Multi-Analyte Testing for the Evaluation of Adnexal Masses
Background: Ovarian cancer is the leading cause of cancer death from gynecologic malignancies in the United States. An important diagnostic problem is the identification of malignancy when a patient presents with an adnexal mass. Some evidence supports the notion that initial treatment of a malignancy by a gynecologic oncologist produces better patient outcomes, due to more thorough staging and initial tumor debulking. Currently, there are several assessment methods possible for differentiating between a benign and malignant adnexal mass. Multi-analyte tests have been developed to supplement current methods for evaluation of adnexal masses.
Objective: The objective of this Assessment is determine whether multi-analyte testing for the evaluation of adnexal masses for the purpose of predicting the presence of malignancy improves outcomes in women with such masses needing surgery.
Search strategy: MEDLINE was searched (via PubMed) using the terms “ovarian cancer,” and “risk assessment” and “adnexal mass.” The search was performed with no time limitations through August 2012, limited to English-language articles on human subjects. Review articles and meta-analyses provided background information and additional references. The FDA web site was searched for documents on “OVA1” and “ROMA.”
Selection criteria: The single existing study assessing OVA1 was selected. Studies showing the diagnostic characteristics of ROMA using prespecified cutoff values that assessed diagnostic performance for all types of malignancy, and did not include healthy subjects as non-malignant control subjects were selected.
OVA1. The study of OVA1 had 524 patients of which 31% (n=161) had various types of malignancy including epithelial ovarian cancer, other ovarian cancer, borderline cancer, metastatic cancer, and non-ovarian pelvic cancer. Methods of clinical assessment were not specified, but left to the physicians enrolling subjects in the study. OVA1 in conjunction with clinical assessment had a sensitivity of 96% and a specificity of 35%. Physician assessment alone had a sensitivity of 75% and a specificity of 79%. ACOG referral guidelines reported similar diagnostic performance accompanying physician assessment. OVA1 was positive 98% and 100% of the time for stage I+II and stage III+IV epithelial ovarian cancers. For other cancer types OVA1 was positive 82-84% of the time. In samples of subjects without gynecologic disease outside this study, OVA1 was positive in 31% of healthy subjects, and from 0 to 100% in small samples of subjects with various non-gynecologic cancers and medical conditions.
Author’s Comments and Conclusions on OVA1. Although the sensitivity of OVA1 in conjunction with clinical assessment has a high sensitivity of 96%, specificity is low and results in 75% of subjects testing positive. A policy of referring all subjects to gynecologic oncologists without testing is a rational strategy if the referral rate is so high with a testing policy. Although the method of physician assessment was not specified, its performance was consistent with some prior reviews of risk prediction. However, recent studies of ultrasound-based risk assessment models appear to have diagnostic characteristics with equivalent sensitivity and superior specificity to OVA1. These risk assessment systems have not been directly compared to OVA1. Finally, there is considerable uncertainty that the incremental increase in detection by OVA1 would result in improved health outcomes. The literature supporting initial treatment by gynecologic oncologists largely applies to advanced stage disease, and the mechanism of this treatment effect is not fully understood.
ROMA. Only one study of ROMA evaluates its performance in conjunction with clinical assessment, which is the manner in which it is intended to be used. Out of 461 patients, the prevalence of malignancy was 18.6% (n=86), with all types of malignancies included. ROMA in conjunction with clinical assessment had a sensitivity of 88% and a specificity of 67%. Physician assessment had a sensitivity of 73.3% and a specificity of 84.3%. The sensitivity is improved and the specificity worsens when ROMA is used in conjunction with clinical assessment. ROMA is positive 93-94% of the time in epithelial ovarian cancer, and positive between 50-77% of the time for the various other adnexal malignancies. In samples of subjects without pelvic malignancy outside this study, ROMA was positive in 10% of healthy subjects, and from 23-78% of the time in subjects with various non-gynecologic cancers, benign gynecologic conditions, and medical conditions.
Other studies evaluating ROMA only assess its diagnostic characteristics as a stand-alone test, which is not its intended use. They were reported only to evaluate whether the performance of ROMA in the one study where it is evaluated in conjunction with clinical assessment is representative of its performance in other studies. For the most part, the performance of ROMA as a stand-alone test appeared to be similar across most studies which met selection criteria.
Author’s Comments and Conclusions on ROMA. Use of ROMA in conjunction with clinical assessment produces an increase in sensitivity and a decrease in specificity. The increase in sensitivity detects a proportion of previously undetected cancer, but the sensitivity is still not optimal. The method of clinical assessment used in the study was not specified, but its performance was consistent with some prior reviews of risk prediction. Prior author comments on more recent ultrasound-based risk assessment models, and the uncertainty of improved outcomes through the increase in detection of malignancy apply to ROMA as they apply to OVA1.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether multi-analyte testing for the evaluation of adnexal masses meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC criteria).
1. The technology must have final approval from the appropriate governmental regulatory bodies.
OVA1 and ROMA have received U.S. Food and Drug 510(k) marketing clearance. The tests are indicated for women with adnexal masses in whom surgery is planned. They are intended to be used in patients in whom the physician’s independent clinical and radiological evaluation does not indicate malignancy. They are not intended for use in screening or as stand-alone diagnostic tests.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
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 the use of the tests in conjunction with clinical assessment, there are problems in concluding that this results in 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 some uncertainty regarding the benefit of initial treatment by a gynecologic oncologist beyond the need for reoperation is some cases.
3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.
Whether OVA1 or ROMA improves the net health outcome or is as beneficial as other procedures has not been demonstrated. Referring all patients to a gynecologic oncologist is a reasonable clinical alternative with no harm.
5. The improvement must be attainable outside the investigational setting.
Whether OVA1 or ROMA improves the net health outcome in the investigational setting has not been demonstrated.
Based on the above, multi-analyte testing for evaluation of adnexal masses does not meet the TEC criteria.
NOTICE OF PURPOSE: TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.