Characterizing Chemo-Radiotherapy Treatment-Related Cardiac Changes
Conditions: Clinical Stage 0 Esophageal Adenocarcinoma AJCC v8, Clinical Stage 0 Esophageal Squamous Cell Carcinoma AJCC v8, Clinical Stage I Esophageal Adenocarcinoma AJCC v8, Clinical Stage I Esophageal Squamous Cell Carcinoma AJCC v8, Clinical Stage II Esophageal Adenocarcinoma AJCC v8, Clinical Stage II Esophageal Squamous Cell Carcinoma AJCC v8, Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8, Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Esophageal Squamous Cell Carcinoma AJCC v8, Localized Esophageal Carcinoma, Localized Lung Carcinoma, Pathologic Stage 0 Esophageal Adenocarcinoma AJCC v8, Pathologic Stage 0 Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage I Esophageal Adenocarcinoma AJCC v8, Pathologic Stage I Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IA Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IB Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IC Esophageal Adenocarcinoma AJCC v8, Pathologic Stage II Esophageal Adenocarcinoma AJCC v8, Pathologic Stage II Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIA Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIB Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage III Esophageal Adenocarcinoma AJCC v8, Pathologic Stage III Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage I Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage I Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage II Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage II Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage III Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage III Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8, Stage 0 Lung Cancer AJCC v8, Stage I Lung Cancer AJCC v8, Stage IA1 Lung Cancer AJCC v8, Stage IA2 Lung Cancer AJCC v8, Stage IA3 Lung Cancer AJCC v8, Stage IB Lung Cancer AJCC v8, Stage II Lung Cancer AJCC v8, Stage IIA Lung Cancer AJCC v8, Stage IIB Lung Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8
Sponsor: Mayo Clinic

 
 
 
 
 
MC1723 / 17-008401 
 
 
Characterizing Chemo-Radiotherapy Treatment-Related Cardiac 
Changes 
 
 
NCT04183218 
 
 
Document Date: 02/12/2024 

MC1723 
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Mayo Clinic: Department of Radiation Oncology 
 
MC1723, Characterizing Chemo-Radiotherapy Treatment-Related Cardiac Changes 
 
Study Principal Investigator: 
 
 
 
 
Study Co-investigators: 
 
 
Imaging Co-investigators: 
 
 
 
Biomarkers Co-investigator: 
 
Co-Investigators: 
  
 
 
 
 
 
 
 
Statistician: 
 
√Study contributor(s) not responsible for patient care 

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Document History 
 
Version 1 
October 18, 2018 
Version 2 
February 18, 2019 
Version 3 
August 2, 2019 
Version 4 
August 27, 2019 
Version 5 
April 7, 2020 
Version 6 
July 8, 2021 
Version 7 
April 18, 2022 
Version 8 
February 12, 2024 

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Protocol Resources 
 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment 
delays/interruptions/adjustments, 
dose modifications, adverse events, 
protocol document, consent form, 
regulatory issues, 
forms completion and submission, 
adverse events, forms completion and 
submission 
 
 

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Table of Contents 
Protocol Resources ....................................................................................................................................... 3 
Table of Contents .......................................................................................................................................... 4 
Study Schema ................................................................................................................................................ 5 
List of Abbreviations ..................................................................................................................................... 6 
1.0 
Background ................................................................................................................................... 7 
2.0 
Goals ........................................................................................................................................... 12 
3.0 
Patient Eligibility ........................................................................................................................ 13 
4.0 
Test Schedule .............................................................................................................................. 14 
5.0 
Stratification Factors OR Grouping Factor .................................................................................. 17 
6.0 
Registration/Randomization Procedures .................................................................................... 17 
7.0 
Protocol Treatment ..................................................................................................................... 18 
8.0 
Dosage Modification Based on Adverse Events .......................................................................... 18 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 19 
10.0 
Adverse Event (AE) Monitoring and Reporting ........................................................................... 19 
11.0 
Treatment Evaluation/Measurement of Effect .......................................................................... 24 
12.0 
Descriptive Factors ...................................................................................................................... 25 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 25 
14.0 
Body Fluid Biospecimens ............................................................................................................ 26 
15.0 
Drug Information ........................................................................................................................ 28 
16.0 
Statistical Considerations and Methodology .............................................................................. 28 
17.0 
Pathology Considerations/Tissue Biospecimens ......................................................................... 36 
18.0 
Records and Data Collection Procedures .................................................................................... 36 
19.0 
Budget ......................................................................................................................................... 36 
20.0 
References .................................................................................................................................. 37 
Appendix I ECOG Performance Status ........................................................................................................ 40 

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Study Schema 
 
 
Registration 
↓ 
Cardiac Monitor Placement & 
Standard of Care Baseline 
Evaluation 
↓ 
Standard of Care Treatment 
↓ 
At any time: 
Intolerable adverse effects 
Patient refusal 
↓ 
Event Monitoring 

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List of Abbreviations 
AE 
Adverse Event/Adverse Experience 
ARDS 
Acute Respiratory Distress Syndrome 
AV 
Atrioventricular 
CAD 
Coronary Artery Disease 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRT 
Chemoradiotherapy 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
EBCTCG 
Early Breast Cancer Trialists’ Collaborative Group 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
Fx 
Fractions 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
LRC 
Local Regional Control 
ICM 
Insertable Cardiac Monitoring 
IMRT 
Intensity-Modulated Radiotherapy 
IRB 
Institutional Review Board 
IV 
Intravenous 
MRI 
Magnetic Resonance Imaging 
OS 
Overall Survival 
PBS 
Pencil Beam Scanning 
pCR 
Pathologic Complete Response 
PFS 
Progression Free Survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PRO 
Patient Reported Outcomes 
QOL 
Quality of Life 
RT 
Radiotherapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SBRT 
Stereotactic Body Radiation Therapy 
SOC 
Standard of Care 
SCD 
Sudden Cardiac Death 
SOP 
Standard Operating Procedure 

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1.0 
Background 
 
1.1 
Condition to be studied 
We plan to characterize cardiotoxicity after radiotherapy (RT) for lung and 
esophageal cancer. 
1.2 
Therapy 
 
Therapy will be standard of care (SOC) at the discretion of the treating physician. 
 
1.3 
Study Rationale 
 
Combined radiation and chemotherapy is an integral part of the treatment of thoracic 
malignancies. However, for cancers in close proximity to the heart, excess radiation to 
cardiac tissue may be unavoidable in order to achieve the desired dose to the cancer. 
Irradiated cardiac tissue may develop permanent damage, decreasing the overall benefit 
of chemoradiation (CRT). For example, Radiation Therapy Oncology Group (RTOG) 0617 
(Bradley Lancet Oncol 2015) showed a decreased median survival for higher compared 
to lower radiation doses in the treatment of non-small cell lung cancer with CRT. The 
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Meta-Analysis (EBCTCG 
Lancet 2014) showed a relative decrease in overall survival of 23% for breast cancer 
patients with negative axillary dissection that received post-mastectomy RT. However, 
in the same study, an 11% relative benefit was seen for lymph node positive patients 
treated with RT. The practice changing Cross Trial (van Hagen N Engl J Med 2012) 
showed a large survival benefit despite employing lower RT dose than previous trials. 
The large survival benefit from CRT seen for esophageal cancer patients in this trial 
could have been related to lower cardiac radiation exposure. 
To develop heart-saving treatment strategies, it is imperative to improve our 
understanding of early cardiac damage and its association with fatal events occurring 
within the first year after treatment. Unfortunately, this is currently an unmet need, as 
we poorly understand early cardiac damage due to CRT, especially for lung and 
esophageal cancer. This area of study is significant since treatment-related mortality 
decreases the substantial survival benefit that treatment otherwise confers to patients 
with various cancers. More importantly, the pathophysiologic mechanism of these 
potential fatal cardiac events is unknown. A recent study of early lung cancer patients 
treated with SBRT indicated that RT dose to the superior vena cava and left atrium show 
the greatest association with survival (Stam ESTRO Abstract 2016), suggesting cardiac 
conduction disorder as the etiology of treatment-related mortality. Furthermore, a 
pooled analysis of dose-escalation trials in locally advanced lung cancer showed about 
10% symptomatic arrhythmia at 2 years (Wang J Clin Oncol 2017), and high-dose cardiac 

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radiation has been shown to ablate ventricular tachycardia (Cuculich N Engl J Med 
2017). Given this growing body of evidence, SCD due to cardiac conduction disorders 
could account for the unexplained increased mortality on the high-dose RT arm of RTOG 
0617. Unfortunately, cardiac conduction disorders are often transient and 
asymptomatic. For example, up to 90% of atrial fibrillation can be asymptomatic (Verma 
JAMA Intern Med 2013, Strickberger Heart Rhythm 2005, Orlov Pacing Clin 
Electrophysiol 2007). This makes identifying cardiac conduction disorder as a cause of 
SCD exceedingly difficult. As reviewed in section 1.3, ICM allows for continuous highly 
sensitive cardiac rhythm monitoring and the unique opportunity to record cardiac 
conduction leading up to and including the time of death after RT. 
 
Timeline of Events 
 
The currently established paradigm for cardiotoxicity after radiotherapy involves long- 
term vascular changes that increase the risk of coronary artery disease (CAD). However, 
extensively evaluated cohorts of patients have demonstrated only minimal increase in 
cardiac death associated with radiation induced CAD (van den Bogaard J Clin Oncol 
2017). In this recent study, only 30 out of 910 patients (3.3%) developed adverse 
coronary event during 9-year follow-up, 10 of whom died of ischemic heart disease. 
Their model estimated only 1.13% excess cumulative risk of adverse coronary event 
related to RT, indicating that 10 of the aforementioned 30 adverse coronary events 
could be attributed to RT. This translates to about 3 deaths in 910 patients (0.3%) due 
to RT-related CAD. Unfortunately, RTOG 0617 demonstrated over 10% absolute 
decrease in overall survival by 12 months for lung cancer patients receiving a modest 14 
Gy increase in RT dose (Bradley Lancet Oncol 2015). The EBCTCG meta-analysis showed 
a relative decrease of 23% for node-negative breast cancer patients receiving post- 
mastectomy RT (EBCTCG Lancet 2014). The Cross Trial doubled the median overall 
survival with the use of smaller RT fields and a 10 Gy reduction in RT dose (van Hagen N 
Engl J Med 2012). Clearly, survival differences of these magnitudes cannot be 
accounted for by RT-related CAD. 
 
Interestingly, in RTOG 0617, the separation between the survival curves for the high and 
low-dose arms began to accelerate at about 6 months and stabilized at about 12 
months, with approximately 10% absolute difference in overall survival. This difference 
remained relatively constant for the remainder of the follow-up period.  Thus, the 
excess death on the high-dose arm of RTOG 0617 occurred within 12 months. The 
definitive cause of these deaths was not detected or explained by the patients’ medical 
records or follow-up monitoring with the trial. However, secondary analysis of RTOG 
0617 revealed strong association between overall survival and the volume of heart 
receiving 40 Gy (V40) (Chun J Clin Oncol 2017). Therefore, the excess mortality 
associated with thoracic RT is likely cardiac in nature. 

MC1723 
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Sudden cardiac death without any other signs or symptoms is usually related to 
electrophysiological changes in the heart. To ensure that we capture these events, we 
plan for continuous monitoring of cardiac conduction using implanted cardiac monitors. 
Information can be uploaded daily and events appropriately managed per standard of 
care. 
 
Summary 
 
Large observational studies provide further information regarding the effectiveness and 
safety of thoracic RT in a more generalized population of patients. 
 
To address the specific objectives of this study, a longitudinal observational approach 
will allow comprehensive characterization of the electrophysiological cardiac changes in 
non-metastatic, non-recurrent lung and esophageal cancer patients who are receiving 
thoracic radiotherapy. 
We propose an innovative and exploratory study on early cardiac toxicity and 
permanent cardiac damage after CRT for esophageal and lung cancer by using 
continuous ambulatory cardiac monitoring with an implanted cardiac device. Standard 
of care cardiac monitoring would be done by our cardiology group including 
echocardiography and MRI, and other necessary medical procedures as seen clinically 
necessary. Bio-banking of whole blood samples for future correlative biomarker studies 
would be done. Dried blood spots for RNA analysis would provide additional correlative 
data. We have formed a multidisciplinary team with radiation oncologists, radiologists, 
cardiologists, a cancer geneticist, and imaging scientists to evaluate this important 
question. 
 
Although this is an observational study, findings seen with the implanted cardiac 
monitor can be addressed as part of the routine medical care of these patients, 
addressing cardiac conduction changes that otherwise may have been fatal. 
 
Our hope is that we can identify potentially fatal radiation induced cardiac changes that 
otherwise would remain unnoticed, facilitate the treatment of these early cardiac 
changes as part of the standard of care, and therefore prevent RT-related cardiac death. 
 
1.4 
Rationale on any research related tests being done 
 
Insertable Cardiac Monitoring: In a recent multi-national, multi-institutional study, RT 
dose to the superior vena cava and left atrium was significantly associated with survival 
after lung stereotactic body RT (Stam ESTRO Abstract 2016). Sudden cardiac death 
(SCD), particularly as caused by cardiac conduction disorders, is a potential culprit when 
considering the fatal events that may originate in the superior vena cava or atria and 
may account for the otherwise unexplained mortality associated with cardiac dose in 
recent clinical trials of thoracic RT. To identify potential SCD after thoracic RT that has 

MC1723 
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thus far been unappreciated, we need a more sensitive test.  Insertable cardiac 
monitors (ICM) are small wireless cardiac devices placed under the skin in the chest area 
by a minimally invasive technique. ICM are used for long-term heart rhythm monitoring 
of patients with suspicion of rare or infrequent rhythm abnormalities that are unlikely to 
be diagnosed with short-term monitoring. These devices have been studied in the 
investigation of atrial fibrillation, cryptogenic stroke, syncope, and post-myocardial 
infarction SCD. The Medtronic Reveal LINQ™ ICM has 99.4% accuracy for atrial 
fibrillation detection (Sanders Heart Rhythm 2016). In the year after cryptogenic stroke, 
ICM finds 7.3x more atrial fibrillation than conventional follow-up (Sanna N Engl J Med 
2014). After ablation of atrial fibrillation, ICM detects more recurrent arrhythmia than 
conventional monitoring, which would miss at least 61% of recurrent arrhythmia (Kapa J 
Cardiovasc Electrophysiol 2013). In unexplained recurrent syncope or pre-syncope, ICM 
helped establish cardiac etiology in 75% of patients (Edvardsson Europace 2011). 
Furthermore, ICM is significantly cheaper per patient and per diagnosis for unexplained 
syncope than conventional testing with external loop recorder, tilt testing, and 
electrophysiologic testing (Krahn J Am Coll Cardiol 2003). The expanded role of ICM as 
“biological monitors” helping to understand mechanisms of SCD in special populations 
has also been established (Gang Europace 2010, Bloch Thomsen Circulation 2010). In 
patients after acute myocardial infarction with ejection fraction ≤ 40%, ICM 
demonstrated a high incidence of brady and tachyarrhythmia and an association of high 
degree atrioventricular (AV) block with SCD. Post-mortem interrogation of ICM showed 
ventricular tachycardia/fibrillation (VT/VF) and bradyarrhythmia each accounting for 
half of the events at the time of death. ICMs can remain in place for the duration of the 
study. 
 
Whole Blood Biobanking: Whole blood samples will be obtained via peripheral blood 
draw at time-points corresponding to SOC clinic appointments: prior to RT initiation, 4 
weeks after RT completion, 3 months after RT completion, 9 months after RT 
completion, and 12 months after RT completion. The samples will be stored for future 
biomarker studies to be correlated with cardiac conduction and imaging findings. 
 
Dried Blood Spot Biomarker Analysis: In conjunction with the above-mentioned whole 
blood biobanking and biomarker studies, we plan to obtain a dried blood spot on filter 
paper at time-points corresponding to SOC clinic appointments: prior to RT initiation, 4 
weeks after RT completion, 3 months after RT completion, 9 months after RT 
completion, and 12 months after RT completion. We have developed RNA sequencing 
approaches using nucleic acid isolated from single  drops  of  dried  blood.  The 
collection of dried blood spot can be done at home by the patient using an approach 
analogous to finger prick blood glucose checks used by millions of patients with 
diabetes. This novel approach to RNA biomarker profiling may identify novel nucleic 
acid signatures associated with cancer treatment induced cardiac toxicity and provides a 

MC1723 
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potentially powerful correlate to standard whole blood biobanking and biomarker 
studies. 
 
1.5 Description of the Study 
 
This is an observational study designed to follow non-metastatic, non-recurrent lung and 
esophageal cancer patients who are receiving thoracic radiotherapy. 
 
Patients will be followed prospectively in the PCG-registry, through a separate consent. The only 
testing (beyond standard of care evaluation) for the current study would include ambulatory 
arrhythmia monitoring with ICM, whole blood samples to be biobanked for future biomarker 
studies, and dried blood spot collection for RNA analysis.. 
 
Approximately 24 patients total will be enrolled. 
 
Please refer to the UCM Procedural/Treatment Guidelines for (Disease)/ AZ treatment 
guidelines. No study-specific visits or evaluations will be required. Patients will be evaluated 
according to the physician’s standard practice and discretion. Patient data will be drawn from 
the patients’ medical records. Patients will be considered “on study” until one year after 
completion of RT, withdrawal of consent, lost to follow-up, or study closure, or death 
 
1.6 Rationale for Study Design 
 
Large observational studies provide further information regarding the effectiveness and 
safety of thoracic RT in a more generalized population of patients. 
To address the specific objectives of this study, a longitudinal observational approach will allow 
comprehensive characterization of the electrophysiological cardiac changes following thoracic 
RT. 
 
Patients’ cardiac conduction will be monitored constantly by the electrophysiology lab as part of 
the standard of care. 

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2.0 
Goals  
This is an observational study designed to follow non-metastatic, non-recurrent 
lung and esophageal cancer patients who are receiving thoracic radiotherapy. 
However, even with the relatively small sample size, we can assess the value and 
utility of continuous ambulatory arrhythmia monitoring with an implanted 
cardiac device and correlate findings with SOC cardiac follow-up, imaging, and 
biomarker analysis on biobanked whole blood samples. Our findings can help 
achieve the following objectives: 
2.1 
Primary Goal 
2.11 
To determine the 12-month cardiac event rate as defined in 
section 11.1 after radiation or chemo-radiation for the treatment 
of lung or esophageal cancer. 
2.2 
Exploratory Goals 
2.21 
Define the spectrum of cardiac toxicity among CRT patients at 
highest risk of cardiac toxicity. 
2.22 
Establish the timeline of cardiac toxicity development and identify 
early predictive findings of permanent damage. 
2.23 
Characterize the areas of the heart at highest risk for persistent 
cardiac damage. 
2.24 
Identify a dose response threshold for RT damage in different 
areas of the heart. 
2.25 
Improve survival by alerting the cardiology team of the need for 
life-saving standard of care interventions. If we can show that 
excess RT-related deaths are related to electrophysiological 
changes, life-saving strategies may be possible. 
2.26 
Describe medical interventions employed for the cardiac events 
identified in the study. 

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3.0 
Patient Eligibility 
3.1 
Inclusion Criteria 
3.11 
Age ≥18 years. 
 
3.12 
Planned standard of care curative thoracic RT or CRT with anticipated 
heart V40 > 20cc (At least 20cc of the heart should receive a dose of 40Gy 
or higher) 
3.13 
Able to follow-up at all specified standard of care time-points. 
 
3.14 
Patients can receive treatment as part of the standard of care or in a 
different study. 
3.15 
Receiving radiation treatment to an area close to the heart, for example 
gastroesophageal junction cancer, hilar lung cancer, or mainstem 
bronchus lung cancer. 
3.16 
Any type of systemic therapy or surgery before during or after radiation is 
acceptable 
3.17 
Prior Radiation to other areas is acceptable. 
 
3.18 
Planned radiation doses equal or higher than 40Gy 
 
3.2 
Exclusion Criteria 
3.21 
Metastatic disease. 
3.22 
Recurrent disease. 
3.23 
Patient receiving radiation prescription doses lower than 40 Gy. 
3.24 
No prior radiation that included any part of the heart is acceptable 
3.25 
No thoracic re-irradiation 

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Cardiac Labs 
(troponin, CK, 
CKMB, pro- 
BNP,BMP, 
CBC) 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Implanted 
cardiac 
monitorr6 
X7 
 
 
 
 
 
 
Explant cardiac 
monitorr6 
 
 
 
 
 
 
X 
Cardiac 
recordings via 
implanted 
cardiac 
monitorr6 
 
X7 
 
 
X 
 
X 
 
X 
 
X 
 
X 
SOC RT 
Treatment 2 
 
X  
 
 
 
 
ECOG 
X 
 
 
 
 
 
X 
AE 
X 
X 
X 
X 
X 
X 
X 
Bio- 
banking(blood)r 
X 
 
X 
X 
X 
X 
 
Dried blood 
spots (TGEN)r 
X 
 
X 
X 
X 
X 
 
Cardiac MRIr 
X3, 7 
 
 
X3 
 
X3 
 
Pulmonary 
Function Test 
X4 
 
 
 
 
X 
 
1 Additional cardiac follow-up visits as clinically indicated per standard of care treatment. 
2Additional radiation oncology follow-up visits; scheduled per standard of care treatment. 
3Cardiac MRI as clinically indicated as per SOC cardiology evaluation; however study will pay for all 
patients as a research cost. 
4Pulmonary function tests obtained pre-treatment (within 6 months of the start of treatment) 
5Time is measured from the date radiation therapy is completed. 
6Patient care costs covered by Mayo Clinic Cardiology 
7Highly recommended before the start of RT. If this is not clinically possible due to scheduling, conduct 
as soon as possible after the start of RT 
rIndicates paid by research 

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After enrollment and prior to initiation of RT or CRT, cardiac testing will be per 
SOC at our Cardio-Oncology Clinic (e.g. ECG, strain echocardiography, cardiac 
MRI). Pulmonary function tests would also be obtained per SOC. ICM will be 
inserted subcutaneously by a cardiologist in the left para-sternal area, using 
standard sterile technique with local anesthesia. Risks of this insertion are truly 
minimal but may include bleeding or infection. For reference, this in-office 
minimally invasive procedure is analogous to the upper arm 
Implanon/Nexplanon® birth control implant. Whole blood samples will be drawn 
via peripheral blood draw and biobanked. Dried blood spots will be collected at 
home by patients and returned for analysis. For reference, the approach for 
dried blood spot collection is analogous to a finger prick blood glucose check. 
Dried blood spot collection would only require a single finger prick at each time 
point and would be truly minimal risk but may carry very low risk of infection. 
STANDARD OF CARE cardiac testing, STANDARD OF CARE pulmonary function 
tests, and peripheral blood draw for whole blood biobanking will be performed 
at STANDARD OF CARE follow-up appointments after RT, including 4 weeks after 
RT, 3 months after RT, 9 months after RT, and 12 months after RT. Data from the 
ICM will be collected via wireless data transfer. Data will be transferred on 
scheduled monthly remote follow-ups or unscheduled in case there is a rhythm 
alert notification automatically sent (when the arrhythmia event meets pre- 
determined criteria). The follow-up data will be monitored by the Mayo Clinic 
Cardiac Implantable Electronic Devices Remote Follow-up Clinic. Alerts from any 
devices are monitored within 24 hours, 365 days per year uninterrupted. All 
abnormal cardiac rhythm strips are initially adjudicated by a Certified Cardiac 
Device Specialist Registered Nurse and confirmed by a cardiac 
electrophysiologist.  The programmed criteria for automatic arrhythmia storage 
is: sinus bradycardia ≤ 30 bpm for ≥ 8 seconds, sinus arrest with pauses ≥ 4.5 
seconds, and 2nd or 3rd degree degree AV block ≤ 30 bpm lasting ≥ 8 seconds. 
Tachycardia is defined as a heart rate ≥ 150 bpm for ≥ 16 beats. Sustained VT is 
defined as lasting ≥ 30 seconds. Post-mortem device interrogation will be 
performed in cases of patient death. Patients will undergo limited chest autopsy, 
if they agree and consent. 
 
 
4.1 
Event Monitoring/Survival Follow-up 
 
Patients will be “on study” until one year after completion of RT, withdrawal of consent, lost to follow- 
up, study closure, or death. 

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5.0 
Stratification Factors OR Grouping Factor: None 
 
6.0 
Registration/Randomization Procedures 
6.1 
Registration 
Patient will be registered to the study when they have consented, met eligibility 
criteria and have been logged into the Research Participant Tracking System 
(Ptrax). 
6.11 
Verify the following procedures are completed prior to Registration to 
the study. 
6.12 
IRB approval at the registering institution 
6.13 
Existence of a signed informed consent 
6.14 
Patient eligibility complete 
Note: Radiation Therapy on this protocol must be performed at Mayo Clinic Arizona 
under the supervision of a radiation oncologist. 

MC1723 
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7.0 
Protocol Treatment 
7.1 
Standard Treatment (Per UCM Procedural/ Treatment Guidelines for lung and 
esophageal cancer/Mayo Clinic treatment guidelines). 
 
Esophageal 
 
 
 
Lung 
 
 
 
 
8.0 
Dosage Modification Based on Adverse Events 
8.1 
 Treatment delivered as per SOC. No changes to the SOC will be done during this 
study (Per UCM Procedural/ Treatment Guidelines for lung and esophageal 
cancer/Mayo Clinic treatment guidelines; see section 7.1). 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 
5.0* unless otherwise specified  

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9.0 
Ancillary Treatment/Supportive Care: None, except as indicated per SOC. 
 
10.0 Adverse Event (AE) Monitoring and Reporting 
 
10 .1 Definitions 
 
10. 11 Adverse Event: Any untoward medical occurrence associated with 
standard of care treatment involved in this study. 
10.12 Serious Adverse Event: Adverse events are classified as serious or non- 
serious. Serious problems/events can be well defined and include; 
• Death 
• Life threatening adverse experience 
• Hospitalization 
• Inpatient, new, or prolonged; disability/incapacity 
• Persistent or significant birth defect/anomaly 
or problems/events that in the opinion of the sponsor investigator may 
have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially comprised the research data. All adverse events 
that do not meet any of the criteria for serious, should be regarded as 
non-serious adverse events. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO)- 
Any unanticipated problem or adverse event that meets the following 
three criteria: 
• Serious: Serious problems or events that results in significant harm, 
(which may be physical, psychological, financial, social, economic, or 
legal) or increased risk for the subject or others (including individuals 
who are not research subjects). These include: (1) death; (2) life 
threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, 
events, or new information (i.e. publications, DSMB reports, interim 
findings, product labeling change) that in the opinion of the local 
investigator may adversely affect the rights, safety, or welfare of the 
subjects or others, or substantially compromise the research data, 
AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are 
not already described as potential risks in the protocol, consent 

MC1723 
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document, not listed in the Investigator’s Brochure, or not part of an 
underlying disease. A problem or event is "unanticipated" when it was 
unforeseeable at the time of its occurrence. A problem or event is 
"unanticipated" when it occurs at an increased frequency or at an 
increased severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the 
research procedures. 
• Preexisting Condition- A preexisting condition is one that is present at 
the start of the study. A preexisting condition should be recorded as 
an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. At screening, any clinically 
significant abnormality should be recorded as a preexisting condition. 
At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event 
must also be recorded and documented as an adverse event. 
10.12 Suspected Adverse Reaction: Any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. 
10.2 
Recording Adverse Events/ Treatment being studied 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site: 
 
 
10.21 Adverse event monitoring and reporting is a routine part of every clinical 
trial. First, identify and grade the severity of the event using the CTCAE 
version 5.0. Next, determine whether the event is expected or 
unexpected and if the adverse event is related to the study procedure. 
With this information, determine whether the event must be reported as 
an expedited report (see Section 10.25). 
 
Expedited and routine reports are to be completed within the timeframes 
and via the mechanisms specified in Sections 10.4 and 10.6. All expected 
AE reports must also be sent to the local Institutional Review Board (IRB) 
according to local IRB’s policies and procedures. 

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10.211 
When assessing whether an adverse event (AE) is related to a 
medical agent(s) medical or procedure, the following attribution 
categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.22 Exceptions to Expedited Reporting 
An expedited report may not be required for specific Grade 1, 2 and 3 
serious Adverse Events. Any protocol specific reporting procedures MUST 
BE SPECIFIED BELOW and will supersede the standard Expedited Adverse 
Event Reporting Requirements: Hospitalizations for reasons deemed to 
be disease or SOC related will not be reported. 
10.23 Solicited Adverse Events Grade 2 or higher: 
Dyspnea 
Conduction disorders 
Chest pain/cardiac pain 
Congestive Heart Failure 
Myocardial infarction 
Myocarditis 
Pericardial effusion 
Pericarditis 
Lung Adverse Events 
Gastrointestinal Adverse Events 
 
10.3 
Other Required Reporting 
 
10.31 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
in general, include any incident, experience, or outcome that meets all of 
the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 

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documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject 
population being studied; 
2. Related or possibly related to participation in the research (in this 
guidance document, possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of 
the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased 
risk of harm, but no harm occurs. 
Note 1: If there is no language in the protocol indicating that pregnancy is 
not considered an adverse experience for this trial, and if the consent 
form does not indicate that subjects should not get pregnant/impregnate 
others, then any pregnancy in a subject/patient or a male patient’s 
partner (spontaneously reported) which occurs during the study or 
within. 
Note 2: research procedures include: cardiac monitoring device 
placement and extraction, cardiac monitoring employing the cardiac 
monitoring device, cardiac MRI, dried blood collection, and blood 
biobanking. Cancer treatment is per SOC and at the discretion of the 
treating physicians and not part of the research procedures. Expected 
toxicities as part of the SOC cancer treatment will not be considered for 
IRB reporting. 
10.32 Death 
 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment 
or other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 

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Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death 
 
• Death attributable to a CTCAE term. 
• Death Neonatal: A disorder characterized by cessation of life during 
the first 28 days of life. 
• Death NOS: A cessation of life that cannot be attributed to a CTCAE 
term associated with Grade 5. 
• Sudden death NOS: A sudden (defined as instant or within one hour 
of the onset of symptoms) or an unobserved cessation of life that 
cannot be attributed to a CTCAE term associated with Grade 5. 
• Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified  (including  cysts 
and polyps) – Other (Progressive Disease)” under the system organ 
class (SOC) of the same name. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
10.5 
Monitoring and Auditing 
 
The investigator will permit study-related monitoring, audits, and inspections by 
the IRB, and government regulatory agencies, of all study related documents 
(e.g. source documents, regulatory documents, data collection instruments, 
study data etc.). The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable compliance 
offices 
 
10.51 Medical Monitoring 
 
It is the responsibility of the Principal Investigator to oversee the safety of 
the study at his/her site. This safety monitoring will include careful 
assessment and appropriate reporting of adverse events as noted above, 
as well as the construction and implementation of a site data and safety- 
monitoring plan (see section 10.7 “Monitoring and Auditing”). Medical 
monitoring will include a regular assessment of the number and type of 

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serious adverse events. “Any serious adverse events will be followed up 
by the sentinel event reporting procedure” 
 
10.52 Internal Data and Safety Monitoring Board 
 
The trial will be reviewed by the Cancer Center Auditing area on a bi- 
annual or yearly basis dependent on random study selection to assess 
accrual, adverse events, and any endpoint problems. Any safety issues 
requiring protocol changes will be communicated through protocol 
amendments. 
 
 
 
 
 
 
11.0 Treatment Evaluation/Measurement of Effect 
 
This will be measured based on retrospective clinical outcomes. 
 
11.1 
Effectiveness Outcome Measures 
Cardiac Events: 
Any cardiac event after registration including electrophysiological changes as 
defined by the continuous insertable cardiac monitor (ICM); CHF; Miocardial 
infarction; pericarditis or myocarditis; cardiac ablation or cardiac pacemaker; 
cardiac stent placement or any coronary procedure for coronary damage; or any 
cardiac event as defined by the patients’ medical records or autopsy if done. 
 
Cardiac event determined by the ICM would include: Bradycardia: asystole > 3 
seconds, bradycardia HR < 40 bp; Tachy: HR > 150 bpm for any number of beats; 
Atrial Fibrillation lasting ≥ 8 seconds. Post-mortem device interrogation will be 
performed when possible in cases of patient death and included as per ICM 
criteria. Patients will undergo limited chest autopsy, if they agree and consent. 
 
 
11.2 
Safety Outcome Measures 
 
In-office placement of the device with local anesthetic is very safe. Likewise, the 
device itself is very safe. Risks of this insertion are truly minimal but may include 

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bleeding or infection. We will monitor any adverse events related to the 
placement of the device. 
 
11.3 
This is an observational study designed to follow cardiac changes in patients with 
esophageal or lung cancer who receive curative SOC thoracic RT or CRT. Data 
regarding the adverse events per SOC, surgery, RT, chemotherapy, and regular 
standard of care follow-up will be observed and collected as part of the SOC. 
 
11.4 
A patient is deemed ineligible if he/she is removed from the study for any reason 
before any study data is obtained. On-study material and Cancel 
Notification/Termination Form must be completed in CRF. No further data 
submission is necessary. Subject will be replaced in accrual number. 
 
11.5 
If the subject participated in study, all data up until the point of confirmation of 
ineligibility must be submitted. 
 
12.0 Descriptive Factors 
3D radiation, IMRT, vs Proton therapy 
 
Esophageal cancer, lung cancer, other thoracic malignancy 
 
 
 
13.0 Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
A patient is deemed ineligible if after registration, it is determined that at the 
time of registration, the patient did not satisfy each and every eligibility criteria 
for study entry. The patient will go off study and continue in the monitoring 
phase. 
• If the patient received MR and PET for radiotherapy planning, all data up 
until the point of confirmation of ineligibility must be submitted. 
13.2 
Those patients who will not receive any radiation treatment or who will receive 
radiation treatment elsewhere will go off study. 

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14.0 Body Fluid Biospecimens 
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this 
Protocol 
 
 
Correlative Study 
(Section for more 
information) 
 
 
 
Mandatory or 
Optional 
 
Blood or 
Body Fluid 
being 
Collected 
 
Type of 
Collection 
Tube (color of 
tube top) 
 
Volume to 
collect per tube 
(# of tubes to be 
collected) 
Before treatment, 4 
weeks, 3 months, 9 
months, and 12 
months post 
treatment 
 
 
 
Process 
at site? 
Biobanking 
Mandatory 
Whole 
blood 
EDTA Tubes 10mL (1) in 1 
mL aliquots 
X 
Yes - 
frozen 
 
Biobanking 
 
Mandatory 
 
Blood; 
serum only 
2 No 
additive 
tubes (for 
serum) 
 
10mL (1) in 1 
mL aliquots 
 
X 
 
Yes - 
frozen 
 
Biobanking 
 
Mandatory 
Blood; 
plasma 
only 
2 EDTA 
Tubes 
6 mL in 1 mL 
aliquots 
 
X 
Yes - 
frozen 
RNA Analysis 
Mandatory 
Dried 
Blood 
Dried blood 
kit 
5 – 10 
drops 
X 
N/A 
14.2 
Collection and Processing 
Collected biobank samples will be drawn according to the test schedule and 
summary in Table 5.0. Collect and process pre-treatment, 4 weeks post-RT, 3 
months post-RT, 9 months post-RT, and 12 months post-RT, blood/blood 
products according to the above table. Label specimen tube(s) with protocol 
number, study patient ID number, and time and date blood is drawn. 
14.3 
Shipping and Handling 
 
 
14.31 Specimen Storage 
 
BAP will process and store biobank specimens per standard operating 
procedures. Blood samples will be collected prospectively and stored until 
funding sources have been identified for molecular studies. 

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14.32 Shipping Specimens 
 
No shipping for the collected biobank samples. 
A dried blood kit provided by TGEN will be collected at Mayo Clinic Arizona 
during the pre-treatment visit. The study coordinator will assist the patient with 
instructions on how to take the sample and ship it to TGEN. The remaining 
collection time points (4 weeks, 3 months, 9 months, and 12 months post- 
treatment) will be collected by the participant at home and shipped to TGEN for 
analysis using a pre-paid shipping label included in the kit. 
 
 
 
 

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15.0 Drug Information 
Not applicable 
 
 
16.0 Statistical Considerations and Methodology 
 
16.1 
Study Design 
 
This is a single-arm, observational study designed to determine the 12- 
month cardiac event rate after radiation or chemo-radiation for thoracic 
malignancies meeting the eligibility criteria. 
16.11 
Primary Endpoint: 
 
A cardiac event will be defined according to section 11.1 and occurring 
during the first 12 months after radiation or chemo-radiation. An 
evaluable patient will be classified as a failure (cardiac event) for the 
primary endpoint if the patient had any of the events listed in section 
11.1 during the time period. All patients meeting the eligibility criteria 
who have signed a consent form, have begun RT, and have not 
experienced a major treatment violation within the first month of 
treatment will be evaluable for response. 
16.2 
Statistical Design: 
 
This is an observational study intended to provide preliminary estimates 
of cardiac event rate in patients receiving radiation or chemo-radiation. 
Safety of the implanted cardiac monitoring device will be described. 
Point estimates and two-sided 95% confidence intervals will be 
computed. All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be included in the 
descriptive estimates. 
16.22 
Sample Size 
 
The largest clinical benefit (detection of cardiac event) where the 
proposed cardiac monitoring device would be considered ineffective in 
this population is 1%, and the smallest clinical benefit rate that would 
warrant subsequent studies is 10%. With 18 patients, this study has 80% 

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29 
 
power with a 1-sided alpha of 0.1 to test the null hypothesis that the 
event rate in the given population is at most 1%. 
Assuming that about 10% of patients would be lost to follow-up or found 
ineligible and accounting for the approximately 20% death rate at 12 
months in the standard arm of RTOG 0617, we would require a total 
sample size of 24 patients to fulfill those of the 6 necessary 18 possibly 
missing at 12 months. 
16.23 
Accrual Time and Study Duration 
 
The anticipated accrual rate is approximately 2 patients per month. 
Therefore, the accrual period for this study is expected to be 12 months. 
Analysis can begin approximately 24 months after the trial begins, i.e., as 
soon as the last patient has been followed for up to 12 months. 
16.24 
Other Considerations 
 
Adverse events, observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to 
terminate the study. 
16.3 
Analysis Plan 
 
The analysis for this trial will commence at the time the patients have 
become evaluable for the primary endpoint. Such a decision will be made 
by the Statistician and Study Chair, availability of data for secondary 
endpoints and the level of data maturity. Summary statistics will be 
presented for demographic and baseline clinical characteristic variables 
for all subjects. All continuous parameters will be summarized using 
standard summary statistics as appropriate (n, mean, standard deviation, 
median, minimum, maximum, 25th percentile, and 75th percentile). 
Summary statistics for categorical variables will include frequency counts 
and percentages. Summaries will be presented for all patients. 
16.31 
Primary Endpoint 
 
Definition: The primary endpoint of this trial is cardiac event rate at 12 
months as defined in Section 11. 
16.312 
Estimation: The proportion of failures (cardiac event) will be estimated by 

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30 
 
the number of cardiac events divided by the total number of evaluable 
patients. Confidence intervals for the true success proportion will be 
calculated according to the exact Clopper – Pearson.. 
16.313 
Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making processes; however, they will be included in final 
point estimates and confidence intervals as though they were accrued in 
the final stage. 
16.32 
Definitions and Analyses of Secondary Endpoints 
 
16.321 
Analysis Plan 
The analysis for this trial will commence when 24 patients have either 
died or reached the 12 month data point. Cardiac event as recorded in 
section 11.1 would be used for our analysis. We expect to see 3 or more 
cardiac events grade 3 or higher based on the CTC AE V5.0. 
 
16.322 
The following definitions are used for the secondary endpoints of 
interest: 
All end points would be measured studied from the date of patient 
registration 
• 
Acute adverse events: all AEs occurring within the first 6 months 
from the date of enrollment. 
• 
Late adverse events: all AEs occurring after the first 6 months 
from the date of enrollment. 
• 
Loco-regional recurrence: local recurrences of the cancer in the 
same location where the disease was found on any diagnostic or 
staging study. 
• 
Distant recurrence: metastatic cancer that has either been biopsy 
confirmed or clinically diagnosed as recurrent. 
• 
Disease- free survival: the time from study registration any local, 
regional, distant failure, or death. 
• 
Cause specific survival: the time from registration to death due to 
cancer. If the cause of death is unknown or difficult to establish, 

MC1723 
31 
 
patients with a distant failure at the time of death would be 
censored as dying from cancer. 
• 
Cardiac event free survival: the time from registration to cardiac 
event or death. 
• 
Cardiac death: the time from registration to death due to cardiac 
reasons. Cardiac death would include documented congestive 
heart failure, myocardial infarction, arrhythmia*, heart block*, or 
any other cardiac cause documented in the medical records, 
death certificate, or autopsy as one of the major contributing 
causes of death. 
*Any lethal electrophysiologic change documented by the ICD 
before death would also be included. 
• 
Overall survival: the time from registration to death due to any 
cause. 
 
 
16.323 
Adverse events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
 
Analyses for secondary endpoints will be descriptive in nature. 
Adjustment for multiple comparisons for the secondary analyses will not 
be done due to the exploratory nature of this research.  Statistical tests 
on endpoints (t-test for continuous data; Wilcoxon rank-sum test, Fisher’s 
exact test, or Chi-square test for ordinal data) will be utilized to 
determine differences at any particular time point. Graphical displays will 
be produced, such as mean profile plots or bar charts. Descriptive 
statistics of frequency (percentage) will be used to summarize AE 
incidence and severity as measured by the CTCAE 5.0. 95% confidence 
intervals will be constructed around point estimates. 
16.33 
Exploratory Endpoints 

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32 
 
 
 
16.331 
Imaging Changes: Imaging changes in the heart substructures associated 
with occurrence of cardiac events will be an exploratory component of 
this trial. Changes will be described at each time point using frequency 
distributions. 
 
16.4 
Data & Safety Monitoring: 
 
16.41 Safety review 
 
The principal investigator(s) and the study statistician will review the 
study monthly to identify accrual, adverse event, and any endpoint 
problems that might be developing. The Mayo Clinic Cancer Center 
(MCCC) Data Safety Monitoring Board (DSMB) is responsible for 
reviewing accrual and safety data for this trial at least biannually, based 
on reports provided by the MCCC Statistical Office. 
 
 
16.41 
Adverse Event Stopping Rules: The stopping rules specified below are 
based on the knowledge available at study development. The stopping 
rule applies to the overall study. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re- 
opening to accrual or (2) at any time during the conduct of the trial and in 
consideration of newly acquired information regarding the adverse event 
profile of the treatment(s) under investigation. The study team may 
choose to suspend accrual because of unexpected adverse event profiles 
that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment 
(i.e. an adverse event with attribute specified as “possible”, “probable”, 
or “definite”) that satisfy the following: 
Adverse Events stopping rule 
 
More than 3 patients with at least one grade 3 adverse events in the first 
10 patients related or likely related to the cardiac monitor device would 
be used as a stopping rule for our observation protocol. We note that 
we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the 
emergence of a previously 

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33 
 
unrecognized treatment-related adverse event. If at any point after the 
first 10 patients we see more than 30% of patients experiencing 
attributable grade 3 or higher adverse events then the study may be 
stopped at the investigator’s discretion. 
 
 
 
 
16.5 
Results Reporting on ClinicalTrials.gov 
 
At study activation, this study will have been registered within the 
“ClincialTrails.gov” website. The Primary and Secondary Endpoints (i.e., 
“Outcome Measures”) along with other required information for this 
study will be reported on ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary 
Endpoint of this study is 36 months after the study opens to accrual. The 
definition of “Primary Endpoint Completion Date” (PECD) for this study is 
at the time the last patient registered has completed treatment. 
16.6 
Inclusion of Women and Minorities 
 
This study will be available to all eligible patients, regardless of race, 
gender, or ethnic origin. 
16.62 
There is no information currently available regarding differential effects 
of this regimen in subsets defined by race, gender, or ethnicity, and there 
is no reason to expect such differences to exist. Therefore, although the 
planned analysis will, as always, look for differences in treatment effect 
based on racial and gender groupings, the sample size is not increased in 
order to provide additional power for subset analyses. Inclusion based on 
minorities and gender will represent current patient demographics of 
patients treated at our institution. However, children under 18-years of 
age will be excluded because cardiac complications in the pediatric 
population are different than in adults. 
 
16.63 
The geographical region served by this study, has a population which 
includes approximately 5% minorities and 50% women. Based on prior 
MMC studies involving similar disease sites, we expect about 5% of 
patients will be classified as minorities by race and about 50% of patients 

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34 
 
will be women. Expected sizes of racial by gender subsets for patients 
registered to this study are shown in the following table: 
 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
1 
0 
2 
Not Hispanic or Latino 
11 
11 
0 
22 
Ethnic Category: Total of all subjects* 
12 
12 
0 
24 
Racial Category 
American Indian or Alaska Native 
0 
0 
0 
0 
Asian 
1 
0 
0 
1 
Black or African American 
0 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
11 
11 
0 
22 
Racial Category: Total of all subjects* 
12 
12 
0 
24 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 

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35 
 
 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, 
and Vietnam. (Note: Individuals from the Philippine Islands have been 
recorded as Pacific Islanders in previous data collection strategies.) 
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition 
to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 

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17.0 Pathology Considerations/Tissue Biospecimens 
None 
 
 
18.0 Records and Data Collection Procedures 
18.1 
CRF Completion 
This study will use Medidata Rave for remote data capture (RDC) of all study 
data. Forms should be submitted within 2 weeks of the visit occurring. 
 
19.0 Budget 
19.1 
Costs charged to patient: routine clinical care 
19.2 
Tests to be research funded: cost of insertable cardiac monitor, impant/explant, 
biobanking, cardiac MRI, dried blood spot 

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20.0 
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Mayo AZ procedures manual would be reviewed by the Radiation research committee and the specific 
Disease site group at Mayo AZ. UMC procedures manual would be also reviewed by the research 
committee and disease site groups at Mayo AZ. Alternatively, procedures manual elaborated at Mayo AZ 
can be incorporated into the UCM. 

MC1723 
39 
 
 

MC1723 
40 
 
 
Appendix I 
ECOG Performance Status 
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. 
 
The ECOG Performance Status is in the public domain therefore available for public use. To 
duplicate the scale, please cite the reference above and credit the Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
From http://www.ecog.org/general/perf stat.html