A Multicentre Study to Examine the Short and Long Term Outcomes of the Conservative Management of Benign-looking Adnexal Masses and the Pre-operative Characterisation of Ovarian Tumours
Conditions: Adnexal Masses, Ovarian Cysts, Ovarian Tumors
Sponsor: KU Leuven

International Ovarian Tumour Analysis (IOTA) Phase 5 
 
A multicentre study to examine the short and long term outcomes of the 
conservative management of benign-looking adnexal masses and the pre-
operative characterisation of ovarian tumours  
 
STUDY CO-ORDINATORS 
 
Tom Bourne, Lil Valentin, Dirk Timmerman 
 
Contact details: 
Dirk Timmerman, MD, PhD 
Department of Obstetrics and Gynaecology, University Hospitals Leuven,  
Herestraat 49, B-3000 Leuven, BELGIUM.  
Telephone:  
+ 32 16 344201 (office) 
 
Fax: + 32 16 344205  
 
 
 
+ 32 16 344215 (secretary) 
E-mail: dirk.timmerman@uzleuven.be 
 
 
STEERING COMMITTEE 
 
Dirk Timmerman (University Hospitals, KU Leuven) 
Tom Bourne (Imperial College, London) 
Antonia C. Testa (Università Cattolica di Sacro Cuore, Roma) 
Lil Valentin (University of Lund / Malmö) 
Ben Van Calster (KU Leuven) 
Sabine Van Huffel (ESAT-SISTA, KU Leuven) 
Ignace Vergote (University Hospitals, KU Leuven) 
 
 
Summary 
 
The medium to long term behaviour of benign-looking adnexal masses that do not undergo surgery is 
unknown. It is possible for these masses to undergo malignant transformation, rupture or torsion. 
Furthermore they may undergo changes in volume and/or morphology that may or may not predict any of 
these behaviours. To date, no research has rigorously investigated the long-term behaviour of such 
masses. Consequently, there are no evidence-based guidelines on the optimal management of the majority 
of adnexal tumours. It is therefore not surprising that clinical practice is highly variable, with some 
clinicians preferring to operate on virtually any mass. When a clinician decides not to operate, the time 
intervals selected for follow up scans is often arbitrarily chosen. On the other hand, we do have some 
convincing data to suggest that simple cysts are rarely malignant and so it is generally thought that 
operating on these common tumours is probably not necessary and simply increases costs and morbidity. 
Developing new insights into the natural history of benign looking conservatively managed ovarian 

masses would potentially change the management of thousands of women, by avoiding surgery or even 
further surveillance for some and detecting cancer earlier or even preventing it for others.  
In this international multicentre study IOTA phase 5 we aim to develop the optimal evidence-based 
algorithm for the management of all adnexal tumours in order to improve the detection of ovarian cancer 
while at the same time reducing the number of unnecessary operations. At least three thousand patients 
with an adnexal mass will undergo an ultrasound examination and if no operation is needed they will be 
followed up for at least 5 years. At each visit the investigator will assess the tumour and decide whether 
surgery is necessary based on the available information and local protocols. Survival and logistic 
regression analysis will be used to develop decision aids to assist clinicians in making decisions regarding 
surgery and follow up.  
 
Relation with other IOTA studies 
The IOTA study (International Ovarian Tumour Analysis) is a multicentre collaborative project for 
the pre-operative characterisation of ovarian tumours..  
IOTA phase 1: The first phase of IOTA was conducted between 1999 and 2002. Several new 
mathematical models were developed based on the prospectively collected data of 1066 patients with a 
persisting adnexal tumour from  9 European centres (1). Between 2002 and 2005 three centres 
continued the prospective collection in order to be able to perform an internal validation of 
mathematical models developed in IOTA phase 1. In this so-called IOTA phase 1b study a dataset of 
507 new patients was prospectively collected in 3 out of the 9 original IOTA centres (2). All models 
proved to perform excellently with areas under the ROC curves of more than 0.94. 
IOTA phase 2: The second phase of IOTA consisted of an external validation of the models and this 
was conducted between 2005 and 2007. The diagnostic algorithms were prospectively validated on 
1938 patients with adnexal tumours in 19 centres in Belgium, Italy, UK, Sweden, Poland, Czech 
Republic, Canada, and China (3). A first analysis showed that overall performance of the logistic 
regression models was excellent (area under the ROC curve 0.94). We concluded that a subgroup of 
“uncertain” tumours needs a reliable second stage test in order to help even experienced ultrasound 
examiners. 
IOTA phase 3: The third phase of the IOTA study started in 2010.  
The aim was  to validate the added value of mathematical models as new diagnostic tool in the 
prediction of ovarian cancer in clinical practice in centres that were involved in IOTA phase 1 or 2. It  
is a temporal validation of IOTA mathematical models as a first stage examination. However  in cases 
where the prediction is unreliable, we aim to further improve the predictive performance of this 
diagnostic tool with second stage tests, such as new sets of tumor markers, proteomics and three-
dimensional Power Doppler ultrasonography.  
 
IOTA phase 4: Randomised controlled trial in 7 London hospitals. Clinical implementation of IOTA 
logistic regression models LR2 vs. the routinely used Risk of Malignancy Index. Assessment of efficacy, 
referral pattern and costs. 
 
 
Introduction  
 

There is very little evidence on which to base a recommendation on how apparently benign looking 
adnexal masses should be managed. Because the natural history of  such adnexal masses is not known, 
and because of the fear of “missing” ovarian cancer, many adnexal masses are currently surgically 
removed, even if they do not manifest any signs of malignancy. This is not optimal, because every 
surgical procedure is associated with risks of both short-term and long-term complications, for example 
pulmonary embolism, deep vein thrombosis, and bowel perforation or obstruction (4). Furthermore we do 
not know if benign ovarian lesions impact on fertility, although we know that surgery on ovaries may 
cause adhesions, which in turn may cause infertility, chronic pelvic pain and bowel obstruction. We do 
not know the frequency of these complications,  nor do we know how often benign adnexal masses are 
associated with complications such as torsion if they are not removed. There is some evidence, however, 
that expectant management of  presumed ovarian dermoid cysts  less than 6 cm is safe and does not seem  
to interfere with pregnancy or delivery (5-7). The available data also suggest that expectant management 
of simple cysts less than 5 cm in post-menopausal women is a safe strategy (8,9).  
 
On the other hand ovarian cancer is associated with a high mortality rate and significant morbidity. It is 
the fifth leading cause of cancer-related deaths (10). The lifetime risk of developing ovarian cancer is 
around 1 in 50 to 1 in 70 (11,12). Every year more than 200,000 new cases are diagnosed worldwide. The 
disease has a poor prognosis, with five-year relative survival strongly depending on disease stage (12,13). 
For example, Cancer Research UK reports survival rates of 73% for stage I versus 16% for stage IV 
ovarian cancer.  
 
New diagnostic strategies to decrease mortality are needed, as treatment advances have not decreased 
mortality over the past 20 years (14). Effective screening programmes may help, but current candidate 
tests remain unsatisfactory (15). A crucial issue is that ovarian cancer is typically asymptomatic in its 
early stages. Screening algorithms have generally resulted in high sensitivity at the cost of a large number 
of false positives. As a result a large number of surgical interventions are made in order to find relatively 
few cancers. However although one study has suggested that there is no benefit in removing benign 
ovarian tumors (16), there are no conclusive data to inform us regarding the long term behaviour of 
presumed benign ovarian cysts left in situ. Should benign cysts have malignant potential, then a policy of 
removing such masses may have a significant impact on mortality from this disease.  
Research directed towards the use of diagnostic tests and models to predict malignancy in ovarian 
tumours has focused on masses that have been subsequently surgically removed in order to provide a clear  
histological end point.  Clinicians decide whether to operate on an ovarian mass depending on a number 
of factors. These may include the subjective characterisation of the mass using ultrasound, the use of 
simple models such as the risk of malignancy index, the age of the patient, the serum CA 125 level and 
the presence or absence of symptoms such as pain.  The management of cysts that are not removed 
surgically is not evidence based and often subject to wide variation. In the absence of rigorous follow up 
data, we do not know how many false negative results for cancer are associated with these cysts, or if they 
sometimes undergo malignant transformation. We will only gain this knowledge by long term systematic 
follow up of a large cohort of ovarian cysts.   
 
A number of studies have focused on the prediction of malignancy in surgically removed masses (for 
overviews, see references 2,17-19). There is  strong scientific evidence that subjective evaluation of a 
mass using ultrasound by an experienced examiner is a very good method for discriminating between 
benign and malignant adnexal masses (2,3,20-21), and that a correct histological diagnosis can be 
suggested on the basis of ultrasound findings in many cases (22,23). We have previously established the 
International Ovarian Tumor Analysis (IOTA) group to develop and validate prediction models based on 
large, multi-centre datasets with standardised definitions and data collection procedures (25). The aim was 

to develop  robust models to predict malignancy that performed well, and were widely generalisable. In 
doing so we aimed to overcome the shortcomings of earlier studies such as small sample sizes, single 
centre recruitment, and lack of standardised data collection. These models (1, 25-27) successfully passed 
temporal and external validation (2,3,28). Following these validation studies, we  selected two logistic 
regression models for further study. The first (LR1) is a model with 12 predictors, the second (LR2) 
contains only six predictors. Even in postmenopausal women conservative management and sonographic 
follow up of incidental unilocular and multilocular cysts <7cm may be a valuable option (29). 
 
 
Objectives  
 
The general aim of this study is the development of the optimal algorithm for the management of all 
adnexal masses. This can be broken down into different specific objectives: 1) to study the occurrence of 
complications such as rupture, torsion, or malignancy in patients with benign looking conservatively 
treated masses; 2) to test the published IOTA diagnostic models for predicting that a mass is malignant at 
first visit or benign (either on the basis of histology following surgery or by the absence of malignant 
features on an ultrasound scan one year after the initial visit), and to predict complications (e.g. ocurrence 
of malignancy and other) during long-term follow-up;  3) to investigate factors that may be related to the 
need for surgery during long-term follow up; 4) to study the natural history of conservatively treated 
benign looking masses and to establish descriptive curves of the longitudinal changes seen in parameters 
from conservatively managed benign tumors (e.g. change in diameter, size of any solid component, 
number of papillations, or color score). We hope these curves will allow us to determine if any particular 
growth pattern is associated with complications or malignancy 
Related to these four objectives, we aim to carry out the following analyses: 1) descriptive analysis of 
complications overall and by participating center (anonymised) and overall Kaplan-Meier curves for the 
need for surgery among benign looking masses; 2) estimation of discriminatory ability of LR1 for 
malignancy at the initial visit using the c-index and ROC curves and for complications during long-term 
follow-up using the hazard ratio and c-index within the context of survival analysis; 3) survival analysis to 
investigate predictors of the need for surgery during long-term follow-up of non-operated masses; 4) the 
development of longitudinal curves of the changes seen  in the characteristics of non-operated masses 
using longitudinal analysis techniques such as mixed models and functional linear discriminant analysis 
(FLDA). 
  
 
 
Methods 
 
Study design 
International multicenter prospective observational cohort study 
 
Eligible for inclusion 
 
Any woman at least 18 years old with an adnexal mass.  
 
Any mass with benign ultrasound morphology may be suitable for conservative management.  
 
Pregnant patients can be included, but their data will be analysed separately. 

 
Exclusion Criteria 
.  
 
Cysts that are deemed to be clearly physiological and less than 3 cm in maximum diameter are 
not eligible for inclusion.  
 
Any cyst with features of malignancy is excluded from the  conservative management  
 
The denial or withdrawal of oral informed consent 
 
 
Official approval by the Ethics Committee 
 
The multicentre project IOTA phase 5 will be submitted to the Ethics Committee of the University 
Hospitals Leuven as main investigating centre as well as in each participating centre.  
The study will be performed in accordance with generally accepted standards of Good Clinical 
Practice and the investigators will adhere to all applicable laws and regulations governing the conduct 
of clinical trials, including but not limited to the ICH Harmonized Tripartite Guidelines for Good 
Clinical Practice and the Declaration of Helsinki (2008). 
 
Insurance policy 
This multicentre international study is initiated by the University Hospitals Leuven, Belgium. Each 
participating centre outside Belgium is fully responsible for patient care within its own hospital in 
agreement with local laws. Each centre is also responsible for all legal aspects of patient care and for 
its own insurance for all matters related to this study. 
 
Financial Support 
The IOTA phase 3 project is supported by an Applied Biomedical Research grant (Toegepast 
Biomedisch Onderzoek, TBM) from the Flanders Institute for Scientific and Technological Research:  
IWT Flanders, Belgium (IWT-TBM 070706). This grant covers costs of central data collection, 
proteomic analysis, analysis of new tumour markers and statistical analyses. For IOTA phase 5 we 
received a research grant for a doctoral researcher by the Flemish Fund for Scientific Research (FWO 
Vlaanderen 06260, IOTA5). 
There is no financial compensation for principal investigators nor patients. 
 
 
Definition of benign ultrasound morphology  
This is defined on the basis of subjective assessment of ultrasound findings by an experienced 
ultrasound examiner. Only lesions where the ultrasound examiner is certain or almost certain that the 
lesion is benign can be managed conservatively. The management of benign masses will be decided 
according to local protocols. 
 
Number of study patients and recruitment period 
This is an observational study and therefore a sample size cannot be calculated. We aim to collect at 
least 3000 women with an adnexal mass and at least 1000 women with an adnexal mass managed 
conservatively. We plan an initial recruitment period of eighteen months. Patients will be followed up for 
at least 5 years, unless surgical intervention is necessary.  

 
Follow-up  
Ultrasound (and clinical) follow up will be organised by the ultrasound examiner who entered the 
patient into the study. Follow-up will be after 3 months (maximal range 1-4 months), 6 months 
(maximal range 4-8 months) and then every 12 months (maximal range 10-14 months). 
Although measurement of serum CA 125 levels is encouraged, it is not mandatory for inclusion in the 
study. If CA125 is measured it should be recorded in the study screen and preferably measured on 
each visit.  
 
Duration of follow-up 
A yearly analysis will be carried out in order to evaluate acute complications. The duration of follow 
up will be for at least 5 years and is not limited as long as the patient is compliant with the study and 
the study is ongoing.  
Departments (e.g. radiology departments) that are not involved with clinical decision making about 
plans for follow up or surgery cannot participate in the full IOTA 5 study. In these centres data can be 
prospectively collected as an observational study.  Only patients with appropriate outcome measures 
(i.e. follow up ultrasonography after one or more years or patients with complete details of clinical 
history or surgical procedures) will be included in any statistical analysis.  
 
 
 
Collection of clinical data 
 
Family history: Number of first degree relatives with ovarian cancer (0-...) 
 
Medical history: 
Personal history of ovarian cancer and breast cancer 
 
 
 
Age (years)  
 
 
 
Previous hysterectomy (yes/no) 
Previous oophorectomy (yes/no) 
Contraception (drop down list) (None/oral combined  contraceptive 
pill/progestogen only pill/ patch/vaginal ring/Mirena coil/copper IUD) 
 
 
 
Hormonal therapy (yes, no). 
 
Is the patient currently wishing to conceive? (yes/no)  
Menopausal status (pre- or postmenopausal) 
History of subfertility? Yes/no 
History of ovarian stimulation for subfertility? Yes/no 
 
 
For ALL patients before menopause two extra questions pop up:  
Patient is currently pregnant? (No/Yes)  
Patient became pregnant during the last year?  (No/Yes) 
 
 
If Yes: Outcome of pregnancy (it should be possible to enter more than one date, should there 
be more than one pregnancy during follow-up): 

o Ongoing pregnancy 
o Miscarriage; date:  … 
o Ectopic; date:  … 
o Termination; date:  … 
o Delivery; date:  … 
o Complications from the lesion during pregnancy? No/Yes (pop up list):  
 Acute pain 
 Chronic pain 
 Suspected torsion 
 Infection 
 Haemorrhage related to the cyst 
 Cyst rupture 
 Required surgery 
 Other, please specify:  …. 
o Complications from the lesion during delivery?  No/Yes (pop up list):   
 Acute pain 
 Suspected torsion 
 Haemorrhage 
 Cyst rupture 
 Obstructed labour  
 Malpresentation (e.g. breech or unstable lie) 
 Other, please specify:  ….…. 
 
 
 
 
Ultrasound examination  
A standardized ultrasound examination following the IOTA protocol is carried out. 
 
All ultrasound variables are included in the dedicated software.  In the database 0 always means NO 
and 1 always means YES. 
The adnexal lesion is that part of an ovary or of an adnexal mass that is judged by ultrasonography to 
be not consistent with normal physiology.  This can be a persistent unilocular cyst, surrounded by 
normal looking ovarian stroma with some follicles.  In this case the whole ovary containing the cyst is 
the ‘ovary’, whereas the unilocular cyst is the ‘lesion’.  Both are measured and the cyst is described as 
being ‘unilocular’ and not ‘unilocular-solid’. In other cases the lesion is separate from the ovary (e.g. 
hydrosalpinx).  Again, both ovary and lesion are measured separately.  In other cases no normal 
ovarian stroma is seen.  In these cases the lesion and the ovary are undistinguishable and the 
measurement of lesion and ovary will be the same. 
 
Measurements (in mm): The ovary in two perpendicular planes 
The lesion in two perpendicular planes 
The volume of the tumor is calculated from the three diameters in two perpendicular planes  
 
 
 The presence of ascites (i.e.fluid outside the pouch of Douglas) is noted (yes/no). 

 Fluid in the pouch of Douglas is measured in the sagittal plane (the largest anteroposterior diameter 
is given). 
(see Figure) 
 
 
 
 
 
 
 
 An incomplete septum (as seen in hydrosalpinges) is defined as a thin strand of tissue running 
across the cyst cavity from one internal surface to the contralateral side, butis not complete in some 
scanning planes. If a cyst only has incomplete septa, it is unilocular, despite the fact that in certain 
sections the cyst appears to be multilocular. 
 Solid means echogenicity suggesting the presence of tissue (e.g. the myometrium, the ovarian 
stroma, myomas, fibromas).  Blood clots and the presence of solid tissue can be distinguished by 
looking for internal movement when gently pushing the structure with the transducer. The presence 
of blood flow (with the appropriate color Doppler settings) is diagnostic for solid tissue. The 
absence of flow is not definitive . In cases of doubt the lesion should be classified as solid. 

 Solid papillary projections are defined as any solid projections into the cyst cavity from the cyst 
wall greater than or equal to 3 mm in height 
 
 
 
 
 
 
 
 
 
 
If it is unsure whether solid papillary projections or an incomplete septum are present, the ‘worse case 
scenario’ is used.  E.g. ‘cogwheel excrescences’ and ‘beads-on-a-string’ (as seen in hydrosalpinges) 
should be classified as papillary excrescences if their height is greater than or equal to 3 mm.  The 
‘white ball’ in a dermoid (i.e. Rokitansky node), should not be classified as a solid papillary 
projection. 
The ‘sludge’ on the internal walls of endometriotic cysts is not regarded as a papillary projection. In 
these cases the internal walls are usually ‘irregular’. 
 
 The number of separate papillary projections is noted (1/2/3/more). 
 The presence of flow within some of these projections is noted (yes/no). 
 Solid papillary projections are described as being ‘smooth’ or ‘irregular’ (e.g. cauliflower-like). 
In some cases it is difficult to judge whether it is a papillary projection and from which point to 
measure the projection. In these cases it may be helpful to use an imaginary line as shown in the 
following schematic drawing:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Base 
Height 

All lesions are qualitatively classified into one of 5 categories: 
1.  unilocular (a unilocular cyst without septa and without solid parts or papillary structures).  
Normal ovarian stroma is not regarded as ‘solid’ (e.g. a peritoneal cyst, containing a normal 
ovary, is unilocular and not unilocular-solid). 
 
 
 
 
 
 
 
 
 
 
incomplete septum; e.g. in 
hydrosalpinx) 
2.  unilocular cyst with solid component (a unilocular cyst with a measurable solid component or at 
least one papillary structure).  This category may include pyo- or hydrosalpinges with the so-
called ‘beads-on-a-string’ or ‘cogwheel’ appearance if  3 mm.  If the solid part contains very 
small cysts the mass might be unilocular-solid (see below). 
 
 
 
 
 
 
 
 
 
 
 
3.  multilocular (a cyst with at least one septum but no measurable solid components or papillary 
projections). The ‘lesion’ is measured as indicated by the arrows. 
 
 
 
 
 
 
 
 
 
 
  : : 

 
4.  multilocular with solid component (a multilocular cyst with a measurable solid component or at 
least one papillary structure) 
 
 
 
 
 
 
 
 
5.  solid (a tumour where the solid components comprise 80% or more of the tumour when 
assessed in a two-dimensional section).  
 
 
 
 
 
 
 
 
    (solid tumour with an irregular cyst wall) 
 
A solid tumour may contain papillary projections protruding into the small cysts. 
 
 
 
 

 
Quantitative assessment of morphology 
 
 
 In cystic-solid tumours the largest solid component is measured separately (in three perpendicular 
planes).  The solid component is noted as being smooth or irregular (e.g. cauliflower-like).  In some 
cases a solid papillary projection is the largest solid component and thus the papillary projection is 
recorded both as papillary projection and as solid component. 
 The internal wall is also noted as being smooth or irregular.  
 
 
 
 
 
 
 
 
 
 
Smooth  
Smooth  
Irregular 
 
If there is a solid papillary projection, then the wall is irregular by definition. 
 
 The external wall of tumors are not examined unless they are solid. 
 In cases of solid tumours the description of the internal wall being smooth or irregular is usually 
not applicable but the outline of the tumour is described as smooth or irregular.  
 If there is any irregularity in either the inner wall of any cyst or in the outer wall of a solid tumour 
or on the surface or echogenicity of a solid component, the lesion is described as ‘irregular’. 
 

 
 The dominant feature of the cystic contents is described as anechoic (black), low-level echogenic 
(homogeneous low level echogenic as seen in mucinous tumours), ‘ground glass’ appearance 
(homogeneously dispersed echogenic cystic contents, as often seen in endometriotic cysts), 
hemorrhagic (with internal thread-like structures, representing fibrin strands; it is possible to 
describe the echogenicity as star-shaped, cobweb-like or jelly-like) or mixed echogenic (as often 
seen in teratomas) (see images attached).  
 
 
 
 
 
 
 
 
 
Anechoic 
Low level 
Ground glass        Hemorrhagic     Hemorrhagic 
 
 
 
 
 
 
 
 
Mixed  
Mixed (old blood-fluid level   
         Mixed (e.g. abscess) 
 
 
 
or fat-fluid level) 
 
 
 The presence of acoustic shadows, defined as loss of acoustic echo behind a sound-absorbing 
structure, is noted as well.  Solid tumours are identified by the appearance of the internal texture, 
by the absence of internal movement when moving the transducer or by colour Doppler imaging 
(presence of central flow). 
 In solid tumours the dominant feature of any cystic contents is described only if it can be assessed. 
  ‘Ovarian crescent sign’, defined as the presence of normal ovarian tissue adjacent to an adnexal 
tumour. (“absent” or “present”, mandatory new variable for phase 3 and 5) 
 Ultrasound evidence of metastases (e.g. “omental cake” or peritoneal tumoural implants). (“absent” 
or “present”, mandatory new variable for phase 3 and 5) 
 
: : : : : : 
: 

 
Colour Doppler imaging and blood flow indices 
Subsequently, the entire tumor is surveyed by CDI.  The power, gain and pulse repetition frequency 
are initially adjusted for maximum sensitivity of low blood flow states.  The lowest velocity signals 
are filtered out by gradually increasing the pulse repetition frequency and flow analysis is concentrated 
on the highest velocity signals.  A subjective semiquantitative assessment of the amount of blood flow 
(area and colour scale) within the septa, cyst walls, or solid tumor areas is made: a score of 1 is given 
when no blood flow can be found in the lesion; a score of 2 is given when only a small amount of flow 
can be detected; 3 is given when moderate flow is present and 4 is given when the adnexal mass 
appears highly vascular with marked blood flow using colour Doppler (abundant flow).  This colour 
score refers only to the colour Doppler image and not to Doppler shift spectrum. It is given for the 
tumour as a whole (not for a solid part or a septum only, but for the whole tumour).  Multiple 
photographic prints are made of relevant structures and Doppler signals. 
 
 
Quality control 
 
Several informative images or volumes of all adnexal masses should be made.  Preferably, these are 
stored digitally.  Photographs or video are acceptable as well. 
 
 
 
Subjective assessment 
 
After ultrasonographic examination of the mass the investigator gives his subjective assessment of the 
mass: 
A: Malignant or benign or borderline? 
B: Probability of malignancy:  1 = benign 
 
(=level of certainty) 
 
2 = probably benign 
 
 
 
 
 
3 = uncertain 
 
 
 
 
 
4 = probably malignant 
 
 
 
 
 
5 = malignant 
C: Self impression: presumed histological diagnosis (e.g. dermoid, serous cystadenoma, 
endometrioma, abscess…) 
 
Surgical intervention 
Surgery is performed according to local protocols. The reason for surgery, e.g. symptoms (pain, 
discomfort or pressure symptoms), raised serum CA125 levels or changes in the morphology or 
volume of the mass is recorded in the study screen. 
 
Study screen 
An astraia study screen will be used which will permit the entry  of multiple scans per patient.  
 
 
All centres will receive the IOTA 5 study screen. 
At initial set up centres can choose between the two options:  
 

1. Full IOTA 5 study (with planning of appropriate follow up and conservative 
management whenever feasible). 
2. Observational study only (e.g. in radiology departments that are not involved in 
management decisions)  
 
 
 
Recorded variables (entered in the astraia study screen).  
 
Patient data 
(click one option from list below) 
 New patient with diagnosis of adnexal mass 
 New patient who was already in follow up in your centre for adnexal mass before she was 
enrolled to the IOTA 5 study. How many months in follow up? … 
 Follow up scan of patient that is already enrolled to the IOTA 5 study before 
 
Ultrasound 
 Spontaneous resolution of the adnexal mass (no further details are entered) 
 Adnexal mass present (fill in all variables below) 
 
 
12 variables described in LR 1: 
o Age           
 
  
  
o personal history of ovarian cancer 
o personal history of breast cancer 
o Max diameter of lesion  
o Max diameter of solid component  
 
o Presence of ascites  
 
 
o Presence of blood flow within papillary projection  
o Irregular internal cyst walls  
 
o Presence of a purely solid tumour  
 
o Colour score (1/2/3/4)  
o Presence of acoustic shadows   
o Current hormonal therapy   
 
 
o Presence of pain during the examination 
 
 
 as well as simple rules, RMI and other variables: 
o Type of tumour (unilocular/unilocular-solid/multilocular /multiloc-solid/solid) 
o Ovarian crescent sign  
o Cyst content  
o Incomplete septum 
o Mobility: mobile/reduced mobility/completely fixed  
o Number of locules   
o Number of papillations (0/1/2/3/more) 
o Size of ovary 
o Bilateral tumour 
o Evidence of metastases 
o Menopausal status: premenopausal/postmenopausal 

o Serum CA 125 result (not mandatory)  
 
 
Symptoms during the last year before ultrasound scan (multiple options are possible) 
 
o Pelvic pain   
o Postmenopausal bleeding   
o increased abdominal size   
o persistent abdominal distention (bloating) 
o appetite loss   
o constipation 
o diarrhoea 
o urinary urgency   
o urinary frequency 
o weight changes  
o dyspareunia  
o Other: please specify: …. 
 
 
For centres participating at the full IOTA 5 study only:  Suggested management recorded by 
examiner: “What type of management do you propose for this patient based on ultrasound and 
clinical data?” 
o Conservative management without follow up 
o Conservative management with follow up as specified in the protocol 
o Surgery by a gynaecologist or general surgeon 
o Surgery by an oncological surgeon 
 
Current status of the patient (this new tab should come before the tab “Histology”). A fixed 
query could be made to automatically ask the investigator about the status of all patients that 
were not rescanned 55 weeks after their previous scan as soon as the investigator opens the 
IOTA 5 study screen.  
 
 Lost to follow up (no other pop-up) 
 Patient stopped participating to the  study (please specify why : …..) (no other pop-up) 
 Patient withdrew her consent (data cannot be used for statistical analysis and no reason is 
aked) (no other pop-up) 
 Surgery performed (pop-up of fields about operation below) 
 
 
If Surgery 
 
Date of operation: 
 
 
Type of operation: cystectomy or oophorectomy or staging etc 
o Laparotomy with vertical incision 
o Laparotomy with horizontal incision 
o Operative laparoscopy 
o Diagnostic laparoscopy 
o Primary chemotherapy 
 

 
Indication for operation (more than one possibility may be thicked) 
o Suspicion of malignancy based on ultrasound 
o Suspicion of malignancy based on other information if so what?  
o Malignancy cannot be excluded 
o Acute pain 
o Chronic pain 
o Suspected  torsion 
o Fertility concerns 
o Patient request  
o Increase in size of the tumour 
o Change in morphology of the tumour 
o Increase in CA 125 level 
o Indicated by other imaging technique (CT, MRI…) 
o Other doctor recommended operation. Please specify the reason: … 
o “en passent” removal of the mass when patient was operated for another indication  
o Other: Specify:  …. 
 
 
 
Findings at operation (more than one option may be ticked)  
o No complications of the tumour 
o Torsion 
o Rupture 
o Inflammation/Infection 
o Adhesions 
o Bleeding from tumour 
o Metastatic cancer 
o Other complications of tumour: specify: …. 
o Other non-gynaecological pathology (e.g. appendicitis): specify:  …. 
 
 
 
Complications during operation (within one week of surgery). (more than one option may be 
ticked) : 
o Conversion from laparoscopy to laparotomy 
o Bowel perforation 
o Bleeding requiring transfusion 
o Embolism, deep venous thrombosis 
o Wound Infection 
o Peritonitis 
o Other: Specify:  …. 
 
 
Histological diagnosis (pop up list as before) with open text area (“Details”) 
 
 
If follow up examination: 
 
 
Complications of adnexal mass: no /yes 
 
If yes : date of first complication: …. 

 
And pop up list (you can select more than one): 
o Acute pain 
o Chronic pain 
o Suspected torsion 
o Infection 
o Haemorrhage 
o Rupture 
o Other, please specify:  …. 
 
 
Death: date 
 
Death directly or indirectly relatd to adnexal mass? 
 
cause of death ( 
 
 
Autopsy findings: specify:  …. 
Not needed for IOTA phase 5: second stage tests 
 
Consent / information leaflet 
 
Information leaflets are at the discretion of the participating centres. 
Approval of the local Ethical Committee for clinical studies is necessary. 
 
Serum tumour markers 
 
Serum CA 125 measurements or other tumour markers are performed locally, using a CA 125 II 
immunoradiometric assay  
 
 
Tissue collection 
 
Preferably the whole tumour should be removed. However, representative biopsies may be sufficient 
(e.g. in advanced ovarian cancer or endometrioma).  
 
 
Tumour classification 
 
Tumours are classified according to the criteria recommended by the International Federation of 
Gynecology and Obstetrics (FIGO).  In malignant tumours the degree of differentiation is included. 
 
Statistical analysis 
 
For the first objective, a descriptive analysis of complications on all data and stratified for 
participating center (anonymized) will be performed, as well as an overall Kaplan-Meier curve of 
‘complication free survival’. Complication free survival is defined as the time to the need for surgery 
during long-term follow-up. Patients that did not need surgery at the end of the follow-up period are 
right censored at the time of the last examination.  
 

For the second objective, the discriminatory ability of LR1 and the polytomous model  to detect 
malignancy at the initial visit will be assessed. To this end, the logit of the risk of malignancy given by 
LR1, logit(LR1), is used to predict malignancy using logistic regression, and the performance assessed 
with the odds ratio, the c-index and a ROC curve. Linearity of the effect of logit(LR1) will be assessed 
using spline functions. This analysis is planned one year after the end of the inclusion phase of the 
trial. Non-operated masses will be classified as benign at the initial visit if there is an absence of a 
clinical diagnosis of cancer after 1 year of follow up. In addition, the ability of LR1 to predict 
complications during long-term follow-up will be assessed. This will be done using Cox proportional 
hazards regression with the logit(LR1) as predictor of complication free survival. Performance will be 
assessed using the hazard ratio and the c-index within the context of survival analysis. Linearity of the 
effect of logit(LR1) will be investigated using Schoenfeld residuals.  
 
For the third objective, a multivariable survival analysis will be undertaken using Cox proportional 
hazards regression or more complex alternatives based on support vector machines (30). The models 
will be penalized to prevent overfitting, given that not enough events (i.e., patients that need surgery 
during long term follow-up) are expected for the number of available predictor variables. Internal 
validation will be assessed through bootstrapping rather than a split of the data in training and test sets 
(31).  
 
For the fourth objective, longitudinal normative curves will be derived of the changes seen in the 
characteristics of non-operated masses. Longitudinal analysis techniques such as mixed models, 
longitudinal support vector machines, and functional linear discriminant analysis (FLDA) (32-34).  
 
 
Study supervision 
 
Central supervision: the Steering Committee is responsible for the protocol, quality control, 
interim analyses of the data and final analysis and reporting of the study. 
 
Local supervision: the Principal Investigators are responsible for the data collection in their 
centres. 
 
Dirk Timmerman is responsible for the co-ordination of the overall IOTA project and the 
contact between the centres. 
 
Sabine Van Huffel and Bart De Moor are responsible for the data management and the 
development of new algorithms, in collaboration with Ben Van Calster, Lieveke Ameye and 
Kirsten Van Hoorde. 
 
 
 
 
Publication policy 
 
The steering committee is responsible for publication of the data in scientific journals. As 
such the members are co-authors in all resulting clinically relevant papers, to which they 
made significant contributions.  By the time of the final analysis the principal investigators 

have  to have contributed at least 50 cases to the study.  They are co-authors, according to the 
number of patients they contributed to the study (depending on the journal’s restriction of the 
number of co-authors) on condition that they contribute to  writing the papers and read and 
approve the final version. 
 
Purely mathematical papers without clinical relevance related to the study data are published 
by S. Van Huffel, B. De Moor and co-workers at ESAT with reference to the IOTA group and 
the inclusion of as many as possible of the clinical contributors. 
 
The Katholieke Universiteit Leuven represented by its department K.U.LEUVEN RESEARCH & 
DEVELOPMENT, having its office in 3000 Leuven, Minderbroedersstraat 8A – box 5105, Belgium, 
VAT number BE 419.052.173 holds intellectual property rights that might result from the IOTA 
project.  
 

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