Aims and endpoints
The aim of this study is to evaluate the added value of CEM in standard clinical preoperative staging of breast cancer regarding potential changes in the treatment plan, the number of (unnecessary) mastectomies and the frequency of reoperation. Furthermore, we will assess whether the potential added value of CEM is influenced by age, pre−/postmenopausality, breast density, type of cancer, the presence of micro calcifications and mode of detection (screening or clinical symptoms).
Primary endpoint
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Do preoperative CEM findings lead to significant changes in the primary treatment plan?
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Mastectomy instead of partial mastectomy, or vice versa
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Bilateral surgery instead of unilateral surgery due to findings of contralateral disease
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Neoadjuvant therapy instead of primary surgery
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Axillary clearance instead of sentinel node biopsy
Secondary endpoints
1.
Do preoperative CEM findings affect the frequency of reoperation or the number of pathologically avoidable mastectomies?
2.
Does preoperative CEM show better accuracy in tumor size estimation than mammography and ultrasound, in comparison with histopathological examination?
3.
Do other factors such as age, postmenopausality, breast density, type of cancer, or the presence of micro calcifications influence the added value of CEM regarding changes in the treatment plan and tumor size estimation?
4.
Is there a difference in health-related quality of life between patients that have undergone preoperative CEM and those who have not?
5.
What are the costs and benefits of additional CEM in a health-economic perspective?
6.
Does preoperative CEM affect the number of loco regional recurrences/ipsilateral new cancers or contralateral cancer within 5 years?
Patient enrollment
Potential participants in this prospective multicenter trial will be identified at preoperative multidisciplinary team (MDT) conferences after diagnostic work-up of suspicious breast cancer detected by mammographic screening or clinical symptoms. The study will include 440 patients with strongly suspected or an established diagnosis of primary breast malignancy, for whom surgery is planned to involve either partial or total mastectomy based on mammography, ultrasound and core biopsy or cytological examinations. The participants will be randomized either to additional imaging with CEM or to no further preoperative imaging. The findings of CEM will be considered at a second MDT conference, at which changes may be made to the primary treatment plan. The inclusion and exclusion criteria are given in Table
1.
Table 1
Inclusion and exclusion criteria
Inclusion criteria | Planned primary surgery for suspected or verified primary breast malignancy |
Age ≥ 18 years |
Signed informed consent |
Exclusion criteria | Planned neoadjuvant therapy |
On-going pregnancy |
Iodinated contrast agent allergy |
Renal disease or abnormal S-creatinin (normal range 45–90 μmol/l) |
Untreated thyrotoxicosis (including multinodular goitre) (upon suspicion check P-thyrotropin level, exclusion if < 0.4 mIE/l) |
Severe heart failure |
Myastenia gravis |
Breast implant |
Local recurrence as index lesion |
Inability to understand oral or written information about the study |
Study inclusion started in November 2020 and inclusion of the required number of participants is expected to take between two and 3 years depending on the ongoing pandemic of Covid-19. Patients diagnosed at the breast centers in Helsingborg, Kristianstad and Halmstad in Sweden, will be included.
Pre- and postoperative assessment and data collection
At study inclusion, a primary treatment plan must have been decided upon, based on information obtained from findings at mammography, ultrasound, and core biopsy/cytology, according to current clinical standards. (Additional file
3). This plan may be subject to change after the clinical examination at the appointment when the diagnosis is given to the patient, as a result of findings of a larger or smaller tumor size in relation to breast volume, or due to comorbidity that may contraindicate a certain treatment. Any changes in the primary treatment plan after clinical examination must be clearly documented and motivated before CEM. (Additional file
5).
At the CEM examination, suspicious malignant findings will be noted according to a predefined protocol and if malignant-suspicious areas not previously located are identified by CEM they will be subjected to US-guided biopsy. The results of CEM will then be discussed at a second MDT conference, and taken into consideration in the primary treatment plan. (Additional file
8).
The whole study population will answer a short study-specific questionnaire including questions regarding possible allergy to iodinated contrast agent, weight and height, pre- or post menopausality, use of oral contraceptives, hormone replacement therapy or endocrine treatment after breast cancer, on-going pregnancy or breast-feeding, other diseases, previous surgery or radiotherapy to the breasts, and breast implants. This questionnaire will be administered at the appointment when the patient is informed about the study. Patients will also answer the preoperative version of the Breast-Q™ questionnaires [
23]. These are globally used and validated patient-reported outcome measures. The Breast-Q™ questionnaires are currently the only validated, disease-specific questionnaires designed to evaluate different aspects of health-related quality of life and patient satisfaction related to breast cancer surgery.
The renal function of patients will be checked (normal range of serum creatinine 45–90 μmol/l) before the study inclusion, as the iodinated contrast agent may affect renal function.
A study-specific predefined imaging reporting protocol will be used for all imaging methods (DM, US and CEM), to assess morphological changes (solid tumors and/or micro calcifications), location of the lesions, size of each lesion and total extent of the malignant area (Additional files
1,
2,
6 and
7). The estimates of size will then be compared with the results from histopathological examination, which is considered to be the reference standard. Mammographic breast density will be evaluated according to the classification of American College of Radiation, Breast Imaging Reporting and Data System, 5th Edition (ACR BI-RADS) [
24]. Background parenchymal enhancement on CEM will be classified as minimal, mild, moderate and marked. Findings will be classified as mass/lesion (visible on at least two views) or non-mass enhancement in as focal, linear, segmental regional, multiple regions, diffuse. Visual assessment of level of CEM enhancement in lesion/area will be reported as mild, moderate or marked. Classification of background parenchymal enhancement, findings and level of enhancement are described for MRI in ACR BI-RADS 5th edition [
24], and will in this study be adapted for CEM, as suggested by Lobbes et al. [
25]. Breast volume will be calculated from mammography images from measurements of width,
w, and height,
h, from the cranio-caudal projection of the mammogram, together with the compression,
c (thickness of the breast when compressed during mammography), defining the breast as a half-elliptical cylinder, using the equation:
\( volume\ \left({cm}^3\right)=\raisebox{1ex}{$\pi $}\!\left/ \!\raisebox{-1ex}{$4$}\right.\times whc \) (cm) [
26,
27]. (Additional file
4). A software will also be used to calculate breast density and volume, for example Libra or Volpara™.
Information will be obtained from the histopathological report on the total tumor extent, the size of each tumor if multiple tumors, the type of cancer (ductal, lobular, other), uni−/multifocality, ductal carcinoma in situ (DCIS) / pleomorphic lobular carcinoma in situ (LCIS), histological grade, biomarkers: estrogen receptor, progesterone receptor, Her-2 status and Ki67. The total tumor extent will be given including and excluding classic LCIS (LCIS-C) when present. LCIS-C does not affect treatment and is usually not visible at imaging. Data on adverse events related to CEM, e.g. the use of the iodinated contrast agent, will be collected directly after the examination and recorded. (Additional file
9).
The CEM examinations will be performed using a Senographe Pristina™ mammography system equipped with the software SenoBright™ HD for CEM (GE Healthcare). The CEM images will be read by at least two experienced radiologists in consensus, and with access to the images and results of routine clinical imaging. If additional tumors are found compared to the initial routine clinical imaging, a second-look US examination will be performed.
Data collection
Data will be collected from the study-specific questionnaire, the Breast-Q™ questionnaire, medical records, Sectra IDS7 (the radiology information system, picture archive and communication system) and LIMS (laboratory information management system for histopathology reports) Data will be recorded in REDCap (a web-based application for electronic data capture in research studies) electronic case report forms (e-CRF) administered and monitored by Clinical Studies Sweden – Forum South, Region Skåne.
Health-economic evaluation
Economic evaluation is a technique of identifying, measuring, valuing, and comparing the costs and consequences of two or more alternative programs or interventions [
28]. Therefore, it is an analysis of costs and benefits (effects) between two or more alternatives. In the current study additional CEM will be compared to the current standard procedure i.e. only mammography and ultrasound. The perspective of analysis is important as it determines which costs and benefits should be included. The analysis will be performed from a healthcare perspective. The healthcare perspective is only concerned with costs burdening the healthcare sector, although the health benefits of the patients are the effectiveness measure.
The cost of the intervention and standard procedure for the control group can be calculated based on empirical data collected during the trial. The cost related to healthcare utilization will be obtained from the Skane register database. The effectiveness of trial will be measured as rate of reoperation and number of avoidable mastectomies. Furthermore, the patient-reported health-related quality of life at 1 year measured with the validated Breast-Q™ questionnaire will be used.
Irrespective of the measurement unit of the effectiveness, the results will be presented in terms of incremental cost-effectiveness ratios (ICERs) [
28], which show the cost of an extra benefit for the intervention comparing to the control group. The results will be presented in a cost-effectiveness plane where the effectiveness and costs measures will be included as a distribution. The distribution will be obtained from individual level cost and effects data and the confidence interval will be obtained from bootstrapping [
29]. In sensitivity analysis, a cost-effectiveness acceptability curve will be presented with a well-accepted willingness-to-pay value in Swedish circumstances [
30].
The following broad cost and benefit categories will be included in the evaluation:
Cost categories
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Cost of Intervention – additional CEM – above standard procedure
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Cost of standard procedure
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Healthcare utilization during the trial duration such as inpatient care including operations, outpatient care, primary care visits as well as cost for medication and medical-technical products.
Benefit categories
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Changes in treatment pattern
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Rate of reoperation
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Number of avoidable mastectomies
-
Health-related quality of life
Subgroup analyses of different cost-effectiveness of the intervention based on age-group, will also be performed. Extensive sensitivity analyses will be conducted to capture the uncertainty of the findings. For example, only the cost related to the breast cancer will be considered in sensitivity analysis.