Adoption of single agent anticancer therapy for advanced hepatocellular carcinoma and impact of facility type, insurance status, and income on survival: Analysis of the national cancer database 2004-2014.

BACKGROUND: This study analyzes the pattern of use of single agent anticancer therapy (SAACT) in the treatment and survival of advanced hepatocellular carcinoma (aHCC) before and after sorafenib was FDA approved in 2007. METHODS: Adult patients diagnosed with HCC and treated with only ACT from 2004 - 2014 were identified in NCDB database. Patients were analyzed during three time frames: 2004-2006 (pre-sorafenib (PS)), 2007-2010 (early sorafenib (ES)) and 2011-2014 (late sorafenib (LS)). Cox proportional hazards models and Kaplan-Meier method were used for analyses. RESULTS: The NCDB contained 31,107 patients with HCC diagnosed from 2004-2014 and treated with ACT alone. Patients were generally men (78.0%), >50 years of age (92.5%). A significant increase in the rate of adaption of SAACT was observed over time: 6.2% PS, 15.2% ES, and 22.2% LS (p < 0.0001). During this later period, the highest proportion of SAACT is among academic and integrated network facilities (23.3%) as compared to community facilities (17.0%, p < 0.0001). The median overall survival of patients with aHCC treated only with SAACT improved significantly over time from 8.0 months (m) (95% CI: 7.4-8.8) to 10.7 m (10.4-11.2) to 15.6 m (15.2-16.0, p < 0.001). Multivariate analysis indicates worse outcomes for patients treated at community cancer programs (HR 1.28, (5% CI: 1.23-1.32), patients without insurance (HR 1.11, 1.06-1.16) and estimated household income of <$63,000 (HR 1.09, 1.05-1.13). CONCLUSION: aHCC patients treated only with ACT have experienced an overall improvement in survival, but significant differences exist between facility type, insurance status, and income.

Efficacy and Safety of Sorafenib in a Racially Diverse Patient Population with Advanced Hepatocellular Carcinoma.

BACKGROUND: There are few efficacy and toxicity data on sorafenib for patients treated for hepatocellular carcinoma (HCC) who are not Caucasian or Asian. MATERIALS AND METHODS: A retrospective analysis was carried out on 67 patients treated with sorafenib for advanced HCC at an urban referral center. Patients were categorized by race, age, sex, status, stage, and dose. Primary outcomes were time to progression (TTP), toxicity, and treatment discontinuation by race. RESULTS: African-Americans and Caucasians had significantly shorter TTP than patients of other races (Hispanic, Asian, and unidentified) [African-Americans: hazard ratio (HR)=5.01, p=0.0068; Caucasians: HR=8.25, p=0.0008). There were no significant differences in time to toxicity (p=0.99). Caucasians had the shortest time to therapy discontinuation (p=0.0298). TTP was shorter for males (HR=3.51, p=0.028), and longer for patients experiencing toxicity (HR=0.47, p=0.046). CONCLUSION: Among patients treated with sorafenib for advanced HCC, non African-American/non-Caucasian race, female sex, and toxicity were associated with significantly longer time to progression.

The Impact of Race on Survival After Hepatocellular Carcinoma in a Diverse American Population.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) incidence is increasing at differential rates depending on race. We aimed to identify associations between race and survival after HCC diagnosis in a diverse American population. METHODS: Using the cancer registry from Sylvester Comprehensive Cancer Center, University of Miami and Jackson Memorial Hospitals, we performed retrospective analysis of 999 patients diagnosed with HCC between 9/24/2004 and 12/19/2014. We identified clinical characteristics by reviewing available electronic medical records. The association between race and survival was analyzed using Cox proportional hazards regression. RESULTS: Median survival in days was 425 in Blacks, 904.5 in non-Hispanic Whites, 652 in Hispanics, 570 in Asians, and 928 in others, p < 0.01. Blacks and Asians presented at more advanced stages with larger tumors. Although Whites had increased severity of liver disease at diagnosis compared to other races, they had 36% reduced rate of death compared to Blacks, [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.51-0.8, p < 0.01]. After adjusting for significant covariates, Whites had 22% (HR 0.78, 95% CI 0.61-0.99, p 0.04) reduced risk of death, compared to Blacks. Transplant significantly reduced rate of death; however, only 13.3% of Blacks had liver transplant, compared to 40.1% of Whites, p < 0.01. CONCLUSIONS: In this diverse sample of patients, survival among Blacks is the shortest after HCC diagnosis. Survival differences reflect a more advanced tumor stage at presentation rather than severity of underlying liver disease precluding treatment. Improving survival in minority populations, in whom HCC incidence is rapidly increasing, requires identification and modification of factors contributing to late-stage presentation.

Consensus recommendations and review by an International Expert Panel on Interventions in Hepatocellular Carcinoma (EPOIHCC).

Hepatocellular carcinoma (HCC) presents with a high burden of disease in East Asian countries. Intermediate-stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) staging system poses a clinical challenge as it includes a heterogeneous population of patients that can vary widely in terms of tumour burden, liver function and disease aetiology. Intermediate HCC patients often have unsatisfactory clinical outcomes with repeated transarterial chemoembolization (TACE, due to non-response of the target tumour or the development of further metastasis indicating progressive disease. In September 2011, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was convened in HK in an attempt to provide a consensus on the practice of TACE. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies. This review summarises the evidence discussed at the meeting and provides expert recommendation regarding the available therapeutic options for unresectable intermediate stage HCC. A key consensus of the Expert Panel was that in order to improve patient outcomes and long-term survival, the possibility of using TACE in combination with targeted agents given systemically should be explored. While the currently available clinical data is promising, the expected completion of several pivotal phase II and III RCTs will provide further evidence in support of the rationale for combination therapy regimens.

Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand-foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib-induced HFSR and genetic polymorphisms in Korean patients with HCC. METHODS: For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were measured using enzyme-linked immunosorbent assays before therapy and 1 month after therapy. RESULTS: During a median treatment period of 18 months, 55 patients (93%) developed sorafenib-induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF-α -308GG, VEGF -94GG, VEGF 1991CC, VEGF IVS3-28CC, and uridine diphosphate glucuronosyltransferase 1 family-polypeptide A9 (UGT1A9) IVS1-37431AA were associated significantly with the development of high-grade (grade 2 or 3) HFSR in univariate analysis (P < .05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF-α -308GG (odds ratio, 44.1), and UGT1A9 IVS1-37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high-grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF-α level measured 1 month after sorafenib therapy was correlated significantly with the development of high-grade HFSR (odds ratio, 3.56; P = .026). CONCLUSIONS: Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF-α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF-α after sorafenib therapy.

Drug-eluting bead loaded with doxorubicin versus conventional Lipiodol-based transarterial chemoembolization in the treatment of hepatocellular carcinoma: a case-control study of Asian patients.

OBJECTIVE: Lipiodol transcatheter arterial chemoembolization (TACE) is widely used to treat hepatocellular carcinoma (HCC). Recently, a drug-eluting bead (DEB) has been developed to enhance drug delivery to the tumor and reduce its systemic availability. The purpose of this study was to compare the efficacy and safety of intra-arterial injection of DEB loaded with doxorubicin versus conventional, Lipiodol-based TACE regimens in Asian patients with HCC. METHODS: The study was designed as a case-control, single-institution clinical trial. Twenty patients with HCC who received DEB loaded with 50 mg doxorubicin ('cases') were matched with 20 patients who had undergone conventional TACE ('controls'). The primary efficacy endpoint was tumor response at 1 month according to modified Response Evaluation Criteria in Solid Tumors. The primary safety endpoint was liver toxicity. RESULTS: The rate of objective response by modified Response Evaluation Criteria in Solid Tumors was 85% (17 of 20 patients) in the DEB arm versus 30% (six of 20 patients) in the conventional TACE arm (P=0.001). Subgroup analyses conducted in patients with large (>5 cm) or multinodular tumor confirmed significantly higher objective response rates in patients receiving DEB as compared with those treated with conventional TACE (P=0.003 and P=0.005, respectively). At the dose of 50 mg doxorubicin, there was no statistically significant difference in liver toxicity between DEB and conventional TACE (P>0.05). CONCLUSION: In Asian patients with HCC, transcatheter treatment with DEB loaded with doxorubicin offers a distinct advantage in objective tumor response rate as compared with conventional, Lipiodol-based TACE regimens.

Issues and controversies of hepatocellular carcinoma-targeted therapy clinical trials in Asia: experts' opinion.

Asia has a disproportionate share of the world's burden of hepatocellular carcinoma (HCC). However, the highly regarded clinical practice guidelines and recommendations for the design and conduct of clinical trials for HCC largely reflect Western practice. In order to design mutually beneficial international clinical trials of promising targeted therapies, it is imperative to understand how the aetiology, staging and treatment of HCC differ between Asian and Western countries. Our group, comprising experts in oncology and hepatology from countries that constitute the Eastern Asian region, convened to compare and contrast our current practices, evaluate potential compliance with the clinical trial recommendations, and offer suggestions for modifications that would enhance international collaboration. Here, we describe the results of our discussions, including recommendations for appropriate patient stratification based on potentially important differences in HCC aetiology, identification of practices that may confound interpretation of clinical trial outcomes (traditional Chinese medicine; antivirals that target hepatitis B virus; heterogeneous embolization procedures), suggestions for utilizing a common staging system in study protocols, recognition that sorafenib usage is limited by financial constraints and potentially increased toxicity in Asian patients, and expansion of patient populations that should be eligible for initial clinical trials with new agents.