International Ovarian

Tumor Analysis (IOTA)

Definition
The InternationalOvarian TumorAnalysis (IOTA) group was
formed in 1999 by Dirk Timmerman (KU Leuven, Belgium),
Tom Bourne (Imperial College London, London, UK), and Lil
Valentin (Lund University, Sweden).
Its first aim was to develop standardised terminology, and in
2000 IOTA published a consensus statement on terms,
definitions and measurements to describe
thesonographicfeatures ofadnexal massesthat is now
widely used today.
IOTA now comprises one of a portfolio of studies examining
many aspects of gynaecologicalultrasonographyand early
pregnancy within a network of contributing centres
throughout the world that are co-ordinated from KU Leuven.

IOTA Studies
Having agreed on standardised terminology the principal
IOTA investigators prospectively studied a large cohort of
patients with a persistent adnexal mass in several
different clinical centres.
This database and the close involvement of the civil
engineering department at KU Leuven has enabled both
previously developed prediction models to be tested and
novel prediction models to be developed and externally
validated.
In this way IOTA has been able to refine the optimal
approach to characterise
adnexalpathologypreoperatively.

IOTA Studies
IOTA has also described simple ultrasound based rules
that can be used to classifyovarian cystsand so
diagnose"ovarian cancer".
These can be applied in about 75% of masses. For the
remainder, a further scan by a sub-specialist is
recommended.
Another approach has to use simple descriptors,
which are intuitive features of masses that an
ultrasound examiner can use to easily classify about
50% of masses.
Summaries of the IOTA studies have been published
as reviews.

IOTA phase 1
1066 non-pregnant women
At least one persistent adnexal mass
Nine clinical centers in five countriesd
Training set

Test set

754 (71%) patients

312 (29%) patients

Two logistic regressions models developed

(LR1 and LR2)
Timmerman et al, J Clin Oncol, 2005

Variables used in the logistic regression models

1.

Personal history of ovarian cancer

2.

Current hormonal therapy

3.

Age of the patient*

4.

Maximum diameter of the lesion

5.

Pain during examination

6.

Ascites*

7.

Blood flow within a solid papillary projection*

8.

Purely solid tumor

9.

Maximum diameter of the solid component*

10. Irregular internal cyst wall*

11. Acoustic shadows*

LR1
(12 variables)

*LR2
(6 variables)

12. Color score

Timmerman et al, J Clin Oncol, 2005

IOTA phase 1b
507 consecutive women
Three centers
Prospective validation of the models
IOTA phase 2
997 patients in twelve new centers and
941 patients in seven centers from phase 1
External validation of the models
JVan Holsbeke et al, Clin Cancer Res, 2009 and 2012; Timmerman et al, UOG 2010

Simple ultrasound-based rules

Based on subjective assessment of ultrasound
images
Rules could be applied to 77% of ovarian tumors
Classify tumors as benign, malignant or
inconclusive
Included into RCOG guideline for evaluating
ovarian pathology in premenopausal women
Timmerman et al, UOG, 2008

Features of a benign mass (B-features)

A mass is classified as
benign if at least one
B-feature is present
and no M-features
are present

Features of a malignancy (M-features)

A mass is classified as
malignant if at least
one M-feature is
present and no Bfeatures are present

Simple ultrasound-based rules

If the rules are inconclusive if no B/M-features
are present or both B and M features are
present...
... rely on subjective assessment by an expert
ultrasound examiner as a second stage test

Diagnostic performance of the models and rules

External
validation ROC AUC

Sensitivity

Specificity

LR+

LR-

Similar diagnostic performance between LR1 and LR2

LR1
cut-off 10%

0.96

92%

87%

6.8

0.09

LR2
cut-off 10%

0.95

92%

86%

6.4

0.10

Simples
rules*

N/A

RMI

0.91

90%

93%

67%

12.6

95%

12.7

0.11

0.34

* Simple rules supplemented with subjective assessment of ultrasound

findings when the rules could not be applied. IOTA phase 2.

Diagnostic performance of the models and rules

LR1, LR2 and simple rules had similar diagnostic performance in

IOTA phase 1b and phase 2 datasets
Timmerman et al, BMJ, 2010

Descriptors of an ovarian mass used to make a diagnosis

BD, benign descriptor; MD, malignant descriptor.

The role of CA 125 in diagnosing ovarian

cancer according to IOTA results

CA 125 has no significant impact on performance of logistic regression

model for women at any age

Adding information on serum CA 125 level to subjective assessment of

ultrasound findings does not improve diagnostic performance of
experienced ultrasound examiner

Timmerman et al, J Clin Oncol, 2007; Van Calster et al, J Natl Cancer Inst, 2007,
Valentin et al, UOG, 2009

Current IOTA Studies

Currently IOTA is engaged in several new
studies. The group are studying the long-term
behaviour of expectantly managed adnexal
pathology (IOTA phase 5).
This will answer important questions about
complications and malignant transformation in
masses that are left in situ.
A number of studies are being carried out on
masses that currently are difficult to classify
even for the most experienced examiner.

Current IOTA Studies

These studies involve the use
ofvascularimaging,proteomics,
novelBiomarkersandMRIto name but a few (IOTA
phase 3).
Finally a clinical trial is taking place in London (IOTA
phase 4) to evaluate the performance of IOTA
prediction models and rules in the hands of examiners
with different levels of experience and training.
Two paper have been published from the IOTA 4 study
that suggest that IOTA rules and models to work when
they are not applied by experts.

Reference
1) Timmerman, D.; Valentin, L.; Bourne, T. H.; Collins, W. P.; Verrelst, H.; Vergote, I.; International
Ovarian Tumor Analysis (IOTA) Group (2000). "Terms, definitions and measurements to describe the
sonographic features of adnexal tumors: A consensus opinion from the International Ovarian Tumor
Analysis (IOTA) group".Ultrasound in Obstetrics and Gynecology16(5): 500505.
2) Timmerman, D; Testa, A. C.; Bourne, T; Ferrazzi, E; Ameye, L; Konstantinovic, M. L.; Van Calster, B;
Collins, W. P.; Vergote, I; Van Huffel, S; Valentin, L; International Ovarian Tumor Analysis Group (2005).
"Logistic regression model to distinguish between the benign and malignant adnexal mass before
surgery: A multicenter study by the International Ovarian Tumor Analysis Group".Journal of Clinical
Oncology23(34): 8794801.
3) Van Holsbeke, C; Van Calster, B; Bourne, T; Ajossa, S; Testa, A. C.; Guerriero, S; Fruscio, R; Lissoni, A.
A.; Czekierdowski, A; Savelli, L; Van Huffel, S; Valentin, L; Timmerman, D (2012). "External validation of
diagnostic models to estimate the risk of malignancy in adnexal masses".Clinical Cancer
Research18(3): 81525.
4) Ameye, L; Timmerman, D; Valentin, L; Paladini, D; Zhang, J; Van Holsbeke, C; Lissoni, A. A.; Savelli, L;
Veldman, J; Testa, A. C.; Amant, F; Van Huffel, S; Bourne, T (2012). "Clinically oriented three-step
strategy for assessment of adnexal pathology".Ultrasound in Obstetrics & Gynecology40(5): 58291.
5) Kaijser, J; Bourne, T; Valentin, L; Sayasneh, A; Van Holsbeke, C; Vergote, I; Testa, A. C.; Franchi, D; Van
Calster, B; Timmerman, D (2013). "Improving strategies for diagnosing ovarian cancer: A summary of the
International Ovarian Tumor Analysis (IOTA) studies".Ultrasound in Obstetrics & Gynecology41(1): 920.