An Integrated Consent Model Study to Compare Two Standard of Care Schedules for Monitoring Cardiac Function in Patients Receiving Trastuzumab for Early Stage Breast Cancer
Phase: PHASE4
Conditions: Breast Cancer
Sponsor: Ottawa Hospital Research Institute

An Integrated Consent Model Study to Compare Two Standard of Care schedules for 
monitoring cardiac function in patients receiving Trastuzumab for early stage breast 
cancer: REaCT-EF 
 
Centre:  
 
 
 
The Ottawa Hospital Cancer Centre 
 
 
 
 
 
 
Principal Investigator:  
 
 
John Hilton MD FRCPC 
 
 
 
 
 
The Ottawa Hospital Cancer Centre 
 
 
 
 
 
E-mail: jfhilton@toh.ca  
 
Co-investigator: 
 
  
 
 
 
 
 
 
Mark Clemons MBBS MSc MD 
 
 
 
 
 
The Ottawa Hospital Cancer Centre 
 
 
 
 
 
E-mail: mclemons@toh.ca 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Funding provided by: Internal funding 
 
 
 
 
 

 
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Protocol Version: January 27, 2016 
Amendment 1: April 19, 2017 
Amendment 2: January 29, 2018 
Amendment 3: February 13, 2018 
 
 
 
PROTOCOL SIGNATURE PAGE 
 
My signature below confirms that I have reviewed and approved this protocol, and agree that it contains 
all necessary details for carrying out the study as described. I will conduct this protocol as outlined 
therein, and according to Good Clinical Practice and all applicable local regulations 
 
 
 
 
 
 
 
 
 
 
Qualified Investigator (Please Print) 
 
 
 
 
 
 
 
 
 
 
 
Qualified Investigator Signature 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 

 
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Table of Contents 
 
1 
BACKGROUND .................................................................................................................................. 4 
2 
OBJECTIVES ....................................................................................................................................... 6 
2.1 
Primary objective .......................................................................................................................... 6 
3 
STUDY DESIGN .................................................................................................................................. 6 
4 
METHODS ........................................................................................................................................... 7 
5 
CONSENT SCRIPT .............................................................................................................................. 7 
6 
ELIGIBILITY ....................................................................................................................................... 9 
6.1 
Inclusion Criteria .......................................................................................................................... 9 
6.2 
Exclusion Criteria ....................................................................................................................... 10 
7 
RANDOMIZATION ........................................................................................................................... 10 
8 
DATA COLLECTION ....................................................................................................................... 10 
9 
OUTCOMES ....................................................................................................................................... 11 
9.1 
Primary Outcome ........................................................................................................................ 11 
9.2 
Secondary outcome ..................................................................................................................... 12 
10 
RISKS ............................................................................................................................................. 12 
11 
SAFETY REPORTING .................................................................................................................. 12 
12 
MONITORING ............................................................................................................................... 13 
13 
CRITERIA FOR FEASABILITY SUCCESS ................................................................................ 13 
14 
PREMATURE WITHDRAWAL ................................................................................................... 13 
15 
SAMPLE SIZE AND STATISTICAL ANALYSIS ....................................................................... 14 
16 
PROJECT BUDGET ......................................................................... Error! Bookmark not defined. 
17 
References ....................................................................................................................................... 16 
 
 
 

 
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1 
BACKGROUND 
Approximately 20-25% of breast cancer tumours over-express Her2-neu, a pro-oncogenic 
surface receptor of the epidermal growth factor receptor family (1).  Her2-neu amplification is a 
positive predictor for response to trastuzumab, an antibody which inhibits Her2-neu growth 
signalling. Several large adjuvant trastuzumab trials have demonstrated improved overall 
survival, in patients with early stage breast cancer, with a 33% decrease in risk of death (2). 
However, retrospective analyses of patient outcomes in these trials have demonstrated increased 
risk of cardiotoxicity (i.e. damage to the heart) in a small number of patients (4-8% in NASBP 
B-31) (3). According to the American College of Echocardiology recommendations, cancer 
therapeutics-related cardiac dysfunction is defined as a decrease of at least 10% in left 
ventricular ejection fraction (LVEF) to below a threshold of 53% (4). Left ventricular ejection 
fraction, has traditionally been used to assess cardiac function in patients receiving potentially 
cardiotoxic systemic therapy.   
At this time, we are unable to predict which patients are at increased risk of cardiac-related 
treatment complications. Currently all patients receive regular cardiac imaging throughout their 
one year of trastuzumab treatment. A number of imaging strategies (which measure LVEF) are 
used to screen and monitor for cancer treatment-induced cardiotoxicity, including transthoracic 
echocardiography (ECHO) and multiple gated acquisition scan (MUGA) (4)). However, the vast 
majority of patients, who are at low risk of cardiac complications, may not require such frequent 
monitoring. Imaging significantly increases cost to the health care system and can reduce the 
patient’s quality of life. At this time, the optimal monitoring schedule for trastuzumab-related 
cardiotoxicity remains unknown, and several published consensus guidelines are currently in use 
as “standard of care”. The UK National Cancer Research Institute Breast Clinical Studies group 
recommends cardiac imaging every 4 months while receiving adjuvant trastuzumab therapy (5), 
while both the European Society of Medical Oncology and the National Comprehensive Cancer 
Network (NCCN) guidelines suggest cardiac monitoring every 3 months (6, 7). All published 
guidelines acknowledge a lack of evidence supporting a defined cardiac monitoring schedule.  
Interestingly, a recent SEER study from the USA showed that only 36% of older patients treated 
with trastuzumab received cardiac monitoring according to the NCCN guidelines (8). 

 
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This state of clinical equipoise is demonstrated by breast oncologists within our own institution 
where some oncologists order cardiac scans every 3 months, and others every 4 months.  
Therefore, at this time, it is not known which standard monitoring schedule is optimal. To our 
knowledge, no published clinical trial has ever prospectively compared these two standards of 
care.  All cardiac monitoring schedules are funded in Ontario, and there is little incentive for 
physicians to identify the best strategy. When multiple standards of care exist, clinicians often 
choose their approach based on those of other colleagues, or purely on personal preference.  
Despite this, determining the optimal treatment remains an important medical issue for patients, 
physicians and society.  Defining an optimal and uniform cardiac monitoring schedule will 
streamline the management of patients receiving potentially cardiotoxic therapy, improve quality 
of life for patients, and potentially reduce cost to the health care system without compromising 
safety or efficacy of cancer treatment.   
As demonstrated by variations in practice, physicians do not know the “best” cardiac monitoring 
schedule for their patients and therefore, genuine uncertainty (“clinical equipoise”) exists. A 
novel method to allow comparison of established standards of care is needed as part of an 
increasing internationally mandated incentive to perform more pragmatic clinic trials.  Pragmatic 
clinical trials which commonly incorporate comparative effectiveness research – that is, 
comparing the safety and effectiveness of diagnostic, therapeutic or delivery systems – can help 
overcome these challenges of deciding optimal cardiac monitoring schedules, when multiple 
choices exist and are in common use. These studies, in addition to the ability to leverage patient 
data from electronic health records to increase sample size of trials at much lower costs, is 
enabling major national and international initiatives to generate the data needed to improve care 
(9).  
This study will use a novel method to allow comparisons of established standard of care for 
cardiac monitoring using the “integrated consent model” as part of a pragmatic clinical trial (10). 
By integrating medical and clinical practices, physicians will be able to inform their patients 
about the RCT, akin to a typical conversation between the physician and patient, without written 
informed consent. This clinical interaction would then be documented, as ordinarily done in 
clinical practice.  This study is similar in design to the ongoing React-TC (20140380-01H) and 
React-G (20150316-01H, OCBRE #14-059) studies at the Ottawa Hospital Cancer Centre, and 

 
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extends the concept of integrated consent to the provision of cardiac monitoring. As of January 
1st 2016 these ongoing REaCT trials have accrued over 150 cancer patients with excellent patient 
and physician endorsement. 
We will explore whether the integrated consent model is feasible with regards to ordering routine 
cardiac imaging; whether it can be used to increase the number of physicians and patients who 
take part in clinical trials, and address the critical issue around optimal cardiac monitoring in 
patients receiving trastuzumab therapy for early stage breast cancer. 
2 
OBJECTIVES  
2.1 
Primary objective 
To demonstrate that cardiac monitoring (echocardiogram/MUGA) every 4 months is not inferior 
to every 3 months in the detection of cardiac dysfunction (as defined as a decrease of at least 
10% in LVEF to below a threshold of 53%) in patients receiving trastuzumab-based therapy for 
early breast cancer.  
Secondary objectives 
1) To compare the two study arms for: 1) changes in left ventricular ejection fraction (LVEF); 2) 
delay or discontinuation of trastuzumab therapy;  3) referrals to cardiology; and 4) health-related 
quality of life. 
2) To determine feasibility of study physicians using an integrated consent model to enter 
participants on this study. Feasibility will be reflected through a combination of endpoints 
including physician engagement, accrual rates, and physician compliance. 
 
3 
STUDY DESIGN 
This will be a multi-center unblinded randomized trial. This trial will accrue participants at 
multiple sites across Ontario including the Ottawa Hospital Cancer Centre.  

 
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4 
METHODS 
Investigators will approach potentially eligible patients with early stage breast cancer (stage I to 
III) scheduled to receive trastuzumab-based therapy. The physician will inform their patient 
about the RCT study, akin to a typical conversation between the physician and patient. Patients 
will be asked to provide oral consent to be randomized to cardiac investigations every 3 months, 
or every 4 months while receiving trastuzumab therapy. An oral consent script will be given to 
the patient (see below). Written informed consent will not be sought as the integrated consent 
model is ethically acceptable as the only prominent change to the standard of care treatment is 
the randomization process. Eligible and consented patients will be randomized using a permuted 
block design developed by The Ottawa Hospital’s Methods Centre to receive cardiac evaluation 
(by either transthoracic echocardiography or MUGA) every 3 months, or every 4 months while 
on treatment.  The physician can randomize a patient either through a secure web-based 
randomization system on the clinic desktop or mobile device, or through the designated site 
study CRA. The CRA will ensure that the dictated consent process has taken place.  
Patients will be asked to complete a health questionnaire and the EQ-5D 5L quality of life 
questionnaire (11) before starting chemotherapy, at the time of the first cardiac scan and at the 
end of 1 year follow up. To enhance the ability of patients being able to complete the 
questionnaire, depending on the patient’s preference, the questionnaire may be emailed (from 
secured TOH e-mail address) or mailed from the CRA. 
 
5 
CONSENT SCRIPT 
In this study the investigator will obtain oral consent using the following prepared REB approved 
script. 
An Integrated Consent Model to Compare Two Standard of Care Schedules for 
Monitoring Cardiac Function in Patients Receiving Trastuzumab for Early Stage Breast 
Cancer: REaCT-EF 
Principal Investigator:  Dr. Susan Dent of the Ottawa Hospital Cancer Centre (613-737-
7700, ext. 70167) 

 
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Our discussion today is a new approach of informing and consenting patients to participate in 
this study. The traditional approach is to provide a paper copy of the detailed information sheet 
and consent form for you to sign. Using this integrated model for consenting we will have a 
discussion and you may give a verbal consent to participate or not to participate. I will document 
our discussion and your decision in your progress notes that are part of your health records. 
 As we've talked about, you will be receiving trastuzumab as part of your breast cancer therapy. 
Because this medication can cause a reduction in your heart function, we will monitor your heart 
with routine scans throughout treatment. At this time, we do not know the best schedule for 
monitoring your heart. However, we do know that unnecessary scans are an inconvenience to 
patients, and considerably increase health care costs. Some physicians order heart scans every 
three months while on therapy and others order scans every four months. There are published 
guidelines which support both schedules; however they have never been compared directly. 
Because we really don't know if one is better than the other, we are conducting this study to 
answer this question. Study participants will be randomly (like a flip of a coin, so that we can 
obtain an unbiased answer) assigned to either an every three month or every four month scanning 
schedule, and then we will compare the results over a period of 1 year. We are also looking at 
how feasible it is for study doctors to enter participants on this study using this integrated 
consent model. If you choose to participate there won't be any special procedures or visits 
required of you. Your verbal consent would simply allow us to randomly assign you to the three 
month scanning schedule or the four month scanning schedule and then collect the results of 
those scans for 1 year.  
You will be asked to complete a health questionnaire about your quality of life and health while 
you are receiving treatment at 3 different timepoints. The timepoints of the questionnaire will be 
before starting chemotherapy, at the time of your first scan and at the end of the 1 year follow up 
period. As this study does not involve any additional visits to the cancer clinical beyond your 
usual visits, if you wish we can email or mail you the questionnaires. If you agree, we will obtain 
your email or mail address. Your email or mail address will be stored in a de-identified 
electronic file on the secure hospital network and will only be accessible by the study 
coordinator. The questionnaires will take you approximately 5-10 minutes. You do not have to 
answer any questions that make you uncomfortable. 
Your medical records will be consulted in order for us to conduct a cost-effectiveness analysis 
from the perspective of the health care system.  
If you choose to participate and then change your mind later, we can discuss together how to 
proceed; likely this would mean switching to the preferred follow up schedule of your treating 
oncologist. 
Your participation in this study is voluntary.  If you choose not to participate, your decision will 
not affect the care you receive at this institution at this time, or in the future. You will not have 
any penalty or loss of benefits to which you are otherwise entitled to. 

 
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 All research-related records will be kept for 10 years after termination of the study.  No 
identifiable information will leave this institution. On all study related documentation, you will 
be identified with an independent study code rather than your name or other personal identifying 
information. The Ottawa Health Science Network Research Ethics Board (OHSN-REB) and the 
Ottawa Hospital Research Institute may review your original medical records and relevant study 
records for audit purposes, under the supervision of Dr. Dent. 
If you have any questions about this study please contact one of the study investigators, Dr. 
Susan Dent (613-737-8899, ext. 70167) at TOHCC.  
The OHSN-REB has reviewed this protocol. The Board considers the ethical aspects of all 
research studies involving human participants at the Ottawa Hospital Cancer Centre.  If you have 
any questions about your rights as a study participant, you may contact the Chairperson at 613-
798-5555, extension 16719. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov.  This 
website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
Do you have any questions? 
You will receive a copy of this document for your reference. 
  
If the patient agrees to participate the physician will dictate in the progress note they have had 
the above conversation with the patient. There will be no need for the patient to sign an informed 
consent form.  
6 
ELIGIBILITY 
6.1 
Inclusion Criteria 
• Histologically confirmed early stage HER2-positive breast cancer 
• Planned trastuzumab therapy for early stage breast cancer 
• ≥18 years of age 
• Able to provide verbal consent 
• Normal LVEF (>53%) before trastuzumab therapy 

 
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6.2 
Exclusion Criteria 
• Contraindication to transthoracic echocardiography or MUGA 
7 
RANDOMIZATION 
We will randomize participants using a web-based system developed by the Methods Centre at 
The Ottawa Hospital. Each site investigator will have the web-based randomization system 
short-cut uploaded to their device in order to randomize participants. The physician must dictate 
that the verbal consent and eligibility review has taken place prior to randomization. The 
investigators will then forward the randomization confirmation email indicating the selected 
cardiac monitoring schedule to the local study CRA. Stratification will be performed for 
anthracycline and non-anthracycline-based chemotherapy. Screening and randomization logs 
will be kept on file. 
8 
DATA COLLECTION 
Once the patient has been randomized, the study CRA will collect participant information on 
LVEF, delay/discontinuation of trastuzumab therapy, referral to cardiology, or rates of 
hospitalization, all recorded in real-time via electronic health records. To facilitate timely data 
collection, the treating physician will automatically receive an email (generated at the time of 
randomization) at the time of the next patient clinic visit. This email will ask for details of any 
cardiac complications the patient may have had since the last clinic visit. From a study 
standpoint only the CRA will access this information. Data not available at the time of visit will 
be collected from the dictated physician note. CRAs will complete the paper case report forms 
(CRF). The data will then be transcribed onto case report forms.  
Participant data to be collected over the treatment period: 
• Date of birth (month, year) 
• Past medical history (history of cardio-vascular co-morbities) 
• Body mass and height to calculate body mass index (kg/m2) (cardio-vascular co-
morbidity) 
• Type and dose of current or new cardiac medications 

 
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• Chemotherapy treatment received 
• Type of cardiac monitoring -  echocardiography  or MUGA 
• Schedule of cardiac monitoring ( 3 vs. 4 months)  
• Baseline and follow-up LVEF (%) 
• Rate of treatment delay/discontinuation 
• Referral to cardiology 
• Estrogen and progesterone receptor status 
• Hospitalisations or visits to the emergency room and reason while on study 
• Changes to chemotherapy, trastuzumab or cardiac medications while on study 
• Health related quality of life at baseline, the first cardiac monitoring (3 or 4 month) and 
the end of the follow-up using the EQ-5D-5L questionnaire 
• Health related questionnaire at baseline, , the first cardiac monitoring (3 or 4 month) and 
the end of the follow-up  
• To assess physician engagement (i.e. the proportion of patients who enter the study) 
pharmacy records will be assessed in order to calculate the number of patients receiving 
trastuzumab on the study and off the study 
• To assess Percentage of medical oncologists who attend the site initiation visit and have 
agreed to participate in the trial compared to the percentage of medical oncologists that 
actually approached patients regarding the trial log of initiation visit will be collected.    
If the patient is randomized and either the patient or physician refuses the randomization 
selection, reasons for this will be recorded. If physicians choose to break the protocol, they must 
inform the patient and investigative team as to why the allocated selection should not be used 
from the randomization process. We will monitor the charts to ensure that this reason has been 
recorded. 
9 
OUTCOMES 
9.1 
Primary Clinical Outcome  
1. Changes in LVEF (by echocardiography or MUGA) throughout the course of trastuzumab 
based therapy   

 
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9.2 
Secondary Clinical Outcomes  
1. Rates of trastuzumab delay/discontinuation  
2.  Referral to cardiology  
3. Rate of cardiac events 
4. Health system cost analysis and quality of life adjusted years measured by EQ-5D-5L 
questionnaire (11)  
9.3 
Secondary Feasibility Outcomes 
Feasibility of performing this study will be measured with combination of endpoints: 
1. Percentage of patients who receive trastuzumab therapy for early stage breast cancer compared 
to the number of participants who agree to randomization. The total number of patients receiving 
adjuvant trastuzumab at each site will be provided by pharmacy.   
2. Percentage of participants who complete their assigned cardiac monitoring schedule compared 
to the percentage who discontinue their cardiac monitoring schedule while on study (compliance) 
will be calculated using the medical record. 
3. Percentage of medical oncologists who attend the site initiation visit and have agreed to 
participate in the trial compared to the percentage of medical oncologists that actually 
approached patients regarding the trial.  At the Ottawa Hospital Cancer Centre, patients are 
assigned to a primary medical oncologist. Therefore, all approached patients with have their 
primary oncologist documented on the medical record, which will be compared to the list of all 
oncologists agreeing to participate in the trial.   
10 RISKS 
There are no risks associated with this study as both arms are standard of care schedules. 
11 SAFETY REPORTING 
For the purpose of this feasibility study SAE reporting is not required. Adverse events specific to 
the secondary outcome will be captured on the CRFs. However, as with all investigator-initiated 
trials in Ottawa a regular meeting of study staff will take place every 6-8 weeks. 

 
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12 MONITORING 
Monitoring will be performed remotely by Nancy Page at The Ottawa Hospital Cancer Centre. 
The de-identified source documents and CRFs will be reviewed according to the approved 
monitoring plan. 
13 CRITERIA FOR FEASABILITY SUCCESS 
The following criteria were established a priori and needed to be met to deem this feasibility trial 
successful:  
1) over 50% of appropriate patients approached agree to participate in the RCT,  
2) over 50% of physicians who agree at study commencement to participate in the study do 
indeed approach patients for the study. Prior to study commencement and at study closure, all of 
the medical oncologists who treat breast cancer patients will be sent an email requesting 
feedback on their enthusiasm for the study and how they feel optimal methods of patient accrual 
can be incorporated into the feasibility of this study.  
 
14 PREMATURE WITHDRAWAL 
Participants have the right to withdraw from the study treatment at any time for any reason 
Investigator has the right and obligation to withdraw subjects from the study treatment in the 
event of: 
• 
Intercurrent illnesses which would, in the judgment of the investigator, affect assessment 
of clinical status to a significant degree, and require discontinuation of the assigned 
cardiac monitoring schedule 
• 
Any toxicity that would produce further harm if continued on the protocol 
• 
Request by the participant or of their legally authorized representative (consent 
withdrawal) 
• 
Non-compliance to the study protocol or logistic consideration 
• 
Participant is lost to follow-up 

 
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15 SAMPLE SIZE AND STATISTICAL ANALYSIS  
As per protocol one of the outcome points will be change in LVEF (by ECHO or MUGA) 
throughout the course of trastuzumab-based therapy (%) in both groups. It is known, that normal 
LVEF is >53% (average – 61% with standard deviation 8%). In adjuvant clinical trials. the 
majority of patients during trastuzumab treatment experienced reversible decrease in LVEF of 
between 4-6%. As a criteria of non-inferiority the Mean of last measured LVEF while on 
trastuzumab treatment can be used to prove the same safety and sensitivity of both schedules. 
Our non-inferiority margin between groups is 4% (MLVEF3m-MLVEF4m<±4%) with a standard 
deviation of the mean change of 8%.  To demonstrate non-inferiority of 4 versus 3 monthly 
monitoring mean LVEF in two independent groups with t tests (Means: Difference between two 
independent means) and our non-inferiority margin of 4%, we require 87 patients in each group – 
total 174 +10% (drop rate) = 200. We assumed a significance level α=0.05, power (1-β) of 95%, 
and effect size d = 0.5 (G*Power 3.1.9.2.). 
 
Analysis: 
Descriptive analysis: Baseline characteristics and management data will be presented with 
means (continuous measures) or proportions (categorical or ordinal data) with 95% confidence 
intervals. 
Intention-to-treat analysis: In both studies, all statistical analyses of the data will be based on an 
intention-to-treat approach (based on subjects who underwent randomization). In addition, a 
treatment received as per protocol analysis of the primary outcome measure will be conducted.  
Analysis of the primary outcome (LVEF): The primary outcome (LVEF) will be measured at 
baseline and every 3 or 4 months with the primary (and common) time point measure at 1 year. 
As the primary outcome is a continuous variable, the mean difference between both treatment 
groups at one year of follow up and the last measured LVEF while on trastuzumab treatment will 
be assessed using repeated-measures analysis of variance, which control for study sites (random 
effect) and eventually control for differences in confounding variables, should any arise despite 
randomization. The purpose of our model is not inferential, but rather to estimate the expected 

 
Page 15 of 17 
 
change in treatment effect and confidence interval i.e. whether or not the 4 monthly group is 
found to be inferior by non-inferiority by a margin of 4%.  
Analysis of secondary feasibility and clinical outcomes: Secondary feasibility outcomes will be 
reported using descriptive statistics. Protocol adherence will be reported as a proportion. 
Dichotomous clinical outcomes will be compared using a one-sided Z-test while continuous 
variables will be compared using a one-sided t-test in an analogous manner. Relative risk 
(dichotomous) and mean differences (continuous) along with their 95% confidence intervals will 
also be calculated and presented. 
Compliance and loss to follow-up: Secondary analyses will be considered to better understand 
the influence of compliance, and losses to follow-up on the robustness of the intention-to-treat 
analysis.  The general approaches will include an analysis of primary and secondary outcomes 
including only participants who completed the study as per their assigned diagnostic schedule 
protocol. 
Economic analysis. We will use a decision analytic model to compare total health system cost 
and quality-adjusted life years (QALYs) among patients receiving 4 versus 3 monthly cardiac 
monitoring. We will obtain health resource use, relative efficacy of 4 versus 3 monthly cardiac 
monitoring and health utility values from the trial. Aggregate and individual average costs of 
hospital and emergency visits among patients with and without cardiac events will be obtained 
from the Ottawa Hospital Data Warehouse Database (Ottawa site only). Unit costs of physician 
visit will be based on the Ontario’s Schedule of Benefits for Physician Services (12), while the 
costs of outpatient medications will be sought from the Ontario Drug Benefit Formulary. QALYs 
will be estimated for each patient within the clinical trial using the total area under the curve 
method (13).  We will calculate an incremental cost per QALYs gained and an incremental cost 
per one unit change in LVEF. We will perform a series of one-way and probability sensitivity 
analyses to assess the robustness of the study findings. Results from the probabilistic sensitivity 
analysis will also be used to create cost-effectiveness acceptability curves, which link the 
probability of the intervention being cost-effective to a range of potential threshold values that 
the health system may be willing to pay for an additional unit of effect. All analyses will be 
performed in Microsoft Excel. All patients will be asked to complete a baseline health 
questionnaire about any cardiac risk factors (i.e. diabetes, smoking status, prior heart health 

 
Page 16 of 17 
 
history) and current cardiac medications. Patients in the 3-monthly arm will be asked 3 months 
after their first trastuzumab if in the previous 3 months; number of visits to ER, number of night 
at the hospital, type, changes to any cardiac medications. Patients in the 4-montly group will be 
asked 4 months after their first trastuzumab the same questions relating to the previous 4 months. 
Both groups will be asked the same question at the 12 month time point.   At screening visits 
physicians will document any hospitalizations, ER visits, changes in chemotherapy, trastuzumab 
or cardiac medications, any drop in LVEF and referrals to cardiology. 
16 References  
 
1. 
Tan-Chiu E, Yothers G, Romond E, Geyer CE, Jr., Ewer M, Keefe D, et al. Assessment of cardiac 
dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, 
with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor 
receptor 2-overexpressing breast cancer: NSABP B-31. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2005;23(31):7811-9. 
2. 
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Jr., Davidson NE, et al. Trastuzumab plus 
adjuvant chemotherapy for operable HER2-positive breast cancer. The New England journal of medicine. 
2005;353(16):1673-84. 
3. 
Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the 
trastuzumab clinical trials experience. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2002;20(5):1215-21. 
4. 
Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. Expert consensus for 
multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the 
American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am 
Soc Echocardiogr. 2014;27(9):911-39. 
5. 
Jones AL, Barlow M, Barrett-Lee PJ, Canney PA, Gilmour IM, Robb SD, et al. Management of 
cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National 
Cancer Research Institute recommendations for monitoring. British journal of cancer. 2009;100(5):684-
92. 
6. 
Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, et al. Cardiovascular 
toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. 
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2012;23 
Suppl 7:vii155-66. 
7. 
Network NCC. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)®: Breast Cancer 
Version 2.2015. National Comprehensive Cancer Network, Fort Washington Accessed. 2015;11. 
8. 
Chavez-MacGregor M, Niu J, Zhang N, Elting LS, Smith BD, Banchs J, et al. Cardiac Monitoring 
During Adjuvant Trastuzumab-Based Chemotherapy Among Older Patients With Breast Cancer. Journal 
of Clinical Oncology. 2015:JCO. 2014.58. 9465. 
9. 
Sugarman J, Califf RM. Ethics and regulatory complexities for pragmatic clinical trials. JAMA. 
2014;311(23):2381-2. 
10. 
Kim SY, Miller FG. Informed consent for pragmatic trials--the integrated consent model. N Engl J 
Med. 2014;370(8):769-72. 

 
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11. 
Group E. EQ-5D-5L 2009 [cited 2017 April 3, 2017]. Available from: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Products/Sample_UK__English__EQ
-5D-5L_Paper_Self_complete_v1.0__ID_24700_.pdf. 
12. 
Care MoHaL-T. Schedule of Benefits for Physician Services under the Health Insurance Act 2015 
[Available from: 
http://www.health.gov.on.ca/en/pro/programs/ohip/sob/PHYSSERV/PHYSSERV_MN.HTML  
13. 
Care MohaL-T. Ontario Drug Benefit Formulary/Comparative Drug Index 2016 [Available from: 
https://www.formulary.health.gov.on.ca/formulary/.