Medical Policy: 02.04.45 

Original Effective Date: September 2011 

Reviewed: April 2018 

Revised: April 2018 

 

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:

A variety of serum biomarkers have been studied for their association with ovarian cancer. Of particular interest have been tests that integrate results from multiple analytes into a risk score to predict the presence of disease. Three tests based on this principle (OVA1, Overa (the second generation OVA1 test), and ROMA) (Risk of Ovarian Malignancy Algorithm) have been cleared by the U.S. Food and Drug Administration (FDA).  The intended use of OVA1 and Overa is to use them as an aid to further assess whether malignancy is present, even when the physician’s independent clinical and radiologic evaluation does not indicate malignancy. The intended use of ROMA is to use it as an aid, in conjunction with clinical assessment, to assess whether a premenopausal or a postmenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery. Currently, there are several assessment methods possible for differentiating between a benign and malignant adnexal mass. Multiple analyte testing to predict the presence of disease have been developed to supplement current methods for evaluation.

 

Ovarian neoplasms consist of several histopathologic entities and treatment depends on the specific tumor type. Epithelial ovarian cancer comprises the majority of malignant ovarian neoplasms (about 90%). Fallopian tube cancer and primary peritoneal cancer, are less common neoplasms that are managed in a similar manner to epithelial ovarian cancer. There is currently no serum biomarkers that can distinguish between these types of carcinoma. Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country’s fifth most common cause of cancer mortality in women. In 2018, it is estimated that 22,240 new diagnoses and 14,070 deaths from this neoplasm will occur in the United States; less than 40% of women with ovarian cancer are cured. The mortality rate depends on 3 variables:

  1. patient characteristics;
  2. tumor biology (grade, stage, type); and
  3. treatment quality (nature of staging, surgery and chemotherapy used).

In particular, comprehensive staging and completeness of tumor resection appear to have a positive impact on patient outcome.

 

In 2011, the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncologists jointly released referral guidelines that addressed criteria for referring women with pelvic masses suspicious for ovarian cancer to gynecologic oncologists:

  • Premenopausal women – refer if any are present
    • Very elevated CA 125 level
    • Ascites
    • Evidence of abdominal or distant metastases
  • Postmenopausal women – refer if any are present
    • Elevated CA 125 level
    • Ascites
    • Nodular or fixed pelvic mass
    • Evidence of abdominal or distant metastases

Three multimarker serum based tests specific to ovarian cancer have been cleared by the Food and Drug Administration (FDA) with the intended use of triaging patients with adnexal masses, they are summarized below. The proposed use of the tests is to identify women with a substantial likelihood of malignant disease who may benefit from referral to a gynecologic oncology specialist. Patients with positive results may be considered candidates for referral to a gynecologic oncologist for treatment.  The tests have been developed and evaluated only in patients with adnexal masses and planned surgeries. Other potential uses, such as selecting patients to have surgery, screening asymptomatic patients, and monitoring treatment, have not been investigated. Furthermore, the tests are not intended to be used as stand-alone tests, but in conjunction with clinical assessment.

 

Summary of FDA-Approved Multimarker Serum Based Tests Specific to Ovarian Cancer

 

Variables OVA1 Overa Roma
Approved

2009

2016

2011

Manufacturer

Vermillion

Vermillion

Roche Diagnostics

Biomarkers Used
CA-125 II

True

True

True

B2-microglobulin

X

False

False

Transferrin

True

True

False

Transthyretin

True

False

False

Apolipoprotein AI

True

True

False

HE4

 

True

True

FSH

 

True

 

Score Range

0-10

0-10

0-10

Risk Categorization
Premenopausal

<5.0: low

≥5:0: high

<5.0: low

≥5:0: high

≥ 1.3: high

Postmenopausal

<4.4: low

≥4.4: high

False

≥ 2.77: high

 

Multimarker Serum Testing Related to Ovarian Cancer – Clinical Context and Test Purpose 

The purpose of multimarker serum is the testing of individuals over age 18 with an ovarian adnexal mass for which surgery is planned and not yet referred to an oncologist is to use the test as an aid to further assess the probability that malignancy is present, even when the physician’s independent clinical and radiologic evaluation does not indicate malignancy.

 

The potential beneficial outcomes of primary interest in the case of a true negative would be the avoidance of unnecessary surgery and its associated consequences (e.g., morbidity, mortality, resource utilization, patient anxiety). The potential harms from a false-positive could be inappropriate assessment and improper management of patients with ovarian malignancies, which could result in the following: inappropriate surgical decisions, high frequency of unnecessary further testing, and unnecessary patient anxiety. The potential harms from a false-negative could be a determination that the patient does not have ovarian malignancy, which would lead to a delay in surgery and tumor diagnosis.

 

Off-label use of the test (e.g., in patients who have not already been identified as needing surgery for pelvic mass, or patients without reference to an independent clinical and radiologic evaluation), might lead to a high frequency of unnecessary testing and surgery due to false-positive results, or to a delay in tumor diagnosis due to false-negative results.

 

Multimarker serum testing for related to ovarian cancer may be performed at any point when an individual presents with an ovarian adnexal mass for which surgery is planned, but physician’s independent clinical and radiologic evaluation does not indicate malignancy and referral to an oncologist is being considered.

 

Technically Reliable 

OVA1 Test 

OVA1 Test is a qualitative serum test that combines immunoassay results for five analytes (CA 125 [cancer antigen 125], transthyretin [prealbumin], apolipoprotein AI [apo AI], B2 microglobulin, and transferrin) into a single numeric score. 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.

 

Analytic performance of the test demonstrated good test precision (coefficient of variation [CV] range, 1%-7.4%, depending on the sample levels studied) and good reproducibility (CV range, 2.8%-8.9%). The test appears linear, reagent and samples stable, and there was no observed interference evaluating common endogenous substances (eg, hemoglobin, bilirubin).

  

Overa Test 

Overa is a second generation multivariate index assay (MIA2G) serum test for women with a pelvic mass who are planned for surgery. Overa is a qualitative serum test that combines immunoassay results for 5 analytes (CA 125 [cancer antigen 125], apolipoprotein AI [apo AI], transferrin, follicular stimulating hormone [FSH], human epididymis protein 4 [HE4]) into a single numeric score.  A high Overa test score is not a diagnosis of cancer, rather it indicates an increased risk for malignancy.

 

Analytic performance for the test demonstrated good test precision (CV range, 1.54%) and good reproducibility (overall percent CV, 1.63%). The test appears linear, reagent and samples stable, and there was no observed interference evaluating common endogenous substances (eg, hemoglobin, bilirubin). 

 

ROMA Test (Risk of Ovarian Malignancy Algorithm) 

ROMA test is a qualitative serum test that combines 2 analytes (HE4 [human epididymis protein 4] and CA 125 [cancer antigen 125]) along with menopausal status into a numeric 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.

 

Analytic performance for ROMA also exhibited good precision, with a total CV ranging from 0.49% to 7.72%, depending on both sample values and menopausal status. The reproducibility of the test was acceptable, with a CV that ranged from 0.98% to 25.9%, with highest values observed in patients with low scores, as expected. The reagents are variably stable, and users are instructed to follow package inserts for stability on each analyte used. The test was unaffected by interference with hemoglobin, bilirubin, lipids, or human antimouse antibodies. However, high levels of rheumatoid factor (>500 IU/mL) did appear to cause elevations in test values, and testing in patients with elevated rheumatoid factor is not recommended.

 

Summary Technically Reliable

These three serum multimarker tests have been cleared by the U.S. Food and Drug Administration (FDA). Evidence for analytic validity of these tests is provided in the FDA database. This data indicates that the analytic validity of the individual analytes that comprise these multimarker tests using commercial approved methods meets the acceptable criteria for high analytic validity.

 

Clinical Validity 

Ova1 Test 

Descriptions of the developmental process for the OVA1 test have been published in the FDA documents and in a perspective by Fung (2010). Candidate biomarkers were selected based on initial studies using mass spectroscopy but were converted to standard immunoassays to improve analytic performance. Seven final markers were evaluated, none of which individually appears to be highly specific for malignant ovarian disease. However, the choice of five of these (CA-125, transthyretin [prealbumin], apolipoprotein AI [apo AI], B2- microglobulin, and transferrin) produced a composite profile that did not appear to have discriminatory ability. The test, as cleared by the FDA, is performed on a blood sample, which is sent to a reference laboratory for testing using the 5 immunoassays previously described. Results of the 5 determinations are entered manually into an Excel spreadsheet used by the OvaCalc software. This software contains an algorithm that combines the 5 discrete values into a single unit-less numeric score from 0.0 to 10.0.

 

Details of the algorithm appear proprietary, but the development is described as an empirical process; it is a process based on several different factors; the use of banked samples from academic partners; a small prospective study of samples from Europe; and a designated subset of samples from the clinical study used to support the submission to the FDA. It appears that, at an undisclosed point in the developmental process as a result of interaction with the FDA, separate cut-points were developed for premenopausal and postmenopausal women.

 

The clinical validity was evaluated in a prospective, double-blind, clinical study using 27 enrollment sties. The study was supported by the commercial sponsor of the test. Patients underwent a complete clinical evaluation before surgical intervention, and only patients with adnexal masses who had a planned surgical intervention, and only patients with adnexal masses who had a planned surgical intervention were included. The study enrolled 743 patients, with 146 subjects used in the training set and 516 in the testing set. Seventy-four patients were excluded because of missing information or samples. The final prevalence of cancer in the population was 27%.

 

Using pathologic diagnosis is the criterion standard, OVA1 test performance, when combined with a clinical assessment by non-gynecological oncologists, was as follows (see table below). The method used for combing clinical assessment and OVA1 result was to consider the test positive if either clinical assessment or OVA1 test was positive. Thus, in practice, OVA1 testing would not be necessary if clinical assessment alone indicated cancer. Using OVA1 testing in this manner guarantees that OVA1 testing will be more sensitive and less specific than clinical assessment alone, even if it has no better than chance capability of detecting ovarian cancer. Sensitivity improved from 72% to 92%, and specificity decreased from 83% to 42%.

 


Clinical Validity of the OVA1 Test Among 269 Patients Evaluated by Non-gynecologic Oncologists

 

Diagnostic Characteristics Clinical Assessment Alone, % Clinical Assessment with OVA1 Test, %

Sensitivity

72

92

Specificity

83

42

Positive Predictive Value

61

37

Negative Predictive Value

89

93

Note: Confidence intervals not provided

 

One additional 2015 study (Grenache et. al.) was identified; it evaluated the diagnostic performance of the OVA1 test. However, it did not evaluate diagnostic performance in conjunction with clinical assessment, as the test was intended to be used. By itself, OVA1 was 97% sensitive and 55% specific. This means that with clinical assessment (as intended to be used), the test would be no worse than 97% sensitive and no better than 55% specific, but these characteristics cannot be determined from the study.

 

Overa Test 

Descriptions of the developmental process for the Overa test have been published in FDA documents. The FDA documents do not provide details on how biomarkers were selected. The test, as cleared by the FDA, is performed on a blood sample, which is to be sent to a reference laboratory for testing using the 5 immunoassays previously described. Results of the 5 determinations are entered into a proprietary algorithm, called OvaCalc software (v4.0), which combines the 5 discrete values into a single unit-less numeric score from 0.0 to 10.0.    

 

Clinical validity was evaluated in a non-concurrent prospective study of 493 preoperatively collected serum specimens from premenopausal and postmenopausal women presenting with an adnexal mass requiring surgical intervention. Overa test scores were determined based on the analysis of archived serum specimens from a previous study, and the patient was stratified into a low or high risk group for finding malignancy on surgery. The analysis examined whether patient referral to a gynecologic oncologist was supported when dual assessment was determined to be positive (either Overa or clinical assessment was positive, or both were positive) A dual assessment was considered negative when both Overa and clinical assessment were negative.

 

Using pathologic diagnosis as the criterion standard, Overa test performance, when combined with clinical assessment by non-gynecologic oncologists, was as follows (see below table). The method used for combining clinical assessment and Overa test result was to consider the test positive if either clinical assessment or Overa test was positive. Thus, in practice, Overa testing would not be necessary if clinical assessment alone indicated cancer. Using Overa testing in this manner guarantees that Overa testing will be more sensitive and less specific than clinical assessment alone, even if it has no better than chance capability of detecting ovarian cancer. Sensitivity improved from 74% to 94% and specificity decreased from 93% to 65%.

 

Clinical Validity of the Overa Test Among 493 Patients Evaluated by Non-gynecologic Oncologists

 

Diagnostic Characteristics Clinical Assessment Alone, % Dual Assessment with Overa Test, %

Sensitivity (95% Confidence interval)

74 (64 to 82)

94 (87 to 97)

Specificity (95% sCIConfidence interval)

93 (90 to 95)

65 (60 to 70)

Positive predictive value (95% Confidence interval)

70 (62 to 77)

38 (35 to 41)

Negative predictive value

94 (92 to 96)

98 (95 to 99)

Note: CI: confidence interval

 

ROMA Test

The FDA labelling for ROMA, unlike that for OVA1, does not indicate how ROMA is to be used in conjunction with clinical assessment. All previously cited literature assessed ROMA as a stand-alone test for ovarian cancer and did not provide a comparison with clinical assessment alone. The study by Moore et. al. (2014) evaluated ROMA in conjunction with clinical assessment, using either a positive clinical assessment or a positive ROMA as a positive test (similar to the recommended usage for OVA1). Using this method of combining tests guarantees a higher sensitivity and lower specificity for the combined test than for either test alone. Used in this way, ROMA would only need to be given to patients with a negative clinical assessment. In this study, 461 women were enrolled, of whom 86 (19%) had a malignancy. Combined assessment improved sensitivity from 77.9% to 89.7%, but specificity worsened from 84.3% to 67.2%.

 

Moore et. al. (2008) described the development of the ROMA test. The authors studied 9 biomarkers and chose HE4 and CA 125 because these markers in tandem produced the best performance. The algorithm developed was subsequently modified to include menopausal status and was independently validated. Again, separate cutoffs were used for premenopausal and postmenopausal women.

 

In 2014, Wang et. al. published a meta-analysis of studies evaluating the clinical validity of the ROMA test algorithm and comparing it with the performance of single biomarkers HE4 and CA 125. To be included in the meta-analysis, studies had to investigate both HE4 and CA 125 or calculate ROMA, enroll women with ovarian cancer and benign gynecologic disease, use pathology diagnosis as the reference standard, and collect blood samples before treatment was initiated. Thirty-two studies met these inclusion criteria; six were conducted in the United States. Findings of the overall pooled analysis of diagnostic accuracy are in the below table.

 

Meta-Analytic Findings for Diagnostic Performance of the ROMA Test vs HE4 and CA-125

 

Test Number of Studies Sensitivity (95% Confidence interval), % Specificity (95% Confidence interval), %

ROMA Test

14

85.3 (81.2 to 88.6)

82.4 (77.4 to 86.5)

Human epididymis secretory protein 4

28

76.3 (72.0 to 80.1)

93.6 (90.0 to 95.9)

Cancer antigen 125

28

79.2 (74.0 to 83.6)

82.1 (76.6 to 86.5)

Note: CI: confidence interval

 

 

Findings were similar when diagnostic performance in premenopausal women and postmenopausal women were evaluated separately. ROMA had similar or higher sensitivity than HE4 and CA125, and HE4 had the highest specificity.

 

In 2016, Dayyani et. al. conducted a meta-analysis comparing ROMA with HE4 and CA 125 in patients with suspected ovarian cancer. Six studies met the inclusion criteria, four of which were included in the 2014 Wang meta-analysis. Two studies were published in 2014 or later. Based on area under the curve analysis, ROMA had higher values than either HE4 (0.921; 95% CI, 0.855 to 0.960) or CA 125 alone (0.899; 95% CI, 0.835 to 0.943) and HE4 plus CA 125 (0.883; 95% CI, 0.771 to 0.950).

 

The point estimates for sensitivity and specificity were lower in pre- and postmenopausal women, with wider confidence intervals.

Since the Wang and Dayyani meta-analyses, multiple studies have described the use of the ROMA test in populations of women in whom decisions to pursue surgery had been made, including Al Musalhi et al (2016; n=213 cases), Cho et al (2015; n=90 cases), and Terlikowska et al (2016; n=224 cases).

 

Summary: Clinical Validity

Evidence for the clinical validity for the OVA1 and Overa tests include prospective, double-blind studies that have evaluated the clinical validity of these tests in predicting the likelihood of malignancy in women who are planning to have surgery for an adnexal mass. They have not been studied for ovarian cancer screening. The prospective studies showed that, in patients with adnexal mass who had a planned surgical intervention, use of OVA1 and Overa in conjunction with a clinical assessment by non-gynecologic oncologists increased the sensitivity but decreased the specificity compared with clinical assessment alone. When used with clinical assessment in this manner, the sensitivity to ovarian malignancy was 92%, and the specificity was 42%. ROMA is intended for use in conjunction with clinical assessment, but no specific method has been defined. One study, which used clinical assessment and ROMA results, showed a sensitivity of 90% and a specificity of 67%. Two meta-analysis reported less than 90% sensitivity and specificity with ROMA testing.

 

Clinical Utility 

 

The ideal study design to evaluate clinical utility of multimarker serum based testing would be a randomized controlled trial comparing health outcomes (e.g. mortality) in patients managed using the tests with those managed according to best current clinical practices.  According to the chain of logic, greater numbers of persons referred for initial surgical treatment with ovarian cancer should result in improved overall health outcomes.  No randomized or nonrandomized studies with these comparisons were identifiied.

 

Although OVA1, Overa and ROMA, when used in conjunction with clinical assessment, improve the sensitivity for detection of malignancy, the specificity also declines. In studies using either positive ROMA or clinical assessment as a positive tests, sensitivity improved, but it was still less than 90%. It is uncertain whether there is meaningful clinical benefit from using a test that avoids a high number of referrals and does not contain sensitive data (even though incrementally better). Because there is no established or recommended method for using ROMA in conjunction with clinical assessment, diagnostic performance characteristics are uncertain since it would vary depending on how it is used.

 

It is also uncertain whether the incremental yield of malignancy resulting from use of the tests would actually result in improved patient outcomes. Although prior studies revealed an improvment of outcomes when women with ovarian cancer are initially managed by gynecologic oncologists, it is uncertain whether improved outcomes would occur in the additional cases detected by use of these tests. These additional cancer cases may differ from other cases detected by clinical assessment alone. If they tend to be earlier stage cancers or biologically less aggressive cancers, initial treatment by a gynecologic oncologist may not provide incremental benefit.

 

TEC Assessment by BlueCross BlueShield Association

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.”  

 

Summary: Clinical utility

There is no direct evidence in terms of assessing patient outcomes based on the use of such testing prior to undergoing surgery. It is uncertain whether discrimination is sufficient to alter decision-making based on clinical assessment alone, thus offering a meaningful benefit to patients. Therefore, the chain of evidence supporting improved outcomes is incomplete.

 

Summary of Evidence

For individuals who have adnexal masses undergoing surgery for possible ovarian cancer who receive multimarker serum testing with clinical assessment preoperatively to assess ovarian cancer risk, the evidence includes studies assessing the technical performance and diagnostic accuracy. OVA1 and Overa are intended for use in patients for whom clinical assessment does not indicate cancer. When used in this manner, sensitivity for ovarian malignancy was 92% and specificity was 42% with OVA1; with Overa, sensitivity was 94% and specificity was 65%. ROMA is intended for use with clinical assessment, but no specific method has been defined. One study, which used clinical assessment and ROMA results, showed a sensitivity of 90% and specificity of 67%. However, there is no direct evidence in terms of assessing patient outcomes based on the use of such testing prior to undergoing surgery. Moreover, it is uncertain whether discrimination is sufficient to alter decision making based on clinical assessment alone and, therefore, it is uncertain whether patients will find the testing to be of meaningful benefit. Thus, the chain of evidence supporting improved outcomes is incomplete. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Practice Guidelines and Position Statements

Society of Gynecologic Oncologists (SGO)

In 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."

 

American College of Obstetricians and Gynecologists (ACOG) and Society of Gynecology Oncology

In March 2011, the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecology Oncology issued a joint committee opinion No. 477, on the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer in women at average risk, which included the following:

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.

 

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:

  • Postmenopausal women: elevated CA 125 level, ascites, a nodular or fixed pelvic mass, or evidence of abdominal or distant metastasis
  • Premenopausal women: very elevated CA 125 level, ascites, or evidence or distant metastasis

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.  

Conclusions
  • 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.

In 2017, the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecology Oncology issued a joint committee opinion No. 716 (replaces number 477 March 2011) on the role of obstetrician – gynecologists in the early detection of epithelial ovarian cancer in women at average risk which included the following:

 

The U.S. Food and Drug Administration has approved laboratory panels of multiple tumor markers (including CA 125) to categorize women found to have adnexal masses on imaging as low risk or high risk of ovarian malignancy. However, these panels have not been rigorously evaluated among asymptomatic women without adnexal masses and have not been shown to improve early detection and survival rates for ovarian cancer in average risk women. Use of these markers for the management of adnexal masses is discussed in other publications.

 

Direct-to-consumer marketing of ovarian cancer screening tests: Ovarian cancer screening tests and early detection tests, such as those using the Risk of Ovarian Cancer Algorithm and laboratory panels of multiple tumor markers are being marketed directly to women. At this time, there is insufficient evidence to support the use of any of these tests or algorithms for the early detection of ovarian cancer in average-risk women. Women considering purchasing these test which are approved nor cleared by the U.S. Food and Drug Administration for ovarian cancer screening are not financially covered by medical insurance, should be counseled on the risk of such tests.

 

The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecology Oncology offer the following recommendations and conclusions:

  • Currently there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality.
  • The use of transvaginal ultrasonography and tumor markers (such as CA-125), alone or in combination, for the early detection of ovarian cancer in average-risk women have not been proved to reduce mortality, and harms exist from invasive diagnostic testing (e.g. surgery) resulting from false-positive test results.
  • Epithelial ovarian cancer is most commonly detected in an advanced stage (65% of cases are stage III or stage IV) when the cure rate is only 18%.
  • Early stage (localized) ovarian cancer is associated with improved survival.
  • Taking a detailed personal and family history for breast, gynecologic, and colon cancer facilitates categorizing women based on their risk (average risk or high risk) of developing epithelial ovarian cancer.
  • The patient and her obstetriction-gynecologist should maintain an appropriate level of suspicion on potentially relevant signs and symptoms of ovarian cancer are present.

National Comprehensive Cancer Network (NCCN)

Ovarian Cancer - Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 2.2018

Screening
The Society of Gynecologic Oncology (SGO) the FDA and the Mayo clinical have stated that the 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 asses who should undergo surgery by an experienced gynecologic oncologist and who can have surgery in the community. The Simple Rules algorithm attempts to preoperatively classify adnexal masses as benign or malignant and suggests that patients can be assessed for who should undergo surgery by an experienced gynecologic oncologist and who can have surgery in the community. Based on data documenting an increased survival, NCCN Guidelines Panel Members recommend that all patients should undergo surgery by an experienced gynecologic oncologist (category 1).

 

Undiagnosed Pelvic Mass

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 pelvic mass.  Currently, the NCCN Panel does not recommend the use of these biomarkers for determining the status of an undiagnosed pelvic mass.

 

National Institute for Health and Clinical Excellence (NICE)
In 2017, the National Institute for Health and Clinical Excellence (NICE) issued a guideline regarding tests in secondary care to identify people at high risk of ovarian cancer which included the following recommendations:

  • There is currently not enough evidence to recommend the routine adoption of the IOTA ADNEX model, Overa (MIA2G), RMI I (at thresholds other than 200 or 250), ROMA or IOTA Simple Rules in secondary care in the NHS to help decide whether to refer people with suspected ovarian cancer to a specialist multidisciplinary team (MDT).  
  • The NICE guideline on ovarian cancer recommends that people with an RMI I of 250 or more are referred to a specialist MDT. Evidence suggests that there is no substantial change in accuracy if the threshold for RMI I is lowered to 200.
  • The IOTA ADNEX model, Overa (MIA2G), RMI I (at thresholds other than 250), ROMA and IOTA Simple Rules show promise. Further research is recommended on test accuracy and the impact of the test results on clinical decision making.  

Regulatory Status

In July 2009, the OVA1 test (Vermillion Inc. Fremont, CA) was cleared for marketing by the U.S. Food and Drug Administration (FDA) as a 510(k) submission.   OVA1 was designed as a tool to further assess the likelihood that malignancy is present when the physician’s independent clinical and radiologic evaluation does not indicate malignancy. 

 

In September 2011, the Risk of Ovarian Malignancy Algorithm (ROMA test, Fujirebio Diagnostics, Inc., Sequin, TX) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. The intended use of ROMA is an aid, in conjunction with clinical assessment, in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at high or low liekelihood of finding malignancy on surgery. 

 

In March 2016, a second-generation test called Overa (also referred as next-generation OVA1), in which 2 of the 5 biomarkers in OVA1 are placed with human epididymis secretory protein 4 and follicle stimulating hormone, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. Similar to OVA1, Overa, generates a low or high risk of malignancy on a scale from 0 to 10.   

 

Black Box Warning: In December 2011, the FDA amended its regulation for classifying ovarian adnexal mass assessment score test systems.  The change required that off-label  risks be highlighted using 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 to proceed with surgery. Considering the history and currently unmet medical needs for ovarian cancer testing, the FDA concluded that there is a risk of off-label use of this device. To address this risk, the FDA requires that manufacturers provide notice concerning the risks of off-label uses in the labeling, advertising, and promotional material of ovarian adnexal mass assessment score test systems. Manufacturers must address the following risks:

  • Women without adnexal pelvic masses (ie, for cancer “screening”) are not part of the intended use population for the ovarian adnexal mass assessment score test systems. Public health risks associated with false-positive results for ovarian cancer screening tests are well described in the medical literature and include morbidity or mortality associated with unneeded testing and surgery. The risk from false-negative screening results also includes morbidity and mortality due to failure to detect and treat ovarian malignancy.
  • Analogous risks, adjusted for prevalence and types of disease, arise if test results are used to determine the need for surgery in patients who are known to have ovarian adnexal masses. 
  • If used outside the “OR” rule that is described in this special control guidance, results from ovarian adnexal mass assessment score test systems pose a risk for morbidity and mortality due to nonreferral for oncologic evaluation and treatment.

 

Prior Approval:

 

Not applicable.

 

Policy:

Multiserum marker testing panels including OVA1, Overa, and ROMA 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

Based on review of the peer reviewed medical literature, for individuals who have adnexal masses undergoing surgery for possible ovarian cancer who receive multimarker serum testing with clinical assessment preoperatively to assess ovarian cancer risk, the evidence includes studies assessing the technical performance and diagnostic accuracy. However, there is no direct evidence in terms of assessing patient outcomes based on the use of such testing prior to undergoing surgery. It is uncertain whether discrimination is sufficient to alter decision making based on clinical assessment alone and, therefore, it is uncertain whether patients will find the testing to be of meaningful benefit. The chain of evidence supporting improved outcomes is incomplete. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 81500 Oncology (ovarian), biochemical assays of two proteins (CA 125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score. (ROMA Test)
  • 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. (OVA1 Test)
  • 0003U Oncology (ovarian) biochemical assays of five proteins (apolipoprotein A-1, CA 125 II, follicle stimulating hormone, human epididymis protein 4, transferrin), utilizing serum, algorithm reported as a likelihood score. (Overa Test)

 

Selected References:

  • 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).
  • U.S. Food and Drug Administration (FDA) 510(k) Substantial Equivalence Determination Decision Summary: Ova1™ Next Generation Test (K150588).
  • U.S. Food and Drug Administration 510(k) Substantial Equivalence Determination Decisin Summary ROMA™ test K103358.
  • 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. 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
  • Vermillion, Inc. OVA1 testing Product Information.
  • 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   
  • American Cancer Society ACS) What are the Key Statistics About Ovarian Cancer?  and What’s New in Ovarian Cancer Research and Treatment.
  • Clinical Laboratory News Ovarian Cancer, March 2013 Clinical Laboratory News: Volume 39, Number 3.
  • ECRI. Product Brief OVA1 and ROMA Multivariate Biomarker Blood Tests for Aiding Diagnosis of Ovarian Cancer. November 2013.
  • 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. 
  • 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.
  • 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.
  • American Association for Clinical Chemistry (AACC), Ovarian Cancer A Review of Current Serum Markers and Their Clinical Applications, March 2013
  • Surveillance Epidemology and End Results (SEER) Program. SEER Stat Fact Sheets: Ovary Cancer.   
  • Fung ET. A recipe for proteomics diagnostic test development: the OVA1 test, from biomarker discovery to FDA clearance. Clin Chem. Feb 2010;56(2):327-329.
  • Moore RG, Brown AK, Miller MC, et al. The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol. Feb 2008;108(2):402-408. PMID 18061248
  • 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. Aug 2011;118(2 Pt 1):280-288. PMID 21775843
  • Grenache DG, Heichman KA, Werner TL, et al. Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass. Clin Chim Acta. Jan 1 2015;438:358-363. PMID 25283731
  • Wang J, Gao J, Yao H, et al. Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumour Biol. Jun 2014;35(6):6127-6138. PMID 24627132
  • Karlsen MA, Sandhu N, Hogdall C, et al. Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass. Gynecol Oncol. Nov 2012;127(2):379-383. PMID 22835718
  • Kaijser J, Van Gorp T, Van Hoorde K, et al. A comparison between an ultrasound based prediction model (LR2) and the risk of ovarian malignancy algorithm (ROMA) to assess the risk of malignancy in women with an adnexal mass. Gynecol Oncol. May 2013;129(2):377-383. PMID 23360924
  • Moore RG, Hawkins DM, Miller MC, et al. Combining clinical assessment and the Risk of Ovarian Malignancy Algorithm for the prediction of ovarian cancer. Gynecol Oncol. Dec 2014;135(3):547-551. PMID 25449569
  • National Center for Clinical Excellence (NICE) The recognition and initial management of ovarian cancer. Clinical Guideline CG 122. Published April 2011
  • National Comprehensive Cancer Network (NCCN) Version 2.2018 Ovarian Cancer.
  • U.S. Preventative Services Task Force (USPSTF) Screening for Ovarian Cancer.
  • UpToDate. Management of Adnexal Masses. Michael G Muto M.D., Topic last updated April 25, 2016.
  • 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 24, 2017.
  • Simmons AR, Clarke CH, Badgwell DB, et. al. Validation of a biomarker panel and longitudinal biomarker performance for early detection of ovarian cancer. Int J Gynecol Cancer. July 2016;26(6):1070-1077. PMID 27206285
  • Dayyani F, Uhlig S, Colson B, et. al. Diagnostic performance of risk of ovarian malignancy algorithm against CA125 and HE4 in connection with ovarian cancer: a meta analysis. Int J Gynecol Cancer. Nov 2016;26(9):1586-1593. PMID 27540691
  • Al Musalhi K, Al Kindi M, Al Aisary F, et. al. Evaluation of HE4, CA-125, Risk of Ovarian Malignancy Algorithm (ROMA) and Risk of Malignancy Index (RMI) in the preoperative assessment of patients with adnexal mass. Oman Med J. Sep 2016;31(5):336-344. PID 27602187
  • Terlikowska KM, Dobrzycka B, Witkowska AM, et. al. Preoperative HE4, CA125 and ROMA in the differential diagnosis of benign and malignant adnexal masses. J Ovarian Res. Jul 19 2016;9(1):43. PMID 27436085
  • Im SS, Gordon AN, Buttin BM, et. al. Validation of referral guidelines for women with pelvic masses. Obstet Gynecol 2005 Jan;105(1):35-41. PMID 15625139
  • Yanaranop M, Tiyayon J, Siricharoenthai S, et. al. Rajavithi-ovarian cancer predictive score (R-OPS): a new scoring system for predicting ovarian malignancy in women presenting with a pelvic mass. Gynecol Oncol Jun 2016;141(3):479-484. PMID 26996662    
  • Bristow RE, Smith A, Zhang Z, et. al. Ovarian malignancy risk stratification of the adnexal mass using multivariate index assay. Gynecol Oncol. Feb 2013;128(2):252-259. PMID 23178277
  • Cho HY, Park SH, Park YH, et. al. Comparison of HE4, CA125, and risk of ovarian malignancy algorithm in the prediction of ovarian cancer in Korean women. J Korean Med Sci. Dec 2015;30(12):1777-1783. PMID 26713052
  • The American College of Obstetricians and Gynecologists and the Society of Gynecology Oncology Committee Opinion Number 716 September 2017, The role of the obstetrician-Gynecologist in the early detection of epithelial ovarian cancer in women at average risk. (Replaces Committee Opinion Number 477, March 2011).
  • The American College of Obstetricians and Gynecologists Committee Opinion No. 174 Evaluation and Management of Adnexal Masses. Obstet Gynecol. Nov 2016;128(5):e210-e226. PMID 27776072
  • National Institute for Health and Clinical Excellence (NICE) Tests in Secondary Care to Identify People at High Risk of Ovarian Cancer. Diagnostic Guidance DG31 Published November 2017.
  • Moore RG, Jabre-Raughley M, Brown AK, et. al. Comparison of novel multiple marker assay vs the risk of malignancy index for the prediction of epithelial ovarian cancer in patients with a pelvic mass. Am J Obstet Gynecol 2010 Sep;203(3):228. PMID 20471625
  • Vermillion Announces Reimbursement Code Updates for Overa and OVA1, January 9, 2017.
  • Overa.
  • Forde GK, Homberger J, Michalopoulos S, et. al. Cost effectiveness of a multivariate index assay compared to modified ACOG criteria and CA-125 in the triage of women with adnexal masses. Presented at the Annual Meeting of the American College of Medical Quality, March 26, 2015.
  • Goodrich ST, Bristow RE, Santoso JT, et. al. The effect of ovarian imaging on the clinical interpretation of a multivariate index assay. Am J Obstet Gynecol 2014 Jul;211(1):65
  • Ware Miller R, Smith A, DeSimone CP, et. al. Performance of the American College of Obstetricians and Gynecologists ovarian tumor referral guideline with a multivariate index assay. Obstet Gynecol 2011 Jun;117(6):1298-306
  • Longoria TC, Ueland FR, Zhang Z, et. al. Clinical performance of a multivariate index assay for detecting early stage ovarian cancer. Am J Obstet Gynecol 2014 Jan;210(1):78
  • Coleman R, Herzog T, Chan D, et. al. Validation of a second generation multivariate idex assay for malignancy risk of adnexal masses. Am J Obstet Gynecol 2016 March 10
  • Ueland F, Desimone C, Seamon L, et al. Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors. Obstet Gynecol 2011;117:1289-97
  • Roma Score (Ovarian Malignancy Risk Algorithm).

 

Policy History:

  • April 2018 - Annual Review, Policy Revised
  • April 2017 - Annual Review, Policy Renewed
  • April 2016 - Annual Review, Policy Renewed
  • May 2015 - Annual Review, Policy Renewed
  • June 2014 - Annual Review, Policy Revised
  • August 2013 - Annual Review, Policy Revised
  • April 2013 - Interim Review, Policy Retired
  • September 2011 - Evidence Review, New Policy

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.

 

*CPT® is a registered trademark of the American Medical Association.