Background: Most patients with hepatocellular carcinoma (HCC) present at advanced stages. The prevalence and clinical impact of delays during diagnostic evaluation among patients with HCC is unclear. Purpose: To identify and characterize factors associated with diagnostic delays among patients with HCC. Methods: Records were reviewed for consecutive patients with cirrhosis and HCC at a large urban hospital between January 2005 and July 2012. Time from presentation to diagnosis was determined using Kaplan-Meier analysis. Diagnostic delay was defined as time to diagnosis exceeding 3 months, and multivariate logistic regression was used to identify correlates of diagnostic delays. Results: Among 457 patients with HCC, 226 (49.5%) were diagnosed as outpatients. Among these, median time-to-diagnosis was 2.2 months, with 87 patients (38.5%) experiencing a diagnostic delay. Diagnostic delays were positively associated with the presence of hepatic encephalopathy (odds ratio [OR], 2.29; 95% CI, 1.03–5.07) and negatively associated with presentation after implementation of the electronic medical records (EMR) (OR, 0.28; 95% CI, 0.15–0.52) and presentation with an abnormal ultrasound (OR, 0.36; 95% CI, 0.19–0.67) on multivariate analysis. Higher rates of diagnostic delays were observed among those with hepatic encephalopathy (56% vs 35%), whereas lower rates were seen in those who presented after EMR implementation (26% vs 60%) and those who presented with an abnormal ultrasound with or without an elevated alpha fetoprotein level (27% vs 50%). Among 49 patients with mass-forming HCC and diagnostic delay, 18% had interval tumor growth of 2 cm or greater. Conclusions: Nearly 20% of patients with HCC wait more than 3 months from presentation to diagnosis, which can contribute to interval tumor growth.
Nishant Patel, Adam C. Yopp, and Amit G. Singal
Amit G. Singal, Jorge A. Marrero, and Adam Yopp
More than 60% of patients with hepatocellular carcinoma (HCC) are diagnosed at a late stage, suggesting potential breakdowns in the HCC screening process. Understanding which steps in the screening process are not being performed is essential for designing effective interventions. To characterize HCC screening process failures, a retrospective cohort study of patients with cirrhosis diagnosed with HCC at a large urban safety-net hospital was conducted between 2005 and 2012. Screening process failures during the year before HCC diagnosis were characterized into 3 categories: absence of surveillance, failure of detection, and delayed follow-up. Univariate and multivariate analyses were performed to identify predictors of screening process failures. A total of 185 patients with cirrhosis and HCC were identified, of whom 91 (49%) were diagnosed at an early stage (Barcelona Clinic Liver Cancer system stage A). Only 16 (8.6%) patients successfully completed the screening process. Absence of surveillance was the most common screening process failure, found in 75.7% of all patients, and was associated with trends toward lower rates of early tumor detection (odds ratio, 0.51; 95% CI, 0.23-1.09) and worse overall survival (hazard ratio, 0.79; 95% CI, 0.49-1.25). Failure of detection and delayed follow-up were found in 11.4% and 2.7% of patients, respectively.
Ali A. Mokdad, Amit G. Singal, Jorge A. Marrero, Hao Zhu, and Adam C. Yopp
Background: Patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) have variable long-term outcomes. Better delineation of prognosis is important for clinical trial enrollment and clinical practice in an era of precision medicine. We hypothesized that stratification of patients with BCLC stage C HCC by presence of vascular invasion and/or metastasis improves prognostic discrimination. Methods: Using a prospectively maintained database, we identified 234 patients diagnosed with BCLC stage C HCC between 2005 and 2015. Patients were stratified into 3 groups based on tumor characteristics: (1) vascular invasion alone, (2) metastasis alone, and (3) vascular invasion and metastasis. Overall survival (OS) was compared using a Cox model. A subgroup analysis was performed based on extent of vascular invasion and site of metastasis. Results: The cohort comprised 123 patients (53%) with vascular invasion alone, 34 (15%) with metastasis alone, and 77 (33%) with both vascular invasion and metastasis. Median survival was 5.7, 3.9, and 3.0 months, respectively (P<.01). Patients with vascular invasion or metastasis alone had significantly better survival compared with those with vascular invasion and metastasis (adjusted hazard ratio [HR],0.68; 95% CI, 0.49–0.94, and HR, 0.61; 95% CI, 0.39–0.96, respectively). Compared with tumoral invasion of branch portal veins, involvement of the main portal vein was associated with worse survival (HR, 2.13; 95% CI, 1.29–3.49). OS did not differ by site of metastasis. Conclusions: Stratification of patients within the BCLC stage C staging subgroup by vascular invasion and presence of metastasis further discriminates patient prognosis. This substratification may have implications for therapy and more accurate prognostic features.
Caitlin A. Hester, Nicole E. Rich, Amit G. Singal, and Adam C. Yopp
Background: Despite an increasing burden of nonalcoholic steatohepatitis (NASH), limited data are available comparing outcomes of NASH-related hepatocellular carcinoma (HCC) versus other etiologies. Methods: Patient demographic and tumor characteristics were collected for 1,051 patients diagnosed with NASH-, alcohol-related liver disease (ALD)–, hepatitis C virus (HCV)–, and hepatitis B virus (HBV)–related HCC at 2 large health systems from January 2008 through December 2016. Patient demographics, clinical characteristics, and survival were compared. Risk-adjusted treatment receipt and overall survival (OS) were examined using multivariable analysis. Results: A total of 92 patients with NASH-related HCC were compared with 153 patients with ALD-, 719 with HCV-, and 87 with HBV-related HCC. Patients with NASH were older, more likely female, and more likely Hispanic white. Patients with NASH and HBV had more compensated liver disease than those with ALD or HCV, including significantly higher proportions having noncirrhotic HCC. Despite similar surveillance receipt and Barcelona Clinic Liver Cancer (BCLC) tumor stage at diagnosis, patients with NASH had higher rates of curative-intent therapy than those with other diseases. Unadjusted median OS was 16 months for NASH, 15 months for ALD, 14 months for HCV, and 8 months for HBV. In multivariable analysis, NASH was associated with worse OS compared with ALD (hazard ratio, 1.92; 95% CI, 1.3–2.5), but there was no difference between NASH- and HCV- or HBV-related HCC. Conclusions: Patients with NASH-related HCC present with more preserved liver function, including a higher proportion having noncirrhotic HCC, than other diseases. Despite patients having similar tumor stage at diagnosis, NASH is independently associated with worse survival compared with ALD, but similar survival compared with HCV and HBV.
Amit G. Singal, Akbar K. Waljee, Nishant Patel, Emerson Y. Chen, Jasmin A. Tiro, Jorge A. Marrero, and Adam C. Yopp
Although prior studies have shown underuse of appropriate therapy in patients with hepatocellular carcinoma (HCC), no studies to date have assessed the prevalence and clinical impact of therapeutic delays among patients with HCC. The goal of this study was to characterize and identify factors associated with underuse and delays in treatment of these patients. A retrospective cohort study was conducted of patients with cirrhosis diagnosed with HCC at a large urban safety net hospital between January 2005 and June 2012. Dates for HCC diagnosis and any treatments were recorded. Univariate and multivariate analysis was used to determine factors associated with treatment underuse and delayed treatment, which was defined as time from diagnosis to treatment exceeding 3 months. The authors identified 267 treatment-eligible patients with HCC, of whom only 62% received HCC therapy. On multivariate analysis, tumor stage (odds ratio [OR], 0.48; 95% CI, 0.36-0.65), Child-Pugh class (OR, 0.49; 95% CI, 0.28-0.84), and black race (OR, 0.55; 95% CI, 0.31-0.99) were associated with lower rates of treatment use. The median time to treatment was 1.7 months, with 31% of patients experiencing delayed treatment. Delayed treatment was associated with the presence of ascites (hazard ratio [HR], 2.8; 95% CI, 1.3-6.1) and current treatment with transarterial chemoembolization (HR, 4.8; 95% CI, 1.8-12.5). After adjusting for tumor stage and Child-Pugh class, treatment underuse (HR, 0.33; 95% CI, 0.24-0.46) and delayed treatment (HR, 0.50; 95% CI, 0.30-0.84) were both associated with significantly worse survival. Results showed that, in addition to one-third of patients not receiving HCC-directed therapy, another 30% experienced significant therapeutic delays, leading to worse survival.
Ashwin Rao, Nicole E. Rich, Jorge A. Marrero, Adam C. Yopp, and Amit G. Singal
Background: Delays in diagnosis and treatment have been reported for many cancers, with resultant stage migration and worse survival; however, few data exist in patients with hepatocellular carcinoma (HCC). These data are of particular importance in light of the COVID-19 pandemic, which has caused disruptions in healthcare processes and may continue to impact cancer care for the foreseeable future. The aim of our study was to characterize the prevalence and clinical significance of diagnostic and treatment delays in patients with HCC. Methods: We performed a retrospective cohort study of consecutive patients diagnosed with HCC between January 2008 and July 2017 at 2 US health systems. Diagnostic and treatment delays were defined as >90 days between presentation and HCC diagnosis and between diagnosis and treatment, respectively. We used multivariable logistic regression to identify factors associated with diagnostic and treatment delays and Cox proportional hazard models to identify correlates of overall survival. Results: Of 925 patients with HCC, 39.0% were diagnosed via screening, 33.1% incidentally, and 27.9% symptomatically. Median time from presentation to diagnosis was 37 days (interquartile range, 18–94 days), with 120 patients (13.0%) experiencing diagnostic delays. Median time from HCC diagnosis to treatment was 46 days (interquartile range, 29–74 days), with 17.2% of patients experiencing treatment delays. Most (72.5%) diagnostic delays were related to provider-level factors (eg, monitoring indeterminate nodules), whereas nearly half (46.2%) of treatment delays were related to patient-related factors (eg, missed appointments). In multivariable analyses, treatment delays were not associated with increased mortality (hazard ratio, 0.90; 95% CI, 0.60–1.35); these results were consistent across subgroup analyses by Barcelona Clinic Liver Cancer stage and treatment modality. Conclusions: Diagnostic and therapeutic delays exceeding 3 months are common in patients with HCC; however, observed treatment delays do not seem to significantly impact overall survival.
Ali Mokdad, Travis Browning, John C. Mansour, Hao Zhu, Amit G. Singal, and Adam C. Yopp
Background: The diagnosis and treatment of cancer is a continuum, with multiple steps and interfaces between patients and providers allowing for potential delays in cancer recognition and subsequent treatment. The diagnosis and treatment of hepatocellular carcinoma (HCC) is especially prone to missteps along the continuum, leading to treatment delays due to non–tissue-based diagnosis and multiprovider treatments. The aim of this study was to evaluate outcome measures after implementation of a voice messaging system (VMS) designed to streamline patient referrals to downstream treatment physicians and ultimately reduce delays in HCC treatment, thereby improving outcome measures. Methods: A retrospective study of outpatients with HCC was conducted in a safety net hospital between February 2008 and January 2012. In February 2010, VMS notification of HCC to the ordering physician and downstream treating physicians was implemented. Patients were divided into 2 groups: (1) preintervention: diagnosis 2 years before implementation or failure of notification following implementation, and (2) postintervention: diagnosis 2 years after implementation. Demographics, tumor characteristics, treatment, and survival were compared. Results: This study included 96 patients diagnosed with HCC: 51 in the preintervention group and 45 in the postintervention group. The main cause of chronic liver disease was HCV infection, and no differences in symptoms, liver dysfunction, tumor characteristics, or treatment were observed between groups. The time from diagnosis to clinic contact (0.5 vs 2.9 months; P=.003) and time from detection to treatment (2.2 vs 5.5 months; P=.005) was significantly shorter after implementation of the VMS. Barcelona Clinic Liver Cancer stage A status (hazard ratio [HR], 3.1; 95% CI, 2, 6), treatment (HR, 1.9; 95% CI, 1, 4), and VMS (HR, 1.8; 95% CI, 1, 3) were independently associated with overall survival. Patients diagnosed after implementation of the VMS had a median survival of 28.5 versus 15.7 months (P=.02). Conclusions: Implementation of VMS reduces time to treatment and time to clinic visit. Reduction in time to treatment is associated with improved outcome independent of tumor stage, underlying liver function, and treatment.
Ali A. Mokdad, Rebecca M. Minter, Adam C. Yopp, Matthew R. Porembka, Sam C. Wang, Hong Zhu, Mathew M. Augustine, John C. Mansour, Michael A. Choti, and Patricio M. Polanco
Background: Preoperative therapy is being increasingly used in the treatment of resectable pancreatic cancer. Because there are only limited data on the optimal preoperative regimen, we compared overall survival (OS) between preoperative chemotherapy (CT) and preoperative chemoradiotherapy (CRT) in resectable pancreatic adenocarcinoma. Patients and Methods: Patients receiving preoperative therapy and resection for clinical T1–3N0–1M0 adenocarcinoma of the pancreas were identified in the National Cancer Database for 2006 through 2012. We constructed inverse probability of treatment weights to balance baseline group differences, and compared OS between CT and CRT, as well as pathologic and postoperative findings. Results: We identified 1,326 patients (CT: 616; CRT: 710). Differences in OS were not significant between CRT and CT (median survival, 25 vs 26 months; P=.10; weight-adjusted hazard ratio, 0.89; 95% CI, 0.77–1.02). Compared with patients in the CT group, those in the CRT group had lower pathologic T stage (ypT0/T1/T2: 36% vs 21%; P<.01), less lymph node involvement (ypN1: 35% vs 59%; P<.01), and fewer positive resection margins (14% vs 21%; P=.01), but had more postoperative unplanned readmissions (9% vs 6%; P=.01) and increased 90-day mortality (7% vs 4%; P=.03). Those in the CRT group were also less likely to receive postoperative therapy (26% vs 51%; P<.01). Conclusions: Preoperative CT and CRT have similar OS, but CRT is associated with more favorable pathologic features at the cost of higher postoperative morbidity and mortality. Additional trials investigating preoperative therapy are needed for patients with resectable pancreatic cancer.
Al B. Benson, Michael I. D’Angelica, Daniel E. Abbott, Daniel A. Anaya, Robert Anders, Chandrakanth Are, Melinda Bachini, Mitesh Borad, Daniel Brown, Adam Burgoyne, Prabhleen Chahal, Daniel T. Chang, Jordan Cloyd, Anne M. Covey, Evan S. Glazer, Lipika Goyal, William G. Hawkins, Renuka Iyer, Rojymon Jacob, R. Kate Kelley, Robin Kim, Matthew Levine, Manisha Palta, James O. Park, Steven Raman, Sanjay Reddy, Vaibhav Sahai, Tracey Schefter, Gagandeep Singh, Stacey Stein, Jean-Nicolas Vauthey, Alan P. Venook, Adam Yopp, Nicole R. McMillian, Cindy Hochstetler, and Susan D. Darlow
The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.