An Assessment of the Impact of CONTrast ENhanceD Mammography (CESM) on Patient Management and Comparison With MRI (CONTEND Study)
Phase: NA
Conditions: Breast Cancer
Sponsor: Cambridge University Hospitals NHS Foundation Trust

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Study Title:  An assessment of the impact of CONTrast ENhanceD Spectral Mammography 
(CESM) on patient management and comparison with MRI  (CONTEND Study) 
Ethics Ref:  
15/EE/0279 
Version no:  
4.0  
 
Date:  
23rd February 2016 
 
Chief Investigator: 
Professor Fiona J Gilbert 
University Department of Radiology, Level 5, Addenbrooke’s 
Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge, 
CB2 0QQ 
fjg28@medschl.cam.ac.uk 
01223 746439 
Co-Investigator:  
Dr Matthew Wallis 
Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge 
Biomedical Campus, Hills Road, Cambridge, CB2 0QQ 
matthew.wallis@addenbrookes.nhs.uk 
01223 585992 
Co-Investigator: 
Dr Vasiliki Papalouka 
Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge 
Biomedical Campus, Hills Road, Cambridge, CB2 0QQ 
vasiliki.papalouka@addenbrookes.nhs.uk 
01223 585992 
Trial Manager / Coordinator: 
Ms Paula Willsher 
Cambridge Breast Unit, Box 97, Addenbrooke’s Hospital, 
Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 
0QQ 
Paula.willsher@addenbrookes.nhs.uk 
01223 348931 
Trial Statistician: 
None 
Other Collaborators: 
Dr Penelope Moyle 

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Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge 
Biomedical Campus, Hills Road, Cambridge, CB2 0QQ 
penelope.moyle@addenbrookes.nhs.uk 
01223 585992 
 
Sponsor:  
Cambridge University NHS Foundation Trust 
Cambridge Biomedical Campus, Hills Road, Cambridge 
CB2 0QQ 
 
University of Cambridge 
Cambridge Biomedical Campus, Hills Road, Cambridge 
CB2 0QQ 
 

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1. PROTOCOL SIGNATURES: 
I give my approval for the attached protocol entitled ‘An assessment of the impact of 
Contrast Enhanced Spectral Mammography (CESM) on patient management and 
comparison with MRI (CONTEND Study)’ dated 24th March 2015. 
Chief Investigator 
Name:             Professor Fiona J Gilbert 
Signature: 
________________________________________ 
Date: 
____________________________ 
 
Site Signatures 
I have read the attached protocol entitled ‘An assessment of the impact of Contrast 
Enhanced Spectral Mammography (CESM) on patient management and comparison with 
MRI (CONTEND Study)’, dated 24th March 2015 and agree to abide by all provisions set 
forth therein. 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in 
the European Clinical Trials Directives 2001/20/EC and the GCP Directive 2005/28/EC. 
I agree to ensure that the confidential information contained in this document will not be used 
for any other purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of the Sponsor 
 
Principal Investigator 
Name:  
Signature: 
________________________________________ 
Date: 
____________________________ 
 
Principal Investigator 
Name:  
Signature: 
________________________________________ 
Date: 
____________________________ 

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2. AMENDMENT HISTORY 
List details of all protocol amendments here whenever a new version of the protocol is 
produced. 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) of changes 
Details 
of 
Changes 
made 
01 
2.0 
11.05.15 
Lorraine Tucker 
Insertion 
of 
text 
to 
Section 5, Study design, 
page 8, following peer 
review. 
02 
3.0 
02.09.15 
Lorraine Tucker 
Following 
provisional 
opinion from REC: 
Removal of all reference 
to Stage-1:Pre-Pilot. 
02 
3.0 
02.09.15 
Lorraine Tucker 
Following 
provisional 
opinion from REC: 
Amendments 
to 
flow 
chart (page 24) and 
patient 
contrast 
questionnaire (page 25). 
02 
3.0 
02.09.15 
Lorraine Tucker 
Following 
provisional 
opinion from REC: 
Amendments 
to 
9.1, 
Serious 
Adverse 
Effects. 
03 
4.0 
24.02.16 
Fiona J Gilbert 
Change 
of 
trial 
coordinator 
03 
4.0 
24.02.16 
Fiona J Gilbert 
Change 
of 
contrast 
agent and risk profile 
03 
4.0 
24.02.16 
Fiona J Gilbert 
Contact name changes 
on PIS and consent 
form. 
03 
4.0 
24.02.16 
Paula Willsher 
In accordance with trust 
policy 
an 
additional 
question 
has 
been 
added to the patient 
contrast questionnaire 
 
 
 
 
 
 
 
 
 
 

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3. TABLE OF CONTENTS 
1 
Protocol Signatures: ........................................................................................................... 3 
2 
Amendment History ............................................................................................................ 4 
3 
Table of Contents ............................................................................................................... 5 
4 
Abbreviations ..................................................................................................................... 7 
5 
Study Synopsis .................................................................................................................. 8 
6 
Background and Rationale ............................................................................................... 12 
7 
Objectives ........................................................................................................................ 15 
7.1 
Primary objective ...................................................................................................... 15 
7.2 
Secondary objective(s) ............................................................................................. 15 
8 
Study Design .................................................................................................................... 15 
8.1 
Summary of Study Design ........................................................................................ 15 
8.2 
Primary and Secondary Enpoints / Outcome Measures ............................................ 16 
8.3 
Sudy Participants ...................................................................................................... 16 
8.3.1 
Description of Study Participants .............................................................................. 16 
8.3.2 
Inclusion Criteria ....................................................................................................... 16 
8.3.3 
Exclusion criteria ...................................................................................................... 16 
8.4 
Study Procedures ..................................................................................................... 17 
8.4.1 
Informed Consent ..................................................................................................... 18 
8.5 
End of study ............................................................................................................. 18 
9 
Safety Reporting .............................................................................................................. 18 
9.1 
Definition of Serious Adverse Event .......................................................................... 18 
9.2 
Reporting Procedure for Serious Adverse Event ....................................................... 19 
9.3 
Expected Adverse Events ......................................................................................... 19 
10 
Statistics ........................................................................................................................... 19 
10.1 
Number of Participants ............................................................................................. 19 
10.2 
Analysis of Endpoints ............................................................................................... 20 
11 
Ethics ............................................................................................................................... 20 

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11.1 
Consent .................................................................................................................... 20 
11.2 
Ethical Committee Review ........................................................................................ 20 
11.3 
Protocol Amendments .............................................................................................. 21 
11.4 
Declaration of Helsinki and Good Clinical Practice(GCP) ......................................... 21 
11.5 
GCP Training ............................................................................................................ 21 
12 
Data Handling and Record Keeping ................................................................................. 21 
12.1 
Case Report Form (CRF) ......................................................................................... 21 
12.2 
Source Data ............................................................................................................. 22 
12.3 
Electronic Data Storage ............................................................................................ 22 
12.4 
Data Protection and Patient Confidentiality ............................................................... 22 
13 
Financing and Insurance .................................................................................................. 22 
14 
Protocol Compliance and Breaches of GCP ..................................................................... 23 
15 
Publications Policy ........................................................................................................... 23 
16 
References ....................................................................................................................... 23 
17 
Appendices ...................................................................................................................... 24 
17.1 
Appendix I -   Patient pathways during CONTEND study  ......................................... 25 
17.2 
Appendix II – Patient Contrast Questionnaire ........................................................... 26 

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4. ABBREVIATIONS 
CBU 
Cambridge Breast Unit (including Cambridge Breast Cancer Research 
Unit) 
CESM 
Contrast Enhanced Spectral Mammography 
CRF 
Case Report Form 
CT 
Computed Tomography 
GP 
General Practitioner 
GCP 
Good Clinical Practice 
ID 
Identification 
LCC 
Left cranio-caudal view 
LMLO 
Left medio-lateral oblique view 
MDT 
Multi-disciplinary Team Meeting 
MRI 
Magnetic Resonance Imaging 
NICE 
National Institute for Health and Care Excellence 
NRES 
National Research Ethics Service 
RCC 
Right cranio-caudal view 
REC 
Research Ethics Committee 
RMLO 
Right medio-lateral oblique view 
ROC 
Receiver Operating Characteristic 
SAE 
Serious Adverse Event 

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5. 
STUDY   SYNOPSIS 
Study Title 
An assessment of the impact of CONTrast ENhanceD Spectral 
Mammography (CESM) on patient management and comparison with 
MRI (CONTEND Study) 
Internal ref. no. 
RADIOL/2015/CONTEND 
 
Study Design 
The aim of this pilot study is to establish the Contrast Enhanced 
Spectral Mammography (CESM) technique and study procedures.  
Results of this pilot and feedback from staff will inform Phase 2 of the 
study which will be a larger, multi-centre, randomised control trial.  
The study will be undertaken by members of the Cambridge Breast Unit 
(CBU) at Addenbrooke’s Hospital, Cambridge using CESM technology 
provided by GE Healthcare as an upgrade to the GE Senographe 
Essential digital mammography system.  This technology is already 
established throughout the world and has FDA approval and is CE 
marked. 
This will be a randomised, sequential cohort study. Following standard 
mammography and ultrasound all women with lesions of suspicion 3, 4 
or 5 will be randomised to either receive CESM in addition to their 
assessment procedure or to receive usual care.  Sealed envelopes will 
be held at CBU reception desk containing either ‘CESM’ or ‘Usual Care’ 
and one will be selected at random to determine to which arm of the 
study the woman is allocated.  
After providing informed consent, those women randomised to receive 
CESM will undergo the procedure either during the same clinic visit or 
on a day following the initial clinic visit. This will be dependent upon 
clinic time and staff availability and the woman’s own preferences / 
circumstances. 
The index lesion and any additional disease detected by CESM will be 
biopsied as appropriate and results will be discussed at the multi-
disciplinary meeting (MDT).  For those with biopsy confirmed disease a 
decision will be made at that meeting regarding conservation surgery, 
mastectomy or neo-adjuvant therapy. For those with benign disease 
confirmed by core biopsy standard care will be followed.  

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MRI will be performed on appropriate women in line with standard 
practice.  Additional disease detected by MRI will be biopsied if this will 
influence patient management.  Biopsies will be undertaken using either 
ultrasound or MRI guidance.  These cases will be discussed at the MDT 
and a decision made regarding conservation surgery, mastectomy or 
neo-adjuvant therapy.   
The pathway for women randomised to receive usual care will be the 
same as for those randomised to receive CESM, excluding the CESM 
procedure, i.e. they will undergo biopsy during their initial clinic visit and 
results will be discussed at the MDT where a decision regarding their 
future management will be made. 
A flowchart illustrating patient pathways during the CONTEND Study 
can be found in Appendix I of this document. 
A proforma will be used for each case to record patient pathway, results 
of biopsies and MDT patient management decisions.  
Staff will be asked to provide feedback on patient acceptability and 
ease of undertaking the CESM procedure.  They will also be asked to 
record any incidents of note, e.g. patient related problems; impact on 
clinic; issues with equipment.  Time taken to undertake the examination 
will be recorded. 
In order to compare the diagnostic accuracy of CESM with MRI, CESM 
images and MRI images will be anonymised and read by different 
readers - CESM images will be reported without the knowledge of the 
MRI results and vice versa.  Mammography and ultrasound images will 
be available. A completed report on a proforma will be the basis for 
statistical analysis. 
Histopathology data collected following surgery or from core biopsy if 
surgery is not undertaken and will be used as the gold standard for 
measurement of tumour size and extent of disease.  If the patient is 
having primary drug therapy, tumour size will be determined from the 
mammogram. 
Study Participants 
Women attending CBU who have lesions of suspicion 3, 4 or 5 following 
routine mammography and ultrasound. 

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Planned Sample Size 
50 patients with successful CESM examinations will be required to 
establish the technique, study procedures and to provide sufficient data 
to inform further study.  It is estimated, due to randomisation procedure, 
approximately 100 patients will need to be recruited in order to obtain 
this number. 
Planned Study 
Period 
Recruitment to the study is planned to run for 12 months or until 
sufficient number of participants has been accrued.  The study will end 
once data analysis is complete. 
 
Primary Objective 
To assess the impact the addition of CESM has on patient 
management.  
Secondary 
Objectives 
To compare the sensitivity and specificity of CESM with MRI.   
 
Primary Endpoint 
The detection of additional disease by CESM that changes patient 
management.  Analysis will be undertaken to determine the impact of 
CESM on patient management decisions (actual or hypothetical).  
These will be extracted from details recorded on the proforma. 
Secondary 
Endpoints 
Secondary endpoints are the sensitivity and specificity of CESM and 
MRI on a per lesion basis – including comparison of the maximum 
dimension of the index tumour – as assessed by independent readers 
and compared with surgical histopathology. 
The efficacy of each technique at detecting additional lesions and the 
number of false positives identified by each will also be determined.  
False positives will be confirmed through follow up at 6 months. 
Analysis of results will inform further study, e.g. sample size and power 
calculations, and will include an assessment of clinical technique and 
study procedures from staff questionnaires. 

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6. 
BACKGROUND AND RATIONALE 
The advent of digital mammography has presented opportunities for new technologies and 
techniques to be developed within the field of breast disease diagnosis.  One such 
technology is Contrast Enhanced Spectral Mammography (CESM). 
CESM is a technique intended for use as an adjunct following inconclusive mammography 
and ultrasound examinations.  Contrast enhanced images are produced using an x-ray 
specific contrast media (dye) commonly used for CT scans which is injected intravenously 
into the patient’s arm.  A conventional mammography machine – similar or the same as the 
one on which a woman’s initial mammogram would have been taken - is modified to take two 
images at different x-ray exposures in each of the four standard mammographic views (RCC, 
RMLO, LMLO, LCC).  The first exposure is low energy and the second is high energy.  The 
fully automated procedure creates a standard mammographic image and also produces a 
contrast enhanced image in exactly the same position with the background subtracted out.  
This reduces image noise and helps to highlight lesions.  The whole procedure from injection 
of contrast media to production of images takes less than 10 minutes. 
Potentially, clinical applications for this technique include clarification of mammographic 
equivocal lesions, detection of occult lesions and determination of extent of disease.  
Published studies also indicate that contrast enhanced mammography could play an 
important role in imaging breasts where dense overlapping tissue can present difficulties 
when viewing standard mammograms (1,2). 
 
Summary of literature 
There are few published studies comparing diagnostic accuracy of CESM with MRI in 
patients with newly diagnosed breast cancer.  Most published data are a small sub-study of 
investigations comparing CESM with conventional mammography and/or ultrasound.  
Studies generally report detectability, multi-focality, correct diagnosis and compare size 
measurement for extent of tumour against surgical histopathology.  Badr et al (3) discussed 
the implementation of CESM into routine clinical practice.  They stated it was easier and 
quicker to access than MRI but that a disadvantage is being unable to perform a biopsy 
during the procedure.   
Results from two studies comparing mammography plus CESM with mammography plus 
ultrasound support the view that CESM may be comparable with MRI (4,5).  They show CESM 
improves sensitivity without decreasing specificity, provides a better estimation of extent of 
tumour and is more effective at demonstrating additional foci than both mammography alone 

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and mammography plus ultrasound.  In 2013 Lobbes et al published a summary on contrast 
enhanced mammography techniques and studies to date (6).  They also concluded contrast 
enhanced mammography had been shown to be better at detecting breast cancer than 
mammography - and may be similar to MRI - though MRI may be better for multi-focal 
disease.  Conclusive findings were limited by small study populations and larger studies 
need to be conducted in order to produce more definitive results.  
In a recent study comparing the diagnostic accuracy of CESM with mammography in 
patients referred from a breast screening programme – which included a cohort of 24 
patients who had breast MRI - good agreement was found between tumour size measured 
by CESM, MRI and histopathology (7).  Previous studies comparing assessment of tumour 
size include a pilot study of 20 patients which showed the correlation between assessed 
tumour diameters using CESM and histopathology to be good (8) and one in which 142 breast 
lesions were evaluated by mammography, ultrasound and CESM (5). 
Two studies which do directly compare the diagnostic accuracy of CESM with MRI have 
been reported recently.  Jochelson et al studied 52 patients, measuring maximum diameter 
of the index (main) tumour on imaging (9).  Of the 52 lesions, conventional mammography 
detected 42 and both MRI and CESM detected 50.  CESM was accurate for tumour extent in 
all but 2 index lesions, whereas MRI gave accurate size estimation for all.  Jochelson et al 
concluded that CESM detected known primary tumours at a rate comparable to that of MRI 
(both 96%) and higher than that of conventional digital mammography (81%).  CESM had a 
lower sensitivity (56%) for detecting additional cancers than MRI (88%), but the specificity 
was higher.  On the other hand MRI found 13 false positive cases, 8 having surgery for 
ultimately benign change, whereas CESM found 2 false positives, not requiring surgery. 
In the second study, Fallenberg et al also reported on the detection of breast cancer and 
tumour size assessment for CESM compared with MRI (10). They studied 80 patients with 
newly diagnosed breast cancer of which there was post-op histology for 59.  Images were 
reviewed by an independent reader blinded to other findings.  All index tumours (100%) were 
detected by CESM, 77 (97.4%) by MRI and 66 (82.5%) by conventional mammography.  In 
the correlation of tumour size measurements, there were significant differences between 
both CESM and MRI compared to mammography.  Between CESM and MRI there was no 
significant difference observed.  The best correlation was between CESM and 
histopathology. There was no evaluation of additional lesions reported. 
CESM is a developing technology and the optimum design of equipment and mechanism is 
still under debate.  The addition of digital breast tomosynthesis (DBT) to CESM should further 
enhance the performance of CESM compared to MRI.  Schmitzberger et al (2011) 
successfully demonstrated the clinical feasibility of CESM DBT as a diagnostic tool but stated 

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further studies were needed to assess diagnostic sensitivity and specificity (11). 
 
Rationale 
Treatment options for women with proven invasive breast cancer depend on the size of the 
tumour and the presence and location of any additional disease (12).  Breast MRI, using MRI 
specific contrast media, is currently recognised as the most sensitive imaging technique in 
determining the extent of disease identified on mammogram or by ultrasound.  This means 
the patient can go straight to definitive surgery rather than having surgical under treatment, 
i.e. the identification of additional disease may mean the woman has a mastectomy rather 
than a wide local excision (lumpectomy).   
There are several disadvantages of MRI.  It is usually performed in a different department 
from mammography and ultrasound, which can pose problems with accessibility and may 
delay patient care.  Image acquisition takes an average of 40 minutes and the whole 
procedure can take up to 90 minutes.  MRI is also known to produce a higher frequency of 
false positives than conventional mammography and this can lead to unnecessary surgery 
and patient anxiety.  Some patients may be excluded from undergoing MRI due to 
claustrophobia or presence of metal within their body. In the UK, MRI is currently used 
selectively, based on NICE guidelines (13).  There are also economic considerations - MRI is 
expensive.  
CESM is being heralded as a diagnostically comparable, less labour-intensive and cost 
effective technique to breast MRI.  Like MRI, CESM can be used to identify lesions not seen 
on mammography or ultrasound and to assess the size of lesions and stage of disease.  The 
procedure can be performed on the same day using the same equipment and in the same 
department as a woman’s initial clinic visit.  This should reduce patient anxiety and has the 
potential of a definitive decision on patient management being made earlier in the patient 
pathway.  CESM also has the potential to be used as a screening tool in certain groups of 
women which is not clinically viable with MRI. 
The purpose of this study is to refine the CESM technique, assess acceptability of the test 
and recruitment levels, establish study procedures and examine effect of CESM on patient 
management decisions.  We also hope to demonstrate an increase in sensitivity and 
specificity compared to MRI.  Analysis of results will inform further study, including power 
calculations. On completion of this project we intend to apply to the UK NIHR Health 
Technology Assessment Programme for funding to undertake a multicentre trial comparing 
the diagnostic accuracy of CESM with MRI (perhaps with an extension to CESM DBT if this 

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technique becomes available and minimally proven in terms of clinical performance and 
workflow). 
 
7. 
OBJECTIVES 
7.1 
Primary objective 
To assess the impact the addition of CESM has on patient management. The 
hypothesis is that CESM should afford a definitive management decision earlier in 
the patient pathway. 
7.2 
Secondary objectives 
To compare the sensitivity and specificity of CESM with MRI.  Analysis will include: 
• 
index lesion size 
• 
detection of additional lesions 
• 
detection of lesions in contralateral breast 
• 
total extent of disease 
• 
number of false positives identified 
 
8. 
STUDY DESIGN 
8.1 
Summary of Study Design 
This study will be a sequential cohort study with participants randomised to receive either the 
addition of CESM or standard care.  All women with lesions of suspicion 3, 4 or 5 following 
mammography and ultrasound will be eligible.   
Number of Centres 
This will be a single centre study performed by members of the CBU at Addenbrooke’s 
Hospital, Cambridge. 
Number of Subjects 
We plan to include 100 subjects in this study – approximately 50 to receive CESM and 50 to 
receive usual care.   
Trial duration 
Subjects will be recruited into the study following their routine assessment results 
consultation.  Participation in the study will end once the patient has undergone CESM 
procedure and is returned to standard care.  Target recruitment is estimated to take 
approximately 12 months and the study will end once data analysis is complete. 

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Subject withdrawal criteria 
Subjects that suffer ill-effects from contrast media or procedure, or are unable to complete 
the procedure for whatever reason, will be withdrawn from the study.  Data held on subjects 
who are withdrawn and on those who elect to withdraw from study will not be used in 
analysis. 
8.2 
Primary and Secondary Endpoints/Outcome Measures 
The primary endpoint is the detection of additional disease that changes patient 
management.  Analysis will be undertaken to determine the impact of CESM on patient 
management decisions (actual or hypothetical).  These will be extracted from details 
recorded on the proforma. 
Secondary endpoints are the sensitivity and specificity of CESM and MRI on a per lesion 
basis - including comparison of the maximum dimension of the index tumour - as assessed 
by independent readers and compared with surgical histopathology. The efficacy of each 
technique at detecting additional lesions and the number of false positives identified by each 
will also be determined. 
 
8.3 
Study Participants  
8.3.1 Overall Description of Study Participants 
Participants in the study will be women aged 18 and above with a lesion of suspicion 3, 4 or 
5 following mammography and ultrasound. 
8.3.2 Inclusion Criteria 
To be included in the study the patient must: 
• 
Be willing and able to give written informed consent for participation in the study. 
• 
Be female, aged 18 years or above. 
 
8.3.3 Exclusion Criteria 
The presence of any of the following will preclude patient inclusion:  
• 
Known or suspected pregnancy 
• 
Breast implant 
• 
Previous breast cancer 
• 
Known renal impairment 
• 
History of anaphylactoid or anaphylactic reaction to any contrast media 

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• 
Contrast media within 24 hours prior to CESM 
• 
Commencement of neo-adjavant chemotherapy, hormone treatment, radiotherapy or 
surgery for this episode 
8.4 
Study Procedures 
Screening and enrolment 
Patients who have been identified as suitable for the study will be approached at the routine 
post-biopsy consultation when their diagnosis and treatment plan is being discussed.  At this 
meeting, patients will be given both written and verbal information about the study. 
If a patient wishes to enter the study, their eligibility will be checked by a Research 
Radiographer or Research Nurse and signed informed consent will be obtained.  The patient 
will then be randomised and if she is in the CESM arm an appointment will be arranged for 
the procedure. 
 
CESM procedure 
Patients will be given an intravenous injection (via a power injector), into their arm, of an 
iodine based contrast media.  This type of contrast media is used routinely in CT imaging 
procedures and the Cambridge University Hospitals NHS Trust Patient Group Directive for its 
administration will be adhered to.  Patients will be asked to complete the Patient Contrast 
Questionnaire prior to the procedure (see Appendix II) and have their creatinine level 
checked using a Point of Care (PoC) device in the CT department.  If serum creatinine is 
elevated >150 mmol/l the procedure will not be performed. 
Two minutes after the injection, two mammographic exposures will be taken automatically, 
within approximately one second of each other, in each of the standard mammographic 
views (RCC, RMLO, LCC, LMLO).  
 
Assessment of CESM images 
Paired images will be examined to see if the tumour has been enhanced by the contrast 
media and to assess its extent.  Images will also be assessed for additional foci and 
contralateral lesions. 
 
Comparison of CESM and MRI 

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CESM images and MRI images will be anonymised and read by different readers - CESM 
images will be reported without the knowledge of the MRI results and vice versa.  
Mammography and ultrasound images will be available. A completed report on a proforma 
will be the basis for statistical analysis. 
 
Analysis 
Analysis will be undertaken to determine the impact of CESM on patient management 
decisions (actual or hypothetical).  These will be extracted from details recorded on the 
proforma. 
We will also compare the sensitivity and specificity of CESM and MRI on a per lesion basis - 
including comparison of the maximum dimension of the index tumour - as assessed by 
independent readers and compared with surgical histopathology. 
Analysis of results will also be undertaken in order to inform further study, e.g. sample size 
and power calculations, and will include an assessment of clinical technique and study 
procedures from staff questionnaires. 
 
8.4.1 
Informed Consent 
Eligible patients for this study will be identified in the out-patient clinic by members of the 
breast team.  Patients will be given written and verbal information about the study.  Consent 
will be taken by experienced Research Radiographer or Research Nurse.  Following their 
CESM imaging, patients will return to normal standard of care.  Safety reporting requirements 
will end 72 hours after the procedure. 
8.4.2  
Definition of End of Study  
The study will end once the last patient recruited has undergone surgery and the surgical 
histopathology results are available. 
 
9. 
SAFETY REPORTING 
9.1 
Definition of Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that: 
• 
Results in death, 
• 
Is life-threatening, 

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NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect. 
• 
Other important medical events* 
  *Other events that may not result in death, are not life threatening, or do not require 
hospitalisation, may be considered a serious adverse event when, based upon appropriate 
medical judgement, the event may jeopardise the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
After injection into an artery or vein, it is uncommon (1% risk = 1-10 in 1,0000) to experience 
pain and discomfort 
Rare effects (0.1% risk=1-10 in 10,000) include diarrhoea, irregular heartbeat, kidney problems, 
cough, fever, general discomfort or dizziness 
Very rare (0.01%=less than1in 10,000) include seizures (fits), clouding consciousness, 
disturbance of senses like touch, trembling, flushing, difficulty breathing including severe 
breathing difficulty due to fluid in the lungs, short term brain disorders (encephalopathy), short 
term memory loss, coma and stupor or myocardial infarction . 
Any allergic or anaphylactic reactions to the contrast media used in CESM are likely to occur 
soon after the injection.  These will be managed according to local policies by members of 
the breast team.  Minor reactions, e.g..skin rashes, hives (urticaria), itching (pruritus), 
nausea, dizziness, runny nose (rhinorrhea), brief retching and /or vomiting will be monitored 
until symptoms have alleviated or further action is needed.   
Moderate reactions,e.g. headache, persistent vomiting, wheezing (mild bronchospasm), 
palpitations, facial swelling, raised blood pressure (hypertension), abdominal cramps; may 
require an injection of antihistamine and/or adrenaline.  An emergency drugs pack will be 
available in the room during CESM procedures for this purpose. 
In the exceptional event of a serious reaction  which has the potential to be life-threatening, 
e.g. difficulty breathing (overt bronchospasm), chest pain, irregular heartbeat (arrhythmia), 
collapse, seizure, cardiac arrest; a ‘crash’ call will be made to summon the emergency 
medical team. 

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9.2 
Reporting Procedures for Serious Adverse Events 
A serious adverse event (SAE) occurring to a participant will be reported to the REC that 
gave a favourable opinion of the study where in the opinion of the Chief Investigator the 
event was: ‘related’ – that is, it resulted from administration of any of the research 
procedures; and ‘unexpected’ – that is, the type of event is not listed in the protocol as an 
expected occurrence. Reports of related and unexpected SAEs should be submitted within 
15 days of the Chief Investigator becoming aware of the event, using the NRES report of 
serious adverse event form (see NRES website).  
9.3 
Expected Adverse Events 
The following adverse events are known possible side effects of CESM procedure. They are 
generally not serious in nature and will not be recorded as part of this study. 
• 
Bruising from site of injection 
• 
Allergic reaction to contrast media 
 
 
10. 
STATISTICS 
10.1 
The Number of Participants 
There will be approximately 100 participants in order to provide 50 who will undergo CESM. 
10.2 
Analysis of Endpoints  
Data from all eligible subjects will be included in the analyses.  These will be patients for 
whom we have data from MRI, CESM and surgical histopathology. 
Statistical significance of differences between CESM and MRI will be calculated using 
McNemar’s test (14). Receiver operating characteristic (ROC) curves will be constructed for 
both imaging modalities. 
Agreement between maximum lesion diameter based on CESM and MRI or CESM and 
histopathology will be expressed in Bland-Altman plots. 
 
11. 
ETHICS 
11.1 
Consent 
The Informed Consent form will be approved by the REC and be in compliance with GCP, 
local regulatory requirements and legal requirements.  The investigator will ensure that each 

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study participant, or his/her legally acceptable representative, is fully informed about the 
nature and objectives of the study and possible risks associated with their participation. 
The investigator will obtain written informed consent from each patient or the patient’s legally 
acceptable representative before any study-specific activity is performed.  The informed 
consent form used for this trial and any change made during the course of this trial, will be 
prospectively approved by the REC.  The investigator will retain the original of each patients 
signed informed consent form. 
Should a patient require a verbal translation of the trial documentation by a locally approved 
interpreter/translator, it is the responsibility of the individual investigator to use locally 
approved translators.   
11.2 
 
Ethical Committee Review 
Before the start of the trial or implementation of any amendment we will obtain approval of 
the trial protocol, protocol amendments, informed consent forms and other relevant 
documents e.g., advertisements and GP information letters if applicable from the REC.  All 
correspondence with the REC will be retained in the Trial Master File/Investigator Site File. 
The Chief Investigator will submit annual reports to the REC in accordance with national 
requirements. 
11.3 
 
Protocol Amendments 
Protocol amendments will be reviewed and agreement received from the Sponsor for all 
proposed amendments prior to submission to the REC.  
The only circumstance in which an amendment may be initiated prior to REC approval is 
where the change is necessary to eliminate apparent, immediate risks to the patients (Urgent 
Safety Measures).  In the case, accrual of new patients will be halted until the REC approval 
has been obtained.  In the event of an Urgent Safety Measure being instigated during Phase 
2 of the study, the investigator at each participating centre will be notified within 48 hours. 
11.4 
 
Declaration of Helsinki and Good Clinical Practice 
The study will be performed in accordance with the spirit and the letter of the declaration of 
Helsinki, the conditions and principles of Good Clinical Practice, the protocol and applicable 
local regulatory requirements and laws. 

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11.5 
 
GCP Training 
All study staff will hold evidence of appropriate GCP training or undergo GCP training prior to 
undertaking any responsibilities on this study.  This training should be updated every 2 years 
or in accordance with individual Trust policy. 
 
12. 
DATA HANDLING AND RECORD KEEPING 
12.1 
Case Report Form 
All data will be transferred into a Case Report Form (CRF) which will be anonymised.  All 
study data in the CRF will be extracted from and be consistent with the relevant source 
documents.  The CRFs will be completed, dated and signed by the investigator or designee 
in a timely manner.  It will remain the responsibility of the investigator for the timing, 
completeness, legibility and accuracy of the CRF pages.  The CRF will be accessible to 
study coordinator, data manager and the investigators as required. 
All CRF pages must be clear, legible and completed in black ink.  Any errors should be 
crossed with a single stroke so that the original entry can still be seen.  Corrections should 
be inserted and the change dated and initialled by the investigator or designee.  If it is not 
clear why the change has been made, an explanation should be written next to the change.  
Typing correction fluid must not be used.  Changes must not be made to the CRF pages 
once the original has been returned to the study coordination centre. 
12.2 
Source Data 
To enable peer review, monitoring, audit and/or inspection investigators must agree to keep 
records of all participating patients (sufficient information to link records e.g., CRFs, hospital 
records and samples), all original signed informed consent forms and copies of the CRF 
pages.  Source data will include CSEM, MRI and histopathology reports. 
12.3 
Electronic Data Storage 
All study data will be entered into a database administered by University of Cambridge.  The 
participants will be identified by a study specific participants number and/or code - their name 
or any other identifying details will not be included in any study data electronic file.  
12.4 
Data Protection & Patient Confidentiality 
All investigators and site staff involved in this study must comply with the requirements of the 
Data Protection Act 1998 and Trust Policy with regards to the collection, storage, processing 
and disclosure of personal information and will uphold the Act’s core principles.  The study 

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staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by initials and a participants ID number on the CRF and any electronic 
database.  All documents will be stored securely and only accessible by study staff and 
authorised personnel. The study will comply with the Data Protection Act which requires data 
to be anonymised as soon as it is practical to do so.  Study data will be stored for 10 years. 
 
13. 
FINANCING AND INSURANCE 
The trial will be sponsored jointly by Cambridge University Hospitals NHS Foundation Trust 
and University of Cambridge.  The study will be funded by a grant from GE Healthcare,  
Cambridge University Hospitals NHS Foundation Trust, as a member of the NHS Clinical 
Negligence Scheme for Trusts, will accept full financial liability for harm caused to 
participants in the clinical trial caused through the negligence of its employees and honorary 
contract holders.  There are no specific arrangements for compensation should a participant 
be harmed through participation in the trial, but no-one has acted negligently.  
The University of Cambridge will arrange insurance for negligent harm caused as a result of 
protocol design and for non-negligent harm arising thorough participation in the clinical trial. 
 
14. 
PROTOCOL COMPLIANCES AND BREACHES OF GCP 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK 
regulations on Clinical Trials and must not be used.  
Protocol deviations, non-compliances, or breaches are departures from the approved 
protocol. They can happen at any time, but are not planned. They must be adequately 
documented on the relevant forms and reported to the Chief Investigator and Sponsor 
immediately.   
Deviations from the protocol which are found to occur constantly again and again will not be 
accepted and will require immediate action and could potentially be classified as a serious 
breach.  
Any potential/suspected serious breaches of GCP must be reported immediately to the 
Sponsor without any delay. 
 
15.        PUBLICATIONS POLICY 

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Ownership of the data arising from this trial resides with the study team.  The investigators 
have complete control over data.  On completion of the study the data will be analysed and 
tabulated and a report prepared.  GE Healthcare will not have the right to review data prior to 
publication.  All data and images collected during the study and made available to GE 
Healthcare following publication will be anonymised to comply with data protection and 
patient confidentiality.  Funding from GE Healthcare will be acknowledged within 
publications. 
 
16.   
 REFERENCES 
1. Carney P A, Miglioretti D L, Yankaskas B C et al. Individual and Combined Effects of Age, 
Breast Density and Hormone Replacement Therapy Use on the Accuracy of Screening 
Mammography. Ann Intern Med 2003; 138: 168-175 
2. Diekmann F, Freyer M, Diekmann S et al. Evaluation of contrast-enhanced digital 
mammography. Eur J Radiology 2011; 78:112-121 
3. Badr S, Laurent N, Régis C et al. Dual-energy contrast-enhanced digital mammography in 
routine clinical practice in 2013. Diagnostic and Interventional Imaging 2014; 95:245-258 
4. Dromain C, Thibault F, Muller S et al. Dual-energy contrast-enhanced digital 
mammography: initial clinical results. Eur Radiology 2011; 21:565-574 
5. Dromain C, Thibault F, Diekmann F et al. Dual-energy contrast-enhanced digital 
mammography: initial clinical results of a multireader, multicase study. Breast Cancer 
Research 2012; 14:R94 
6. Lobbes M B I, Smidt M L, Houwers J et al. Contrast enhanced mammography: 
Techniques, current results and potential indications. Clin Radiology 2013; 68:935-944 
7. Lobbes M B I, Lalji U, Houwers J et al. Contrast-enhanced spectral mammography in 
patients referred from the breast screening programme. Eur J Radiology 2014; Published 
online: 03 April 2014 
8. Dromain C, Balleyguier C, Muller S et al. Evaluation of Tumour Angiogenesis of Breast 
Carcinoma Using Contrast-Enhanced Digital Mammography. Am J Roentgenology 2006; 
187:528-537 
9. Jochelson M S, Dershaw D D, Sung J S et al. Bilateral Contrast-enhanced Dual-Energy 
Mammography: Feasibility and Comparison with Conventional Digital Mammography and 
MR Imaging in Women with Known Breast Carcinoma. Radiology 2013; Vol 226: Number 3, 
743-751 

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10. Fallenberg E M, Dromain C, Diekmann F et al. Contrast-enhanced spectral 
mammography versus MRI: Initial results in the detection of breast cancer and assessment 
of tumour size. Eur J Radiology 2014; 24:256-264 
11. Schmitzberger FF, Fallenberg EM, Lawaczeck R et al. Development of low-dose hhoton-
counting contrast-enhanced tomosynthesis with spectral imaging.  Radiology. 2011; 
259(2):558-564 
12. Schell A M, Rosenkranz K, Lewis P J. Role of Breast MRI in the Preoperative Evaluation 
of Patients with Newly Diagnosed Breast Cancer. Am J Roentgenology 2009; 192:1438-1444 
13. www.nice.org.uk/nicemedia/pdf/CG80NICEGuideline.pdf 
14. McNemar Q. Note on the sampling error of the difference between correlated proportions 
or percentages. Psychometrika 1947; 12:153-157 
 
 
17.   
 APPENDICES     
I.  Patient pathways during CONTEND Study 
II. Patient Contrast Questionnaire 

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Mammography and US 
Patient pathways during CONTEND study 
Consent and randomisation 
CESM 
(within 1 week) 
Usual care 
Biopsy of 10 by US or 
Mammography 
MDT 
MDT 
Surgery / 
Treatment
Suspicion M3, M4 or M5 
No additional disease detected 
Return to usual care 
Additional disease detected 
2nd look US 
MRI 
F/U or 
discharge 
Additional disease 
No additional disease 
Biopsy of additional disease 
by US or MRI 
F/U or 
discharge 
Biopsy of 10 by US or 
Mammography 
MDT 
No MRI 
No MRI 
Surgery / 
Treatment
No additional disease 
Additional disease 
MDT 
MRI 
Biopsy of additional disease by US or Mammo 
Return to usual care 
Biopsy of 10 by US or Mammo 
2nd look US 
2nd look US 
Biopsy of additional disease 
by US or MRI 
Surgery / Treatment 
(Mastectomy; WLE; Neo-
adjavant therapy) 
Surgery / Treatment 
(Mastectomy; WLE; Neo-
adjavant therapy) 
US 
Ultrasound 
MDT 
Multidisciplinary Team Meeting 
F/U 
Follow up 
WLE 
Wide Local Excision 

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CONTEND study   
Patient contrast questionnaire 
 
As part of the Contrast Enhanced Spectral Mammography (CESM) procedure, we 
are seeking your permission to administer an injection of contrast medium (dye) as 
part of your examination. 
We need to ask you the following questions prior to your injection: 
Have you had injections of contrast medium in any past examinations 
in x-ray? 
Yes 
No 
If yes, did you have any problems related to this injection? 
Yes 
No 
If yes, please state: 
 
Are you allergic to anything? 
Yes 
No 
If yes, please state: 
 
 
 
Do you have asthma? 
Yes 
No 
Are you diabetic? 
Yes 
No 
If you are diabetic, do you take metformin? 
Yes 
No 
Do you have an overactive thyroid? (hyperthyroidism) 
Yes 
No 
Are you on interleukin 2 therapy? 
Yes 
No 
Do you suffer from sickle cell anaemia? 
Yes 
No 
Do you suffer from Chronic Kidney Disease (CKD)? 
Yes 
No 
Affix patient ID label here: 

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Do you suffer from any brain pathology? Tumour, epilepsy, seizures? 
 
Yes 
No 
If yes, are you currently taking any medication for this? Please state: 
………………………………………………………………………………. 
Yes  
No 
Please state the date of the first day of your last menstrual period: 
Please state the date of the first day of your last menstrual period: 
 
Is there any chance you might be pregnant? 
Yes 
No 
Do you use oral contraceptive pill? 
Yes 
No 
Do you take hormone replacement therapy (HRT)? 
Yes 
No 
 
Please do not sign this form until you are with the radiographer. 
Print name 
Signature 
Date 
 
 
 
 
 
For official use only 
Date of blood test: 
 
eGFR: 
Serum creatinine: 
 
Practitioner  
Signature 
Date 
 
 
 

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