Medical Policy: 02.04.45
Original Effective Date: September 2011
Reviewed: April 2016
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 geno typical 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 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.
ROMA™ Test 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. No randomized or nonrandomized studies with these comparisons were identifiied
The evidence for use of proteomics-based testing (OVA1 test and ROMA test) in conjunction with clinical assessment in patients who have adnexal masses undergoing surgery includes studies assessing the technical performance and diagnostic accuracy of the tests. Relevant outcomes are overall survival and test accuracy. OVA1 is intended to be used in patients for whom clinical assessment does not indicate cancer. ROMA is intended to be used in conjunction with clinical assessment, but no specific method has been defined. Studies on the diagnostic accuracy of these tests compared with other diagnostic tools have had mixed findings, but do 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.
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.
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.
When physical examination and imaging techniques have detected the presence of a pelvic mass that is suspicious for a malignant ovarian neoplasm, the presence of at least one of the following indicators warrants consideration of referral to or consultation with a physician trained to appropriately stage and debulk ovarian cancer, such as a gynecologic oncologist:
When a patient with a suspicious or persistent complex adenexal mass requires surgical evaluation, a physician trained to appropriately stage and debulk ovarian cancer, such as a gynecologic oncologist, should perform the operation. This should be done in a hospital facility that has the necessary support and consultative services (e.g. frozen section pathology) to optimize the patient’s outcome. When a malignant ovarian tumor is discovered and the appropriate operation cannot be properly performed, a gynecologic oncologist should be consulted intraoperatively if possible.
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 (category 1).
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:
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.
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