statistical adjustments. While the authors acknowledge this
limitation, the impact of combining RCTs and PSM studies on heterogeneity and validity
is underdiscussed. Sensitivity analyses excluding observational studies would strengthen the
findings.
2. Imprecision in Effect Estimates
- Key results, such as the 1-year survival benefit of TACE+HIFU (OR: 8.04; 95% CI: 1.54–
126.53), have extremely wide confidence intervals, indicating substantial uncertainty. The
clinical relevance of such estimates is questionable and should be interpreted cautiously.
3. Limited Data on HAIC
- Only one RCT compared HAIC to TACE, limiting the reliability of conclusions about
HAIC’s efficacy. The authors should explicitly state that HAIC-related findings are hypothesis-
generating and require validation in larger trials.
4. Safety Outcomes Interpretation
- The conclusion that combination therapies “did not increase serious adverse events” is
misleading. The analysis found no *statistically significant differences*, but this does not equate
to equivalence. A discussion of absolute risk differences and power limitations is needed.
5. Language Restriction and Publication Bias
- Restricting the search to English-language studies may exclude relevant data, particularly from
Asian regions where uHCC is prevalent. The funnel plots (Supplementary Figure S2) suggest
low publication bias, but with only 30 studies, the power to detect bias is limited. Expanding the
search to non-English databases (e.g., CNKI, Japana Centra Revuo Medicina) would improve
comprehensiveness.
Minor Comments
1. The statistical model (consistency vs. inconsistency) is not fully detailed. Clarify how closed-
loop inconsistencies were handled and whether node-splitting was performed.
2. While SUCRA rankings are useful, their clinical significance should be emphasized. For
example, a 90.6% SUCRA for TACE+MWA does not quantify the magnitude of benefit over
other therapies.
3. Abbreviations and Formatting
- Some abbreviations (e.g., RECIST, CTCAE) are undefined at first use. Standardize decimal
places (e.g., “0.040” vs. “0.04”) and ensure consistent formatting in tables (e.g., “ND” usage).
4. Figure and Table Accessibility
- Figures 1–4 are referenced but not visible in the manuscript. Ensure high-resolution images
are provided, and label network nodes in Figure 2 with sample sizes to aid interpretation.
5. Discussion of HAIC Guidelines
- The manuscript notes that HAIC is omitted from Western guidelines but included in Asian
ones. Expand this discussion to explore regional practice variations and potential reasons (e.g.,
differences in drug regimens, patient selection).
6. Reference to Novel Therapies
- References to immunotherapies (e.g., nivolumab) and targeted therapies (e.g., cabozantinib)
are cursory. Briefly contextualize how combination interventional therapies compare to systemic
options in current treatment algorithms.
assistant