Limits of Systemic Treatments for HCC in Decompensated Patients

Introduction

Pathophysiology and Clinical Implications of Decompensated Liver Disease

• Portal Hypertension (PH): is the most important and early pathophysiological event in cirrhosis, which contributes significantly to the clinical manifestations of DLD. It occurs due to increased resistance to portal blood flow caused by structural changes in the cirrhotic liver, such as fibrosis, regenerative nodules, and vascular remodeling. These changes lead to intrahepatic shunting, and portal venous pressure (PVP) rises above 10 mmHg, a threshold considered to trigger clinically significant complications such as ascites, variceal bleeding, and encephalopathy. The hemodynamic consequences of PH significantly affect the systemic circulation, particularly through splanchnic vasodilation, which is mediated by the release of vasodilators such as nitric oxide (NO) and prostacyclin. This process not only worsens hepatic hypoxia, but also triggers the systemic inflammatory response that further exacerbates liver dysfunction. Several studies have confirmed that hepatic venous pressure gradient (HVPG) is related to the risk of decompensation. A study by Garcia-Tsao et al. [10] demonstrated that patients with HVPG ≥ 16 mmHg had a 3-fold increased risk of developing ascites and variceal bleeding, compared to those with lower HVPG. Moreover, this haemodynamic imbalance also appears to exacerbate the response to systemic therapies. A study by Ripoll et al. [11] observed that patients with PH-related complications and HVPG ≥ 16 mmHg had an increased rate of discontinuation of systemic treatment for HCC due to associated adverse effects, such as liver failure or gastrointestinal bleeding, following the use of sorafenib and other targeted therapies.
• Systemic inflammation and immune dysfunction: It has been well established that systemic inflammation plays a central role in the progression of liver disease and the development of decompensation [12]. The chronic inflammatory state in cirrhosis is driven by the release of pro-inflammatory cytokines and the activation of innate immune cells [13]. The most significant contributors to this inflammation include bacterial translocation and the altered gut-liver axis, in which endotoxins from the gastrointestinal tract activate immune responses [13] Elevated levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) in patients with decompensated cirrhosis were significantly higher than in compensated patients [14,15]. These markers were correlated with both poor liver function and a reduced response to systemic treatments. For example, patients with elevated IL-6 were found to have a 40% lower overall survival rate when treated with sorafenib, compared to patients with lower IL-6 levels [16]. Similarly, TNF-α [17] has been implicated in inducing liver cell apoptosis and promoting fibrosis, worsening both the progression of liver disease and the adverse effects of cancer therapies. Decompensated cirrhosis is also associated with a significant immunosuppressive state, in which both innate and adaptive immune responses are impaired [18]. This dysfunction is partly due to impaired T-cell responses, impaired antigen presentation, and defective natural killer (NK) cell function [19]. Immune response to infections and malignancies is severely impaired in these patients, increasing their susceptibility to infections and reducing the effectiveness of immunotherapy, such as checkpoint inhibitors [20]. Interestingly, activation of the PD-1/PD-L1 pathway, which is a crucial mechanism of immune evasion in HCC [21], is often more pronounced in decompensated cirrhosis. Atezolizumab, an anti-PD-L1 antibody, has shown limited efficacy in patients with advanced cirrhosis due to this immune dysfunction [22]. In a update efficacy and safety data from Imbrave150, patients with Child-Pugh B cirrhosis had a 25% reduction in response rate to immunotherapy compared to those with Child-Pugh A cirrhosis. This highlights the impact of the immunosuppressive environment in advanced liver disease, which reduces the efficacy of immune checkpoint inhibitors.
• Impaired Drug Metabolism: The liver is a critical organ for the metabolism of most drugs, including those used in the treatment of HCC. In patients with decompensated cirrhosis, impaired liver function significantly alters drug pharmacokinetics, leading to reduced drug clearance and an increased risk of toxicity. The cytochrome P450 (CYP450) enzyme system, particularly the CYP3A subfamily, is responsible for the metabolism of a wide range of anticancer agents. When liver function is impaired, the activity of these enzymes can be significantly reduced, resulting in drug accumulation and an increased likelihood of adverse drug reactions, particularly for drugs with a narrow therapeutic index [23], such as sorafenib, lenvatinib, and immune checkpoint inhibitors.
• Altered vasculature and tumor microenvironment: decompensated cirrhosis alters the vascular architecture in the liver, creating a unique tumor microenvironment that appears to impact the efficacy of systemic therapies, particularly those that target the vasculature, such as anti-VEGF therapies (e.g., bevacizumab) and multikinase inhibitors (e.g., sorafenib). In cirrhotic livers, the hepatic vasculature is distorted, leading to hypoxia, increased expression of pro-angiogenic factors, and a more fibrotic microenvironment. This creates a barrier to drug delivery, and therapeutic agents, particularly those that target angiogenesis or VEGF, may not reach sufficient tissue concentrations in the tumor. In a post hoc analysis of the REFLECT study [24], lenvatinib, a multikinase inhibitor targeting Vascular endothelial growth factor (VEGF) receptors, was found to have limited efficacy in Child-Pugh B patients and treatment failure occurred in up to 35% of patients within the first 3 months, likely due to compromised vascular architecture in the liver. Interestingly, patients with variceal bleeding and severe PH had a 50% higher dose reduction rate due to associated bleeding risks.

Table 1. Pathophysiology of Decompensated Liver Disease and Its Impact on Systemic Therapies in HCC.

Systemic Treatment Options for HCC in Decompensated Patients

Tyrosine Kinase Inhibitor (TKI) Therapies

• Sorafenib was assessed in the SHARP study, which primarily involved patients with Child-Pugh A cirrhosis. The study demonstrated a median overall survival (OS) of 10.7 months with sorafenib, compared to 7.9 months with placebo (HR: 0.69; 95% CI: 0.55-0.87, p < 0.001) [25]. Sorafenib, a standard systemic treatment for advanced hepatocellular carcinoma (HCC), is predominantly metabolized by CYP3A4 and UGT1A9 enzymes. In patients with Child-Pugh B cirrhosis, pharmacokinetic studies [26] have revealed significant variability in drug exposure. A specific analysis of sorafenib in this cohort [27] found that the area under the curve (AUC) increased by approximately 45% compared to patients with preserved liver function. In the GIDEON real-world study [28], 21% of Child-Pugh B patients discontinued sorafenib due to toxicity, versus 9% in Child-Pugh A patients (p < 0.01). A subgroup analysis of the SHARP trial [29] also highlighted that Child-Pugh B patients had a median OS of 5.2 months when treated with sorafenib, in contrast to 10.7 months for those with Child-Pugh A (p < 0.05). Real-world studies suggest that outcomes for Child-Pugh B patients are generally poorer, with median OS ranging from 3 to 5 months and an increased likelihood of treatment discontinuation due to adverse events [30]. Additionally, Cheng et al. [31] reported that bleeding complications, particularly gastrointestinal bleeding, occur in 10–20% of sorafenib-treated patients, with a heightened risk in those with significant portal hypertension (PH) and varices, as the anti-VEGF effects may exacerbate variceal bleeding. In a retrospective cohort study by Marrero et al. [32], dose reduction was necessary in 43% of patients with decompensated liver disease receiving sorafenib.
• Lenvatinib: The REFLECT study [33] demonstrated that lenvatinib is non-inferior to sorafenib in patients with Child-Pugh A liver function, showing a median overall survival (OS) of 13.6 months versus 12.3 months, respectively (HR: 0.92; 95% CI: 0.79-1.06). However, the study excluded patients with significant hepatic dysfunction, limiting its applicability to decompensated populations. In a pharmacokinetic analysis by Tamai et al. [34], it was found that patients with Child-Pugh B cirrhosis had a significantly higher area under the curve (AUC) of lenvatinib compared to those with normal liver function, leading to an increased risk of adverse effects such as hypertension, fatigue, and gastrointestinal disorders. This underscores the need for dose adjustments and careful monitoring in cirrhotic patients receiving lenvatinib. Additionally, a pooled analysis [35] revealed a 52% dose reduction rate in Child-Pugh B patients, indicating poorer tolerability compared to 25% in Child-Pugh A patients.

Immune Checkpoint Inhibitors (ICIs)

• Atezolizumab and Bevacizumab: the IMbrave150 study [3] demonstrated superior efficacy of atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGF) compared to sorafenib in treatment-naïve HCC patients. The combination therapy achieved a median OS of 19.2 months versus 13.4 months with sorafenib (HR: 0.66; 95% CI: 0.52-0.85, p < 0.001). However, the study excluded patients with Child-Pugh B or C cirrhosis, leaving a knowledge gap for this subgroup. A small prospective study evaluating atezolizumab-bevacizumab in Child-Pugh B patients reported a median progression-free survival of 3.9 months [36], with treatment-related liver toxicity occurring in 25% of cases.
• Nivolumab and Pembrolizumab: Nivolumab (anti-PD-1) received accelerated FDA approval based on the CheckMate-040 study [37], which included a cohort of Child-Pugh B patients. While the overall response rate (ORR) in these patients was 14%, the study showed increased hepatotoxicity, with adverse events of grade ≥3 occurring in 26% of cases. Similarly, pembrolizumab demonstrated modest efficacy in the KEYNOTE-224 study [38], but its applicability in decompensated cirrhosis remains questionable due to limited sample size and high rates of immune-related adverse events. Pinter et al. [39] conducted a study examining the use of pembrolizumab in patients with advanced HCC, some of whom had cirrhosis. The study found that patients with more severe hepatic impairment (Child-Pugh C) were at higher risk for immune-related adverse events, particularly hepatotoxicity, which may require dose modification or discontinuation of therapy. A pooled analysis of trials [40,41] involving ICIs in HCC reported bleeding rates of 4–8%, with variceal bleeding accounting for a significant proportion of these events in patients with underlying PH.

Emerging Therapies and Combinations

Strategies for HCC Treatment in Decompensated Patients

• Risk stratification, plays a pivotal role in identifying patients who may derive benefit from systemic treatment, despite the presence of liver decompensation. Several prognostic tools have been developed to guide these decisions, each with its strengths and limitations:

o 

Child-Pugh score: Although commonly used, this score has limitations in predicting outcomes with systemic therapy, particularly for ICIs, as it does not account for systemic inflammation or tumor burden.

o 

ALBI grade: The Albumin-Bilirubin (ALBI) grade provides a more refined assessment of liver function and has shown promise in predicting outcomes with sorafenib. A meta-analysis demonstrated [48] that grade 1 ALBI patients had a significantly better OS than grade 2 ALBI patients treated with sorafenib (median OS: 14.0 vs. 6.5 months; HR 0.63, 95% CI 0.51-0.78).

o 

MELD Score: The Model for End-Stage Liver Disease (MELD) score provides information on the risk of liver decompensation and mortality, but has limited utility in oncology-specific decision making.

• A Multidisciplinary Management, is critical to optimizing outcomes in decompensated patients. Collaboration between hepatologists, oncologists, and palliative care specialists ensures a comprehensive assessment and personalized treatment plans [49]. Integration of supportive care is essential in the management of decompensated patients receiving systemic therapy.
• Pre-treatment optimization of liver function, such as management of ascites, control of encephalopathy, and prevention of variceal bleeding, may improve tolerance to systemic therapies. Mayr et al [50], reported that a large-volume paracentesis combined with albumin infusion has been shown to reduce portal hypertension and improve symptom control. In patients with refractory ascites, careful fluid management and diuretic adjustment before starting systemic therapy have been shown to reduce treatment interruptions. Similarly, proactive nutritional support and management of sarcopenia may improve resilience to treatment-related toxicities. In a cohort study of patients treated with sorafenib [51], those who received concomitant management for hepatic encephalopathy had a significantly lower rate of dose reductions (25% vs. 40%, p < 0.05).
• Proactive monitoring for adverse events: regular liver function tests, including weekly assessments, along with early intervention for rising bilirubin levels, can prevent catastrophic outcomes such as acute liver failure. Adjusting drug dosages based on hepatic reserve is also an important strategy to minimize toxicity while maintaining therapeutic efficacy. For example, dose modifications of lenvatinib in patients with hepatic dysfunction have been shown to achieve comparable efficacy to standard dosing regimens, with reduced toxicity.

Conclusions

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