RAD4649-19: Prospective Study of Intensity-Modulated Proton Therapy (IMPT) for Small Cell Lung Cancer
Phase: NA
Conditions: Small-cell Lung Cancer
Sponsor: Emory University

Prospective Study of Intensity-Modulated Proton Therapy (IMPT) for Small Cell Lung 
Cancer 
 
 
Principal Investigators 
 
Kristin A. Higgins, MD 
Associate Professor 
Department of Radiation Oncology 
Winship Cancer Institute 
Emory University School of Medicine 
1365 Clifton Road NE 
Atlanta, GA 30322 
Tel:     404-778-3473 
Fax:     404-778-4139 
Email:  kristin.higgins@emory.edu 
 
Co-Investigators 
Karen M. Xu, MD 
Resident Physician 
Department of Radiation Oncology 
Winship Cancer Institute  
Emory University School of Medicine 
1365 Clifton Road NE 
Atlanta, GA 30322 
Tel: 585-355-9360 
Fax: 404-778-4139 
Email: karen.mann.xu@emory.edu 
 
 
 
 
 
Matthew J. Ferris, MD 
Resident Physician 
Department of Radiation Oncology 
Winship Cancer Institute 
Emory University School of Medicine 
1365 Clifton Road NE 
Atlanta, GA 30322 
Tel:    410-241-4504Fax:    404-778-4139 
Email:  mjferri@emory.edu 
 
Study Physicist 
Liyong Lin, PhD, DABR 
Assistant Professor 
Department of Radiation Oncology 
Winship Cancer Institute 
Emory University School of Medicine 
1365 Clifton Road NE 
Tel: 404-778-3473 
Email: liyong.lin@emory.edu 
 
Study Statistician 
Zhengjia Nelson Chen, PhD 
Department of Biostatistics & 
Bioinformatics  
Rollins School of Public Health 
1 
 

Emory University 
1518 Clifton Rd, Atlanta, GA 30322 
Email: zchen38@emory.edu 
 
 
 
 
 
2 
 

Drug Under Investigation: None 
 
1. Objectives 
 
1.1 Primary Objective 
The primary objective of this prospective trial is to assess the safety of intensity-
modulated proton therapy (IMPT) for small cell lung cancer (SCLC)  
 
1.2 Secondary Objectives 
• 
To determine the optimal schedule for three-dimensional verification imaging and 
necessary re-planning of patients undergoing IMPT for a rapidly changing tumor 
(small cell lung cancer)  
• 
To determine the rate of cardiac toxicities from IMPT in patients with small cell 
lung cancer compared with historical controls receiving photon-based treatment.   
• 
To determine the rate of pneumonitis and esophagitis from IMPT and compare with 
historical controls receiving photon based treatment 
 
2. Background 
2.1 Proton-beam Therapy for Small Cell Lung Cancer (SCLC) 
 
An estimated 234,030 new cases of lung cancer will be diagnosed in the United States in 2018. 
Small cell lung cancer (SCLC) represents approximately 15% of all lung cancers. Extensive 
stage SCLC (ES-SCLC) accounts for about 70% of all small cell lung cancers, with an estimated 
absolute number of 25,000 cases [1].  Historically, the prognosis of ES-SCLC is poor with a 
median survival of 12 months and 2-year overall survival (OS) of 5% [2]. Although distant 
failure is the predominant cause of mortality, local failure is also common (36%-52%) [3].  
 
Several studies have shown that addition of thoracic radiotherapy for patients with ES-SCLC 
who responded to chemotherapy is associated with improved local control and overall survival 
[4-5]. Early thoracic radiotherapy with concurrent chemotherapy is the standard of care for 
limited-stage SCLC (LS-SCLC).   However, SCLC usually arises submucosally in central 
airways, appearing as large hilar mass with bulky mediastinal adenopathy [6].  As a result, the 
tumor is often in close proximity to critical organs at risk (OARs) including normal lung 
parenchyma, heart, esophagus, spinal cord and bronchus.  Proton-beam therapy (PBT) allows 
delivery of conformal high-dose radiation to the target while sparing surrounding normal tissues. 
Studies have shown PBT is associated with both dosimetric and clinical benefits for locally 
advanced non-small cell lung cancer (NSCLC) [7-12].  An ongoing phase III randomized trial is 
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investigating PBT versus photon radiation for locally advanced NSCLC (Radiation Therapy 
Oncology Group [RTOG] 1308) [13].   
 
However, there is very limited evidence on the use of PBT for SCLC.  Further study of PBT for 
SCLC is critical for advancing the treatment of SCLC. Colaco et al published a single-institution 
experience of 6 patients who underwent concurrent chemoradiation for limited-stage SCLC (LS-
SCLC).  PBT allowed better sparing of lung and esophagus without acute grade 3+ esophagitis 
or acute grade 2+ pneumonitis [14].  Rwigema et al recently published a prospective institutional 
study of PBT for LS-SCLC [15].  Thirty patients were enrolled in the study. The median dose 
was 63.9 cobalt gray equivalents delivered in 33 to 37 fractions daily (n = 18 [60.0%]) or twice 
daily (n = 12 [40.0%]). The concurrent chemotherapy was cisplatin/etoposide (n = 21 [70.0%]) 
or carboplatin/etoposide (n = 9 [30.0%]). In comparison with the backup intensity-modulated 
radiotherapy (IMRT) plans, PBT allowed statistically significant reductions in the spinal cord, 
heart, and lung mean doses and the volume receiving at least 5 Gy but not in the esophagus mean 
dose or the lung volume receiving at least 20 Gy.  The median OS was 28.2 months. There was 1 
case each (3.3%) of grade 3 or higher esophagitis, pneumonitis, anorexia, and pericardial 
effusion. Grade 2 pneumonitis and esophagitis were seen in 10.0% and 43.3% of patients, 
respectively.  Notably, only 1 out of 30 patients received pencil-beam scanning IMPT. The 
remaining patients received passive-scattering PBT.  
 
Currently, PBT can be delivered using two methods. The older method, referred to as passive-
scattering PBT, uses a three-dimensional (3-D) conformal technique. It combines passively 
scattered proton beams of differing energies to form a “spread-out Bragg peak” (SOBP) that 
fully encompasses the target. The most common beam arrangement uses two opposed lateral 
beams, and customized apertures and compensators are fabricated to shape the field and alter the 
dose–depth profile to conform the SOBP to the actual tumor better.  Recent technological 
advances enabled us to utilize pencil-beam scanning (PBS) PBT, which allows more conformal 
and complex “IMRT-like” distribution. This is known as intensity-modulated proton therapy 
(IMPT) with a greater ability to conform the dose to irregularly shaped target [16]. In our 
prospective study, all patients will be treated with IMPT.  
 
Respiratory motion of lung tumors and changes in lung density during respiration poses unique 
challenges for the accuracy and planning of PBT. In addition, SCLC is known to be 
radiosensitive and the tumor volume can shrink significantly during the radiation course. 
Therefore, adaptive radiotherapy (ART) is crucial in PBT planning as it can adjust the treatment 
plan for geometrical uncertainties and tumor regression, allowing dose escalation to target and 
dose reduction to OARs [28]. There is very limited data on IMPT treatment for small cell lung 
cancer, thus a feasibility study utilizing this approach is necessary to advance the applications of 
PBT.  Small cell lung cancer is a particular unique patient group given large tumors prone to 
respiratory motion as well as characteristically rapid response to radiation that creates a variable 
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target volume. Determining the best schedule of tumor monitoring during treatment and 
determining the rate at which adaptive re-planning is necessary with IMPT is crucial and 
necessary before this technology can have greater applicability within this small cell lung cancer 
population. 
 
 
2.2 Cardiac Effects of Radiation Therapy in SCLC 
 
Radiation therapy (RT) is increasingly appreciated as a cause of cardiac morbidity following the 
management of lung cancer [18-27]. The non-small cell lung cancer (NSCLC) trial Radiation 
Therapy Oncology Group (RTOG) 0617 unexpectedly yielded lower overall survival (OS) for 
the high-dose (74 Gy) RT arm compared to the standard-dose (60 Gy) RT arm, and cardiac RT 
dose was subsequently posited as a potential contributor to this finding [17]. Heart V5 (volume 
of heart receiving 5 Gy) and heart V30 were associated with increased risk of death on 
multivariable analysis (MVA) [17]. A secondary dosimetric analysis of the trial was performed 
and demonstrated that heart V40 was an independent predictor of inferior OS [19]. Outside the 
randomized setting, a large single institutional analysis of 332 patients demonstrated a significant 
relationship on MVA between increasing heart volume and heart V50 with OS. A meta-analysis 
of 25 randomized NSCLC dose-escalation trials demonstrated association between higher RT 
doses and worse OS; again, dose-escalation here has been a presumed surrogate for increased 
cardiac dose [18].  
 
Until recently, there were no correlate studies in small cell lung cancer (SCLC); and the 
differences between NSCLC and SCLC precludes direct extrapolation. A recently published 
analysis from our group utilized SEER-Medicare data to report on rates of cardiac events for 
patients receiving chemotherapy(CTX) and RT as compared to matched patients receiving CTX-
only in a mixed population of limited-stage (LS-SCLC) and extensive-stage (ES-SCLC) patients. 
This study demonstrated photon-based RT was associated with cardiac events (p= 0.008), with 
cumulative incidence as follows for the CTX + RT and CTX-only groups: 36.4% (95% 
confidence interval [CI] 34.8%-37.9%) versus 35.4% (33.8%-36.9%) at 12 months and 44.1% 
(42.5%-45.7%) versus 39% (37.4%-40.6%) at 60 months, respectively [28].  
 
3. Participating Institution 
Winship Cancer Institute of Emory University School of Medicine (Atlanta, GA) is the only 
participating institution. Study/trial information will be made available to the Georgia Center for 
Oncology Research and Education (CORE) at https://www.georgiacancerinfo.org. Detailed trial 
information, including the protocol and all supplemental information will be submitted to, and 
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made 
available 
to 
the 
Online 
Collaborative 
Research 
Environment 
(OnCore) 
at 
https://oncore.emory.edu in accordance with institutional regulations. 
 
4. Study Design and Methods 
This is the first prospective study to investigate the safety and efficacy of IMPT for the treatment 
of SCLC. We will utilize adaptive planning throughout the radiation course. In addition, we will 
study the dosimetric parameters of IMPT and their correlation with treatment-related toxicities, 
particularly cardiac events.  
 
      4.1 Duration of Study 
We plan to enroll a total of 30 patients with small cell lung cancer, including limited stage and 
extensive stage. Our Department sees approximately 50 eligible small cell lung cancer patients 
per year.  It is estimated that it will take about 1 year to accrue 15 patients to this study. 
Radiation will last 6 weeks, and the total proposed follow-up time for this study is 12 months. 
We therefore project that this study will require approximately 2.5-3 years to complete.  
 
     4.2 Pre-treatment Evaluation  
All patients will receive pre-treatment consultation. A detailed history and physical exam will be 
performed in each patient.  Pre-treatment whole-body PET-CT and Brain MRI are required for 
all enrolled patients. 
 
5. Patient Selection 
      5.1    Inclusion Criteria 
5.1.1 Pathologically confirmed small cell lung cancer, limited or extensive stage. 
5.1.2 Patients who are offered thoracic radiotherapy with intensity-modulated proton 
therapy (IMPT) techniques delivering 30-66 Gy in 15-33 fractions at 2 Gy per fraction, at 
the recommendation of the treating radiation oncologist. 
  
5.1.3  Age 18 or greater 
 
5.2    Exclusion Criteria 
5.2.1    Prior radiation therapy which would provide significant dose overlap with the 
planned target volume(s)  
 
 
5.2.2 Pregnancy 
 
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5.3    INCLUSION OF WOMEN AND MINORITIES 
Both men and women and members of all ethnic groups are eligible for this trial. No 
special recruitment will be performed based on gender or minority status. No person 
shall, on the grounds of race, color, or national origin, be excluded from participation in, 
or be denied the benefits of, enrollment in this protocol. 
 
5.4    SOURCES OR METHODS OF RECRUITMENT 
PATIENTS WILL BE RECRUITED FROM THOSE SEEN AT THE DEPARTMENT OF RADIATION 
ONCOLOGY AT WINSHIP CANCER INSTITUTE. AFTER ELIGIBILITY CRITERIA HAVE BEEN 
REVIEWED, ELIGIBLE PATIENTS WILL BE OFFERED THE OPPORTUNITY TO PARTICIPATE IN THE 
STUDY. A BRIEF DESCRIPTION OF THE STUDY WILL BE GIVEN VERBALLY TO THE PATIENTS, 
FOLLOWED BY WRITTEN INFORMED CONSENT, AND ANY RELEVANT SUPPLEMENTAL 
MATERIAL AS NEEDED. THE PATIENTS WILL BE GIVEN AMPLE TIME TO REVIEW THE CONSENT 
AND A TIME FOR QUESTIONS AND ANSWERS WILL BE PROVIDED. NO FINANCIAL INCENTIVES 
WILL BE PROVIDED TO THE PATIENTS. 
 
5.5    STUDY ENROLLMENT PROCEDURES  
A copy of the institution’s IRB-approved informed consent document and written 
justification for any changes made to the informed consent for this protocol must be on 
file 
at 
the 
Online 
Collaborative 
Research 
Environment 
(OnCore, 
https://oncore.emory.edu) and available to the Emory University Office for Clinical 
Research) before any patients may enter. The Winship Cancer Center institution consent 
form must be reviewed and approved and all documents must be received (i.e., IRB 
approved documentation, IRB approved consent form, etc.). 
 
6. Patient Registration 
All patients entering this study will be registered with the Clinical Trials Office (CTO) at 
the Winship Cancer Institute, Atlanta, GA. The CTO is open Monday through Friday 
from 8am-5pm (EST). OnCore will be used to record information for all registered 
patients including their assigned patient ID. 
 
7. Study Plan 
        7.1    Radiation Therapy 
Aspects of radiation therapy, i.e. simulation, treatment planning and delivery should 
follow standard of care practices, and are at the discretion of the treating radiation 
oncologist. A multi-disciplinary approach should be implemented when applicable. 
Guidelines for the delivery of radiation therapy are provided below. 
 
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        7.1.1 Required Criteria/Technical Factors 
The goal of intensity-modulated proton therapy (IMPT) is to deliver radiation to the 
tumor while minimizing exposure to surrounding normal tissues. Commercially available 
linear accelerators with image guidance capabilities should be used.  
 
        7.3.2   Dose Prescription and Fractionation 
Patients will receive between 30- 66 Gray Equivalent (GyEq) in 15-33 fractions at 2 
GyEq per fraction.  Twice daily treatment is not allowed. Dose prescription will be at the 
discretion of the treating radiation oncologist. It should be in accordance with standards 
of care and acceptable to peer review. Dose constraints to organs at risk likewise should 
follow institutional standards and acceptable to peer review.  Patients who do not have 
evidence of brain metastases on initial staging MRI will be offered prophylactic cranial 
irradiation. 
 
        7.3.3    Patient Positioning and Immobilization 
Patients should be immobilized in a position capable of accurately reproducing the target 
position from treatment to treatment. Positions that are uncomfortable should be avoided 
to reduce the risk of unexpected patient movements during treatments. Immobilization 
systems designed for lung IMPT setups should be used, examples include CIVCO with 
Vac-LokTM. 
 
        7.3.4    Simulation 
Patients should undergo CT-based treatment planning in custom-made immobilization 
devices. The CT scanning parameters should allow for the accurate target volume 
delineation of all treated lesions and relevant organs at risk. High-resolution 4D-CT scans 
should be obtained with uniform slice thickness of ≤3mm throughout.  
  
        7.3.5    Isocenter Placement 
The isocenter is defined as the intersection of gantry, collimator, and couch rotational 
axes for linear accelerator based treatment systems. If multiple target lesions are planned 
to receive radiation therapy, multiple isocenters, each centered on a separate lesion, 
should be used. Localization is optimal if the isocenter is placed in the center of each 
target and image guidance is performed individually. 
         
        7.3.6    Management of Internal Organ Motion 
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Special considerations should be made to account for the effects of respiratory motion on 
target positioning and reproducibility. Tumors with significant (≥1cm) of maximum 
displacement should be limited with motion management solutions, such as respiratory-
gated treatment, abdominal compression, active-breath control or breath-holding 
techniques. Methods of limiting internal organ motion should be sufficiently reliable to 
ensure that the gross tumor volume does not deviated beyond the confines of the planning 
target volume with any significant probability. An ITV approach may be sufficient for 
tumors with minimal (<1cm) tumor motion. 
 
        7.3.7    Localization and Imaging 
Image-guidance implementation is considered a standard component of IMPT treatment. 
kV localization images should be acquired prior to delivery of each IMPT fraction to 
ensure the proper alignment of the geometric center of the simulated fields. Cone-beam 
CTs will be acquired daily to verify the target volume and assess for shrinkage of the 
tumor that may necessitate adaptive re-planning. 
 
        7.3.8    Target Volume Determination 
The gross tumor volume (GTV) should compass all CT-defined visible disease, using the 
CT lung windows, aided by co-registered PET/CT. For tumors with significant 
displacement (≥1cm) due to respiratory motion, gated treatment will be utilized. GTV is 
contoured on the free breathing CT scan for patients who do not need gated treatment. 
For those who require gated treatment, GTV is contoured on the averaged CTs of the 
gated phases. Selection of the gated phases is at the discretion of the treating radiation 
oncologist. The CT-defined visible disease on a reconstructed maximum intensity 
projection (MIP) image is used to create the internal target volume (ITV). A uniform 
5mm margin around ITV is added to create the clinical target volume (CTV).  Planning 
target volume (PTV) will not be utilized in IMPT. The use of any additional diagnostic 
studies to aid planning is at the discretion of the treating physician. 
 
       7.4    Concomitant Therapies 
7.4.1    Systemic therapy 
The regimen, dosing and timing of concurrent chemotherapy will be decided by the 
treating medical oncologist.  Most commonly used regimen at Emory University Hospital 
is 4 cycles of cisplatin and etoposide given every 3 weeks. Etoposide dosing will be 100 
mg/m2 intravenously on days 1-3, and cisplatin dosing will be 75 mg/m2 intravenously on 
day 1. Immunotherapies can be given at the discretion of the treating medical oncologist. 
 
7.4.2    Other Treatments 
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Other treatments are allowed as long as they do not preclude the patient from either 
receiving radiation therapy or undergoing imaging studies as intended. 
 
8. Patient Assessments  
 
Patients will be seen by radiation oncology for an on-treatment visit once per week 
during treatment. During these visits, adverse events (AEs) will be logged. Patients will 
be seen for a history and physical at 4 weeks post-treatment, then at 3 months, 6 months 
and 1 year.  Thereafter, visits will be every 4-6 months.   Follow-up imaging will include 
a CT of the chest every 6 months for 5 years.  Initial imaging following treatment 
completion will occur at the discretion of the treating radiation oncologist and can consist 
of a chest CT or a PET/CT.  Follow-up PET imaging will be obtained at the discretion of 
the treating physician.  For calendar schedule of events, see Appendix A.  
 
Case report forms (at end of radiation and every 6 months in follow up) will contain 
detailed questions regarding development of cardiac events including unstable angina, 
myocardial infarction, arrhythmia, pericarditis, myocarditis, congestive heart failure, or 
valvular dysfunction during and after treatment.   
 
8.1.1 Adverse Events (AEs) 
Any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of a medical treatment or procedure regardless of whether it is considered related 
to the medical treatment or procedure (attribution of unrelated, unlikely, possible, 
probable, or definite).  CTCAE version 4.0 will be used to assign AE term and grade.  If 
specific grading is not available in the CTCAE for a particular AE’s severity, the 
investigator will use general definitions of grade 1-5 using his/her best judgment (Grade 
1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening or disabling, 
Grade 5 = death). These events will be recorded for each subject during treatment at 
weekly on treatment visits with radiation oncology and at each follow up visit. All AEs 
will be entered into the OnCore database by research coordinators within 14 calendar 
days of data capture.  AEs are subject to review by the investigators and data safety 
monitoring committee (DSMC).  Dose limiting toxicities (DLTs) are considered to be 
any grade 3 or higher AEs that are possibly, probably, or definitely treatment related. 
Non-treatment related AEs, grade 3 or higher, will not be considered to be a DLT. 
Subsites must report DLTs within 48 hours. The following symptoms will be considered 
to be treatment related: 
 
10 
 

• Grade 3-5 Cardiac Disorders: acute heart disease, acute myocardial infarction, 
cardiomyopathy, dysrhythmia, heart failure, pericarditis, pericardial effusion 
• Grade 3-5 Gastrointestinal Disorders: dysphagia, esophagitis, esophageal fistula, 
esophageal ulcer, esophageal hemorrhage, esophageal perforation, esophageal 
obstruction 
• Grade 3-5 Central Nervous System Disorders: myelitis, brachial plexopathy 
• Grade 3-5 Pulmonary Disorders: bronchial fistula, tracheal fistula, pneumonitis, 
pulmonary fibrosis, bronchopulmonary hemorrhage 
• Any Grade 5 event attributed to treatment 
             
            8.1.2 Serious Adverse Events (SAEs) 
Any adverse event that results with any of the following outcomes:  
• Death 
• Life-threatening experience 
• Inpatient Hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Other medically important events 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition.  These events will also be recorded for each 
subject and is subject to review by the investigators and data safety monitoring 
committee (DSMC).  In addition, these events will be reported to the responsible 
Institutional Review Board (IRB) and the study PI.  All SAEs will be reported within 24 
hours of discovery to Study Coordinator and the study PI, Dr. Kristin Higgins 
(kristin.higgins@emory.edu, 404-778-0603). SAEs will be reported using the SAE form 
in Appendix B. SAE should be emailed to both the study coordinator and Dr. Higgins as 
well as inputted into OnCore. 
 
9. Removal of Patient from Study 
Participation in the study should continue until one of the following criteria applies: 
9.1    Intercurrent illness that prevents delivery of planned radiation therapy 
9.2    Unacceptable treatment-related adverse event(s), including patient death 
9.3    Withdrawal of informed consent (subject’s decision to withdraw for any reason)  
11 
 

9.4    Noncompliance with treatment plan, including delays to treatment or acquisition of   
additional diagnostic imaging that significantly exceeds the proposed timeline of 
study events 
9.5    General or specific changes in the patient's condition that render the patient  
unacceptable to receive further treatment in the judgment of the investigator 
 
10. Data Collection and Records 
Data to be collected will include patient’s name and medical record number, date of birth, 
basic disease characteristics, including staging information, location of and extent of 
involvement, relevant imaging characteristics of the tumor, prior cancer-directed 
therapies. Information will also be collected regarding radiation treatment parameters 
including dose and fractionation, dosimetric details, and regarding any concomitant 
therapies received, such as chemotherapy or immunotherapy. Information will also be 
collected regarding CTCAE-graded toxicities.  Emory approved case report forms 
(CRFs) for data collection will be used and data entered into OnCore. For participating 
subsites, initial visit CRFs and eligibility checklist must be submitted within 14 days of 
patient registration. 
 
11. Data and Safety Monitoring 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study.  The DSMC functions independently within 
Winship Cancer Institute to conduct internal monitoring functions to ensure that research being 
conducted by Winship Cancer Institute Investigators produces high-quality scientific data in a 
manner consistent with good clinical practice (GCP) and appropriate regulations that govern 
clinical research.    Depending on the risk level of the protocol, the DSMC review may occur 
every 6 months or annually.  For studies deemed High Risk, initial study monitoring will occur 
within 6 months from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed.  For studies deemed Moderate Risk, initial study monitoring will occur within 1 year 
from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed.  Subsequent monitoring will occur in routine intervals per the Winship Data and 
Safety Monitoring Plan (DSMP).   
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 
accuracy and availability of source documents, AEs/SAEs, and essential regulatory 
documents.  Following the monitoring review, monitors will provide a preliminary report of 
monitoring findings to the PI and other pertinent individuals involved in the conduct of the 
study.  The PI is required to address and respond to all the deficiencies noted in the preliminary 
report.  Prior to the completion of the final summary report, monitors will discuss the 
preliminary report responses with the PI and other team members (when appropriate).  A final 
monitoring summary report will then be prepared by the monitor.  Final DSMC review will 
12 
 

include the final monitoring summary report with corresponding PI response, submitted CAPA 
(when applicable), PI Summary statement, and available aggregate toxicity and safety data.    
The DSMC will render a recommendation and rating based on the overall trial conduct.  The PI 
is responsible for ensuring that instances of egregious data insufficiencies are reported to the 
IRB.  Continuing Review submissions will include the DSMC recommendation letter.  Should 
any revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the 
PI will be responsible for notifying the DSMC of such changes.  The Committee reserves the 
right to conduct additional audits if necessary.  
 
12. Multi-Institutional Guidelines 
This is a single-institution study at Winship Cancer Institute. 
 
13. Statistical Considerations 
13.1    Study Endpoints13.1.1 Primary Endpoint 
• The primary objective of this prospective trial is to assess the safety of intensity-
modulated proton therapy (IMPT) for small cell lung cancer. Primary endpoints 
will be the following: 
Patients enrolled will experience <35% incidence of cardiac events at 1-year. 
Cardiac events included: acute heart disease, acute myocardial infarction, 
cardiomyopathy, dysrhythmia, heart failure, pericarditis, pericardial effusion 
 
 
13.1.2 Secondary Endpoints 
• Determination of the optimal frequency of conebeam CT during treatment and 
subsequent need for adaptive re-planning 
• Local control 
• Distant metastases 
• Patterns of failure 
• Radiation pneumonitis 
• Radiation esophagitis  
• Overall survival at 1, 2, and 5 years 
 
13.2  Sample Size and Power Calculations 
This pilot study is designed to enroll 30 patients, and criteria for patient selection are 
outlined in sections 5. The power and sample size calculation is based on the primary 
objective of the study to study Cardiac events rate at 1 year. A sample size of 30 produces 
a two-sided 95% confidence interval with a width equal to 0.281 assuming the true 
cardiac events rate at 1 year is 0.15. Therefore, the sample of 30 patients in the study will 
13 
 

demonstrate a cardiac event rate < 35% at the confidence level of 95%.  
 
13.3 Study Analysis/Statistics 
Statistical analysis will be conducted using SAS Version 9.4. The significance level was 
set at 0.05. Summary statistics will be first estimated for all variables collected. 
Continuous variables will be presented as means, standard deviation, and the range, while 
categorical variables will be summarized with frequencies and percentages.   
 
For the primary objective in terms of safety, Cardiac events rate at 1 year will be 
estimated among all patients and the 95% confidence interval will be constructed 
assuming a binomial distribution. The association of Cardiac events with categorical 
covariates will be tested with Chi-square test. Logistics regression model will be 
employed to measure the association of Cardiac events with continuous covariates with 
and without adjusting for other factors.  
 
A mixed model will be employed to determine the optimal frequency of conebeam CT 
during treatment and subsequent need for adaptive re-planning. The local control, distant 
metastases, patterns of failure will first be summarized as frequency and percentage. Chi-
square test will be further used to test their relationships with other categorical variables. 
General linear model will be employed to measure their association with continuous 
covariates with and without adjusting for other factors.    
 
The rates of cardiac toxicities, pneumonitis, and esophagitis from IMPT will be estimated 
among all patients and their 95% confidence interval will be constructed assuming 
binomial distribution, respectively. Exact binomial test will be employed to compare the 
rates of cardiac toxicities, pneumonitis and esophagitis from IMPT with historical 
controls receiving photon based treatment, respectively. Logistics regression model will 
be employed to estimate the associations of cardiac toxicities, pneumonitis, and 
esophagitis with other factors.  
 
The overall survival curve of all patients will be generated with Kaplan-Meier method 
and overall survival rates at 1, 2, and 5 years will be also estimated along with 95%CI. 
Log-rank tests will be used to compare overall survival difference between different 
groups stratified by other factors. Cox proportional hazards models will be applied for 
multivariate analysis of the survival data in the study.  
 
 
14. Human Subjects 
14 
 

14.1    Subject Population 
 
This study will enroll patients with small cell lung carcinoma with good response to 
chemotherapy who are candidates for thoracic radiotherapy with intensity-modulated 
proton therapy techniques delivering 30-66 GyEq in 10-33 fractions at 2 GyEq per 
fraction, at the recommendation of the treating radiation oncologist. 
 
14.2    Potential Risks 
 
Risks of IMPT is specific to the treatment volume, location of disease site, and proximity 
to critical organs at risk. Patients will be provided the opportunity to provide written 
informed consent for treatment separately, per institutional and departmental standards. 
Protected health information (PHI) will be collected for this study, and efforts will be 
made to keep PHI private. Results input into the main research database will be de-
identified. Patient identifiers can only be accessed by key members of the study team. A 
file containing patient identifiers will be password protected; information transfer, if 
performed by means of memory storage devices, will also be password protected. 
Physical forms used for collecting information will contain a minimum of personal 
information, and will utilize study numbers for identification. 
 
14.3    Consent Procedures 
Informed consent is to be obtained prior to commencing any research procedures. A 
study investigator shall seek such consent only under such circumstances that provide the 
prospective patient opportunity to consider whether or not to participate and that 
minimizes the possibility of coercion or undue influence. The information given to the 
patient, or the representative, shall be in a language understandable to the subject or 
representative. The informed consent document may not include any exculpatory 
language through which the subject or representative is made to waive any of the 
subject’s legal rights or releases, or appears to release the investigator, the sponsor or the 
institution from liability for negligence. 
 
14.4    Potential Benefits 
Patients enrolled on this study will receive IMPT according to accepted standard of care 
per the treating physician as clinically indicated.  
 
14.5    Gender and Minorities 
No person shall, on the grounds of race, color, or national origin, be excluded from 
participation in, or be denied the benefits of, enrollment in this protocol. 
15 
 

 
15. Economic/Financial Considerations 
The costs of the patient’s primary treatment, including pre-treatment consultation and 
necessary evaluations, 4D- CT simulation, IMPT treatment course and pre-, during- and 
post-treatment imaging are expected to be covered by the patient’s insurer/primary payor.  
16. Publication of Research Findings 
The policies and procedures of Emory University School of Medicine, Winship Cancer 
Institute will govern publication of this pilot study. It is expected that the results of this 
study will be submitted for publication in a timely manner following its conclusion. The 
Winship Cancer Institute PI(s), and all other co-authors prior to submission or use, must 
review any abstract or manuscript.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 
 

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19 
 

APPENDIX A 
 
Study 
Procedures 
Pre-
treatment 
evaluation 
CTX + 
RT 
Treatment 
1 
month 
3 
month 
6 
month 
Year 
1 
Year 
1.5 
Year 
2 
Year 
2.5 
Year 
3 
Year 
3.5 
Year 
4 
Year 
4.5 
Year 
5 
PET-CT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Brain 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4D CT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT 
simulation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cone beam 
CT 
 
With 
every RT 
fraction 
 
 
 
 
 
 
 
 
 
 
 
 
RT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CTX 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT-chest 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
20