The PROCEM study protocol: Added value of preoperative contrast-enhanced mammography in staging of malignant breast lesions - a prospective randomized multicenter study

- Background: Correct preoperative estimation of the malignant extent is crucial for optimal planning of breast cancer surgery.
- CEM may be more cost- effective than MRI, and may provide better identification of the tumor extent, however, no randomized trials have been performed to date to investigate the added value of CEM..
- The purpose of the present study is to evaluate the added value of CEM in preoperative staging of breast cancer in a randomized study..
- Patients will be randomized 1:1 using a web-based randomization tool to additional investigation with CEM or no further imaging.
- The CEM findings will be taken into consideration, which may lead to changes in primary treatment, which is the primary endpoint of this study.
- Patient-reported health-related quality of life will be investigated at 1 year with the validated Breast-Q ™ questionnaire.
- The rate of local recurrence or new cancer ipsi- or contralaterally within 5 years will be assessed from medical records and pathology reports..
- Full list of author information is available at the end of the article.
- Regardless of the method of detection, “triple assess- ment” should be performed.
- In screening mammography, two projections of the breast are used, the cranio-caudal and medio-lateral oblique, while in the diagnostic work- up the medio-lateral view is added, and additional spe- cial projections may also be acquired.
- It is, however, important to note that the added value of hand-held US depends largely on the experience of the examiner.
- Accurate preoperative delineation of the tumor is important in optimizing the results of surgery and reducing the risk of reoperation and unnecessary mastectomy.
- It has been reported that US provides better estimates of the extent of the tumor than DM [7, 8], although both methods were found to underestimate the extent of the tumor compared with the results of histopathological examination [7]..
- Final images of the enhancement are obtained using a subtraction technique.
- CEM has also been reported to provide better delineation of the extent of malignant changes than mammography.
- Results of the feasibility study.
- partial mastectomy instead of mastectomy due to improved demarcation of the tumor in one patient.
- Agreement with histopathological findings re- garding preoperative estimation of the size of the malig- nant changes was better with CEM (Bland Altman statistics: mean difference − 1.36, SD ± 18.45) than with mammography.
- 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 participants will be randomized either to additional imaging with CEM or to no further preoperative imaging.
- The find- ings of CEM will be considered at a second MDT con- ference, at which changes may be made to the primary treatment plan.
- Study inclusion started in November 2020 and inclu- sion of the required number of participants is expected to take between two and 3 years depending on the on- going pandemic of Covid-19.
- Patients diagnosed at the breast centers in Helsingborg, Kristianstad and Halmstad in Sweden, will be included..
- At the CEM examination, suspicious malignant find- ings 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.
- This ques- tionnaire 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™ ques- tionnaires [23].
- 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).
- 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.
- Visual assessment of level of CEM enhancement in lesion/area will be re- ported as mild, moderate or marked.
- Breast vol- ume 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 ð cm 3 Þ ¼ π = 4 whc (cm) [26, 27].
- Information will be obtained from the histopatho- logical 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.
- The total tumor extent will be given including and excluding clas- sic LCIS (LCIS-C) when present.
- the use of the iodin- ated contrast agent, will be collected directly after the examination and recorded.
- The CEM examinations will be performed using a Seno- graphe Pristina™ mammography system equipped with the software SenoBright™ HD for CEM (GE Healthcare).
- The CEM images will be read by at least two experienced radi- ologists 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 will be collected from the study-specific questionnaire, the Breast-Q ™ questionnaire, medical records, Sectra IDS7 (the radiology information system, picture archive and com- munication system) and LIMS (laboratory information management system for histopathology reports) Data will be recorded in REDCap (a web-based application for elec- tronic data capture in research studies) electronic case re- port forms (e-CRF) administered and monitored by Clinical Studies Sweden – Forum South, Region Skåne..
- Web-based un-blinded simple randomization will be performed in REDCap by a randomization tool.
- will be randomized 1:1 to either arm A, additional pre- operative CEM or arm B, no further preoperative im- aging.
- Randomization will be stratified between sites.
- All patients who fulfil the inclusion criteria will be registered in a screening log on-site..
- A study nurse on each site will register data in REDCap and members of the steering committee will monitor data regularly.
- All patients will be followed up according to Swedish national guidelines after breast cancer treatment with annual mammography up to 10 years and physical examination after 1 year.
- At the 1- year follow-up patients will answer the postoperative version of the Breast-Q™ questionnaire, which will be ad- ministered either by post or at the one-year check-up appointment.
- After 5 years, the patient’s medical records will be reviewed to evaluate the number of local recur- rences or a new primary cancer ipsi- or contralaterally..
- Based on the assumption that treatment planning will be modified in 18% of patients undergoing CEM, 195 pa- tients will be needed in each arm to show that this pro- portion is significantly larger than a null proportion of 10%, using a power of 90% and an alpha value (two- sided) of 5%.
- The power calculation for the number of partici- pants in this study is based partly on the result of the feasibility study, in which changes were made in the treatment plan in 10 out of 47 cases (21%) after CEM [21].
- The results of the present study will thus also be compared with those of the POMB study in which preoperative MRI was used [13] resulting in changes in the treatment plan in 18% of cases..
- Descriptive statistics for parametric variables will be expressed as the median, interquartile range and range..
- Descriptive statistics for non-parametric variables will be presented as frequencies and percentages.
- Fisher’s exact test will be used to identify differences between groups and subgroups when applicable..
- Pearson’s correlation coefficient and Bland–Altman statistics will be used for each modality regarding pre- operative size estimation of the malignant changes com- pared with histopathological examination.
- median values of the largest individual lesion and the total extent will be presented.
- A separate analysis will be carried out for an extent maximum of 5 cm due to the limitations in assessment by US due to the size of the probe..
- In the current study additional CEM will be compared to the current standard procedure i.e.
- The analysis will be performed from a healthcare perspective.
- The healthcare perspec- tive is only concerned with costs burdening the health- care 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 empir- ical 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 mea- sured as rate of reoperation and number of avoidable mastectomies.
- related quality of life at 1 year measured with the vali- dated Breast-Q™ questionnaire will be used..
- Irrespective of the measurement unit of the effective- ness, the results will be presented in terms of incremen- tal 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 distribu- tion will be obtained from individual level cost and ef- fects 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 cir- cumstances [30]..
- The following broad cost and benefit categories will be included in the evaluation:.
- Subgroup analyses of different cost-effectiveness of the intervention based on age-group, will also be performed..
- Extensive sensitivity analyses will be conducted to cap- ture the uncertainty of the findings.
- For example, only the cost related to the breast cancer will be considered in sensitivity analysis..
- The results of this study will be published in scientific journals.
- Patient data will be replaced by Study ID.
- The data will be stored securely and will only be accessible by the investigators by personal login on both the com- puter and the database.
- Im- portant changes in the protocol will be directly reported to investigators and to the register..
- However, the benefit of the reduced risk of reoperation may outweigh this discomfort..
- However, a thorough analysis of the tumor biol- ogy of the additional findings will provide important infor- mation to indirectly address these questions..
- Both oral and written in- formation on possible allergy will be obtained before examination to minimize this risk.
- Participation in the study may result in improved size estimation of the malignant changes and possible detection of pathological lesions in the other breast.
- The CEM examination may detect changes in the breast that may not be relevant for the health of the patient and would perhaps never develop into any disease that would harm the patient or threaten the patient’s life..
- Some of the findings of CEM may lead to further assess- ment and/or operations that are not necessary.
- However, it is today not known which malignant changes will be- come hazardous and which will remain harmless.
- However, as the CEM ex- aminations in this study will be performed in patients who will be undergoing surgery for a malignancy, the enhanced area will either be removed during surgery or be subjected to radiotherapy.
- However, these cases will be discussed at MDT conferences and followed up according to clinical routine, or an individ- ual follow-up plan if considered necessary..
- We gratefully acknowledge the contributions of the radiologists Rogvi Rasmussen, for his knowledge of the CEM imaging technique, Catharina Behmer, for making equipment available for this study, Eva Johansson, Tamara Kadezabek, Maria Madestam and Katarina Rönnow, for valuable input in conducting the imaging reporting protocols.
- KÅ is the sponsor and the coordinating investigator of the PROCEM study..
- KÅ, SZ, LR and EN are members of the steering committee.
- None of the funding bodies has any part in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript.
- This study will be conducted in accordance with the Declaration of Helsinki and according to national guidelines and regulations.
- Oral and written information about the study will be given to the patient by the surgeon at the appointment when the patient is informed of her diagnosis and the plan for primary surgery is discussed.
- Written informed consent will be obtained from all the participants..
- https://doi.org/10.1016/S .
- https://doi.org/10.1007/s .
- The potential of multiparametric MRI of the breast.
- Mammography: an update of the EUSOBI.
- Preoperative MRI of the breast (POMB) influences primary treatment in breast cancer: a prospective, randomized, multicenter study.
- https://doi.org/10.1007/s z..
- https://doi.org .
- Breast Cancer (Auckl)

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