Evaluating the risk of ovarian cancer before surgery using the ADNEX model: a prospective multicenter external validation study Sayasneh A *, 1,2 , Ferrara L *,2,3 , De Cock B 4 , Saso S 1,2 , Al-Memar M 2 , Johnson S 5 , Kaijser K 4 , Carvalho J 2 , Husicka R 2 , Smith A 6 , Stalder C 2 , Ettore G 3 , Van Calster B 4 , Timmerman D 4 , Bourne T 1,2,4 * : The authors consider that the first two authors should be regarded as joint First Authors. 1 : Department of Surgery and Cancer, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0HS, UK. 2 : Early Pregnancy and Acute Gynecology Unit, Queen Charlottes and Chelsea Hospital, Imperial College London, Du Cane Road, London W12 0HS, UK. 3 : Department of Obstetrics and Gynecology - Garibaldi Nesima Hospital, Catania, Italy. 4 : Department of Development and Regeneration, KU Leuven, Leuven, Belgium. 5 : Southampton University Hospitals, Princess Anne Hospital, Southampton, UK, SO16 5YA. 6 : Ultrasound Scan Department, Queen Charlottes and Chelsea Hospital, Imperial College London, Du Cane Road, London W12 0HS, UK Corresponding author: Mr. Ahmad Sayasneh Locum Consultant Gynecological Oncologist, Guys and St Thomas’ Hospital, and Honorary Senior Clinical Lecturer, Imperial College London. Department of Surgery and Cancer Hammersmith Campus Imperial College London Du Cane Road London W12 0HS Email: [email protected]Tel: 00442083835131 Fax: 00442083835115
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Evaluating the risk of ovarian cancer before surgery using the ADNEX model: a prospective multicenter external validation study
Sayasneh A*, 1,2, Ferrara L*,2,3, De Cock B4, Saso S1,2 , Al-Memar M2, Johnson S5, Kaijser K4, Carvalho J2, Husicka R2, Smith A6, Stalder C2, Ettore G3, Van Calster B4, Timmerman D4, Bourne T1,2,4
*: The authors consider that the first two authors should be regarded as joint First Authors.1: Department of Surgery and Cancer, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0HS, UK.2: Early Pregnancy and Acute Gynecology Unit, Queen Charlottes and Chelsea Hospital, Imperial College London, Du Cane Road, London W12 0HS, UK.
3: Department of Obstetrics and Gynecology - Garibaldi Nesima Hospital, Catania, Italy.
4: Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
5: Southampton University Hospitals, Princess Anne Hospital, Southampton, UK, SO16 5YA.
6: Ultrasound Scan Department, Queen Charlottes and Chelsea Hospital, Imperial College London, Du Cane Road, London W12 0HS, UK
Corresponding author: Mr. Ahmad SayasnehLocum Consultant Gynecological Oncologist, Guys and St Thomas’ Hospital, and Honorary Senior Clinical Lecturer, Imperial College London.Department of Surgery and CancerHammersmith CampusImperial College LondonDu Cane Road LondonW12 0HSEmail: [email protected]: 00442083835131Fax: 00442083835115
Running title: characterizing ovarian masses using ADNEX multiclass model
PURPOSE: To externally validate the International Ovarian Tumor Analysis (IOTA) ADNEX model
(The Assessment of Different NEoplasias in the adnexa model) for the multiclass characterization of
ovarian masses. The secondary aim was to assess the performance of the ADNEX model by level II
ultrasound examiners with varied training and experience.
EXPERIMENTAL DESIGN: This was a cross-sectional multicenter cohort study for diagnostic
accuracy. Patients were recruited from three cancer centers (two in the UK and one in Italy). Patients
with an ovarian mass underwent transvaginal ultrasonography. Only patients who had a histological
diagnosis of surgically removed tissue were included. The diagnostic performance of the ADNEX
model with and without CA125 was calculated.
RESULTS: 610 women were included in the final analysis. The prevalence of malignancy was 30 %
(182) with 7% borderline tumors, 8% stage I primary ovarian cancers, 11% stage II-IV primary
ovarian cancers and 4% secondary metastatic cancers. The area under the curve AUC for the
diagnostic performance for the ADNEX model to differentiate between benign and malignant masses
was 0.937 (95% CI: 0.915-0.954) when CA125 was included, and 0.925 (95% CI: 0.902-0943) when
CA125 was excluded. The ADNEX model showed good discrimination between the different
subtypes (benign, borderline, stage I primary cancer, stages II-IV primary cancers and metastatic
secondary cancers).
CONCLUSION: The performance of the ADNEX model retains its performance on external
validation. Furthermore the model performs well in the hands of ultrasound examiners with varied
training and experience.
Introduction
According to the latest statistics from the National Cancer Institute in USA, there were 12.1 per
100,000 women new cases of ovarian cancers per year between 2008 and 2012, with a mortality of
7.7 per 100,000 women (1). The overall five year survival is estimated to be around 45.6 % for all
stages of the disease (1). However, for early localized ovarian cancers the five year survival exceeds
90% (1). A combination of early diagnosis and centralized management are thought to be key factors
to optimize survival (1-3). For early diagnosis, trials to evaluate ovarian cancer screening have not
been successful (4, 5). Recently, the United Kingdom Collaborative Trial of Ovarian Cancer
Screening showed that screening using the risk of ovarian cancer algorithm (ROCA), doubled the
number of detected primary invasive epithelial ovarian or tubal cancers (iEOCs) compared with a
fixed cutoff of CA 125 (6). However, until the follow up of these patients is complete, the impact of
screening on ovarian cancer mortality will not be known (6).
A further important aspect of clinical management is that an accurate diagnosis is made when a
woman presents with an ovarian mass. The International Ovarian Tumor Analysis group (IOTA) have
developed and validated models and rules to characterize ovarian masses as benign or malignant (7-
11). These models and rules have also been validated in the hands of less experienced (level II)
ultrasound examiners (12).
The IOTA group has developed the multiclass ADNEX model which can differentiate between benign
tumors, borderline tumors, early stage primary cancers, late stage primary cancers (stage II to IV) and
metastatic cancers (validation area under the receiver operating characteristic curves (AUCs) between
0.85 and 0.99). This model should facilitate the management of ovarian masses more efficiently as it
allows patients to be triaged to the correct management pathway, whether for conservative follow up,
surgery at a general gynecology unit, or management at high volume specialized cancer centers.
Correctly classifying the subtype of malignancy if also of critical importance as borderline ovarian
tumors and early stage ovarian cancers can be treated less aggressively, leading to the possibility of
Tom Bourne, 08/20/15,
Need this reference as well:A multicenter prospective external validation of the diagnostic performance of IOTA simple descriptors and rules to characterize ovarian masses.Sayasneh A, Kaijser J, Preisler J, Johnson S, Stalder C, Husicka R, Guha S, Naji O, Abdallah Y, Raslan F, Drought A, Smith AA, Fotopoulou C, Ghaem-Maghami S, Van Calster B, Timmerman D, Bourne T.Gynecol Oncol. 2013 Jul;130(1):140-6.
fertility preservation in younger women (13, 14). On the other hand metastatic ovarian cancers should
be managed according to the origin of the primary cancer (14).
ADNEX is based on three clinical and six ultrasound parameters (15). The model was developed and
temporally validated using parameters collected by experienced (or level III) ultrasound examiners
(15, 16). The primary aim of this project was to externally validate the ADNEX model. The secondary
aim was to assess the performance of the model by level II examiners with varied training (MDs and
sonographers) (15, 16).
Methods
Settings and design
This was a cross-sectional multicenter cohort study for diagnostic accuracy. Data was collected
prospectively, including the ultrasound variables required for the ADNEX model, from transvaginal
ultrasound examinations performed by level II ultrasound examiners (ref for level II). Results using
the ADNEX model were calculated by a single investigator AS using a dedicated excel spreadsheet.
The final histological outcome was then added to the same spreadsheet at a later date when results
became available. Accordingly the ultrasound examiners and investigator calculating the result of the
ADNEX model were blind to the results of the reference test. Patients were recruited from three
cancer centers (Queen Charlotte’s Chelsea Hospital (QCCH), London, UK; Princess Ann Hospital
(PAH), Southampton, UK; Garibaldi Nesima Hospital (GNH), Catania, Italy). The study was
approved as a service evaluation audit at the UK centers and as a validation study by the hospital
authority at the Italian center. The guidelines of the STARD (Standards for Reporting of Diagnostic
Accuracy) initiative were used (17). Patients were recruited consecutively from September 2010 to
November 2014 at QCCH, May 2012 to May 2014 at PAH and September 2012 to February 2015 at
GNH. All patients from GNH and 12 patients from QCCH were recruited into the IOTA 5 study
(https://clinicaltrials.gov/ct2/show/NCT01698632). Patients at QCCH and PAH were recruited also to
the IOTA 4 study (12). All ultrasound examiners received a half-day theoretical training session on
IOTA terminology and the ultrasound variables included in IOTA models. Transvaginal
Table 2. The area under the receiver operator curve for the discrimination between benign and malignant lesions for ADNEX with and without CA 125 according to type of center and sonographer
Area under the ROC curve
Lower confidence limit
Upper confidence limit
ADNEX without CA-125
All patients 0.925 0.902 0.943
Profession operator
MD 0.924 0.900 0.943
Sonographer 0.916 0.818 0.964
Center GNH 0.983 0.950 0.995
QCCH 0.931 0.900 0.953
PAH 0.889 0.828 0.930
Menopausal status
Premenopausal 0.935 0.901 0.958
Postmenopausal 0.873 0.824 0.910
ADNEX with CA-125
All patients 0.937 0.915 0.954
Profession operator
MD 0.939 0.917 0.956
Sonographer 0.912 0.809 0.962
Center GNH 0.990 0.959 0.998
QCCH 0.942 0.913 0.962
PAH 0.900 0.841 0.938
Menopausal status
Premenopausal 0.939 0.901 0.963
Postmenopausal 0.899 0.855 0.931
ROC: Receiver operator curve, MD: medically qualified doctor, QCCH: Queen Charlottes and Chelsea Hospital, PAH: Princess Anne Hospital, Southampton, GNH: Garibaldi Nesima Hospital
Table 3. The overall sensitivity and specificity (Benign vs. Malignant) of the ADNEX model with and without the inclusion of serum CA125