Clinical trials investigating systemic therapies for uHCC have traditionally excluded patients with CP B cirrhosis, reflecting concerns regarding safety and diminished liver reserve. This study addresses this crucial gap by performing a single-center, retrospective analysis of 94 uHCC patients treated with ICIs plus AAs between 2020 and 2024. Among them, 63 had Child-Pugh A (CP A) cirrhosis, while 31 presented with CP B cirrhosis, allowing for a comparative evaluation of treatment outcomes and tolerability.

The study’s findings reveal an encouraging overall objective response rate (ORR) of 44.7% across the whole cohort, with a disease control rate (DCR) of 72.3%. These clinical endpoints offer a promising perspective on the tumor response to combination therapy in a population with traditionally poor prognoses. Median progression-free survival (mPFS) was reported at 6.3 months, and notably, the median overall survival (mOS) reached 28.3 months, underscoring sustained benefits in systemic therapy for uHCC patients.

When stratified by liver function status, patients with CP A cirrhosis exhibited higher ORR (50.8%) compared to those with CP B cirrhosis (32.3%), though this difference approached but did not reach statistical significance (P = 0.089). Similarly, DCR and mPFS were numerically superior in the CP A group but lacked statistical significance. Intriguingly, mOS demonstrated a marked and statistically significant disparity, favoring the CP A group (39.2 months) over CP B patients (15.9 months, P = 0.035). This dichotomy highlights the profound impact of hepatic functional reserve on long-term survival despite comparable response rates to therapy.

Several prognostic factors independent of cirrhosis status emerged from the analysis. Poor performance status, denoted by an Eastern Cooperative Oncology Group (ECOG) score of 2, prior treatments, and absence of concurrent locoregional therapies were associated with diminished objective responses. Additionally, CP B cirrhosis and advanced Barcelona Clinic Liver Cancer (BCLC) stages C or D independently predicted worse overall survival, underscoring the nuanced interactions between tumor burden, liver function, and systemic therapy efficacy.

The safety profile of ICIs combined with AAs was carefully assessed, revealing that an overwhelming majority (93.6%) of patients experienced at least one treatment-related adverse event (TRAE), with 27.7% encountering grade 3 or higher toxicities. Crucially, the incidence and severity of TRAEs did not differ significantly between CP A and CP B subgroups, suggesting that the addition of ICIs and AAs does not disproportionately increase treatment-related risks even in patients with moderately impaired liver function.

Remarkably, 32.3% of patients with CP B cirrhosis demonstrated improvement in their Child-Pugh score following systemic therapy, indicating a potential for therapeutic intervention to not only control tumor progression but also enhance hepatic functional reserve. This finding challenges conventional therapeutic nihilism associated with CP B patients and advocates for a more inclusive approach in clinical practice.

Understanding the mechanistic underpinnings of ICIs combined with AAs in uHCC is essential. Immune checkpoint inhibitors function by unleashing the immune system’s cytotoxic T cells against tumor cells, a mechanism often suppressed in the tumor microenvironment. Antiangiogenic agents complement this by inhibiting vascular endothelial growth factor (VEGF) pathways, effectively starving the tumor of its blood supply and promoting an immunologically active milieu. Their synergy is thought to enhance antitumor immunity and counteract resistance pathways frequently encountered in hepatocellular carcinoma.

The study’s retrospective design, although inherently limited by potential selection biases and confounding variables, offers valuable real-world insights. Incorporating patients with CP B cirrhosis, typically excluded from randomized trials, enhances the generalizability of findings and contributes toward personalized treatment paradigms. However, larger, prospective studies are essential to validate these observations and elucidate optimal treatment sequencing and combination strategies.

Previous research on systemic therapies in uHCC mainly focused on patients with preserved liver function, limiting evidence for CP B populations. This study significantly advances the field by demonstrating that systemic immunotherapy combined with antiangiogenic treatment can be both efficacious and tolerable in these patients, opening new therapeutic avenues. The observed survival benefit and Child-Pugh score improvements further emphasize the need to reconsider exclusion criteria in future clinical trials.

Translating these findings into clinical practice necessitates careful patient selection and monitoring. While ICIs plus AAs show robust efficacy, attention to adverse events remains paramount, particularly in patients with compromised liver function. The comparable safety profiles between Child-Pugh groups provide reassurance but warrant vigilant management to optimize outcomes.

The integration of locoregional therapies alongside systemic treatments appeared to improve objective response rates, underscoring the potential benefit of multimodal approaches in managing uHCC. Combining transarterial chemoembolization, radiofrequency ablation, or other localized interventions with ICIs and AAs may potentiate antitumor effects and prolong survival, as suggested by the independent predictive value of simultaneous locoregional therapy.

Moreover, patient performance status remained a critical determinant of treatment success, emphasizing the importance of pre-treatment evaluation and supportive care to maintain functional capacity. Incorporating comprehensive assessments and potential interventions to improve performance status might broaden eligibility and enhance clinical benefit.

This study’s implications extend beyond clinical outcomes, prompting a paradigm shift in conceptualizing systemic therapy candidacy for uHCC patients with advanced liver disease. By demonstrating safety and efficacy in CP B patients, it challenges existing treatment algorithms and supports a more nuanced, inclusive therapeutic approach balancing risk and benefit.

In conclusion, the retrospective analysis conducted at Beijing You’an Hospital highlights the promise of combining immune checkpoint inhibitors with antiangiogenic agents in the management of unresectable hepatocellular carcinoma among patients with varied liver function statuses. While significant survival differences remain linked to hepatic reserve, the overall favorable safety profile and some improvements in liver function underscore the potential to expand treatment access and improve outcomes for historically underserved patient groups in oncology.

Further well-structured prospective trials with larger cohorts and longer follow-up are imperative to refine patient stratification, optimize dosing regimens, and elucidate combinatory strategies involving ICIs, AAs, and locoregional therapies. Such investigations will be foundational to establishing new standards of care in hepatocellular carcinoma treatment, ultimately aiming to enhance survival and quality of life for patients within this challenging clinical context.

Subject of Research: Evaluation of the efficacy and safety of immune checkpoint inhibitors combined with antiangiogenic agents in unresectable hepatocellular carcinoma patients with Child-Pugh A versus B cirrhosis.

Article Title: Comparative efficacy and safety of immune checkpoint inhibitors combined with antiangiogenic agents for unresectable hepatocellular carcinoma in patients with Child-Pugh A versus B cirrhosis: a single-center, retrospective study.

Article References:
Liu, D., Yang, Z., Wang, L. et al. Comparative efficacy and safety of immune checkpoint inhibitors combined with antiangiogenic agents for unresectable hepatocellular carcinoma in patients with Child-Pugh A versus B cirrhosis: a single-center, retrospective study. BMC Cancer 25, 1651 (2025). https://doi.org/10.1186/s12885-025-15126-4

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-15126-4

Hepatocellular carcinoma remains one of the most lethal malignancies worldwide, largely due to late-stage diagnosis and limited therapeutic options once tumors reach an unresectable stage. Systemic therapies, including targeted agents and immune checkpoint inhibitors, have shown survival benefits but often fall short in achieving significant tumor downstaging. HAIC, which delivers high concentrations of chemotherapeutic agents directly into the liver’s arterial supply, has increasingly garnered attention as a locoregional approach with the potential to reduce tumor burden effectively while minimizing systemic toxicity.

This novel trial enrolled 19 patients diagnosed with advanced uHCC, all initially deemed unsuitable candidates for surgery. Participants received a carefully timed regimen combining apatinib, camrelizumab, and HAIC administered with the FOLFOX chemotherapy protocol, which includes oxaliplatin, leucovorin, and fluorouracil. The treatment cycles spanned 21-day intervals, extending to a maximum of eight cycles to maximize clinical response. Such an approach reflects an intricate balance of leveraging local chemotherapy infusion alongside systemic immune activation and angiogenesis inhibition.

The most striking outcome from this study was the achievement of conversion to resectability in nearly three-quarters of the patients. Specifically, 14 out of 19 participants exhibited sufficient tumor regression and favorable biological responses, making surgical intervention viable. Among them, nine patients proceeded to margin-free (R0) resections—surgical removals with no residual cancer cells detected at the margins—a gold standard for curative intent in oncologic surgery. These results underscore the potential that aggressive multimodal treatment harbors in transforming the clinical trajectory of traditionally inoperable liver cancers.

Notably, the pathological assessments post-surgery revealed that a third of these resected tumors demonstrated a major pathological response to the treatment, including two cases achieving complete pathological remission. This indicates that the combination therapy not only shrinks tumors radiographically but can also eliminate microscopic disease, an encouraging sign for long-term survival prospects. Furthermore, objective response rates approximated 47%, with disease control rates nearing 90%, according to RECIST (Response Evaluation Criteria In Solid Tumors) standards, highlighting a robust anti-tumor effect.

Importantly, the safety profile of this demanding regimen was manageable, albeit with considerable but expected toxicities. Over 70% of patients experienced grade 3 or higher treatment-related adverse events. Elevated liver enzymes and increased lymphocyte counts were the most frequent severe side effects. Encouragingly, no treatment-related mortality occurred, affirming that with vigilant monitoring and supportive care, this therapeutic strategy is tolerable for a majority of patients.

The underlying scientific rationale for this triple combination rests on synergistic mechanisms: HAIC delivers concentrated cytotoxic drugs directly to tumor vasculature, apatinib acts as a potent anti-angiogenic agent restricting tumor blood supply by inhibiting vascular endothelial growth factor receptor-2 (VEGFR-2), and camrelizumab unleashes the immune system by blocking PD-1 immune checkpoints. Together, these agents mount a multifaceted attack capable of overcoming tumor immune evasion and chemoresistance, which are critical challenges in advanced HCC.

This trial’s findings pave the way for further exploration of HAIC combined with immunotherapy and targeted agents as a conversion strategy, opening new doors to potentially curative surgery for patients previously resigned to palliative care. While survival data remain immature, the initial signals of tumor control and margin-negative resection bode well for improved outcomes. Future randomized controlled trials will be essential to validate these findings, optimize dosing schedules, and refine patient selection criteria.

Given the complexity of hepatocellular carcinoma’s biology and the heterogeneous nature of patient responses, the multidisciplinary integration of locoregional treatment, targeted therapy, and immunotherapy represents a tailored therapeutic frontier. This approach underscores a shift toward personalized oncology where combination regimens can be fine-tuned to elicit maximal tumor regression while maintaining quality of life.

The study also raises intriguing questions about the timing and sequencing of therapies. Administering camrelizumab shortly after apatinib initiation and preceding hepatic arterial infusion likely maximizes immune modulation and tumor microenvironment alteration, facilitating enhanced efficacy. Such precise coordination highlights the importance of understanding pharmacodynamics and immune interactions in devising effective treatment algorithms.

Beyond clinical efficacy, the trial exemplifies how advancements in interventional radiology and immuno-oncology can converge to extend the boundaries of cancer care. Hepatic artery infusion requires specialized expertise and infrastructure, underscoring the need for centers of excellence capable of delivering complex multimodal therapies safely and effectively.

While this treatment strategy currently applies to a select cohort of patients with unresectable hepatocellular carcinoma, its success may inspire similar combinatory frameworks for other solid tumors where surgical options are limited by advanced disease. The concept of conversion therapy, pushing tumors from inoperable to operable states, embodies a proactive and aggressive stance in cancer management.

In summary, the integration of HAIC using the FOLFOX regimen with camrelizumab and apatinib represents a significant leap forward in the therapeutic landscape of advanced hepatocellular carcinoma. The trial’s encouraging outcomes justify continued investigation and hope for a new standard of care that can improve survival and quality of life for a challenging patient population. As the oncology community anticipates further data, this innovative treatment offers a beacon of optimism for patients facing limited options.

Subject of Research: Conversion therapy for unresectable hepatocellular carcinoma using hepatic arterial infusion chemotherapy combined with immune checkpoint inhibition and targeted therapy.

Article Title: Hepatic artery infusion chemotherapy combined with camrelizumab and apatinib as conversion therapy for patients with unresectable hepatocellular carcinoma: a single-arm exploratory trial.

Article References:
Yalikun, K., Li, Z., Zhang, J. et al. Hepatic artery infusion chemotherapy combined with camrelizumab and apatinib as conversion therapy for patients with unresectable hepatocellular carcinoma: a single-arm exploratory trial. BMC Cancer 25, 838 (2025). https://doi.org/10.1186/s12885-025-14250-5

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14250-5