Key Points
Question
What are the efficacy and tolerability of immune checkpoint inhibitors (ICIs) for patients with advanced hepatocellular carcinoma (HCC) with Child-Pugh B liver function?
Findings
In this systematic review and meta-analysis of 22 studies involving 699 patients with Child-Pugh B and 2114 patients with Child-Pugh A advanced HCC, ICI therapy in the Child-Pugh B group appeared to be safe and showed a significant number of radiologic responses, but survival outcomes were inferior compared with the Child-Pugh A group.
Meaning
These findings suggest that although the overall prognosis is still poor for patients with HCC, a proportion of patients with Child-Pugh B liver function might benefit from ICI therapy.
This systematic review and meta-analysis evaluates the efficacy and safety of immune checkpoint inhibitors in the treatment of advanced hepatocellular carcinoma with Child-Pugh class B liver function.
Abstract
Importance
Immune checkpoint inhibitors (ICIs) are increasingly used in patients with advanced hepatocellular carcinoma (HCC). However, data on ICI therapy in patients with advanced HCC and impaired liver function are scarce.
Objective
To conduct a systematic review and meta-analysis to determine the efficacy and safety of ICI treatment for advanced HCC with Child-Pugh B liver function.
Data Sources
PubMed, Embase, Web of Science, and Cochrane Library were searched for relevant studies from inception through June 15, 2022.
Study Selection
Randomized clinical trials, cohort studies, or single-group studies that investigated the efficacy or safety of ICI therapy for Child-Pugh B advanced HCC were included.
Data Extraction and Synthesis
The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline was followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 > 50%); otherwise, a fixed-effect model was used.
Main Outcomes and Measures
The objective response rate (ORR) and overall survival (OS) were considered to be the primary efficacy outcomes of ICI treatment for Child-Pugh B advanced HCC, and the incidence of treatment-related adverse events (trAEs) was set as the primary measure for the safety outcome.
Results
A total of 22 studies including 699 patients with Child-Pugh B and 2114 with Child-Pugh A advanced HCC comprised the analytic sample (median age range, 53-73 years). Upon pooled analysis, patients treated with ICIs in the Child-Pugh B group had an ORR of 14% (95% CI, 11%-17%) and disease control rate (DCR) of 46% (95% CI, 36%-56%), with a median OS of 5.49 (95% CI, 3.57-7.42) months and median progression-free survival of 2.68 (95% CI, 1.85-3.52) months. The rate of any grade trAEs in the Child-Pugh B group was 40% (95% CI, 34%-47%) and of grade 3 or higher trAEs was 12% (95% CI, 6%-23%). Compared with the Child-Pugh A group, the ORR (odds ratio, 0.59; 95% CI, 0.43-0.81; P < .001) and DCR (odds ratio, 0.64; 95% CI, 0.50-0.81; P < .001) were lower in the Child-Pugh B group. Child-Pugh B was independently associated with worse OS in patients with advanced HCC treated with ICIs (hazard ratio, 2.72 [95% CI, 2.34-3.16]; adjusted hazard ratio, 2.33 [95% CI, 1.81-2.99]). However, ICIs were not associated with increased trAEs in the Child-Pugh B group.
Conclusions and Relevance
The findings of this systematic review and meta-analysis suggest that although the safety of ICI treatment was comparable between patients with HCC with vs without advanced liver disease and the treatment resulted in a significant number of radiologic responses, survival outcomes are still inferior in patients with worse liver function. More study is needed to determine the effectiveness of ICI treatment in this population.
Introduction
Liver cancer is the third leading cause of cancer-related deaths, is sixth in global incidence for cancers,1 and has been increasing in many regions of the world.2 Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer.3 Due to late-stage diagnosis, most patients with HCC are not eligible for surgical or locoregional treatment, making systemic treatment the mainstay treatment option.4 However, varying degrees of hepatic dysfunction resulting from underlying liver disease are associated with the prognosis and efficacy of systemic treatment.5
Sorafenib was the standard first-line treatment for advanced HCC,6 but its therapeutic effect in patients with impaired liver function is poor. Prior studies have shown that overall survival (OS) is significantly lower in patients with Child-Pugh class B vs Child-Pugh class A liver function.7,8,9,10 Hence, treatment should be individualized for patients with Child-Pugh B cirrhosis.11
The emergence of immune checkpoint inhibitors (ICIs) has shown promising results in trials of advanced HCC.12,13 Compared with sorafenib, nivolumab treatment has been associated with improved OS and better tolerability in patients with Child-Pugh B HCC .14 Subgroup analysis of cohort 5 of the prospective CheckMate 040 study, which included 49 patients with Child-Pugh B cirrhosis, showed similar radiologic response and safety but worse survival compared with patients with Child-Pugh A cirrhosis. Some patients with Child-Pugh B cirrhosis, particularly responders, even showed an improvement in liver function.15
Despite the considerable knowledge gap, the majority of patients participating in clinical trials assessing ICI treatment typically are required to have Child-Pugh A liver function, although many patients with advanced HCC actually present with impaired liver function and higher Child-Pugh classes. Therefore, we performed a systematic review and meta-analysis with original data collected from the primary studies to evaluate the efficacy and safety of ICI therapy in patients with Child-Pugh B advanced HCC.
Methods
Search Strategy and Selection Criteria
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline16 (eAppendix 3 in Supplement 1), and its protocol was registered with PROSPERO (CRD42022379407). We searched PubMed, Embase, Web of Science, and Cochrane Library from inception to June 15, 2022, without language restrictions. References in eligible articles were also searched when necessary. The search strategy is detailed in eAppendix 1 in Supplement 1. Two reviewers (E.X. and Y.Z.) independently completed the title and abstract screening for eligibility using a preplanned list of inclusion and exclusion criteria (eAppendix 2 in Supplement 1), with discrepancies resolved by consensus or discussion with either Y.H.Y. or F.J. The institutional review board of the Second Affiliated Hospital of Xi’an Jiaotong University waived the need for review and informed consent because the study did not involve direct interaction with human participants or the collection of new data.
Data Extraction and Quality Assessment
Two reviewers (E.X. and Y.Z.) independently extracted data from each study, including the first author’s name, study characteristics, therapeutic method, patient demographic characteristics, HCC etiology, liver function, Barcelona Clinic Liver Cancer stage, duration of follow-up, and relevant outcomes. We collected but did not analyze data on sex due to unavailability of detailed subgroup data. Data on race and ethnicity were not collected due to heterogeneity in data availability and classification methods. When necessary, original authors were contacted to supplement missing or unclear information. The 2 reviewers independently assessed study quality, resolving disagreements through consensus or consultation with authors Y.H.Y. or F.J. The Newcastle-Ottawa Scale was used for observational studies,17 designating those scoring 7 or higher as high quality and those scoring 4 to 6 as fair quality. For single-group studies, an Institute of Health Economics (IHE) case series studies quality appraisal tool was used,18 with those meeting 70% or more of the 20 criteria deemed acceptable.
Statistical Analysis
The primary outcomes of this meta-analysis were objective response rate (ORR), OS, and treatment-related adverse events (trAEs) among patients with Child-Pugh B advanced HCC treated with ICIs and how these compared with patients with Child-Pugh A advanced HCC. The secondary outcomes were disease control rate (DCR), progression-free survival (PFS), and immunotherapy-related adverse events (irAEs) in patients with Child-Pugh B vs those with Child-Pugh A. For dichotomous data, we calculated odds ratios (ORs) and 95% CIs as summary statistics. Hazard ratios (HRs) were used as a measure of the prognostic value to analyze PFS and OS. Unadjusted or adjusted HRs and 95% CIs were extracted from studies and then pooled separately. Considering that some studies did not report HRs and 95% CIs, the methods described by Liu et al19 were used to obtain the survival data from the reported Kaplan-Meier (K-M) curves. In the single-group study that only included patients with Child-Pugh B HCC, outcomes including ORR, DCR, PFS, OS, and incidence of trAEs or irAEs were pooled with the same variable derived from the randomized clinical trials or cohort studies with both Child-Pugh A and B groups. A generalized linear mixed model was used for the meta-analysis of single proportions. Heterogeneity across included studies was assessed using the Cochran Q and I2 statistics. If the I2 statistic was less than 50% or the P value greater than .10, the heterogeneity was considered to be low, and the fixed-effect model was applied. Otherwise, the random-effects model was applied. We also performed meta-regression analyses to explore potential sources of heterogeneity among the studies. The following study characteristics were included for analytic purposes: year of publication, study design (retrospective or prospective), sample size, proportion of nonviral etiology, proportion of Barcelona Clinic Liver Cancer C/D stage, median follow-up, ICI regimens (monotherapy, combined with targeted therapy, with or without other therapy), and median age. Publication bias was evaluated using the Begg test and funnel plot. The survival, ggplot2, IPDfromKM, and meta packages in R, version 4.1.3 software (R Project for Statistical Computing) were used for statistical analyses. The threshold of statistical significance was set at a 2-sided P < .05.
Results
Study Selection and Characteristics
Our search yielded 11 200 articles, with 22 studies including 699 patients with Child-Pugh B and 2114 with Child-Pugh A advanced HCC comprising the analytic sample14,15,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39 (eFigure 1 in Supplement 1). Additional data were acquired from 7 studies (220 patients with Child-Pugh B and 787 with Child-Pugh A advanced HCC) through author correspondence.23,24,26,27,30,33,35
Study characteristics are shown in eTable 1 in Supplement 1. In summary, 19 of the 22 studies were retrospective,14,20,21,22,23,24,25,27,28,29,30,31,32,33,34,35,36,37,38 3 were prospective,15,26,39 6 evaluated nivolumab,14,15,21,22,23,26 4 evaluated nivolumab and pembrolizumab,24,25,27,28 1 evaluated camrelizumab,29 1 evaluated pembrolizumab,39 5 evaluated atezolizumab,31,32,33,34,35 and the remaining 5 did not describe detailed agents.20,30,36,37,38 The median patient age ranged from 53 to 73 years among included studies. Median follow-up time ranged from 3.3 to 30.0 months. All studies were rated as high quality based on a Newcastle-Ottawa Scale score greater than 7 or meeting more than 14 IHE criteria (eTables 2 and 3 in Supplement 1).
Evaluation of Response to Treatment
There were 14 studies that reported ORR and DCR data for patients with Child-Pugh B advanced HCC treated with ICIs.15,20,21,23,24,26,27,28,30,31,32,33,35,39 The pooled ORR was 14% (95% CI, 11%-17%), and the pooled DCR was 46% (95% CI, 36%-56%) (Figure 1A and B). Comparison of pooled cohorts of patients with Child-Pugh B vs Child-Pugh A liver function showed that the ORR and DCR of the Child-Pugh B group were lower, with pooled ORs of 0.59 (95% CI, 0.43-0.81; P < .001) and 0.64 (95% CI, 0.50-0.81; P < .001), respectively (Figure 1C and D).
Figure 1. Immune Checkpoint Inhibitor Treatment in Patients With Advanced Hepatocellular Carcinoma (HCC) and Child-Pugh B Liver Function.
Squares indicate estimates; size of squares, study weights; whiskers, 95% CIs; diamonds, mean estimates; DCR, disease control rate; OR, odds ratio; and ORR, objective response rate.
aMantel-Haenszel test, fixed effects.
Five studies evaluated ICI monotherapy,15,21,23,24,26 and 5 investigated ICI combinations with targeted therapy.31,32,33,35,39 Upon single-group meta-analysis, subgroup analyses based on ICI regimens showed that the ORR of the Child-Pugh B group was 12% (95% CI, 6%-20%) for ICI monotherapy and 19% (95% CI, 13%-27%) for ICIs combined with targeted therapy. The DCR of the Child-Pugh B group was 42% (95% CI, 31%-54%) for ICI monotherapy and 62% (95% CI, 54%-70%) for ICIs combined with targeted therapy (eFigure 2 in Supplement 1). Significant differences in ORR and DCR between the Child-Pugh B and Child-Pugh A groups were also observed for ICI monotherapy, with ORs of 0.58 (95% CI, 0.36-0.94; P = .03) and 0.67 (95% CI, 0.48-0.93; P = .02), respectively. For ICIs combined with targeted therapy, the ORR was not significant between the 2 groups, while the DCR was significantly lower in the Child-Pugh B group (eFigure 3 in Supplement 1). Furthermore, we performed a subgroup analysis based on Child-Turcotte-Pugh (CTP) scores (CTP8/9 vs CTP7) in the Child-Pugh B group.23,24,26,27,33,35 There were no significant differences in ORR (OR, 0.79; 95% CI, 0.38-1.63; P = .52) and DCR (OR, 0.67; 95% CI, 0.37-1.20; P = .18) (eFigure 4A and B in Supplement 1).
Evaluation of Survival Outcomes
For the 4 trials not reporting HRs of patients with Child-Pugh B vs Child-Pugh A advanced HCC but providing K-M curves,22,32,34,35 time-to-event outcomes were reconstructed from the K-M curves. A side-by-side comparison of the original curves and the reconstructed curves showed a close match to the original K-M curves on visual inspection and comparisons of the number-at-risk tables (eFigure 5 in Supplement 1). We next used the reconstructed individual patient data to calculate the HR. From 15 studies that provided data on univariable analysis of OS,20,21,22,25,26,27,28,29,32,33,34,35,37,38,39 Child-Pugh B was associated with an increased mortality risk compared with Child-Pugh A, with a pooled HR of 2.72 (95% CI, 2.34-3.16; P < .001) and low heterogeneity (I2 = 13%; P = .31) (Figure 2A). According to data from multivariable analysis reported by 6 studies,21,26,27,28,37,39 Child-Pugh B remained associated with increased mortality, with a pooled adjusted HR of 2.33 (95% CI, 1.81-2.99; P < .001) and with very low heterogeneity (I2 = 0%; P = .77) (Figure 2B). In addition, 8 studies provided data on univariable analysis of PFS.21,25,27,32,35,37,38,39 The pooled unadjusted HR was 1.69 (95% CI, 1.41-2.03; P < .001) (Figure 2C). An adjusted HR for PFS was unavailable, as only 2 studies reported the adjusted HR.21,37 The pooled median OS and median PFS following ICI treatment for Child-Pugh B advanced HCC were 5.49 months (95% CI, 3.57-7.42 months) and 2.68 months (95% CI, 1.85-3.52 months), respectively (Figure 3).
Figure 2. Estimated Overall Survival (OS) and Progression-Free Survival (PFS) in Patients With Advanced Hepatocellular Carcinoma and Child-Pugh B vs A Liver Function .
Squares indicate estimates; size of squares, study weights; whiskers, 95% CIs; diamonds, mean estimates; AHR, adjusted hazard ratio; HR, hazard ratio; TE, estimate of treatment effect; and seTE, standard error of treatment effect estimate.
Figure 3. Association of Immune Checkpoint Inhibitors With Median Overall Survival (OS) and Progression-Free Survival (PFS) in Patients With Hepatocellular Carcinoma and Child-Pugh B Liver Function.
Squares indicate estimates; size of squares, study weights; whiskers, 95% CIs; and diamonds, mean estimates.
aWeights are from random-effects analysis.
Because of the limited number of studies, we only performed subgroup analyses of unadjusted HRs of OS based on ICI regimens. Regardless of ICI regimens, patients with Child-Pugh B advanced HCC had a poorer prognosis than those with Child-Pugh A (eFigure 6 in Supplement 1). Notably, we did not observe any differences in OS (HR, 1.08; 95% CI, 0.73-1.60; P = .69) and PFS (HR, 1.19; 95% CI, 0.66-2.13; P = .57) between patients with CTP8/9 and CTP7 (eFigure 4D and E in Supplement 1).
Adverse Events
In the Child-Pugh B group, the incidence rate of any grade trAEs was 40% (95% CI, 34%-47%); grade 3 or higher trAEs, 12% (95% CI, 6%-23%); any grade irAEs, 31% (95% CI, 19%-46%); and grade 3 or higher irAEs, 7% (95% CI, 4%-13%). Importantly, the rate of any grade trAEs or grade 3 or higher trAEs was not increased in the Child-Pugh B group vs the Child-Pugh A group. Similarly, the incidence of trAEs was comparable between patients with CTP8/9 and CTP7 (eFigure 4C in Supplement 1). Notably, the risk of irAEs was even lower in the Child-Pugh B group than the Child-Pugh A group, with a pooled OR of 0.49 (95% CI, 0.32-0.73; P < .001). Further details on trAEs and irAEs and the number of included studies and patients are shown in the Table.
Table. Pooled Incidence of Adverse Events.
Group | Child-Pugh A | Child-Pugh B | Child-Pugh B vs A |
---|---|---|---|
Any grade trAEs | |||
IR (95% CI), % or OR (95% CI)a | 47 (24-71) | 40 (34-47) | 0.75 (0.31-1.77) |
Heterogeneity | I2 = 90%, P < .001 | I2 = 38%, P = .16 | I2 = 81%, P < .001 |
No. of studies | 515,20,24,26,39 | 615,20,23,24,26,39 | 515,20,24,26,39 |
No. of patients | 596 | 211 | 789 |
Grade ≥3 trAEs | |||
IR (95% CI), % or OR (95% CI)a | 11 (6-19) | 12 (6-23) | 1.01 (0.62-1.64) |
Heterogeneity | I2 = 85%, P < .001 | I2 = 68%, P = .008 | I2 = 0%, P = .91 |
No. of studies | 515,20,21,24,26 | 615,20,21,23,24,26 | 515,20,21,24,26 |
No. of patients | 677 | 262 | 921 |
Any grade irAEs | |||
IR (95% CI), % or OR (95% CI)a | 45 (32-58) | 31 (19-46) | 0.49 (0.32-0.73) |
Heterogeneity | I2 = 93%, P < .001 | I2 = 74%, P = .004 | I2 = 0%, P = .88 |
No. of studies | 413,15,32,36 | 515,23,30,32,36 | 415,30,32,36 |
No. of patients | 580 | 176 | 738 |
Grade ≥3 irAEs | |||
IR (95% CI), % or OR (95% CI)a | 12 (8-17) | 7 (4-13) | NA |
Heterogeneity | I2 = 70%, P = .07 | I2 = 31%, P = .24 | |
No. of studies | 215,32 | 315,23,32 | |
No. of patients | 416 | 115 |
Abbreviations: IR, incidence rate; irAE, immunotherapy-related adverse event; NA, not available; OR; odds ratio; trAE, treatment-related adverse event.
Incidence rates are reported for the individual Child-Pugh A and Child-Pugh B groups. Odds ratios are reported for Child-Pugh B vs Child-Pugh A.
Meta-Regression Analyses
We conducted meta-regression analyses on primary outcomes with high heterogeneity (eTables 4 and 5 in Supplement 1). We found no significant associations among the pooled incidence of trAEs in patients with Child-Pugh B vs Child-Pugh A advanced HCC, pooled median OS in the Child-Pugh B group, and the variables of interest.
Sensitivity Analysis and Publication Bias
To assess whether any single study had a dominant effect on the meta-analysis, we excluded 1 study at a time and analyzed its effect on the main summary estimate. In this analysis, no single study significantly affected the outcome or the heterogeneity (eFigure 7 in Supplement 1). In addition, there was no evidence of publication bias based on the Begg test (eFigure 8 in Supplement 1).
Discussion
In this systematic review and meta-analysis of data from 22 studies14,15,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39 including 699 patients with Child-Pugh B and 2114 with Child-Pugh A advanced HCC, we found very low heterogeneity across the majority of primary outcome measures analyzed. We obtained original data from 7 main studies23,24,26,27,30,33,35 and found that the ORR and DCR of patients with Child-Pugh B advanced HCC treated with ICIs were 14% and 46%, respectively, with a median OS of 5.49 months and a median PFS of 2.68 months. The incidence rate of any grade trAEs was 40%, including 12% for grade 3 or higher. Furthermore, the incidence rate of any grade irAEs was 31%, including 7% for grade 3 or higher. Although patients with Child-Pugh B HCC achieved lower ORRs and DCRs and had shorter OS and PFS than those with Child-Pugh A HCC, ICI treatment was not associated with a significantly higher risk of any or severe trAEs, and a subset of patients even experienced prolonged responses and improvement in Child-Pugh score in some cases.15,23 Notably, the pooled risk of irAEs was lower in the Child-Pugh B group, although this could be attributed to the shorter duration of therapy.
A recent meta-analysis assessed immunotherapy outcomes for patients with HCC and liver dysfunction but lacked the breadth of our systematic literature search and omitted studies involving immunotherapy plus locoregional treatments or tyrosine kinase inhibitors.40 Our study extends this work by acquiring patient data from 7 primary studies,23,24,26,27,30,33,35 which enabled comprehensive subgroup analyses that consider efficacy outcomes (ie, ORR, DCR, OS, and PFS) and safety profiles, screening more potential studies, and excluding overlapping cohorts.
A meta-analysis of sorafenib use in patients with Child-Pugh B advanced HCC showed a 4.2% response rate.10 However, recent investigations into ICIs, either alone or combined with tyrosine kinase inhibitors, showed promising clinical efficacy, manageable toxic effects, and favorable safety in patients with advanced HCC and Child-Pugh B liver function.26,32,35 Although indirect comparisons should be interpreted with caution, the response rate observed in our study was 14%, suggesting a potential therapeutic benefit from ICI therapy in a relevant proportion of these patients.
Additionally, the median OS reported for sorafenib therapy in the previous meta-analysis was 4.6 months for patients with Child-Pugh B HCC,10 and in some retrospective or prospective studies, the median OS was approximately 3 to 5 months.8,41,42 Notably, our research revealed that with ICI treatment, the median OS was 5.5 months. Although a median OS of less than 6 months still requires much work to improve the efficacy of our treatment options, this finding denotes an improvement over the median OS following sorafenib therapy. However, our findings suggest that in patients with advanced HCC and Child-Pugh B liver function, the efficacy of immunotherapy may be lower compared with Child-Pugh A despite competing comorbidity and a much higher risk of death from liver failure and other cirrhosis-related complications independent of cancer. Results were similar between ICI monotherapy and combination treatments (ie, ICIs combined with targeted therapy) separately.
Advanced liver dysfunction was postulated to polarize the liver microenvironment toward a more profound immunosuppression,43 implying reduced responsiveness to ICIs. Combination therapy, such as transcatheter arterial chemoembolization, radiofrequency ablation, and radiation therapy, was used in some studies.15,20,25,29,36 Since better liver function is an important factor for maximizing the therapeutic outcome of systemic therapy,44 the synergistic effect of ICIs combined with other therapies may be more pronounced in patients with Child-Pugh A liver function, which may have contributed to the significant difference in ORR and DCR between the 2 groups in our overall meta-analysis. Additionally, the smaller number of patients in the Child-Pugh B group, shorter follow-up and survival times, and different baseline characteristics between the Child-Pugh B and A groups may have contributed to the observed differences in response rates.
Regarding OS and PFS outcomes, among the 6 studies in the meta-analysis reporting a multivariable comparison of the Child-Pugh status,21,26,27,28,37,39 the pooled adjusted HR showed that Child-Pugh B liver function was associated with significantly worse OS. The unadjusted HR also indicated a reduced PFS for Child-Pugh B. Overall, ICI therapy was associated with a worse prognosis in patients with Child-Pugh B vs Child-Pugh A advanced HCC. Similar results were observed in subgroups of patients treated with ICI monotherapy and in combination with targeted therapies. However, because of the lack of an untreated Child-Pugh B control group, solid conclusions regarding a potential benefit of ICIs cannot be made. In fact, the prognosis of advanced HCC is determined not only by tumor burden but also by liver function.45,46 Our results confirm that liver function is associated with survival of patients with advanced HCC treated with ICIs. In patients with HCC, liver function is, in most cases, compromised due to the underlying liver fibrosis or cirrhosis but occasionally may also be impaired due to a high tumor burden. In patients with high tumor burden, response to treatment may stabilize or even improve liver function. Indeed, approximately 10% of patients enrolled in cohort 5 of the CheckMate 040 study experienced a significant improvement in liver function that lasted 6 months or longer.15
Our study also affirmed the safety of ICIs in patients with Child-Pugh B advanced HCC, revealing no significant differences in incidence of trAEs between the Child-Pugh A and B groups. This finding aligns with prior studies, including CheckMate 040,15 Ng et al,20 and Fessas et al,26 that have shown comparable safety between the groups. Interestingly, we observed a lower risk of irAEs for patients with Child-Pugh B, possibly due to their shorter exposure to ICIs because of shorter survival. Overall, our study suggests that ICIs, even in patients with advanced HCC with poor liver function, present manageable adverse effects and are safe. Notably, further subgroup analyses did not reveal any significant differences in radiologic response, survival, or incidence of trAEs between patients with CTP7 and CTP8/9 scores. However, due to the limited sample size (fewer than 100 cases with CTP8/9 across 6 studies23,24,26,27,33,35), further multicenter prospective cohort studies are needed to evaluate the association of CTP score with the efficacy and tolerability of ICI treatment in these patients.
Limitations
Several limitations should be acknowledged. First, the majority of the included studies were retrospective, which may be subject to selection bias, and larger randomized clinical trials are recommended. Second, the smaller number of patients with Child-Pugh B liver function and baseline differences between the Child-Pugh B and A cohorts may represent potential sources of bias. However, the pooled adjusted HR was similar to the pooled unadjusted HR. Third, the confounding factors analyzed in multivariable Cox proportional hazards regression models varied across studies, although the pooled adjusted HR in the overall patient cohort showed low heterogeneity. Fourth, there may be potential underreporting of AEs in some studies, and the lack of an untreated Child-Pugh B cohort prevents definite conclusions regarding a potential survival benefit of ICI therapy in these patients. Fifth, we noticed high heterogeneity in some of our results, particularly in single-arm studies. Our attempts to detect potential sources of heterogeneity through meta-regression analyses did not yield any results. The high heterogeneity observed in the single-group meta-analysis may be attributable to the combination of single-group and comparative research data. Therefore, these results should be interpreted with caution. Sixth, 5 studies did not provide detailed information on the specific ICI agents used,20,30,36,37,38 which may limit the relevance of the data from these studies and highlights the importance of reporting detailed information on the ICI agents used in future studies.
Conclusions
The findings of our systematic review and meta-analysis show that ICI therapy in patients with Child-Pugh B advanced HCC appears to be safe and associated with a significant number of radiologic responses, even though survival is inherently lower than in patients with Child-Pugh A HCC. Our data support the use of immunotherapy in well-selected patients with HCC and Child-Pugh B liver function, but randomized studies are needed to confirm the outcomes of ICI treatment in patients with advanced liver disease.
eFigure 1. Flowchart of Study Selection
eFigure 2. Subgroup Analyses Based on the ICI Regimens by Single-Arm Meta-Analysis
eFigure 3. Comparative Efficacy of ICI Treatment According to ORR and DCR Between Advanced HCC With Child-Pugh A and Child-Pugh B, Categorized by ICI Monotherapy and ICIs Combined With Targeted Therapy
eFigure 4. Subgroup analysis based on the CTP Score in Child-Pugh B Group.
eFigure 5. Example of Comparison of the Original Curves and the Reconstructed Curves of D’Alessio (2022)
eFigure 6. Subgroup Analyses of Hazard Ratio of Overall Survival Based on the ICI Regimens
eFigure 7. Sensitivity Analysis of the Main Outcomes
eFigure 8. Funnel Plot for Assessing Potential Publication Bias of the 2 Main Outcomes
eTable 1. Summary of Included Studies
eTable 2. Quality Assessment of the Included Cohort Studies Using the Newcastle-Ottawa Scale
eTable 3. The Case Series Report Quality Evaluation Form for the Included Single-Arm Studies
eTable 4. Meta-Regression of Incidence of trAEs Among Patients With Child-Pugh B HCC vs Child-Pugh A HCC
eTable 5. Meta-Regression of mOS in Patients With Advanced HCC With Child-Pugh B Liver Function
eAppendix 1. Detailed Search Strategy
eAppendix 2. Inclusion and Exclusion Criteria for Study Selection
eAppendix 3. Supporting PRISMA Checklist Items
Data Sharing Statement
References
- 1.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660 [DOI] [PubMed] [Google Scholar]
- 2.Arnold M, Abnet CC, Neale RE, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159(1):335-349.e15. doi: 10.1053/j.gastro.2020.02.068 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.European Association for the Study of the Liver . Management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182-236. doi: 10.1016/j.jhep.2018.03.019 [DOI] [PubMed] [Google Scholar]
- 4.Allemani C, Weir HK, Carreira H, et al. ; CONCORD Working Group . Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015;385(9972):977-1010. doi: 10.1016/S0140-6736(14)62038-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Grandhi MS, Kim AK, Ronnekleiv-Kelly SM, Kamel IR, Ghasebeh MA, Pawlik TM. Hepatocellular carcinoma: from diagnosis to treatment. Surg Oncol. 2016;25(2):74-85. doi: 10.1016/j.suronc.2016.03.002 [DOI] [PubMed] [Google Scholar]
- 6.Bruix J, Sherman M; American Association for the Study of Liver Diseases . Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020-1022. doi: 10.1002/hep.24199 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Marrero JA, Kudo M, Venook AP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol. 2016;65(6):1140-1147. doi: 10.1016/j.jhep.2016.07.020 [DOI] [PubMed] [Google Scholar]
- 8.da Fonseca LG, Barroso-Sousa R, Bento AD, et al. Safety and efficacy of sorafenib in patients with Child-Pugh B advanced hepatocellular carcinoma. Mol Clin Oncol. 2015;3(4):793-796. doi: 10.3892/mco.2015.536 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Chiu J, Tang YF, Yao TJ, et al. The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits. Cancer. 2012;118(21):5293-5301. doi: 10.1002/cncr.27543 [DOI] [PubMed] [Google Scholar]
- 10.McNamara MG, Slagter AE, Nuttall C, et al. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer. 2018;105:1-9. doi: 10.1016/j.ejca.2018.09.031 [DOI] [PubMed] [Google Scholar]
- 11.Peck-Radosavljevic M, Greten TF, Lammer J, et al. Consensus on the current use of sorafenib for the treatment of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2010;22(4):391-398. doi: 10.1097/MEG.0b013e328333df23 [DOI] [PubMed] [Google Scholar]
- 12.Yau T, Hsu C, Kim TY, et al. Nivolumab in advanced hepatocellular carcinoma: sorafenib-experienced Asian cohort analysis. J Hepatol. 2019;71(3):543-552. doi: 10.1016/j.jhep.2019.05.014 [DOI] [PubMed] [Google Scholar]
- 13.Xu J, Shen J, Gu S, et al. Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin Cancer Res. 2021;27(4):1003-1011. doi: 10.1158/1078-0432.CCR-20-2571 [DOI] [PubMed] [Google Scholar]
- 14.Chapin WJ, Hwang WT, Karasic TB, Mccarthy AM, Kaplan DE. Comparison of nivolumab and sorafenib for first systemic therapy in patients with hepatocellular carcinoma and Child-Pugh B cirrhosis. Cancer Med. 2023;12(1):189-199. doi: 10.1002/cam4.4906 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Kudo M, Matilla A, Santoro A, et al. CheckMate 040 cohort 5: a phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol. 2021;75(3):600-609. doi: 10.1016/j.jhep.2021.04.047 [DOI] [PubMed] [Google Scholar]
- 16.Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. The Ottawa Hospital Research Institute . 2019. Accessed May 24, 2023. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
- 18.Case series studies quality appraisal tool. Institute of Health Economics. 2014. Accessed May 24, 2023. https://www.ihe.ca/research-programs/rmd/cssqac/cssqac-about
- 19.Liu N, Zhou Y, Lee JJ. IPDfromKM: reconstruct individual patient data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2021;21(1):111. doi: 10.1186/s12874-021-01308-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Ng KYY, Wong LWJ, Ang AJS, et al. Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: experience of a tertiary Asian center. Asia Pac J Clin Oncol. 2021;17(5):e249-e261. doi: 10.1111/ajco.13454 [DOI] [PubMed] [Google Scholar]
- 21.Choi WM, Lee D, Shim JH, et al. Effectiveness and safety of nivolumab in Child-Pugh B patients with hepatocellular carcinoma: a real-world cohort study. Cancers (Basel). 2020;12(7):1968. doi: 10.3390/cancers12071968 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Finkelmeier F, Czauderna C, Perkhofer L, et al. Feasibility and safety of nivolumab in advanced hepatocellular carcinoma: real-life experience from three German centers. J Cancer Res Clin Oncol. 2019;145(1):253-259. doi: 10.1007/s00432-018-2780-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kambhampati S, Bauer KE, Bracci PM, et al. Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: safety and clinical outcomes in a retrospective case series. Cancer. 2019;125(18):3234-3241. doi: 10.1002/cncr.32206 [DOI] [PubMed] [Google Scholar]
- 24.Scheiner B, Kirstein MM, Hucke F, et al. Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort. Aliment Pharmacol Ther. 2019;49(10):1323-1333. doi: 10.1111/apt.15245 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Cui H, Dai G, Guan J. Programmed cell death protein-1 (PD-1)-targeted immunotherapy for advanced hepatocellular carcinoma in real world. Onco Targets Ther. 2020;13:143-149. doi: 10.2147/OTT.S234868 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Fessas P, Kaseb A, Wang Y, et al. Post-registration experience of nivolumab in advanced hepatocellular carcinoma: an international study. J Immunother Cancer. 2020;8(2):e001033. doi: 10.1136/jitc-2020-001033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Kuo HY, Chiang NJ, Chuang CH, et al. Impact of immune checkpoint inhibitors with or without a combination of tyrosine kinase inhibitors on organ-specific efficacy and macrovascular invasion in advanced hepatocellular carcinoma. Oncol Res Treat. 2020;43(5):211-220. doi: 10.1159/000505933 [DOI] [PubMed] [Google Scholar]
- 28.Lee PC, Chao Y, Chen MH, et al. Predictors of response and survival in immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. Cancers (Basel). 2020;12(1):182. doi: 10.3390/cancers12010182 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ju S, Zhou C, Yang C, et al. Apatinib plus camrelizumab with/without chemoembolization for hepatocellular carcinoma: a real-world experience of a single center. Front Oncol. 2022;11:835889. doi: 10.3389/fonc.2021.835889 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Xu S, Lai R, Zhao Q, Zhao P, Zhao R, Guo Z. Correlation between immune-related adverse events and prognosis in hepatocellular carcinoma patients treated with immune checkpoint inhibitors. Front Immunol. 2021;12:794099. doi: 10.3389/fimmu.2021.794099 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Chuma M, Uojima H, Hattori N, et al. Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: a multicenter analysis. Hepatol Res. 2022;52(3):269-280. doi: 10.1111/hepr.13732 [DOI] [PubMed] [Google Scholar]
- 32.D’Alessio A, Fulgenzi CAM, Nishida N, et al. Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study. Hepatology. 2022;76(4):1000-1012. doi: 10.1002/hep.32468 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.de Castro T, Jochheim LS, Bathon M, et al. Atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma with impaired liver function and prior systemic therapy: a real-world experience. Ther Adv Med Oncol. Published online February 26, 2022. doi: 10.1177/17588359221080298 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Himmelsbach V, Pinter M, Scheiner B, et al. Efficacy and safety of atezolizumab and bevacizumab in the real-world treatment of advanced hepatocellular carcinoma: experience from four tertiary centers. Cancers (Basel). 2022;14(7):1722. doi: 10.3390/cancers14071722 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Tanaka T, Hiraoka A, Tada T, et al. ; Real-life Practice Experts for HCC (RELPEC) Study Group; HCC 48 Group . Therapeutic efficacy of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma in patients with Child-Pugh class A or B liver function in real-world clinical practice. Hepatol Res. 2022;52(9):773-783. doi: 10.1111/hepr.13797 [DOI] [PubMed] [Google Scholar]
- 36.Ng KYY, Tan SH, Tan JJE, et al. Impact of immune-related adverse events on efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma. Liver Cancer. 2021;11(1):9-21. doi: 10.1159/000518619 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Yao J, Zhu X, Wu Z, et al. Efficacy and safety of PD-1 inhibitor combined with antiangiogenic therapy for unresectable hepatocellular carcinoma: a multicenter retrospective study. Cancer Med. 2022;11(19):3612-3622. doi: 10.1002/cam4.4747 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Sun X, Zhang Q, Mei J, Yang Z, Chen M, Liang T. Real-world efficiency of lenvatinib plus PD-1 blockades in advanced hepatocellular carcinoma: an exploration for expanded indications. BMC Cancer. 2022;22(1):293. doi: 10.1186/s12885-022-09405-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Wu CJ, Lee PC, Hung YW, et al. Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma. Cancer Immunol Immunother. 2022;71(11):2631-2643. doi: 10.1007/s00262-022-03185-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.El Hajra I, Sanduzzi-Zamparelli M, Sapena V, et al. Outcome of patients with HCC and liver dysfunction under immunotherapy: a systematic review and meta-analysis. Hepatology. 2023;77(4):1139-1149. doi: 10.1097/HEP.0000000000000030 [DOI] [PubMed] [Google Scholar]
- 41.Abou-Alfa GK, Amadori D, Santoro A, et al. Safety and efficacy of sorafenib in patients with hepatocellular carcinoma (HCC) and Child-Pugh A versus B cirrhosis. Gastrointest Cancer Res. 2011;4(2):40-44. [PMC free article] [PubMed] [Google Scholar]
- 42.Pressiani T, Boni C, Rimassa L, et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann Oncol. 2013;24(2):406-411. doi: 10.1093/annonc/mds343 [DOI] [PubMed] [Google Scholar]
- 43.Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol. 2014;61(6):1385-1396. doi: 10.1016/j.jhep.2014.08.010 [DOI] [PubMed] [Google Scholar]
- 44.Kudo M, Han KH, Ye SL, et al. A changing paradigm for the treatment of intermediate-stage hepatocellular carcinoma: Asia-Pacific primary liver cancer expert consensus statements. Liver Cancer. 2020;9(3):245-260. doi: 10.1159/000507370 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Cabibbo G, Petta S, Barbara M, et al. ; Italian Liver Cancer (ITA.LI.CA) Group . Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma. J Hepatol. 2017;67(1):65-71. doi: 10.1016/j.jhep.2017.01.033 [DOI] [PubMed] [Google Scholar]
- 46.Iavarone M, Cabibbo G, Biolato M, et al. Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology. 2015;62(3):784-791. doi: 10.1002/hep.27729 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure 1. Flowchart of Study Selection
eFigure 2. Subgroup Analyses Based on the ICI Regimens by Single-Arm Meta-Analysis
eFigure 3. Comparative Efficacy of ICI Treatment According to ORR and DCR Between Advanced HCC With Child-Pugh A and Child-Pugh B, Categorized by ICI Monotherapy and ICIs Combined With Targeted Therapy
eFigure 4. Subgroup analysis based on the CTP Score in Child-Pugh B Group.
eFigure 5. Example of Comparison of the Original Curves and the Reconstructed Curves of D’Alessio (2022)
eFigure 6. Subgroup Analyses of Hazard Ratio of Overall Survival Based on the ICI Regimens
eFigure 7. Sensitivity Analysis of the Main Outcomes
eFigure 8. Funnel Plot for Assessing Potential Publication Bias of the 2 Main Outcomes
eTable 1. Summary of Included Studies
eTable 2. Quality Assessment of the Included Cohort Studies Using the Newcastle-Ottawa Scale
eTable 3. The Case Series Report Quality Evaluation Form for the Included Single-Arm Studies
eTable 4. Meta-Regression of Incidence of trAEs Among Patients With Child-Pugh B HCC vs Child-Pugh A HCC
eTable 5. Meta-Regression of mOS in Patients With Advanced HCC With Child-Pugh B Liver Function
eAppendix 1. Detailed Search Strategy
eAppendix 2. Inclusion and Exclusion Criteria for Study Selection
eAppendix 3. Supporting PRISMA Checklist Items
Data Sharing Statement