Impact of Child Pugh B Stage for the Treatment of Advanced HCC

Introduction

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and one of the leading causes of cancer-related mortality worldwide. Its global incidence continues to rise, largely driven by metabolic dysfunction–associated steatotic liver disease (MASLD) and alcohol-related liver disease.^1,2 Because HCC commonly arises in the setting of cirrhosis, liver function is a critical determinant of treatment feasibility and prognosis.^3–5

The Child–Pugh (CP) classification remains the most widely used system to assess hepatic functional reserve and to guide treatment allocation in patients with HCC.^6,7 While patients with CP class A liver function are typically eligible for most curative or palliative therapies, and those with CP class C are usually limited to supportive care, the optimal management of CP class B patients remains controversial. This intermediate group represents approximately 20–40% of HCC patients at diagnosis and is characterized by substantial heterogeneity in liver function, ranging from compensated (CP-B7) to clearly decompensated disease (CP-B9).^8–11

In clinical practice, CP-B status strongly influences treatment tolerance and survival, yet these patients are consistently underrepresented in pivotal clinical trials evaluating both locoregional and systemic therapies.^9,12–15 Consequently, most therapeutic recommendations are extrapolated from studies conducted in CP-A populations, leaving a major evidence gap in the palliative management of HCC with moderate liver dysfunction. Furthermore, the CP score itself has important methodological limitations, as several of its parameters are subjective, interdependent, or redundant.¹⁰ This has prompted interest in more objective tools such as the albumin–bilirubin (ALBI) grade, which may better capture liver functional reserve and help refine treatment selection.^16,17

The present narrative review provides an updated synthesis of available data on palliative treatments for patients with HCC and CP-B cirrhosis. The recent shift toward immunotherapy-based combinations as first-line standard of care in advanced HCC further underscores the need to re-evaluate how patients with CP B liver dysfunction can be safely and effectively integrated into modern therapeutic algorithms. We summarize the evidence for locoregional and systemic therapies, critically appraise their efficacy and safety, and discuss how emerging prognostic tools can inform personalized therapeutic strategies for this vulnerable population.^10,18

Clinical Relevance and Heterogeneity of Child–Pugh B in HCC

The CP score remains the cornerstone tool for assessing hepatic functional reserve in patients with cirrhosis and HCC.^6,7 It incorporates five parameters—serum bilirubin, albumin, prothrombin time (or INR), ascites, and hepatic encephalopathy—to stratify liver function into three categories: A (well-compensated), B (moderate dysfunction), and C (severe decompensation) (Table 1).

Table 1 Description of Child Pugh Score

CP-B patients, representing approximately 30–40% of HCC cases at diagnosis, exhibit intermediate hepatic dysfunction that profoundly affects both treatment tolerance and prognosis.^19,20 The survival of CP-B patients varies widely depending on the degree of hepatic impairment and the presence of complications such as ascites or encephalopathy. Median overall survival in this subgroup typically ranges from 6 to 12 months, compared to over 20 months for CP-A patients with similar tumour stage.¹⁹

Importantly, the CP-B group is not homogeneous. CP-B7 patients often display compensated disease with near-normal bilirubin levels and limited ascites, whereas CP-B8 and CP-B9 patients usually present with overt decompensation and poor hepatic reserve.^21,22 This distinction has crucial therapeutic implications: patients with CP-B7 liver function may still be candidates for selected locoregional or systemic therapies, while those with CP-B8/B9 generally derive limited benefit and face increased treatment-related toxicity.¹⁶

The CP scoring system, although simple and clinically intuitive, has well-recognized limitations. Several of its variables are interrelated—albumin and ascites both reflect oncotic pressure—and partially redundant—albumin and prothrombin time both indicate hepatic synthetic capacity. Moreover, the subjective assessment of ascites and encephalopathy introduces interobserver variability, and the use of arbitrary cut-offs for continuous variables leads to potential misclassification.^10,23,24 Consequently, two patients with similar biochemical profiles may receive different CP classifications depending on local evaluation, limiting its prognostic accuracy and its use as a stratification tool in clinical trials.¹⁸

Despite these weaknesses, the CP score remains deeply embedded in clinical practice and clinical trial design because of its simplicity and historical validation. Nevertheless, increasing evidence supports the use of complementary, objective tools such as the ALBI grade to refine risk stratification and improve treatment decision-making.^17,25 Combining CP subclassification (B7–B9) with ALBI grading provides a more nuanced picture of hepatic reserve and may help identify those CP-B patients who can safely undergo palliative interventions.

Taken together, these observations highlight the need to move beyond the traditional CP classification toward a functional continuum model that integrates both biological and clinical dimensions of liver dysfunction. This approach is essential to guide therapy in the growing population of HCC patients with moderate hepatic impairment.

Role of Others Liver Function Scores

Alternative Tools for Assessing Liver Function in HCC

Given the limitations of the CP score, several objective indices have been proposed to more accurately quantify hepatic reserve in patients with HCC. Among these, the ALBI grade has gained increasing acceptance as a simple, reproducible, and fully laboratory-based tool.^17,25

The ALBI score is derived from serum albumin and bilirubin levels using a continuous formula that eliminates the subjective variables of ascites and encephalopathy (Figure 1). It stratifies patients into three grades—ALBI 1 (best liver function), ALBI 2 (intermediate), and ALBI 3 (poor)—with each step associated with significantly shorter overall survival.^26–28 Large retrospective studies and meta-analyses have confirmed that ALBI provides a finer prognostic discrimination than CP, particularly within CP-A and CP-B subgroups.^16,26,29

Figure 1 Objective liver function stratification using ALBI grade.

In HCC treated by TACE, ALBI grade has been shown to independently predict both overall survival and the risk of post-procedural hepatic decompensation.^30–34 In advanced HCC, ALBI also correlates with tolerance and outcomes to systemic therapies, including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI).^17,35 Consequently, ALBI grading has been incorporated into several real-world studies and ongoing trials to refine patient selection beyond the CP score.²⁵

Despite these advantages, ALBI is not without limitations. It does not directly account for portal hypertension or the impact of hepatic encephalopathy, two major prognostic drivers in cirrhosis. Moreover, serum albumin and bilirubin values may fluctuate due to transient intercurrent events such as infection or dehydration, potentially leading to misclassification. Therefore, ALBI should be viewed as a complementary rather than a substitutive tool to CP scoring, especially in patients with fluctuating hepatic status (Table 2).

Table 2 Comparative Table: ALBI Grade versus Child Pugh Score

The Model for End-Stage Liver Disease (MELD) score, originally developed for transplant allocation, has also been evaluated in HCC. Although it provides a reliable estimate of short-term mortality, its prognostic value for treatment tolerance is limited, as it primarily reflects renal dysfunction rather than synthetic liver capacity.³⁶

Integrating these alternative models within the functional continuum of liver impairment may help better characterize the wide heterogeneity observed in CP-B HCC. In practice, combining ALBI grade and CP-B subclassification (B7–B9) provides a pragmatic and clinically meaningful approach to identify patients who might still benefit from active therapy versus those for whom supportive care should be prioritized.

This evolution toward objective, multidimensional assessment tools reflects the growing recognition that liver function—not tumor stage alone—remains the principal determinant of therapeutic feasibility and outcomes in HCC.^7,16,23

Locoregional Therapies in Child–Pugh B HCC Patients: Balancing Efficacy and Hepatic Tolerance

Locoregional therapies remain a mainstay in the palliative management of HCC with preserved or moderately impaired liver function. Among them, TACE and selective internal radiation therapy (SIRT) are widely used in patients with intermediate or locally advanced disease.^7,37 Their feasibility and safety in CP-B cirrhosis, however, remain controversial because of the narrow therapeutic window between antitumor efficacy and hepatic decompensation.

Transarterial Chemoembolisation

TACE is the standard of care for intermediate-stage HCC in patients with preserved liver function (BCLC-B, CP-A). Its use in CP-B patients must be carefully individualized, as impaired hepatic reserve increases the risk of post-procedural liver failure.

Patient selection is crucial. Most retrospective and real-world studies included only compensated CP-B7 patients, while those with CP-B8/B9 or radiologic ascites were excluded.^31,38,39 Across cohorts, median overall survival (OS) after TACE in CP-B patients ranges from 6 to 12 months, versus 15–20 months in CP-A patients. In contrast, decompensated CP-B8/B9 patients rarely derive benefit and have a median OS below 6 months.^31,33,34

Recent multicenter data suggest that CP-B7 patients may achieve comparable tumor control and tolerability to selected CP-A cases when liver function and portal hypertension are stable.³⁸ Post-TACE hepatic decompensation occurs in approximately 20–30% of CP-B patients, mostly in those with elevated bilirubin (>2 mg/dL) or low albumin (<3 g/dL).⁴⁰

The ALBI grade provides additional prognostic value beyond the CP score. Multiple studies have shown that ALBI stratifies survival within both CP-A and CP-B patients undergoing TACE.(^{31,33,34,40–42}) For instance, ALBI grade 1 CP-B7 patients experience significantly longer OS than ALBI grade 2–3 counterparts (median 12–14 vs. 6–8 months) and lower rates of post-TACE decompensation.^31,32

Overall, TACE may remain a reasonable option in well-compensated CP-B7 patients with controlled ascites and bilirubin <3 mg/dL, provided that strict post-procedural monitoring and early cessation criteria are applied (ALBI ≥−1.39, bilirubin >35 μmol/L, or CP deterioration ≥8). For CP-B8/B9 patients, the risk–benefit ratio generally favors supportive care or systemic therapy rather than repeated embolization.

Selective Internal Radiation Therapy

SIRT using yttrium-90 microspheres is an increasingly used palliative approach for unresectable or intermediate–advanced HCC. It delivers targeted intra-arterial radiation, achieving local control while sparing non-tumoral parenchyma.

Although pivotal SIRT studies primarily enrolled CP-A patients, several retrospective cohorts have included small subsets of CP-B cases.^43–47 These studies consistently report that baseline liver function is the strongest predictor of outcome, surpassing tumor characteristics. In mixed CP populations, median OS after SIRT ranges from 8 to 16 months in CP-A, versus 6–10 months in CP-B patients.^44,46

Importantly, the risk of radioembolization-induced liver disease (REILD) markedly increases with bilirubin >35 µmol/L or CP ≥8. Therefore, current guidelines restrict SIRT to CP ≤B7 with no or minimal ascites.⁴⁸ In a recent large European series, 37% of patients worsened in ALBI grade after SIRT, and this early decline was an independent predictor of poorer survival.⁴⁷

The ALBI grade has again demonstrated predictive utility in the SIRT setting: patients with baseline ALBI grade 1 or 2 had significantly longer OS (26.4 vs. 8.1 months) and fewer hepatic events compared with ALBI 3.^47,49 This supports the integration of ALBI-based selection for future studies and real-world decision-making.

Emerging data also suggest that SIRT may be preferable to TACE in selected CP-B7 patients with multifocal or portal vein–involved disease, given its lower ischemic stress and better tolerability.⁴⁵ However, prospective validation remains needed, as most available data derive from heterogeneous retrospective cohorts.

In summary (Table 3), both TACE and SIRT can be considered in highly selected CP-B7 patients, ideally with ALBI grade 1–2 and no significant portal hypertension. For CP-B8/B9 patients or those with ascites, these procedures should generally be avoided due to the high risk of irreversible hepatic decompensation. Integrating ALBI grade and dynamic liver monitoring into treatment algorithms may help improve safety and patient selection for locoregional therapies in this fragile population.

Table 3 Synthesis of Criteria for Choosing TACE and SIRT

Immunotherapy-Based Combinations in CP-B HCC

Immune Checkpoint Inhibitors and Combinations: Redefining Systemic Therapy in CP-B HCC

The advent of ICIs has profoundly transformed the therapeutic landscape of advanced HCC. The combination of atezolizumab plus bevacizumab has become the first-line standard of care for patients with unresectable HCC and preserved liver function, based on the landmark IMbrave150 trial.^50,51 However, this pivotal study—like most Phase III trials—almost exclusively enrolled CP class A patients, leaving the management of those with moderate liver dysfunction largely undefined.^7,37,52

Atezolizumab Plus Bevacizumab

Several real-world and retrospective studies have since explored the safety and efficacy of atezolizumab–bevacizumab (Atezo/Bev) in CP-B patients. Across cohorts, CP-B patients represented 10–20% of treated populations, predominantly CP-B7.^16,17,53

These studies consistently report reduced efficacy and survival compared with CP-A patients but acceptable safety in well-compensated CP-B7 cases. Median OS in CP-B7 patients ranges between 6 and 9 months, versus 16–19 months in CP-A.^17,53 In contrast, patients with CP-B8 or B9 exhibit early deterioration of liver function and OS rarely exceeding 4 months.¹⁵

Importantly, treatment tolerance remains a critical issue. The incidence of grade ≥3 treatment-related adverse events is approximately 25–30% in CP-B, compared with 20% in CP-A, with hepatic decompensation and ascites being the main causes of discontinuation.^17,54 Baseline ALBI grade and presence of ascites are the strongest predictors of early progression and toxicity, underscoring the importance of functional stratification beyond CP class.⁵⁵

Collectively, the available data support that Atezo/Bev may be feasible in carefully selected CP-B7 patients, ideally with ALBI grade 1–2 and absence of portal hypertension.⁵⁶ For CP-B8/B9 patients, the benefit appears limited, and early hepatic deterioration is frequent. Ongoing studies (NCT05301842; NCT05640310) are currently assessing reduced-dose or sequential regimens in this setting.

Durvalumab Plus Tremelimumab (“STRIDE Regimen”)

The durvalumab–tremelimumab combination demonstrated overall survival superiority over sorafenib in the HIMALAYA trial⁵⁷ and has been approved as an alternative first-line therapy for advanced HCC. Like IMbrave150, HIMALAYA was restricted to CP-A patients.

Real-world data on the STRIDE regimen in patients with CP B cirrhosis remain limited but are emerging. In a Japanese multicenter cohort (n = 183), approximately 18% of patients were CP B, while another real-world series (n = 120) included 8.4% CP B cases (7 B7 and 3 B8).^58–60 “Immune-related adverse events were comparable to those observed in CP-A, but hepatic decompensation occurred in ~25% of CP-B patients, again emphasizing the fragility of this subgroup.

As both Atezo/Bev and STRIDE rely on preserved hepatic reserve for treatment continuation, careful baseline selection and dynamic monitoring of liver function (CP score and ALBI trend) are essential.

Other Immune-Based Combinations

No prospective trials have yet evaluated immunotherapy-based combinations in CP B HCC. Pivotal phase III studies such as COSMIC-312 (atezolizumab–cabozantinib), EMERALD-1 (durvalumab–based combinations), and LEAP-002 (pembrolizumab–lenvatinib) enrolled only CP A patients.^61,62 Real-world series, however, suggest that combining ICIs with anti-angiogenic agents in CP-B7 patients may yield overall survival around 8–10 months with manageable safety, whereas survival drops sharply beyond CP-B8.^16,17 The absence of prospective CP-B-dedicated trials remains a major unmet need.

In summary (Table 4), immunotherapy-based combinations represent a major advance in HCC treatment, but their benefit in CP-B patients is limited by fragile hepatic reserve. Real-world evidence supports their use in selected CP-B7 patients with close monitoring, ideally within prospective registries. Integration of ALBI and dynamic CP trends appears crucial to identify candidates likely to benefit without precipitating liver failure. The development of CP-B–specific dosing strategies and adaptive treatment algorithms is a key unmet need for this growing population.

Table 4 Synthesis of Evidence for Immunotherapy in Child B Patients

Anti-Angiogenic Agents and TKI in CP-B HCC

Reappraising TKIs in the Immunotherapy Era

Before the advent of ICI, TKIs targeting VEGF and related pathways—such as sorafenib and lenvatinib—represented the cornerstone of systemic therapy for advanced HCC. Despite their established benefit in CP-A patients, the evidence base for their use in CP class B remains limited, as pivotal trials systematically excluded patients with moderate hepatic dysfunction.^63,64 Nevertheless, real-world data have provided valuable insights into feasibility and expected outcomes in this population.

Sorafenib

Sorafenib remains the most extensively studied systemic agent in CP-B HCC. In the pivotal SHARP and Asia-Pacific trials, only CP-A patients were included, with median overall survival (OS) of 10–11 months. Subsequent real-world and expanded-access studies have evaluated sorafenib in CP-B cohorts, reporting median OS of 3–5 months, roughly half that observed in CP-A.^13,14,65,66

Importantly, toxicity and early discontinuation are more frequent in CP-B patients, primarily due to hepatic decompensation. In the GIDEON registry, encompassing over 3000 patients, treatment-related adverse events occurred in 60% of CP-B versus 45% of CP-A patients, and median treatment duration was only 7 weeks for CP-B compared with 12 weeks for CP-A. Subgroup analyses revealed markedly different outcomes between CP-B7 (median OS ≈ 6 months) and CP-B8/B9 (≤ 3 months), highlighting again the prognostic heterogeneity within this class.¹³

Dose-reduction strategies (400 mg once daily instead of twice daily) have been explored to improve tolerance, with some evidence of maintained efficacy in CP-B7 patients and reduced rates of hepatic events. However, survival benefit remains modest, and therapy should be reserved for carefully selected CP-B7 patients with stable liver function and good performance status.

Lenvatinib

Lenvatinib demonstrated non-inferiority to sorafenib in CP A patients in the REFLECT trial, whereas CP-B patients were excluded. Subsequent real-world studies and small prospective series have provided preliminary evidence in CP-B HCC.

In a large Japanese multicenter analysis including approximately 30% CP-B patients, median overall survival was 6.8 months for CP-B7 and 4.5 months for CP-B8/9, with an acceptable safety profile. The incidence of grade ≥ 3 hepatic adverse events was around 20%, comparable to CP-A, although dose reductions and interruptions were more frequent.⁶⁷

In an international multicenter analysis including patients who had deteriorated to CP B during treatment, median overall survival was 6.8 months with a manageable safety profile; most adverse events were grade 1–2, though dose interruptions and reductions were more frequent than in CP-A.⁶⁸

A recent multinational comparison of atezolizumab–bevacizumab versus lenvatinib in CP-B HCC confirmed that outcomes were generally poor regardless of regimen, with median OS around 6–7 months for lenvatinib-treated patients and slightly higher disease-control rates than with immunotherapy.⁶⁹

Collectively, these data suggest that lenvatinib can be safely administered in selected CP-B7 patients with preserved performance status, achieving disease control in roughly one-third of cases. However, outcomes decline rapidly in CP-B8/9 patients due to hepatic decompensation. Baseline ALBI grade and early changes in liver function remain key predictors of benefit.

Lenvatinib may thus be considered a reasonable first-line option for patients with CP-B7 HCC who are ineligible for immunotherapy, provided that liver function is closely monitored and remains stable.

Second-Line and Later-Line TKIs

Data for second-line TKIs—regorafenib, cabozantinib, and ramucirumab—in CP-B patients remain scarce. The pivotal RESORCE, CELESTIAL, and REACH-2 trials all excluded CP-B patients.^70–72

In limited real-world cohorts, regorafenib was feasible only in CP-B7 patients who tolerated prior sorafenib. Median OS typically ranged from 4 to 6 months, and up to 30% discontinued treatment due to hepatic decompensation.^73,74 A post-hoc analysis of the CELESTIAL trial evaluated cabozantinib in patients who had deteriorated to CP-B by week 8, showing a median OS of 8 months in CP-B7 versus 3–4 months in CP-B8/9, with a manageable but increased incidence of hepatic adverse events.⁷⁵ Ramucirumab lacks evidence beyond CP-A and should generally be avoided in CP-B due to the high risk of hypoalbuminemia and ascites.

As with first-line therapy, ALBI grade and CP-B subclass remain critical to identify patients likely to tolerate second-line TKIs. In the immunotherapy era, TKIs still play a role as sequential or alternative options for patients ineligible for, or progressing after, ICI-based regimens. Real-world data suggest that selected CP-B7 patients maintaining stable hepatic function after atezolizumab–bevacizumab may still derive modest benefit from lenvatinib or cabozantinib.

Overall, the survival benefit of TKIs in CP-B remains limited (median OS ≈ 4–6 months), but these agents can offer disease stabilization with acceptable safety in highly selected CP-B7 cases (Table 5). Future studies specifically designed for CP-B HCC are warranted to optimize dosing, sequencing, and discontinuation criteria. Overall, the survival benefit of TKIs in CP-B remains limited (median OS ≈ 4–6 months), but these agents can offer disease stabilization with manageable safety in highly selected CP-B7 cases. Future trials specifically dedicated to CP-B HCC are warranted to define optimal dosing, sequencing with ICIs, and functional criteria for continuation or discontinuation.

Table 5 Summary of Real-World Outcomes of TKIs in Patients with HCC and Child–Pugh B Liver Function

Perspectives

The management of HCC in patients with moderate hepatic dysfunction remains one of the most pressing challenges in hepatology and oncology. CP class B patients represent a large yet underserved population, systematically underrepresented in clinical trials and often excluded from curative or even palliative strategies. As a result, most treatment decisions still rely on extrapolations from CP-A data and on physician experience rather than robust evidence.

Recent advances have nonetheless started to bridge this gap. The integration of objective functional scores such as the ALBI grade, combined with CP subclassification (B7–B9), offers a more granular assessment of hepatic reserve. These tools enable a pragmatic approach to patient selection, allowing identification of those who may still benefit from active locoregional or systemic therapies while minimizing the risk of irreversible hepatic decompensation.

Real-world evidence has demonstrated that selected CP-B7 patients can safely receive modern systemic therapies, including atezolizumab–bevacizumab or lenvatinib, with meaningful clinical benefit and manageable toxicity. However, outcomes remain suboptimal compared to CP-A populations, emphasizing the need for prospective, CP-B–dedicated clinical trials. Such studies should incorporate dynamic liver function assessment, using longitudinal ALBI or MELD trends, rather than static baseline scores, to guide dose adaptation and treatment discontinuation.

Beyond clinical stratification, molecular and immunological profiling of CP-B HCC may uncover novel therapeutic targets and predictive biomarkers. The interplay between hepatic inflammation, fibrosis stage, and tumor immune microenvironment likely contributes to the distinct biology and treatment response of CP-B tumors (Figure 2). Liquid biopsy approaches—such as circulating tumor DNA or cytokine signatures—may help characterize these patients non-invasively and inform therapeutic choices.

Figure 2 Dynamic interplay between tumor and cirrhosis in hepatic decompensation.

In parallel, the development of adaptive treatment algorithms that combine systemic agents with supportive care, tailored according to dynamic liver function, represents a promising step toward functional precision medicine. Integration of artificial intelligence–based tools for individualized prognostication and therapy sequencing could further optimize outcomes in this complex population.

In summary, while the prognosis of CP-B HCC patients remains poor, progress is emerging through refined functional assessment, judicious use of modern therapies, and translational research aimed at personalizing care. The future of palliative management in HCC will depend on our ability to move from rigid score-based exclusion toward dynamic, patient-centered models that balance oncologic efficacy with preservation of hepatic function.