Coverage Policy Manual
Policy #: 1997090
Category: Laboratory
Initiated: November 1993
Last Review: October 2018
  Tumor Antigen, CA 125 (Carcinoembryonic Antigen 125)

Description: Radioimmunoassay and immunohistochemical determination of serum levels of certain proteins or carbohydrates serves as tumor markers.  When elevated, serum concentration of these markers may reflect tumor size and grade and may be helpful in monitoring the progress of the disease and/or affect of the treatment, and in a few cases, for establishing diagnosis of the disease.

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Immunoassay of serum cancer antigen 125 (CA-125) meets primary coverage criteria for effectiveness and is covered:
 
    • For monitoring patients with known carcinoma of the ovary, to monitor clinical response to therapy, or to detect evidence of recurrence of disease
    • When used as a decision-making tool for avoiding the risks of surgery, in patients with ovarian masses documented with noninvasive tests and suspected to be ovarian cancer
    • In patients with known ovarian cancer or gynecologic cancer that is known to produce CA-125, if CA-125 is elevated at the time of diagnosis
    • Annually or semiannually in patients with a known BRCA-1 or BRCA-2 mutation or with at least one first degree relative with a history of ovarian cancer
    • For monitoring patients with known primary peritoneal carcinoma, to monitor clinical response to therapy, or to detect evidence of recurrence of disease.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Immunoassay of serum cancer antigen 125 (CA-125) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following:
 
    • Screening asymptomatic women for ovarian disease;
    • Differential diagnosis of patients with symptoms of ovarian disease
    • Screening with immunoassay for multiple antigens
    • Multiple immunoassay tests on the same day, performed without a specific indication or diagnosis
 
For members with contracts without primary coverage criteria, immunoassay of serum cancer antigen 125 (CA-125) is considered investigational for:
 
    • Screening asymptomatic women for ovarian disease;
    • Differential diagnosis of patients with symptoms of ovarian disease
    • Screening with immunoassay for multiple antigens
    • Multiple immunoassay tests on the same day, performed without a specific indication or diagnosis
 
Investigational services are specific contract exclusions in the member benefit certificate of coverage.
 
Screening tests are exclusions in most member benefit certificates of coverage except for coverage based on the Patient Protection and Affordable Care Act (PPACA) screening recommendations for non-grandfathered plans and those contracts with wellness benefits (which like PPACA, covers specific screening procedures).
 
 
 
 
 
 

Rationale:
CA-125 for Monitoring and Surveillance of Known Ovarian Cancer and Other Gynecologic Cancers
The use of CA-125 to monitor ovarian cancer recurrence in patients with known ovarian cancer is considered standard practice and is not further discussed. In addition, other gynecologic malignancies, particularly endometrial cancer, may also be associated with CA-125 in individual cases. If so, levels of CA-125 may be similarly monitored for cancer recurrence.
 
CA-125 as a Screening Tool for Ovarian Cancer
Most ovarian cancers present in an advanced stage such that complete surgical resection is not possible. Therefore, there has been long-standing interest in developing screening techniques for ovarian cancer. Measurements of CA-125 and transvaginal ultrasound have been the techniques most commonly investigated. Validation of any oncologic screening technique requires data showing that the screening is a sensitive and relatively specific technique to identify cancers early in the course of the disease, such that prompt treatment results in an improved outcome. The largest study published to date included 22,000 postmenopausal women. After the initial baseline screening with CA-125, half the women were randomly selected to receive 3 more annual tests, while the other half received no further tests but were followed up by researchers (Jacobs, 1999). In the group assigned to receive annual screening, 468 women had elevated CA-125 levels, and 29 were ultimately referred for a surgical biopsy. Of those referred for biopsy, 6 were diagnosed with ovarian cancer, while the other 23 had false-positive results. Ten more women in the screening group developed ovarian cancer during the 8 years they were followed up by the researchers. The high false positive rate and subsequent low positive predictive value indicate that many patients will unnecessarily undergo invasive procedures (laparoscopy or laparotomy) to rule out malignancy. In addition, there is inadequate evidence that screening reduces the morbidity and mortality of ovarian cancer. At the present time, the American Cancer Society and the U.S. Preventive Services Task Force recommend against ovarian cancer screening for average risk women.
 
Patients with BRCA mutations, or patients with a strong family history of ovarian cancer, are considered at higher risk of ovarian cancer. For example, in patients with a BRCA1 mutation, the risk of ovarian cancer is estimated at 26% by age 76. For those with BRCA2 mutations, the risk is lower, estimated at 10% by age 70. Similarly, the risk associated with a family history will vary according to the number of affected relatives. Some have suggested that CA-125 screening may be appropriate in this high-risk subset of patients. For example, in 1997, the Cancer Genetic Studies Consortium developed recommendations for the follow-up care of individuals with BRCA1 and BRCA2 mutations (Burke, 1997). These recommendations included annual or semi-annual measurements of CA-125 and transvaginal ultrasound, similar to the recommendations from the American Cancer Society.
 
2011 Update
A search of the MEDLINE database was conducted through February 2011.  There was no literature identified that would prompt a change in the coverage statement.  
 
2013 Update
A literature search was conducted using the MEDLINE database through September 2013.  No new information was identified that would prompt a change in the coverage statement.
  
2014 Update
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Reade and colleagues performed a systematic review and meta-analysis to quantify risks and benefits of screening asymptomatic women for ovarian cancer (Reade, 2013), by researching MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL, without language restrictions, from January 1, 1979 to February 5, 2012. Eligible studies randomly assigned asymptomatic women to screening or usual care. Two reviewers independently screened studies for eligibility, extracted data using a standardized, piloted extraction form, and assessed bias and strength of inference for each outcome using the GRADE framework. Chance-corrected agreement was calculated at each step, and disagreements were resolved through consensus. Ten randomized trials proved eligible. Screening did not reduce all-cause mortality (relative risk (RR)=1.0, 95% confidence interval (CI) 0.96-1.06), ovarian cancer specific mortality (RR=1.08, 95% CI 0.84-1.38), or risk of diagnosis at an advanced stage (RR of diagnosis at FIGO stages III-IV=0.86, 95% CI 0.68-1.11). Transvaginal ultrasound resulted in a mean of 38 surgeries per ovarian cancer detected (95% CI 15.7-178.1) while screening with CA-125 led to 4 surgeries per ovarian cancer detected (95% CI 2.7-4.5). Surgery was associated with severe complications in 6% of women (95% CI 1%-11%). Quality of life was not affected by screening; however, women with false-positive results had increased cancer-specific distress compared to those with normal results (odds ratio (OR)=2.22, 95% CI 1.23-3.99). This study concluded that screening asymptomatic women for ovarian cancer does not reduce mortality or diagnosis at an advanced stage and is associated with unnecessary surgery.
Spinosa and Kanduc determined that Based on the low-similarity hypothesis, which supports the concept that immunogenicity is preferentially associated to sequences with no/low-similarity to the host proteome, and using Protein Information Resource peptide match program, we searched the ovarian tumor antigen CA125 for amino acid sequences unique to CA125 and absent in the remaining human proteins (Spinosa, 2014). A set of 159 pentapeptides unique to CA125 was identified that might be used to design specific and effective immunological tools for diagnosis and treatment of OC.
 
2016 Update
A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Jacobs and colleagues published a randomized controlled trial on postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy (Jacobs, 216). The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032.
 
Between June 1, 2001, and Oct 21, 2005, randomly allocated women (202,638): 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favor of MMS.
 
2017 Update
A search of the MEDLINE database through September 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
86304Immunoassay for tumor antigen, quantitative; CA 125

References: Am Cancer Society Recommendations for ovarian cancer screening. http://www3.cancer.org/cancerinfo/load_cont.asp; 2001.

Am Society of Clinical Oncology CA 125 Tumor Antigen. ASCO guidelines at www.asco.org; 2001.

American Cancer Society Recommendations for ovarian cancer screening. Available at http://www.cancer.org/Cancer/OvarianCancer/DetailedGuide/ovarian-cancer-detection. Last accessed. March 2011.

Bast RC, Ravdin P, Hayes DF, et al.(2000) 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. Clin Oncol 2000; 19(6):1865-78.

Burke W. Daly M. Garber J et al.(1997) Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. JAMA 1997; 277(12): 997-1003.

Devine PL, McGuckin MA, Ramm LE, et al.(1995) Serum mucin antigens CASA and MSA in tumors of the breast, ovary, lung, pancreas, bladder, colon, and prostate: a blind trial with 420 patients. Cancer 1995; 72:2007-2015.

Jacobs IJ, Menon U, Ryan A, et al.(2016) Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016 Mar 5;387(10022):945-56.

Jacobs IJ, Skates SJ, MacDonald N, et al.(1999) Screening of ovarian cancer: a pilot randomized controlled trial. Lancet 1999; 353:1207-10.

Micke O, Bruns F, Kurowski R, et al.(2003) Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiochemotherapy. Int J Radiation Oncology Biol Phys 2003; 57:90-97.

Rocha Lima CM, Savarese D, Bruckner H, et al.(2002) Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. Clin Oncol 2002; 20(5):1182-91.

Serum tumor markers (CA 15-3, CA 27.29 and CA 549) for the monitoring of breast cancer recurrence. 1996 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 24.

Serum tumor markers for the diagnosis and monitoring of breast cancer. 1995 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 19.

Serum tumor markers for the diagnosis and monitoring of gastrointestinal cancer. 1996 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 23.

Smith TJ, Davidson NE, Schapira DV, et al.(1999) American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J Clin Oncol 1999; 17(3):1080-2.

Spinosa JP, Kanduc D.(2014) Ovarian cancer: designing effective vaccines and specific diagnostic tools. Immunotherapy. 2014 Jan;6(1):35-41. doi: 10.2217/imt.13.144.

Ziske C, Schlie C, Gorschluter M, et al.(2003) Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine. Br J Cancer 2003; 89:1413-17.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.