Regional study into the performance and cost-effectiveness of simple ultrasound-based rules compared to the currently used Risk of Malignancy Index (RMI) in the diagnosis of ovarian cancer.

Ovarian cancer is the second most common gynecologic malignancy and in 2008 it
was the seventh leading cause of cancer deaths in women worldwide.
The success of treatment depends on early diagnosis. However in an early stage
ovarian cancer does not cause many symptoms and therefore approximately
two-thirds of the patients are diagnosed in International Federation of
Gynecology and Obstetrics (FIGO) Stage III-IV. Patients diagnosed in FIGO stage
I-IIb have a five-year survival of 75-100%, while patients diagnosed in a
higher stadium, FIGO stage III or IV, have a five-year survival of only 20-60%.
The diagnostic evaluation of woman with an adnexal mass consists of a thorough
anamnesis and physical examination followed by ultrasound imaging and
laboratory studies for tumor markers. However, the definitive diagnosis can
only be made by histopathological diagnosis of the mass following surgery.

Estimating the risk of malignancy is essential in the management of adnexal
masses. In case of malignancy comprehensive surgical staging and cytoreductive
(debulking) surgery is necessary and patients should be treated by a
gynecologic oncologist in order to get optimal surgical management which is
associated with a better median survival. However, when a malignancy is not
suspected, in clinical practice the mass can be managed conservatively or with
laparoscopy, if the mass is not too big. This will limit the morbidity and will
avoid unnecessary costs: laparoscopic staging offers lower estimated blood
loss, shorter hospital stay, and fewer postoperative complications with an
improved quality of life and faster return of normal functioning. Because of
these advantages of laparoscopy over laparotomy overtreatment will take place
when a benign mass is mistaken for a malignant mass. Consequently, the
morbidity, fear and cost price will increase. On the other hand, if a malignant
mass is not identified as such and is treated as a benign mass, a laparoscopy
can induce spillage of cyst fluid, which will deteriorate the prognosis of the
patient.

There are several methods to distinguish benign from malignant adnexal masses.
The commonly most used method in clinical practice is the Risk of Malignancy
Index (RMI). The RMI is a scoring system that is recommended by many national
guidelines in the differential diagnosis of ovarian masses, including the
national guideline in the Netherlands. The advantage of the RMI is that it is
easy to use, because of its simplicity. This scoring system combines serum
CA125, ultrasound and menopausal status into an index score used to predict the
risk of ovarian cancer before surgery. In clinical practice a cut-off value of
200 is usually used to determine if one has a high risk of having ovarian
cancer.
The formula of this scoring system is U x M x serum CA125, where U is the
ultrasound score, M is the menopausal status of the patient (premenopausal or
postmenopausal) and the level of serum CA125 is measured in U/ml. The
ultrasound score is based on five characteristics; multilocular cyst, evidence
of solid areas, evidence of metastases, presence of ascites, and bilateral
lesions. There are three different RMI formulas (RMI-I, RMI-II, and RMI-III)
that differ according to the points attributed to the different ultrasound
variables and the menopausal status of the patient. In the Netherlands RMI-III
is the algorithm of choice to differentiate between benign and malignant
disease. The reported sensitivity and specificity of RMI at a cut-off value of
200 are 75-80% and 85-90%, respectively.

Recently, another method was proposed to distinguish benign from malignant
adnexal masses by only using the morphological features of the mass. This
method is called *simple ultrasound-based rules* (simple rules) and uses
different morphological ultrasound features of adnexal masses (without
including menopausal status or serum CA125 measurement). This method was
described by Timmerman et al. (2008) in order to derive simple and clinically
useful ultrasound-based rules to discriminate between benign and malignant
adnexal masses. Ten simple rules that have high sensitivity and specificity and
are applicable to a large number of tumors have been chosen; five simple
ultrasound-based rules to predict malignancy (M-rules) and five rules to
predict a benign tumor (B-rules).
If one or more M-rules are met and none of the B-rules, the mass is classified
as malignant. On the other hand, if one or more B-rules are met in the absence
of M-rules, the mass is classified as benign. If both or none of the M- and
B-rules are met the test is inconclusive. This is the case in about 20% of the
patients. Recent reports show that simple ultrasound based rules might be
superior to the RMI.

In adnexal masses for which the simple ultrasound rules yield an inconclusive
result, subjective assessment of Gray-scale and color Doppler ultrasound images
by an experienced ultrasound examiner can be used as a second stage test to
achieve an optimal diagnostic performance. This subjective assessment is also
called *pattern recognition*. The downside of subjective assessment is that it
is experience dependent: the more experienced the ultrasound examiner the
better subjective assessment will work.
Nevertheless, subjective assessment by experienced examiners is generally
expected to be the best way to classify adnexal masses prior to surgery.
Several reports have demonstrated that subjective assessment is superior to the
use of scoring systems and mathematical models, such as the Risk of Malignancy
Index or simple ultrasound based rules, when classifying adnexal masses as
benign or malignant. Unfortunately, the expertise of experienced ultrasound
examiners is not easily transferred to less experienced examiners. This is why
many national guidelines concerning the management of ovarian masses still
advocate the use of the RMI in the classification of adnexal masses and
therefore the RMI is still the most commonly used model in clinical practice.
This problem could be circumvented by using subjective assessment in a
two-stage test, where simple rules are used as a first stage test and
subjective assessment as a second stage test for the diagnosis in difficult
cases.

Another option is to use Diffusion Weighted - Magnetic Resonance Imaging
(DW-MRI) as a second stage test, when the simple rules yield an inconclusive
result. The test holds as an advantage that a full body MRI can not only
distinguish a benign from a malignant mass, but can also detect possible
metastasis in case of a malignancy. Furthermore, MRI can be used for the
detection of inoperable tumors and therefore help to select patients who might
be more appropriately managed by neoadjuvant chemotherapy. The use of MRI -
when interpret by specialized radiologists- also seems to be superior to RMI in
the preoperative identification of adnexal masses.

Rationale
The objective of this study is to test the hypothesis that the simple rules
supplemented -if necessary- with either subjective assessment by an expert
sonographer or DW-MRI, will give better diagnostic accuracy and
cost-effectiveness than the RMI and therefore will improve the management of
women with adnexal masses. Furthermore, we estimate that the two-step triage
test has a potential cost saving effect of approximately ¤ 1,3 million a year
in The Netherlands.
Since the RMI is now widely used, any result in favor of the triage test has
the potential to alter future clinical practice. The information gained with
this study can be used to update or construct new national and international
guidelines.
Since in different hospitals different levels of expertise are present for
either ultrasound or DW-MRI, the decision was made to compare both subjective
assessment by an expert sonographer and DW-MRI with the current standard (RMI).
In the event of a positive study (difference in accuracy to the disadvantage of
the RMI), either simple rules in combination with subjective assessment, or
simple rules in combination with DW-MRI can be used depending on the expertise
present in each hospital or region.

This study is performed to compare the diagnostic performance and
cost-effectiveness of different methods in the preoperative characterization of
ovarian masses: RMI compared to
a) simple ultrasound-based rules as a first step test and subjective assessment
by an experience ultrasound examiner in those cases the simple rules yield an
inconclusive result; and
b) simple ultrasound-based rules as a first step test and DW-MRI in those cases
the simple rules yield an inconclusive result.

Secondary Objective(s):
• To perform a subgroup-analysis for premenopausal and postmenopausal women for
the above mentioned comparisons;
• To perform a subgroup-analysis to compare the diagnostic accuracy of
subjective assessment by an experience ultrasound examiner and DW-MRI for those
cases where the simple ultrasound-based rules were inconclusive.
• To assess interobserver-agreement in the interpretation of Simple Rules
between the primary ultrasound and the expert ultrasound.
• To assess interobserver-agreement in the subjective assessment between the
primary ultrasound and the expert ultrasound.
• To assess interobserver-agreement in the interpretation of DW-MRI images
between radiologists.
• To perform translational research and validate new biomarkers in the
diagnosis of ovarian cancer.

A prospective multicenter cohort study.

The burden of patients participating in the study is very low. About 80% of all
patients (in which the simple rules are sufficient for making the diagnosis) do
not have to undergo additional tests, neither are any other additional actions
taken.
About 20% of all participants (in which the simple rules yield an inconclusive
result) will be asked to visit the MUMC+ for either a DW-MRI (patients included
in Maastricht) or both an extra ultrasound performed by an expert and a DW-MRI
(all other patients). These participants will also be asked to give a blood
sample. The extra time spent by this group of participants is minimal
(approximately 2.5 hours plus time needed to travel to Maastricht) .

The risks of participation are negligible.
Risks of venipuncture are hematoma, pain, bleeding, and in immune compromised
patients there is a very small risk of infection.
Risks of an DW-MRI are claustrophobia and self inflicted injuries due to this
claustrophobia, bleeding or burns in case of presence of metal objects,
dizziness and balance disorders.

In summary, the burden and risks of participation are very small.