Serum Tumor Markers in the Management of Malignancies

Medical Policy: 02.01.20 
Original Effective Date: December 2000 
Reviewed: December 2011 
Revised: December 2010 

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: 

While serum tumor markers can be detected in normal or benign lesions, significant circulating levels are associated with malignancy due to one or more of the following mechanisms:

• Over expression of the antigen by individual malignant cells
• A large tumor burden
• The clearance rate of the marker

Clinical applicability of tumor markers depends upon how their measurements are used to influence the management of the patient.

Top

Prior Approval: 

Not applicable

Top

Policy: 

The following serum tumor markers may be considered medically necessary for the specified conditions:

Prostate Specific Antigen (PSA)

• Staging, monitoring response to therapy, and detecting disease recurrence in prostate cancer

Carcinoembryonic Antigen (CEA) in breast cancer

• Serial monitoring of metastatic breast cancer during active treatment

Carcinoembryonic Antigen (CEA) in gastrointestinal cancer

• Preoperative staging and surgical treatment planning in colorectal cancer
• Postoperatively every 3 months in patients with stage II or III colorectal cancer for at least 3 years after diagnosis IF the patient is a candidate for surgery or systemic therapy
• Serial monitoring of metastatic colorectal cancer during systemic therapy

Cancer antigen 125 (CA-125)

• In pre-menopausal and peri-menopausal women with a documented complex ovarian mass
• In post-menopausal women with any documented ovarian mass
• In patients with gynecologic malignancies, including but not limited to carcinoma of the fallopian tube(s) and endometrial carcinoma:
  • To establish a baseline OR
  • To monitor disease progression in patients whose baseline levels have been shown to be elevated

CA 19-9

• To monitor clinical response to therapy in patients with pancreatic cancer, colorectal cancer, gastric cancer, or cholangiocarcinoma
• To aid in the detection of cholangiocarcinoma in patients with primary sclerosing cholangitis

CA 15-3 and CA 27.29

• To monitor response to therapy in patients with breast cancer

Alpha-fetoprotein (AFP)

• Before orchiectomy for all patients suspected of having a testicular germ cell tumor to help establish the diagnosis and interpret post-orchiectomy levels
• Before and after orchiectomy and before chemotherapy in patients with extra-gonadal (i.e., mediastinal or retroperitoneal) non-seminomas
• Before retroperitoneal lymph node dissection and at the start of each chemotherapy cycle for non-seminomas, and periodically to monitor for relapse
• To monitor for relapse in patients treated for advanced seminoma
• Diagnosis, treatment, and identification of residual disease in patients with hepatocellular carcinoma

Beta-human Chorionic Gonadotropin (b-hCG)

• Before orchiectomy for all patients suspected of having a testicular germ cell tumor to help establish the diagnosis and interpret post-orchiectomy levels
• Before and after orchiectomy and before chemotherapy in patients with extra-gonadal (i.e., mediastinal or retroperitoneal) non-seminomas
• Before retroperitoneal lymph node dissection and at the start of each chemotherapy cycle for non-seminomas, and periodically to monitor for relapse
• Post-orchiectomy for patients with seminoma and pre-orchiectomy elevations
• To monitor for relapse in patients treated for advanced seminoma

Lactate dehydrogenase (LDH)

• Before orchiectomy for all patients suspected of having a testicular germ cell tumor to help establish the diagnosis and interpret post-orchiectomy levels
• Post-orchiectomy for patients with seminoma and pre-orchiectomy elevations

Chromogranin A (CgA)

• Diagnosis and surveillance of patients with neuroendocrine tumors, including carcinoids

AFP, β-hCG, and LDH are considered not medically necessary to screen for germ cell tumors, to determine whether orchiectomy is indicated, or to guide treatment decisions for patients with cancer of unknown primary (CUP)

All other applications of serum tumor markers are considered investigational including but not limited to the following:

• CEA for screening, diagnosis, staging, or routine surveillance of breast cancer
• CA 19-9 as a screening or diagnostic test for gastrointestinal cancers including pancreatic and colorectal cancers, and liver, breast, esophageal and uterine cancer
• CA 15-3 and CA 27.29 for screening, diagnosis, staging, or routine surveillance of breast cancer
• CA-125 as a solitary test to screen for ovarian cancer
• HE4 for screening, diagnosing, or monitoring disease progression or recurrence in women with ovarian cancer

Other tumor markers considered investigational include (this list is not exhaustive): 

1. CAM 17-1
2. CAM-26
3. CAM-29
4. MCA
5. MSA
6. TPA
7. TPS
8. CA 72-4
9. CA-50
10. CA-242
11. CA-195
12. CA-549
13. CA-SCC
14. CAR-3
15. DMSA
16. NSE
17. Du-PAN-2
18. MCA
19. TAG-12
20. TAG-72-3
21. TNF-alpha

Top

Procedure Codes and Billing Guidelines: 

• To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9 diagnostic codes.
• The following CPT codes may be used to report serum tumor marker testing:
  • 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, CgA), each
  • 84153 Prostate specific antigen (PSA); total
  • 82378 Carcinoembryonic antigen (CEA)  

Top

Selected References: 

• Burtis C.A., Ashwood E.R., editors. Tietz textbook of clinical chemistry. Third edition. Philadelphia: W.B. Saunders, c1999. Pages 735-740.
• Gion M., Boracchi P., Dittadi R., Biganzoli E., Peloso L., Mione R., Gatti C., Paccagnella A., Marubini E. Prognostic role of serum CA 15.3 in 362 node-negative breast cancers. An old player for a new game. European Journal of Cancer; June 2002; 38 (9): 1165-6.
• Jacobs IJ, et al..  Screening for ovarian cancer: a pilot randomised controlled trial.  Lancet  1999 Apr 10;353(9160):1207-10.
• Jacobs IJ, et al.  Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study.  BMJ  1996 Nov 30;313(7069):1355-8.
• ACOG Committee Opinion: number 280, December 2002. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer.  Obstet Gynecol  2002 Dec;100(6):1413-6.
• Tuxen MK, Soletormos G, Dombernowsky P. Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up.  Scand J Clin Lab Invest  2002;62(3):177-88.
• Smith RA, Cokkinides V, Eyre HJ et al. American Cancer Society Guidelines for the early detection of cancer, 2003. CA Cancer J Clin 2003 Jan-Feb;53(1):27-43.
• Bast RC, Ravdin P, Hayes D et al. 2000 update of recommendations for the use of tumor markers on breast and colorectal cancer:  clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19(6):1865-78.
• Micke O, Bruns F, Kurowski R et al. Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiotherapy.  Int J Radiat Oncol Biol Phys 2003; 57(1):90-7.
• Kurebayashi J, Yamaoto Y, Tanaka K et al.  Significance of serum carcinoembryonic antigen and CA 15.3 in monitoring advanced breast cancer patients treated with systemic therapy: a large-scale retrospective study.  Breast Cancer 2003; 10(1):38-44.
• Harris L, Fritsche H, Mennel R et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007 Nov 20;25(33):5287-312.
• Zatelli MC, Torta M, Leon A et al. Chromogranin A as a marker of neuroendocrine neoplasia: an Italian Multicenter Study. Endocr Relat Cancer. 2007 Jun;14(2):473-82.
• Seregni E, Ferrari L, Bajetta E et al. Clinical significance of blood chromogranin A measurement in neuroendocrine tumours. Ann Oncol. 2001;12 Suppl 2:S69-72.
• Stirling D, Evans DGR, Pichert G et al. Screening for Familial Ovarian Cancer: Failure of Current Protocols to Detect Ovarian Cancer at an Early Stage According to the International Federation of Gynecology and Obstetrics System. J Clin Oncol 2005; 23(24):5588-5596.
• Bast Jr. RC. Status of Tumor Markers in Ovarian Cancer Screening. J Clin Oncol 2003; 21(10s):200s-205s.
• Karlan BY, McIntosh M. The Quest for Ovarian Cancer’s Holy Grail: Can CA-125 Still Be the Chalice of Early Detection? J Clin Oncol 2007;25(11): 1303-1304.
• Marcos CA, Martinez DA, de Los Toyos JR et al. The usefulness of new serum tumor markers in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2009 Mar; 140(3):375-80.
• Tsai HL, Chang YT, Chu KS et al. Carcinoembryonic antigen in monitoring of response to cetuximab plus FOLFIRI or FOLFOX-4 in patients with metastatic colorectal cancer. Int J Biol Markers. 2008 Oct-Dec; 23(4):244-8.
• Li YG, Zhang N. Clinical significance of serum tumor M2-PK and CA 19-9 detection in the diagnosis of cholangiocarcinoma. Dig Liver Dis. 2009 Jan 23. [Epub ahead of print]
• Andriole GL, Crawford ED, Grubb 3^rd RL et al. Mortality Results from a Randomized Prostate-Cancer Screening Trial. N Engl J Med 2009; 360(13): 1310-19.
• Brawley OW, Ankerst DP, Thompson IM. Screening for Prostate Cancer. CA Cancer J Clin 2009[Epub prior to print June 29, 2009].
• Lin K, Lipsitz R, Miller T et al. Benefits and Harms of Prostate-specific Antigen Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149(3):192-99.
• Lim LS, Sherin K, and the American College of Preventive Medicine (ACPM) Prevention Practice Committee. Screening for Prostate Cancer in U.S. Men: ACPM Position Statement on Preventive Practice. Am J Prev Med 2008;34(2):164-70.
• Charatcharoenwitthaya P, Enders FB, Halling KC et al. Utility of Serum Tumor Markers, Imaging, and Biliary Cytology for Detecting Cholangiocarcinoma in Primary Sclerosing Cholangitis. Hepatology 2008;48:1106-1117.
• Juntermanns B, radunz S, Heuer M et al. Tumor markers as a diagnostic key for hilar cholangiocarcinoma. Eur J Med Res. 2010 Aug 20; 15(8):357-61.
• Morris-Stiff G, Teli M, Jardine N et al. CA19-9 antigen levels can distinguish between benign and malignant pancreatobiliary disease. Hepatobiliary Pancreat Dis Int. 2009 Dec; 8(6):620-6.
• Abbas G, Lindor KD. Cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Cancer. 2009; 40(1-2):19-25. Epub 2009 Aug 25.
• Gilligan TD, Seidenfeld J, Basch EM et al. American Society of Clinical Oncology Practice Guideline on Uses of Serum Tumor Markers in Adult Males with Germ Cell tumors. J Clin Oncol 2010; 28(20):3388-3404.
• Moore RG, McKeekin DS, Brown AK et al. A novel multiple marker bioassay utilizing HE4 and CA-125 for the prediction of ovarian cancer in patients with pelvic mass. Gynecol Oncol 2009; 112(1):40-6.
• Nolen B, Velikokhatnaya L, Marrangoni A et al. Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol 2010; 117(3);440-5.
• Andersen MR, Goff BA, Lowe KA et al. Use of a symptom index, CA 125 and HE4 to predict ovarian cancer. Gynecol Oncol 2010; 116(3):378-83.
• Molina R, Escudero JM, Auge JM et al. HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumor Biol 2011; 32:1087-95. doi: 10.007/s13277-011-0204-3.
• Moore RG, Miller MC, Disilvestro P et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. 2011 Aug; 118(2 Pt 1): 280-8.
• Sturgeon CM, Duffy MJ, Hoffmann BR et al. National Academy of Clinical Biochemistry Laboratory Medicine Clinical Practice Guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers. Clin Chem 2010 Jun;56(6): e1-48. Epub 2010 Mar 5.
• Anderson GL, McIntosh M, Wu L et al. Assessing lead tome of selected ovarian cancer biomarkers: a nested case-control study. J Natl Cancer Inst 2010; 102(1):26-38.
• Lenhard M, Steiber P, Hertlein L et al. The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses. Clin Chem Lab Med. 2011 Sep 16 [Epub ahead of print].
• Holcomb K, Vucetic Z, Miller MC et al. Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women. Am J Obstet Gynecol. 2011 Oct;205(4):358.el-6. Epub 2011 May 14. 

Top

Policy History: 

Date                                        Reason                               Action

December 2010                      Annual review                     Policy revised

December 2011                      Annual review                     Policy renewed

Top

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 © 2010 American Medical Association. All Rights Reserved.