Detection of (Sub)Clinical Toxicity in Irradiated vs. Non-irradiated Surgically Treated Esophageal Cancer Patients: a Pilot Study (CROSS SECT)
Conditions: Thoracic Tumor
Sponsor: University Medical Center Groningen

RT2017-06 
 
 
V1.2, dd 30-08-2017 
Protocol ID: 
RT 2017-06 
 
Short title:   
Detection of (sub) clinical toxicity in irradiated vs. non-irradiated 
surgically treated esophageal cancer patients: a pilot study 
 
Acronym: 
CROSS SECT 
 
Version: 
1.2, 30-08-2017 
 
 
 
 
 
Coordinating investigator:  Prof. J.A. Langendijk 
 
Principal investigator:   
J.C. Beukema, MD 
 
Sponsor:  
 
 
UMCG 
 
Independent expert:  dr. W. Noordzij, MD PhD, Nuclear physician 
 
 
Laboratory sites:  routine assessments 
 
Writing committee:   
J.C. Beukema, MD, Radiation oncologist 
C.T. Muijs, MD, PhD, Radiation oncologist 
A. Crijns, MD PhD, Radiation oncologist 
C. de Groot, MD, Radiation oncologist in training 
Prof. J. Plukker, MD, PhD, Oncologic surgeon 
Prof. R. Vliegenthart, MD, PhD, Radiologist 
J.P. van Melle, MD, PhD, Cardiologist 
D.J.A. de Groot, MD, PhD, Medical oncologist 
P. v. Luijk, PhD Senior Researcher 
L. Kors, MSc, Datamanager. 
Prof. J.A. Langendijk, MD, PhD, Radiation oncologist 
 
 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
 
For non-commercial research: 
 
Head of Department: 
Prof. J.A. Langendijk, MD, PhD 
Dept. of Radiation Oncology 
UMCG 
Groningen 
The Netherlands 
j.a.langendijk@umcg.nl 
phone +31 50 361 5532  
 
 
 
Coordinating Investigator/Project 
leader/Principal Investigator: 
 
J.C. Beukema, MD 
Radiation Oncologist 
Dept. of Radiation Oncology 
UMCG 
Groningen 
The Netherlands 
j.c.beukema@umcg.nl 
phone +31 50 361 9382 
 
 
 
 
 
 
 
 
 

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Table of contents  
 
 LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
CTCAE 
Common Terminology Criteria for Adverse Events 
CRT 
ChemoRadiotherapy 
NeoCRT 
Neoadjuvant chemoradiotherapy 
DVH 
Dose Volume Histogram 
EC 
Esophageal cancer 
GCP 
Good Clinical Practice 
hs-CRP 
High sensitivity C-reactive protein 
hs-TNT 
High sensitivity troponin T 
METC 
 
Medical research ethics committee (MREC); in Dutch: Medisch 
 
ethisch toetsing commissie (METC) 
NSCLC 
    Non small cell lung cancer 
NTCP-model 
Normal Tissue Complication Probability model 
NT pro BNP 
N-terminal pro-B-type natriuretic peptide 
PDRP 
Prospective Data Registration Program 
OS 
Overall survival 
RT 
Radiotherapy 
(S)AE 
(Serious) Adverse Event 
Sponsor 
 
The sponsor is the party that commissions the organisation or 
 
performance of the research, for example a pharmaceutical company, 
 
academic hospital, scientific organisation or investigator. A party 
 
that provides funding for a study but does not commission it is not 
 
regarded as the sponsor, but referred to as a subsidising party 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
WMO 
 
Medical Research Involving Human Subjects Act (in Dutch: Wet 
 
Medisch-wetenschappelijk Onderzoek met Mensen 
 
 
 
 
 
 

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Inhoud 
1. 
INTRODUCTION AND RATIONALE 
8 
2. 
OBJECTIVES 
10 
3. 
ENDPOINTS 
11 
4. 
OTHER STUDY PARAMETERS 
11 
5. 
STUDY DESIGN 
12 
6. 
STUDY POPULATION 
12 
6.1. 
Population (base) 
12 
6.2. 
Inclusion criteria 
12 
6.3. 
Exclusion criteria 
12 
7. 
SAMPLE SIZE CALCULATION 
13 
8. 
METHODS 
13 
8.1. 
Randomisation, blinding and treatment allocation 
13 
8.2. 
Study procedures 
13 
8.3. 
Withdrawal of individual subjects 
16 
8.4. 
Replacement of individual subjects after withdrawal 
16 
8.5. 
Follow-up of subjects withdrawn from treatment 
17 
9. 
SAFETY REPORTING 
17 
9.1. 
Section 10 WMO event 
17 
9.2. 
AEs, SAEs and SUSARs 
17 
10. STATISTICAL ANALYSIS 
18 
10.1. Primary study parameter(s) 
18 
 
 
10.3. Other study parameters 
18 
11. ETHICAL CONSIDERATIONS 
18 
11.1. Regulation statement 
18 
11.2. Recruitment and consent 
18 
11.3. Objection by minors or incapacitated subjects 
19 
11.4. Benefits and risks assessment, group relatedness 
19 
11.5. Compensation for injury 
20 
11.6. Incentives (if applicable) 
20 
12. DATA COLLECTION, DATA MANAGEMENT, MONITORING AND PUBLICATION 
20 
12.1. Electronic case report forms 
20 
12.2. Use of computerized systems 
20 
12.3. Retention of records 
20 
12.4. Data Management Plan 
21 
12.5. Monitoring and Quality Assurance 
21 
12.6. Anonymization of data 
21 
12.7. Amendments 
21 
12.8. Annual progress report 
21 

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12.9. Temporary halt and (prematurely) end of study report 
22 
12.10. Public disclosure and publication policy 
22 
13. REFERENCES 
23 
 
 
 

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SUMMARY 
Rationale: Radiation-induced cardiac and pulmonary toxicity after treatment for intra-thoracic 
tumors is a clinically relevant problem, which may jeopardize the benefit of (neo-adjuvant) 
(chemo) radiotherapy. Although cure rates are rising since the introduction of neo-adjuvant 
chemoradiation (neo-CRT) as current standard treatment for esophageal cancer (EC), recent 
studies showed that there is a substantial risk of non-cancer treatment-related death in these 
patients [1–6]. Furthermore, this risk is underestimated as the cause of death of many patients 
remains unknown, since the distinction between tumor related and non-cancer related death 
can be difficult.  
Cardiac and pulmonary toxicity and its interaction as seen in pre-clinical studies might explain 
for these unknown deaths as suggested in several clinical studies [6–9]. Clinical imaging studies 
performed shortly after treatment showed changes in different cardiac function parameters, all 
related to radiation dose parameters [10–13]. Systematic imaging studies analysing subclinical 
toxicities at longer follow up have never been performed, most probably because of poor 
survival rates. However, identification of the magnitude of (subclinical) cardiopulmonary toxicity, 
by performing several cardiopulmonary function tests, is essential in this patient group as this 
toxicity is most likely the cause of the increased mortality after thoracic radiotherapy. For future 
perspectives, these results can be used to select the best diagnostic methods for a prospective 
cohort study to develop prediction tools for cardiopulmonary toxicity. Finally, this might lead to 
optimization of radiotherapy dose-distributions (including patient selection for proton therapy) 
and hopefully reduce radiation induced cardiopulmonary toxicity and improve overall survival. 
Objective:  
The main objective of this study is to determine the most suitable diagnostic test to identify 
cardiopulmonary (dys)function in EC survivors treated with neo-CRT followed by surgical 
resection. Furthermore, we want to estimate the difference in cardiopulmonary (dys)function in 
EC survivors treated with neo-CRT followed by surgical resection compared to EC survivors 
who were treated with surgical resection alone.  
 
Study design: Cross-sectional pilot study  
Study population: 40 EC patients who were treated with curative intent by esophageal 
resection with or without neo-CRT 
Intervention (if applicable): Not applicable. 
Main study parameters/endpoints:  

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As this is an exploratory pilot study to determine the most suitable diagnostic tests for future 
studies, there will be several endpoints related to (sub)clinical cardiopulmonary dysfunction.  
Signs of myocardial ischemia, systolic or diastolic dysfunction, rhythm and valve disorders, 
pericardial effusion and fibrosis, myocardial fibrosis, focal wall motion disorders and coronary 
calcifications will be analyzed. The cardiopulmonary (dys)function in EC survivors treated with 
neo-CRT followed by surgical resection will be compared to cardiopulmonary (dys)function in 
EC survivors treated with surgical resection alone.  
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Several tests will be performed at one time point, 5-10 years after given 
treatment. If the findings of the test indicate cardiovascular complications, the patient will be 
referred to the cardiologist for further analysis and/or preventive measures. As one of the tests, 
cardiac MRI, including gadolinium (Dotarem 0.2 mmol/kg) enhancement will be performed. 
Potential side effects of gadolinium include brief headache, nausea (feeling sick) and dizziness 
for a brief time following the injection. Allergic reactions are rare. Furthermore, a cardiac CT 
scan will be performed with a total radiation exposure of 0.6 mSv (less than a third of the annual 
background radiation dose), the risks will be minimal. 
 

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1. INTRODUCTION AND RATIONALE 
Background  
Increasing numbers of patients with intra-thoracic tumours are currently treated with curatively 
intended combined modality strategies such as chemoradiation (CRT) either in the neo-adjuvant 
setting followed by surgery or as definitive treatment. Due to improved outcome resulting from 
the addition of chemotherapy to radiotherapy (RT) and due to the clinical introduction of neo-
CRT prior to surgery, the prevalence of EC survivors is rising [5,14,15]. Therefore, the absolute 
number of patients at risk for treatment-related toxicity is rising as well.   
 
There is increasing evidence that radiotherapy induces cardiac and pulmonary damage. In 
esophageal cancer patients, pericarditis during and shortly after radiotherapy is the most 
frequently observed side effect, which should be regarded as an acute inflammatory effect [16] .  
In the first year after treatment, wall motion disorders with changes in end diastolic volume have 
been observed [13,17]. These wall motion disorders are most probably caused by changes in 
the microvasculature. In addition, increased rates of coronary artery disease, myocardial 
infarctions, heart failure, as well as pericarditis, arrhythmia and valvular disorders have been 
observed, and may appear after longer latency times [18–20]. Systematic imaging studies 
analysing subclinical toxicities at longer follow up have never been performed, most probably 
because of poor survival rates. Preclinical studies indicate cardiopulmonary changes not only 
relate to the radiation dose given to the heart but also to the dose given to the lung [8,21]. The 
mechanism behind this phenomenon seems to be an increased pressure in the pulmonary 
arteries due to vascular fibrosis which leads to diastolic dysfunctioning of the heart due to a 
volume overload. 
Furthermore, the results of several clinical studies suggested that some severe treatment-
related morbidity and mortality remains unrecognized but is associated with radiation exposure 
to the heart and lungs. For example, the meta-analysis on the added value of postoperative 
radiotherapy after surgical resection for non-small cell lung cancer (NSCLC) revealed 
significantly worse overall survival (OS) in patients receiving post-operative radiotherapy [2], 
suggesting that thoracic radiation causes lethal toxicities of the lungs and/or mediastinal 
structures. In a dose escalation trial in NSCLC a significantly worse OS was seen in the high 
dose group. Overall survival turned out to be associated with the radiation dose to the heart [1].  
In EC the introduction of newer techniques, like IMRT, significantly reduced the risk on cardiac 
death [9,22]. Furthermore, in a randomised trial comparing neo-adjuvant chemotherapy to neo-

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CRT, neo-CRT had a significantly better response rate, however this did not result in a survival 
benefit. An explanation was found in a higher rate of non-cancer related death already during 
the first year of follow up [3]. 
 
In summary these data demonstrate that thoracic radiotherapy induces not only clinical but also 
subclinical toxicity, which might explain the unrecognized grade 5 toxicity, as a result of high 
dose thoracic radiotherapy. Identification of the magnitude of (subclinical) cardiopulmonary 
toxicity, by performing several cardiopulmonary function tests, is essential in this patient group 
as this toxicity is most likely the cause of the increased mortality after thoracic radiotherapy. For 
future perspectives, these results can be used to select the best diagnostic methods for a 
prospective cohort study to develop prediction tools for cardiopulmonary toxicity. 
 
 
Patient population 
As many of our EC patients are older and have cardiopulmonary problems as a result of their 
age, co-morbidities or lifestyle habits, we would like to compare a cohort of patients treated for 
EC who did or did not undergo (chemo)radiotherapy. 
A cohort of these patients is available, as neo-CRT has become standard treatment since 2012 
after the publication of the so-called CROSS trial, demonstrating an important survival benefit in 
the group that received neo-CRT followed by surgery compared to patients treated with surgery 
alone. During this time period and the time period shortly before and after, patients were treated 
either with or without neo-CRT. In this time period we did not select patients on cardiopulmonary 
co-morbidities or age, so we expect comparable groups. Part of these patients were already 
retrospectively analyzed and compared on short term (within 90 days) morbidity and mortality 
after resection [23]. These data were published in 2013. We demonstrated an increased 
incidence of pneumonia and rhythm disorders in patients treated with neo-CRT, but no 
difference was noted in neither hospital and intensive care unit stay nor in mortality or overall 
morbidity between these two groups. As these patients were treated in the time period 2000-
2012 and thus will have a 5-15 years follow up there is a sufficiently large patient cohort 
available to prospectively analyze clinical and subclinical cardiac changes and/or toxicities.  
 
 

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Which tests would be interesting at longer follow up or study parameters 
As mentioned in the introduction, the main focus of this study is (subclinical) cardiopulmonary 
(dys)functioning. The most important late (subclinical) toxicities we expect to find at longer 
follow up are: diastolic dysfunction, coronary artery disease, cardiac wall motion disorders, heart 
failure, pulmonary hypertension, pericardial effusion and/or constriction, cardiac arrhythmia and 
valve disorders. A number of these endpoints will eventually result in heart failure.  
 
 
Anamnesis and physical examinations will be performed in these patients 
 
In case a pulmonologist or cardiologist has been consulted, additional information will be 
collected from hospital records of these specialists.  
 
Radiotherapy treatment parameters will be collected from our database in case the 
patient was treated with radiotherapy. 
 
6 minute walking test 
 
Echocardiogram 
 
CTTC scan  
 
Cardiac MRI scan 
 
ECG  
Laboratory tests: NT-pro BNP, cholesterol, CRP and hs-TNT, eGFR, HbA1c, hematocrit. 
 
2. OBJECTIVES 
 
Primary Objectives:  
The main objective of this study is to determine the most suitable diagnostic test to identify 
cardiopulmonary (dys)function in EC survivors treated with neo-CRT followed by surgical 
resection. Furthermore, we want to estimate the difference in cardiopulmonary (dys)function in 
EC survivors treated with neo-CRT followed by surgical resection compared to EC survivors 
who were treated with surgical resection alone.  
1. To determine the differences in clinical cardiac and pulmonary events, (cardiac ischaemia, 
heart failure, arrhythmia, valve disorders, pulmonary hypertension, COPD) as clinically 
diagnosed since treatment between patients treated with neo-CRT and surgery alone. 
2. To determine the difference in other (subclinical) parameters as tested by echo cardiogram, 
6 minute walking test, CT scan, MRI scan and biomarkers.  
3. To analyse the current CAC scores in both patient groups. 
4. To determine the difference between the baseline and current CAC scores. 

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5. To determine the difference between ECG findings currently and on baseline. 
6. To correlate the different subclinical imaging parameters to the radiation dose given to the 
heart and lungs  
7. To correlate CAC scores with the given dose distribution on plannings CT scan 
 
3. ENDPOINTS 
As this is an exploratory pilot study to determine the most suitable diagnostic tests for 
future studies, there will be several endpoints related to (sub)clinical cardiopulmonary 
dysfunction. Signs of myocardial ischemia, systolic or diastolic dysfunction, rhythm and 
valve disorders, pericardial effusion and fibrosis, myocardial fibrosis, focal wall motion 
disorders and coronary calcifications will be analyzed.  
The cardiopulmonary (dys)function in EC survivors treated with neo-CRT  
followed by surgical resection will be compared to cardiopulmonary (dys)function in EC 
survivors treated with surgical resection alone.  
 
 
4. OTHER STUDY PARAMETERS 
For the purpose of this study, the following parameters will be assessed in all patients:  
 
Cardiac risk factors 
o Smoking status 
o Age 
o Detailed cardiac history including medical letters from cardiologists when 
available  
o Detailed pulmonary history including medical letters from pulmonologists when 
available 
o Alcohol consumption 
o Family history on cardiac events 
o Hypertension 
o D.M.  
o Use of medication 
 
Combination with chemotherapy 
 
Postoperative complications and interventions 
 
Sex 
 
Daily activities and/or sport 

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 
Original clinical tumor stage (TNM) 
 
Original tumour length at endoscopy 
 
Original pathologic tumor stage (TNM) 
 
Volume (cc) of the irradiated planning target volume 
 
For irradiated patients; radiotherapy treatment parameters and dose distributions 
o Dose Volume Histogram of the heart 
o Dose Volume Histogram of different cardiac subvolumes 
o Dose Volume Histogram of the lungs 
 
 
5. STUDY DESIGN 
This is a cross sectional pilot study with patients who were or were not treated with neo-CRT.  
 
6. STUDY POPULATION 
6.1. Population (base)  
Patients with EC treated with or without neo-CRT, alive without evidence of disease, treated 
between 2000 and 2012 at the University Medical Centre Groningen will be eligible. Twenty 
patients will be included in both treatment groups. Length of follow up after treatment does 
not seem to be an important confounding factor as surgery is not considered to be an 
important risk factor for late toxicity.  
  
 
6.2. Inclusion criteria 
 
Treated for EC with a curative resection between 2000 and 2012  
 
Age >= 18 years  
 
Written informed consent 
 
No signs of tumor recurrence or new other malignancies. 
 
6.3. Exclusion criteria 
 
Thoracic radiotherapy for indications other than EC. 
 
Contra indication for cardiac MRI, pacemaker, cochlear implants, metal not compliable 
with MRI. 
 

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7. SAMPLE SIZE CALCULATION 
As this is a pilot study to determine (sub-clinical) cardiopulmonary toxicity, a total of 40 patients, 
20 in each group, will be included in this study.  
 
 
 
8.  METHODS 
8.1. Randomisation, blinding and treatment allocation 
Not applicable 
8.2. Study procedures 
Candidates will be selected from the surgical and radiotherapy database. General practitioners 
will be checked for their survival status. An introduction letter, including patient information for 
this study, will be sent to the surviving patients to explain the study and ask them to consider 
participation in this research project. Patients are given the opportunity to call the researcher for 
further information and questions about the study. Patients can give their informed consent by 
sending the written informed consent. After receiving the informed consent, appointments will be 
made whenever possible on one day in consultation with the patient. 
 
 Interview and physical examination 45 minutes 
 6 minute walking test plus explanation 30 minutes 
 ECG 15 minutes 
 Laboratory tests 5 minutes 
 Echocardiogram 30 minutes 
 Cardiac CT scan 10 minutes 
 Cardiac MRI scan 40 minutes 
 
Anamnesis and physical examination:  
The patients will be interviewed on matters concerning their medical history, cardiopulmonary 
complaints and patients will be asked to fill in the following questionaires: EORTC ACE27, 
EORTC LC13, EuroQOL 5D and the EORTC C30. A general physical examination will be 
performed, including length and weight.  
 
6 minute walking test: 

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Gives an estimate of the general functioning status of the patients during follow up. It is known 
to correlate with maximum oxygen uptake and physical fitness without laboratory test [24].  
 
Laboratory tests:  
NT pro BNP and hs TNT are known  markers in cardiology for myocardial damage and “volume 
overload” like in diastolic dysfunction. Blood markers like cholesterol, CRP, HbA1 will help 
determining the baseline risk on cardiac events. eGFR will be checked before gadolinium is 
infused in order to minimize risks on its possible side effects. It is necessary to determine 
hematocrit for calculation of the extracellular volume (ECV). 
 
ECG 
Simple screening instrument to indicate hypoxia, pericarditis, past infarctions, bundle branch 
blocks and rhythm disorders 
 
Echocardiogram: 
An echocardiogram is performed as a safe non-invasive screening technique, which is able to 
measure hypertrophy of the myocardium, pericarditis, wall motion disorders, blood flows and 
pressures, which are functional parameters who could indicate pulmonary hypertension and 
diastolic- or systolic dysfunction  and valve disorders[25]. 
The echocardiographic assessment will be performed by the Echocardiography Core lab 
(www.G-ICL.com) facility, of the UMCG. The echocardiographic protocol includes assessments 
of systolic and diastolic function of both ventricles according to the guidelines of the European 
Association of Cardiovascular Imaging (EACVI). Specifically we will assess: 
1. Tricuspid annular plane systolic excursion (Tapse) 
2. Velocity of the tricuspid annular systolic motion (RV s’) 
3. Right ventricle fractional area change 
4. Doppler notching of right ventricular outflow tract signal 
5. Tricuspid valve Doppler velocity 
6. Pulmonary valve Doppler velocity 
7. Myocardial performance index (Tei index) 
8. Pulmonary artery acceleration time 
9. Pulmonary valve end diastolic velocity 
10.Cardiac Output 
11.Left ventricle systolic function 

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12.Left ventricle diastolic dysfunction 
13.Valvar abnormalities 
14.Left ventricle eccentricity index 
15.Right ventricle strain 
16.Right atrium volume 
17.Inferior Caval Vein collapsibility 
Also 2D strain echocardiography will be performed to establish subtle changes in myocardial 
function. 
 
 
Cardiac CT imaging :  
CT imaging will be performed on a latest generation dual-source CT scanner (Siemens Medical 
Solutions, Forchheim, Germany). A non-enhanced CT high pitch spiral acquisition in diastole 
with prospective electrocardiography (ECG) triggering will be performed with a standard 
protocol (120 kV tube potential; ref mAs 75) with an associated radiation dose of 0.6 mSv (less 
than a thrird of the annual background radiation dose). On the CT acquisition, the amount of 
coronary calcification will be calculated and expressed as a Coronary Artery Calcium (CAC) 
score based on the Agatston method. 
The CAC score can be used to compare the current and baseline status (using the diagnostic 
CT scans performed before treatment) and is a reliable instrument for coronary disease [26]. 
Furthermore, dose distributions can be correlated with the coronary artery calcifications by 
fusing diagnostic CT scans with the planning CT scans in irradiated patients.  
The CAC score at baseline will be used to estimate the baseline risk on cardiac events 
 
 
Cardiac MRI:  
Cardiac MRI will be performed with a 1.5- or 3.0-Tesla MRI scanner (Siemens Medical 
Solutions, Forchheim, Germany). Imaging is performed during breath-hold at end-expiration. 
During the procedure, ECG is continuously monitored. After acquisition of scout views for the 
determination of the standard orientations of the heart, cine images will be acquired for 
functional evaluation and measurements (4 chamber, 2 chamber, short axis). T1 acquisitions 
are performed before and after injection of 0.2 mmol/kg gadoterate meglumine (Dotarem, 
Guerbet, Villepinte, France). T1 mapping is a parametric quantitative sequence, which provides 
tissue-specific T1 values. For T1 mapping, a 5(3)3 sampling scheme of the heart is performed, 

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using a modified Look Locker sequence. Pixel-wise T1 maps of the myocardium are acquired in 
3 short-axis views with inline motion correction. The major advantage of T1 mapping sequences 
is their potential for quantitative objective assessment of myocardial abnormalities. Myocardial 
pathologies leading to T1 changes include diffuse myocardial fibrosis, edema, inflammation, and 
infiltrative diseases such as amyloidosis, Fabry disease, and hemosiderosis. The comparison of 
T1 values before and after Gadolinium enable the quantitative estimation of myocardial 
interstitial remodeling and extracellular space expansion, to evaluate myocardial extracellular 
volume. Ten minutes after the Gadolinium injection, a late Gadolinium enhancement (LGE) 
series is performed to assess possible myocardial infarction and gross fibrosis. Image post-
processing includes the measuring of cardiac dimensions, ventricular volumes, LV and RV 
function, LV mass, and T1 tissue values.  
 
Radiotherapy treatment plan 
The radiotherapy details, CT scan and delineated structures will be transferred to our current 
planning system in order to extract dose distributions and dose to the critical organs as, dose 
volume histograms will be exported. The cardiac CT scan will be co registered to our planning 
CT scan in order to correlate high dose regions to present coronary artery disease . 
 
Participants will be in the hospital for 6-8 hours, including waiting time in between the tests.  
 
In case, a clinically relevant, (subclinical) abnormality is diagnosed we will contact the patient 
and its general practitioner. The possible clinical consequences will be discussed with the 
cardiologist involved, and, if indicated, the patients will be referred to the cardiologist for further 
analyses or preventive measures. 
 
8.3. Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 
8.4. Replacement of individual subjects after withdrawal 
Patients will be asked to participate in this project when treated in this time period up to a 
maximum of 40 patients . 
 

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8.5. Follow-up of subjects withdrawn from treatment 
No further follow up is required. 
 
9. SAFETY REPORTING 
9.1. Section 10 WMO event 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects 
and the reviewing accredited METC if anything occurs, on the basis of which it appears that the 
disadvantages of participation may be significantly greater than was foreseen in the research 
proposal. The study will be suspended pending further review by the accredited METC, except 
insofar as suspension would jeopardise the subjects’ health. The investigator will take care that 
all subjects are kept informed.  
 
9.2. AEs, SAEs and SUSARs 
Adverse events, serious adverse events and suspected unexpected serious adverse reactions 
will not be assessed in this study as no clinical relevant adverse events, serious events and 
suspected unexpected serious adverse reactions are expected.  
 
 
 
 

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10. STATISTICAL ANALYSIS 
10.1.Primary study parameter(s) 
Different cardiopulmonary parameters will be presented by means and standard deviations and 
will be compared between the groups using and independent t-test, with Bonferroni correction if 
applicable.  
 
10.2.Other study parameters 
Risk factors for cardiac and pulmonary complaints will be presented in frequency tables and 
tested for statistical significant differences between both groups using an independent t-test 
 
Location of focal wall abnormalities and arteriosclerosis and its relation to high dose regions will 
be presented in a table. 
 
11.  ETHICAL CONSIDERATIONS 
11.1.Regulation statement 
This study will be conducted in accordance with the Declaration of Helsinki 2013 (Fortaleza, 
Brazil) and in accordance with the principles of ‘Good Clinical Practice’ and the Medical 
Research Involving Human Subjects Act (WMO). 
 
11.2.Recruitment and consent 
Candidates will be selected from the surgical and radiotherapy database. General practitioners 
will be checked for their survival and disease status. An introduction letter and patient 
information sheet explaining the purpose and procedure of this study will be sent to the patients. 
Patients are given the opportunity to call or email the researcher for further information and 
questions about the study. Patients can give their informed consent by sending the written 
informed consent. If a patient has not given an answer within two weeks after receiving the 
letter, we will sent a second letter as a reminder. After we receive the consent the appointments 
will be made on whenever possible on one day in consultation with the patient. 
 
Patients consent will be noted on an informed consent form compliant with the local and ethical 
regulations.  
 
If during the study the patient for whatever reason no longer wishes to participate, he/she can 
withdraw his/her consent at any time. 

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Prior to the start of the study, the protocol has to be approved by the medical ethics review 
committee of the participating institution. Approval will be indicated in writing with reference to 
the final protocol number and date. 
 
11.3. Objection by minors or incapacitated subjects  
Not applicable. 
 
11.4. Benefits and risks assessment, group relatedness  
The risk of participation in this study is very low. Patients have to visit the hospital once. The 
patient will have to stay in the hospital for approximately 6-8 hours. Within this time period 
anamnesis, questionnaires, physical examination and additional tests will be performed. 
Blood withdrawal may result in local tenderness or hematoma, which are self-limiting. 
Cardiac MRI scan requires IV contrast infusion with gadolinium, with the use of gadolinium there 
is a very low risk of anaphylactic reactions, nausea and headache, besides, the small bore used 
in MRI scanning may trigger claustrophobic feelings 
Echo, ECG and the walking test do not cause any harm to the patients. 
CT scan will give radiation exposure but as the total dose of this cardiac CT scan is relatively 
low total radiation dose of 0.6 mSv (less than a third of the annual background radiation dose), 
the risks will be minimal. 
Patients participating will be evaluated for subclinical cardiopulmonary (dys)funtioning. Patients 
will be referred to a cardiologist or pulmonologist for early intervention if considered necessary, 
this might improve quality of life or even life expectancy. 
 
The results of this pilot study will form the basis for a subsequent prospective observational 
cohort study in which the most promising tests and clinical endpoints will be used to assess 
correlations with radiotherapy dose metrics with the ultimate aim to develop prediction models. 
These models can be used for model-based radiotherapy treatment plan optimization and to 
select patients for the best radiation technique, e.g. proton therapy. 
Furthermore, the result of such a prospective cohort study might indicate the necessity of 
preventive measures for cardiopulmonary toxicity in the future.  
  

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11.5. Compensation for injury 
The sponsor has a liability insurance which is in accordance with article 7, subsection 6 of the 
WMO. The Insurance company Onderlinge Waarborgmaatschappij Centramed, Postbus 191, 
2270 AD Voorburg, takes out the insurance policy. The assurer and the insurance policy comply 
with the requirements laid down by order of “Besluit verplichte verzekering bij medisch-
wetenschappelijk onderzoek met mensen” (Staatsblad, 1 september 2003). 
 
11.6. Incentives (if applicable) 
Additional costs like traveling expenses and meals during the hospital visit will be reimbursed. 
 
 
12. DATA COLLECTION, DATA MANAGEMENT, MONITORING AND PUBLICATION 
12.1.Electronic case report forms 
Wherever possible, all data will be entered directly into the eCRF. Where needed, paper source 
documents can be used. An audit trail will maintain a record of initial entries and changes made; 
reasons for change; time and date of entry; and user name of person authorizing entry or 
change. For each  subject enrolled, an eCRF must be completed and electronically signed by 
the principal investigator or authorized delegate from the study staff. If a subject withdraws from 
the study, the reason must be noted on the end of study form of the eCRF. The investigator 
should ensure the accuracy, completeness and timeliness of the data recorded in the eCRF and 
in all required reports. 
12.2.Use of computerized systems 
When clinical observations are entered directly into an investigational site’s computerized 
medical record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document If original data are modified, the system should maintain a viewable 
audit trail that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
 
12.3.Retention of records 
The principal investigators, involved specialist researchers and the data management will have 
access to the source data. All data will be stored during a period of twenty years. 

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V1.2, dd 30-08-2017 
12.4.Data Management Plan 
If data will be entered directly in the eCRF the DMP will also include a Source Identification List. 
The Source Identification List will identify any data to be recorded directly in the eCRF (i.e., no 
prior written or electronic record of data), and which data should be considered source data. 
 
12.5.Monitoring and Quality Assurance  
The department will be monitored by a trained and qualified monitor. Monitoring frequency is 
dependent on the risk classification for the study.  
 
12.6.Anonymization of data 
All files used for analysis will be anonymized to ensure patient privacy. 
Anonymisation will be performed as follows: RT-CROSS-SECT-nr, where, nr denotes 
consecutive inclusion number. Central data management will give out a study number for each 
participating patient at the end of the registration process and will safeguard the code and 
number. The Principal investigator and the data management will have access to the source 
data.  
 
12.7.Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or 
to the protocol or any other supporting documentation, that is likely to affect to a significant 
degree: 
- 
the safety or physical or mental integrity of the subjects of the trial; 
- 
the scientific value of the trial; 
- 
the conduct or management of the trial; or 
- 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC. 
 
Non-substantial amendments will not be notified to the accredited METC, but will be recorded 
and filed by the sponsor.  
 
12.8.Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 

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V1.2, dd 30-08-2017 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
12.9.Temporary halt and (prematurely) end of study report 
The investigator will notify the accredited METC of the end of the study within a period of eight 
weeks. The end of the study is defined as the last patient’s last visit.  
 
The investigator will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action. 
 
In case the study is ended prematurely, the investigator will notify the accredited METC within 
fifteen days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator will submit a final study report with 
the results of the study, including any publications/abstracts of the study, to the accredited 
METC. 
 
12.10. 
Public disclosure and publication policy 
The trial will be registered at clinicaltrials.gov and published in a major scientific journal 
regardless of its results. The principal investigator and the study statistician will review the data 
and perform the statistical analyses. The results will be published by the principal investigators, 
the study statistician, the study radiologist, the study cardiologist, plus additional persons 
contributing substantially to the analysis and interpretation of study results. 
 
 
 
 

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