The preoperative diagnosis of ovarian masses is essential to provide an appropriate clinical treatment. The introduction of transvaginal ultrasonography has given us the opportunity to obtain preoperative diagnostic parameters which offer extraordinary diagnostic accuracy.
During the 90’s numerous articles were published in the literature regarding the use of ultrasonography in gynaecology. However, the heterogeneity of the scientific experiences was of concern and different groups obtained different results.
One scientific group, in particular, had published results, which provoked considerable perplexity due to the enormous size of the studied patient groups, and the exceptionally good results obtained by utilising the vascular resistance index with colour Doppler imaging.
During that time Lil Valentin and Dirk Timmerman had been working in the same research area but in two different countries (Sweden and Belgium). They both obtained similar results, diverging from what had been published by the above-mentioned group.
During international congresses, Valentin and Timmerman tried to compare their results with these colleagues, but ran into an insurmountable closure and were even exposed to public derision.
It was therefore understood that the true value of ultrasonography and colour Doppler imaging for the pre-operative distinction between benign and malignant ovarian tumours could only be established through international collaboration.
In 1998 they organised a consensus conference to define the terminology to be used in defining the ultrasonographic and color Doppler parameters. Standardising the terminology was essential to understand each other and to be able to compare results. In this way the IOTA group was created (International Ovarian Tumour Analysis Group) and published the afore-mentioned Consensus in an international scientific Journal 1,2.
Then they decided to start an international project with the objective of collecting clinical and ultrasonographic data of more than 1000 patients with ovarian masses in a standardised manner for the development of more universally useful mathematical models to distinguish between malignant and benign adnexal tumors before surgery. Over 50 clinical and sonographic end-points were defined and recorded for analysis. The outcome measure was the histological classification of excised tissues as malignant or benign. The group was extended to 9 European centres (Malmö, Sweden; Leuven, Belgium; Rome, Italy; Milan, Italy; Paris, France; London, UK; and Monza, Italy) and within two years recruitment was completed.
The protocol demanded the interaction of many professionals: doctors, statisticians, information technology specialists.
The protocol, as all scientific protocols, demanded to respond to some key points for a genuine inter-relation: exemplary scientific rigour; sharing progress with the Steering Committee members; combined analysis of the results; evaluation of manuscripts to be sent to international journals for publication.
The scientific methodology in its own right implied all this, but at times there are elements that could threat the relational nature within the group: friction and misunderstandings (e.g., members not respecting the commitments undertaken and deadlines, protocol violations); different characters and attitude (Lil for example has a great talent to be very logical and precise; her evaluation of a drafted manuscript could radically change the text... At times such precision could be heavy for the others...); tiredness, lack of commitment; the temptation not to carry on since the work is not remunerated (“non-sponsored protocol”: reason for drop-out of some originally interested American centres); inability to communicate; attempts not to share data, etc.
Moreover, in the beginning, the group met scepticism and some respected colleagues refused to participate in the project.
At the present stage of this project we can affirm that many positive elements have emerged and the difficultise have been overcome; we have experienced elements that have provided this inter-relation a reciprocal character: passion for research and search for the truth; desire to “create” and find something new; to go beyond any friction and misunderstanding in order not to cool down the collaboration; a profound interpersonal knowledge? with interventions in moments of difficulty; constant openness to the inclusion of new centres for the start of phase II.
A series of joint publications followed 3-15 and many papers are now in preparation.
Leuven has represented the coordinating centre of the whole project and we made all efforts to keep the progress continually active, the collection, the elaboration? (to link the work of the investigators, of statisticians...), while supporting international meetings.
Quote from Antonia: «We could feel that the strength of the group originated from a constant, open and sincere collaboration between the two principal investigators, Dirk Timmerman and Lil Valentin, a kind of collaboration which was also extended towards everybody».
At present the core group has enlarged and spread in different directions also involving those who had been rather sceptic and at first did not want to participate.
In IOTA phase I (2000-2002) data from 1,066 patients recruited from nine European centers were included in the analysis (ref. 12); 800 patients (75%) had benign tumours and 266 (25%) had malignant tumours. The most useful independent prognostic variables for the logistic regression model were: (1) personal history of ovarian cancer; (2) hormonal therapy; (3) age; (4) maximum diameter of lesion; 5) pain, (6) ascites, (7) blood flow within a solid papillary projection, (8) presence of an entirely solid tumor, (9) maximal diameter of solid component, (10) irregular internal cyst walls, (11) acoustic shadows, and (12) a color score of intra-tumoral blood flow.
The logistic regression model containing all 12 variables (M1) gave an area under the receiver operating characteristic curve of 0.95 for the development data set (n=754 patients). The corresponding value for the test data set (n=312 patients) was 0.94; and a probability cutoff value of 0.10 gave a sensitivity of 93% and a specificity of 76%. Furthermore more sopphisticated models, such as artificial neural networks, Bayesian networks, and Least-squares support vector machines were developed based on the multicentre data.
Between 2003 and 2005 Dirk Timmerman, Lil Valentin and Antonia Testa continued the data collection in their centres using the same protocol (IOTA phase IB) while continuing to work on a new and prospective protocol and discussing the results at numerous congresses and symposia. In IOTA IB more than 500 patients were collected and the previuosly developed mathematical models were prospectively tested on the new data. These results were very encouring, but they only proved that models developed in certain centres work well on prospective testing in the same centres and thus the generalization capacity of the models was not known.
Finally in 2006 IOTA phase II was started. Now 45 principal investigators from 34 centres (Leuven, Lund/Malmö, Rome (x2), London (x2), Paris (x2), Milan (x2), Naples (x2), Bejing, Sydney, Melbourne, Lublin, Stockholm, Bergen, Cagliari, Bologna, Mc Master Ontario, Prague, Monza, Helsinki, Göteborg, Oulu, Jerusalem, Calcutta, Feldkirch, Aachen, Brescia, Maastricht, and Genk) take part in a combined effort to test all previously developed models. The aim is to test the models on at least 1,500 new patient data. At this moment more than 800 new patient data have been collected in the central database in Leuven and the civil engineers and statisticians are trying to improve their methods based on the wealth of data collected in Phase I and IB. In the department of electrical engineering 6 doctoral students have worked on the data in order to prepare a PhD thesis. Two doctoral theses have succesfully been defended (Lieveke Ameye, Chuan Lu), and four are in preparation (Ben Van Calster, Vanya Van Belle, Olivier Gevaert, Peter Antal). Dr Caroline Van Holsbeke is a gynaecologist preparing a PhD thesis on this topic.
Currently we are also investigating new technical modalities, such as intravenous contrast agents, 3D colour Doppler imaging, proteomic pattern analysis and microarrays 9,11,14,16.
(International Ovarian Tumour Analysis
by ANTONIA TESTA, DIRK TIMMERMAN and LIL VALENTIN
1. Timmerman D, Valentin L, Bourne TH, Collins WP, Verrelst H, Vergote I. Terms, definitions and measurements to describe the ultrasonographic features of adnexal tumors: a consensus opinion from the international ovarian tumor analysis (IOTA) group. Ultrasound Obstet. Gynecol. 2000; 16: 500-5.
2. Timmerman D. Lack of standardization in gynecological ultrasonography (Editorial). Ultrasound Obstet. Gynecol. 2000; 16: 395-8.
3. Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, Sevelda P, Gore M, Kærn J, Verrelst H, Sjövall K, Timmerman D, Vandewalle J, Van Gramberen M, Tropé CG. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001; 357: 176-182. With commentary by Trimble EL. Prospects for improving staging of ovarian cancers. Lancet 2001; 357: 159-60.
4. Vergote I, Timmerman D, De Brabanter J, Fyles A, Tropé CG. Cyst rupture during surgery. Lancet 2001; 358: 72-3.
5. Timmerman D, Verrelst H, Collins WP, Bourne TH, Vergote I. Distinguishing the benign and malignant adnexal mass: an external validation of prognostic models. Letters to the Editor Gynecol. Oncol. 2001; 83(1): 166-7.
6. Antal P, Fannes G, Timmerman D, De Moor B, Moreau Y. Bayesian applications of belief networks and multilayer perceptrons for ovarian tumor classification with rejection. Artif. Intell. Med. 2003; 29: 39-60.
7. Lu C, Van Gestel T, Suykens JAK, Van Huffel S, Vergote I, Timmerman D. Preoperative prediction of malignancy of ovarian tumors using least squares support vector machines. Artif. Intell. Med. 2003; 28: 281-306.
8. Timmerman D. The use of mathematical models to evaluate pelvic masses; can they beat an expert operator? Best Pract. Res. Cl. Ob. 2004; 18: 91-104.
9. Testa AC, Ferrandina G, Fruscella E, Van Holsbeke C, Ferrazzi E, Leone FPG, Arduini D, Exacoustos C, Bokor D, Scambia G, Timmerman D. The use of contrasted transvaginal sonography in the diagnosis of gynecological diseases. A preliminary study. J. Ultrasound Med. 2005; 24: 1267-78.
10. Fruscella E, Testa AC, Ferrandina G, De Smet F, Van Holsbeke C, Scambia G, Zannoni GF, Ludovisi M, Achten R, Amant F, Vergote I, Timmerman D. Ultrasound features of different histopathological subtypes of borderline ovarian tumors. Ultrasound Obstet. Gynecol. 2005; 26: 644-50.
11. De Smet F, Pochet NLM, De Moor BLR, Van Gorp T, Timmerman D, Vergote IB. Letters to the Editor. Independent test set performance in the prediction of early relapse in ovarian cancer with gene expression profiles. Clin Cancer Research 2005, 11, 7958-7959 (Impact: 5.715)
12. Timmerman D, Testa AC, Bourne T, Ferrazzi E, Ameye L, Konstantinovic ML, Van Calster B, Collins WP, Vergote I, Van Huffel S, Valentin L. Logistic regression model to distinguish between the benign and malignant adnexal mass before surgery: a multicenter study by the International Ovarian Tumor Analysis (IOTA) Group. J Clin Oncol 2005; 23: 8794-801.
13. Valentin L, Ameye L, Testa A, Lécuru F, Bernard JP, Paladini D, Van Huffel S, Timmerman D. Ultrasound characteristics of different types of adnexal malignancies. Gynecol. Oncol. 2006; 102: 41-8.
14. De Smet F, Pochet NLM, Engelen K, Van Gorp T, Van Hummelen P, Marchal K, Amant F, Timmerman D, De Moor BLR, Vergote IB. Predicting the clinical behavior of ovarian cancer from gene expression profiles. Int. J. Gynecol. Cancer. 2006; 16: 147-51.
15. Valentin L, Ameye L, Jurkovic D, Metzger U, Lécuru F, Van Huffel S, Timmerman D. Which extrauterine pelvic masses are difficult to correctly classify as benign or malignant on the basis of ultrasound findings and is there a way of making a correct diagnosis? Ultrasound Obstet. Gynecol. 2006; 27: 438-44.
16. Testa AC, Timmerman D, Exacoustos C, Fruscella E, Van Holsbeke C, Bokor D, Arduini D, Scambia G, Ferrandina G. The role of CNTI-Sonovue in the diagnosis of ovarian masses with papillary projections: a preliminary study. Ultrasound Obstet. Gynecol. 2007 (in press).