A Volume, Motion, and Anatomically Adaptive Approach to Photon and Proton Beam Radiotherapy
Phase: NA
Conditions: Biopsy Proven Non Small Cell Lung Cancer, Head and Neck Cancer, Gastrointestinal Cancer, Colorectal Cancer, Rectal Cancers, Gynecological Malignancy Requiring Definitive Radiotherapy
Sponsor: Abramson Cancer Center at Penn Medicine

 
 
 
 
 
 
 
 
 
Quantification of Tumor and Organ at Risk (OAR) Volume and Motion 
Path Changes during Definitive Photon or Proton Beam Radiotherapy 
 
Protocol #:   
 
IRB# 810302 / UPCC# 08909 
 
Principal Investigators: 
 
 
Charles B. Simone, II. MD 
Assistant Professor 
Department of Radiation Oncology 
Perelman Center for Advanced Medicine 
3400 Civic Center Boulevard 
Philadelphia,  PA  19104 
(215)662-3998 
charles.simone@uphs.upenn.edu 
 
James McDonough PhD 
Associate Professor 
Division of Medical Physics 
Department of Radiation Oncology 
Perelman Center for Advanced Medicine 
3400 Spruce Street 
Philadelphia, PA 19104 
(215) 615-5632 
mcdonough@xrt.upenn.edu 
 
Sub-Investigators: 
Michelle Alonso-Basanta, MD, PhD        Lilie Lin, MD 
Smith Apisarnthanarax, MD                     Robert Lustig, MD 
Keith Cengel, MD, PhD                            James Metz, MD 
John Christodouleas, MD, MPH               John Plastaras, MD PhD 
Jay Dorsey, MD, PhD                               Eli Glatstein, MD                
Zelig Tochner, MD                                   Stephen Hahn, MD              
Neha Vapiwala, MD                                 Ali Kasseea, PhD 
Alex Lin, MD                                            Richard Maughan, PhD   
Nathan Anderson, MA                              Kevin Teo, PhD 
Michael Bieda, MA                                  Timothy Zhu, PhD  
Stefan Both, PhD                                        
Jarod Finlay, PhD                                       
Edgar Ben-Josef, MD 
Statistician: 
Rosemarie Mick 
 
 
 
Date: 
11/13/2009 
Amended: 
05/10/2010   12/18/2013 
Amended: 
06/08/2010 
Amended: 
08/13/2010 
Amended: 
Amended: 
 
10/04/2010 
2/21/2011 
06/06/2011 
06/24/2011 
1/20/2012 
08/13/2012 
03/28/2013 
CONFIDENTIAL This document is confidential and the property of the University of Pennsylvania.  No part of it may be transmitted, 
reproduced, published, or used by other persons without prior written authorization from the study sponsor. 

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Table of Contents  
 
List of Abbreviations 
 
Protocol Overview (including Schema) 
 
1.0 
Abstract 
 
2.0  
Background and Significance 
 
3.0 
Specific Aims/Objectives 
 
4.0 
Study Overview 
 
5.0 
Participant Selection 
 
6.0 
Study Procedures and Risks 
 
7.0 
Data Collection and Management 
 
8.0 
Adverse Events 
 
9.0 
Statistical Considerations 
 
10.0     Medical Monitor 
 
11.0     Records Retention 
 
12.0 
Study Monitoring, Auditing and Inspecting 
 
13.0 
Ethical Considerations 
 
14.0 
Study Finances 
 
15.0 
Publication Plan 
 
16.0 
References 
 
 
 

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List of Abbreviations 
 
4D:  4 Dimensional 
3D:  3 Dimensional 
CT scan:  Computed tomography scan 
MR Scan: Magnetic Resonance Imaging Scan 
NSCLC:  Non Small Cell Lung Cancer 
SCLC:  Small Cell Lung Cancer 
SUV value:  Standardized Uptake Values 
Gy:  Gray 
CTV:  clinical tumor volume  
PTV:  planning target volume 
GTV:  gross tumor volume 
ITV:  internal tumor volume  
PI:  Principal Investigator 
AE:  Adverse Event 
SAE:  Serious Adverse Event 
GI:  Gastrointestinal 
IRB:  Institutional Review Board 
ORP:  Office of Research Protection 
HRPO:  Human Research Protection Office

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Quantification of Tumor and Organ at Risk (OAR) Volume and Motion 
Path Changes during Definitive Photon or Proton Beam Radiotherapy 
 
PROTOCOL OVERVIEW 
 
In recent years, conformal techniques have been developed that allow for precise delivery of 
radiotherapy to the primary tumor and regional lymphatics while minimizing the dose to normal 
tissues. These approaches are predicated upon precise anatomic localization of the regions to be 
irradiated. Unfortunately, at present, most conformal treatment delivery approaches do not account 
for changes in tumor volume, tumor motion or changes in patient anatomy during the time course 
of definitive radiotherapy. Proton beam radiotherapy can potentially allow for ultra-precise delivery 
of treatment due to the physical characteristics of the proton beam. Therapeutic proton beam 
radiotherapy allows for the elimination of exit dose and a significant reduction in the entrance dose 
to the patient while maximizing dose delivered to the tumor (Figure 1). However, accurate treatment 
delivery with proton beam radiation is predicated upon precise definition of tumor volume and 
location. Tumor volume reduction during definitive proton beam radiotherapy has resulted in 
significant dosing errors, with dose deposition in unintended regions (MDACC PTCOG 47). The 
purpose of this protocol is to quantify the extent of tumor volume, motion, and anatomic changes 
that occur during the tumor course of definitive photon beam radiotherapy. As both proton beam 
and photon beam radiotherapy have nearly identical biological efficacy, the changes observed during 
photon beam radiotherapy should closely approximate that which would likely be observed during 
proton beam irradiation.  
 
 

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Figure 1: Comparison of Dose Deposition between Photon and Proton Beam Radiotherapy 
 
SPECIFIC AIMS/OBJECTIVES  
 
Overall Aim 
To estimate the degree of tumor volume, tumor motion, and patient anatomy changes that occur 
during the time course of definitive photon and proton beam radiotherapy.  We further intend to 
quantify the dosimetric error that would occur in patients receiving proton beam radiotherapy if 
these changes are not accounted for. 
 
Primary Aim 
To estimate the degree of tumor volume, tumor motion and patient anatomy change during 
treatment with photon beam radiotherapy using 4D or 3D CT Scans and/or a serial of MR Imaging.  
 
Secondary Aims 
To utilize the data generated from the photon or proton beam patients to simulate and estimate the 
degree of error if tumor volume, tumor motion path and patient anatomy changes are unaccounted 
for during treatment with proton beam radiotherapy by generating simulated serial proton plans with 
this data. 

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METHODS/METHODOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline/Eligibility* 
Informed consent 
History/Physical as per standard of care 
Staging Studies as per standard of care  
Study enrollment 
Radiation Treatment Planning 
3D or 4D CT Photon Treatment Plan, 
3D or 4D CT Proton Treatment Plan, 
and/or Baseline MR Scan per best 
clinical practices and at the discretion of 
the treating physician. 
Radiation Therapy Guidelines 
Definitive treatment (with or without 
chemotherapy)  per appropriate 
standard of care for the primary 
tumor  
Follow-up 
As per standard of care 
During RT 
Up to weekly 3D or 4D CT and/or 
MR Scan (minimum of 3) 
If contrast, blood draw prior to 
each scan 

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*Baseline/eligibility procedures, including informed consent, may occur at any time  
from consultation until radiation therapy treatment begins.  
 
All subjects’ data will receive a standardized analysis.  A descriptive analysis will be performed 
to determine tumor volume changes, tumor motion changes and patient anatomy changes.  We 
will also evaluate the variations in the dose distribution to targeted volumes and normal tissues 
that occur with tumor and patient anatomy changes.  These variations in dose distribution will be 
compared between photon treatment plans and proton treatment plans.   
 
ELIGIBILITY 
• 
Patients with biopsy proven NSCLC, SCLC, Head and Neck Cancer, Gastrointestinal 
cancer (including but not limited to colorectal and rectal cancers), or Gynecological malignancy 
requiring definitive radiotherapy with or without chemotherapy. 
 
REQUIRED SAMPLE SIZE   
• 
30 patients per treatment site for a total of 120 patients. 
 
STUDY DESIGN  
• 
This is a pilot study to evaluate the changes in tumor volume, tumor motion, patient 
anatomy and dose distribution during the course of radiation treatment using up to weekly CT 
and/or MR Scans with the potential usage of contrast during the imaging procedure.  We will 
analyze the effect of tumor changes and patient anatomy changes on radiation treatment efficacy. 
 
 
 

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1.0 
ABSTRACT  
 
In recent years, conformal techniques have been developed that allow for precise delivery 
of radiotherapy to the primary tumor and regional lymphatics while minimizing the dose 
to normal tissues. Unfortunately, at present, most conformal treatment delivery 
approaches do not account for changes in tumor volume, tumor motion or changes in 
patient anatomy during the time course of treatment. Studies have shown that lung, head 
and neck, and gynecological tumors can change significantly during radiation treatment.  
Patients can lose significant weight during the radiation treatment, which can alter the 
patient’s body habitus and anatomy.  These tumor and anatomical changes can alter 
radiation dose distribution, resulting in higher radiation doses to normal tissue and lower 
radiation doses to target volumes.  Adapting for changes in tumor motion, tumor volume 
and patient anatomy can therefore enhance radiation treatment efficacy and widen the 
therapeutic ratio.  Because proton beams require precise target definition, accounting for 
tumor changes should be critical when using proton beam radiation treatment.   
 
This is a pilot study to quantify the tumor and organ at risk volume and motion path 
changes that occur during definitive proton beam or photon beam radiotherapy.  The 
patients will undergo CT scans in treatment planning position at the time of CT 
Simulation.  Photon beam treatment plans and proton beam treatment plans will be 
generated from these images.  Based on the location of the primary tumor, patients will 
undergo either up to weekly 3D or 4D CT and/or a serial of MR scans during treatment.  
These images will be compared to the initial CT and/or MR scans used for treatment 
planning and analyzed for changes in tumor volume and tumor anatomic location.  At the 
end of treatment, the /serial images will be compared to the initial treatment planning 
images to quantify the changes in tumor volume and tumor motion during the course of 
radiation treatment.  Each CT and/or MR scan will also be used to evaluate the changes 
in dose distribution to the target volumes and normal tissues that occur with the initial 
photon treatment plan and initial proton treatment plan.  The changes in tumor volume, 
tumor motion and dose distribution during the course of radiation treatment will be 
analyzed to determine the effect of tumor changes on radiation treatment efficacy.   
 
2.0 
BACKGROUND AND SIGNIFICANCE 
 
Radiation therapy is a form of treatment used to control many cancers including lung 
cancers, head and neck malignancies, cancers of the gastrointestinal tract and 
gynecological cancers.  One important challenge of radiation treatment is the balance 
between delivering adequate radiation dose to the tumor while controlling for radiation 
induced toxicity.  Radiation induced toxicity is caused by incidental radiation delivery to 
critical normal structures in proximity to the tumor.  The amount of incidental radiation 
dose is dependent upon the tumor volume, location and margins needed to account for 
planning and setup error.  The volumes are determined during radiation treatment 
planning and are based on patient imaging done during a simulation appointment prior to 
radiation treatment.  In cancers with a propensity for movement secondary to respiratory 
motion, such as lung, and some gastrointestinal cancers, 4D CT planning is often 
implemented.  This form of image guided treatment planning takes into account 

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respiratory motion when calculating appropriate target volume margins.  The distal 
esophagus can move 0.8cm radially and 1.8cm axially (Yaremko) and the pancreas can 
move 2.4 +/- 1.6 cm axially (Bussels).  Lung tumors are significantly affected by 
respiratory motion and move 5-10 mm during quiet breathing and as much as 4.5 cm 
(Stevens) with deeper breaths. Therefore, accounting for respiratory motion can be 
extremely important for targeted radiation therapy. 
 
The course of radiation treatment often lasts longer than 8 weeks.  For patients with head 
and neck and gastrointestinal cancers, maintaining adequate nutrition during this time can 
be challenging.  Studies have shown that about 35% of patients with head and neck 
cancers experience >10% weight loss and patients with gastrointestinal cancers 
experience weight loss ranging from 0-12% (Milano, Talamonti, Lin).  Significant weight 
loss results in changes in patient anatomy, which can distort radiation dose distribution 
and therefore treatment efficacy.   
 
In addition to patient anatomy the size of the tumor as well as the anatomic location of 
the tumor are subject to change during radiation treatment.  Fox et al. demonstrated a 
median GTV reduction of 44.3% at 50Gy in patients with non-small cell lung cancer.  
Head and neck cancers and cervical cancers are particularly sensitive to radiation effects.  
Barker et al. demonstrated a 69.5% reduction in GTV volume with a median mass 
displacement of 3.3mm at the end of radiation treatment in patients with head and neck 
cancers.  Cervical cancers have a median mid treatment regression rate of 69% at 36-
45Gy when treated with radiation alone and 79% when treated with concurrent 
chemoradiation (Nam).  The resulting anatomic changes during radiation treatment can 
have a significant impact on dosimetric distributions, resulting in inadequate dose 
delivery to the tumor even with 4D CT image guided radiotherapy planning (Britton).  
Britton et al. evaluated the dosimetric consequences of anatomic changes during 
conformal photon beam radiotherapy for 10 patients with NSCLC using weekly 4D CT 
Scans.  The authors noted a substantial decrease (-20.5%) in the PTV dose coverage and 
variable increases in dose to normal tissue structures such as the lung, spinal cord, 
esophagus and heart.  These variations were due to inter and intrafractional variations 
during treatment. 
 
Ideally, one would account for both inter-and intrafraction variability on a daily basis or 
after a given number of fractions. (Vanuytsel, Vansteenkiste et al. 2000) This could 
widen the therapeutic ratio by maximizing dose to the tumor and protecting critical 
normal structures. Harsolia et al. found that in the treatment of patients with NSCLC, 
daily respiratory motion and tumor volume correction yielded the maximal decrease in 
treatment volumes (44% reduction) and the maximal decrease in volume normal lung 
irradiated (31% reduction) and mean lung dose (31% reduction).  
 
At present, the standard of care is to base the entire course of radiation treatment upon the 
initial treatment plan, which is derived from the pre-treatment scan. It is easy to envision 
that treatment re-planning to adjust for anatomical changes may be necessary during the 
course of radiation treatment.  The overall objective of this study is to determine the 

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extent of tumor volume, tumor motion and patient anatomy variation during radiation 
treatment.   
 
While tumor anatomic changes are important in radiation treatment with photon therapy, 
these factors are of particular concern when implementing proton therapy.  Unlike photon 
beams, proton beams can deliver radiation that enters the body at low doses, but then 
uniformly delivers high doses of radiation to the tumor followed by a steep fall-off exit 
dose.  These features allow high doses of radiation to be delivered to the primary tumor, 
with lower toxicity to normal tissue.  Because of the sharp demarcations between low 
dose and high dose areas, proton therapy requires accurate delineation of the primary 
tumor in order to deliver adequate radiation dose to the tumor while limiting normal 
tissue toxicity.  Therefore, adjusting for anatomic changes in tumors during radiation 
treatment is particularly important in proton therapy.  Hui et al. studied the effect of 
anatomic changes on proton therapy dose distribution in lung cancer using weekly 4D CT 
Scans.  Although only 8 patients were examined, there was variation in the CTV density 
as radiation treatment progressed.  The authors concluded, however, that CTV coverage 
is adequate if tumor motion is taken into consideration with 4D CT planning.  
Interestingly, this CTV density variation was correlated with normal tissue toxicity, 
implying that as the tumor shrinks from radiation treatment, the high dose radiation spills 
over to normal tissue.  The secondary objective of our study will be to utilize the serial 
imaging obtained from either the photon beam or proton beam patients to generate serial 
proton beam plans. This will allow us to estimate the dosimetric error with proton beam 
radiotherapy if tumor and patient anatomical changes are not accounted for during 
treatment. 
 
 
We propose to quantify the changes in tumor volume, motion, and anatomic changes that 
occur during the time course of definitive radiotherapy in patients with lung cancers, head 
and neck cancers, gastrointestinal cancers (including but not limited to colorectal and 
rectal cancers) and gynecological cancers. These cancers were chosen as they represent 
the oncologic subsets that experience the greatest dynamic range in these variables during 
treatment.  
  
 
 

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3.0 SPECIFIC AIMS/OBJECTIVES 
Specific Aim 1: To estimate the degree of tumor volume, tumor motion and patient 
anatomy change during treatment with photon beam radiotherapy. 
 
1a. To estimate the degree and impact of tumor volume change during the course 
of definitive photon radiotherapy treatment in lung cancers, head and neck 
cancers, gastrointestinal cancers (including but not limited to colorectal and rectal 
cancers) and gynecological cancers. 
1b. To estimate the degree and impact of tumor motion (anatomic location) 
change during the course of definitive photon radiotherapy treatment in lung 
cancers, head and neck cancers, gastrointestinal cancers (including but not limited 
to colorectal and rectal cancers and gynecological cancers.  
1c. To estimate the degree and impact of changes in patient anatomy during the 
course of definitive photon radiotherapy treatment in head and neck and upper 
gastrointestinal cancers. 
Hypothesis: Tumor volume and motion will change over the course of radiation treatment 
in patients with lung cancers, head and neck cancers, gastrointestinal cancers (including 
but not limited to coloorectal and rectal cancers) and gynecological cancers.  The weight 
loss experienced by patients with upper gastrointestinal and head and neck cancers will 
have a significant impact on their anatomy.  These changes will alter the dose distribution 
of the photon beam treatment plans, possibly limiting radiation dose delivery to the target 
volumes and increasing radiation toxicity to surrounding critical structures. 
 
Specific Aim 2: To estimate the error if tumor volume, tumor motion and patient 
anatomy change during treatment with proton beam radiotherapy. 
 
2a.  To generate simulated proton beam plans using serial CT or MR imaging 
obtained from either photon or proton beam patients to estimate the dosimetric 
error if these changes are unaccounted for during proton treatment. 
Hypothesis: The changes in tumor volume and motion and patient anatomy will have a 
greater effect on appropriate dose distribution in plans using proton beam therapy 
compared to photon beam therapy given the need for more accurate target delineation in 
proton beam therapy.   
4.0 
STUDY OVERVIEW 
 
This is a pilot study to estimate the degree of tumor volume, tumor motion and patient 
anatomy change during treatment with photon or proton beam radiotherapy.  Patients will 
undergo simulation with an MR scan and/or CT scan per best clinical practices, and 4D 

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imaging will be employed as indicated, at the discretion of the treating radiation 
oncologist.  Photon beam treatment plans and Proton beam treatment plans will be 
generated from these images.  Based on the location of the primary tumor, patients will 
undergo either up to weekly 3D or 4D CT and/or serial MR scans during treatment.  
These images will be compared to the initial CT/MR scans used for treatment planning 
and analyzed for changes in tumor volume and tumor anatomic location.  At the end of 
treatment, the frequent 3D or 4D CT and/or serial MR images will be compared to the 
initial treatment planning images to quantify the changes in tumor volume and tumor 
motion during the course of radiation treatment.  Each CT and/or MR Scan will also be 
used to evaluate the changes in dose distribution to the target volumes and normal tissues 
that occur with the initial photon treatment plan and initial proton treatment.  The 
changes in tumor volume, tumor motion and dose distribution during the course of 
radiation treatment will be analyzed to determine the effect of tumor changes on radiation 
treatment efficacy.  
 
 
 
 
5.0 
PARTICIPANT SELECTION 
 
5.1 
Inclusion Criteria 
1. 
Patients aged > 18 
2. 
Biopsy proven diagnosis of non-small cell lung cancer, small cell lung 
cancer, head and neck, esophageal, gastric, pancreatic, hepatic, billiary, 
colorectal, anal , cervical, endometrial, vaginal, vulvar, ovarian cancer and 
any other gastrointestinal or gynecological cancers requiring definitive 
radiotherapy alone with or without concurrent chemotherapy. 
3. 
Able to provide written informed consent and comply with all study 
procedures 
4. 
Entire course of radiotherapy will be delivered at the University of 
Pennsylvania Perelman Center for Advanced Medicine. 
 
5.2 
Exclusion Criteria 
1. 
Pregnancy or women of childbearing potential and men who are sexually 
active and not willing/able to use medically acceptable forms of 
contraception; this exclusion is necessary because the treatment involved 
in this study may be significantly teratogenic. 
 
5.3 
Recruitment Procedures 
 
4D CT Simulation 
Proton Planning 
Definitive RT +/- Chemotherapy 
Up to Weekly 3D or 4D CT 
and/or MR Scans  
Photon Planning 

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Subjects will be recruited from the Oncology practices at Penn Medical Center.  Patients 
will be referred by their physicians and include men and women who will be receiving 
radiotherapy with definitive intent with or without chemotherapy. Subjects will undergo 
an informed consent process in accordance with GCP. Informed consent will be obtained 
prior to the performance of any research specific (i.e. not standard of care) procedures 
and prior to the start of radiation therapy treatment. Subjects must meet all of the 
inclusion and none of the exclusion criteria as determined by baseline/eligibility  
measures. The treating radiation oncologist will approach and inform the patient about 
the study, thereby initiating the informed consent process.  If the patient expresses 
interest in the study, the treating radiation oncologist will contact the Clinical Research 
Coordinator (CRC) in the Radiation Oncology department at the University of 
Pennsylvania and initiate introduction to the CRC.  The treating radiation oncologist 
and/or CRC will interview the potential subject with privacy considerations, explain the 
requirements of the study and provide a copy of the Informed Consent Form.  The 
treating radiation oncologist and/or CRC will state the volunteer nature of research and 
advise the subject to take sufficient time to discuss the study if necessary before making 
their decision to sign the informed consent document.  If a decision to participate is 
made, the informed consent form is signed after which any research specific (i.e. not 
standard of care) procedures will be performed.  Through use of the subject’s electronic 
medical record and questions asked by the treating physician and/or CRC,  patient 
eligibility based upon the inclusion/exclusion criteria will be verified.  After the 
eligibility is established and confirmed with the treating physician/study investigator, a 
subject study number will be issued.    All members of the research team will have 
successfully completed patient oriented research training.  Subjects will receive all 
treatment in the Radiation Oncology clinic of the University of Pennsylvania. 
 
 
6. 0 
STUDY PROCEDURES 
 
6.1 
Institutional and Investigator Requirements 
 
All patients must have a signed Informed Consent Form and a confirmation of eligibility 
form filled out and signed by a participating investigator prior to entering the study. 
Confidential research charts will be kept in locked cabinet to which only members of the 
study team will have access.  Subjects will be assigned a study number at the time of 
study enrollment.  This study number and not the subject’s name will be used on all case 
report forms. 
HIPAA Compliance:   
Patients will be asked to read and sign a combined study consent form and HIPAA 
consent form acknowledging the uses and disclosures of protected health information 
(PHI) in this study as required by The Health Insurance Portability and Accountability 
Act (HIPAA).  PHI will not be shared with any outside institution except as required by 
law.  Any reporting of the results of this study will be done only with de-identified 
patient data.  Confidentiality will be protected as outlined below. 

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• Each subject will sign a combined study informed consent/ HIPAA authorization 
form prior to study entry. 
• Each subject will be assigned a study number.  All research-related material (to 
include specimens for research) will be labeled with the subject study number and 
the subject’s initials.  
• A list of the subject names with the associated subject numbers will be maintained 
by computer to which only members of the study team will have access. 
• All research subject records will be kept in a study chart. 
• An electronic database will be maintained.  No subject names will be used in this 
database.  Study numbers will be used.  Only data which constitutes a limited data 
set (as defined by the University of Pennsylvania Health System in the HIPAA 
Privacy Education website) will be used. 
 
6.1.1 Potential Risks to Patient 
 
Patients have additional radiation exposure with weekly 3D/ 4D CT and/or serial 
MR scans. The additional patient dose from a single CT scan is typically less than 
10 cGy. This dose is less than 0.2% of a typical definitive treatment of 5,000cGy 
to 7,000cGy, and compares to the additive dose from portal images that have been 
used as standard of care in radiation oncology departments throughout the United 
States for decades. The added risk from additional radiation exposure due to these 
weekly scans therefore is minimal. There is no additional radiation risk from an 
MR scan. 
 
Depending on specific diagnosis, the treating physician may elect to order the 
imaging (MR, CT, or MR/CT) with contrast. This involves giving intravenous 
gadolinium (for an MRI) or intravenous iodinated contrast (for a CT) before that 
specific scan to better visualize your tumor and internal anatomy. Gadolinium and 
iodine can pose a risk to people with kidney disease.  This risk is not anticipated 
but this remains a possible risk that will require monitoring through blood drawn 
to measure kidney functions prior to each imaging scan during radiation 
treatment.   
 

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6.2 
IRB Approval and Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Baseline/eligibility procedures, including informed consent, may occur at any time  
from consultation until radiation therapy treatment begins.  
 
Baseline/Eligibility* 
Informed consent 
History/Physical as per standard of care 
Staging Studies as per standard of care  
Study enrollment 
 
Radiation Treatment Planning 
3D or 4D CT Photon Treatment Plan, 
3D or 4D CT Proton Treatment Plan, 
and/or Baseline MR Scan  
per best clinical practices and the  
discretion of the treating physician 
Radiation Therapy Guidelines 
Definitive treatment (with or without 
chemotherapy) per appropriate 
standard of care for the primary 
tumor 
Follow-up 
As per standard of care 
During RT 
Up to weekly 3D/4D CT and/or 
MR Scan (minimum of 3) If 
contrast, blood draw prior to 
each scan 

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6.3. 
Accrual Goals and Monitoring 
 
Patients will be referred by their physician by calling the Clinical Research Coordinator 
(CRC) in the Radiation Oncology department at the University of Pennsylvania. Patient 
eligibility will be verified based upon based upon the criteria outlined in Section 4.1. and 
Section 4.2.  After eligibility is established and confirmed, a subject study number will be 
issued. We anticipate enrollment of four-five patients per month onto this study. 
 
6.4. 
Study Calendar / Schedule 
 
Event 
Baseline/Eligibility 
Prior to RT Initiation 
Weekly 
during 
RT 
Informed Consent 
X* 
X* 
 
History and Physical 
X 
X 
 
Photon 
and 
Proton 
Treatment 
Planning 
and/or Baseline MR scan  
X 
X 
 
3D/4D CT and/or MR 
scans 
(determined 
by 
tumor 
location 
and 
treating physician) 
 
 
X* 
Blood Draw (prior to each 
imaging 
scan 
during 
RT)** 
 
X 
X 
*       These are research specific procedures. All other procedures are standard of care.   
**    Only if receiving contrast with imaging). 
 
6.5. 
Pre-Registration /Pre-Treatment 
Baseline/Eligibility  
See Section 5.3 (Subject Recruitment and Screening) and Section 5.1 and 5.2 (Inclusion 
and Exclusion Criteria). 
 
 
Radiation Treatment Planning 
The radiation dose will be prescribed at mid-separation on the central ray for two equally 
weighted beams.  For all other beam arrangements, the dose will be prescribed at the 
center of the target area or at the intersection of central rays of the beams. 
 
Simulation for all fields is required for treatment planning. Patients will undergo 
simulation with an MR scan and/or CT scan per best clinical practices, and 4D imaging 
will be employed as indicated, at the discretion of the treating radiation oncologist.  The 
4D CT will be used to define the target volumes.  The gross tumor volume (GTV) will 
consist of all known sites of disease including the primary tumor and all pathologically 
enlarged (> 1 cm in short axis) positive lymph nodes prior to accounting for respiratory 
motion. Discontinuous volumes are allowed. In 4D planning CTs, the GTV will be 

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expanded to create an internal tumor volume (ITV), which will include the GTV and the 
extent of GTV respiratory movement as defined by the 4D CT.  The clinical tumor 
volume (CTV) and planning target volume (PTV) will be constructed from the GTV by 
an automatic margining tool supervised and edited by the treating radiation oncologist. 
The irradiation target volume will be defined by shaped ports with custom-made blocks 
or multileaf collimation.  Portal verification shall be done for all treated fields.  
Megavoltage equipment is required with minimum peak photon energies of 6 MV.  SAD 
techniques should be used.  Each field will be treated every session.  Interruptions in 
therapy should be discussed with the principal investigator but will be instituted at the 
discretion of the attending radiation oncologist. 
 
Dose calculation should be performed using inhomogeniety corrections to account for 
differences in tissue density across the thorax.  The total dose to gross disease will be 40-
80 Gy, depending on the standard of care for using radiotherapy to treat the primary 
tumor (with or without concurrent chemotherapy) and on the site of the primary tumor. 
The prescribed total dose and dose per day will be constrained to adjust for the standard 
normal tissue dose limitations.  
 
 
RADIOTHERAPY PLANNING 
 
Forward photon and proton beam plans will be generated on the CT simulation data set. 
These plans will be then be applied to the up to weekly data sets to quantify variance in 
dose deposition.  
 
Treatment planning is not routinely changed during the course of radiation therapy.  
However, if it is found by the treating physician that a significant change has 
occurred in tumor volume, position or anatomy that render the original plan no 
longer optimal, then a new treatment plan will be created for the remainder of 
treatment.  Should this occur, the PI will be notified of the treatment changes.  
 
6.6. 
 On Treatments 
Based on the primary tumor location and the discretion of the treating radiation oncologist, 
atients will undergo 3D/4D CT Scan (up to weekly)) and/or MR Scan (minimum of 3)..  The 
GTV, ITV and critical normal structures will be contoured on each up to weekly/serial scan.   
The up to weekly/serial GTV volume will be compared to the initial GTV volume to determine 
changes in tumor volume.  Each  GTV will be compared to the initial ITV volume to determine 
what percent of the  GTV resides within the initial ITV.  This value will be used to evaluate 
changes in tumor motion.  Each  ITV will be compared to the initial ITV.  The initial photon 
treatment plan and proton treatment plan will be applied to the new scan.  The amount of 
radiation dose to each GTV, ITV and critical normal structures will be recorded to determine the 
changes in dose distribution that occur as treatment progresses.  SUBJECTS WILL RECEIVE 
ALL SCANS IN THE RADIATION ONCOLOGY CLINIC OF THE UNIVERSITY OF 
PENNSYLVANIA. 
 
6.7. 
Post Therapy/Treatment:  

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Subjects will present for an initial post-treatment visit approximately 4-6 weeks after 
completion of radiation treatment as per the standard of care.  Additional follow-up visits 
will be performed as per the standard of care. Subjects will be considered “off study” on 
the date of their last radiation treatment.   
 
6.8. 
Criteria for Removal from Study 
Any subjects experiencing a serious adverse event (SAE) felt to be related to the study 
imaging or imaging contrast will be withdrawn from the study. Subjects will be 
withdrawn from the study if discontinuation of treatment is deemed necessary by the 
principal investigator to be in their best interest (e.g. an abnormal response of the 
subject’s malignancy to radiotherapy outside of normal limits is observed, intolerable 
side effects of radiotherapy occur, clinical deterioration occurs). Subjects may be 
withdrawn at any time at the discretion of the PI. Any subject withdrawing their consent 
to participate in the study or their authorization to use their protected health information 
will be withdrawn from the study. Subjects withdrawn may be replaced at the discretion 
of the principal investigator. 
Subjects may also be withdrawn due to any of the following: 
1. Failure to attend outpatient and treatment visits 
2. Failure to cooperate and provide tolerability measures 
Once the subject has discontinued the study, the primary reason for discontinuing the 
study must be clearly documented in the subject’s records and on the CRF.  The 
investigator will assess each subject for response at the time of withdrawal.   
 
6.9  Imaging Acquisition, Archival, and Interpretation 
 
All images will be acquired at the Hospital of the University of Pennsylvania or the Perelman 
Center for Advanced Medicine. Image acquisition, archival, and interpretation will be through 
the Departments of Radiation Oncology and Radiology at the University of Pennsylvania.  
 
 
7.0 
DATA COLLECTION AND MANAGEMENT 
 
All subjects must have a signed Informed Consent Form and a confirmation of eligibility 
form filled out and signed by a participating investigator prior to receiving a study  
number. 
 Case report forms will be used to standardize data keeping and allow entry to a 
computerized data base. 
Flow of Subject Data 
Study entry:  Each subject will be evaluated for this study based upon the inclusion and 
exclusion criteria.  If a subject is interested in participating, he/she will be asked to sign 
and informed consent document after which an eligibility checklist will be completed and  

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signed. The subject will then be assigned a study number.  All study forms:  eligibility 
forms, on study forms, case report forms (CRF), and data entry forms will be coded with 
the subject’s study number to protect subject confidentiality.   
 
Imaging:  Copies of all imaging for these studies will be maintained by the Department of 
Radiology at the University of Pennsylvania. 
 
Follow-up:  Follow up visits will occur as per the standard of care.  Subjects will be 
considered off study as of the date of their last radiation treatment.  
 
8.0 Safety and Adverse Events 
The investigator and/or designated research staff will be responsible for detecting, 
documenting and reporting all events that meet the definition of an Adverse Event (AE)  
or Serious Adverse Event (SAE) felt to be related to the study imaging or imaging 
contrast.  (see section 6.8) 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 Background:  
Tumor volume, location and proximity to critical normal organs are determined by CT 
scans prior to the start of radiation treatment. Radiation dosimetry plans are not re-
calibrated during the course of a patient’s treatment since it is assumed that changes in 
these variables are negligible. This hypothesis has rarely been studied in a rigorous 
manner. Dramatic tumor shrinkage or patient weight loss, may cause the radiation energy 
beam to over-shoot the treatment target and may also increase the radiation dose to 
nearby critical normal organs. 
 
9.2 Study Design: 
This pilot study will determine changes over time in tumor volume and motion and 
patient anatomy, as well as dose distributions to normal organs. The study will inform 
medical decision-making about the need for (and timing of) re-calibration of radiation 
dosimetry plans. Up to weekly CT and/or serial MR scans  (minimum of 3) will be 
employed to measure changes in tumor volume and motion and patient anatomy in 
patients receiving definitive radiation therapy (with or without concurrent chemotherapy). 
This study is not designed to evaluate the CT or MR procedure. CT or MR is simply the 
imaging method used for precise measurement of tumor volume variables. Enrollment 
will be stratified by disease site: NSCLC, Head & Neck, GI and Gynecologic tumors. 
The study will enroll 30 patients in each stratum. This study is descriptive and not 
powered hypothesis testing.  
 
9.3 Objectives:  To determine changes over time in: 
1. tumor volume variables  
2. tumor motion 
3. patient anatomy  
4. dose distribution to tumor and critical normal organs 

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9.4 Endpoints:  To be measured at baseline and then weekly during 7-8 weeks of 
radiotherapy 
1. GTV (gross tumor volume), the volume of the primary tumor visualized on the CT 
scan 
2. ITV (interior tumor volume), the GTV expanded to include interior motion (i.e., 
breathing or swallowing) such that the tumor resides within the ITV during normal 
motion 
3. CTV (clinical tumor volume), the ITV expanded to include microscopic disease 
(margins) 
4. PTV (planning tumor volume), the CTV expanded by several mm, as determined by 
radiation dosimetry planning, PTV is considered the ultimate target volume 
NOTE the relationship: GTV < ITV < CTV  < PTV  
5. Dose coverage: at each scan time point, determine the percent of the GTV which 
resides within the baseline ITV or CTV 
5. patient weight and percent weight loss from baseline 
6. Radiation dose to critical normal organs based on dose-volume histograms (i.e., 20 Gy 
to 50% of normal lung tissue) 
 
9.5 Plans for Data Analysis: To be conducted within each stratum  
1. Tumor Volume: To determine the distributions of volume variables and percent change 
from baseline. At each scan time point, compute mean, median, range and standard 
deviation of these variables and plot mean values over time. To compare volume 
variables at baseline to the values at selected scan time points by paired Wilcoxon signed 
ranks test. 
2. Tumor Motion: At each scan time point, compute mean, median, range  and standard 
deviation of the dose coverage and plot mean values over time. To compare ITV or CTV 
variables at baseline to the GTV at selected scan time points by paired Wilcoxon signed 
ranks test.  
3. Patient Anatomy: To determine the distribution of patient percent weight loss. At each 
scan time point, compute mean, median, range and standard deviation of percent weight 
loss and plot mean values over time. 
4. Dose distribution: To determine the distributions of radiation dose to GTV, ITV and 
critical normal organs. To correlate radiation dose to normal organs with percent weight 
loss. 
5. Conduct exploratory longitudinal analyses to examine changes over time in the 30 
patients. Random effects linear regression models will be employed to estimate changes 
in variables over time clustered by patient. Natural log transformation will be applied 
prior to modeling. 
6. To assess if changes in volume variables are clinically relevant and if so, identify the 
earliest time point at which re-calibration is warranted. Although it may not be possible 
to identify a single ‘re-calibration solution’ for all patients in a particular stratum, we will 
attempt to identify the earliest scan time point at which the majority of patients have 
clinically important changes in tumor volume or location resulting in over-shoot of the 
target volume and/or increased dose exposure to normal organs. 
 

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9.6 Sample Size/Study Duration 
Patient heterogeneity (e.g., size and location of the tumor, radiation dose/fractions, 
proximity to critical normal organs, tumor shrinkage and dramatic weight loss) are all key 
factors in this evaluation. As such, we seek to enroll a sufficiently large series of diverse 
patients in each stratum. This pilot study will enroll 30 patients per stratum in 
approximately 1 year (e.g., NSCLC) up to 4 years (e.g., gynecologic cancers), depending 
on the particular stratum. Once a stratum has enrolled the target number, the study 
remains open but enrollment to that particular stratum is closed. We expect that the entire 
study will take approximately 5 years to complete. 
 
10   Medical Monitoring  
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site.  This safety monitoring will include careful assessment and appropriate 
reporting of study progress, as well as the construction and implementation of a site data 
and safety-monitoring plan (see section 13, Study Monitoring, Auditing and Inspecting).   
 
The Medical Monitor will be Daniel Pryma, MD. (a physician who is not directly 
involved in the trial and is not collaborating with the sponsor/investigator in any other 
trial).  Because of Dr. Pryma’s background and experience he is an appropriate Medical 
Monitor for this study.   In the role, he will review all study progress, and all other safety 
data and activity data observed in the ongoing clinical trial along with discussing relevant 
animal and toxicology studies and similar investigational agents.  The Medical Monitor 
may recommend reporting of events and relevant safety data not previously reported and 
may recommend suspension or termination of the trial. The investigator will meet with 
the Medical Monitor annually.  Serious and unexpected issues will be handled on an ad 
hoc basis through calls or e-mail.  Documentation of all communication with the Medical 
Monitor will be maintained in the study specific Regulatory Binder.  Copies of a Medical 
Monitor report requiring action on the part of the Principal Investigator (PI) to protect 
subject safety or study integrity will be submitted to the DSMC within 10 business days.   
 
10.1   Data and Safety Monitoring Committee 
The University of Pennsylvania Cancer Center (UPCC) through the Data and Safety 
Monitoring Committee (DSMC) will be reviewing this clinical trial.  It is anticipated that 
with approval, the committee’s role will be to ensure that the rights and well-being of all 
subjects are protected and that patients are treated in full compliance with the study 
treatment and parameters specified in the protocol. The Data and Safety Monitoring 
Committee (DSMC) is responsible for overseeing the process of monitoring of studies 
and the conduct of audits.  The investigators on this study are responsible for the 
continuous, close monitoring of subjects enrolled on this trial. 
A DSMC audit of this trial will be performed twice a year for as long as the trial remains 
open for accrual.  The principal investigator will be notified in advance of the selection of 
their protocol for review.  Three randomly selected patients or 10% of the total accrual, 
whichever is higher will be audited.  A written report is provided to the principal 
investigator following this audit.  Any rating less than satisfactory would warrant a repeat 
full review at the time of the next scheduled audit or sooner, depending upon the extent 
of the deficiencies found.  Substantial protocol deviations will be reported to the Director 

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of the Cancer Center and the Administrative Director of the DSMC for consideration of 
appropriate administrative action, such as suspending accrual to the protocol. 
 
10.2   Protocol Deviations/Exceptions 
Occasionally, the investigator may need to deviate from the approved protocol.  
Deviations are categorized as reportable and non-reportable.  Reportable deviations may 
be urgent or not.  Urgent deviations may occur on the spot as necessary to protect the 
safety of a study subject and do not allow enough time for reporting in advance.  
However, they must be reported as soon as possible.   
 
All deviations from the study protocol will be handled as follows: 
10.2.1 Eligibility 
Deviations from established eligibility criteria will not be encouraged The IRB will be 
notified of the planned deviation and a copy of all applicable amended study documents 
will be sent to the IRB.  The planned deviation will also be submitted to the DSMC for 
evaluation.  The DSMC does not approve deviations but rather provides and unbiased 
assessment of the appropriateness of the request.  Both committees will  be given 
sufficient time to review the request, gather additional information as necessary and make 
a decision.  The Medical Monitor will be consulted first for all such deviations.  
Documentation of the Medical Monitor’s assessment and opinion will be included with 
the initial report to both committees. 
 
10.2.2 Non-Reportable- During the course of a study, there may be times when 
deviations are minor (i.e. does not affect subject safety or research integrity) and/or  are 
outside of the control of the investigator or research staff (i.e. subject not showing up for 
a study visit, lab errors, subject confusion etc.)  These type of deviations are not 
reportable (unless they occur at a level that impacts any of the other reportable 
categories) but must be documented in a timely manner to show the impact of the 
deviation and corrective/follow-up actions that were taken.  Documentation can be in the 
clinic/progress note, note/memo to file or deviation log.  Notes/memos/deviation logs 
should be signed and dated.  
 
10.2.3   Reporting Deviations/Exceptions 
Reports to the IRB will be done via the Human Subjects Electronic Research Application 
system (HS-ERA) and reports to the CTSRMC/DSMC will be done via the electronic 
clinical trials management system, Velos, and email.  Reportable deviations must also be 
sent to the study Medical Monitor.   
 11 Data Handling and Record Keeping 
 All patients must have a signed Informed Consent Form and a confirmation of eligibility 
form filled out and signed by a participating investigator prior to entering the study. 
Confidential research charts will be kept in locked cabinets.  Subjects will be assigned a 
study number at the time of study enrollment.  This study number and not the subject’s 
name will be used on all case report forms. 
 

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HIPAA Compliance:  See section 6.1. 
11.1  Data Entry 
All patients must have a signed Informed Consent Form and aconfirmation of eligibility 
form filled out and signed by a participating investigator prior to entering the study. Case 
report forms will be used to standardize data-keeping. 
 
Imaging:  Copies of all imaging for these studies will be maintained by the Department of 
Radiology at the University of Pennsylvania. 
 
Follow-up:  Follow up visits will occur as per the standard of care.  Subjects will be 
considered off study as of the date of their last radiation treatment. 
11.2  Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require signed consent form containing the required HIPAA 
elements informing the subject of the following:  
• What protected health information (PHI) will be collected from subject(s) in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period.   
 
11.2.1 Unintentional Disclosure 
Upon discovering that PHI may have been or has been disclosed to anyone not 
specified in the HIPAA disclosure consent, the investigator will report the 
disclosure to the Institutional Officer in the Office of Research Compliance and 
Integrity.  The report should contain details about the type of data disclosed and the 
extent of the disclosure (number of subjects, who received it etc.).   
 
12   Records Retention 
 
12.1   Federally Funded Research or Non-IND/IDE Research  
The DHHS regulation (45 CFR 46.115) states that records relating to research conducted 
or supported by any Federal department or agency shall be retained for at least 3 years 
after completion of the research. 
 

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The FDA regulation (21 CFR 56.115) is virtually identical; it also states that IRB records 
must be retained for at least 3 years after completion of the research for these same types 
of studies. 
 
Records for this study will be maintained in a secure location with access limited to the 
investigators and the study specific research team for 3 years from the date of full study 
terminations.  If necessary, after the first year of termination, records may be moved to an 
off-site secure storage facility. 
 
12.2   HIPAA Retention Period (45 CFR164.530(j): 
Protected Health Information (PHI) Research Requests (HIPAA1-008): Records 
documenting research requests, privacy board review or privacy officer expedited review, 
background material, and acceptance or denial of request. Retain 6 years after research 
completed. 
 
Protected Health Information Disclosure Records (HIPAA1-009): Documenting the 
release of PHI, including both authorized and unauthorized releases. Should include 
the date of release, to which the information was released, and the circumstances of the 
release. Retain 6 years after research completed. 
 
Maintenance of HIPAA records is independent of the regulations for clinical study 
records.  All records of PHI research requests and any type of release will maintained for 
6 years after the research is fully terminated. 
 
13   Study Monitoring, Auditing, and Inspecting 
13.1 Study Monitoring Plan 
The study PI is responsible for ensuring the ongoing quality and integrity of the research 
study.  In addition, this study will be monitored or audited in accordance with Abramson 
Cancer Center’s NCI approved Institutional Data and Safety Monitoring Plan.   
The University of Pennsylvania Cancer Center (UPCC) has a formal plan for Data Safety 
and Monitoring of Clinical Trials.  The clinical trial, “A Volume, Motion, and 
Anatomically Adaptive Approach to Photon and Proton Beam Radiotherapy” is a trial 
that is subject to oversight of the UPCC through the Clinical Trials Scientific Review and 
Monitoring Committee (CTSRMC) and the Data Safety Monitoring Committee (DSMC). 
These oversight committees serve to ensure that the rights and well-being of all subjects 
are protected and that patients are treated in full compliance with the study treatment and 
parameters specified in the protocol. The CTSRMC’s role is to serve as a rigorous 
scientific peer review mechanism for all cancer-related non-cooperative group human 
research studies conducted at the University of Pennsylvania.  The Data Safety 
Monitoring Committee (DSMC) is responsible for overseeing the process of monitoring 
of studies and the conduct of audits.  The clinical trial, “A Volume, Motion, and 
Anatomically Adaptive Approach to Photon and Proton Beam Radiotherapy” is 
considered a low-risk study.  The investigators on this study are responsible for the 
continuous, close monitoring of subjects enrolled on this trial. 
 

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13.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.). 
 
A DSMC audit of this trial will be performed approximately every 6 months for the 
duration of the study.  The principal investigator will be notified in advance of the 
selection of their protocol for review.  Three randomly selected patients or 10% of the 
total accrual (up to 10 patients), whichever is higher will be audited. Please note- this 
schedule may be changed at the 
discretion of the DSMC. A written report is provided to the principal investigator 
following this audit.  Any rating less than satisfactory would warrant a repeat full review 
at the time of the next scheduled audit or sooner, depending upon the extent of the 
deficiencies found.  Substantial protocol deviations will be reported to the Director of the 
Cancer Center and the Administrative Director of the DSMC for consideration of 
appropriate administrative action, such as suspending accrual to the protocol. 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
14.  Ethical Considerations 
 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of IRB concerning the conduct of the study 
will be made in writing to the investigator and a copy of this decision will be maintained 
in the study specific Regulatory Binder which contains “Essential Study Documents”.  In 
addition, NCI requires all cancer based studies to have an independent scientific review.  
This protocol must be reviewed and fully approved by the Clinical Trials Scientific 
Review and Monitoring Committee (CTSRMC) prior to enrolling any subjects. 
Documentation of CTSRMC approval must also be maintained in the study specific 
Regulatory Binder.    
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for 
review and approval by the IRB and CTSRMC for the study.  The formal consent of a 

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subject, using the IRB-approved consent form, must be obtained before that subject is 
submitted to any study procedure.  This consent form must be signed and dated by the 
subject or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent.  
 
15  Study Finances 
 
15.1   Funding Source 
This study is being funded by the Department of Radiation Oncology at UPenn. 
 
16  Publication Plan 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study sponsor and Principal Investigator.  Any investigator involved with 
this study is obligated to provide the sponsor with complete test results  
 

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17.0 
REFERENCES 
 
1. 
Fox, J., E. Ford, et al. (2008). "Quantification of Tumor Volume Changes During 
Radiotherapy for Non-Small-Cell Lung Cancer." Int J Radiat Oncol Biol Phys. 
 
2.   
Barker, J. L., Jr., A. S. Garden, et al. (2004). "Quantification of volumetric and 
geometric changes occurring during fractionated radiotherapy for head-and-neck 
cancer using an integrated CT/linear accelerator system." Int J Radiat Oncol Biol 
Phys 59(4): 960-70. 
 
3. 
Britton, K. R., G. Starkschall, et al. (2009). "Consequences of anatomic changes 
and respiratory motion on radiation dose distributions in conformal radiotherapy 
for locally advanced non-small-cell lung cancer." Int J Radiat Oncol Biol Phys 
73(1): 94-102. 
 
4. 
Hui, Z., X. Zhang, et al. (2008). "Effects of interfractional motion and anatomic 
changes on proton therapy dose distribution in lung cancer." Int J Radiat Oncol 
Biol Phys 72(5): 1385-95. 
 
5.  
Vanuytsel LJ, Vansteenkiste JF, Stroobants SG, et al: The impact of (18)F-fluoro-
2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node 
staging on the radiation treatment volumes in patients with non-small cell lung 
cancer. Radiother Oncol 55:317-24, 2000 
 
6. 
Harsolia A, Hugo GD, Kestin LL, et al: Dosimetric advantages of four-
dimensional adaptive image-guided radiotherapy for lung tumors using online 
cone-beam computed tomography. Int J Radiat Oncol Biol Phys 70:582-9, 2008 
 
7.   
Stevens, C. W., R. F. Munden, et al. (2001). "Respiratory-driven lung tumor 
motion is independent of tumor size, tumor location, and pulmonary function." Int 
J Radiat Oncol Biol Phys 51(1): 62-8. 
 
8.         Yaremko, B. P., T. M. Guerrero, et al. (2008). "Determination of respiratory 
motion for distal esophagus cancer using four-dimensional computed 
tomography." Int J Radiat Oncol Biol Phys 70(1): 145-53. 
 
9.         Zhang, X., K. L. Zhao, et al. (2008). "Four-dimensional computed tomography-
based treatment planning for intensity-modulated radiation therapy and proton 
therapy for distal esophageal cancer." Int J Radiat Oncol Biol Phys 72(1): 278-87. 
 
 
10.       Bussels, B., L. Goethals, et al. (2003). "Respiration-induced movement of the 
upper abdominal organs: a pitfall for the three-dimensional conformal radiation 
treatment of pancreatic cancer." Radiother Oncol 68(1): 69-74. 
 

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11.       Nam, H., W. Park, et al. (2007). "The prognostic significance of tumor volume 
regression during radiotherapy and concurrent chemoradiotherapy for cervical 
cancer using MRI." Gynecol Oncol 107(2): 320-5. 
 
12.       Lin, A., S. Jabbari, et al. (2005). "Metabolic abnormalities associated with weight 
loss during chemoirradiation of head-and-neck cancer." Int J Radiat Oncol Biol 
Phys 63(5): 1413-8. 
 
13.       Milano, M. T., M. C. Garofalo, et al. (2006). "Intensity-modulated radiation 
therapy in the treatment of gastric cancer: early clinical outcome and dosimetric 
comparison with conventional techniques." Br J Radiol 79(942): 497-503. 
 
14.       Talamonti, M. S., W. Small, Jr., et al. (2006). "A multi-institutional phase II trial 
of preoperative full-dose gemcitabine and concurrent radiation for patients with 
potentially resectable pancreatic carcinoma." Ann Surg Oncol 13(2): 150-8.