UOG Journal Club: January 2013 Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumor Analysis (IOTA) studies J. Kaijser, T. Bourne, L. Valentin, A. Sayasneh, C. Van Holsbeke, I. Vergote, A. Testa, D.Franchi, B. Van Calster, D. Timmerman Volume 41, Issue 1, Date: January 2013, pages 9–20 Journal Club slides prepared by Ligita Jokubkiene (UOG Editor for Trainees)

Correct discrimination between benign and malignant ovarian masses Previous studies limited by: small sample size single-center population different tumor types not standardized ultrasound terms and definitions lack of consistency in histological reports

Aims of the IOTA studies Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumor Analysis (IOTA) studies Kaijser et al., UOG 2013 Aims of the IOTA studies To develope rules and models to characterize ovarian pathology To test the diagnostic performance of rules and models by external validation with examiners of different levels of ultrasound experience To establish the role of CA 125 and other serum tumor markers for the diagnosis of ovarian cancer To identify the characteristics of ovarian tumors that are difficult to classify as benign or malignant To validate these models or rules in non-operated patients by studying the outcome of adnexal masses classified as benign

IOTA phase 1 Training set Test set 1066 non-pregnant women At least one persistent adnexal mass Nine clinical centers in five countries Training set 754 (71%) patients Test set 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 Personal history of ovarian cancer Current hormonal therapy Age of the patient* Maximum diameter of the lesion Pain during examination Ascites* Blood flow within a solid papillary projection* Purely solid tumor Maximum diameter of the solid component* Irregular internal cyst wall* Acoustic shadows* Color score LR1 (12 variables) *LR2 (6 variables) Timmerman et al, J Clin Oncol, 2005

Prospective validation of the models 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 B-features 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 90% 93% 12.6 0.11 RMI 0.91 67% 95% 12.7 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

Diagnostic performance of the models and simple rules to detect Stage 1 ovarian cancer LR1 and LR2 had higher detection rate of Stage 1 primary ovarian cancer than RMI Simple rules combined with subjective assessment when rules did not apply missclassified fewer Stage 1 ovarian cancer than RMI and CA 125 JVan Holsbeke et al, Clin Cancer Res, 2012; Timmerman et al, BMJ, 2010

Summary of the IOTA project Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumor Analysis (IOTA) studies Kaijser et al., UOG 2013 Summary of the IOTA project Pattern recognition of ultrasound features of an ovarian mass by an experienced examiner is the best way to characterize ovarian pathology A small proportion of solid tissue makes a malignant mass more likely to be a borderline tumor or a Stage 1 primary invasive epithelial ovarian cancer CA 125 does not improve diagnostic performance of assessment by experienced ultrasonographers Two main approaches to classify ovarian masses have been developed: Risk prediction models – LR1 and LR2 Simple rules or ”easy descriptors” Multiclass models have been created to distinguish between benign, borderline, primary invasive and metastatic disease

Recommendations for clinical practice Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumor Analysis (IOTA) studies Kaijser et al., UOG 2013 Recommendations for clinical practice 1. IOTA simple rules can be used as a triage test in 75% of all adnexal masses for estimating the risk of malignancy 2. A two-step strategy with referral to a specialist in gynecological ultrasound of unclassifiable masses rules has excellent diagnostic performance 3. An alternative to the simple rules is the LR2 model 4. LR2 or the simple rules should be adopted as the principal test to characterize masses as benign and malignant in premenopausal women 5. Measurement of serum CA 125 marker is not necessary for characterization of ovarian pathology in premenopausal women and is unlikely to improve the performance of experienced ultrasound examiners even in postmenopausal women.

Different approaches to estimate risk of malignancy Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumor Analysis (IOTA) studies Kaijser et al., UOG 2013 Different approaches to estimate risk of malignancy

Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumor Analysis (IOTA) studies Kaijser et al., UOG 2013 Discussion points Does serum CA 125 level help to discriminate between benign and malignant ovarian tumors? Which test should be used for discriminating between benign and malignant ovarian tumors by a non-expert ultrasound examiner? Can logistic regression models better predict malignancy than the IOTA simple rules or subjective evaluation by an experienced ultrasound examiner? Do we need to use IOTA simple rules or logistic regression models when classifying an adnexal mass as benign and malignant? Should we use the same models and rules for both premenopausal and postmenopausal patients? Are the IOTA logistic regression model and simple rules superior to the Risk of Malignancy Index (RMI) in discriminating between benign and malignant ovarian tumors?