Medical Policy: 02.04.45
Original Effective Date: September 2011
Reviewed: May 2015
Revised: June 2014
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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.
Ovarian cancer is the leading cause of cancer death from gynecologic malignancies in the U.S. An important diagnostic problem is the identification of malignancy when a patient presents with an adnexal mass. Some evidence supports the notion that initial management of a malignancy by a specialist in ovarian cancer treatment produces better outcomes, due to more thorough staging and tumor debulking at the initial operation. Currently, there are several assessment methods possible for differentiating between a benign and malignant adnexal mass. Proteomics-based testing have been developed to supplement current methods for evaluation.
Proteomics-based testing integrate results into a risk score to predict the presence of disease. Two tests based on this principle (OVA1TM test, ROMATM test) have been cleared by the U.S. Food and Drug Administration (FDA) for use in women with adnexal masses as an aid to further assess the likelihood that a malignancy is present. A suggested use of the test is to identify women with a positive test who have a higher likelihood of malignant disease and may benefit from a referral to a gynecologic oncologist for treatment.
OVA1™ Test (Vermillion, Inc., Fremont, CA) is a qualitative test that combines immunoassay results for five analytes believed to be biomarkers of ovarian cancer (CA 125, transthyretin, apolipoprotein A-1, beta2 microglobulin, and transferrin). A proprietary software called OvaCalc, which contains an algorithm combines the five separate results into a single numeric score between 0.0 and 10.0 to indicate the likelihood that the pelvic mass is benign or malignant. Women who are premenopausal have a cut off of 5.0, whereas postmenopausal women have a 4.4 cutoff, for a likelihood of finding malignancy. A high OVA1 test score is not a diagnosis of cancer, rather it indicates an increased risk for malignancy.
OVA1 Criteria for Testing:
- Woman is 18 years or older; and
- Have an ovarian mass; and
- Have surgery planned; and
- Have not yet been referred to an oncologist; and
- Have not had cancer in the past 5 years; and
- Have a rheumatoid factor <250IU/mL
ROMA™ Test (The Risk of Ovarian Malignancy Algorithm (ROMA)) is a qualitative serum test that combines the results of HE4 (human epididymis protein 4 enzyme immunometric assay) and CA 125 (cancer antigen) into a numerical score between 0.0 and 10.0, which is calculated using the separate algorithm both manually and by using ROMA Calculator Tool Software. Women who are premenopausal have a cut off of 1.31, whereas postmenopausal women have a cut off of 2.77, for a likelihood of finding malignancy. ROMA is intended to assist in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy upon surgery.
In 2012 Tec Assessment by BlueCross BlueShield Association was completed on “Multianalyte Testing for the Evaluation of Adnexal Masses”, The Assessment included evaluation of both the OVA1 and ROMA tests in regards to their impact on health outcomes. The following conclusions were made:
“The evidence regarding the effect of OVA1 and ROMA and effects on health outcomes is indirect and based on studies of diagnostic performance of the tests in patients undergoing surgery for adnexal masses. Although the studies show improvements in sensitivity and worsening of specificity with use of the tests in conjunction with clinical assessment, there are problems in concluding that these results improved health outcomes. The clinical assessment performed in the studies is not well characterized. Although OVA1 improves sensitivity, specificity declines so much that most patients test positive. ROMA does not improve the sensitivity of testing to a great extent. Underlying these issues is uncertainty regarding whether there would be actual health benefits based on altering patient referral based on these tests. Whether use of OVA1 or ROMA improves the net health outcome or is as beneficial as other diagnostic strategies has not been demonstrated. Referring all patients to a physician with expertise in staging and debulking ovarian cancer is a reasonable clinical alternative with no harm.”
The ideal study design to evaluate clinical utility of proteomics-based testing would be randomized controlled trial comparing patient management decisions (e.g. referral patterns) and/or health outcomes (e.g. mortality) in patients managed with tests with those managed according to best current clinical practices.
The OVA1 and ROMA tests have both been analytically validated and clinical performance has been reported in prospective multicenter clinical studies. Changes in the observed sensitivity and negative predictive value testing compared with clinical assessment has been small and of uncertain diagnostic value. Studies on the diagnostic accuracy of these tests compared with other diagnostic tools have had mixed findings, but not report that these tests are superior to other risk prediction tools that use standard clinical information or single markers. No studies have been performed that directly evaluated the impact on patient management e.g. referral patterns, and no studies have evaluated the impact on health outcomes. As a result of the evidence in the medical literature, these tests are considered investigational pending more information about their performance and impact on outcomes.
Practice Guidelines and Position Statements
May 2013 the Society of Gynecologic Oncologists (SGO) issued the following statement on multiplex serum testing for women with pelvic mass: Blood levels of five proteins in women with a known ovarian mass have been reported to change when ovarian cancer is present. Tests measuring these proteins may be useful in identifying women who should be referred to a gynecologist oncologist. Recent data have suggested that such tests, along with physician clinical assessment, may improve detection rates of malignancies among women with pelvic masses planning surgery. Results from such tests should not be interpreted independently, nor be used in place of a physician’s clinical assessment. Physicians are strongly encouraged to reference the American Congress of Obstetricians and Gynecologists 2011 Committee Opinion “The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer” to determine an appropriate care plan for their patients. It is important to note that no such test has been evaluated for use as, nor cleared by, the FDA as a screening tool for ovarian cancer.
March 2011 American College of Obstetricians and Gynecologists (ACOG) Committee Opinion “The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer”
Evaluation of Women with Signs or Symptoms: The U.S. Food and Drug Administration has recently cleared for marketing a qualitative serum test, which appears to improve the predictability of ovarian cancer in women with pelvic masses. This is not a screening test, but may be useful in evaluating women with a pelvic mass. The test evaluates five biomarkers: 1) transthyretin, 2) apolipoprotein A-1, 3) B2 microglobulin, 4) transferrin, and 5) CA 125. This test is cleared for use in women older than 18 years, with an already detected ovarian adnexal mass needing surgery. Clinical utility is not yet established.
- Epithelial ovarian cancer is most commonly detected in an 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 a surgical evaluation, a physician trained to appropriately stage and debulk ovarian cancer, such as a gynecologic oncologist, should perform the operation.
National Comprehensive Cancer Network (NCCN)
Ovarian Cancer Version 1.2015
The Society of Gynecologic Oncology (SGO), the FDA, and the Mayo Clinic have stated that OVA1 test should not be used as a screening tool to detect ovarian cancer. The OVA1 test uses 5 markers (including transthyretin, apolipoprotein A1, transferrin, beta-2 microglobulin, and CA 125) to assess who should undergo surgery by an experienced gynecologic oncologist and who can have surgery in the community. Based on data documenting increased survival, NCCN Panel Members recommend that all patients should undergo surgery by an experienced gynecologic oncologist.
It has been suggested that specific biomarkers (serum HE4 and CA-125) along with an algorithm (Risk of Ovarian Malignancy Algorithm (ROMA)) may be useful for determining whether a pelvic mass is malignant or benign. The FDA has approved the use of HE4 and CA-125 for estimating the risk for ovarian cancer in women with a pelvic mass. Currently, the NCCN Panel does not recommend the use of these biomarkers for determining the status of an undiagnosed pelvic mass.
On July 16, 2009, the OVA1™ test (Vermillion Inc. Fremont, CA) was cleared for market by the U.S. Food and Drug Administration (FDA) as a 510(k) submission. On September 1, 2011 the Risk of Ovarian Malignancy Algorithm (ROMA™ test, Fujirebio Diagnostics, Inc., Malvern, PA) was cleared by the U.S. Food and Drug Administration (FDA) as a 510(k) submission. Because the OVA1 test had been found to be a class II medical device by virtue of the July 2009 clearance, ROMA was found to be substantially equivalent to that predicate device.
Black Box Warning: On December 10, 2011, the FDA published an amendment to the regulation for classifying ovarian adnexal mass assessment score test systems to restrict these devices so that a prescribed warning statement that addresses off-label risks be highlighted by a black box warning. The warning is intended to mitigate the risk to health associated with off-label use as a screening test, stand-alone diagnostic test, or as a test to determine whether or not to proceed with surgery.
Proteomics based testing panels including OVA1™ test and ROMA™ tests are considered investigational for all indications including but not limited to:
- Screening for ovarian cancer or
- Preoperative evaluation of adnexal masses to triage for malignancy, or
- Selecting patients for surgery for an adnexal mass, or
- Evaluation of patients with clinical or radiological evidence of malignancy, or
- Evaluation of patient with nonspecific signs or symptoms suggesting possible malignancy, or
- Postoperative testing and monitoring to assess surgical outcome and/or to detect recurrent malignant disease following treatment
The OVA1 and ROMA tests have both been analytically validated and clinical performance has been reported in prospective multi-center clinical trials. Changes in the observed sensitivity and negative predictive value of testing compared to clinical assessment has been small and of uncertain diagnostic value. Studies on the diagnostic accuracy of these tests compared to other diagnostic tools have had mixed findings. No studies have been performed that directly evaluate the impact on referral patterns, and no studies have evaluated the impact on health outcomes. Clinical input from academic medical centers and specialty societies did not show consensus that this test improved outcomes when used as a tool to triage patients with adnexal masses. As a result of the evidence and clinical input, these tests are considered investigational pending more information about its performance and impact on outcomes.
All other uses of this test, including use as a screening tool for ovarian cancer, are also considered investigational.
Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
- 81500 Oncology (ovarian), biochemical assays of two proteins (CA 125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score
- 81503 Oncology (ovarian), biochemical assays of five proteins (CA 125, apolipoprotein A1, beta-2 microglobulin, transferring and pre-albumin), utilizing serum, algorithm reported as a risk score
- Bristow RE, Zahurak ML, Diaz-Montes TP et al. Impact of surgeon and hospital ovarian cancer surgical case volume on in-hospital mortality and related short-term outcomes. Gynecol Oncol 2009; 115(3):334-8.
- du Bois A, Rochon J, Pfisterer J et al. Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: a systematic review. Gynecol Oncol 2009; 112(2):422-36.
- Vernooij F, Heintz P, Witteveen E et al. The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review. Gynecol Oncol 2007; 105(3):801-12.
- Giede KC, Kieser K, Dodge J et al. Who should operate on patients with ovarian cancer? An evidence-based review. Gynecol Oncol 2005; 99(2):447-61.
- Goff BA, Matthews BJ, Larson EH et al. Predictors of comprehensive surgical treatment in patients with ovarian cancer. Cancer 2007; 109(10):2031-42.
- Van Holsbeke C, Van Belle V, Leone FP et al. Prospective external validation of the "ovarian crescent sign" as a single ultrasound parameter to distinguish between benign and malignant adnexal pathology. Ultrasound Obstet Gynecol 2010; 36(1):81-7.
- Dearking AC, Aletti GD, McGree ME et al. How relevant are ACOG and SGO guidelines for referral of adnexal mass? Obstet Gynecol 2007; 110(4):841-8.
- 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.
- U.S. Food and Drug Administration. 510(k) Substantial Equivalence Determination Decision Summary: OVA1&trade Test (K081754). Last accessed August 2011.
- Ueland F, DeSimone C, Seamon L et al. The OVA1 test improves the preoperative assessment of ovarian tumors. Gynecol Oncol 2010; 116(3 suppl 1):S23.
- Zhang Z, Chan DW. The road from discovery to clinical diagnostics: lessons learned from the first FDA-cleared in vitro diagnostic multivariate index assay of proteomic biomarkers. Cancer Epidemiol Biomarkers Prev 2010; 19(12):2995-9.
- Miller RW, Smith A, Desimone CP et al. Performance of the American College of Obstetricians and Gynecologists' Ovarian Tumor Referral Guidelines with a Multivariate Index Assay. Obstet Gynecol. 2001; 117(6).
- ECRI Institute. OVA1 Test for Detection and Monitoring of Ovarian Cancer. Plymouth Meeting (PA): ECRI Institute; 2011 May 26. 5 p. [ECRI Hotline Response].
- American College of Obstetricians and Gynecologists (ACOG) Committee Opinion: The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer, March 2011
- Society of Gynecologic Oncology: Multiplex Serum Testing for Women with Pelvic Mass, May 2013
- NCCN Guidelines Version 2.2013 Ovarian Cancer, Discussion, Screening
- Vermillion, Inc. OVA1 testing Product Information. www.vermillion.com
- National Institute for Health and Clinical Excellence (NICE) Ovarian Cancer, The Recognition and Initial Management of Ovarian Cancer, NICE clinical guideline 122, Issued April 2011
- National Comprehensive Cancer Network (NCCN), Ovarian Cancer Version 3.2014. Available at: www.nccn.org
- American Cancer Society (ACS) What are the Key Statistics About Ovarian Cancer? and What’s New in Ovarian Cancer Research and Treatment. www.cancer.org
- Clinical Laboratory News, Ovarian Cancer, March 2013 Clinical Laboratory News: Volume 39, Number 3. Available at: http://www.aacc.org/publications
- ECRI. Product Brief OVA1 and ROMA Multivariate Biomarker Blood Tests for Aiding Diagnosis of Ovarian Cancer. November 2013. Available at: http://www.ecri.org
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Multianalyte Testing for the Evaluation of Adnexal Masses. TEC Assessment Program, 2012; Volume 27, Tab 8.
- National Comprehensive Cancer Network (NCCN), Ovarian Cancer Version 1.2015. Also available at www.nccn.org
- Samuel S. Im, M.D., Alan N. Gordon, M.D. et. al. Validation of Referral Guidelines for Women With Pelvic Masses, The American College of Obstetricians and Gynecologists, Obstetrics and Gynecology Vol 150, No. 1, January 2005
- American Family Physician (AAFP), Practice Guidelines: ACOG Releases Guidelines on Management of Adnexal Masses, Am Fam Physician 2008 May 1, 77(9):1320-1323
- National Guideline Clearinghouse: Management of Adnexal Masses, The American College of Obstetricians and Gynecologists (ACOG), reaffirmed this guideline in 2011. Also available at www.guideline.gov
- Rachel Ware Miller, M.D., Alan Smith, M.D., et. al. Performance of the American College of Obstetricians and Gynecologists’ Ovarian Tumor Referral Guidelines with a Multivariate Index Assay, The American College of Obstetricians and Gynecologists, Vol. 117, No. 6, June 2011.
- Frederick R. Ueland, M.D., Christopher P. Desimone, M.D., et. al. Effectiveness of a Multivariate Index Assay in the Preoperative Assessment of Ovarian Tumors, The American College of Obstetricians and Gynecologists Vol 117, No. 6, June 2011
- PubMed. Management of Complex Pelvic Masses Using a Multivariate Index Assay: A Decision Analysis, Gynecol Oncol, 2012 Sep;126(3):364-8
- PubMed. Using a Multivariate Index Assay to Assess Malignancy in a Pelvic Mass. Obstet Gynecol 2012 Feb; 119(2 Pt 1):365-7
- Andrew John Li, M.D., New Biomarkers for Ovarian Cancer: OVA1 and ROMA in Diagnosis, Contemporary OB/GYN, April 1, 2012. Also available at http://contemporaryobgyn.modernmedicine.com
- American Association for Clinical Chemistry (AACC), Ovarian Cancer A Review of Current Serum Markers and Their Clinical Applications, March 2013
- UpToDate. Serum Biomarkers for Evaluation of an Adnexal Mass for Epithelial Carcinoma of the Ovary, Fallopian Tube or Peritoneum, Frederick Rand Ueland,M.D., Andrew John Li, M.D.. Topic last updated April 20, 2015
Date Reason Action
September 2011 Evidence review New policy
April 2013 Interim Review Policy retired
August 2013 Annual Review Policy Revised
June 2014 Annual Review Policy Revised
May 2015 Annual review Policy renewed
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