Trending Topics in Gastroenterology | GastroAGI

PRISM Study: Real-World Outcomes of First-Line Systemic Therapy for Unresectable HCC: Liver Cancer | May 2026

* PRISM is one of the largest prospective real-world studies evaluating systemic therapy for unresectable hepatocellular carcinoma in routine clinical practice across Japan. * This analysis reports outcomes from the first 1,000 prospectively enrolled patients, providing important validation of results seen in clinical trials. * Among evaluable patients, the vast majority received atezolizumab plus bevacizumab (82.8%), while 15.2% received lenvatinib as first-line therapy. * Median overall survival reached 21.8 months with Atezo+Bev and 20.8 months with lenvatinib, demonstrating excellent real-world outcomes. * Survival outcomes were numerically better than those reported in the original registration trials, suggesting that careful patient selection, multidisciplinary management, and effective sequential therapy may be improving outcomes in practice. * Progression-free survival remained consistent with clinical trial data at 7.7 months for Atezo+Bev and 6.7 months for lenvatinib. * Objective response rates were impressive for both regimens, confirming that real-world effectiveness closely mirrors clinical trial efficacy. * Sorafenib was rarely used and showed substantially lower response rates compared with modern first-line therapies. * Grade 3 or higher treatment-related adverse events occurred in approximately 22% of patients, with no unexpected safety concerns. * Importantly, nearly 50% of patients were able to receive second-line therapy, highlighting the growing importance of sequential treatment strategies in advanced HCC. * The most common sequencing pattern was: * Atezolizumab + bevacizumab → lenvatinib * Lenvatinib → atezolizumab + bevacizumab * Second-line therapy provided a median progression-free survival of approximately 4 months, while benefit progressively decreased with later treatment lines. * The study demonstrates that modern systemic therapies can be safely delivered to a broad real-world population, not just highly selected clinical trial patients. * PRISM also highlights the importance of maintaining liver function and performance status to allow access to sequential therapies, which likely contributes significantly to prolonged survival. * Future analyses are expected to provide valuable information regarding special populations, including elderly patients, those with impaired liver function, and different molecular or clinical subgroups. Bottom line: The PRISM study confirms that atezolizumab plus bevacizumab and lenvatinib achieve reproducible real-world outcomes in unresectable HCC, with median overall survival exceeding 20 months and nearly half of patients successfully receiving subsequent lines of therapy.

ARTE Score Predicts Decompensation on Atezo-Bev : J Hepatol | May 2026

Introduction: Introduction: Atezolizumab plus bevacizumab (Atezo-Bev) is the standard first-line systemic therapy for many patients with unresectable hepatocellular carcinoma (uHCC). However, treatment success depends not only on tumor control but also on preservation of liver function. Hepatic decompensation remains a major cause of treatment interruption, reduced survival, and impaired quality of life. Identifying patients at greatest risk before therapy initiation is therefore crucial for optimal treatment selection and monitoring. Problem Statement: Problem Statement: Existing prognostic models primarily focus on survival outcomes and do not specifically predict hepatic decompensation during Atezo-Bev therapy. Clinicians lack a simple, validated tool that can identify patients at increased risk of liver failure despite having Child-Pugh A liver function at treatment initiation. Summary: Summary: This multicenter study analyzed 453 Child-Pugh A patients with unresectable HCC receiving first-line atezolizumab plus bevacizumab from the ARTE database and externally validated findings in an independent cohort of 292 patients from the AB-real database. During a median follow-up of 14 months, hepatic decompensation occurred in 16.3% of patients. Multivariable Cox regression identified three independent predictors of decompensation: neoplastic portal vein thrombosis, elevated bilirubin levels, and thrombocytopenia. These variables were integrated into a simple point-based risk stratification model termed the ARTE Score. Based on the cumulative score, patients were classified into three risk categories: Low risk (0–1 points) Intermediate risk (2 points) High risk (3–4 points) The model demonstrated clear separation of decompensation risk across all categories. Compared with low-risk patients, intermediate-risk patients experienced nearly a twofold increase in decompensation risk, while high-risk patients had more than a fourfold increased risk. Decompensation-free survival showed marked differences between groups. At 12 months, decompensation-free survival remained high in low-risk patients but progressively declined in intermediate- and high-risk groups. These differences persisted at 24 months, highlighting the score’s ability to identify clinically meaningful long-term risk. Importantly, the model maintained its predictive performance in the independent external validation cohort, supporting its reproducibility and generalizability across different clinical settings. The biological rationale behind the score is intuitive. Portal vein tumor thrombosis reflects advanced tumor burden and impaired hepatic perfusion. Elevated bilirubin indicates reduced hepatic reserve even within Child-Pugh A patients. Thrombocytopenia serves as a surrogate marker of clinically significant portal hypertension and advanced underlying cirrhosis. Together, these variables capture the combined impact of tumor aggressiveness and baseline liver vulnerability. Clinically, the ARTE Score may assist in treatment planning before initiating Atezo-Bev. High-risk patients may benefit from closer laboratory surveillance, earlier recognition of liver deterioration, optimization of portal hypertension management, and consideration of alternative therapeutic strategies when appropriate. The score is particularly valuable because it relies exclusively on routinely available clinical variables, making implementation feasible in everyday practice without specialized testing or biomarkers. Overall, this study introduces the ARTE Score as a simple, externally validated tool for predicting hepatic decompensation in patients with unresectable HCC receiving atezolizumab plus bevacizumab, providing an important step toward more personalized risk assessment and treatment decision-making in advanced liver cancer.

Carbon-Ion Radiotherapy Matches Surgery in Early HCC : Hepatol Commun | June 2026

Introduction: Hepatocellular Carcinoma surgical resection remains a standard curative treatment for early-stage disease, but many patients are poor surgical candidates because of cirrhosis, portal hypertension, advanced age, or comorbidities. Carbon-ion radiotherapy (CIRT), an advanced particle radiotherapy technique with superior dose localization and enhanced biological effectiveness, has emerged as a potential non-surgical curative option for HCC. Problem Statement: Despite increasing interest in particle therapy, comparative real-world data evaluating long-term oncologic outcomes between CIRT and surgical resection are limited. Whether CIRT can provide equivalent survival and disease control to surgery in early-stage HCC remains uncertain, particularly after adjusting for differences in baseline patient characteristics. Summary: This multicenter Japanese retrospective study compared clinical outcomes between 116 patients treated with carbon-ion radiotherapy and 947 patients undergoing surgical resection for HCC between 2010 and 2022. Because patients selected for CIRT often differ significantly from surgical candidates, the investigators used inverse probability of treatment weighting (IPTW) analysis to balance baseline characteristics and improve comparability between groups. Before adjustment, recurrence-free survival was similar between surgery and CIRT, with median recurrence-free survival of approximately 2.3 years in both groups. Although unadjusted overall survival initially appeared superior with surgical resection, this difference disappeared after IPTW adjustment, suggesting that baseline patient selection rather than treatment efficacy largely explained the survival disparity. Following adjustment, neither recurrence-free survival nor overall survival differed significantly between surgical resection and CIRT. Importantly, multivariable analyses confirmed that treatment modality itself was not an independent predictor of recurrence or survival outcomes. These findings suggest that CIRT may offer oncologic outcomes comparable to surgery in appropriately selected patients with early-stage HCC. The study is clinically important because many HCC patients have limited hepatic reserve or comorbidities that increase operative risk. Unlike surgery, CIRT is non-invasive and can deliver highly conformal radiation with minimal damage to surrounding liver tissue, making it particularly attractive in cirrhotic patients or those unsuitable for resection. The results also support the growing role of advanced radiotherapy as a definitive treatment strategy rather than merely a bridge or palliative option. Carbon-ion therapy possesses unique radiobiological advantages over conventional photon radiotherapy, including higher relative biological effectiveness and improved targeting precision through the Bragg peak phenomenon, potentially enhancing tumor control while preserving non-tumorous liver parenchyma. Although recurrence rates remained substantial in both groups, reflecting the multicentric carcinogenic nature of HCC in cirrhosis, survival equivalence suggests that local tumor control with CIRT is clinically meaningful. The study further reinforces the evolving multidisciplinary management paradigm in HCC, where surgery, ablation, transplantation, and particle radiotherapy may increasingly function as complementary curative strategies tailored to patient-specific hepatic reserve, tumor anatomy, and comorbidity profile. Limitations include the retrospective design, relatively smaller CIRT cohort, and potential residual confounding despite IPTW adjustment. In addition, accessibility and cost remain major barriers to widespread CIRT implementation globally. Overall, this study provides important real-world evidence that carbon-ion radiotherapy can achieve survival and recurrence outcomes comparable to surgical resection in selected patients with early-stage HCC, supporting its role as a potentially curative non-surgical treatment modality.

Immune-Related Adverse Events Strongly Predict Post-Transplant Rejection After Pretransplant Immunotherapy in HCC : Gut | May 2026

Introduction Hepatocellular Carcinoma management increasingly incorporates Immune Checkpoint Inhibitors for downstaging and bridging prior to Liver Transplantation. Although checkpoint inhibitors can successfully expand transplant eligibility and improve tumor control, they also create a major immunological dilemma because persistent immune activation may increase the risk of catastrophic post-transplant allograft rejection. Problem Statement Reliable predictors of post-transplant rejection after pretransplant immune checkpoint inhibitor exposure remain poorly defined, limiting safe patient selection and peri-transplant immunotherapy planning. Summary This national multicentre retrospective study evaluated predictors of allograft rejection in hepatocellular carcinoma patients receiving immune checkpoint inhibitors before liver transplantation, with particular emphasis on the role of immune-related adverse events (irAEs). The study identified immune-related adverse events as the strongest independent predictor of post-transplant rejection. Patients experiencing irAEs during checkpoint inhibitor therapy had an approximately ninefold higher risk of subsequent allograft rejection after transplantation. This is a highly important and clinically actionable observation because irAEs may represent a real-time biomarker of sustained systemic immune activation. Post-transplant rejection occurred in 17% of patients overall, typically developing early after transplantation, with a median onset of only 10 days. This rapid temporal pattern supports the concept that pre-existing activated immune pathways persist into the peri-transplant period despite surgical organ replacement and immunosuppression. Additional independent risk factors included younger recipient age and shorter washout intervals below 30 days between checkpoint inhibitor exposure and transplantation. These findings align with previous concerns that insufficient immune de-escalation time before transplantation may leave residual T-cell activation capable of targeting the allograft. Importantly, the study moved beyond clinical associations and explored mechanistic correlates through a prospective observational cohort. Patients developing irAEs demonstrated significantly increased circulating CD8+ T-cell populations and elevated inflammatory cytokines including IFN-α and TNF-α, suggesting a hyperactivated cytotoxic immune phenotype. These data provide biologic plausibility for the observed clinical association between irAEs and rejection risk. Immune-related toxicities may not merely reflect isolated organ-specific inflammation but instead indicate a globally primed immune system capable of heightened alloimmune reactivity. Clinically, the findings have major implications for transplant hepatology and multidisciplinary tumor boards. Occurrence of irAEs during checkpoint inhibitor therapy may need to be incorporated into transplant eligibility assessment, perioperative risk counseling and individualized immunosuppression planning. The predictive model generated in the study achieved good discriminatory performance, suggesting that integrated risk stratification incorporating irAEs, recipient age and washout duration may help identify patients at particularly high rejection risk. The study also contributes to the evolving discussion regarding optimal timing of transplantation after checkpoint inhibitor therapy. Although no universally accepted washout interval exists, these findings support caution with very short intervals, especially in patients who experienced clinically significant immune toxicities. From an oncologic perspective, the work highlights the increasingly complex balance between maximizing antitumor immunity and preserving transplant tolerance. Checkpoint inhibitors may simultaneously improve tumor control while destabilizing alloimmune equilibrium. The findings are especially relevant because checkpoint inhibitors are increasingly being used earlier in HCC treatment algorithms, including neoadjuvant and bridging settings. As immunotherapy exposure before transplantation becomes more common, reliable biomarkers for rejection prediction will become critically important. The study further underscores the need for close collaboration between oncology, transplant hepatology and transplant immunology teams when managing these patients. Decisions regarding checkpoint inhibitor selection, duration, toxicity management and transplantation timing will likely require increasingly individualized approaches. Overall, this multicentre study identifies immune-related adverse events as a powerful predictor of post-transplant rejection in HCC patients exposed to pretransplant checkpoint inhibitors. The findings suggest that irAEs may serve as clinically accessible markers of persistent immune activation and provide an important framework for risk stratification and peri-transplant immunotherapy management.

Liver Transplantation Defines Long-Term Survival in HCC : Hepatol Commun | May 2026

Introduction Hepatocellular Carcinoma remains one of the leading causes of cancer-related mortality worldwide. Although curative-intent therapies such as liver transplantation, surgical resection and ablation can achieve durable disease control, long-term survival remains limited by tumor recurrence, progressive cirrhosis and competing liver-related complications. Data defining predictors of true long-term survival beyond 10 years have remained scarce. Problem Statement Most HCC outcome studies focus on short- or intermediate-term survival, whereas determinants of ≥10-year survival are poorly characterized. In particular, the relative long-term impact of liver transplantation compared with resection or ablation in real-world populations requires further clarification. Summary This large National Cancer Database analysis evaluated nearly 250,000 patients diagnosed with HCC between 2004 and 2022 to identify factors associated with survival beyond 10 years. Long-term outcomes remained poor overall, with only 3.3% of patients achieving ≥10-year survival, emphasizing the aggressive biologic and cirrhotic burden associated with HCC. Among all treatment modalities, Liver Transplantation emerged as the dominant determinant of long-term survival. Compared with ablation, liver transplantation increased the odds of surviving ≥10 years nearly twelvefold, substantially outperforming surgical resection and all non-curative therapies. Decision-tree analyses further confirmed transplantation as the single most important predictor of durable survival. The superiority of transplantation likely reflects its unique ability to simultaneously eliminate both tumor burden and the underlying cirrhotic liver substrate responsible for de novo carcinogenesis and hepatic decompensation. In contrast, resection and ablation remove or destroy focal tumors while leaving the diseased liver in place, allowing continued risk for recurrence and liver-related mortality. Surgical resection also significantly improved long-term survival compared with ablation, although the magnitude of benefit remained considerably lower than transplantation. Non-curative therapies were associated with substantially worse outcomes, underscoring the importance of early-stage diagnosis and access to definitive treatment strategies whenever feasible. One of the most important findings was the persistence of racial disparities in transplant access and survival. Black patients demonstrated lower odds of receiving liver transplantation and correspondingly lower likelihood of ≥10-year survival. These observations reinforce longstanding concerns regarding inequities in transplant referral, waitlist access, socioeconomic barriers and healthcare delivery within HCC management pathways. Clinically, the study reinforces that long-term cure in HCC depends not only on oncologic control but also on management of the underlying liver disease. The exceptional survival associated with transplantation highlights the central importance of careful candidate selection, surveillance-based early detection and equitable access to transplant evaluation. The findings additionally support ongoing efforts to expand transplant eligibility through downstaging protocols, improved locoregional bridging therapies and optimized organ allocation systems. As systemic therapies improve and multidisciplinary HCC care evolves, transplantation may become increasingly integrated into broader biologic treatment algorithms rather than purely anatomy-based selection models. Overall, this large national analysis demonstrates that liver transplantation provides the greatest likelihood of achieving ≥10-year survival in HCC, far surpassing other curative-intent therapies. The study also highlights persistent disparities in transplant access and emphasizes that equitable delivery of transplantation remains essential for improving long-term outcomes in hepatocellular carcinoma.

IMbrave050 Update Questions Adjuvant Atezo-Bev in HCC : J Hepatol | May 2026

Introduction Recurrence after curative-intent resection or ablation remains one of the greatest challenges in Hepatocellular Carcinoma management, with early relapse rates remaining high even after apparently successful treatment. Following the landmark IMbrave150 study, the combination of Atezolizumab plus Bevacizumab became standard first-line therapy for unresectable HCC, generating major interest in extending this strategy into the adjuvant setting for high-risk disease. Problem Statement The initial interim analysis of the IMbrave050 trial demonstrated a significant recurrence-free survival benefit with adjuvant atezolizumab plus bevacizumab after curative-intent therapy for high-risk HCC. However, whether this early benefit would remain durable with longer follow-up and ultimately translate into overall survival improvement remained uncertain. Summary IMbrave050 randomized patients with high-risk HCC following curative-intent resection or ablation to receive one year of adjuvant atezolizumab plus bevacizumab or active surveillance. The original interim analysis generated considerable enthusiasm after demonstrating improved recurrence-free survival with combination immunotherapy and antiangiogenic therapy. However, this updated analysis substantially alters interpretation of the study. With longer follow-up, the initially observed recurrence-free survival advantage was no longer sustained. The updated recurrence-free survival hazard ratio moved from the previously significant 0.72 to 0.90, indicating loss of the earlier statistical and clinical benefit signal. Overall survival data also remained immature at the second interim analysis, with no evidence of survival advantage emerging thus far. Importantly, the overall survival hazard ratio numerically favored the surveillance arm, although confidence intervals remained wide and definitive conclusions cannot yet be drawn because of limited event maturity. Despite the disappointing efficacy update, the long-term safety profile remained manageable and consistent with known toxicities of both agents. No unexpected safety concerns emerged with prolonged follow-up, reinforcing the relative tolerability of the regimen in appropriately selected patients with preserved liver function. These findings are highly important because IMbrave050 represented the first positive immunotherapy-based adjuvant trial in HCC at initial reporting and had raised hopes for a paradigm shift in postoperative management. The updated results now emphasize the complexity of interpreting early recurrence-free survival signals in immunotherapy studies and highlight the necessity of mature longitudinal follow-up before widespread adoption of perioperative strategies. Biologically, the findings suggest that residual micrometastatic disease after curative-intent HCC therapy may possess heterogeneous immune sensitivity. It is also possible that recurrence dynamics in HCC are influenced not only by metastatic relapse but also by de novo carcinogenesis within chronically diseased cirrhotic liver tissue, potentially limiting the durability of adjuvant immune-based approaches. Importantly, exploratory subgroup analyses suggested that certain patient subsets may still derive benefit, indicating that biomarker-guided perioperative immunotherapy strategies remain an important future research direction. Effective perioperative therapy continues to represent a major unmet need in HCC given persistently high recurrence rates after surgery or ablation. Overall, the updated IMbrave050 analysis does not support routine use of adjuvant atezolizumab plus bevacizumab for all patients with high-risk HCC following curative-intent treatment. The study nevertheless provides critical lessons for future perioperative immunotherapy trial design and reinforces the importance of refined patient selection strategies in early-stage hepatocellular carcinoma.

EBRT Achieves Competitive Survival in Early HCC : J Clin Oncol | May 2026

Introduction External Beam Radiation Therapy has historically played a limited role in the management of Hepatocellular Carcinoma because of concerns regarding radiation-induced liver injury and limited survival data. However, advances in image guidance, stereotactic body radiotherapy and conformal radiation delivery have substantially improved precision and safety. Despite increasing integration into treatment algorithms, robust multinational survival data supporting EBRT as a first-line curative-intent modality have remained limited. Problem Statement Although modern EBRT demonstrates excellent local tumor control in HCC, uncertainty persists regarding long-term survival outcomes compared with established curative therapies such as resection and thermal ablation. The absence of large individual patient-level datasets has limited broader incorporation of EBRT into global HCC treatment algorithms. Summary This multinational collaborative analysis evaluated individual patient data from 4,913 patients with HCC treated using technically validated EBRT protocols, representing the largest international EBRT cohort reported to date. Patients were stratified according to Barcelona Clinic Liver Cancer (BCLC) stage and prior treatment exposure to assess long-term overall survival outcomes. Survival outcomes for very early- and early-stage HCC were particularly notable. Median overall survival reached 6.8 years for BCLC-0 disease and 4.6 years for BCLC-A disease. Among treatment-naïve patients, outcomes were even more impressive, with median survival not reached in BCLC-0 patients and exceeding five years in BCLC-A disease. These results compare favorably with many contemporary surgical and ablative series and strongly support EBRT as a potentially curative locoregional strategy in selected patients. Multivariable analyses identified several prognostic determinants consistent with established HCC biology. Advanced BCLC stage, higher tumor burden, impaired performance status and Child-Pugh B/C cirrhosis independently predicted worse survival outcomes. Conversely, delivery of ablative radiation doses and treatment in more recent eras were associated with improved survival, likely reflecting ongoing technological advancements in radiation planning and patient selection. Importantly, the study reinforces the evolving role of EBRT within multidisciplinary HCC management. Modern radiation therapy offers several advantages in patients unsuitable for surgery or thermal ablation, including treatment of lesions adjacent to vascular structures, biliary anatomy or subdiaphragmatic regions where ablative approaches may be technically difficult or high risk. The findings further challenge historical perceptions that radiation therapy should remain only a salvage or palliative modality in HCC. The study additionally highlights the growing convergence between radiation oncology and hepatology within contemporary liver cancer care. Improved survival associated with ablative dosing strategies suggests that biologically effective dose escalation and stereotactic techniques may further optimize outcomes in early-stage disease. Overall, this landmark multinational individual patient-level analysis provides strong evidence that modern EBRT achieves survival outcomes comparable to other curative locoregional therapies for selected early-stage HCC patients. The findings strongly support broader incorporation of EBRT into BCLC clinical decision-making pathways and reinforce its emerging role as a first-line treatment option within multidisciplinary hepatocellular carcinoma management.

Precision Genomics in Refractory PLC : J Hepatol | May 2026

Introduction Advanced Hepatocellular Carcinoma, Cholangiocarcinoma and rare primary liver cancers remain therapeutically challenging after progression on standard systemic therapy. Conventional targeted next-generation sequencing panels identify actionable alterations in only a minority of patients, particularly outside biliary tract cancers. This multicenter French Genomic Medicine 2025 (FMG2025) initiative evaluated whether comprehensive molecular profiling using whole-genome sequencing (WGS), whole-exome sequencing (WES) and RNA sequencing could expand precision oncology opportunities in advanced primary liver cancers. Problem Statement Precision medicine approaches in primary liver cancers are limited by inadequate genomic characterization, delayed profiling and restricted access to actionable biomarkers beyond standard panels. The clinical utility of broad genomic sequencing in refractory liver cancers, especially HCC and rare histologies, remains insufficiently defined. Summary This nationwide French initiative enrolled 120 patients with advanced or refractory primary liver cancers across eight tertiary centers. The cohort included HCC, cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and rare tumors such as fibrolamellar carcinoma and hepatic epithelioid hemangioendothelioma. Comprehensive genomic profiling was successfully completed in 86% of tumors using integrated WGS, WES and RNA sequencing. Actionable molecular alterations were identified in 65% of patients, substantially exceeding the yield achievable with standard targeted sequencing panels. Common alterations included TP53, TERT and CTNNB1 in HCC, while cholangiocarcinoma demonstrated frequent TP53, ARID1A, BAP1 and FGFR2 alterations. cHCC-CCA displayed hybrid genomic signatures involving TP53 and PI3K pathway abnormalities. RNA sequencing added clinically meaningful information through identification of oncogenic pathway activation, immune-related transcriptomic signatures and fusion transcripts. Among 67 patients with actionable alterations, 31 ultimately received genomically matched therapies, predominantly directed against ESCAT II–III targets involving FGFR, MET, ERBB2, PI3K–AKT–mTOR, homologous recombination deficiency and cell-cycle pathways. Disease control was achieved in 32.3% overall and exclusively occurred in patients treated for ESCAT I–III alterations, while ESCAT IV-directed therapies failed to demonstrate clinical benefit. Disease control rates were particularly notable in cholangiocarcinoma and cHCC-CCA. Median progression-free survival was significantly longer in responders compared with non-responders (11.8 vs 2.4 months). The study also highlighted important translational insights. Whole-genome analysis identified mutational signatures linked to aflatoxin exposure and aristolochic acid carcinogenesis, while germline cancer-predisposition variants were detected in 5% of patients. Importantly, many patients could not receive matched therapies because of progressive liver failure or clinical deterioration before genomic results became available, emphasizing the need for earlier molecular profiling in liver cancers. Overall, this landmark real-world study demonstrates that broad genomic profiling in advanced primary liver cancers is feasible and clinically relevant, particularly for identifying therapeutically actionable ESCAT II–III alterations beyond standard sequencing panels. The findings support earlier integration of comprehensive molecular profiling into hepatobiliary oncology workflows and reinforce the emerging role of precision oncology in advanced liver cancers.

Liver Function Dominates Risk Prediction After HCC Locoregional Therapy : Liver Transpl | May 2026

Introduction Locoregional therapy (LRT) remains a cornerstone treatment strategy for patients with early- and intermediate-stage Hepatocellular Carcinoma. Although procedures such as transarterial chemoembolization and ablative therapies are routinely performed, post-procedural hepatic decompensation remains a major determinant of morbidity, treatment interruption and mortality. Identifying patients at highest risk for short-term liver dysfunction is therefore essential for treatment selection and peri-procedural planning. Problem Statement Current risk assessment for LRT often incorporates tumor burden, demographic variables and clinician judgment, but the relative contribution of hepatic reserve versus tumor-related factors in predicting post-LRT liver failure remains uncertain. Reliable prediction models for short-term hepatic dysfunction following LRT are still lacking in routine clinical practice. Summary This retrospective Veterans Health Administration cohort study evaluated 1,183 patients with early- to intermediate-stage HCC undergoing locoregional therapy to determine predictors of severe liver dysfunction within 30 and 90 days after treatment. Multiple clinical, laboratory and tumor-related variables were assessed for prognostic performance using discrimination and calibration analyses. Measures of baseline hepatic reserve consistently outperformed tumor-related and demographic factors in predicting post-LRT liver dysfunction. Among all evaluated metrics, the MELD=3.78ln(bilirubin)+11.2ln(INR)+9.57ln(creatinine)+6.43 score demonstrated the strongest predictive discrimination for both 30-day and 90-day outcomes, followed closely by MELD-Na and serum bilirubin levels. In contrast, total tumor diameter and demographic characteristics provided limited prognostic value. Model calibration remained acceptable across multiple risk strata, supporting the robustness of liver function–based prediction approaches. The findings reinforce the concept that hepatic reserve, rather than tumor burden alone, is the principal determinant of peri-procedural vulnerability following LRT. Even among patients with relatively early-stage HCC, impaired baseline liver function substantially increased the likelihood of post-treatment decompensation. These data support prioritization of liver severity metrics when selecting candidates for locoregional therapies and may help refine multidisciplinary decision-making regarding treatment intensity, monitoring and transplant referral timing. Overall, this study provides important real-world evidence that objective liver function assessment should remain central to procedural risk stratification in HCC and highlights the need for future prospective models integrating dynamic hepatic reserve measurements into LRT treatment algorithms.

Multinational EBRT Data Support Curative-Intent Role in Early HCC : J Clin Oncol | May 2026

Introduction External Beam Radiation Therapy has historically played a limited role in the management of Hepatocellular Carcinoma because of concerns regarding hepatic toxicity and limited survival data. However, advances in stereotactic body radiation therapy, image guidance and conformal radiation planning have substantially improved the safety and precision of liver-directed radiotherapy. Despite growing incorporation of EBRT into international guidelines, robust multinational survival data comparable to surgery or ablation have remained limited. Problem Statement The absence of large individual patient-level datasets has hindered accurate assessment of long-term survival outcomes following EBRT in HCC. Whether EBRT can provide outcomes comparable to established curative-intent therapies such as resection or thermal ablation—particularly in early-stage disease—has remained controversial. Summary This multinational individual patient data analysis evaluated outcomes in nearly 5,000 patients with HCC treated using EBRT across multiple international centers, representing the largest collaborative dataset reported to date. Survival outcomes were stratified according to Barcelona Clinic Liver Cancer (BCLC) stage and prior treatment status. Patients with very early-stage and early-stage disease demonstrated particularly favorable outcomes. Median overall survival reached 6.8 years in BCLC-0 disease and 4.6 years in BCLC-A disease. Among treatment-naïve patients, survival outcomes were even more impressive, with median overall survival not reached in BCLC-0 patients and exceeding five years in BCLC-A disease. Multivariable analysis identified established prognostic factors associated with mortality, including advanced BCLC stage, greater tumor burden, impaired performance status and poorer liver function. Importantly, delivery of ablative radiation doses and more contemporary treatment eras were independently associated with improved survival, highlighting the impact of modern radiation techniques and evolving patient selection strategies. The study provides compelling evidence that modern EBRT can achieve long-term survival outcomes in very early and early-stage HCC that appear comparable to established curative locoregional therapies including resection and thermal ablation. These findings are particularly relevant for patients unsuitable for surgery or ablation because of tumor location, vascular proximity, comorbidity or impaired hepatic reserve. Overall, this landmark multinational analysis strengthens the evidence base supporting EBRT as a legitimate curative-intent treatment modality in selected patients with early-stage HCC. The findings further reinforce the integration of EBRT into contemporary BCLC treatment algorithms and multidisciplinary HCC decision-making pathways.