mp-195
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Serum Tumor Markers for Breast and Gastrointestinal Malignancies

Policy Number: MP-195

Latest Review Date: December 2020

Category: Laboratory

Policy Grade: A

POLICY:

Measurement of serum tumor marker CA 15-3 (27.29) for monitoring patients with known breast cancer may be considered medically necessary.

Measurement of serum tumor marker CA 15-3 (27.29) when used as a diagnostic or screening test for breast cancer is considered not medically necessary and investigational.

Measurement of serum tumor marker CA 19-9 for monitoring patients with known pancreatic or biliary cancer (i.e., gallbladder, intrahepatic biliary and extrahepatic biliary) may be considered medically necessary.

Measurement of serum tumor marker CA 19-9 when used as a technique to screen, diagnose, determine prognosis, assess response to therapy, or monitor for recurrence of gastrointestinal malignancies* (except as indicated above) is considered not medically necessary and investigational

Measurements of serum tumor marker CA 72-4 when used as a technique to screen, diagnose, determine prognosis, assess response to therapy, or monitor for recurrence of gastrointestinal malignancies* is considered not medically necessary and investigational.

*Gastrointestinal malignancies include cancers associated with the esophagus, stomach, small intestine, appendix, colon, rectum, anus, liver, biliary tract and pancreas.

DESCRIPTION OF PROCEDURE OR SERVICE:

Serum tumor markers are substances produced by cells in response to cancer or certain noncancerous conditions. Most tumor markers are made by normal cells as well as cancer cells; however, they are produced at much higher levels in cancerous conditions. Serum tumor markers have been investigated in many malignancies, including most prominently myeloma, germ cell tumors, and prostate cancer. This policy focuses on specific tumor markers for breast and gastrointestinal malignancies.

For breast cancer, the most extensively investigated serum tumor markers besides HER2 are those associated with the MUC-1 gene. For gastrointestinal cancer (including gastric, pancreatic, and colorectal cancer) the most extensively studied tumor markers, other than CEA, are those related to mucinous glycoproteins. The MUC-1 gene encodes a cell-associated mucin-like antigen, and different antibodies may be used to detect different epitopes. CA 15-3 and CA 27.29 are two related monoclonal antibodies that detect epitopes encoded by the MUC-1 gene. While much of the literature has focused on the use of CA 15-3, it has been largely replaced by CA 27.29, which is reportedly more sensitive. The mucinous glycoproteins of the gastrointestinal tract include CA 19-9, and CA 72-4, depending on which antibody is used.

Since serum tumor markers can also be detected in normal or benign lesions, significantly elevated circulating levels may occur with malignancy by one or more of the following mechanisms: (1) overexpression of the antigen by malignant cells; (2) a large tumor burden; and/or (3) slower clearance of the marker. For example, since most tumor markers are cleared by the liver, liver abnormalities (whether benign, malignant, or inflammatory) may elevate tumor marker concentrations due to impaired clearance. Because most tumor markers are not unique to malignancy, cut-off points must be established for normal versus abnormal marker levels. In contrast, serial monitoring of serum tumor markers in a setting of established malignancy may not require such cutoff points. Various clinical applications of serum tumor markers can be broadly divided into two categories, those involving a single measurement and those involving serial measurements.

The CA 15-3 antigen is a protein released into the bloodstream by certain types of cancer. This tumor marker is most useful in evaluating the effect of treatment for women with advanced breast cancer.

The CA 19-9 marker is associated with cancers in the colon, stomach, and bile duct. Elevated levels of CA 19-9 may indicate advanced cancer in the pancreas, but it is also associated with noncancerous conditions, including gallstones, pancreatitis, cirrhosis of the liver, and cholecystitis.

The CA-72-4 marker testing is most commonly used for the diagnosis and management of gastrointestinal cancers. It has also been studied for use in gynecological cancers.

*For serum tumor markers for bladder cancer refer to medical policy #433: Urinary Biomarkers for Cancer Screening, Diagnosis, and Surveillance

KEY POINTS:

This policy was created in 2004 with the most recent literature review performed on December 31, 2020.

Summary of Evidence

Recommendations for the use of a given tumor marker test are based on whether there are high levels of published evidence of analytical validity and clinical utility, regardless of whether the test has been approved, cleared, or never reviewed by the FDA.

CA 15-3 is a serum cancer antigen that has been used in the management of patients with breast cancer. Its low detection rate in early stage disease indicates that CA 15-3 cannot be used to screen or diagnose patients with breast cancer.  It has been widely used to monitor the effectiveness of treatment for metastatic cancer. Elevated serum CA 15-3 concentrations are found in 5 percent of stage I, 29 percent of stage II, 32 percent of stage III and 95 percent of stage IV carcinoma of the breast. Most (96 percent) patients with a CA 15-3 increase of greater than 25 percent have disease progression. Most (nearly 100 percent) patients with a CA 15-3 decrease of greater than 50 percent are responding to treatment. The evidence is insufficient to support the use of tumor marker CA15-3 as medically necessary for diagnosis or screening of breast cancer. Serial measurements of CA 15-3 in following the course of treatment in women diagnosed with breast cancer, especially advanced metastatic breast cancer, has been shown to adequately suggest treatment failure; therefore, the evidence is sufficient to support the use of CA15-3 in the monitoring of patients with breast cancer.

CA 19-9 is a tumor-associated antigen, which was originally defined by a monoclonal antibody, most notably used in pancreatic cancer patients. Reports are mixed regarding this antigen and pre and postoperative determinations, as well as CA 19-9 measurements to monitor patients receiving chemotherapy or radiotherapy. The specificity and sensitivity of CA 19-9 is inadequate for reliable diagnosis in pancreatic cancer if used alone. High levels of CA 19-9 are increased in biliary disease due to the enhanced production of CA 19-9 from the biliary epithelial cells. Extreme increases in CA 19-9 levels can lead to a misdiagnosis of pancreatic or biliary malignancy. CA 19-9 should never be considered the gold standard for diagnosis. The evidence is insufficient to consider the use of tumor marker CA19-9 as medically necessary for the diagnosis of patients with GI cancer.

Although limited, there exists some studies that suggest that the use of CA 19-9 for monitoring of patients with GI cancers is beneficial to providing information regarding the progression of disease and have practical value in the management of GI cancers. Recruitment for large scale studies is challenging, but the value to this technology is believed to be of value and thus is considered to have sufficient evidence to prove utility for the use of tumor marker CA 19-9 in the monitoring of patients with GI cancer.

A study has been identified in which a prospective, single center study by enrolling 96 patients between March 2013 and August 2016 with various de novo or previously diagnosed locally advanced, unresectable and/or metastatic cancers known to express CA72-4. Quantification of CA72-4 was performed according to manufacturer’s instructions using the DRG TM-CA72-4 ELISA kit, which was developed by DRG International (Germany) utilizing the CC-49 monoclonal mouse antibody directed against an epitope on the CA72-4 antigen. Positivity was calculated as greater than A) 0.8 U/mL or B) 4.0 U/mL based on systematic review of prior studies. Positivity rates of CA72-4 varied based on different assay cut-off levels with the highest positivity noted in the pancreatic, ovarian and colorectal carcinomas indicating a potential role for disease monitoring. More well designed studies need to be identified that prove a convincing role of CA 72-4 for use in GI cancer. The evidence is insufficient to prove the utility of CA 72-4, and is therefore, considered not medically necessary as a technique to diagnose, determine prognosis, select therapy, assess response to therapy, or monitor for recurrence of either breast or gastrointestinal malignancies. Gastrointestinal malignancies include gastric, pancreatic, and colorectal cancer.

Controlled studies showing the clinical utility of the serum tumor markers addressed in this policy and improved health outcomes in patients with breast, pancreatic, gastric, or colon cancer are lacking. In terms of monitoring response to therapy of metastatic disease, the serial measurement of serum tumor markers correlates well with clinical response criteria. However, of concern is the lack of valid criteria for interpreting changes in marker levels. Criteria have been suggested, but these have not been universally accepted. The evidence is insufficient to support the use of tumor markers for monitoring response to therapy.

Practice Guidelines and Position Statement

National Comprehensive Cancer Network (NCCN)

NCCN guidelines for breast cancer (v1.2019) state that rising tumor markers (e.g., CEA, CA 15-3, CA 27.29) are concerning for tumor progression, but may also be seen in the setting of responding disease. An isolated increase in tumor markers should rarely be used to declare progression of disease. Changes in bone lesions are often difficult to assess on plain or cross-sectional radiology or on bone scan. For these reasons, patient symptoms and serum tumor markers may be more helpful in patients with bone-dominant metastatic disease.

NCCN recommends the use of serum marker CA 19-9 in pancreatic cancers. The NCCN guidelines also note that elevated CA 19-9 does not necessarily indicate cancer or advanced disease, as an elevated CA 19-9 may be the result of biliary infection. They further note that either CEA or CA 19-9 or both can be used in the management of hepatobiliary cancers under certain circumstances.

American Society of Clinical Oncology (ASCO)

In 2007, the American Society of Clinical Oncology (ASCO) updated their recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast cancer.

Table. Overview of the 2007 ASCO Guidelines for the Use of Tumor Markers in Breast Cancer

Marker

Recommendation

CA 15-3 and CA 27.29 as markers for breast cancer, as screening, diagnostic, or staging tests

Present data are insufficient to recommend CA 15-3 or CA 27.29 for screening, diagnosis, and staging.

CA 15-3 and CA 27.29 to detect recurrence after primary breast cancer therapy

Present data do not support the use of CA 15-3 and CA 27.29 for monitoring patients for recurrence after primary breast cancer therapy.

CA 15-3 and CA 27.29 to contribute to decisions regarding therapy for metastatic breast cancer

For monitoring patients with metastatic disease during active therapy, CA 15-3 or CA 27.29 can be used in conjunction with diagnostic imaging, history, and physical examination. Present data are insufficient to recommend the use of CA 15-3 or CA 27.29 alone for monitoring response to treatment. However, in the absence of readily measurable disease, an increasing CA 15-3 or CA 27.29 level may be used to indicate treatment failure. Caution should be used when interpreting a rising CA 15-3 or CA 27.29 level during the first 4-6 weeks of a new therapy, as spurious early rises may occur.

In its 2006 update, the American Society of Clinical Oncology (ASCO) expanded the scope of the guidelines for use of tumor markers in gastrointestinal cancer to include CA 19-9 as a marker for pancreatic cancer. The recommendations for evaluation of CA 19-9 levels are as follows:

  • CA 19-9 is least sensitive for small, early-stage pancreatic carcinomas and thus is not effective for the early detection of pancreatic cancer or as a screening tool
  • Use of CA 19-9 levels alone is not recommended for use in determining operability
  • Rising levels of CA 19-9 postoperatively may predict recurrent disease, but confirmation with imaging studies and/or biopsy is required.
  • CA 19-9 can be measured at the start of treatment for locally advanced metastatic disease and every 1-3 months during active treatment; elevation of levels in serial determinations may be an indication of progressive disease, but confirmation with other studies is required
  • 5-10% of patients lack the enzyme necessary to produce CA 19-9; in these patients with low or absent titer of CA 19-9, monitoring disease with this tumor marker will not be possible

U.S. Preventative Services Task Force Recommendations

Not applicable.

KEY WORDS:

Serum tumor markers, CA 19-9, CA 72-4, CA 15-3, CA 27.29, pancreatic cancer, biliary cancer, breast cancer, GI malignancies, gastrointestinal malignancies, gastrointestinal cancer, GI cancer, gallbladder cancer, intrahepatic biliary cancer, extrahepatic biliary cancer, esophageal cancer, stomach cancer, small intestine cancer, appendix cancer, colon cancer, rectum cancer, anus cancer, liver cancer, biliary tract cancer, pancreas cancer

APPROVED BY GOVERNING BODIES:

Some tumor markers are FDA approved.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and may be reviewed for medical necessity. Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT codes:

86300

Immunoassay for tumor antigen, quantitative; CA 15-3 (27.29)

86301

Immunoassay for tumor antigen, quantitative, CA 19-9

86316

Immunoassay for tumor antigen, other antigen quantitative (e.g. CA 50, 72-4, CA 549), each

REFERENCES:

  1. 1995 TEC Assessment; Tab 19: Serum tumor markers for the diagnosis and monitoring of breast cancer.
  2. 1996 TEC Assessment; Tab 23: Serum tumor markers for the diagnosis and monitoring of gastrointestinal cancer.
  3. 1996 TEC Assessment; Tab 24: Serum tumor markers (CA 15-3, CA 27.29, and CA 549) for the monitoring of breast cancer recurrence.
  4. Abrams RA, Grochow LB, Chakravarthy A, et al. Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: Survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels. Int J Radiat Oncol Biol Phys. 1999; 44(5):1039-1046.
  5. American Society of Clinical Oncology (2017). Retrospective analysis of the role of CA 15-3 as a biomarker for breast cancer relapse. Retrieved August 7, 2018 from meetinglibrary.asco.org/record/146482/abstract
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  23. Hess V, Glimelius B, Grawe P, et al. CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomized controlled trial. Lancet Oncol 2008; 9(2):132-8.
  24. Huang, Z., & Liu, F. (2014). Diagnostic value of serum carbohydrate antigen 19-9 in pancreatic cancer: a meta-analysis. Tomour Biology, 35 (8), 7459-7465. Abstract retrieved August 26, 2016 from PubMed database.
  25. Humphris, J., Chang, D., Johns, A., Scarlett, C., Pajic, M., Jones, M. (2012). The prognostic and predictive value of serum CA19.9 in pancreatic cancer. Annals of Oncology, 23, 1713-1722.
  26. John AR, Haghighi KS, Taniere P, et al. Is a raised CA 19-9 level diagnostic for a cholangiocarcinoma in patients with no history of sclerosing cholangitis? Dig. Surg. 2006; 23(5-6):319-24.
  27. Katz A, Hanlon A, Lanciano R et al. Prognostic value of CA 19-9 levels in patients with carcinoma of the pancreas treated with radiotherapy. Int J Radiat Oncol Biol Phys 1998; 41(2): 393-6.
  28. Kau SY, Shyr YM, Su CH, et al. Diagnostic and prognostic values of CA 19-9 and CEA in periampullary cancers. J Am Coll Surg. 1999; 188(4):415-420.
  29. Khatcheressian JL, Wolff AC, Smith TJ, et al. American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 2006; 24(31):5091-7.
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  33. Levy C, Lymp J, Angulo P, et al. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci. 2005; 50(9):1734-1740.
  34. Locker GY, Hamilton S, Harris J, et al. 2006 Update of ASCO recommendations for the use of tumor markers in gastrointestinal cancer. Journal of Oncology Practice 2006, Vol. 2, Issue 6.
  35. Micke O, Bruns F, Kurowski R, et al. Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiochemotherapy. Int J Radiat Oncol Biol Phys 2003; 57(1): 90-7.
  36. National Academy of Clinical Biochemistry. (2009). Use of tumor markers in testicular, prostate, colorectal, breast and ovarian cancers. Retrieved December 22, 2017 from https://www.aacc.org/science-and-practice/practice-guidelines/major-tumor-markers.
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  39. National Comprehensive Cancer Network. (2018, August). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Hepatobiliary cancers. Version 3.2018. Retrieved October 4, 2018 from www.nccn.org.
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  41. National Comprehensive Cancer Network. (2018, August). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Rectal cancer. Version 3.2018. Retrieved October 4, 2018 from www.nccn.org.
  42. National Institute for Health and Care Excellence. (2011). Colorectal cancer: diagnosis and management. Retrieved October 18, 2017 from www.nice.org.uk.
  43. NCCN Guidelines Version 1.2019 Invasive Breast Cancer. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
  44. Ohara K, Tatsuzaki H, Molotkova NG et al. Utility of serum CA 19-9 monitoring in preoperative radiotherapy for pancreatic cancer. Hepatogastroenterology 2001; 48(39): 859-63.
  45. Osayi, S., Bloomston, M., Schmidt, C., Ellison, E., & Muscarella, P. (2014). Biomarkers as predictors of recurrence following curative resection for pancreatic ductal adenocarcinoma: a review. Biomed Research International, 2014:468959.
  46. Perkins GL, Slater ED, et al. Serum tumor markers. American Family Physician 2003; 68(6).
  47. Primrose, J., Perera, R., Gray, A., Rose, P., Fuller, A., Corkhill, A., et al. (2014). Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial. Journal of American Medical Association, 311 (3), 263-270.
  48. Rocha Lima CM, Savarese D, Bruckner H et al. Irinotecan plus gemcitabine inducs both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 2002; 20(5): 1182-91.
  49. Rosselli Del Turco, M, Palli D, Cariddi A, et al. Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. JAMA 1994; 271(20): 1593-7.
  50. Sorensen, C., Karisson, W., Pommergaard, H., Burcharth, J., & Rosenberg, J. (2016). The diagnostic accuracy of carcinoembryonic antigen to detect colorectal cancer recurrence -a systematic review. International Journal of Surgery, 25, 134-144.
  51. Shukla VK, Gurubachan, Sharma D, et al. Diagnostic value of serum CA-242, CA 19-9, CA15-3 and CA 125 in patients with carcinoma of the gallbladder. Trop Gastroenterol 2006; 27(4):160-5.
  52. Sinakos E, Saenger AK, Keach J, et al. Many patients with primary sclerosing cholangitis and increased serum levels of carbohydrate antigen 19-9 do not have cholangiocarcinoma. Clin Gastroenterol Hepatol. 2011; 9(5):434-439.
  53. Steinberg W. The clinical utility of the CA19-9 tumor associated antigen. Am J Gastroenterol. 1990; 85:350-355.
  54. Sun, Z. and Zhang, N. (2015) Clinical evaluation of CEA, CA19-9, CA72-4 and CA125 in gastric cancer patients with neoadjuvant chemotherapy. World Journal of Surgical Oncology, 12 (1), 397.
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  56. Wang, W., Xu, X., Tian, B., Wang, Y., Du, L., Sun, T., et al. (2017). The diagnostic value of serum tumor markers CEA, CA19-9, CA125, CA15-3, AND TPS in metastatic breast cancer. Clinica Chimica Acta, 470, 51-55. Abstract retrieved December 22, 2017 from PubMed database.
  57. Yaegashi H, Izumi K, Kadomoto S, et al. High serum CA19-9 concentration indicates high chemosensitivity and better survival in advanced urothelial carcinoma. Anticancer Res. 2019; 39(1):375-380.
  58. Ziske C, Schlie C, Gorschluter M et al. Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine. Br J Cancer 2003; 89(8): 1413-7.

POLICY HISTORY:

Medical Policy Group, August 2004 (2)

Medical Policy Administration Committee, August 2004

Available for comment October 5-November 18, 2004

Medical Policy Group, March 2005 (2)

Medical Policy Administration Committee, April 2005

Available for comment April 13-May 27, 2005

Medical Policy Group, July 2005 (2)

Medical Policy Administration Committee, July 2005

Available for comment July 28-September 10, 2005

Medical Policy Group, December 2006 (1)

Medical Policy Administration Committee, December 2006

Available for comment January 30-March 8, 2007

Medical Policy Group, March 2007 (2)

Medical Policy Administration Committee, March 2007

Medical Policy Group, November 2008 (2)

Medical Policy Administration Committee, April 2009

Available for comment April 1-May 15, 2009

Medical Policy Group, June 2010 (3)

Medical Policy Administration Committee July 2010

Available for comment July 2-August 16, 2010

Medical Policy Group, June 2011 (1): Updated Description, narrowed number of serum markers under Policy; policy statement unchanged, updated Key Points and References; completely removed all aspects of bladder cancer tumor markers and placed on policy 433

Medical Policy Administration Committee, August 2011

Medical Policy Group, October 2013 (1): Policy updated with literature review; clarification to policy criteria and reformatting of policy section, no change to coverage criteria; removed ICD-9 diagnosis codes; addition of pancreatic, biliary and breast cancer to Key Words

Medical Policy Administration Committee, December 2013

Medical Policy Group, June 2016: Changed Category from Medical to Laboratory

Medical Policy Group, August 2018 (9): 2018 Updated Key Points, References. No change to policy statement.

Medical Policy Group, October 2019 (9): 2019 Updates to Description, Key Points, References. Reformatted policy statement for clarity, no change to intent. Added key words: GI malignancies, gastrointestinal malignancies, gastrointestinal cancer, GI cancer, gallbladder cancer, intrahepatic biliary cancer, extrahepatic biliary cancer, esophageal cancer, stomach cancer, small intestine cancer, appendix cancer, colon cancer, rectum cancer, anus cancer, liver cancer, biliary tract cancer, pancreas cancer.

Medical Policy Group, December 2020 (9): 2020 Updates to Description, Key Pointed, References. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.