Clinical trial NCT02847832: Prospective Validation and Comparison of Different Ultrasound Methods for Discrimination Between Benign and Malignant Ovarian/Tubal Masses Prior to Surgery
Official title: Prospective Validation and Comparison of Subjective Assessment, the International Ovarian Tumor Analysis (IOTA) ADNEX Model, Logistic Regression Model LR2, Simple Rules and the Risk of Malignancy Index (RMI) for Discrimination Between Benign and Malignant Adnexal Masses in the Hands of Ultrasound Examiners With Different Levels of Experience
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Patients With Adnexal Mass Prior to Surgery
Keywords: Adnexal Diseases
Ovary
Ovarian Neoplasms
Ovarian Cysts
Ovarian Diseases
Ultrasonography
Ultrasonography, Doppler
Diagnosis
Early Diagnosis
Early Detection of Cancer
Genital Neoplasms, Female
Genital Diseases, Female
Urogenital Neoplasms
Cysts
Endocrine System Diseases
Gonadal Disorders
Neoplasms
Endocrine Gland Neoplasms
International Ovarian Tumor Analysis
Simple Rules
Preoperative evaluation
Prediction Models
Logistic Regression Models
Mathematical Models
Adnexal Masses
Ovarian Tumors
Risk of Malignancy
Lead sponsor: KU Leuven
Sponsor class: OTHER
First posted: 2016-07-28
Enrollment: 1700
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Consecutive patients with a known or suspected adnexal mass examined with transvaginal (or transrectal if vaginal is not possible) ultrasound by an IOTA certified ultrasound examiner and confirmed to have an adnexal mass judged not to be physiological but likely to undergo surgery (primarily planned for surgical management based on subjective assessment by the ultrasound investigator).

Different types of ultrasound centers (general gynecologic outpatient clinic or specialized ultrasound centers) and examiners with different levels of ultrasound experience will be involved.

Brief summary: The ability of different methods to discriminate between benign and malignant adnexal masses has been compared in a meta-analysis showing that the IOTA Simple Rules and the IOTA logistic regression model LR2 were superior to RMI and to all other methods for predicting malignancy in an adnexal mass included in the meta-analysis. However, a fair comparison of methods requires them to be applied on the same tumor population.

The general objective of this study is to prospectively validate the Simple Rules, ADNEX, the Simple Rules risk model, LR2, and RMI on a large multicenter dataset to allow direct comparison of these tools.

IOTA7 is an international multicenter prospective observational study including different types of ultrasound centers and examiners with different levels of ultrasound experience. In total, about 1700 adnexal masses with histological outcome will be included in IOTA 7.

Detailed description: Ovarian cancer is a common and lethal disease for which early detection and treatment in high volume centers and by specialized clinicians is known to improve survival. Hence, accurate methods to preoperatively characterize the nature of an ovarian tumor are pivotal.

The best ultrasound method for discrimination between benign and malignant adnexal masses is subjective assessment, i.e. subjective evaluation of ultrasound findings. Subjective assessment, however, requires a very experienced ultrasound examiner. More objective methods may be preferred by less experienced examiners who are not confident with using subjective assessment. The Risk of Malignancy Index (RMI) is one such method. There are also more recently developed methods. The International Ovarian Tumor Analysis (IOTA) group have created logistic regression models (LR1, LR2, and the ADNEX model) including clinical and ultrasound information to calculate the likelihood of malignancy in adnexal masses.

The IOTA group has also suggested simple ultrasound rules that can be used to classify adnexal masses as benign or malignant.

The ability of different methods to discriminate between benign and malignant adnexal masses has been compared in a meta-analysis showing that the IOTA Simple Rules and the IOTA logistic regression model LR2 were superior to RMI and to all other methods for predicting malignancy in an adnexal mass included in the meta-analysis. However, a fair comparison of methods requires them to be applied on the same tumor population.

The general objective of this study is to prospectively validate the Simple Rules, ADNEX, the Simple Rules risk model, LR2, and RMI on a large multicenter dataset to allow direct comparison of these tools. The patients will be examined by operators of varying levels of experience, such that the investigators can study how experience might affect diagnostic performance.

IOTA7 is an international multicenter prospective observational study including different types of ultrasound centers and examiners with different levels of ultrasound experience. In total, about 1700 adnexal masses with histological outcome will be included in IOTA 7.

Patients with a known or suspected adnexal mass examined with transvaginal (or transrectal if vaginal is not possible) ultrasound by an IOTA certified ultrasound examiner and confirmed to have an adnexal mass judged not to be physiological but likely to undergo surgery (primarily planned for surgical management based on subjective assessment by the ultrasound investigator) will be recruited consecutively Upon inclusion in the study, an oral or written (depending on the requirements of the local Ethics Committee) informed consent is obtained from the patient.

Data collection is done through the web-based clinical data miner (CDM) software. Data are stored on a secure server.

First, clinical information about the patient is entered into CDM. Second, the ultrasound examiner provides a diagnosis based on subjective assessment, and notes the suggested management. Third, detailed ultrasound information needed for the different models to be validated is entered. When these data have been frozen (so they can no longer be changed) the examiner gets access to the results of the Simple Rules and ADNEX. The ultrasound examiner then records whether these results make him/her change the management suggested on the basis of subjective assessment. If so the new management is specified.

Gold standard for validation of discriminative ability and calibration is the histology of the adnexal mass within 180 days after the ultrasound examination following surgical removal by laparotomy or laparoscopy as considered appropriate by the surgeon. In case of malignancy, the stage of the malignant tumors using the classification of the International Federation of Gynecology and Obstetrics (FIGO) is noted.

Eligibility criteria: Inclusion Criteria:

* Any woman presenting with an adnexal mass judged not to be physiological and likely to undergo surgery (primarily planned for surgical management based on subjective assessment by the ultrasound examiner; however, the ultrasound examiner is allowed to change the advised management to conservative management after the results of Simple Rules or ADNEX are known).
* Pregnant patients can be included but will be analysed separately.
* Patients finally selected for conservative management can be included but will not be used for all statistical analyses.
* For patients selected for surgery, delay of surgery is not an exclusion criterion for this study, but for selected objectives only those patients in whom surgery was performed within 180 days after the ultrasound examination will be assessed.
* Patients can be selected at any age, but for patients \<18 years old, a guardian's permission should be obtained.
* Patients that only underwent transabdominal scanning can be included in the study, but will be analysed separately.

Exclusion Criteria:

* Previous bilateral adnexectomy
* Denial or withdrawal of informed consent

Primary outcomes:
measure: Sensitivity, specificity, positive and negative likelihood ratios with regard to detection of malignancy for different ultrasound methods
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: AUCs for discrimination between benign and malignant masses for prediction models.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
Secondary outcomes:
measure: Flexible calibration curves based on local regression (loess) to assess calibration of the estimated risks on malignancy given by the risk prediction models.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: Sensitivity, specificity, positive and negative likelihood ratios with regard to detection of malignancy for different ultrasound methods, in hands of examiners with different level of experience.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: AUCs for prediction models, in hands of examiners with different level of experience.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: Sensitivity, specificity, positive and negative likelihood ratios with regard to detection of malignancy for different ultrasound methods, where the Simple Rules are inconclusive.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: AUCs for prediction models, where the Simple Rules are inconclusive.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: Change of the suggested management based on subjective assessment depending on the level of expertise of the ultrasound examiner, after results of the Simple Rules have been shown.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: Polytomous discrimination index for the ADNEX model to discriminate between different classes of histology.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: AUCs for each pair of outcome categories using the conditional risk method for the ADNEX model to discriminate between different classes of histology.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: Multinomial calibration curves for the ADNEX model to predict benign tumors, borderline tumors, stage 1 primary ovarian cancer, stage 2-4 primary ovarian cancer and metastatic cancer.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: Adjusted odds ratios with regard to malignancy for selected ultrasound characteristics, mainly papillation characteristics, in the subgroup of unilocular cysts with papillations.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: Sensitivity and specificity with regard to malignancy at different risk cutoffs, for a risk prediction model in unilocular cysts with papillations based on a limited number of variables selected a priori.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
measure: AUC for a risk prediction model in unilocular cysts with papillations based on a limited number of variables selected a priori.
timeFrame: During estimated recruitment period of 2 years. Gold standard is histopathology diagnosis within 180 days after ultrasound examination.
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospitals Leuven
Study officials:
affiliation: Queen Charlotte's & Chelsea Hospital, Imperial College London, London, UNITED KINGDOM
name: Tom Bourne, MD, PhD
role: STUDY_CHAIR
affiliation: Department Development & Regeneration, KU Leuven, Leuven, BELGIUM
name: Ben Van Calster, MSc, PhD
role: STUDY_CHAIR
affiliation: Department of Obstetrics and Gynecology, University Hospitals KU Leuven, Leuven, BELGIUM
name: Ignace Vergote, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Obstetrics and Gynecology, Skåne University Hospital, Malmö, SWEDEN
name: Lil Valentin, MD, PhD
role: STUDY_CHAIR
affiliation: Unità Operativa di Ginecologia Oncologica Dipartimento Tutela della Salute della Donna e della Vita Nascente, Università Cattolica di Sacro Cuore, Roma, ITALY
name: Antonia C Testa, MD, PhD
role: STUDY_CHAIR
affiliation: Department of electrical engineering (ESAT SCD-SISTA), KU Leuven, Heverlee-Leuven, BELGIUM
name: Sabine Van Huffel, MSc, PhD
role: STUDY_CHAIR
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