Singal, Amit G.

BackgroundCurative surgical treatments afford the best prognosis for patients with intrahepatic cholangiocarcinoma (iCCA); however, the comparative effectiveness of treatment options and factors associated with curative treatment receipt for early stage iCCA remain unknown.MethodsThe authors identified patients who were diagnosed with early stage iCCA, defined as a unifocal tumor <3 cm, during 2004–2018 from the National Cancer Database. Multivariable logistic and Cox regression analyses were used to identify the factors associated with curative treatment and overall survival (OS), respectively.ResultsThe proportion of patients with early stage iCCA increased from 4.5% in 2004 to 7.3% in 2018, with the odds of early stage detection increasing by 3.1% per year (odds ratio [OR], 1.031; 95% CI, 1.015–1.049). Of 1093 patients who had early stage iCCA, 464 (42.5%) underwent resection, 113 (10.3%) underwent ablation, 62 (5.7%) underwent liver transplantation, and 454 (41.5%) received noncurative treatments. Hispanic patients (adjusted OR [aOR], 0.57; 95% CI, 0.33–0.97) and Black patients (aOR, 0.47; 95% CI, 0.28–0.77) were less likely to receive curative treatments than White patients. Compared with patients who underwent surgical resection, those who underwent liver transplantation had a trend toward improved OS (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.37–1.08), whereas those who underwent local ablation (aHR, 1.39; 95% CI, 1.01–1.92) and noncurative treatments (aHR, 3.97; 95% CI, 3.24–4.88) experienced worse OS.ConclusionsMore than one third of patients with early stage iCCA did not receive curative treatment, with Hispanic and Black patients being less likely to receive curative treatments than White patients. Surgical resection and liver transplantation were associated with improved survival compared with local ablation. Future studies should investigate disparities in curative treatment receipt and outcomes for early stage iCCA.

AbstractBackgroundTransarterial radioembolization (TARE) is increasingly used as an alternative to transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). We aimed to perform an overall and individual patient data (IPD) meta‐analysis of studies comparing TACE and TARE.MethodsWe performed a systematic literature search using pre‐specified keywords with the aid of an informationist for articles from inception to 3/2020. The primary endpoint was overall survival (OS), and the secondary endpoint was time to progression (TTP).ResultsSeventeen studies met inclusion criteria with 2465 unique patients, with one randomized trial, 4 prospective studies and 12 retrospective studies. Barcelona Clinic Liver Cancer (BCLC) stage B (42.8%) was the most common stage followed by BCLC A (30.3%) and BCLC C (29.0%). There was no difference in OS between the two modalities (−0.55 months, 95% CI −1.95 to 3.05). In three studies with available TTP data, TARE resulted in a longer TTP than TACE (mean TTP 17.5 vs. 9.8 months; mean TTP difference 4.8 months, 95% CI 1.3–8.3 months). IPD‐level meta‐analysis of 311 patients from three studies showed no difference in overall OS between the two modalities including among subgroups stratified by tumor stage and liver function. Limitations of the current literature include inconsistent length of follow‐up, inconsistency in response criteria, and safety reporting.ConclusionsCurrent data suggest TARE provides significantly longer TTP than TACE, although the two treatments do not significantly differ in terms of OS. Given limitations of the current data, there is rationale for prospective studies comparing these modalities.

Abstract Background and Aims Immunotherapy has emerged as an effective treatment for patients with advanced‐stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy. Approach and Results We used the US National Cancer Database to identify patients with tumor‐node‐metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first‐line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65–0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46–0.83) and Black patients (aOR: 0.71, 95% CI: 0.54–0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race‐ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004). Conclusions Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial‐ethnic disparities in the management of advanced HCC is urgently needed.

405 Background: Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer mortality in the United States. Although clinical guidelines recommend ultrasound (U/S), with or without the serum biomarker alpha fetoprotein (AFP) for HCC surveillance in at-risk patients, only 24% of patients adhere to surveillance and only one-third of HCCs are detected before developing symptoms. A multi-target HCC blood-based test (mt-HBT) was recently shown to have promising sensitivity for early HCC detection and may help improve surveillance adherence given its blood-based nature. Our objective was to evaluate the comparative clinical effectiveness of mt-HBT with the current standard-of-care surveillance strategy in patients with cirrhosis. Methods: We simulated a virtual trial by developing a microsimulation model of the natural history of HCC in patients with compensated (Child Pugh A) cirrhosis over a 30-year horizon. To inform model parameters, we used published data on tumor progression, competing risks of mortality, and real-world HCC surveillance adherence. Test performance characteristics were informed by a network meta-analysis. We simulated the life course of 51-year-old patients with cirrhosis and compared no surveillance with biannual surveillance using (1) AFP only, (2) U/S only, (3) U/S+AFP, (4) mt-HBT, and (5) mt-HBT with improved adherence. We assumed a blood-based test—without U/S—would improve surveillance adherence by 10% compared with current adherence (̃4% absolute improvement). Results: Per 100,000 cirrhosis patients, mt-HBT detected 6,220 more early-stage HCC than no surveillance, 2,250 (+57%) more than AFP, 1080 (+21%) more than U/S, and 200 (-3%) less than U/S+AFP. mt-HBT with improved adherence detected 210 (+3%) more early-stage HCC than U/S+AFP (Table). The remaining HCC cases were either symptomatic or the patients died per other competing causes prior to detection. The number of screening tests needed to detect one HCC were 296 for AFP, 287 for U/S, 253 for U/S+AFP, 254 for mt-HBT and 262 for mt-HBT with improved adherence. The number of diagnostic MRI/CT needed to detect one HCC were 40 for AFP, 38 for U/S, 45 for U/S+AFP, 37 for mt-HBT, and 38 for mt-HBT with improved adherence. Conclusions: mt-HBT detects more early-HCC cases than U/S and similar number of early-HCC cases with U/S+AFP. By decreasing surveillance barriers and increasing adherence, mt-HBT could improve early HCC detection and could be promising option for HCC surveillance in patients with cirrhosis. [Table: see text]

Abstract The burden of HCC is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process‐based measures and patient‐reported outcomes (PROs) along the HCC care continuum. We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13‐member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate PROs based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha‐fetoprotein [AFP]) every 6 months, need for surveillance in high‐risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging‐Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high‐risk population.

Prognosis of hepatocellular carcinoma (HCC) could be affected by lack of or delayed therapy. We aimed to characterize the prevalence, correlates, and clinical impact of therapeutic underuse and delay in patients with HCC. Patients with HCC diagnosed between 2010 and 2017 were analyzed from the United States National Cancer Database. Logistic regression analysis identified factors associated with no and delayed (>90 days after diagnosis) HCC treatment. Cox proportional hazards regression with landmark analysis assessed the association between therapeutic delay and overall survival (OS), accounting for immortal time bias. Of 116,299 patients with HCC, 24.2% received no treatment and 18.4% of treated patients had delayed treatment. Older age, Black, Hispanic, lower socioeconomic status, earlier year of diagnosis, treatment at nonacademic centers, Northeast region, increased medical comorbidity, worse liver dysfunction, and higher tumor burden were associated with no treatment. Among treated patients, younger age, Hispanic, Black, treatment at academic centers, West region, earlier tumor stage, and receipt of noncurative treatment were associated with treatment delays. In multivariable Cox regression with a landmark of 150 days, patients with and without treatment delays had similar OS (adjusted hazard ratio [aHR], 1.01; 95% confidence interval [CI], 0.98‐1.04) with a median survival of 33.7 vs. 32.1 months, respectively. However, therapeutic delay was associated with worse OS in patients who had tumor, nodes, and metastases (TNM) stage 1 (aHR, 1.06; 95% CI, 1.01‐1.11) or received curative treatment (aHR, 1.12; 95% CI, 1.05‐1.18). Conclusion: One‐fourth of patients with HCC receive no therapy and one‐fifth of treated patients experience treatment delays. Both were associated with demographic, socioeconomic, and clinical characteristics of patients as well as facility type and region. The association between therapeutic delay and survival was stage and treatment dependent.

Background and Aims Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers (PLCs). Differences in their clinical features and outcomes are open for investigation in a large‐scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC. Approach and Results The Surveillance, Epidemiology, and End Results Program 18 Database (2000‐2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis versus HCC. Cox regression analysis was used to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (<50 or ≥65), female sex, non‐Hispanic White race, higher income, rural area, and higher tumor burden were independently associated with iCCA diagnosis versus HCC. Patients with iCCA had worse OS than those with HCC (9 vs. 13 months; P < 0.001). However, OS was comparable between iCCA and HCC in multivariable analysis (adjusted hazard ratio [aHR] = 1.02; 95% CI = 0.99‐1.05). In subgroup analyses, iCCA was associated with better OS than HCC in patients with tumor ≥5 cm (aHR = 0.83; 95% CI = 0.80‐0.86), lymph node involvement (aHR = 0.76; 95% CI = 0.72‐0.81), distant metastasis (aHR = 0.76; 95% CI = 0.73‐0.79), poorly/undifferentiated tumors (aHR = 0.88; 95% CI = 0.83‐0.94), and those receiving noncurative treatment (aHR = 0.96; 95% CI = 0.93‐0.98). Conclusions We identified the demographic, socioeconomic, and clinical features associated with iCCA diagnosis over HCC among patients with PLC. Although iCCA patients presented at an advanced stage, OS was similar between iCCA and HCC in multivariable analysis. iCCA was associated with longer OS for subgroups with poor prognostic features.

4577 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Though biannual ultrasound surveillance with or without alpha-fetoprotein (AFP) testing is recommended for at-risk patients, its sensitivity for early-stage HCC detection is suboptimal. We therefore evaluated performance of a biomarker panel incorporating methylated DNA markers (MDMs) and proteins for early HCC detection in at-risk patients with chronic liver disease. Methods: In an international, multicenter, case-control study, blood specimens were collected from patients with HCC per AASLD criteria and controls matched for age and liver disease etiology. All patients had underlying cirrhosis or chronic HBV infection. Whole blood was collected in cell-free DNA stabilizing and serum-separation tubes and shipped to a central laboratory for processing. The levels of 5 MDMs, AFP, and AFP-L3 were assessed along with age and sex. We used 537 samples in a 5-fold validation for developing a LASSO regression algorithm to classify samples as HCC positive or negative. Model robustness was tested by perturbing the data in silico and analyzing results with the predictive algorithm. Algorithm performance was compared to AFP alone and the GALAD score (Gender, Age, AFP-L3, AFP, and DCP). Results: The study included 136 HCC cases (81 early-stage—BCLC stage 0/A) and 401 controls. With specificity set at 89%, we developed a model using sex, AFP, and 3 MDMs (HOXA1, TSPYL5, B3GALT6) with higher sensitivity (70%) for early-stage HCC compared to GALAD (54%) or AFP (31% at 20 ng/mL or 52% at ≥7.7 ng/mL) (Table). The AUC for the HCC marker panel was 0.91 (95% CI 0.89 – 0.94) compared to GALAD (0.88; 95% CI 0.85 – 0.91) or AFP (0.84; 95% CI 0.81 – 0.87). The panel performed similarly in viral (AUC = 0.94) and non-viral (AUC = 0.89) etiologies. Conclusions: The robust algorithm based on novel blood-based biomarkers presented here provides higher sensitivity for early-stage HCC compared to other available blood-based biomarkers and, therefore, could significantly impact HCC clinical management and patient outcomes. Further clinical studies to validate the algorithm are ongoing. Clinical trial information: NCT03628651 . [Table: see text]

Abstract Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2–5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

Abstract Background: The utility of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is controversial. We aimed to identify factors associated with elevated AFP and define the patients for whom AFP is effective for surveillance. Methods: Data from the NCI Early Detection Research Network phase II HCC biomarker study (233 early-stage HCC and 412 cirrhotic patients) were analyzed. We analyzed 110 early-stage HCC and 362 cirrhotic hepatitis C virus (HCV) patients for external validation. Sensitivity, specificity, and area under the ROC curve (AUC) for HCC were calculated. Results: HCV etiology, non-White race, and serum alanine transaminase (ALT) predicted elevated AFP in cirrhotics. Non-White race and ALT predicted elevated AFP in HCC patients. Higher AUC of AFP for HCC was noted in patients with HBV (0.85) and alcohol (0.84), whereas it was lower in patients with hepatitis C virus (HCV; 0.80) and nonviral/alcohol etiology (0.76). The AUC was higher in HCV patients with serum ALT ≤40 U/L than patients with serum ALT &gt;40 U/L (0.91 vs. 0.75, P &lt; 0.01). At 90% specificity, the sensitivity of AFP increased from 44% to 74% in Whites with HCV and from 50% to 85% in non-Whites with HCV. There was a trend toward higher AUC in HCV patients with serum ALT ≤40 U/L than those with serum ALT &gt;40 U/L (0.79 vs. 0.69, P = 0.10) in the validation cohort. Conclusions: The satisfactory performance of AFP in HCV patients with normal ALT should be further validated. Impact: The AFP may serve as a valuable surveillance test in HCV patients with normal ALT. Cancer Epidemiol Biomarkers Prev; 26(7); 1085–92. ©2017 AACR.