In contrast to countries such as China and Japan, hepatocellular carcinoma (liver cancer) is not a common malignancy in the United States. However, it does occur at an increased rate in patients with chronic liver disease such as chronic hepatitis C. As with other cancers, research is being conducted on techniques that permit earlier diagnosis of this malignancy.

Alpha-fetoprotein (AFP) is one marker that has been used in following up patients with chronic liver disease. However, as noted in a recent study, the clinical usefulness of AFP in hepatocellular cancer (HCC) is debatable. This study looked at serum AFP levels at diagnosis in 1,158 patients with HCC and found a sensitivity of 54%.

Researchers are studying AFP-L3 (lens culinaris agglutinin-reactive AFP) as an improved biomarker in patients with HCC. AFP-L3 is a glycoform of AFP. It is generally reported as a percent of the total AFP level. This policy deals only with use of this biomarker in patients with suspected or known HCC.

The Wako LBA AFP-L3 test received 510(k) marketing clearance from the U.S. Food and Drug Administration (FDA) in May 2005 to assist the physician in determining the risk of developing liver cancer in patients with chronic liver disease. Center for Devices and Radiological Health (CDRH) consumer information indicates that the Wako LBA AFP-L3 test helps to determine the risk of developing liver cancer for a patient with chronic liver disease within the next 21 months. If the AFP-L3% is greater or equal to 10%, the risk is (increased) seven-fold.

Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)

Evaluation of AFP-L3 biomarkers is considered investigational in the screening, diagnosis, or monitoring of patients with suspected or known hepatocellular cancer.


Medicare Coverage:
There is no National Coverage Determination (NCD) regarding evaluation of AFP-L3 biomarkers in the screening, diagnosis, or monitoring of individuals with suspected or known hepatocellular cancer. In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon Policy. Note that serum alpha- fetoprotein (CPT code 82105) may be covered for certain diagnoses as per National Coverage Determination (NCD) for Alpha-fetoprotein (190.25). For eligibility and coverage of CPT code 82105, please refer to NCD 190.25 for. Available at: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=121&ncdver=1&bc=AAAAgAAAAAAAAA%3d%3d&.

Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE-SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[INFORMATIONAL NOTE: Taketa reported results on AFP-L3 (as a % of AFP) in a group of 424 patients with acute and chronic liver disease including cirrhosis and hepatocellular carcinoma. Using a cutoff level of 15% (15% or more was abnormal) they found sensitivity of 55% and specificity of 95% for hepatocellular carcinoma. Thirty-eight percent of tumors less than 20 mm in diameter were positive for AFP-L3. AFP-L3 exceeded the cutoff level of 15% an average of 4.0 months before detection by imaging techniques.

Oka and colleagues reported on a prospective study of AFP-L3 (lens culinaris agglutinin-reactive fraction of alpha-fetoprotein) in 388 patients with newly diagnosed hepatocellular cancer (HCC) at 9 Japanese hospitals. The cutoff level for an abnormal value was reduced from >15% to >10% during the study. Patients with abnormal levels were found to have more aggressive cancers. Tada reported that AFP-L3 percentage of >10% was associated with pathologic features of HCC that indicated aggressive tumor such as capsule infiltration and portal vein invasion.

Of note, neither the US Preventive Services Task Force (USPSTF) nor the National Comprehensive Cancer Network clinical guidelines discuss the use of this test in screening or clinical care for patients with known or suspected hepatocellular cancer.

In a prospective cohort of 332 HCV patients observed for 2 years at 7 North American institutions, Sterling et al compared AFP-L3% with or without AFP to AFP. The authors used cutoff points of 10% for AFP-L3 and 20 ng/ml for AFP. Overall sensitivity of AFP-L3 was 44.1%, increasing with AFP from 31% for AFP values less than 20 ng/ml to 60% for AFP values greater than 200 ng/ml; sensitivity for AFP was 52.9%. Overall specificity of AFP-L3 was 91.6%, varying with AFP from 86.6% to 100%; specificity for AFP was 71.1%. Using area under the ROC curves, there was no statistical difference (p=0.586) between AFP-L3 (r=0.75) and AFP (r=0.72). Investigators were blinded to AFP-L3% results, which were therefore not guiding treatment decisions. A retrospective analysis of 272 patients referred to a single center for HCC, chronic liver disease or liver masses evaluated the performance characteristics of AFP-L3%. The objective was to determine the added benefit of the AFP-L3% test over AFP alone. Because all patients in the cohort with AFP of 200ng/ml or greater had HCC and the AFP-L3% is often not reported if AFP is less than 10 ng/ml, the relevant group was the subset of patients with AFP 10ng/ml or greater but less than 200ng/ml. In this group, the areas under the ROC curve for distinguishing between HCC and chronic liver disease were nearly significant (p=0.074), with areas of 0.76 and 0.59 for AFP-L3% and AFP, respectively. The sensitivity and specificity (using the 10% cutoff point for AFP-L3%) were 71% and 63%, respectively. In this cohort, both AFP of 200 or greater and AFP-L3% of 10% or more were predictive of poor survival, but once the AFP level was taken into account, there was no prognostic value of the AFP-L3%.

An updated search of the literature identified studies that compared AFP, AFP-L3% and des-Γ-carboxyprothrombin (DCP), an abnormal prothrombin produced by malignant hepatocytes. The prognostic use of AFP-L3% as a predictor of post-treatment survival or recurrence of HCC was addressed in 3 studies from Japan that addressed different aspects of prognosis; AFP-L3% values did not affect treatment decisions in any of them. Kitai and colleagues incorporated biomarker information into the Japan Integrated Staging (JIS) tool, where, within strata of the existing JIS staging system, patients with elevated values of 2 or 3 biomarkers had poorer survival compared to those with no biomarker elevations. The 2 other studies used either pretreatment biomarker levels, or pre- and post-treatment biomarker levels as prognostic indicators for survival and recurrence of HCC treated with ablation or hepatectomy. The Owaga study noted a statistically significant prognostic effect in a subset (n=19) of the study population of 124 patients; in a multivariate model, only AFP-L3% elevated (>15%) before and reduced after treatment (radiofrequency ablation) compared to AFP-L3% elevated both before and after treatment showed statistically significant improvement in both survival and recurrence. Neither post-treatment improvements in AFP (from >200ng/ml to <200ng/ml) nor DCP (from >100mAU/ml to <100mAU/ml) levels showed statistical improvements despite comprising slightly larger subsets of the main population. In the Toyoda cohorts, multivariate analyses showed that pretreatment levels of none of the 3 studied tumor markers significantly affected survival when hepatectomy was the treatment (n=345), but that elevated pretreatment AFP-L3% (15% or greater) and DCP (100mAU/ml or greater) levels were prognostic indicators of survival among patients treated with locoregional thermal ablation (n=456). Elevated pretreatment DCP was the only biomarker to statistically predict tumor recurrence.

A fourth study was the only one to address test characteristics and their utility for surveillance in high risk patients. In this study from the US, 240 patients with either HBV or HCV with (n=144) or without (n=96) HCC attending a liver center were identified. Stored samples were tested for AFP, AFP-L3%, and DCP. Receiver-operator curves identified optimal cutpoints for the 3 biomarkers (25ng/ml, 10%, and 84mAU/l respectively). HCC was diagnosed using the American Association for the Study of Liver Diseases Practice Guidelines. The sensitivity, specificity and positive predictive value for each marker was as follows: 69%, 87% and 70% for AFP; 56%, 90%, and 56% for AFP-L3%; and 87%, 85%, and 87% for DCP. Combining tests yielded no additional improvements in predictive power. The biomarkers were not used for surveillance, nor were they used to guide treatment decisions; rather this was a retrospective assessment of their potential to guide surveillance activities.

The roll of AFP-L3% in improving health outcomes of patients with known or suspected HCC has yet to be determined, particularly in comparison or conjunction with DCP. Adding biomarker data may be helpful when staging HCC, as shown by Katai, although the contribution made by each biomarker was not demonstrated in this study.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Alpha-Fetoprotein-L3 for Detection of Hepatocellular (Liver) Cancer
AFP-L3
Lens Culinaris Agglutinin-Reactive AFP
Wako LBA

References:
1. Farinati F, Marino D, De Giorgio M et al. Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am J Gastroenterol 2006; 101(3):524-32.

2. www.fda.gov/cdrh/pdf4/k041847.pdf . Accessed January 24, 2007.

3. Taketa K, Endo Y, Sekiya C et al. A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of Hepatocellular carcinoma. Cancer Res 1993; 53(22):5419-23.

4. Oka H, Saito A, Ito K et al. Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of lens culinaris agglutinin-reactive alpha-fetoprotein. J Gastroenterol Hepatol 2001; 16(12):1378-83.

5. Tada T, Kumada T, Toyoda H et al. Relationship between lens culinaris agglutinin-reactive alpha-fetoprotein and pathologic features of hepatocellular carcinoma. Liver Int 2005; 25(4):848-53.

6. www.ahrq.gov/clinic/cps3dix.htm#caner . Accessed January 24, 2007.

7. www.nccn.org/professionals/physician_gls/default.asp . Accessed January 24, 2007.

8. Sterling RK, Jeffers L, Gordon F et al. Clinical utility of AFP-L3% measurement in North American patients with HCV-related cirrhosis. Am J Gastroenterol 2007; 102(10):2196-205.

9. Leerapun A, Suravarapu SV, Bida JP et al. The utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: evaluation in a United States referral population. Clin Gastroenterol Hepatol 2007; 5(3):394-402.

10. Kitai S, Kudo M, Minami Y et al. A new prognostic staging system for hepatocellular carcinoma: value of the biomarker combined Japan integrated staging score. Intervirology 2008; 51(Suppl 1):86-94.

11. Toyoda H, Kumada T, Kaneoka Y et al. Prognostic value of pretreatment levels of tumor markers for hepatocellular carcinoma on survival after curative treatment of patients with HCC. J Hepatol 2008; 49(2):223-32.

12. Ogawa C, Kudo M, Minami Y et al. Tumor markers after radiofrequency ablation therapy for hepatocellular carcinoma. Hepatogastroenterology 2008; 55(85):1454-7.

13. Durazo FA, Blatt LM, Corey WG et al. Des-gamma-carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol 2008; 23(10):1541-8.

14. UpToDate. Clinical features and diagnosis of primary hepatocellular carcinoma. Literature review current through May 2016; topic last updated June 10, 2015.

15. National Comprehensive Cancer Network (NCCN) Guidelines. Hepatobiliary Cancers. Version 1.2016, 12/15/2015.

16. Yi X, Yu S, Bao Y. Alpha-fetoprotein-L3 in hepatocellular carcinoma: a meta-analysis. Clin Chim Acta 2013 Oct 21;425:212-20.

17. Jia Z, Wang L, Liu C, et al. Evaluation of a-fetoprotein-L3 and Golgi protein 73 detection in diagnosis of hepatocellular carcinoma. Contemp Oncol (Pozn) 2014;18(3):192-6.

18. Cheng J, Wang W, Zhang Y, et al. Prognostic role of pre-treatment serum AFP-L3% in hepatocellular carcinoma: systematic review and meta-analysis. PLoS One 2014 Jan 30;9(1):e87011.

19. Tampaki M, Doumba PP, Deutsch M, et al. Circulating biomarkers of hepatocellular carcinoma response after locoregional treatments: New insights. World J Hepatol 2015 Jul 18;7(14):1834-42.

20. Dai M, Chen X, Liu X, et al. Diagnostic Value of the Combination of Golgi Protein 73 and Alpha-Fetoprotein in Hepatocellular Carcinoma: A Meta-Analysis. PLoS One 2015 Oct 6;10(10);e0140067.

21. Hussein TD. Serological tumor markers of hepatocellular carcinoma: a meta-analysis. Int J Biol Markers 2015 Feb 24;30(1):e32-42.

22. UpToDate. Staging and prognostic factors in hepatocellular carcinoma. Literature review current through April 2016; topic last updated April 7, 2015.

23. Curley SA, Barnett CC, Abdalla EK. Staging and prognostic factors in hepatocellular carcinoma. In: UpToDate, Tanabe KK, Savarese DMF (Eds), UpToDate, Waltham, MA. (Accessed on April 9, 2017.)

24. Schwartz JM, Carithers RL. Clinical features and diagnosis of primary hepatocellular carcinoma. In: UpToDate, Savarese DMF (Eds), UpToDate, Waltham, MA. (Accessed February 28, 2018.)

25. Schwartz JM, Carithers RL, Sirlin CB. Clinical features and diagnosis of hepatocellular carcinoma. In: UpToDate, Chopra S, Kressel HY, Robson KM, Savarese DMF, Lee SI (Eds), UpToDate, Waltham, MA. (Accessed March 6, 2019.)

26. Curley SA, Barnett CC, Abdalla EK. Staging and prognostic factors in hepatocellular carcinoma. In: UpToDate, Tanabe KK, Savarese DMF (Eds), UpToDate, Waltham, MA. (Accessed on March 6, 2019.)

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

82107