Feasibility Study of the Utility of Pulmonary Dynamic Contrast Enhanced MRI for Assessment of Tumor Response and Lung Injury and for Treatment Planning for Stereotactic Body Radiation Therapy for Early Stage Non-Small Cell Lung Cancer
Phase: NA
Conditions: Non Small Cell Lung Cancer
Sponsor: Dana-Farber Cancer Institute

Title: Feasibility study of the utility of pulmonary dynamic contrast enhanced MRI for 
assessment of tumor response and lung injury and for treatment planning for stereotactic body 
radiation therapy for early stage Non-small Cell Lung Cancer 
 
NCT Number: NCT01799135 
 
IRB Approval Date: 03/28/2021 

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Title: A Feasibility Study of the Utility of Pulmonary Dynamic Contrast Enhanced MRI for 
Assessment of Tumor Response and Lung Injury and for Treatment Planning for Stereotactic 
Body Radiation Therapy for Early Stage Non-small Cell Lung Cancer 
 
NCI Protocol #: N/A 
 
Local Protocol #: 12-004 
 
Principal Investigator: Raymond H. Mak, M.D.  
 
Study Statistician: 
 
 
Version Date: 1/6/2015 
 
 

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Index 
 
 
Schema 
1.0 
Introduction …………………………………………………….  1 
2.0 
Objectives ……………………………………………………… 4 
3.0 
Participant Selection …………………………………………… 5 
4.0 
Pretreatment Evaluations/Management ………………………… 6 
5.0 
Registration Procedures ………………………………………… 6 
6.0 
Study Design ……………………………………………………. 7 
7.0 
Study Imaging Procedures ……………………………………… 8 
8.0 
Radiation Therapy ……………………………………………… 11 
9.0 
Drug Therapy …………………………………………………… 16 
10.0 Surgery …………………………………………………………. 16 
11.0 Other Therapy ………………………………………………….. 16 
12.0 Tissue/Specimen Submission …………………………………... 17 
13.0 Participant Assessments ………………………………………... 17 
14.0 Data Collection ………………………………………………… 17 
15.0 Statistical Considerations ……………………………………… 19 
16.0 Regulatory Considerations …………………………………….. 21 
17.0 Publication Plan ………………………………………………… 23 
18.0 References ………………………………………………………. 23 
19.0 Appendices ……………………………………………………… 27 

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SCHEMA 
 
 
 
DCE-MRI: Pulmonary dynamic contrast-enhanced magnetic resonance imaging 
PET-CT: Positron emission tomography 
PFT: Pulmonary function test 
4D-CT: 4-dimensional computed tomography 
 
 
 
R
E
G
I
S
T
E
R 
Patients with 
medically 
inoperable stage I 
non-small cell lung 
cancer 
Candidates for 
stereotactic body 
radiation therapy 
Pre-
Treatment 
DCE-MRI 
Day -14 to 
0 
3-5 SBRT 
treatments 
Day 1-15 
Standard Treatments and Studies 
On Study Imaging: 
• 
Pulmonary Dynamic 
Contrast-Enhanced 
MRI 
• 
4D-CT 
P
E
T
/
C
T 
P
F
T 
Early Post-
Treatment 
DCE-MRI 
Day 8 to 29 
(1-2 weeks 
post- SBRT) 
Late Post-
Treatment 
DCE-MRI 
and 
4D-CT 
Day 90-120 
P
E
T
/
C
T 
P
F
T 
4D 
CT 
DCE-MRI 
During 
SBRT 
Day 2-3  
(1-2 Days 
after first 
SBRT 
treatment) 

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1. INTRODUCTION 
 
1.1 Study Disease 
 
The standard of care for treatment of early-stage non-small cell lung cancer is surgical 
resection.  However, many patients with this disease have other medical co-morbidities, 
which may preclude them from undergoing a surgical procedure.  Historically, patients 
with medically inoperable  stage I non-small cell lung cancer (i.e., patients who are not 
surgical candidates due to medical co-morbidities) have been treated with 
conventionally fractionated radiation therapy, which typically entails treatment with 30 
to 35 small doses of radiation given in 2- to 2.5-Gray (Gy)  fractions daily over 6 to 8 
weeks.  Outcomes with this approach have been poor, with local control rates of less 
than 50% and overall survival of less than 10 to 15% (Dosoretz et al. 1993; Sibley et al. 
1998). 
 
 
Recent advances in image-guided radiation therapy have allowed the safe delivery of 
hypofractionated radiation therapy (fewer fractions of treatment with a higher dose per 
fraction).  In theory, the use of high doses per fraction may overcome radioresistance 
and reduce the influence of tumor repopulation (Hall and Giaccia 2006). This technique 
of using high doses of highly precise, image-guided radiotherapy in only a few fractions 
of radiotherapy is called stereotactic body radiotherapy (SBRT). SBRT provides 
patients with medically inoperable lung tumors a promising new treatment, and surgical 
candidates with a less invasive alternative.  Several single-institution series (Onishi, 
Araki et al. 2004; Grills, Mangona et al. 2011) and phase II studies (Timmerman et al. 
2006; Baumann et al. 2009; Fakiris et al. 2009; Timmerman et al. 2010), including a 
multi-institutional Radiation Therapy Oncology Group (RTOG) study, have 
demonstrated high local control rates of greater than 80-90% with this approach, and a 
low risk of severe toxicity (<10%) when patients are appropriately selected.   
 
1.2 
Rationale 
 
Perfusion-Based Imaging to Assess Tumor Response  
Since SBRT is a novel treatment for early stage lung cancer, predictors of response to 
treatment and tumor control have not been clearly identified.  Radiological evaluation 
of changes in lung tumor perfusion after the high-dose radiation therapy delivered by 
SBRT may provide a novel, early predictor of response to treatment.  Magnetic 
resonance imaging (MRI) provides high resolution imaging, and dynamic contrast- 
enhanced MRI (DCE-MRI) utilizes intravenous gadolinium contrast to evaluate 
differential enhancement of tumors compared with normal tissue (Tofts et al. 1999; 
Brasch et al. 2000). Because tumors have increased angiogenesis and vascular 
permeability, DCE-MRI can be used to distinguish between tumor and normal tissue by 
assessment of the pharmacokinetic properties of contrast agent uptake in tissues as 
changes of signal intensity over time, referred to as time–intensity curves. 
Pharmacokinetic parameters, including the volume transfer constant (Ktrans; 
permeability surface area product per unit volume of tissue), the fractional volume of 
extravascular extracellular space per volume of tissue (ve), and the rate constant (kep; 

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efflux rate from extravascular extracellular space back to plasma), can be estimated by 
fitting a pharmacokinetic model to the actual time–intensity curves obtained from the 
DCE-MRI. 
 
DCE-MRI has been utilized to provide high resolution spatial imaging of the extent of 
soft-tissue tumors such as prostate adenocarcinomas (Cheikh, Girouin et al. 2009), and 
to monitor changes in tumor perfusion in response to therapy (Low, Fuller et al. 2011).  
Work conducted at Brigham and Women’s Hospital has demonstrated that DCE-MRI 
can be utilized to assess perfusion in pulmonary nodules, with the addition of motion 
correction to pharmacokinetic measurements (Tokuda et al. 2011). 
 
DCE-MRI is currently under active study as a potential imaging tool for response 
assessment after SBRT.  A preliminary study using DCE-MRI to assess changes in 
tumor perfusion after SBRT has been conducted for prostate cancer, and demonstrated 
decreases in prostate tumor perfusion as early as 2 months after treatment (Low, Fuller 
et al. 2011).  This study demonstrated a 40% decrease in average tumor perfusion 
(measured by Ktran) at 2 months, 75% decrease at 6 months, 82% decrease at 12 months 
and 87% decrease at 24 months after SBRT. A small series from Cai et al demonstrated 
that lung tumor perfusion changes after SBRT can be assessed by pulmonary DCE-MRI 
(Cai, Sheng et al. 2007).  Thus, further exploration of this imaging technology in 
conjunction with SBRT is of great interest. 
 
SBRT Toxicity 
Since SBRT is a new technology and novel method of radiation therapy delivery, the 
long-term toxicity of its use for lung cancers remains to be seen, and the 
pathophysiology of radiation-induced injury at such high doses is not fully 
characterized.  Of particular concern is the potential development of long-term 
pulmonary toxicity, which may manifest as radiation pneumonitis or more subacute 
gradual worsening of dyspnea, hypoxia, and/or decline in pulmonary function test 
metrics.  This spectrum of potentially radiation-related lung injury was observed at a 
moderate to severe grade (Grade 3-4) in 16% of patients in the phase II RTOG 0236 
study (Timmerman, Paulus et al. 2010). 
 
Since the majority of patients receiving SBRT for early stage lung cancer in the United 
States have significant co-morbidities and/or compromised pulmonary function from 
underlying lung disease such as chronic obstructive pulmonary disease (COPD), 
minimizing radiation-induced lung injury is of paramount importance.  Prior studies 
have established the importance of maintaining tight constraints on the volume of lung 
receiving low to moderate doses of radiation (5 Gy to 20 Gy) to minimize the risk of 
radiation pneumonitis with both conventionally fractionated radiation therapy (Kwa, 
Lebesque et al. 1998; Graham, Purdy et al. 1999; Hernando, Marks et al. 2001; Wang, 
Liao et al. 2006) and SBRT (Barriger et al. 2010; Ong et al. 2010).  However, theses 
studies did not distinguish whether the volumes of lung receiving these doses of 
radiation were functional or not.  
 
Incorporating Functional Lung Imaging into SBRT Treatment Planning 

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It would be of great interest to utilize functional imaging to guide SBRT treatment 
planning and to assess treatment response and potential toxicity.  Prior studies have 
attempted to incorporate functional imaging into conventional radiation therapy 
planning.  For instance, studies have demonstrated that functional information from 
perfusion single positron emission computed tomography (SPECT)  can be used to plan 
radiation therapy (Christian, Partridge et al. 2005; Lavrenkov, Christian et al. 2007; 
Lavrenkov, Singh et al. 2009) and used to quantify radiation-induced lung injury 
(Marks, Spencer et al. 1993; Abratt and Willcox 1995; Boersma, Damen et al. 1995; 
Seppenwoolde, De Jaeger et al. 2004). Furthermore, ventilation/perfusion (V/Q) SPECT 
has been shown in one study to provide additional useful information for treatment 
planning beyond perfusion-SPECT (Yuan, Frey et al. 2011).  While these nuclear 
medicine approaches are of interest, they require radioactive tracers that may expose 
patients to additional radiation, and have inherent limitations in image resolution. 
 
Other groups have studied the role of hyperpolarized helium (He) magnetic resonance 
imaging (MRI) as a means of incorporating functional imaging into radiation therapy 
planning.  Ireland et al demonstrated in 6 patients that fusion of He-MRI images with 
planning CT is feasible (Ireland, Bragg et al. 2007; Ireland, Woodhouse et al. 2008), 
and subsequently demonstrated that incorporating He-MRI images into radiation 
planning allowed for sparing of functional lung (Bates, Bragg et al. 2009).  Cai et al 
applied this functional imaging technology for SBRT planning using tomotherapy, and 
demonstrated potential modest sparing of functional lung (Cai, McLawhorn et al. 2011).   
 
In our department, Allen et al studied the role of He-MRI both before and after RT in 
individuals with locally advanced non-small cell lung cancer, and demonstrated that CT 
and PET target volumes correlated well, but had poor correlation with He-MRI target 
volumes defined based on ventilation defects (Allen, Albert et al. 2011).  These findings 
may be related to the decreased spatial resolution seen with He-MRI, and may be one of 
the key limitations in adapting this modality for radiation treatment planning and 
assessment of response. 
 
Recently, studies have been published on the potential use of 4D-CT to define regions 
of functional lung base on voxelized ventilation maps (Guerrero, Sanders et al. 2006; 
Castillo, Castillo et al. 2010; Nyeng, Kallehauge et al. 2011; Yamamoto, Kabus et al. 
2011; Yamamoto, Kabus et al. 2011). These techniques perform deformable image 
registration between phases of 4D-CT images, and use the density or volume changes as 
a surrogate for ventilation. Such a technique would be appealing for SBRT because 4D-
CT scans are routinely acquired for treatment planning, and no additional imaging 
studies would be required. However, the physiological accuracy of these novel methods 
has not yet been thoroughly validated in patient data (Yamamoto, Kabus et al. 2011; 
Yamamoto, Kabus et al. 2011). Also, the method can only be used to determine lung 
ventilation, and does not include critical information about perfusion. 
 
Functional Lung Imaging and Radiation-Induced Lung Injury 
Another potential application of functional lung imaging includes assessment of 
radiation-induced lung injury.  Preliminary studies by Ireland et al demonstrated that 

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He-MRI findings can be correlated with CT-based emphysematous changes and also 
with areas of potential radiation pneumonitis seen on CT (Ireland, Din et al. 2010).  
Ward et al demonstrated in rat models that after high dose radiation (5 x 8 Gy), He-MRI 
correlated well with radiation-induced fibrosis (Ward et al. 2004). 
 
Advantages of Perfusion-Based Functional Lung Imaging 
Perfusion-based MRI scans have the potential advantages of assessing early tumor 
response to radiation therapy via changes in tumor perfusion after treatment, higher 
spatial resolution, improved registration, and patient convenience (routine scan that 
does not require gas inhalation).  Furthermore, these studies may allow assessment of 
tumor motion while still allowing identification of areas of functional lung, which may 
allow improved SBRT planning. 
 
Study Rationale 
To our knowledge, pulmonary DCE-MRI has not been systematically studied as both an 
early predictor of tumor response and lung injury and as a SBRT treatment planning 
tool. 
 
Thus, in this pilot study, we propose to explore the feasibility of pulmonary DCE-MRI 
in 1) assessing tumor response during and after SBRT treatment; 2) characterizing 
regions of radiation-induced lung injury after SBRT treatment, and correlating these 
regions of injury with ventilation changes found on 4D-CT; and 3) identifying regions 
of functional lung for SBRT treatment planning. 
 
2. OBJECTIVES 
 
2.1 
Primary Objective 
To determine the feasibility of utilizing pulmonary DCE-MRI to assess for changes in 
tumor perfusion during SBRT (1-2 days after the first treatment) and post-treatment (at 1-
2 weeks and at 3-4 months after SBRT treatment) for stage I NSCLC  
 
2.2 
Secondary Objective(s) 
 
2.2.1 To evaluate the feasibility of pulmonary DCE-MRI in characterizing acute and 
subacute (3 months) radiation-induced lung injury after SBRT, and correlate these 
findings with clinical outcomes 
2.2.2 To evaluate the feasibility of integrating 4D-CT ventilation imaging with DCE-MRI 
perfusion imaging in characterizing subacute (3 months) radiation-induced lung 
injury after SBRT  
2.2.3 To determine the feasibility of using pulmonary DCE-MRI to identify regions of 
functional lung for SBRT treatment planning 

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3. PARTICIPANT SELECTION 
 
 
3.1 
Conditions for Participant Eligibility 
3.1.1 Participants should preferably have histologically confirmed non-small cell lung 
cancer, but patients with a clinical and radiographic diagnosis of non-small cell lung 
cancer who are candidates for stereotactic body radiation therapy may also be 
eligible. 
3.1.2 The tumor must be ≥ 1 cm and ≤ 6 cm 
3.1.3 Participants must have no evidence of nodal involvement (N0) or distant metastases 
(M0) on staging studies, which may include positron emission tomography (PET), 
computed tomography (CT), and/or mediastinoscopy.  
3.1.4 Participants must be age 18 years or older 
 
3.1.5 ECOG performance status <2 (see Appendix A) 
3.1.6 Participants must be evaluated by radiation oncology and deemed to be a candidate 
for stereotactic body radiation therapy for NSCLC. 
3.1.7 Ability to lie still during DCE-MRI which may last for up to 60 minutes 
3.1.8 Adequate renal function to tolerate intravenous gadolinium contrast injection 
(estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 prior to initial DCE-MRI 
and  estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 for subsequent DCE-
MRI scans). 
 
3.1.9 Ability to understand and the willingness to sign a written informed consent 
document 
 
3.2 Conditions for Participant Ineligibility  
 
3.2.1 Primary tumor size > 6 cm 
 
3.2.2 Prior thoracic radiotherapy directed to the ipsilateral lung or prior surgical wedge 
resection in the involved lobe 
 
3.2.3 An implanted pacemaker or cardiac defibrillator 
 
3.2.4 Contraindications to receiving intravenous gadolinium contrast injection including 
prior allergic reaction and/or chronic renal insufficiency (estimated glomerular 
filtration rate < 45 mL/min/1.73 m2 prior to initial DCE-MRI and  estimated 
glomerular filtration rate < 30 mL/min/1.73 m2 for subsequent DCE-MRI scans). 

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3.2.5 Any contraindication to undergoing MRI (e.g., pacemakers, cochlear implants, 
shrapnel injuries, or other types of metal or electric devices in the body, severe 
claustrophobia, cataract surgery with certain ocular implants—see below) 
 
3.2.5.1 The following ocular implant models from Bausch & Lomb are 
considered unsafe for MRI: Intraocular Lens, Models 12A, 12P, 
12S, 24P, 31P, 42P, 61P, 71, 71B, 71M, 71P, 71PC, 71R, 75M, 
75P, EXP D 
3.2.6 Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements 
 
3.2.7 Pregnant women are excluded from this study because radiotherapy has the potential 
for teratogenic or abortifacient effects. Because there is an unknown but potential risk 
of adverse events in nursing infants secondary to treatment of the mother with 
radiotherapy, breastfeeding should be discontinued if the mother is treated with 
radiotherapy. These potential risks may also apply to other agents used in this study. 
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Women, minorities and other underrepresented populations are all at risk to develop 
non-small cell lung cancer, with smoking as the critical risk factor for the disease. 
Socioeconomically-deprived populations tend to have higher rates of smoking, and 
therefore it is possible this study will be more likely to enroll these individuals. 
However, the proposed MRI studies and the standard SBRT treatment will not have a 
differential effect on these populations. The eligibility criteria should not substantially 
differentially affect their enrollment in the trial, although some minority populations are 
more likely to have renal failure, which may preclude them from the trial. 
 
4. PRETREATMENT EVALUATIONS/MANAGEMENT 
4.1 
Screening and Non-Study Pretreatment Evaluations 
 
This visit will be performed within 4 weeks prior to the initiation of the stereotactic 
body radiation therapy.  Potential participants will be evaluated for their performance 
status, and interviewed for their medical history and concomitant medications, followed 
by a physical examination. Vital signs (oral body temperature, heart rate and blood 
pressure) will be measured. Baseline blood tests will be performed. In addition, a blood 
pregnancy test will be performed for females of child-bearing potential.  
 
Eligibility in the context of the study inclusion and exclusion criteria will be evaluated 
by the investigator. Potential participants will be asked to sign the informed consent and 
will be assigned a participant study number in a sequential order. If participants do not 
have a FDG PET/CT scan within 10 weeks and a pulmonary function test within 6 

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months prior to the scheduled date of initiation of SBRT, they will undergo a repeat 
FDG PET/CT and/or pulmonary function test at the study site, as part of standard of 
care procedures. 
 
 
5. REGISTRATION PROCEDURES  
 
5.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. 
Any participant not registered to the protocol before protocol therapy begins will be 
considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will 
complete the protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator (PI). 
If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled. Registration cancellations must 
be made in OnCore as soon as possible. 
 
5.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed.   
 
 
 
 
6. STUDY DESIGN 
6.1 
Design/Study Type 
 
This study is a non-randomized single-arm prospective study evaluating the feasibility 
of utilizing pulmonary DCE-MRI to assess for treatment response during and after 
SBRT and to guide SBRT treatment planning. The primary objective of this study is to 
test the feasibility of using pulmonary DCE-MRI scans to assess for changes in tumor 
perfusion during treatment (1-2 days after the first SBRT fraction) and after SBRT 
treatment (at 1-2 weeks and 3 months after SBRT) for early stage NSCLC.  The study 
will have a two-stage design with a preliminary assessment of feasibility after 
enrollment of 7 eligible participants (see Section 15.1, Statistical Considerations).  If 
the feasibility criteria are met, a total of 20 eligible participants will be enrolled. 
 
Secondary objectives include determining the feasibility of 1) using pulmonary DCE-
MRI to assess for lung injury 3 months after SBRT; 2) correlating ventilation changes 

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Participants will undergo pulmonary DCE-MRI at baseline before the stereotactic body 
radiation therapy, during treatment (1-2 days after the first SBRT fraction) and post-
treatment (1-2 weeks and then 3-4 months).  Pulmonary DCE-MRI scans will be 
performed per the standard protocol of the Brigham and Women’s Hospital’s 
Department of Radiology.  MR images will be obtained following the intravenous bolus 
injection of 0.1 mM/kg of body weight of gadolinium at the rate of 3 milliliters 
(mL)/second, followed by 20 mL of saline at the rate of 3 mL/second.  Each scan is 
approximately 60 minutes. 
 
The devices and software that will be used for DCE-MRI have FDA (510K) approval 
and are commercially available.   
 
Time to peak perfusion signal and enhancement ratio (defined as post- to pre-contrast 
perfusion signal) at the time of maximal parenchymal enhancement (TMPE) will be 
measured on each DCE-MRI scan.  Pharmacokinetic parameters, including the volume 
transfer constant (Ktrans), the fractional volume of extravascular extracellular space of 
the target tissue (ve), and the rate constant (kep), will be estimated by fitting a 
pharmacokinetic model to the actual time–intensity curves obtained from the DCE-
MRI. 
 
We will adopt the generalized kinetic model (Tofts, Brix et al. 1999), which is 
described as follows 
 
 dCt / dt = Ktrans (Cp – Ct / ve) =  KtransCp – kep Ct 
where   Ct : tracer concentration in tissue,  Cp : tracer concentration in arterial blood 
plasma, Ktrans : transfer constant,  ve: extravascular extracellular space fraction volume,  
kep: rate constant.  
 
The solution to the above mentioned equation with the initial condition that Cp = Ct = 0 
at t=0, is 
 
 Ct (t) =  Ktrans ∫ Cp (τ) exp( –kep(t- τ) ) dτ 
The tissue response to a short arterial pulse of concentration = 1/ (pulse duration), i.e., a 
delta function, is 
 
 h(t) = Ktransexp(-kep t) 
Thus Ktrans determines the amplitude of the initial response (the amount of tracer 
entering the extravascular extracellular space), and kep determines the washout rate from 
the extravascular extracellular space back into the blood plasma.  
The mean residence time is then: 
 
 τ = =∫0 t h(t)dt  /  ∫0 h(t)dt  

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The response to a step change in arterial plasma concentration, from 0 to Cp, at time 
t=0, is 
 
 Ct(t) = Ktrans Cp0 / kep (1- exp(-kep t)) = ve Cp0 (1- exp(-kep t)) 
The response to a step change from Cp0 to zero is 
 
 Ct(t) = Ktrans Cp0 / kepexp(-kep t) = ve Cp0exp(-kep t) 
 
During the analysis, intra-tumor heterogeneity will be corrected for using the recently 
published method of pixel-wise pharmacokinetic analysis for DCE-MRI of the lung, 
utilizing pixel-by pixel fitting (Tokuda, Mamata et al. 2011). 
 
Pulmonary DCE MRI scans will be performed at the following time points: 
 
7.2.1 Pre-treatment:  The first pulmonary DCE-MRI will be performed within 2 weeks 
prior to the start of SBRT.  Protocol DCE-MRI must begin within 4 weeks of 
registration. 
7.2.2 During SBRT MRI: 1-2 days after the first SBRT treatment (Day 2-3) 
7.2.3 Early post-SBRT MRI: 1-2 weeks after completion of SBRT 
7.2.4 Late post-SBRT MRI: 3-4 months after completion of SBRT  
7.3 
DCE-MRI Adverse Events 
As this study involves pulmonary DCE-MRI with gadolinium contrast, which is a 
FDA approved procedure, severe adverse reactions related to the study imaging 
would not be expected to occur.  Any adverse events that do occur will be 
reported to the IRB and the patient’s primary radiation oncologist.  See Appendix 
C for Adverse Event Reporting Guidelines. 
7.3.1 DCE-MRI Anticipated reactions 
 
As a consequence of participation in the study, participants may experience 
frustration or anxiety related to time spent obtaining the additional study MRI 
scans.  Participants would also be at risk of the typical reactions from MRI with 
gadolinium contrast administration: 
 
Occasional (occurring in 2 or 3 out of 100 patients): 
• Mild nausea (with or without vomiting), tingling sensation, headache, 
dizziness, coldness at the injection site, headache, warmth or pain at the 
injection site, paresthesias, dizziness, and itching 
 
Rare (occurring in 1 patient or less out of 100): 
• Severe anaphylactic reaction  

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• Severe Nephrogenic Systemic Fibrosis (NSF) in patients with chronic 
renal insufficiency 
7.4 
Description of Study 4D-CT 
 
4D-CT scanning will be performed per standard protocol in the Brigham and Women’s 
Hospital’s Department of Radiation Oncology.  4D-CT is an FDA-approved imaging 
technique in which a longer-duration CT scan is acquired that accounts for the 
breathing motion of the patient. In anatomic regions where motion is present (e.g., the 
lung), 4D-CT is better for  determining the tumor volume (Keall, Starkschall et al. 
2004) than conventional CT which is insensitive to periodic motion.  Each scan is 
approximately 15 minutes in duration. 
 
The devices and software that will be used for 4D-CT have FDA (510K) approval and 
are commercially available.   
 
Participants receive an additional radiation dose of 30 mSv-50 mSv (Murphy et al. 
2007) when subjected to a 4D-CT scan.  This dose is equivalent to 5-8 times the annual 
radiation dose to the general public (National Council on Radiation Protection and 
Measurements., National Council on Radiation Protection and Measurements. 
Scientific Committee 6-2 on Radiation Exposure of the U.S. Population. et al. 2009) 
and is not associated with deterministic effects of radiation.   
 
7.5 
4D-CT Adverse Events and Anticipated Reactions 
 
As a consequence of participation in the study, participants may experience frustration 
or anxiety related to time spent obtaining the additional study 4D-CT scan.   Additional 
adverse events due to 4D-CT are extremely rare but potentially severe: 
 
Extremely Rare (occurring in 1 patient or less out of 1000) 
• Radiation-induced tumors 
 
8. RADIATION THERAPY 
8.1 
Radiotherapy: Stereotactic Body Radiation Therapy (SBRT) 
 
All SBRT treatment planning, plan evaluation and treatment delivery will be conducted 
per the standard of care, and there is no investigational aspect to the radiotherapy 
delivered to participants on this study.  The following description is for guidance but 
the treating radiation oncologist may alter the plan if circumstances warrant after 
discussion with the Principal Investigator. 
 
8.2 
Dose Specifications: Stereotactic Body Radiation Therapy (SBRT) 

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8.2.1 Dose will be normalized such that 95% of the PTV receives the prescription dose as 
per normal treatment protocol. The minimum allowable dose within the PTV is >95% 
of the prescribed dose. 
8.2.2 Patients shall receive prescription doses to the PTV (with the above constraints). All 
attempts should be made to deliver the PTV dose with the above heterogeneity 
constraints with adherence to the critical structure parameters listed below in Table 1.  
See Section 8.6 below for specifics regarding when to implement a dose reduction. 
The final prescription dose will be recorded on a patient-by-patient basis. 
8.2.3 The treating radiation oncologist will use our standard risk-adapted SBRT treatment 
approach to select the prescription dose.  If critical-structure dose constraints are met 
(see Table 1), then the standard dose prescription would be 54 Gray in 3 fractions.  
However, if dose constraints to critical organs such as the bronchial tree and chest 
wall cannot be met at this dose prescription, than the treating radiation oncologist 
may chose to deliver the treatment over 5 fractions with a dose of 10 to 12 Gray.  
 
 
Table 1. Critical-Structure Dose Constraints 
 
Constraints for 3 Fractions  
 
 
 
 
 
   
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy) 
Spinal cord and medulla 
<0.35 cc 
<1.2 cc 
18 Gy (6 Gy/fx) 
12.3 Gy (4.1 Gy/fx) 
21.9 Gy (7.3 Gy/fx) 
Spinal cord subvolume (5-
6 mm above and below 
level treated per Ryu) 
<10% of 
subvolume 
18 Gy (6 Gy/fx) 
21.9 Gy (7.3 Gy/fx) 
Esophagus* 
<5 cc 
17.7 Gy (5.9 Gy/fx) 
25.2 Gy (8.4 Gy/fx) 
Brachial plexus 
<3 cc 
20.4 Gy (6.8 Gy/fx) 
24 Gy (8 Gy/fx) 
Heart/pericardium 
<15 cc 
24 Gy (8 Gy/fx) 
30 Gy (10 Gy/fx) 
Great vessels 
<10 cc 
39 Gy (13 Gy/fx) 
45 Gy (15 Gy/fx) 
Trachea and large 
bronchus* 
<4 cc 
15 Gy (5 Gy/fx) 
30 Gy (10 Gy/fx) 
Bronchus-smaller airways 
<0.5 cc 
18.9 Gy (6.3 Gy/fx) 
23.1 Gy (7.7 Gy/fx) 
Rib 
<1 cc 
28.8 Gy (9.6 Gy/fx) 
36.9 Gy (12.3 Gy/fx) 
Skin 
<10 cc 
30 Gy (10 Gy/fx) 
33 Gy (11 Gy/fx) 
Parallel Tissue 
Critical 
Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Lung (Right & Left) 
1500 cc 
10.5 Gy (3.5 Gy/fx) 
 
Lung (Right & Left) 
1000 cc 
11.4 Gy (3.8 Gy/fx) 
 
Liver 
700 cc 
17.1 Gy (5.7 Gy/fx) 
 
*Avoid circumferential irradiation 
 
Constraints for 5 Fractions  
 
 
 
 
 
 
   
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy) 
Spinal cord and medulla 
<0.35 cc 
<1.2 cc 
23 Gy (4.6 Gy/fx) 
14.5 Gy (2.9 Gy/fx) 
30 Gy (6 Gy/fx) 
Spinal cord subvolume (5-
<10% of 
23 Gy (4.6 Gy/fx) 
30 Gy (6 Gy/fx) 

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6 mm above and below 
level treated per Ryu) 
subvolume 
Esophagus* 
<5 cc 
19.5 Gy (3.9 Gy/fx) 
35 Gy (7 Gy/fx) 
Brachial plexus 
<3 cc 
27 Gy (5.4 Gy/fx) 
30.5 Gy (6.1 Gy/fx) 
Heart/pericardium 
<15 cc 
32 Gy (6.4 Gy/fx) 
38 Gy (7.6 Gy/fx) 
Great vessels 
<10 cc 
47 Gy (9.4 Gy/fx) 
53 Gy (10.6 Gy/fx) 
Trachea and large 
bronchus* 
<4 cc 
16.5 Gy (3.3 Gy/fx) 
40 Gy (8 Gy/fx) 
Bronchus-smaller airways 
<0.5 cc 
21 Gy (4.2 Gy/fx) 
33 Gy (6.6 Gy/fx) 
Rib 
<1 cc 
35 Gy (7 Gy/fx) 
43 Gy (8.6 Gy/fx) 
Skin 
<10 cc 
36.5 Gy (7.3 Gy/fx) 
39.5 Gy (7.9 Gy/fx) 
Parallel Tissue 
Critical 
Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Lung (Right & Left) 
1500 cc 
12.5 Gy (2.5 Gy/fx) 
 
Lung (Right & Left) 
1000 cc 
13.5 Gy (2.7 Gy/fx) 
 
Liver 
700 cc 
21 Gy (4.2 Gy/fx) 
 
*Avoid circumferential irradiation 
 
 
Constraints for 3 or 5 Fractions 
Serial Tissue 
Dose-Volume 
Histogram 
Parameter 
Constraint 
Lung (Right & Left) 
V20 
<10% 
Lung (Right & Left) 
V10 
<12% 
Lung (Right & Left) 
Mean lung dose 
4 Gray 
Chest wall 
V30 
< 30 cc 
 
 
8.3 
Technical Factors: Stereotactic Body Radiation Therapy (SBRT) 
8.3.1 SBRT will be delivered with linear accelerators at energies ≥6 MV. 
8.3.2 SBRT immobilization, simulation, planning, localization, and image-guidance will be 
utilized in all participants per standard clinical care as described below.   
8.3.3 SBRT may be delivered using 3D-conformal or volumetric modulated arc therapy 
(VMAT) techniques per standard clinical care as described below.   
8.4 
SBRT Localization, Simulation, and Immobilization 
 
Participants will be simulated using four-dimensional computed tomography (4DCT), 
which incorporates tumor motion into planning. The free-breathing scan will be 
performed with 2.5 mm slice thickness, and the use of contrast at the time of simulation 
is preferred if feasible, which is our departmental standard protocol for lung 
simulations. Patients will be simulated in the Elekta Stereotactic frame or similar 
stereotactic custom immobilization device for stabilization and setup reproducibility. 
Abdominal compression will be used if the tumor moves more than 1 cm with 
respiratory motion.  Target volumes and normal critical structures will be defined in the 

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slices in which they are visualized. The 3D conformal cases must utilize “beam’s eye 
view” representations to define final beam aperture. 
8.5 
Treatment Planning/Target Volumes 
8.5.1 The definition of volumes will be in accordance with the ICRU Report #50: 
Prescribing, Recording, and Reporting Photon Beam Therapy. 
8.5.1.1 The Gross Tumor Volume (GTV) is defined by the physician as 
all known disease as defined by the planning CT.  The internal 
target volume (ITV) will include the GTV and the movement of 
the GTV as measured by 4D-CT. 
8.5.1.2 The Planning Target Volume (PTV) will provide a margin 
around the ITV to compensate for the variability of treatment set 
up and internal organ motion. A margin of 5 mm around the ITV 
is required to define each respective PTV. Superior and inferior 
margins (capping) should be 5-10 mm depending on the 
thickness 
and 
spacing 
of 
the 
planning 
CT 
scan.  
 
8.5.1.3 The ICRU Reference Points are to be located in the central part 
of the PTV and, secondly, on or near the central axis of the 
beams. Typically these points should be located on the beam 
axes or at the intersection of the beam axes. 
8.5.1.4 Normal Critical Structures to be defined on the treatment 
planning CT scan will include the following:  All structures will 
be contoured in their entirety as solid organs. See the ITC web 
site (http://atc.wustl.edu) to view examples of target and normal 
tissue contours. 
8.5.1.5 The PTV forms the entire target as described. 3D conformal 
beams will be shaped to include the entire PTV and minimize 
dose to surrounding critical structures as described. Intensity 
modulated radiotherapy (IMRT) using inverse planning is 
permitted with constraints placed to adhere to critical structure 
dose limitations as defined above. 
8.6 
Critical Structures  
Critical-structure dose constraints shall remain consistent with Table 1 above. While 
every effort should be made to deliver prescription doses to the PTV as specified while 
adhering to these constraints, it is recognized that certain anatomical factors may prevent 
this.  A dose reduction should be considered at the discretion of the treating radiation 
oncologist (for instance, in the case of an increase in critical-structure volume greater 
than 5% receiving more than the specified dose). 

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8.7 
Treatment Verification  
8.7.1 Per standard clinical treatment protocols, prior to each SBRT treatment, localization 
will include initial alignment to infrared markers attached to the stereotactic board.  
On-line target localization will then be performed first by using kV imaging with the 
ExacTrac system, and then by cone beam CT.  The use of image guidance or daily 
target localization including the specific type implemented must be documented by 
the treating physician per normal clinical practice. 
8.7.2  Management of Radiation Dose to the Patient from Daily Localization 
According to the literature, the estimates of patient dose per imaging study for 
various imaging systems vary considerably. The doses are in the range of 0.1 cGy 
for BrainLab’s ExacTrac planar kV-systems and can be considered negligible 
compared with doses from MV portal imaging and kV and MV CT. The doses from 
kV cone beam CT on Elekta Synergy machine are estimated to range from 1 to 3 
cGy.  Thus, the doses for 3D imaging systems used one time each day are in the 
range of 0.1 to 10 cGy and can contribute from 0.006 to 0.6% to a daily dose of 18 
Gy. As a technique of controlling patient dose, it is recommended that a QA 
procedure be established at each institution to verify the accuracy of the image 
registration software on a daily basis. This QA check should be performed by the 
therapists operating a particular treatment device and is aimed at reducing the use of 
repeat imaging to check that the registration software has functioned properly when 
a shift of patient position is carried out. Additionally, it is not recommended that an 
institution use a daily imaging technique that delivers greater than 3 cGy/dy to the 
patient. This limit dictates that repeat imaging on a particular day is held to a 
minimum when systems that deliver up to 3 cGy per study are used. 
8.8 
Quality Assurance 
8.8.1 Documentation Requirements 
The institution will archive treatment prescription and verification images for later 
review as per standard practice. 
8.9 
Radiation Quality Assurance Reviews  
Since there are no experimental components to radiation therapy on this study, SBRT 
treatment plans will be subject to standard peer-review and departmental quality 
assurance reviews per departmental standards.  RT quality assurance reviews will be 
facilitated by the study chair. 
8.10 Radiation Adverse Events 
8.10.1 All participants will be seen at each SBRT treatment and 1 week after treatment by 
their treating radiation oncologist. Any observations with respect to the following 
symptoms/side effects will be recorded: 

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Immediate Reactions  
 
Long Term Reactions 
 
Common: 
 
Common: 
  
• 
Moderate tiredness 
• 
Moderate skin reddening & irritation 
 
• 
Mild to moderate cough 
• 
Mild to moderate trouble swallowing/sore throat 
 
• 
Mild decreased blood cell count 
• 
Mild temporary loss of hair in the treated area 
 
  
• 
Mild scarring of the lung, not requiring treatment 
 
• 
Mild shortness of breath 
 
• 
Mild dryness of the skin in the area of treatment 
  
Uncommon 
 
Uncommon 
 
• 
Moderate inflammation of the lung 
 
• 
Moderate scarring or inflammation of the lung requiring 
treatment 
 
• 
Mild to moderate inflammation of the heart 
 
• 
Mild permanent darkening of the skin 
 
• 
Mild to moderate cough 
 
• 
Rib fracture causing moderate pain 
 
• 
Mild to moderate inflammation of the muscle of the 
chest wall 
 
 
Rare: 
 
Rare: 
 
• 
Mild to moderate nausea   
 
• 
Severe brachial plexus injury 
 
 
Extremely Rare: 
 
Extremely Rare: 
 
  
• 
Severe swallowing difficulties requiring surgery  
• 
Heart attack (severe) 
 
• 
Severe nerve damage 
• 
Severe spinal cord injury 
 
• 
Fatal inflammation or scarring of the lungs 
• 
Tumors caused by radiation 
 
 
 
8.10.2 Clinical discretion may be used in managing radiotherapy-related side effects. 
8.11 Radiation Adverse Event Reporting 
See Appendix B for Adverse Event Reporting Guidelines. 
 
9. DRUG THERAPY 

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N/A 
 
10. SURGERY 
N/A 
 
11. OTHER THERAPIES  
 
As per standard clinical care, participants that require pre-medication for anxiety or 
claustrophobia prior to MRI may be given lorazepam 0.5-1 mg by mouth (or equivalent 
medications) prior to the MRI at the discretion of the treating physician.  As per standard 
clinical care, participants will be pre-medicated with a single dose of dexamethasone 4 
milligrams by mouth the morning prior to each SBRT treatment.  Participants may receive 
medications for management of potential expected adverse effects secondary to SBRT per 
standard clinical care.    
 
12. TISSUE/SPECIMEN SUBMISSION  
N/A 
 
13.  PATIENT ASSESSMENTS  
13.1 Schedule of Patient Assessments 
 
 
 
See Table of patient assessments in Section 7.1. 
13.2 Study Pulmonary DCE-MRI 
The participants will undergo a pulmonary DCE-MRI prior to SBRT, during SBRT (1-
2 days after the first SBRT treatment) and then two post-treatment DCE-MRI scans, 
the first within 1-2 weeks after the final treatment and then 3-4 months after SBRT.  
13.3 PET-CT and PFT 
As part of the standard pre-treatment work-up, participants will undergo a baseline 
PET-CT and PFT, and then repeat studies 3-4 months after completion of the SBRT 
treatment.  The PFTs will include forced expiratory volume in 1 second (FEV1), forced 
vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) 
will be measured. 
13.4 Blood Tests 
Each participant will have a BUN and creatinine sent within three weeks of each of the 
four DCE-MRI scans to document eligibility to receive gadolinium contrast based on 
renal clearance per the eligibility criteria (Section 3.2.4).  If the estimated glomeular 
filtration rate is < 30 mL/min/1.73 m2 the participant will not receive gadolinium contrast 
and will not undergo the scheduled DCE-MRI at that time point and will be re-evaluated 

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with repeat BUN and creatinine at the next time point.  A serum pregnancy test will be 
obtained in the baseline blood tests if the participant is a female of child-bearing age.  
13.5 History and Physical Exam 
For the baseline visit, a complete history and physical exam will be done to determine 
eligibility for the study.  At subsequent visits, focused history and physical exams will 
be performed to assess for side effects of SBRT treatment as per standard care.  
 
14. DATA COLLECTION 
14.1 Data Reporting Methods 
The QACT will collect, manage, and monitor data for this study. Note: All adverse 
events that have occurred on the study, including those reported through AdEERS, 
must be reported via CTMS or CDUS. 
14.2 QACT Data Submission 
The schedule for completion and submission of case report forms (paper or electronic) 
to the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 21 days of registration 
Adverse Event Report Form 
Within 14 days of completing last DCE-MRI 
scan 
Off Study Form  
Within 21 days of completing last DCE-MRI 
or being taken off study for any reason 
14.3 Study Imaging Data Elements 
 
Pulmonary DCE-MRI and 4D-CT data will be transferred electronically to the Hatabu 
and Lewis laboratories for analysis of tumor and lung parenchyma perfusion.   
Additionally, images will be imported into our departmental radiation treatment 
planning software for further analysis of the utility of the pulmonary DCE-MRI and 
4D-CT data for SBRT treatment planning. Images will be identified only by a study ID 
number. The patient’s identifying information (name, MR#, DOB) will be removed 
before the images are transferred.  
 
Routine clinical data such as demographics, performance status, disease status and 
treatment characteristics will be obtained at baseline and at each subsequent clinic visit 
when a research scan is obtained.  This clinical data is all collected as part of standard 
of care for follow-up visits. It does not contain any study-specific procedures or 
information. Thus, non co-investigator MDs or NPs may perform the exam and collect 
the data in standard consultation and follow-up notes.  The standard of care studies 

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including PET-CT, PFTs, and pathology reports will be obtained from the electronic 
medical record. 
 
Radiation treatment for this protocol is exactly the same as it would be if the participant 
were not enrolled on the protocol.  Radiation treatment data such as dose, dose per 
fraction, number of fractions and dose-volume histogram data will be obtained from the 
radiation oncology electronic archives. 
14.4 Timing of Collection of Data Elements 
 
Scan data will be transferred to the cooperating labs for analysis within a month of the 
scan date.  All other data will be transcribed from the clinical records within a month of 
the last protocol-related treatment/examination. 
 
14.5 Data Storage and Protection 
Non-image data will be maintained in a web-based REDCap database developed 
specifically for this study. The REDCap database is password-protected. The PI will 
grant permission for specific study staff to have access to the portion of data pertinent 
to their role on the study. 
 
Imaging data will be securely transferred to the Hatabu and Lewis laboratories, where 
they will be stored in a password protected data archive housed behind the Partner's 
firewall. The MRI data to be transferred will be coded with the subject’s study ID and 
not by name, to ensure confidentiality. 
14.6 Data and Safety Monitoring 
 
 The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 
The DSMC will meet annually and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; all grade 2 or higher unexpected adverse events that have been 
reported; audit results, and a summary provided by the study team. Other information 
(e.g. scans, laboratory values) will be provided upon request.  
  
15. STATISTICAL CONSIDERATIONS  
15.1 Study Design/Endpoints 
The primary objective of this study is to determine the feasibility of utilizing pulmonary 
DCE-MRI to assess changes from baseline in tumor perfusion during SBRT treatment 

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(after 1 fraction of SBRT), and 1-2 weeks and 3-4 months after completion of SBRT 
treatment for stage I NSCLC.  Feasibility (success) is defined as successfully 
enrolling patients, processing the pulmonary DCE-MRI data, and observing 
an analyzable change in tumor perfusion between the pre-treatment DCE-
MRI and any of the DCE-MRI scans during SBRT (after 1 fraction) or after 
completion of SBRT treatment.   Analyzable change will be defined as a 20% 
change in tumor perfusion.  A recent publication by Ng et al reported the rate 
of reproducibility of DCE-MRI parameters was between 10-20% (Ng, Raunig 
et al. 2010), and we have chosen the upper limit of this range to be 
conservative. 
 
A total of 20 participants with stage I NSCLC will be enrolled on this study, and a 
two-stage design will be used.  Seven eligible participants in the first stage and 10 
eligible participants in the second stage will be accrued. To allow for participants that 
are unable to complete scans and/or are ineligible to continue on the study, 3 additional 
participants will be accrued, so up to 8 participants in stage I and 12 participants in 
stage II will be accrued to this study.  If at least 5 successes are observed among the 
7 eligible participants in the first stage, up to an additional 12 participants (10 
eligible) will be entered.  If 14 or more successes are observed among the 17 
eligible participants, utilizing pulmonary DCE-MRI to assess changes in tumor 
perfusion will be considered feasible for this group.  With this design, there is a 
90% probability of declaring the pilot study feasible if the true feasibility rate is 
90%, and a 10% probability of declaring the DCE-MRI worthy of further study if 
the true feasibility rate is 65%.  With 17 eligible participants, we have 90% power 
to detect a difference of 0.75 standard deviation in the change of tumor perfusion 
from baseline (prior to SBRT treatment) to post treatment (either right after SBRT 
treatment or 3-4 months after SBRT treatment) using a 0.1 level two-sided 
Wilcoxon signed-rank test. 
After stage I accrual is met, the pulmonary DCE-MRI data will be reviewed. If the 
changes in tumor perfusion could only be observed in one or two of the scans 
during and after treatment compared to the pre-SBRT scan, patients enrolled in the 
2nd stage won’t be required to undergo all three during and after treatment 
pulmonary DCE-MRIs and only the time points with useful information will be 
obtained to save resources. 
15.2 Sample Size/Accrual Rate 
Twenty participants will be enrolled in this pilot study.  We estimate that 
approximately 20 patients a year would meet the eligibility criteria for enrollment on 
this study.  Assuming that one third of the eligible patients would consent to enrolling 
on the study, the accrual rate would be 6 patients per year and accrual will be complete 
within 3.5 years.  After the last post-treatment DCE-MRI scan (3-4 months after 
treatment), participants will be off study, but will continue to undergo follow-up per 
standard care.  Thus, the study will be complete after 4 years. 
15.3 Stratification Factors 

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None 
15.4 Analysis of Secondary Endpoints 
Secondary endpoints include the feasibility of pulmonary DCE-MRI in characterizing 
acute and subacute radiation-induced lung injury after SBRT as well as the feasibility 
of using pulmonary DCE-MRI to identify regions of functional lung for SBRT 
treatment planning.  The feasibility rates of these two endpoints will be calculated 
along with a 95% confidence interval based on the binomial distribution, and the 
confidence interval will be no wider than 50%.   
15.4.1 To evaluate the feasibility of pulmonary DCE-MRI in characterizing acute (1-2 
weeks) and subacute (3 months) radiation-induced lung injury after SBRT, and 
correlate these findings with clinical outcomes.  Feasibility (success) is defined as 
successfully enrolling patients, processing the pulmonary DCE-MRI data, 
and observing an analyzable change in lung perfusion on the 3-month scan. 
15.4.2 To evaluate the feasibility of integrating 4D-CT ventilation imaging with DCE-MRI 
perfusion imaging in characterizing subacute (3 months) radiation-induced lung 
injury after SBRT.  Feasibility (success) is defined as successfully enrolling 
patients, processing the pulmonary DCE-MRI and 4D-CT data, and 
observing an analyzable change on the 3-month scan. 
15.4.3 To determine the feasibility of using pulmonary DCE-MRI to identify regions of 
functional lung for planning SBRT for peripheral lung tumors.  Feasibility will be 
defined as the ability to perform a retrospective comparative treatment planning 
study using the DCE-MRI images acquired prior to treatment for each 
participant. Regions of functional and non-functional lung will be defined on each 
MRI, and the images will be registered to the 4DCT used for treatment planning. The 
functional-lung contours will be transferred to the 4D-CT based on this registration. 
The target volume and other critical structures will be defined as per standard 
treatment protocol, as described in Section 6 of this document. In addition to the 
normal-tissue constraints outlined in Section 6, the treatment plan will attempt to 
maximize sparing of functional-lung regions while maintaining adequate target 
coverage and not exceeding other normal-tissue constraints. The functional-lung 
based treatment plans generated in this manner will be compared to the corresponding 
standard plans that were used to treat the patient. Changes in the functional-lung V20 
and V5 will be used to analyze changes in functional-lung sparing. 
 
15.5 Reporting and Exclusions 
15.5.1 Evaluation of toxicity. All participants will be evaluable for toxicity from the time 
of their first DCE MRI. 
15.5.2 Evaluation of primary endpoint.  All participants who undergo a pre-treatment 
DCE-MRI and at least one post-treatment DCE-MRI will be included in the study.   

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15.5.3 Stopping Rules.  There is no experimental component to the radiation treatment or 
radiological imaging (both SBRT and the DCE-MRI are utilized in routine clinical 
care).  However, the study will be stopped if preliminary study results determine that 
it is not feasible to utilize DCE-MRI to achieve any of the primary or secondary 
objectives including assessing tumor perfusion (primary objective) and lung injury or 
assisting SBRT treatment planning. 
 
16. REGULATORY CONSIDERATIONS 
16.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
16.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
16.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  

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• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr11 02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC 
research 
policies 
and 
procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
16.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
16.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
 

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17. PUBLICATION PLAN 
We intend to publish the results of this study in a peer-reviewed journal, and the principal 
investigator will be responsible for publication of the study results.  The preliminary results, 
which may be presented in an abstract at a professional meeting, will be made public within 
24 months of the end of data collection.  A full report of the outcomes will be made public 
no later than three (3) years after the end of data collection.  
 
18. REFERENCES  
 
Abratt, R. P. and P. A. Willcox (1995). "The effect of irradiation on lung function and perfusion 
in patients with lung cancer." Int J Radiat Oncol Biol Phys 31(4): 915-919. 
Allen, A. M., M. Albert, et al. (2011). "Can Hyperpolarized Helium MRI add to radiation 
planning and follow-up in lung cancer?" J Appl Clin Med Phys 12(2): 3357. 
Bates, E. L., C. M. Bragg, et al. (2009). "Functional image-based radiotherapy planning for non-
small cell lung cancer: A simulation study." Radiother Oncol 93(1): 32-36. 
Boersma, L. J., E. M. Damen, et al. (1995). "Estimation of overall pulmonary function after 
irradiation using dose-effect relations for local functional injury." Radiother Oncol 36(1): 
15-23. 
Cai, J., R. McLawhorn, et al. (2011). "Helical Tomotherapy Planning for Lung Cancer Based on 
Ventilation Magnetic Resonance Imaging." Med Dosim. 
Cai, J., K. Sheng, et al. (2007). "Evaluation of Lung Tumor Response to Stereotactic Body 
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19.0 Appendices 
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 

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Appendix B: Adverse Event Reporting Requirements 
 
Definitions 
Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more sever form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 

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Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
• respite care 
 
Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   
 
Refer to protocol Sections 6 and 7 for a listing of expected adverse 
events associated with the study therapy. 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 

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Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal 
investigator, each participating investigator is required to abide by the reporting 
requirements set by the DF/HCC. The study must be conducted in compliance with 
FDA regulations, local safety reporting requirements, and reporting requirements of the 
principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that 
institution to their respective IRB. It is the responsibility of each participating 
investigator to report serious adverse events to the study sponsor and/or others as 
described below 
 
Reporting to the Study Sponsor 
Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the DF/HCC Overall Principal Investigator on the local institutional SAE form. 
This includes events meeting the criteria outlined above, as well as the following: 
 
• Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention. 

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• All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
• All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  
 
Participating investigators must report each serious adverse event to the DF/HCC 
Overall Principal Investigator within 24 hours of learning of the occurrence. In 
the event that the participating investigator does not become aware of the serious 
adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it 
and document the time of his or her first awareness of the adverse event. Report 
serious adverse events by telephone, email or facsimile to: 
 
 
 
Raymond H. Mak, M.D. 
 
 
  
 
 
 
 
 
 
 
 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information should 
describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study 
participation. 
Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms.   
Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the 
DFCI Office for Human Research Studies (OHRS). 
 
Other investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events. A 
copy of the submitted institutional SAE form should be forwarded to: 
 
 
 
Raymond H. Mak, M.D.