HCC Biomarkers

AFP-L3 and DCP

HCC Surveillance

Hepatocellular carcinoma (HCC) could be detected early enough to apply curative treatment if patients at risk for HCC development are closely monitored under advanced surveillance strategies. The use of serum biomarkers lectin-reactive alpha-fetoprotein (AFP-L3) and des-gamma-carboxy prothrombin (DCP) in surveillance can improve your chances of detecting early HCC.

HCC Surveillance Improves Patient Outcome

Early detection of HCC is crucial for the application of curative therapies and improving patient outcome. Since the underlying cause of HCC is usually identifiable, patients who are at-risk for HCC development are highly encouraged to enroll in HCC surveillance programs for early detection of HCC.

  • A 2008 HCC surveillance study conducted in the USA concluded that the application of a surveillance program for patients with cirrhosis can identify patients with early-stage HCC. In turn, HCC surveillance improves long-term, tumor-free survival of HCC patients receiving early treatment [1].
  • The American Association for the Study of Liver Diseases (AASLD) identify patients with cirrhosis and patients with chronic hepatitis B infection (even if without cirrhosis) as being at high risk for HCC development. The AASLD guidelines recommend patients at risk for HCC should be entered into surveillance programs [2].
  • Detection of HCC tumors at earlier stages allows for a greater number of treatment options for curative intent such as resection, radiofrequency ablation and transplantation. The 5-year survival after these treatments can exceed 50% [2]. Patients with advanced stage HCC are limited to more palliative treatments such as chemoembolization and sorafenib, which marginally impact patient survival.

Better Surveillance Strategies Are Needed

The quality of surveillance impacts the ability to find HCC at an early stage which is when curative treatment options are available.

  • A survey study in the USA reported in 2010 shows that less than 20% of patients with cirrhosis who developed HCC received regular surveillance [3].
  • The AASLD guidelines recommend that at risk patients be screened at 6 month intervals using ultrasound [2]. However, the use of ultrasound alone to monitor patients with chronic liver disease can lead to surveillance missing many patients whose small tumors can go undetected [3].
  • Ultrasound is highly user dependent with operator experience and expertise directly correlating with its sensitivity. The performance of ultrasound can be further limited when used on patients who are obese or have severe background liver cirrhosis. Ultrasound sensitivity varies between 44% and 80%, with a specificity of over 90% [2,4].
  • The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C) study group which consisted of premier care centers in the USA retrospectively found that only 20% of the patients who developed HCC in their study were found at 2 cm or less and over one-fourth of tumors were found beyond Milan Criteria [5].
  • The HCC management guideline of the Japan Society of Hepatology includes serum biomarker testing for surveillance (AFP, AFP-L3, and DCP) [6]. A 2010 survey report on surveillance efficacy in Japan concluded that out of all patients with HCC, 33.5% had tumors of 2 cm or less and more than 62% had undergone surgery or local ablation therapy, treatment options only available for early stage HCC [7].

HCC Biomarkers Help Detect Early HCC

Serological biomarkers AFP-L3 and DCP are associated with HCC development and elevated values for either of the biomarkers are early indicators that a patient with chronic liver disease will develop HCC. Several studies have shown that AFP-L3 and DCP increase before HCC is detectable by imaging. Therefore, adding the two biomarkers to a regular surveillance program such as AFP and ultrasound can help physicians identify HCC tumors earlier in at risk patients.

  • AFP-L3 and DCP can alert about early development of HCC before it can be detected by imaging modalities and is useful for identifying patients at risk for HCC [7-11].
  • A study including 438 patients with HCC shows that AFP-L3 and DCP are independent markers from each other for HCC tumor progression [12]. Elevation of AFP-L3 has been reported to be indicative of greater malignant potential of HCC and is correlated to shorter doubling time of tumor volume and increased hepatic arterial supply [13]. The elevation is also correlated to pathologic features of HCC such as infiltrative tumor growth pattern, capsule infiltration, and vascular invasion [14]. DCP has been reported to be a specific marker for microinvasion and a high DCP level is associated with development of portal vein invasion [15,16].
  • The biomarkers AFP-L3 and DCP are complementary and have been shown to be effective for the early detection of HCC [10,17-20].
  • Physicians from the University of California, San Diego (UCSD) have developed a surveillance algorithm that combines the use of serum based highly sensitive biomarkers AFP-L3 and DCP and the use of standard of care imaging.

AFP-L3 and DCP Tests Are Available in the United States and Canada

The combined use of AFP-L3 and DCP tests is currently available and can be ordered with a single test code at most major reference laboratories in the United States. Laboratories can measure serum levels of AFP-L3 and DCP with a single serum sample on a single analyzer, μTASWako i30 [19,21]. The tests can also be ordered from Canada. For information on how to order the tests in Canada, please contact liver@wakousa.com

References

  1. Stravitz RT, et al. Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome. Am J Med. 2008;121:119-26.
  2. Bruix J, Sherman M. Management of Hepatocellular Carcinoma: An Update. Hepatology. 2011;53:1020-2
  3. Davila JA, et al. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology. 2010;52:132-41.
  4. Singal AG, et al. Effectiveness of Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis. Cancer Epidemiol Biomarkers Prev. 2012;21:793-9.
  5. Singal AG, et al. Detection of Hepatocellular Carcinoma at Advanced Stages Among Patients in the HALT-C Trial: Where Did Surveillance Fail? Am J Gastroenterol. 2013;108:425-32.
  6. Makuuchi M, et al. Development of evidence-based clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res. 2008;38:37-51.
  7. Ikai I, et al. Survey Report of the 18th follow-up survey of primary liver cancer in Japan. Hepatol Res. 2010;40:1043-59.
  8. Taketa K, et al. A collaborative study for the evaluation of lectin-reactive a-fetoproteins in early detection of hepatocellular carcinoma. Cancer Res 1993;53:5419-23.
  9. Shiraki K, et al. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients. Hepatology 1995;22:802-7.
  10. Shimauchi Y, et al. A simultaneous monitoring of Lens culinaris agglutinin A-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin as an early diagnosis of hepatocellular carcinoma in the follow-up of cirrhotic patients. Oncol Rep 2000;7:249-56.
  11. Oda K, et al. Highly sensitive lens culinaris agglutinin-reactive a-fetoprotein is useful for early detection of hepatocellular carcinoma in patients with chronic liver disease. Oncol Rep 2011;26:1227-33.
  12. Toyoda H, et al. Diagnosis of hepatocellular carcinoma using a GALAD model by objective clinical and serological factors. The Liver Meeting 2013 Poster 2112 [cited 24 Jan 2014]. http://www.wakodiagnostics.com/ documents/diagnosis_of_hepatocellular_carcinoma_using_a_galad_ model_by_objective_clinical_and_serological_factors_by_toyoda_ presented at the_liver_meeting_2013.pdf
  13. Kumada T, et al. Clinical utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in small hepatocellular carcinoma: special reference to imaging diagnosis. J Hepatol 1999;30:125-30.
  14. Tada T, et al. Relationship between Lens culinaris agglutinin-reactive alpha-fetoprotein and pathologic features of hepatocellular carcinoma. Liver Int 2005;25:848-53.
  15. Koike Y, et al. Des-gamma-carboxy prothrombin as a useful predisposing factor for the development of portal venous invasion in patients with hepatocellular carcinoma: a prospective analysis of 227 patients. Cancer 2001;91:561-9.
  16. Yamashita Y, et al. Predictors for Microinvasion of Small Hepatocellular Carcinoma =2 cm. Ann Surg Oncol. 2012;19:2027-34
  17. Arii S, et al. Management of hepatocellular carcinoma: Report of Consensus Meeting in the 45th Annual Meeting of the Japan Society of Hepatology (2009). Hepatol Res. 2010;40:667-85.
  18. Nomura F, et al. Serum des-gamma-carboxy prothrombin levels determined by a new generation of sensitive immunoassays in patients with small-sized hepatocellular carcinoma. Am J Gastroenterol 1999;94:650-4.
  19. Choi JY, et al. Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP. World J Gastroenterol. 2013;19:339-46.
  20. Hann HW, et al. Usefulness of highly sensitive AFP-L3 and DCP in surveillance for hepatocellular carcinoma in patients with a normal alphafetoprotein. J Med Microb Diagn. 2014;3:130.
  21. Kagebayashi C, et al. Automated immunoassay system for AFP-L3% using on-chip electrokinetic reaction and separation by affinity electrophoresis. Anal Biochem. 2009;388:306-11.