Medical Policy: 02.01.20 
Original Effective Date: December 2000 
Reviewed: August 2016 
Revised: August 2016 


Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.


Description:

Tumor markers are substances normally produced by cancer or other cells in the body in response to cancer, or certain benign conditions. Most tumor markers are proteins but may also be patterns of gene expression and changes to DNA. Tumor markers are made by normal cells but are produced at a much higher level in the presence of cancer. Tumor markers may be found in the blood, plasma, other bodily fluids (e.g., urine, saliva, cerebrospinal fluid) and/or tissue. Although an abnormal tumor marker level may suggest cancer, their presence alone does not confirm a diagnosis. Tumor makers are typically combined with other diagnostic studies (e.g. laboratory tests, biopsy, radiological imaging) to confirm the diagnosis. These markers may not be elevated in the presence of some diseases or cancers, especially in early stages of the disease, they may not be specific to a particular type of disease or cancer, and/or they may be elevated by more than one type of disease or cancer. 

   
In some types of cancers, tumor marker levels may reflect the extent or stage of the disease and can be useful in determining the most effective treatment and how the disease will respond to the treatment. Typically, the primary use of tumor markers is to monitor a cancer’s response to treatment with periodic measurements following therapy. Following therapy, a decrease in the maker level may indicate a response to therapy as opposed to consistently elevated or rising marker levels which may be indicative of lack of response to treatment or recurrence of the disease. The evidence in the published peer reviewed literature and professional societies support tumor markers for the diagnosis and management of some cancers, while other tumor markers are still evolving and their clinical utility has not been proven.

    

Summary
Recommendations and guidelines by professional societies and organizations and evidence in the published peer reviewed scientific literature support the use of defined tumor markers for the screening, diagnosis, treatment planning, treatment monitoring and/or follow up of specific cancers.

 
However, improvements in meaningful health outcomes for numerous other tumor markers have not been proven and they are still under investigation to determine their clinical utility in the management of individuals with various types of cancers. Overall, clinical trials have primarily been in the form of retrospective validation studies with small heterogeneous patient populations and short term follow ups. Studies comparing the tumor markers to established treatment options are lacking and management of patients based on the results of these markers have not been published.

 

Practice Guidelines and Position Statements
The American College of Obstetricians and Gynecologists (ACOG), Committee Opinion Number 477, March 2011: Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer

  • Epithelial ovarian cancer is most commonly detected in advanced stage, when the overall 5 year survival rate is 20-30%.
  • Detection of early stage ovarian cancer results in improved survival.
  • There is currently no effective strategy for ovarian cancer screening.
  • The obstetrician-gynecologist should be aware that there may be symptoms (including increased abdominal size or bloating, abdominal or pelvic pain, or feeling full quickly or difficulty eating) associated with ovarian cancer that should be investigated.
  • Evaluation of the symptomatic patient includes physical examination and may include transvaginal ultrasonography and measurement of levels of the serum tumor marker CA-125.
  • When a patient with a suspicious or persistent complex adnexal mass requires surgical evaluation, a physician trained to appropriately stage and debulk ovarian cancer, such as a gynecologist oncologist, should perform the operation

American Society of Clinical Oncology (ASCO) 
2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer
Different tumor markers are used at different points in the diagnosis and treatment process. ASCO recommends that the following tumor markers may be used in the following situations:

  • CA 15-3 and CA 27.29:
    • Data is insufficient to recommend CA 15-3 or CA 27.29 for screening, diagnosis and staging.
    • Data does not support the use of CA 15-3 or CA 27.29 for monitoring patients for recurrence after primary breast cancer therapy.
    • Monitoring patients with metastatic disease during active therapy, CA 27.29 or CA 15-3 can be used in conjunction with  the patient’s health history, a physical examination, and diagnostic imaging.
    • Data is insufficient to recommend the use of CA 15-3 or CA 27.29 for monitoring response to treatment. However, in the absence of readily measurable disease, an increasing CA 15-3 or CA 27.29 may be used to indicate treatment failure.
  • CEA:
    • CEA is not recommended for screening, diagnosis, staging or routine surveillance of breast cancer patients after primary therapy
    • CEA is used for monitoring patients with metastatic disease during active therapy, CEA can be used in conjunction with  the patient’s health history, a physical examination, and a diagnostic imaging tests.
    • Data is insufficient to recommend the use of CEA for monitoring response to treatment. However, in the absence of readily measurable disease, an increasing CEA may be used to indicate treatment failure.

p53 as a marker for breast cancer: 

  • Data is insufficient to recommend the use of p53 measurements for management of patients with breast cancer.

Breast Cancer Follow-Up and Management After Primary Treatment: American Society of Clinical Oncology Clinical Practice Guideline Update
In 2012 Update Committee reviewed the evidence to determine whether the recommendations were in need of updating. The Update Committee concluded that no revisions to the existing ASCO recommendations were warranted.

 

Recommendation: The use of complete blood counts, chemistry panels, bone scans, chest radiographs, liver ultrasounds, pelvic ultrasounds, computed tomography scans, PET scans, magnetic resonance imaging, and/or tumor markers (carcinoembryonic antigen, CA 15-3, and CA 27.29) is not recommended for routine follow up in an otherwise asymptomatic patient with no specific findings on clinical examination.

   

Breast Cancer Tumor Marker Testing
The use of CA 15-3 or CA 27.29 is not recommended for routine surveillance of patients with breast cancer after primary therapy.

  • CEA testing is not recommended for routine surveillance of patients with breast cancer after primary therapy.

Use of Biomarkers to Guide Decisions on Systemic Therapy for Women with Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline
In 2015 ASCO provided recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer.

 

Recommendations: In patients with accessible metastases, biopsy for confirmation of disease process and retesting of estrogen receptor, progesterone receptor, and HER2 status should be offered, but evidence is lacking to determine whether changing anticancer treatment on the basis of change in receptor status affects clinical outcomes. With discordance of results between primary and metastatic tissues, the Panel consensus is to use preferentially the estrogen receptor, progesterone receptor and HER2 status of the metastasis to direct therapy if supported by the clinical scenario and patient’s goals for care.  Carcinoembryonic antigen, cancer antigen 15-3, and cancer antigen 27-29 may be used as adjunctive assessments, but not alone, to contribute to decisions regarding therapy. Recommendations for tumor rebiopsy and use of circulating tumor markers are based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments. 

 

ASCO 2006 Update of Recommendations for the Use of Tumor Markers for Gastrointestinal Cancers (Colorectal cancer and Pancreatic Cancer)

Tumor Marker Recommendations for Colorectal Cancer

Tumor Marker Screening Staging/Treatment Planning Testing for the Spread of Cancer After Surgery Finding out how the Treatment is Working

CEA

No

Only to assist in treatment planning or staging; not making decisions about adjuvant therapy

Yes, every three months for at least three years after diagnosis, for patients with stage II or III cancer if the patient is a condidate for surgery or systemic therapy

Yes, CEA should be measured at the start of treatment for metastatic disease and every one to three months during treatment

CA 19-9

No

No

No

No

DNA ploidy

Not Applicable

No

Not Applicable

Not Applicable

p53

No

No

No

No

ras oncogene

No

No

No

No

TS, DPD, TP

No

No

No

No

MSI

Not Applicable

No

Not Applicable

No

18q-LOH/DCC

Not Applicable

No

Not Applicable

No

 

Tumor Marker Recommendations for Pancreatic Cancer

Tumor Marker Screening Staging/Treatment Planning Finding out if the Cancer Has Come Back Finding out how the Treatment is Working

CA 19-9

No

No

CA 19-9 determinations by themselves cannot provide definitive evidence of disease recurrence without seeking confirmation with imaging studies for clinical findings and/or biopsy

Yes, can be measured at the start of treatment for locally advanced metastatic disease and every one to three months during active treatment

 

National Comprehensive Cancer Network (NCCN) 
 

Breast Cancer Version 2.2016
Suggested Intervals for Follow-Up for Patients with Metastatic Disease
Serum Tumor Markers (CEA, CA 15-3, CA 27.29)

Baseline Prior to New Therapy Chemotherapy Endocrine Therapy Restaging if Concern for Progression of Disease
Optional Optional Optional Optional

 

 

 

 

Ovarian Cancer Version 1.2016
Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer
Serum Tumor Marker Surveillance for Malignant Germ Cell and Sex Cord Stromal Tumors
(Serum Tumor Marker CA-125)

Germ Cell Tumors
<1 Year Years 1-2 Years 2-3 Years 3-5 >5 years

Every 2-4 months

Every 2-4 months

Not indicated

Not indicated

Not indicated

Sex Cord Stromal Tumors
<1 Year Years 1-2 Years 2-3 Years 3-5 >5 years

Every 2-4 months

Every 2-4 months

Every 6 months

Every 6 months

Every 6 months

Recurrence Suspected – CA - 125

 

 

 

 

 

 

 

 

 


Prior Approval:

 

Not applicable


Policy:

The following serum tumor markers are considered medically necessary for the diagnosis and management/monitoring of the specific condition(s) noted:
Note: See information above in the Description secion regarding when tumor markers should be performed. 

Tumor Marker Condition(s)

Carcinoembryonic Antigen (CEA)_(82378)

  • Metastatic Breast Cancer
  • Colorectal Cancer (colon and rectal)
  • Hepatobilliary Cancers including:
    • Intrahepatic Cholangiocarcionoma
    • Extrahepatic Cholangiocarcinoma
    • Gallbladder Cancer
  • Medullary Thyroid Carcinoma
  • Post-treatment surveillance of pseudomyxoma peritonei 
Cancer Antigen 125 (CA-125)
(86304)
  • Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
  • Ovarian low malignant potential tumors (borderline epithelial ovarian tumors) 
  • Undiagnosed pelvic mass: Less Common Ovarian Histopathologies (malignant germ cell neoplasms; carcinosarcoma (MMMT); malignant sex cord stromal tumors
  • Endometrial Cancer: suspected extrauterine disease (endometrioid histologies)
  • Occult Primary - Adenocarcinoma or Carcinoma not otherwise specified
    • Chest (multiple nodules) or pleural effusion (women) 
    • Peritoneal/Ascites (women)
    • Retroperitoneal mass (women) 
    • Inguinal nodes (women)
CA 19-9
(86301)
  • Pancreatic Cancer
  • Hepatobilliary Cancers including:
    • Intrahepatic Cholangiocarcionoma
    • Extrahepatic Cholangiocarcinoma
    • Gallbladder Cancer
  • To aid in the detection of cholangiocarcinoma in patients with primary sclerosing cholangitis
  • Occult Primary – Adenocarcinoma or Carcinoma not otherwise specified
    • Peritoneal/Ascites – if pancreatic or biliary tract primary suspected
    • Liver – if pancreatic or biliary tract primary suspected
  • Post treatment surveillance of pseudomyxoma peritonei

CA 15-3 and CA 27.29
(86300)

  •  Metastatic Breast Cancer

Gene expression classifier for thyroid nodule (i.e., Afirma® Thyroid FNA Analysis) (81545)

  • For assessing fine needle aspiration samples from thyroid nodules that are indeterminate

5-HIAA (5 Hydrocyindoleascetic Acid) (24 hour urine) (83497)

  • Neuroendocrine/Carcinoid Tumors
    • Primary tumors in the GI tract (jejunal; ileal; duodenal; colon; rectal; appendix)

Chromogranin A (CgA) (86316)

  • Neuroendocrine/Carcinoid Tumors
    • Primary tumors in the GI tract (jejunal: ileal; duodenal; colon; rectal; appendix)
    • Pancreastic neuroendocrine tumor (NET)

KIT (81272)

  •  Acute Myeloid Leukemia
  • Gastrointestinal stromal tumors (GIST)

  

Any of the tumor markers listed above for any cancer indication not otherwise listed and all other applications of serum tumor markers are considered investigational including but not limited to the following:

  • Ova-1 (CA-125, apolipoprotein A1, beta 2 microglobulin transferin and pre-albumin) and ROMA (CA-125 and HE4). See Medical Policy Proteomics Based Testing for Evaluation of Ovarian Cancer
  • Human epididymis protein (HE4)
  • A2-PAG (pregnancy associated alpha2 glycoprotein)
  • BCM (breast cancer mucin)
  • CAM 17-1 (antimucin monoclonal antibody)
  • CAM-26 (carcinoma associated mucin antigen)
  • CAM-29 (carcinoma associated mucin antigen)
  • MCA (mucinous carcinoma associated antigen)
  • TPA (tissue polypeptide antigen)
  • TPS (tissue polypeptide specific antigen)
  • CA 72-4 (cancer antigen 72-4)
  • CA-50 (cancer antigen 50)
  • CA-242 (cancer antigen 242)
  • CA-195 (cancer antigen 195)
  • CA-549 (cancer antigen 549)
  • CA-SCC (squamous cell carcinoma antigen)
  • CAR-3 (antigenic determinant recognized by monoclonal antibody AR-3)
  • DMSA (pentavalent technetium-99mm dimercaptosuccinic acid)
  • NSE (neuron specific enolase)
  • Du-PAN-2 (sialylated carbohydrate antigen)
  • EPCA-2 (early prostate cancer antigen)
  • TAG-12 (tumor associated glycoprotein 12)
  • TAG 72 (tumor associated glycoprotein 72)
  • TAG-72-3 (tumor associated glycoprotein 72-3)
  • TNF-alpha (TNF-a) (tumor necrosis factor alpha)
  • TATI (tumor associated trypsin inhibitor)
  • P-LAP (placental alkaline phosphatase)
  • PNA-ELLA (peanut lectin bonding assay)
  • P53 (monocolonal antibody)
  • SLEX (sialylated Lewis-X antigen)
  • SLX (sialylated SSEA-1 antigen)
  • SPAN-1 (sialylated carbonated antigen SPAN-1) 
  • Afirma Thyroid FNA Analysis (gene expression classifier for thyroid nodule) except as indicated above
  • ThyGenX and ThyraMIR (Interpace Diagnostics) molecular testing for indeterminate thyroid nodules

Based on the peer reviewed medical literature, improvements in meaningful health outcomes have not been proven and are still under investigation to determine their clinical utility in the management of individuals with various types of cancers. Studies comparing the tumor markers to established treatment options are lacking and management of patients based on the results of these markers have not been published and does not support these tests having sufficient sensitivity or specificity to define their clinical role and are therefore, considered investigational.



Procedure Codes and Billing Guidelines:

  • To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • The following CPT codes may be used to report serum tumor marker testing:
    • 81272 KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (e.g. gastrointestinal stromal tumor (GIST), acute myeloid leukemia, melanoma), gene analysis, targeted sequence analysis (e.g. exons 8, 11, 13, 17, 18)
    • 81545 Oncology (thyroid), gene expression analysis of 142 genes, utilizing fine needle aspirate, algorithm reported as a categorical result (e.g. benign or suspicious)
    • 82378 Carcinoembryonic antigen (CEA)
    • 83497 Hydroxyindolacetic acid 5-HIAA
    • 86300 Immunoassay for tumor antigen, quantitative; CA 15-3 (27.29)
    • 86301 Immunoassay for tumor antigen, quantitative; CA 19-9
    • 86304 Immunoassay for tumor antigen, quantitative; CA 125
    • 86305 Human epididymis protein
    • 86316 Immunoassay for tumor antigen; other antigen, quantitative (eg. CA 50, 72-4, 549), each (this code is used for CgA)
    • 81479 Unlisted molecular pathology
    • 81599 Unlisted multi-analyte assay with algorithmic analysis
    • 84999 Unlisted chemistry procedure  

Selected References:

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  • American Society of Clinical Oncology (ASCO). Guideline for Tumor Markers for Testicular Cancer and Extragonadal Germ Cell Tumors in Teenage Boys and Men.
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  • American Society of Clinical Oncology (ASCO). ASCO 2006 Update of Recommendations for the Use of Tumor Markers for Gastrointestinal Cancers, Journal of Clinical Oncology Volume 24, Number 33, November 2006.
  • National Comprehensive Cancer Network (NCCN): Version 2.2013 Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Periotoneal Cancer; Less Common Ovarian Histopathologies: Version 1.2014 Colon Cancer: Version 2.2013 Carcinoid Tumors and Neuroendocrine Tumors: Version 1.2013 Testicular Cancer (nonseminoma and pure seminoma): Version 2.2013 Hepatobiliary Cancers: Version 2.2014 Small Cell Lung Cancer: Version 1.2013 Pancreatic Adenocarcinoma: Version 4.2013 Prostate Cancer: Version 2.2013 Gastric Cancer: Version 3.2013 Breast Cancer: Version 2.2013 Thyroid Carcinoma-Medullary Carcinoma.
  • National Comprehensive Cancer NetworkExternal Site (NCCN) Version 1.2013 Endometrial Carcinoma.
  • National Comprehensive Cancer NetworkExternal Site (NCCN) Version 2.2013 Thyroid Carcinoma.
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  • National Comprehensive Cancer NetworkExternal Site (NCCN):  Version 1.2016 Thyroid Carcinoma; Version 2.2016 Breast Cancer; Version 2.2016 Colon Cancer; Version 2.2016 Rectal Cancer; Version 2.2016 Hepatobiliary Cancers;  Version 1.2016 Ovarian Cancer; Version 1.2016 Pancreatic Adenocarcinoma; Version 2.2016 Uterine Neoplasm; Version 2.2016 Occult Primary.
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  • Interpace Diagnostics - Value Dossier ThyGenX and ThyraMIR. Prepared by Interpace Diagnostics, LLC September 16, 2015
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  • Bernet Victor, Hupart Kenneth, et. al. AACE/ACE Disease State Commentary: Molecular Diagnostic Testing of Thyroid Nodules with Indeterminate Cytopathology. Endocrine Practice April 2014 Vol. 20. No. 4, pp. 360-363
  • CMS. National Coverage Determination (NCD) for Tumor Antigen by Immunoassay CA-125 (190.28)
  • CMS. National Coverage Determination (NCD) for Tumor Antigen by Immunoassay CA 15-3/CA 27.29 (190.29)
  • CMS National Coverage Determination (NCD) for Tumor Antigen by Immunoassay CA 19-9 (190.30)
  • National Comprehensive Cancer NetworkExternal Site (NCCN) Soft Tissue Sarcoma Version 2.2016, Gastrointestinal Stromal Tumors.
  • National Comprehensive Cancer NetworkExternal Site (NCCN) Acute Myeloid Leukemia Version 2.2016.
  • National Comprehensive Cancer NetworkExternal Site (NCCN) Vulvar Cancer (Squamous Cell Carcinoma) Version 1.2016.
  • UpToDateExternal Site Cancer of the Appendix and Pseudomyxoma Peritonei. Richard Swanson M.D., Jeffrey A Meyerhardt M.D., PhD. Topic last updated February 26, 2016.
  • UpToDateExternal Site Thyroid Biopsy. Douglas S Reed, M.D., Topic last updated January 20, 2016.
  • UpToDateExternal Site Screening for Ovarian Cancer. Karen J. Carlson M.D., Topic last updated March 1, 2016.
  • UpToDateExternal Site Clinical Presentation, Diagnosis, and Staging of Colorectal Cancer. Finlay A Macrae M.D., Johanna Bendell M.D., Topic last updated April 11, 2016.
  • UpToDateExternal Site Overview of the Classification and Management of Cancers of Unknown Primary Site. John D. Hainsworth M.D., F. Anthony Greco, M.D., Topic last updated December 17, 2014
  • UpToDateExternal Site Overview of the Management of Rectal Adenocarcinoma. David P. Ryan, M.D., Miguel A. Rodriguez-Bigas M.D., Topic last updated May 24, 2016.
  • UpToDateExternal Site Clinical Manifestations and Diagnosis of Cholangiocarcinoma. Robert C Lowe, M.D., Nezam H. Afdel M.D., FRCPI, Christopher D. Anderson M.D., FACS, Kris V. Kowdley M.D., FACP, FACG, GASGE, AGAF. Topic last updated July 8, 2016.
  • Di Fabio F, Aston W, Mohamed F, Chandrakumaran K. et. al. Elevated tumor markers are normalized in most patients with pseudomyxoma peritonei 7 days after complete tumor removal. Colorectal Dis 2015 Aug;17(8):698-703
  • National Cancer InstituteExternal Site Tumor Markers. Last reviewed November 4, 2015.

Policy History:

  • August 2016 - Annual Review, Policy Revised
  • December 2015 - Interim Review, Policy Revised
  • September 2015 - Annual Review, Policy Revised
  • July 2015 - Interim Review, Policy Revised
  • October 2014 - Annual Review, Policy Revised
  • March 2014 - Interim Review, Policy Revised
  • November 2013 - Interim Review, Policy Revised
  • October 2013 - Annual Review, Policy Revised
  • December 2012 - Annual Review, Policy Renewed
  • December 2011 - Annual Review, Policy Renewed
  • December 2010 - Annual Review, Policy Revised

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.