Clinical trial NCT02638935: Evaluation of Virtual Touch Tissue Imaging Quantification (VTIQ - 2D-SWE) in the Assessment of BI-RADS® 3 and 4 Lesions
Official title: Evaluation of Virtual Touch Tissue Imaging Quantification (VTIQ - 2D-SWE) in the Assessment of BI-RADS® 3 and 4 Lesions: Can Patient Selection for Biopsy be Improved? - A Confirmatory Multi-Center-Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Breast Neoplasms
Keywords: Virtual Touch Tissue Imaging
VTIQ
Elastography
Breast Cancer
BI-RADS
Differentiation of breast lesions
Breast Lesion
Lead sponsor: Heidelberg University
Sponsor class: OTHER
Collaborators: name: Siemens Medical Solutions
First posted: 2015-12-23
Enrollment: 1304
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: The primary aim of this study is to evaluate if VTIQ in addition to BI-RADS® categorization can improve the diagnostic accuracy with respect to detection of malignancies, in particular for BI-RADS® categories 3 and 4a. The idea of the study is to restage all patients in categories 3 and 4a according to a predefined VTIQ cut-off value of ≥ 3.5 m/s (37 kPa).

Detailed description: Elastography is a method of imaging tissue stiffness. It is based on shear wave velocity information that can be mapped to create an image of the stiffness in the region of interest.

Sonoelastography is used to differentiate benign from malignant lesions since malignant lesions alter tissue elasticity.

Adding Shear Wave elastographic features to BI-RADS® feature analysis- especially in lesions scored BI-RADS® 3 and 4a- improved specificity of breast US mass assessment without loss of sensitivity.

The BI-RADS® categories are defined by the risk for a malignant lesion varying from benign BI-RADS® 2 lesions, up to a 2% malignancy rate in BI-RADS® 3 and 2- 95% in BI-RADS® 4 (4a 2-10%; 4b 10-50%; 4c 50-95%). Based on these probabilities, biopsies are recommended for BI-RADS® 4 and 5 lesions and short-term follow-up examinations for BI-RADS® 3. Consequently, up to 2% of the in Ultrasound visible breast cancers are not directly detected as such and put into the BI-RADS® 3 category. In contrast, in the BI-RADS® 4a category more than 90% of the biopsies are unnecessary.

The main aim of the confirmatory study is to use Virtual Touch Tissue Imaging Quantification in order to reduce unnecessary benign biopsies without a reduction of the number of detected cancers.

This multi-center study is planned to involve 12 sites in 7 countries. Recruitment started at the first sites in February 2016. Recruitment takes place in the course of the patient's routine visit at a certified breast unit. All study participants will receive VTIQ in addition to standard ultrasound.

Enrollment goal is a total of 1000 cases, split into groups of a minimum of n= 300 BI-RADS® 3, n= 400 BI-RADS® 4a, n= 100 BI-RADS® 4b, n= 100 BI-RADS® 4c. All patients will be documented in a screening list. Monitoring will be performed by the Coordination Center for Clinical Trials (KKS Heidelberg). Completeness, validity and plausibility of data will be checked in time of data entry (edit-checks) and using validating programs, which will generate queries. The investigator or the designated representatives are obliged to clarify or explain the queries. If no further corrections are to be made in the database it will be closed and used for statistical analysis. All data management procedures will be carried out on validated systems and according to the current Standard Operating Procedures (SOPs) of the Institute of Medical Biometry and Informatics.

The standard BI-RADS® Ultrasound (US) category (BI-RADS® 3-4c) and VTIQ values will be correlated with the histological result. Additionally, local (BI-RADS® given at each site) and central expert BI-RADS® assessment will be compared (BI-RADS® assessment and assessment of the variables leading to the BI-RADS® value separately) to assess the inter-rater reliability. In addition, the BI-RADS® assessments will be compared with the histological results.

The variable "measurement lesion (in m/s)" is derived from three VTIQ measurements as follows:

I. For confirmatory analysis of primary objectives an algorithm was established,

1. using the first measurement for analysis if the value is smaller than 2.5 m/s or if the value is larger than 4.5 m/s. If the first measurement is smaller than 2.5 m/s, the lesion can be considered benign and no further diagnostics is needed. If the lesion is larger than 4.5 m/s the lesion should be considered suspicious and further diagnostics is required.
2. requiring two additional measurements (in total three measurements) if the first measurement is in the range of ≥ 2.5 m/s to ≤ 4.5 m/s. In this case the average of all three measurements is used for analysis.

II. For descriptive analysis other options for derivation of this variable from the three VTIQ measurements will be calculated for discussion:

1. First measurement only
2. Average of all three measurements
3. Median of all three measurements
4. Maximum of all three measurements

In conjunction with the maximum VTIQ shear wave velocity the quality display will be used to aid in the classification of lesions as malignant or benign as follows:

1. If the shear wave velocity ≥ the cut-off value (3.5 m/s), the lesion is considered potentially malignant, regardless of the outcome of the quality factor
2. If a lesion or lesion rim has a completely high quality factor (all green) and a shear wave velocity \< the cut-off value (3.5 m/s), the lesion is considered benign.
3. If a lesion or lesion rim has mixed high and low quality factors (there are areas with low quality within the mass) and the only area of high quality (green) has a shear wave velocity \< the cut-off value (3.5 m/s), then the lesion is indeterminate and malignancy cannot be excluded.

Eligibility criteria: Inclusion Criteria:

* Female
* Age ≥18 years
* Patients with a lesion ≥ 0.5 cm in largest diameter size, initially scored BI-RADS® 3, 4a, 4b or 4c in B-mode ultrasound
* Informed consent about histological examination (core cut biopsy (CCB), vacuum-assisted biopsy (VAB), fine needle aspiration (FNA) or surgery) has already been given in the course of clinical routine
* Signed informed consent of study participation

Exclusion Criteria:

* Pregnant or lactating women
* Women with breast implants on the same side as the lesion
* Women that underwent local radiation or chemotherapy within the last 12 months
* Women with history of breast cancer or breast surgery in the same quadrant
* Lesions in or close to scar tissue (\< 1cm)
* Skin lesions or lesions that have been biopsied previously
* Lesion larger than 4 cm in the longest dimension
* No lesion should be included when more than 50% of the lesion is further down than 4 cm beneath the skin level.

Primary outcomes:
measure: Standard chi-square test at a two-sided significance level of 5% to test the diagnostic accuracy of Virtual Touch Tissue Imaging Quantification (VTIQ) in the differentiation of BI-RADS® 3 and 4a lesions
timeFrame: 2 years
measure: Standard Binomial-test according to Bonferroni-Holm to test the null hypothesis H0_2
timeFrame: 2 years
measure: Standard Binomial-test according to Bonferroni-Holm to test the null hypothesis H0_3
timeFrame: 2 years
Secondary outcomes:
measure: Corresponding chi-square tests for descriptive analysis of Virtual Touch Tissue Imaging Quantification (VTIQ) in the assessment of BI-RADS® 3, 4b, 4c lesions
timeFrame: 2 years
measure: BI-RADS® vs. BI-RADS® + Virtual Touch Tissue Imaging Quantification (VTIQ)
timeFrame: 2 years
measure: Corresponding chi-square tests for descriptive analysis of the strain ratio in the differentiation of BI-RADS® 3, 4a, 4b or 4c lesions
timeFrame: 2 years
measure: Robust regression models to test the INTRA-RATER reliability for the original continuous scale
timeFrame: 2 years
measure: Cohens's Kappa to test the INTRA-RATER reliability for the dichotomized values
timeFrame: 2 years
measure: Robust regression models to test the INTER-RATER reliability for the original continuous scale
timeFrame: 2 years
measure: Cohens's Kappa to test the INTER-RATER reliability for the dichotomized values
timeFrame: 2 years
measure: Descriptive analysis of predictive factors of the continuous VTIQ-value
timeFrame: 2 years
measure: Skin to breast lesion surface depth (cm)
timeFrame: 2 years
measure: Quality factor within the lesion assessed using a color coded scale
timeFrame: 2 years
measure: Breast density/ tissue composition assessed using the morphologic characteristics on US (homogeneous background texture fat, homogeneous background texture fibroglandular, heterogeneous background texture)
timeFrame: 2 years
measure: Lesion size in B-mode Ultrasound (in cm)
timeFrame: 2 years
measure: Normal fatty tissue shear wave velocity (ratio between measurement in the fatty tissue and in the lesion)
timeFrame: 2 years
measure: Pathology (fibroadenoma, lipoma, atypia, cyst condense, "non special type" (NST), invasive lobular carcinoma (ILC), invasive tubular carcinoma (ITC), carcinoma with medullary features, papillary cancer, ductal carcinoma in situ (DCIS), others)
timeFrame: 2 years
measure: Grading (G1, G2, G3, Gx)
timeFrame: 2 years
measure: Immunohistology (estrogen receptor (ER) status positive/ negative, progesterone receptor (PgR) status positive/ negative, human epidermal growth factor receptor 2 (HER2-neu) status positive/ negative, Ki-67 status (%))
timeFrame: 2 years
measure: Cohens's Kappa to determine the inter-rater reliability of BI-RADS® Assessment (local vs. central assessment)
timeFrame: 2 years
measure: Interclass correlation coefficient (ICC) values to determine the inter-rater reliability of BI-RADS® Assessment (local vs. central assessment)
timeFrame: 2 years
measure: BI-RADS® vs. histological results
timeFrame: 2 years
measure: Chi-square test to examine whether the cut-off value of ≥ 3.5 m/s (37kPa) might be increased by increasing the cut-off value step-by-step by a small amount and repeat the primary analysis
timeFrame: 2 years
Other outcomes:
Locations:
city: Youngstown
country: United States
facility: Radiology Consultants, Inc.
state: Ohio
city: Villejuif
country: France
facility: Institut Gustave Roussy, Service de Radiologie, Villejuif Cedex
city: Bielefeld
country: Germany
facility: Franziskus Hospital
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald, Klinik für Frauenheilkunde und Geburtshilfe
city: Heidelberg
country: Germany
facility: University of Heidelberg
city: Marburg
country: Germany
facility: Universitätsklinikum Marburg, Klinik für Gynäkologie, gyn. Endokrinologie und Onkologie Senologische Diagnostik & Gynäkologischer Ultraschall
city: München
country: Germany
facility: LMU Klinikum der Universität München
city: Tubingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Kagoshima
country: Japan
facility: Sagara Hospital
state: Matsubaracho, Kagoshima-shi
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Hospital
city: Coimbra
country: Portugal
facility: Centro Hospitalar e Universitário de Coimbra, Departamento de Radiologia
Study officials:
affiliation: University of Heidelberg, Department of Gynecology, Breast Unit
name: Michael Golatta, PD Dr. med., MHBA
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Cosgrove DO, Berg WA, Dore CJ, Skyba DM, Henry JP, Gay J, Cohen-Bacrie C; BE1 Study Group. Shear wave elastography for breast masses is highly reproducible. Eur Radiol. 2012 May;22(5):1023-32. doi: 10.1007/s00330-011-2340-y. Epub 2011 Dec 31.
citation: Balleyguier C, Canale S, Ben Hassen W, Vielh P, Bayou EH, Mathieu MC, Uzan C, Bourgier C, Dromain C. Breast elasticity: principles, technique, results: an update and overview of commercially available software. Eur J Radiol. 2013 Mar;82(3):427-34. doi: 10.1016/j.ejrad.2012.03.001. Epub 2012 Mar 24.
citation: Barr RG, Destounis S, Lackey LB 2nd, Svensson WE, Balleyguier C, Smith C. Evaluation of breast lesions using sonographic elasticity imaging: a multicenter trial. J Ultrasound Med. 2012 Feb;31(2):281-7. doi: 10.7863/jum.2012.31.2.281.
citation: Barr RG. Sonographic breast elastography: a primer. J Ultrasound Med. 2012 May;31(5):773-83. doi: 10.7863/jum.2012.31.5.773.
citation: Evans A, Whelehan P, Thomson K, Brauer K, Jordan L, Purdie C, McLean D, Baker L, Vinnicombe S, Thompson A. Differentiating benign from malignant solid breast masses: value of shear wave elastography according to lesion stiffness combined with greyscale ultrasound according to BI-RADS classification. Br J Cancer. 2012 Jul 10;107(2):224-9. doi: 10.1038/bjc.2012.253. Epub 2012 Jun 12.
citation: Golatta M, Pfob A, Busch C, Bruckner T, Alwafai Z, Balleyguier C, Clevert DA, Duda V, Goncalo M, Gruber I, Hahn M, Kapetas P, Ohlinger R, Rutten M, Togawa R, Tozaki M, Wojcinski S, Rauch G, Heil J, Barr RG. The potential of combined shear wave and strain elastography to reduce unnecessary biopsies in breast cancer diagnostics - An international, multicentre trial. Eur J Cancer. 2022 Jan;161:1-9. doi: 10.1016/j.ejca.2021.11.005. Epub 2021 Dec 5.