The Future Role of Abdominal US in Hepatocellular Carcinoma Surveillance.

Abdominal US is currently the best-validated surveillance strategy for hepatocellular carcinoma (HCC) in at-risk patients. It is the only modality shown to have completed all five phases of validation and can achieve high sensitivity and specificity for HCC detection, especially when conducted by expert sonographers in high-volume centers. However, US also has limitations, including operator dependency and varying sensitivity in clinical practice. Further, the sensitivity of US for early-stage HCC detection is lower in patients with obesity or nonviral liver disease, increasingly common populations undergoing surveillance. Imaging-based and blood-based surveillance strategies, including abbreviated MRI and biomarker panels, may overcome some limitations of US-based surveillance. Both strategies have promising test performance in phase II and phase III biomarker studies and are undergoing prospective validation. Considering the variation in HCC risk and test performance between patients, there will likely be a shift away from a one-size-fits-all approach and toward precision screening, in which the "best" test is selected based on individual patient characteristics. In this upcoming era of precision HCC screening among patients with cirrhosis, US will likely continue to have an important, albeit reduced, surveillance role.

Natural History of Indeterminate Liver Nodules in Patients with Advanced Liver Disease: A Multi-Center Retrospective Cohort Study.

BACKGROUND: Indeterminate liver nodules (ILNs) are frequently encountered on diagnostic imaging after positive hepatocellular carcinoma (HCC) surveillance results, but their natural history remains unclear. METHODS: We conducted a multi-center retrospective cohort study among patients with ≥1 newly detected LI-RADS 3 (LR-3) lesion ≥1 cm or LI-RADS 4 (LR-4) lesion of any size (per LI-RADS v2018) between January 2018 and December 2019. Patients were followed with repeat imaging at each site per institutional standard of care. Multivariable Fine-Gray models were used to evaluate associations between potential risk factors and patient-level time-to-HCC diagnosis, with death and liver transplantation as competing risks. RESULTS: Of 307 patients with ILNs, 208 had LR-3 lesions, 83 had LR-4 lesions, and 16 had both LR-3 and LR-4 lesions. HCC incidence rates for patients with LR-3 and LR-4 lesions were 110 (95%CI 70 - 150) and 420 (95%CI 310 - 560) per 1000 person-years, respectively. In multivariable analysis, incident HCC among patients with LR-3 lesions was associated with older age, thrombocytopenia (platelet count ≤150 x109/L), and elevated serum alpha-fetoprotein (AFP) levels. Among those with LR-4 lesions, incident HCC was associated with a maximum lesion diameter >1 cm. Although most patients had follow-up CT or MRI, 13.7% had no follow-up imaging and another 14.3% had follow-up ultrasound only. CONCLUSION: ILNs have a high but variable risk of HCC, with 4-fold higher risk in patients with LR-4 lesions than those with LR-3 lesions, highlighting a need for accurate risk stratification tools and close follow-up in this population.

Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

INTRODUCTION: The LT evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures (PREMs) along the continuum of pre-LT care to reduce care variation and guide patient-centered care. METHODS: Following a systematic literature review, candidate pre-LT measures were grouped into four phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care and social work selected the final set. Candidate PREMs spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. RESULTS: Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures and 10 were outcome measures that focused on elements not typically measured in routine care. Among the PREMs, LT candidates rated items from understanding the LT process domain as the most important. CONCLUSION: The proposed pre-LT measures provide a framework for quality improvement and care standardization among LT candidates. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local QI initiatives to improve access and quality of care.

Association between bridging therapy and posttransplant outcomes in patients with HCC within Milan criteria: A systematic review and meta-analysis.

Liver transplantation is the curative therapy of choice for patients with early-stage HCC. Locoregional therapies are often employed as a bridge to reduce the risk of waitlist dropout; however, their association with posttransplant outcomes is unclear. We conducted a systematic review using Ovid MEDLINE and EMBASE to identify studies published between database inception and August 2, 2023, which reported posttransplant recurrence-free survival and overall survival among patients transplanted for HCC within Milan criteria, stratified by receipt of bridging therapy. Pooled HRs were calculated for each outcome using the DerSimonian and Laird method for a random-effects model. We identified 38 studies, including 19,671 patients who received and 20,148 patients who did not receive bridging therapy. Bridging therapy was not associated with significant differences in recurrence-free survival (pooled HR: 0.91, 95% CI: 0.77-1.08; I2 =39%) or overall survival (pooled HR: 1.09, 95% CI: 0.95-1.24; I2 =47%). Results were relatively consistent across subgroups, including geographic location and study period. Studies were discordant regarding the differential strength of association by pretreatment tumor burden and pathologic response, but potential benefits of locoregional therapy were mitigated in those who received 3 or more treatments. Adverse events were reported in a minority of studies, but when reported occurred in 6%-15% of the patients. Few studies reported loss to follow-up and most had a risk of residual confounding. Bridging therapy is not associated with improvements in posttransplant recurrence-free or overall survival among patients with HCC within Milan criteria. The risk-benefit ratio of bridging therapy likely differs based on the risk of waitlist dropout.

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Proportion of Time Covered by Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis.

INTRODUCTION: Hepatocellular carcinoma (HCC) surveillance is associated with improved early tumor detection, but effectiveness is limited by underuse. We characterized adherence to HCC surveillance using proportion of time covered (PTC) and estimated its association with clinical outcomes among patients with cirrhosis. METHODS: We conducted a retrospective cohort study of patients diagnosed with HCC between January 2008 and December 2022 at 2 large US health systems. We characterized PTC by imaging in the 12 and 24 months before HCC diagnosis. We used multivariable logistic and Cox regression analyses to assess the association between PTC and early HCC detection, receipt of curative treatment, and overall survival. RESULTS: Among 2,027 patients with HCC, 331 (51.4% Barcelona Clinic Liver Cancer 0/A) had been followed up for at least 12 months before diagnosis. The median PTC was 24.9% (interquartile range 1.1%-50.7%), with only 16.0% having semiannual imaging and 42.0% having annual surveillance. Semiannual and annual surveillance decreased to 6.3% and 29.6% when assessed over 24 months, although the median PTC remained unchanged at 24.9%. Receipt of gastroenterology/hepatology care had the strongest association with PTC, with median PTC of 36.7% and 3.8% for those with and without gastroenterology/hepatology care, respectively. PTC was independently associated with improved early HCC detection, curative treatment receipt, and overall survival. The median survival was 15.7, 26.8, and 32.7 months among those with PTC of <25% (n = 168 patients), PTC 25%-50% (n = 69 patients), and PTC >50% (n = 94 patients), respectively. DISCUSSION: The proportion of time covered by HCC surveillance in patients with cirrhosis remains low, highlighting a need for multilevel interventions.

Association between Patient Experience Scores and Low Utilization of Hepatocellular Carcinoma Treatment in the United States: A Surveillance, Epidemiology, and End Results-Consumer Assessment of Healthcare Providers and Systems Analysis (SEER-CAHPS).

PURPOSE: To study the experiences of patients with hepatocellular carcinoma (HCC) contributing to treatment discrepancy in the United States. MATERIALS AND METHODS: Using Surveillance, Epidemiology, and End Results data from National Cancer Institute (NCI), Medicare (2002-2015) beneficiaries with HCC who completed a Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey were included. Six CAHPS items (3 global scores: global care rating [GCR], primary doctor rating [PDR], and specialist rating [SR]; 3 composite scores: getting needed care [GNC], getting care quickly [GCQ], and doctor communication [DC]) assessed patient experience. Covariates assessed between treated and nontreated groups included patient, disease, hospital, and CAHPS items. RESULTS: Among 548 patients with HCC, 211 (39%) received treatment and 337 (61%) did not receive treatment. Forty-two percent (GCR), 29% (PDR), 30% (SR), 36% (GNC), 78% (GCQ), and 35% (DC) of patients reported less-than-excellent experiences on the respective CAHPS items. Chronic liver disease (CLD) was present in 52% and liver decompensation (LD) in 60%. A minority of the hospitals were NCI-designated cancer centers (47%), transplant centers (27%), and referral centers (9%). On univariable analysis, patients with at least a high school degree (odds ratio [OR], 1.9), admittance to a ≥400-bed hospital (OR, 2.7), CLD (OR, 3.0), or LD (OR, 1.7) were more likely to receive treatment, whereas older patients (≥75 years) (OR, 0.5) were less likely to receive treatment. On multivariable, patients with CLD (OR, 6.8) and an excellent experience in GNC with a specialist (OR, 10.6) were more likely to receive treatment. CONCLUSIONS: HCC treatment discrepancy may be associated with patient-related factors, such as lack of specialist care (GNC), and disease-related factors, such as absence of underlying CLD.

Regional Differences in Clinical Presentation and Prognosis of Patients With Post-Sustained Virologic Response Hepatocellular Carcinoma.

BACKGROUND & AIMS: Widespread use of direct-acting antivirals for hepatitis C virus infection has been paralleled with increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response (post-SVR HCC) worldwide. Few data compare regional differences in the presentation and prognosis of patients with post-SVR HCC. METHODS: We identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March 2015 and October 2021 from 30 sites in Europe, North America, South America, the Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis. RESULTS: Among 8796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of patients detected by surveillance (range: 59.5%-100%), median maximum tumor diameter (range, 1.8-5.0 cm), and the proportion with multinodular HCC (range, 15.4%-60.8%). The prognosis of patients highly varied by region (hazard ratio range, 1.82-9.92), with the highest survival rates in East Asia, North America, and South America, and the lowest survival rates in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early stage detection (Barcelona Clinic Liver Cancer stage 0/A, 71.0% vs 21.3%; P < .0001) and lower mortality rates (adjusted hazard ratio, 0.29; 95% CI, 0.18-0.46). CONCLUSIONS: Clinical characteristics, including early stage detection, and prognosis of post-SVR HCC differed significantly across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally.

Hepatocellular Carcinoma Surveillance Patterns and Outcomes in Patients With Cirrhosis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance is associated with improved early detection and reduced mortality, although practice patterns and effectiveness vary in clinical practice. We aimed to characterize HCC surveillance patterns in a large, diverse cohort of patients with HCC. METHODS: We conducted a retrospective cohort study of patients diagnosed with HCC between January 2008 and December 2022 at 2 large US health systems. We recorded imaging receipt in the year before HCC diagnosis: ultrasound plus α-fetoprotein (AFP), ultrasound alone, multiphasic contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI), and no liver imaging. We used multivariable logistic and Cox regression analysis to compare early tumor detection, curative treatment receipt, and overall survival between surveillance strategies. RESULTS: Among 2028 patients with HCC (46.7% Barcelona Clinic Liver Cancer stage A), 703 (34.7%) had ultrasound plus AFP, 293 (14.5%) had ultrasound alone, 326 (16.1%) had multiphasic CT/MRI, and 706 (34.8%) had no imaging in the year before HCC diagnosis. Over the study period, proportions without imaging were stable, whereas use of CT/MRI increased. Compared with no imaging, CT/MRI and ultrasound plus AFP, but not ultrasound alone, were associated with early stage HCC detection and curative treatment. Compared with ultrasound alone, CT/MRI and ultrasound plus AFP were associated with increased early stage detection. CONCLUSIONS: HCC surveillance patterns vary in clinical practice and are associated with differing clinical outcomes. While awaiting data to determine if CT or MRI surveillance can be performed in a cost-effective manner in selected patients, AFP has a complementary role to ultrasound-based surveillance, supporting its adoption in practice guidelines.

An Emulated Clinical Trial of Deprescribing Proton Pump Inhibitors in Patients With Cirrhosis.

INTRODUCTION: Proton pump inhibitors (PPI) are overused and carry harms in cirrhosis. Deprescribing is advocated but has not been trialed. METHODS AND FINDINGS: We emulated a clinical trial using Medicare data. All patients were receiving chronic PPI therapy before a compensated cirrhosis diagnosis. We compared the risk death/decompensation over 3 years between continuous users and deprescribers. We find that PPI deprescription is associated with less ascites and that cumulative PPI use is associated with more ascites and encephalopathy. Ultimately, 71% of deprescribers restart PPIs. DISCUSSION: PPI deprescribing has benefits but requires ongoing support and alternative therapies for gastrointestinal symptoms.

In-Depth Proteome Profiling of Small Extracellular Vesicles Isolated from Cancer Cell Lines and Patient Serum.

Extracellular vesicle (EV) secretion has been observed in many types of both normal and tumor cells. EVs contain a variety of distinctive cargoes, allowing tumor-derived serum proteins in EVs to act as a minimally invasive method for clinical monitoring. We have undertaken a comprehensive study of the protein content of the EVs from several cancer cell lines using direct data-independent analysis. Several thousand proteins were detected, including many classic EV markers such as CD9, CD81, CD63, TSG101, and Syndecan-1, among others. We detected many distinctive cancer-specific proteins, including several known markers used in cancer detection and monitoring. We further studied the protein content of EVs from patient serum for both normal controls and pancreatic cancer and hepatocellular carcinoma. The EVs for these studies have been isolated by various methods for comparison, including ultracentrifugation and CD9 immunoaffinity column. Typically, 500-1000 proteins were identified, where most of them overlapped with the EV proteins identified from the cell lines studied. We were able to identify many of the cell-line EV protein markers in the serum EVs, in addition to the large numbers of proteins specific to pancreatic and HCC cancers.

FIB-4 and APRI for cirrhosis detection in a privately insured national cohort.

Background and Aims: Non-invasive laboratory-based fibrosis indices have been proposed as a tool for population-based screening for advanced fibrosis. We aimed to examine the performance of fibrosis indices at the time of and prior to cirrhosis diagnosis. Methods: We included adult patients with cirrhosis diagnosis codes in a privately insured database (Optum) from 2010-2018 with 1:4 birth year-matched controls without cirrhosis diagnosis codes. We analyzed aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 index (FIB-4) up to 30 months prior to the entry of cirrhosis diagnosis codes. Cut-offs of <1 and ≥2 were used for APRI and <1.3 and ≥2.67 were used for FIB-4. Results: We included 10,650 patients with cirrhosis (median age 62 years), who were predominantly white (57.8%) and male (51.9%). The most common etiologies of cirrhosis were non-alcoholic steatohepatitis (23.8%), hepatitis C (23.0%), and alcohol-related liver disease (20.5%). At the time of cirrhosis diagnosis (±3 months), 9.3% of patients with cirrhosis had APRI ≥2 and 41.3% had a FIB-4 ≥2.67 compared to 1.2% and 8.9% in control patients, respectively. In the periods spanning 3-12, 12-21, and 21-30 months prior to cirrhosis diagnosis, APRI was ≥2 in 9.4%, 6.6%, and 6.5% of patients, respectively; FIB-4 was ≥2.67 in 42.1%, 37.1%, and 34.3% of patients, respectively. The sensitivity and specificity of APRI at the time of cirrhosis diagnosis were 9.3% and 98.8%, respectively, while the sensitivity and specificity of FIB-4 were 41.3% and 91.0%, respectively. Lower cut-off values for APRI and FIB-4 showed similar performance. Conclusions: Existing non-invasive fibrosis makers are suboptimal when used for advanced fibrosis identification, missing over half of patients with cirrhosis at the time of and prior to clinical diagnosis. Impact and implications: Commonly available laboratory-based indices, including APRI and FIB-4, have been proposed to rule in or rule out advanced fibrosis in the general population. In a study of a large privately insured cohort from the US, FIB-4 and APRI were not sufficient for screening for advanced fibrosis at the time of or prior to clinical diagnosis. While performance for screening out advanced fibrosis was better, a significant percentage of patients with cirrhosis have lab indices below threshold values. Future studies to develop laboratory-based algorithms to help stratify liver fibrosis for population-based screening are warranted.

Controversies of Direct-Acting Antivirals in Hepatocellular Carcinoma.

Therapy for chronic hepatitis C virus infection with direct-acting antiviral agents (DAAs) has been highly successful in achieving sustained virological response (SVR) with associated improvements in liver dysfunction, liver-related mortality, and transplant-free survival. There is a high risk of hepatocellular carcinoma (HCC) with an annual incidence of 2% to 4% in patients with cirrhosis. Following DAAs treatment and achievement of SVR, the risk of incident and recurrent HCC drops significantly over time, with risk associated with demographic and liver disease-related factors. Several risk factors have been described including age, male, diabetes comorbidities, alcohol abuse, hepatitis B virus or human immunodeficiency virus-coinfection, and advanced liver disease or increased liver fibrosis. Recurrence risk after DAA therapy has been associated with baseline tumor burden, with increased risk with larger lesion(s), multifocal disease, elevated alpha-fetoprotein level, treatment type (curative vs palliative), and shorter interval between HCC complete response and DAA initiation. Overall, due to the heterogeneity among individual patient data and lack of adequately controlled data, there are no conclusive statements that can be drawn that DAAs exposure is directly associated with HCC occurrence or recurrence. However, the best available data suggest a decreased risk of incident HCC with DAA therapy and no increased risk of recurrence with DAAs after complete tumor response.

A Phase II Study of Optimized Individualized Adaptive Radiotherapy for Hepatocellular Carcinoma.

PURPOSE: We hypothesized that optimizing the utility of stereotactic body radiotherapy (SBRT) based on the individual patient's probability for tumor control and risk of liver injury would decrease toxicity without sacrificing local control in patients with impaired liver function or tumors not amenable to thermal ablation. PATIENTS AND METHODS: Patients with Child-Pugh (CP) A to B7 liver function with aggregate tumor size >3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an Institutional Review Board-approved phase II clinical trial to undergo SBRT with baseline and midtreatment dose optimization using a quantitative, individualized utility-based analysis. Primary endpoints were change in CP score of ≥2 points within 6 months and local control. Protocol-treated patients were compared with patients receiving conventional SBRT at another cancer center using overlap weighting. RESULTS: A total of 56 patients with 80 treated tumors were analyzed with a median follow-up of 11.2 months. Two-year cumulative incidence of local progression was 6.4% [95% confidence interval (CI, 2.4-13.4)]. Twenty-one percent of patients experienced treatment-related toxicity within 6 months, which is similar to the rate for SBRT in patients with CP A liver function. An analysis using overlap weighting revealed similar local control [HR, 0.69; 95% CI (0.25-1.91); P = 0.48] and decreased toxicity [OR, 0.26; 95% CI (0.07-0.99); P = 0.048] compared with conventional SBRT. CONCLUSIONS: Treatment of individuals with impaired liver function or tumors not amenable to thermal ablation with a treatment paradigm designed to optimize utility may decrease treatment-related toxicity while maintaining tumor control.

Efficacy of a Second Course of Radiation for Patients With Metachronous Hepatocellular Carcinoma.

PURPOSE: Liver-directed radiation therapy is an effective treatment for hepatocellular carcinoma (HCC), but metachronous lesions develop outside the irradiated field in >50% of patients. We hypothesized that irradiation of these new lesions would produce an outcome like that of patients receiving a first course (C1) of treatment. METHODS AND MATERIALS: We included patients with HCC who received a second course (C2) of radiation therapy >1 month after C1. Toxicity was defined as Child-Pugh score increase ≥2 within 6 months posttreatment (binary model) and as the change in albumin-bilirubin during the year after treatment (longitudinal model). Overall survival (OS) and local failure (LF) were captured at the patient and lesion level, respectively; both were summarized with Kaplan-Meier estimates. Predictors of toxicity and OS were assessed using generalized linear mixed and Cox regression models, respectively. RESULTS: Of 340 patients with HCC, 47 underwent irradiation for metachronous HCC, receiving similar prescription dose in C1/C2. Median follow-up was 17 months after C1 and 15 months after C2. Twenty-two percent of patients experienced toxicity after C1, and 25% experienced toxicity after C2. Worse baseline albumin-bilirubin predicted toxicity in both binary (odds ratio, 2.40; 95% CI, 1.46-3.94; P = .0005) and longitudinal models (P < .005). Two-year LF rate was 11.2% after C1 and 8.3% after C2; tumor dose (hazard ratio [HR], 0.982; 95% CI, 0.969-0.995; P = .007) and tumor size (HR, 1.135; 95% CI, 1.068-1.206; P < .005) predicted LF. Two-year OS was 46.0% after C1 and 42.6% after C2; tumor dose (HR, 0.986; 95% CI, 0.979-0.992; P < .005) and tumor size (HR, 1.049; 95% CI, 1.010-1.088; P = .0124) predicted OS. Reirradiation was not associated with toxicity (P > .7), LF (P = .79), or OS (P = .39). CONCLUSIONS: In this largest series in the Western hemisphere, we demonstrate that irradiation for metachronous HCC offers low rates of LF with acceptable toxicity and OS like that of patients receiving a C1. These findings support judicious selection of patients for reirradiation in metachronous HCC.