Factors Associated With Detection and Survival of T1 Hepatocellular Carcinoma in the United States: National Cancer Database Analysis

Authors:
Ju Dong Yang Division of Digestive and Liver Diseases,
Comprehensive Transplant Center,
Samuel Oschin Comprehensive Cancer Institute, and

Search for other papers by Ju Dong Yang in
Current site
Google Scholar
PubMed
Close
 MD, MS
,
Michael Luu Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, West Hollywood, California; and

Search for other papers by Michael Luu in
Current site
Google Scholar
PubMed
Close
 MPH
,
Amit G. Singal Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas.

Search for other papers by Amit G. Singal in
Current site
Google Scholar
PubMed
Close
 MD
,
Mazen Noureddin Division of Digestive and Liver Diseases,
Comprehensive Transplant Center,

Search for other papers by Mazen Noureddin in
Current site
Google Scholar
PubMed
Close
 MD
,
Alexander Kuo Division of Digestive and Liver Diseases,
Comprehensive Transplant Center,

Search for other papers by Alexander Kuo in
Current site
Google Scholar
PubMed
Close
 MD
,
Walid S. Ayoub Division of Digestive and Liver Diseases,
Comprehensive Transplant Center,

Search for other papers by Walid S. Ayoub in
Current site
Google Scholar
PubMed
Close
 MD
,
Vinay Sundaram Division of Digestive and Liver Diseases,
Comprehensive Transplant Center,

Search for other papers by Vinay Sundaram in
Current site
Google Scholar
PubMed
Close
 MD
,
Honore Kotler Comprehensive Transplant Center,

Search for other papers by Honore Kotler in
Current site
Google Scholar
PubMed
Close
 ACNP
,
Irene K. Kim Comprehensive Transplant Center,

Search for other papers by Irene K. Kim in
Current site
Google Scholar
PubMed
Close
 MD
,
Tsuyoshi Todo Comprehensive Transplant Center,

Search for other papers by Tsuyoshi Todo in
Current site
Google Scholar
PubMed
Close
 MD
,
Georgios Voidonikolas Comprehensive Transplant Center,

Search for other papers by Georgios Voidonikolas in
Current site
Google Scholar
PubMed
Close
 MD
,
Todd V. Brennan Comprehensive Transplant Center,

Search for other papers by Todd V. Brennan in
Current site
Google Scholar
PubMed
Close
 MD
,
Kambiz Kosari Comprehensive Transplant Center,

Search for other papers by Kambiz Kosari in
Current site
Google Scholar
PubMed
Close
 MD
,
Andrew S. Klein Comprehensive Transplant Center,

Search for other papers by Andrew S. Klein in
Current site
Google Scholar
PubMed
Close
 MD
,
Andrew Hendifar Samuel Oschin Comprehensive Cancer Institute, and

Search for other papers by Andrew Hendifar in
Current site
Google Scholar
PubMed
Close
 MD
,
Shelly C. Lu Division of Digestive and Liver Diseases,
Samuel Oschin Comprehensive Cancer Institute, and

Search for other papers by Shelly C. Lu in
Current site
Google Scholar
PubMed
Close
 MD
,
Nicholas N. Nissen Comprehensive Transplant Center,
Samuel Oschin Comprehensive Cancer Institute, and

Search for other papers by Nicholas N. Nissen in
Current site
Google Scholar
PubMed
Close
 MD
, and
Jun Gong Samuel Oschin Comprehensive Cancer Institute, and

Search for other papers by Jun Gong in
Current site
Google Scholar
PubMed
Close
 MD
Restricted access

Background: It remains unknown to what extent hepatocellular carcinomas (HCCs) are detected very early (T1 stage; ie, unifocal <2 cm) in the United States. The aim of this study was to investigate the trends and factors associated with very early detection of HCC and resultant outcomes. Methods: Patients with HCC diagnosed from 2004 through 2014 were identified from the National Cancer Database. Logistic regression was used to identify factors associated with T1 HCC detection, and Cox proportional hazard analyses identified factors associated with overall survival among patients with T1 HCC. Results: Of 110,182 eligible patients, the proportion with T1 HCC increased from 2.6% in 2004 to 6.8% in 2014 (P<.01). The strongest correlate of T1 HCC detection was receipt of care at an academic institution (odds ratio, 3.51; 95% CI, 2.31–5.34). Older age, lack of insurance, high Model for End-Stage Liver Disease (MELD) score, high alpha-fetoprotein, increased Charlson-Deyo comorbidity score, and nonsurgical treatment were associated with increased mortality, and care at an academic center (hazard ratio [HR], 0.27; 95% CI, 0.15–0.48) was associated with reduced mortality in patients with T1 HCC. Liver transplantation (HR, 0.27; 95% CI, 0.20–0.37) and surgical resection (HR, 0.67; 95% CI, 0.48–0.93) were independently associated with improved survival compared with ablation. This is the first study to examine the trend of T1 HCC using the National Cancer Database, which covers approximately 70% of all cancer diagnoses in the United States, using robust statistical analyses. Limitations of the study include a retrospective study design using administrative data and some pertinent data that were not available. Conclusions: Despite increases over time, <10% of HCCs are detected at T1 stage. The strongest correlates of survival among patients with T1 HCC are receiving care at an academic institution and surgical treatment.

Submitted February 3, 2020; accepted for publication March 25, 2020.

Author contributions: Study concept: Yang, Singal, Noureddin, Kuo, Ayoub, Sundaram, Kotler, Kim, Todo, Voidonikolas, Brennan, Kosari, Klein, Hendifar, Lu, Nissen, Gong. Study design: Yang. Data acquisition: Yang. Data interpretation: All authors. Manuscript preparation: Yang. Statistical analysis: Luu. Critical revision of the manuscript: Luu, Singal, Noureddin, Kuo, Ayoub, Sundaram, Kotler, Kim, Todo, Voidonikolas, Brennan, Kosari, Klein, Hendifar, Lu, Nissen, Gong.

Disclosures: Dr. Yang has disclosed that he serves as a consultant for Exact Sciences. Dr. Singal has disclosed that he serves as a consultant for Glycotest, Exact Sciences, Wako Diagnostics, TARGET Pharmasolutions, Bayer, Eisai, Bristol-Myers Squibb, Exelixis, and Roche/Genentech. Dr. Noureddin has disclosed that he has received grant/research support from Allergan, Bristol-Myers Squibb, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Novartis, Shire, and Zydus, and he is a scientific advisor for Gilead, Intercept, Pfizer, Novartis, Allergan, Blade, EchoSens North America, Fractyl, OWL, Siemens, Roche Diagnostic, and Abbott. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health (R01 MD12565 and R01 CA222900).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Correspondence: Ju Dong Yang, MD, MS, Cedars-Sinai Medical Center, 8900 Beverly Boulevard, Los Angeles, CA 90048. Email: judong.yang@cshs.org

Supplementary Materials

    • Supplemental Materials (PDF 586.58 KB)
  • Collapse
  • Expand
  • 1.

    Yang JD. Detect or not to detect very early stage hepatocellular carcinoma? The western perspective. Clin Mol Hepatol 2019;25:335343.

  • 2.

    Roskams T. Anatomic pathology of hepatocellular carcinoma: impact on prognosis and response to therapy. Clin Liver Dis 2011;15:245259.

  • 3.

    European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69:182236.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Marrero JA, Kulik LM, Sirlin CB, et al.. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723750.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Yang JD, Harmsen WS, Slettedahl SW, et al.. Factors that affect risk for hepatocellular carcinoma and effects of surveillance. Clin Gastroenterol Hepatol 2011;9:617623.e1.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med 2014;11:e1001624.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Tzartzeva K, Obi J, Rich NE, et al.. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology 2018;154:17061718.e1.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Kudo M. Management of hepatocellular carcinoma in Japan as a world-leading model. Liver Cancer 2018;7:134147.

  • 9.

    Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:12081236.

  • 10.

    Yang JD, Kim WR, Park KW, et al.. Model to estimate survival in ambulatory patients with hepatocellular carcinoma. Hepatology 2012;56:614621.

  • 11.

    Ho SY, Liu PH, Hsu CY, et al.. Prognostic performance of ten liver function models in patients with hepatocellular carcinoma undergoing radiofrequency ablation. Sci Rep 2018;8:843.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Johnson PJ, Berhane S, Kagebayashi C, et al.. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach—the ALBI grade. J Clin Oncol 2015;33:550558.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Edeline J, Blanc JF, Johnson P, et al.. A multicentre comparison between Child Pugh and albumin-bilirubin scores in patients treated with sorafenib for hepatocellular carcinoma. Liver Int 2016;36:18211828.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399424.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Mehta N, Sarkar M, Dodge JL, et al.. Intention to treat outcome of T1 hepatocellular carcinoma with the “wait and not ablate” approach until meeting T2 criteria for liver transplant listing. Liver Transpl 2016;22:178187.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals [abstract]. Biometrika 1994;81:515526.

  • 17.

    Kokudo N, Hasegawa K, Akahane M, et al.. Evidence-based clinical practice guidelines for hepatocellular carcinoma: the Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines) [abstract]. Hepatol Res 2015;45:1.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Roberts LR, Sirlin CB, Zaiem F, et al.. Imaging for the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatology 2018;67:401421.

  • 19.

    Kim SY, An J, Lim YS, et al.. MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma. JAMA Oncol 2017;3:456463.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Kim HL, An J, Park JA, et al.. Magnetic resonance imaging is cost-effective for hepatocellular carcinoma surveillance in high-risk patients with cirrhosis. Hepatology 2019;69:15991613.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Berhane S, Toyoda H, Tada T, et al.. Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol 2016;14:875886.e6.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Yang JD, Addissie BD, Mara KC, et al.. GALAD score for hepatocellular carcinoma detection in comparison with liver ultrasound and proposal of GALADUS score. Cancer Epidemiol Biomarkers Prev 2019;28:531538.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Cotton RT, Tran Cao HS, Rana AA, et al.. Impact of the treating hospital on care outcomes for hepatocellular carcinoma. Hepatology 2018;68:18791889.

  • 24.

    Mokdad AA, Zhu H, Marrero JA, et al.. Hospital volume and survival after hepatocellular carcinoma diagnosis. Am J Gastroenterol 2016;111:967975.

  • 25.

    Serper M, Taddei TH, Mehta R, et al.. Association of provider specialty and multidisciplinary care with hepatocellular carcinoma treatment and mortality. Gastroenterology 2017;152:19541964.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Rich NE, Hester C, Odewole M, et al.. Racial and ethnic differences in presentation and outcomes of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2019;17:551559.e1.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Hepatocellular Carcinoma EASL Guideline. Accessed June 30. 2020. Available at: https://easl.eu/publication/easl-clinical-practice-guidelines-management-of-hepatocellular-carcinoma/

    • PubMed
    • Export Citation
  • 28.

    Cho YK, Kim JK, Kim WT, et al.. Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis. Hepatology 2010;51:12841290.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Cucchetti A, Piscaglia F, Cescon M, et al.. Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma. J Hepatol 2013;59:300307.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Pompili M, Saviano A, de Matthaeis N, et al.. Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey. J Hepatol 2013;59:8997.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Heimbach JK, Kulik LM, Finn RS, et al.. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358380.

  • 32.

    Huang J, Yan L, Cheng Z, et al.. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg 2010;252:903912.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Feng K, Yan J, Li X, et al.. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol 2012;57:794802.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Uhlig J, Sellers CM, Stein SM, et al.. Radiofrequency ablation versus surgical resection of hepatocellular carcinoma: contemporary treatment trends and outcomes from the United States National Cancer Database. Eur Radiol 2019;29:26792689.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Yang JD, Larson JJ, Watt KD, et al.. Hepatocellular carcinoma is the most common indication for liver transplantation and placement on the waitlist in the United States. Clin Gastroenterol Hepatol 2017;15:767775.e3.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Mehta N, Heimbach J, Harnois DM, et al.. Validation of a risk estimation of tumor recurrence after transplant (RETREAT) score for hepatocellular carcinoma recurrence after liver transplant. JAMA Oncol 2017;3:493500.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Roayaie S, Obeidat K, Sposito C, et al.. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology 2013;57:14261435.

  • 38.

    Kim YS, Lim HK, Rhim H, et al.. Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: analysis of prognostic factors. J Hepatol 2013;58:8997.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Rich NE, Parikh ND, Singal AG. Hepatocellular carcinoma and liver transplantation: changing patterns and practices. Curr Treat Options Gastroenterol 2017;15:296304.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Palma DA. National Cancer Data Base: an important research tool, but not population-based. J Clin Oncol 2017;35:571.

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 3804 867 200
PDF Downloads 947 123 10
EPUB Downloads 0 0 0