This is a non-coverage policy for all multi marker serum tests related to
ovarian cancer testing.

**History/Background and/or General Information**

Ovarian cancer accounts for 2.5% of all malignancies in women and 5% of all
cancer deaths due to the disease's relatively high fatality rate.1 The most
common histologic subtype of ovarian cancer is epithelial ovarian cancer which
is most commonly detected in advanced stage (65% of cases are stage II or IV)
when the cure rate is only 18%.2 The incidence rate of ovarian cancer has
dropped 29%, from 16.6 (per 100,000) in 1985 to 11.8 in 2014 and the mortality
rate for ovarian cancer has declined 33% from 1976 (10.0 per 100,000) to 2015
(6.7 per 100,000) due to reductions in incidence and improvements in
treatment.3 Nevertheless, improving early detection and prevention is a
research priority because local-stage disease (confined to the ovary) has a
5-year relative survival rate of 93%.1 Currently, there is no strategy for
early detection of ovarian cancer that reduces ovarian cancer mortality.2

Ovarian cancer is staged surgically and the prognosis of ovarian cancer is
closely related to the stage of the tumor at the time of diagnosis. The early
involvement of the gynecologic oncologist is associated with improved survival
and outcomes due to increased adherence to guidelines including optimal
cytoreductive surgery and chemotherapy.4-8 As a result, NCCN guidelines
recommend that all patients with suspected ovarian malignancies undergo
primary assessment and debulking by a gynecologic oncologist as this results
in a survival advantage.9 The proportion of women with ovarian cancer who
undergo this surgery by a gynecologic oncologist can be as low as 33%.10,11

Per the American College of Obstetrics and Gynecology (ACOG), the evaluation
of an adnexal mass should consider individual patient characteristics,
physical examination findings, imaging results, and serum marker levels to
help separate masses into the categories of probably benign, uncertain, and
likely malignant, which can then guide appropriate management.12 Per ACOG, the
most extensively studied serum marker is cancer antigen 125 (CA 125), which is
a protein associated with epithelial ovarian malignancies, but it is also
frequently expressed at lower levels by nonmalignant conditions. In evaluating
adnexal masses, CA 125 measurement is most useful in postmenopausal women and
in identifying nonmucinous epithelial cancer. The CA 125 level is elevated in
80% of patients with epithelial ovarian cancer but in only 50% of patients
with stage I disease.12 Therefore, CA 125 is not considered to be an
appropriate screening test for ovarian cancer.

Current NCCN guidelines recommend that patients with a suspicious pelvic mass
and/or symptoms (bloating, pelvic/abdominal pain, difficult eating) have a CA
125 or other tumor markers as clinically indicated as part of the workup.9
ACOG guidelines (Level B evidence) state "the combination of an elevated CA
125 level and a pelvic mass in a postmenopausal woman is highly suspicious for
malignancy, and patients with these findings should be referred to or treated
in consultation with a gynecologic oncologist". 12

Various serum based tests have been proposed to triage patients with adnexal
masses. A suggested use of the tests is to identify women who have a higher
likelihood of malignant disease and may benefit from referral to a gynecologic
oncologist. These tests are combinations of several individual serum
laboratory tests known as multi-analyte assays with algorithmic analyses
(MAAA) and are performed on a blood sample by a reference laboratory using a
proprietary algorithm.

There are currently three FDA cleared tests: Ova1, Overa, and ROMATM.



**Ova 1 **

The OVA1 test uses proprietary OvaCalc Software to incorporate the values for
five analytes from separately run immunoassays into a single numerical score
between 0.0 and 10.0. The five analytes are Cancer Antigen 125 (CA 125),
Transferrin (TRF), Apolipoprotein A-1 (APO A-1), Beta-2 Microglobulin (B2M),
and Prealbumin (TT). This score is then interpreted in the context of
menopausal or premenopausal status.

According to the FDA 510K decision summary, the Ova1 test is intended for
women greater than or equal to 18 years of age who present with an ovarian
adnexal _mass for which surgery is planned and who are not yet referred to an
oncologist_.13 The assay is intended for use as a prognostic indicator of a
woman's likelihood that malignancy is present when the physician's independent
clinical and radiological evaluation does not indicate malignancy. The test is
not intended to be used as a screen or standalone diagnostic assay and is
intended for use in conjunction with imaging studies and clinical assessments
in women for whom surgical intervention is planned.

**Overa **

This is an assay that uses 5 protein biomarkers: Cancer Antigen 125 (CA 125),
Transferrin (TRF), Apolipoprotein A-1 (APO A-1), Follicle-Stimulating Hormone
(FSH),and Human Epididymis Protein 4 (HE4) the results of which are combined
to calculate a single cancer risk score using proprietary software - OvaCALC.
This score is then interpreted using menopausal or premenopausal status.
According to the FDA 510K decision summary document, Overa (referred to as
OVA1 Next Generation or Multivariate Index Assay (MIA2G)) is intended for
women greater than or equal to 18 years of age who present with an ovarian
adnexal mass for which surgery is planned and who are not yet referred to an
oncologist. The assay is intended for use as a prognostic indicator of a
woman's likelihood that malignancy is present when the physician's independent
clinical and radiological evaluation does not indicate malignancy.14

**Risk of Ovarian Malignancy Algorithm (ROMA TM )**

This is an assay that combines HE4, CA 125 and menopausal status into a
numerical score. According to the initial FDA 510K clearance received, ROMATM
is intended to aid in assessing whether a premenopausal or post-menopausal
woman who presents with an ovarian adnexal mass is at high or low likelihood
of finding malignancy on surgery. It is indicated for women who meet the
following criteria: over age 18; ovarian adnexal mass present for which
surgery is planned, and not yet referred to an oncologist. ROMATM must be
interpreted in conjunction with an independent clinical and radiological
assessment. 15,16

Each of the above tests have black box warnings stating "PRECAUTION: Test
should not be used without an independent clinical and imaging evaluation and
is not intended to be a screening test or to determine whether a patient
should proceed to surgery. Incorrect use of this test carries a risk of
unnecessary testing, surgery, and/or delayed diagnosis."

A literature search was performed in PubMed. Studies identified for potential
inclusion were obtained from searches in PubMed with no date limits. Search
terms included "OVA1", "multivariate index assay", "adnexal mass", "Overa",
"OVA1 next generation", "second generation multivariate index", "Risk of
Ovarian Malignancy Algorithm", "ovarian mass assessment" or "adnexal mass
assessment". Studies had to have been published in peer reviewed journals and
include a patient population that met the FDA clearance criteria which
includes over age 18, ovarian adnexal mass present for which surgery is
planned, and not yet referred to an oncologist.

OVA1

Fifteen studies were identified for OVA1. Nine were excluded due to a variety
of reasons including: OVA1 was not the index test, OVA1 performance assessed
as an individual test; test not performed with the intended FDA-cleared
intended usage as an adjunct test, the primary endpoint of the study was to
examine how pelvic imaging influenced the OVA1 score, not the performance of
the OVA1 test, cost-evaluation studies, and use of OVA1 for indications
other than adnexal mass assessment.17-25

Five of the six studies had limitations such as including patients who had
been evaluated by a gynecologic oncologist prior to being tested and the
studies contained overlapping patient populations.26-30 Therefore, the results
may not be generalizable or broadly applicable. All the studies were funded by
the test manufacturer.

There were 5 studies that evaluated the clinical validity of Ova1.

The initial study was a prospective multi institutional cohort study of 590
women from 27 sites across the United States which sought to assess the
effectiveness of OVA1 in identifying high-risk ovarian tumors.26 Assessment
by a non-gynecologic-oncologist physician plus Ova1 had a sensitivity of 92%,
a Negative Predictive Value (NPV) of 93%, and a Positive Predictive Value
(PPV) of 36% for predicting an ovarian malignancy. Over half the patients were
enrolled by gynecologic oncologists, which may have biased these results.
Given that this test is meant to determine the need for involvement of a
gynecologic oncologist when it has already been predetermined that an adnexal
mass requires surgery, including gynecologic oncologists in the trial was a
significant limitation in determining the clinical validity of Ova1.
Additionally, the low PPV may be associated with increased false positives,
creating potential patient anxiety/stress and unnecessary procedures. Lastly,
not all results were reported separately for patients enrolled by non-
gynecologic oncologists. This study was designated as "Level III Evidence" by
the journal _Obstetrics and Gynecology._

  |

Non-Gynecologic Oncologist - Physician Assessment plus Multivariate Index
Assay

|

Gynecologic Oncologist -Physician Assessment plus Multivariate Index Assay  
  
---|---|---  
  
Sensitivity (%)

|

92

|

99  
  
Specificity (%)

|

42

|

26  
  
Positive Predictive Value (%)

|

36

|

43  
  
Negative Predictive Value (%)

|

93

|

98  
  
Ueland, 2011

In a subsequent study of 494 patients, OVA1 demonstrated an overall
sensitivity and NPV of 95.7% and 98.1% when combined with clinical impression,
respectively.28 Similar to the initial trial, the specificity and PPV were low
(50.7% and 30.8%, respectively) and clinical assessment was by non-gynecologic
oncologists in half the patients. OVA1 correctly identified ovarian
malignancy in 91.4%, compared to 65.7% for CA 125. The study also found that
both clinical impression and CA 125 were more accurate than OVA1 in correctly
identifying benign disease. Menopausal status did not appear to have an impact
on the OVA1 test performance; receiver operating characteristic (ROC) curves
stratified by menopausal status showed similar discriminative ability at
premenopausal area under the curve (AUC) of 0.906 (95% CI, 0.847-0.975) and a
postmenopausal AUC of 0.898 (95% CI, 0.847-0.948).

The objective of the third study was to determine the projected impact on
referral patterns of patients undergoing surgery for an adnexal mass after
initial evaluation by a nongynecologic oncologist using OVA1, CA 125,
modified-ACOG referral guidelines, and clinical assessment using the combined
datasets of the two previously reported studies.30 The Dearking modified ACOG
guidelines for consultation with a gynecologic oncologist were used for
postmenopausal patients meeting one or more of the following criteria: an
elevated CA 125 (>35 units/mL), nodular or fixed pelvic mass, ascites, or
evidence of abdominal or distant metastasis. OVA1 demonstrated higher
sensitivity (90.2%) compared with clinical assessment (73.2%), CA 125 (68.3%)
and modified ACOG guidelines (79.3%). The authors also found that use of OVA1
as a risk stratification test was associated with a gynecologic oncology
referral rate of 55.7% comparable to actual clinical practice (60.0%). The
authors noted that "the factors affecting utilization of gynecologic oncology
resources at the time of suspected ovarian cancer diagnosis appear to be
multifactorial".

Stratification of test performance for detection of malignancy by menopausal
status did not appear to have an impact on the test performance.



  | Premenopausal | Postmenopausal  
---|---|---  
  
Sensitivity %

|

87.7

|

91.6  
  
Specificity %

|

60.5

|

43.1  
  
PPV %

|

25.6

|

41.9  
  
NPV %

|

96.9

|

92.0  
  
  Bristow, 2013

Utilizing the same patient pool as the previously noted studies, Ware-Miller
et al aimed to estimate the performance of OVA1 with ACOG guidelines and the
effect of replacing CA 125 with the multivariate index assay.27 This study
demonstrated that replacing the CA125 with OVA1 in the ACOG guidelines
increased the sensitivity from 77% to 94% and NPV from 87% to 93%. However,
there was a concomitant decrease in the specificity from 68% to 35%, and in
the PPV from 52% to 40%. The ACOG guidelines with OVA1 identified 79% (15/19)
of missed malignancies in premenopausal, and 67% (12/18) of malignancies
missed in postmenopausal women compared with the ACOG criteria alone. This
study was limited due to the fact that some patient included in the study were
already under a gynecologic oncologist's care, results were not presented
separately by physician specialty and there was no long-term follow-up on
outcomes.

Longoria et al analyzed of the effectiveness of OVA1 in identifying early-
stage ovarian malignancy compared to clinical assessment, CA 125, and modified
ACOG guidelines among women undergoing surgery for an adnexal mass.29 The
performance of OVA1 demonstrated a high sensitivity in identifying early-
stage ovarian malignancy when compared with clinical assessment, CA 125, and
modified ACOG guidelines. The sensitivity was found to be 91.9% for OVA1
testing alone and 95.3% when OVA1 testing was combined with clinical
assessment. The specificity with and without clinical assessment was 44.2% and
49.4%, respectively. Twenty-five percent of the patient population was
enrolled by a gynecologic oncologist which may have inflated the prevalence of
malignancy in the study population versus the OVA1 intended use population.
This study was designated as "Level III Evidence" by the journal _Obstetrics
and Gynecology_.

The sixth study by Eskander et al was a chart review assessing the ability of
OVA1 to drive referrals of ovarian cancer patients to gynecologic oncologists
prior to their first surgical intervention.31 Data for the study were
retrospectively collected through an online medical chart review from 22
obstetrician/gynecologists. The study included 136 patients who had received
an elevated-risk OVA1 score, with 122 of 136 patients undergoing surgery for
the removal of an adnexal mass. Data were collected through chart extraction
forms. Completed forms were aggregated for analysis and assessed for the rates
at which obstetrician/gynecologists referred patients with an elevated OVA1
score to a gynecologic oncologist prior to surgery. Results showed that 80% of
patients with an elevated OVA1 score were referred to a gynecologic
oncologist prior to surgery, with postmenopausal and premenopausal patients
showing similar referral rates of 82% and 78%, respectively. Additionally, an
appropriate referral to a gynecologic oncologist was seen in 95% of patients
with primary ovarian malignancies with an elevated OVA1 score. The study was
limited by a small patient population and biases inherent to a retrospective
chart review study, which could impact the rates of malignancy and referrals.
Lastly, patient outcomes such as morbidity and mortality were not assessed,
nor were other long-term outcomes.

Overa

Only one study met inclusion criteria and it addressed clinical validity.
There were no peer reviewed studies addressing analytical or clinical utility
that met inclusion criteria.19

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 from the
same population from the aforementioned study by Bristow.28 Overa test scores
were determined based on the analysis of archived serum specimens, and the
patients were stratified into low or high risk groups 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.

Among the 493 study participants, 92 (19%) had a final pathology diagnosis of
malignancy. The clinical performance of the Overa assay, when combined with
presurgical physician assessment demonstrated:

  * Sensitivity of 93.5%
  * Specificity of 64.8%
  * PPV of 37.9%
  * NPV of 97.7%

Overall, the addition of Overa testing to presurgical physician assessment
correctly identified 75% (P<0.001) of the malignancies missed by physician
assessment alone.

This study had several limitations, including a small patient population and a
retrospective study design. Additionally, preoperative physician assessment
was not uniform across the patient population and this may have introduced
bias into the study. Also the method used for combining clinical assessment
and Overa test results 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%. Finally,
this study was funded by the manufacturer. This single study provides very-
low-quality evidence for the clinical validity of the Overa test.



ROMATM

Wang et al 2014 published a meta-analysis of studies evaluating the diagnostic
accuracy of the ROMATM algorithm and comparing it to the performance of single
markers HE4 and CA 125.32 To be included in the meta-analysis, studies had to
investigate both HE4 and CA 125 or calculate ROMATM, include women with
ovarian cancer and benign gynecologic disease, use pathology diagnosis as the
reference standard, and collect blood samples before treatment was initiated.
A total of 32 studies met these inclusion criteria; six of these were
conducted in the United States. Findings of the overall pooled analysis of
diagnostic accuracy are presented in Table 1. Findings were similar when
diagnostic performance in premenopausal women and postmenopausal women were
evaluated separately. ROMATM had similar or higher sensitivity than HE4 and CA
125, and HE4 had the highest specificity.

Table 1. Diagnostic Performance of ROMATM compared with HE4 and CA 125 from
Wang et al: Meta-analysis findings

  |

No. Studies

|

Sensitivity

|

Specificity  
  
---|---|---|---  
  
ROMATM

|

14

|

85.3 (81.2-88.6)

|

82.4 (77.4-86.5)  
  
HE4

|

28

|

76.3 (72.0-80.1)

|

93.6 (90.0-95.9)  
  
CA 125

|

28

|

79.2 (74.0-83.6)

|

82.1 (76.6- 86.5)  
  
Dayyani et al conducted a meta-analysis comparing ROMATM with HE4 and CA 125
in patients with suspected ovarian cancer.33 Six studies met the inclusion
criteria, four of which were included in the Wang et al meta-analysis. Two
studies were published in 2014 or later. ROMATM had statistically higher area
under the curve (AUC) values than either HE4 or CA 125 alone (0.921, vs 0.899,
and 0.883 for HE4 and CA 125, respectively). Findings of the pooled analysis
of diagnostic accuracy are shown in Table 2.

Table 2. Diagnostic Performance of ROMATM compared with HE4 and CA 125 from
Dayyani et al: Meta-analysis findings ROMATM



  |

No. Studies

|

Sensitivity % (95% CI)

|

Specificity %, 95% CI  
  
---|---|---|---  
  
ROMATM

|

6

|

87.3 (75.2-94.0)

|

85.5 (71.9-93.2)  
  
HE4

|

6

|

68.2 (69.3-90.1)

|

85.1 (71.6-92.8)  
  
CA 125

|

6

|

79.6 (66.3-88.5)

|

82.5 (66.2- 91.9)  
  
Since the publication of the Wang et al and Dayyani et al meta-analyses,
multiple studies have described the use of ROMATM in populations of women in
whom decisions to pursue surgery had been made, including Al Musalhi et al34
(n=213 cases), Cho et al35 (n=90 cases), Terlikowska et al36 (n=224 cases),
and Minar et al37 (n=267).

Diagnostic performance of the ROMATM test was evaluated for FDA approval in a
prospective, blinded clinical trial using thirteen demographically mixed
subject enrollment sites with company sponsorship (K103358).16 Patients all
presented with an adnexal mass and were scheduled to undergo surgery. An
Initial Cancer Risk Assessment (ICRA) was performed to determine the detection
of benign versus malignant lesions before testing. The prevalence of cancer
was 15%.

Using pathologic diagnosis as the gold standard, test performance, when
combined with presurgical assessment for benign disease, was as follows in the
hands of a mixed population of generalist and specialist physicians:

  |  

ICRA alone

|

ICRA with ROMA testing  
  
---|---|---  
Sensitivity | 77% |

91%  
  
Specificity | 84% |

67%  
  
PPV | 46% |

33%  
  
NPV

| 96% | 98%  
  
Both tests, when added to pre-testing clinical assessment, produced a fall in
the positive predictive value of diagnosis with a small increase in the
negative predictive value. The changes observed in the negative predictive
value were of uncertain statistical and clinical significance.

A study by Moore et al evaluated ROMATM in conjunction with clinical
assessment, using either positive clinical assessment or positive ROMATM as a
positive test (similar to the recommended usage for OVA1).38 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, ROMATM would only need to be evaluated in patients with a negative
clinical assessment. In this study, 461 women were enrolled, of whom a total
of 86 (19%) had a malignancy. Combined assessment improved sensitivity from
77.9% to 89.7%, but worsened specificity from 84.3% to 67.2%.

It is important to note that all of the above literature assessed ROMATM as a
stand-alone test and did not evaluate diagnostic performance in conjunction
with clinical assessment, as the test was intended to be used. Therefore, the
ability to draw conclusions regarding the test's diagnostic performance is
limited.

_Evidence-Based Practice Guidelines, Position Statements, and Third Party
Review_

The American Congress of Obstetricians and Gynecologists (ACOG)

ACOG recommend at level C scientific evidence (based primarily on consensus
and expert opinion) that physicians can use serum biomarker panels as an
alternative to CA125 level alone when evaluating women with adnexal masses to
determine the need for referral to or consultation with a gynecologic
oncologist when an adnexal mass requires surgery. Consultation with or
referral to a gynecologic oncologist is recommended at a level B scientific
evidence (based on limited or inconsistent scientific evidence) for patients
with an elevated score on a formal risk assessment test.12



The Society for Gynecologic Oncology (SGO)

In May 2013, the Society for Gynecologic Oncology (SGO) issued the following
position statement on multiplex serum testing for women with pelvic masses39:

"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
gynecologic 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." SGO does not formally endorse or promote any specific products or
brands.

A review by Hayes regarding the use of the OVA1 test to assess malignancy
risk in adnexal masses in women with planned surgery was rated as "D2" (there
is insufficient published evidence to assess the safety and/or impact on
health outcomes or patient management).40 The review concluded that "there is
no peer-reviewed evidence for analytical validity, very-low-quality evidence
for clinical utility, and low-quality evidence for clinical validity for the
use of the OVA1 test. Individual study quality for publications supporting
the OVA1 test ranged from poor to very poor. The lack of studies supporting
analytical validity and clinical utility downgrades the overall body of
evidence for OVA1. Additionally, clinical validity studies evaluated had
several limitations and consisted of low-quality and very-low-quality
evidence".



The National Cancer Institute (NCI)41

[Level of evidence:
5](https://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=526280&version=HealthProfessional&language=English)



Proteomics

Initially, mass spectroscopy of serum proteins was combined with complex
analytic algorithms to identify protein patterns that might distinguish
between ovarian cancer cases and controls.42 This approach assumed that
pattern recognition alone would be sufficient to permit such discrimination,
and that identification of the specific proteins responsible for the patterns
identified was not required. This strategy was modified, using similar
laboratory tools, to identify finite numbers of specific known serum markers
that may be used in place of, or in conjunction with, CA 125 measurements for
the early detection of cancer.43 These studies 44,45 have generally been small
case-control studies that are limited by sample size and the number of early-
stage cancer cases included. Further evaluation is needed to determine whether
any additional markers identified in this fashion have clinical utility for
the early detection of ovarian cancer in the unselected clinical population of
interest.



National Comprehensive Cancer Network (NCCN)

The NCCN ovarian cancer guidelines (v1.2020) includes the following
statement46:

"It has been suggested that specific biomarkers (serum HE4 and CA 125) along
with an algorithm (Risk of Ovarian Malignancy Algorithm [ROMATM]) 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 of 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."

Of note is the fact that the NCCN Ovarian Cancer panel has twice (2016, 2017)
unanimously voted down the request by manufacturer to modify the wording in
the guidelines to replace CA 125 by OVA1 and /or MIA or other tumor markers
in the work up section of the guidelines, to revise the primary treatment
section to include establishing a baseline CA 125 as clinically indicated
either from OVA1 and or MIA result or separately and to change the wording in
section M-5 to indicate that the guidelines recommend that anyone with an
elevated OVA1result undergo surgery by an experienced gynecologic oncologist.





National Institute for Health and Care Excellence

  * There is currently not enough evidence to recommend the routine adoption of the IOTA ADNEX model, Overa, RMI I (at thresholds other than 200 or 250), ROMATM 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](http://www.nice.org.uk/guidance/cg122) 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, RMI I (at thresholds other than 250), ROMATM and IOTA Simple Rules show promise. Further research is recommended on test accuracy and the impact of the test results on clinical decision-making.47

In summary, improving early detection and prevention of ovarian cancer is a
priority in women's health. To date, none of the multimarker serum tests
addressed in this policy have been shown to reliably screen, improve quality
of life, or decrease mortality in women with ovarian cancer. Given that the
literature has the limitations as outlined above and in conjunction with the
position of the American College of Obstetrics and Gynecology, The Society for
Gynecologic Oncology, and the National Cancer Institute, coverage of these
tests must await larger, prospective, non-industry funded data on long term
outcomes including quality of life, improvement in survival and impact on
mortality in women with ovarian cancer.