Proton Radiotherapy for Extremity Soft Tissue Sarcoma
Phase: PHASE2
Conditions: Soft Tissue Sarcoma of the Extremities
Sponsor: Abramson Cancer Center at Penn Medicine

Protocol “Proton Radiotherapy for Extremity Soft Tissue Sarcoma” (PI: Stephen Hahn, MD) 
Protocol Version_4 March 2013 
University of Pennsylvania 
 
PROTON RADIOTHERAPY FOR EXTREMITY SOFT TISSUE SARCOMA 
 
SPONSOR:   This study is being funded by funds provided by the Department of Radiation 
Oncology and Penn Medicine 
 
 
 
Investigator: 
Curtiland Deville, MD 
Radiation Oncology 
3400 Civic Center Blvd. 
PCAM West 4th floor 
215-662-2428 
deville@uphs.upenn.edu 
 
Sub-Investigators 
Stephen M. Hahn, MD 
Douglas Fraker, MD 
Michelle Alonso-Basanta, MD 
Keith Cengel, MD, PhD 
Eli Glatstein, MD 
William Levin, MD 
Andrea Evenski, MD 
Giorgos Karakousis, MD 
Robert Roses, MD 
 
Biostatistics 
Rosemarie Mick MS 
 
Protocol Number: 
UPCC # 09510 
IRB# 811583 
IND/IDE Number: 
Exempt, Ref# 78,264 
 
 
 
 
 
Date: 
2 Apr 2010 
Amended: 
17 May 2010  
17 June 2011 
4 March 2013  
Administrative 
Change: 
 
 
 
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. 

Protocol “Proton Radiotherapy for Extremity Soft Tissue Sarcoma” (PI: Stephen Hahn, MD) 
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Table of Contents 
 
STUDY SUMMARY 
 
INTRODUCTION 
 
1 
STUDY OBJECTIVES 
2 
SUBJECT SELECTION AND WITHDRAWAL 
3 
RADIATION THERAPY 
4 
SURGERY, CHEMOTHERAPY AND IMAGING 
5 
STUDY PROCEDURES 
6 
STATISTICAL PLAN 
7 
SAFETY AND ADVERSE EVENTS 
8 
MEDICAL MONITOR 
9 
DATA HANDLING AND RECORD KEEPING 
10 
RECORDS RETENTION 
11 
STUDY MONITORING, AUDITING, AND INSPECTING 
12 
ETHICAL CONSIDERATIONS 
13 
PUBLICATION PLAN 
14 
REFERENCES 
 

Protocol “Proton Radiotherapy for Extremity Soft Tissue Sarcoma” (PI: Stephen Hahn, MD) 
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Abbreviations 
EBRT:  
external beam radiotherapy 
Gy: 
 
Gray 
LET: 
 
Linear Energy Transfer 
RBE:  
Relative Biologic Effectiveness 
SOBP:  
Spread Out Bragg Peak 
OER:  
Oxygen Enhancement Ratio 
STS:  
Soft Tissue Sarcoma

Protocol “Proton Radiotherapy for Extremity Soft Tissue Sarcoma” (PI: Stephen Hahn, MD) 
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Protocol Version_4 March 2013 
STUDY SUMMARY 
 
Title 
Proton Radiotherapy for Extremity Soft Tissue Sarcoma 
Short Title 
Proton Radiotherapy for Extremity Soft Tissue Sarcoma 
Protocol Number 
UPCC# 09510 ; IRB# 811583 
Phase 
Feasibility and Phase II 
Methodology 
Open 
Study Duration 
7 years (min.) 
Study Center(s) 
University of Pennsylvania  
Objectives 
 
1. To determine the feasibility and toxicity of pre-operative and 
post-operative proton radiotherapy for soft tissue sarcomas of 
the extremities 
2. To evaluate the wound complication rate of pre-operative proton 
radiotherapy in patients with soft tissue sarcomas of the 
extremity 
3. To evaluate the functional outcome at one year after post-
operative proton radiotherapy in patients with soft tissue 
sarcomas of the extremity 
4. To examine the relationship between pre-treatment hypoxia as 
determined by F18-EF5 scanning and treatment outcome 
 
Number of Subjects 
 
Feasibility – 12 in each stratum (subtotal = 24) 
Phase II – (a) Pre-op: 50 “enrolled” to obtained 40 “eligible” 
                 (b) Post-op: 50 “enrolled” to obtained 40 “eligible” 
                 (subtotal = 80) 
 
Study Total = 124 (max.) / 104 (min.) 
 
Diagnosis and Main 
Inclusion Criteria 
Soft tissue sarcoma the extremities -- resectable preoperative or 
postoperative patients 
 

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INTRODUCTION 
 
Rationale for Proton Therapy 
 
The goal of radiation therapy is to deposit most of the dose to the target while minimizing the dose to the 
surrounding normal tissues.  Conventional photon radiotherapy deposits its dose along the entire beam path to 
the tumor or target volume as well as beyond the depth of the target.  Techniques to minimize the dose to 
surrounding tissues such as using multiple beam angles, modulating the intensity of the radiation delivered 
through each beam have been utilized, however, these techniques still entail both entrance dose to normal 
tissue as it penetrates to reach a tumor at depth in tissue, and an exit dose as it exits the body in a straight 
path beyond the tumor.  Proton radiotherapy differs from photon radiotherapy in that most of the energy is 
deposited at a specific depth known as the Bragg peak. The dose immediately beyond the Bragg peak is 
essentially zero, which allows tissues on the side of the tumor distal to the beam to be spared.  The clinical 
application of protons provides an improvement over photons in its ability to deliver a high-dose-volume to any 
configuration within an anatomical site while maintaining lower doses to surrounding normal tissues, which 
may result in decreased short and long-term morbidity. Theoretically, this should improve the therapeutic 
index, allowing for greater dose to be delivered to the tumor/target volume and decreasing dose to normal 
tissues.  
 
Protons have a similar biologic effect to photons against tumors.  The biological effect of radiation is dependent 
on its linear energy transfer (LET).  LET is defined as the rate of energy transferred by ionizing radiation per 
unit path length.  To compare different types of radiation, we use the relative biologic effectiveness (RBE), 
which is defined as the ratio of the dose of particle radiation to the dose of 60Co radiation producing the same 
biological endpoint.  Standard photon radiation therapy has a RBE of 1.0; the RBE of protons is thought to be 
between 1.05 to 1.251-3.  A recent review of in vivo and in vitro experiments concluded that RBE varies with 
dose or dose per fraction and increases with an increasing depth in the spread out Bragg Peak (SOBP) and is 
most significant at the distal edge of the SOBP.  Overall though, based on the data to date, an average RBE of 
approximately 1.1 in the entrance of the SOBP is reasonable to assume4.  Therefore, one would expect that for 
any given dose of radiation, the biological effect of protons would be similar to photons.  The clinical advantage 
of proton beam radiotherapy over standard photon radiation, therefore, results from the more favorable dose 
distributions achievable given the physical properties described above.  The advantage of protons has been 
demonstrated for medulloblastoma, chordoma and uveal melanoma, and comparative treatment planning 
using protons versus photons have shown a clear advantage to protons in terms of dose distribution5-10. 
 
Treatment of soft sarcoma with conventional therapy 
 
Soft tissue sarcomas (STS) are relatively rare tumors of mesenchymal origin that arise in nearly all locations of 
the body11.  Although, these neoplasms represent a heterogeneous group of tumors from a histological 
perspective, the treatment principles are similar for STS that arise in the extremity, retroperitoneum, and trunk 
12-18.  Studies have demonstrated that limb preservation using a combination of wide local excision of the 
primary tumor and radiotherapy has equivalent survival compared to amputation.  Therefore, limb preservation 
has become the preferred approach for patients with extremity STS.   
 
The mainstay of therapy, however, is surgical resection.  Wide local excision is favored, if technically feasible.  
Radiotherapy either in the pre-operative or post-operative setting is considered standard treatment particularly 
for high or intermediate grade sarcomas.  The combination of surgery and radiotherapy leads to local control 
rates of 90% or greater for these patients12,17 
 
There is considerable heterogeneity in the use of post-operative vs. pre-operative radiotherapy.  The 
advantages of pre-operative radiotherapy compared to the post-operative setting include the use of smaller 
radiation fields, and a lower overall total radiation dose.  However, this comes with the risk of increased 
surgical morbidity, particularly wound healing.  Post-operative radiotherapy increases the amount of normal 

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tissue exposed to radiation (through larger radiation fields) and requires the use of a higher total radiation dose 
but avoids the risk of increased surgical morbidity associated with pre-operative treatment.  One Phase III 
randomized clinical trial has evaluated pre-operative vs. post-operative radiotherapy in patients with extremity 
STS19.  The authors found no increased difference in disease free or overall survival but did observe an 
increase in short term wound complications in the pre-operative arm.  However, preoperative radiation did lead 
to better long-term function20  
 
Other morbidity from the combination of surgery and radiation can be substantial in patients with STS of the 
extremity regardless of whether it is delivered in the pre-operative or post-operative setting.  Complications 
include acute and late damage to skin and soft tissues, lymphedema, and bone fracture.  In patients with 
retroperitoneal sarcomas, proximity of the target volume to small bowel, kidneys, liver, and spinal cord limit 
lead to a risk of both acute and late toxicities and limit the doses that can safely delivered.  Clearly, new 
radiotherapy techniques such as proton therapy are needed to improve the therapeutic index of sarcoma 
therapy20,21. 
 
Hypoxia and F18-EF5 
 
The assessment of hypoxia in human tumors has been a subject of intense interest in recent years.  The ability 
to identify hypoxia is considered important in radiation therapy because there is an oxygen dependence of 
radiation cytotoxicity (1).  Knowledge of tumor hypoxia could help direct radiation dose prescription, the use of 
hypoxic cell modifiers (for example see (2)), hypoxic cell cytotoxins (3), oxygenation therapies such as 
hyperbaric oxygen (4) or blood flow/oxygen-modifying therapies (for example, see (5)).  Recently, the model 
regarding the importance of hypoxia has been expanded because of observations that patients treated with 
surgery alone for uterine cervix cancers had better local control if their tumors were better oxygenated pre-
operatively (6).  These observations led to the suggestion that hypoxic tumors were intrinsically more 
biologically aggressive than well-oxygenated ones.  Further support for this idea was provided by a study of 
high-grade extremity soft tissue sarcomas (STS) demonstrating that these cancers were more likely to 
metastasize if they were hypoxic at the time of initial therapy (for example see (7)).  In order to treat STS more 
effectively, it is necessary to know which tumors contain clinically significant levels of hypoxia.  This can be 
accomplished with non-invasive imaging techniques such as 18F-EF5 PET and should allow the optimization of 
image-directed therapy.  We have chosen to assay 18F-EF5 because the non radioactive form of this drug, EF5 
has proven uniform biodistribution (9) and unique predictive properties in rat models (10). 
 
Clinical Data to Date 
The safety of EF5 has previously been demonstrated in a phase I study (24).  To date, colleagues in 
our Department including the PI of this study have given EF5 to over 132 subjects.  One serious 
adverse event thought to be possibly or probably related to EF5.  A subject with a glioblastoma was 
admitted to the hospital with worsening neurological symptoms.  It was thought that his symptoms were 
related to the volume of fluid associated with the EF5 infusion.  He was treated with diuretics, and his 
symptoms improved.  One episode of Grade 1 hypotension associated with symptoms of 
lightheadedness was observed.  [18F]-EF5 has been administered to 7 subjects with brain tumors and 
17 subjects with other tumor types without any adverse events related to [18F]-EF5.  It is important to 
recognize that toxicity from [18F]-EF5 may potentially be due to its biochemical structure and/or the 
radiation from fluorine-18.  Biochemically, the dose of EF5 that is administered is significantly less than 
that administered in studies with unlabeled EF5 which has demonstrated very minimal toxicities to date 
in over 132 study subjects (11, 17, 19, 25, 30).  The amount of labeled drug is less than 5 mg, 
compared to 1500 mg (for a 70 kg subject) of unlabeled drug (factor of ≈300).  Drugs similar to EF5 (i.e. 
misonidazole), given at much higher doses for extended periods of time as radiation sensitizers, have 
caused nausea, vomiting, temporary loss of sensation, numbness or tingling of the hands or feet, and 
temporary hearing loss.  These side effects have not been observed with EF5 to date. 
 
 

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18F-EF5 dosimetry 
Based on our Phase I human clinical trial, unlabelled EF5 was found to be near equilibrium at the end 
of the intravenous infusion and its subsequent half life was 11.7+/-2.6 (SD) hr (24).  Since the amount 
of EF5 in the 18F-EF5 bolus injection is very small compared to the unlabelled drug (approximately 3 mg 
compared to 1500 mg for a 70 kg person), we expect the radioactivity to provide drug distribution 
information without significantly affecting the drug concentration.  18F-EF5 is likely to be uniformly 
distributed with primarily renal and some biliary excretion.  Because of the long biological half-life of 
EF5, we expect less than 20% of the total EF5 injected to be eliminated during the study. 
 
In order to determine the radiation dose-limiting organ we compared the biodistribution and elimination 
of 18F-EF5 and [F-18]-F-Miso in rats.  120 minutes after injection of either radiolabeled drug, rats were 
sacrificed and various organs were analyzed for 18F-EF5 and [F-18]-FMiso by gamma counting.  In 
most tissues, the ratio of 18F-EF5 / [F-18]-FMiso was close to one.  There were some differences in 
biodistribution, with the level of [F-18]-FMiso 2-fold higher in the urine compared with 18F-EF5.  
Therefore, the dose absorbed by the bladder wall would be expected to be 2-fold higher for [F-18]-FMiso 
than 18F-EF5.  The amount of radioactivity in various organs was also measured.  However, the renal 
dose of 18F-EF5 was 2-fold higher than that of [F-18]-FMiso.  The organ that receives the highest dose 
for either drug is the urinary bladder (0.78 mGy/mCi).  Based on this data, it may be reasonable to 
extrapolate from the results examining [F-18]-FMiso dosimetry in humans.  In one study (37) patients 
were injected with 5 mCi of [F-18]-FMiso.  The calculated total-body dose for a 70-kg man was 0.013 
mGy/MBq (0.48mGy/mCi) and for a 57-kg woman 0.016 mGy/MBq (0.59mGy/mCi).  In this study, the 
organ that received the maximal dose was the urinary bladder (0.021 mGy/MBq).  Another [F-18] 
labeled agent for which there is significant experience is 2-(F-18) fluoro-2-deoxy-D-glucose (FDG).  The 
total body dose for this agent has been calculated to be 0.39 mGy/mCi ref similar to the total body dose 
resulting from [F-18]-FMiso administration in humans. 
 
18F-EF5 Biodistribution and clinical data 
We have recently completed a Phase I biodistribution study of 18F-EF5 in cancer patients.  The primary 
goal of this Phase I study was to determine the biodistribution and excretion of 18F-EF5 and to estimate 
the radiation absorbed dose, metabolism, and safety of this drug.  Sixteen patients (8 men, 8 women) 
with histologically confirmed malignancy received a mean intravenous infusion of 217 MBq (range 107-
364 MBq) of 18F-EF5 at the University of Pennsylvania(10) and University of Turku(6).  Over a 4-6 hour 
period, four to five serial PET or PET/CT scans were obtained.  To calculate the time-activity curves, 
residence times, and radiation dosimetry estimates, volumes of interest were drawn over the source 
organs for each PET scan or on the CT for each PET/CT scan.  Serial blood samples were obtained to 
measure blood clearance.  Bladder wall dose was calculated based on urine activity measurements.  
Safety was assessed by vital sign, ECG, and blood and urinalysis monitoring.  The mean urinary 
bladder radiation absorbed dose was the largest at 0.077 ± 0.043 mSv/MBq (mean ± SD).  There were 
no other mean organ radiation doses exceeding 0.10 mSv/MBq.  The average effective dose equivalent 
of 18F-EF5 was determined to be 0.018mSv/MBq calculated on a 4.8 hour voiding interval.  18F-EF5 was 
well tolerated in all subjects. No serious adverse events were noted.  
 
In conclusion, the average effective dose equivalent (EDE) and effective dose of 18F-EF5 was 0.018 
mSv/MBq and 0.016 mSv/MBq, respectively, which is less than that of 18F-FDG (EDE = 0.030 
mSv/MBq).  The dose to the bladder wall was the highest.  
 
Summary 
 
The Roberts Proton Therapy Center within the Department of Radiation Oncology at Penn Medicine will be the 
largest proton therapy center in the world and will employ advanced technologies such as multileaf collimators.  
Although proton therapy has been used elsewhere to treat patients with soft tissue sarcoma and proton 

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therapy is approved by the US Food and Drug Administration, we propose this study to determine the 
feasibility and safety of proton therapy delivered at the Roberts Center for patients with STS of the extremity.  
Patients may, as part of their standard treatment regimen, also undergo other therapies as per the standard of 
care. 
 
There will be 2 cohorts of patients:  (1) extremity STS patients undergoing pre-operative radiotherapy and (2) 
extremity STS patients undergoing post-operative radiotherapy.  There will be two phases of this study.  In the 
first part of the study, the feasibility and safety (as defined below) of proton therapy will be evaluated in 12 
patients within each cohort.  In this feasibility study, patients with STS of either the upper or lower extremity will 
be evaluated.  If proton radiotherapy is found to be feasible and safe, the study will proceed to Phase II.  Since 
a majority (80%) of patients seen in the Department will have lower extremity STS and complication rates are 
high in this subgroup, we will restrict enrollment to STS of the lower extremity in the Phase II study.  In Phase II 
(for the pre-operative group), we will evaluate the risk of wound complications within 4 months of surgery 
compared to historical data from the randomized clinical trial described above19.  In Phase II (for the post-
operative group), we will evaluate the functional outcome (e.g., fibrosis, joint stiffness, edema) of patients at 
two years after the completion of therapy compared to historical data from the randomized clinical trial 
described above 19. 
 
1 
STUDY OBJECTIVES 
 
This study will be performed in two phases.  In the first phase, feasibility will be established using the primary 
objectives set below.  The second part will begin no earlier than 30 days after the last patient in the initial 
phase has completed treatment and once safety and feasibility has been verified. 
   
Primary Objectives for feasibility phase of study 
The primary objective of this study is feasibility.  The study will be deemed infeasible if 10% or 
more of pts experience one of the following: 
a. 
Patient cannot be given treatment because anatomy is such that a dosimetrically satisfactory 
treatment plan cannot be devised (95% of planning target volume covered by 95% of the dose). 
b. 
Patient is unable to tolerate more than 25% of treatments (for any reason—unable to set patient 
up within acceptable limits of tolerance, patient unable to tolerate treatment position or 
immobilization for duration of treatment) using proton radiotherapy.  Note: this end-point is 
proton-therapy specific, and indicates feasibility of proton as opposed to photon radiotherapy.  
For example, if the proton-specific patient immobilization/positioning is not well tolerated or extra 
time in the treatment position is too long or uncomfortable, protons delivered per protocol would 
be deemed not feasible compared to photons.  Any treatments that cannot be delivered with 
protons will be delivered using photons, so that the patient receives the prescribed 
tumor dose.   
c. 
Patient is unable to complete all of his/her treatments within 10 days of estimated date of 
treatment completion or requires a treatment break greater than 5 days.   
d. 
Additionally, no greater than 33% of patients experience a significant toxicity (defined in Section 
7.1.2). 
 
Primary Objectives for second phase of study: 
o The primary objective of Phase II in the pre-operative group will be to evaluate the wound complication 
rate of pre-operative proton radiotherapy in patients with STS of the lower extremity. 
o The primary objective of Phase II in the post-operative group will be to evaluate the functional outcome 
(e.g., fibrosis, joint stiffness, edema) at two years after post-operative proton radiotherapy in patients 
with STS of the lower extremity. 
 

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Secondary Objectives for both phases of study: 
o To assess the local control rate, progression-free survival and overall survival of proton radiotherapy for 
STS of the extremity. 
o To determine the acute and late toxicities of proton radiotherapy to the extremities. 
o To monitor for effects of proton treatment on tumor and normal tissues using radiographic imaging 
(both cohorts) or ex-vivo analysis of tissue samples (pre-operative cohort only). 
o To examine the relationship between pre-treatment hypoxia as determined by F18-EF5 scanning and 
treatment outcome. 
 
2 
SUBJECT SELECTION AND WITHDRAWAL 
 
This study plans to enroll 80 evaluable subjects (40 evaluable patients in each cohort) over 7 years.  For pre-
operative patients, evaluablility requires a minimum of 4 months of follow-up after surgery.  For post-operative 
patients, evaluablility requires a minimum of 2 years of follow-up from the end of radiotherapy.  
 
Inclusion Criteria 
o Patients with a histologic diagnosis of soft tissue sarcoma of the extremities are eligible for this study.   
o Patient must be ≥ 18 years of age. 
o Patients must have evidence of disease limited to the extremities.  
o For the pre-operative group, patients must be considered operable/resectable and a candidate for pre-
operative radiotherapy as judged by the attending surgeon and radiation oncologist.  The clinical 
evaluation of patients will include a work up as per the standard of care.  All patients in the pre-
operative group will be evaluated for this protocol PRIOR to the initiation of therapy. 
o For the post-operative group, patients must be considered operable/resectable (if evaluated prior to 
resection) and a candidate for post-operative radiotherapy by the attending surgeon and radiation 
oncologist.  The clinical evaluation of patients will include a work up as per the standard of care.  
Patients in the post-operative group may be evaluated PRIOR to the initiation of any therapy or may be 
referred for evaluation after surgical resection. 
o ECOG status of 0-2.  
o Patients must sign a document that indicates that they are aware of the investigative nature of the 
treatment of this protocol, and the potential benefits and risks.  Patients unwilling or unable to sign 
informed consent are excluded from the study. 
o Women of child-bearing potential as long as she agrees to use a recognized method of birth control 
(e.g. oral contraceptive, IUD, condoms or other barrier methods etc.).  Hysterectomy or menopause 
must be clinically documented. 
o Negative urine pregnancy test for females of childbearing potential on the day of the F18-EF5 PET 
scan prior to F18-EF5 injection 
 
 
 
Exclusion Criteria 
o Pregnant women, women planning to become pregnant and women that are nursing. 
o Patients who experience surgical complications that prevent radiation from starting for 5 months or 
more, unless there is evidence of gross residual disease. 
 
Subject Recruitment and Screening 
Subjects will primarily (but not solely) be recruited from either at Penn Medical Center or the Department of 
Defense Oncology practices.  The treating radiation oncologist will determine if the patient is a potential 
research candidate and has the capacity to consent.  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 a qualified member of the research team in the 

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Radiation Oncology department at the University of Pennsylvania and request availability for enrollment.  
Should slots be available, a qualified member of the research team will initiate the formal consent process.  
This person will interview the potential subject with privacy considerations, explain the requirements of the 
study and provide a copy of the Informed Consent Form.  The person obtaining consent will state the volunteer 
nature of research and advise the subject to take sufficient time to discuss the study 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 screening procedures will be performed.  A series of questions will be asked by the 
person obtaining consent to verify patient eligibility based upon the criteria outlined in Section 3.1 and Section 
3.2.  After the eligibility is established, a subject study number will be issued.  Eligibility is confirmed with the 
study investigator.  All members of the research team will have successfully completed patient oriented 
research training.  Subjects will receive all proton radiotherapy in Penn Medicine’s Department of Radiation 
Oncology.  Subjects will not be paid for participating in the study.  All medical costs will be the responsibility of 
the subjects and/or their insurers.  Cost of living will be the responsibility of the subjects. 
 
At the University of Pennsylvania, we see approximately 20 cases of extremity STS per year. We anticipate 
that with the availability of proton radiotherapy, these numbers may increase.  We estimate an annual accrual 
of 12 subjects per year for each cohort.  We will also treat patients either preoperatively or postoperatively from 
Walter Reed Army Medical Center.  In addition, this protocol will be listed on our web site as a formal protocol 
and information of its availability will be made known to treating professionals throughout our satellites as well 
as other referring physicians.  These patients, if treated preoperatively with radiation therapy, will be required 
to have their surgery at the Hospital of the University of Pennsylvania.   
 
Early Withdrawal of Subjects 
When and How to Withdraw Subjects? 
Recurrent or Progressive Disease: Subjects who have clinical or radiologic evidence of 
recurrent disease will undergo an evaluation to document the nature of the abnormality.  If 
recurrent or progressive cancer is diagnosed, the subject will be considered off study at that 
time. 
Subject Participation:  Subjects may be withdrawn if the subject decides to refuse continuation 
of treatment or follow-up.  Subjects may also be withdrawn for non-compliance with the protocol 
or withdrawal of consent.  The reasons for withdrawal will be documented. 
PI Decision:  Subjects may be withdrawn at any time during the study if the PI believes it is in 
the subject’s best interest.  In this event, the reasons for withdrawal will be documented. 
 
Once the subject has discontinued treatment, the primary reason for discontinuing treatment 
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.   
 
Every effort will be made to follow subjects off study for toxicity and survival.  Survival will be 
followed for a minimum of 5 years by means of scheduled appointments and available medical 
records.  Every effort will be made to follow for overall survival. 
 
3 
RADIATION THERAPY  
 
Treatment Planning, Imaging and Localization Requirements 
Immobilization:  As per standard of care, all subjects will be immobilized in a custom designed device in the 
appropriate position as determined by the attending radiation oncologist.  Radiotherapy treatment planning CT 
scans and/MRI scans (with or without contrast, as per standard of care) will be required to define gross target 
volume (GTV) and clinical target volume (CTV).  The treatment planning CT scan (or MRI scan) should be 
acquired with the subject in the same position and using the same immobilization device as for treatment. 
Treatment planning will be done using a 3D treatment planning system.  All tissues to be irradiated must be 
included in the CT/MRI scan. The planning CT/MRI scan will be done at ≤5 mm intervals.  A second treatment 

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planning CT/MRI scan may be performed during the course of radiotherapy as necessary.  Imaging including 
FDG-PET/CT and/or MR imaging maybe fused with the planning CT images to better visualize the anatomy 
when clinically indicated. 
 
Target Contouring 
Pre-operative patients: 
Gross Tumor Volume (GTV) is defined as all known gross disease determined from CT, MRI, and 
clinical information.   
Clinical Target Volume 1 (CTV1) is defined as the GTV plus areas that are considered to contain 
potential microscopic disease which typically would be 5 cm inferior and superior to the GTV and 
2 cm either medially or laterally. 
High risk CTV (CTV2) for pre-operative cases will be determined by the attending radiation 
oncologist in conjunction with the attending surgeon and will include areas of the GTV that are 
thought to be difficult to resect or at high risk for positive margins.   
Planning Target Volume (PTV) will provide a margin as determined by the attending radiation 
oncologist around each GTV or CTV to compensate for the variability in treatment set up and 
internal organ motion. 
 
Post operative patients: 
GTV will represent any gross residual disease. 
Clinical Target Volume 1 (CTV1) is defined as the GTV and the resection bed plus areas that are 
considered to contain potential microscopic disease which typically would be 7-10 cm inferior and 
superior and 2 cm either medially or laterally to the resection bed. 
Clinical Target Volume 2 (CTV2) is defined as the GTV and the resection bed plus areas that are 
considered to contain potential microscopic disease which typically would be 5 cm inferior and 
superior and 2 cm either medially or laterally to the resection bed. 
Clinical Target Volume 3 (CTV3) is defined as the GTV and the resection bed plus areas that are 
considered to contain potential microscopic disease which typically would be 3 cm inferior and 
superior and 1-2 cm either medially or laterally to the resection bed. 
Clinical Target Volume 4 (CTV4) will be determined by the attending radiation oncologist in 
conjunction with the attending surgeon and will include areas of the resection bed that contain or 
are thought to be at high risk for positive margins.   
Planning Target Volume (PTV) will provide a margin as determined by the attending radiation 
oncologist around each GTV or CTV to compensate for the variability in treatment set up and 
internal organ motion. 
o Volumes may be modified (reduced) to reflect a compromise between the desired CTV dose to 
be achieved and the radiation dose limits and the cost-function parameters for the organs at 
risk.  
 
Normal Structures  
The dosimetrist will define two structures: Skin-2 (2mm thick surface) and Skin-PTV (all PTVs will 
be subtracted from the surface contour).  Skin-PTV is the normal tissue structure that is all tissue 
other than what is contoured as something else. 
Organs at risk (OAR) are normal tissue structures in or near the radiation field that may put the 
patient at risk for toxicities.  The OAR volumes are contoured as visualized on the planning scan.  
Planning OAR is the OAR expanded for setup uncertainty or organ motion.  The PAR may be 
created as determined by the attending radiation oncologist.   
 
Dose fractionation and specification  
Preoperative radiotherapy:  Doses for preoperative radiotherapy will be delivered 1.8-2.0 Gy (RBE)/fx/day 
delivered to PTV1.  The total dose will be 50-50.4 Gy(RBE) to PTV1.  A simultaneous in field boost of up to 4-

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5.4 Gy(RBE) to PTV2 [total dose 54-55.8 Gy(RBE)] may be given as deemed appropriate by the attending 
radiation oncologist. 
Postoperative radiotherapy:  A shrinking field technique will be used.  CTV1 will be treated in the initial field at 
1.8 Gy(RBE)/fx/day delivering a total dose of 45 Gy(RBE) to PTV1.  CTV2 will be treated with 1.8 
Gy(RBE)/fx/day delivering 9 Gy(RBE) to PTV2 for a cumulative dose of 54 Gy(RBE).  CTV3 will be treated with 
1.8 Gy(RBE)/fx/day delivering 9 Gy(RBE) for a cumulative dose of 63 Gy(RBE).  In patients with close or 
positive margins, CTV4 will be treated with 1.8 Gy(RBE)/fx/day delivering for a cumulative dose of between 66-
72 Gy(RBE) as determined by the attending radiation oncologist.  Higher doses may be delivered to localized 
areas of gross residual disease if clinically indicated. 
 
For the pre-operative cohort, additional postoperative may be performed for patients with close or positive 
margins, patients felt to be at high risk for positive margins, or patients with gross residual disease.  The dose 
specifications are as follows: PTV (area of concern for recurrence + margin) dose:  16-22 Gy(RBE) for close, 
positive, or ‘at risk’ margins; 22 – 32 Gy(RBE) for gross residual disease that cannot or will not be resected in a 
second surgical procedure.   
 
Treatment Planning  
3.1.1 Dose specification:  95% of PTV to receive ≥ 95% of the prescribed dose.   
 
Treatment Duration 
Proton radiation therapy will in most instances be completed within 6 or 8 weeks of the start of treatment for 
the feasibility.  This may be extended if subjects require a break from treatment. Criteria for break could include 
any Grade 4 toxicity, depending on the clinical situation as determined by the attending radiation oncologist.  
Further treatment plans will be decided at the discretion of the treating physician.   
 
External Beam Equipment and Beam Delivery  
Protons:  Treatments will be administered at the University of Pennsylvania Roberts Proton Facility, which 
houses a high energy cyclotron with fixed angle and rotating gantries that produce scattered or pencil beam 
scanned proton beams.  All charged particle treatment will be given with the patient in the appropriate 
immobilization device.  Film or digital images will be taken prior to the initial treatment to verify the position of 
the patient and the aperture and as appropriate.  A radiation oncologist will check the first film on all fields.  A 
radiation therapist will check subsequent films taken before treatment.  All set-up films will be permanently filed 
for all subjects.  Subjects will be treated with respiratory gating to account for respiration as appropriate. 
 
Quality Assurance  
Daily portal films, and/or daily online radiographic imaging will be performed during therapy.  Fiducials will help 
reproduce daily set up and minimize set-up variations as appropriate.  All periodic and patient-based quality 
assurance for patient treatment will conform to established Penn Radiation Oncology Department standards 
and all treatment plans will be reviewed at weekly quality assurance meetings (chart rounds).   
 
4 
SURGERY , CHEMOTHERAPY AND IMAGING 
 
Radiation therapy will be performed either preoperatively or postoperatively.  This decision will be made by the 
attending surgeon and radiation oncologist.  For patients in the preoperative cohort, surgery will be performed 
4-12 weeks after completion of radiotherapy.  This will consist of resection of all gross tumor with adequate 
margins, sampling of lymph nodes and any other areas suspicious for involvement by the sarcoma as clinically 
appropriate.  For patients in the postoperative cohort, radiotherapy will begin 3-8 weeks following surgery.   
 
Chemotherapy (standard of care as determined by medical oncology) may be given no sooner than day 30 
after radiation therapy for the post-operative patients or day 30 after surgery if radiotherapy is pre-operative as 
deemed clinically appropriate by the attending surgeon and radiation oncologist.  
 

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18F-EF5 PET Scan 
Up to 4 weeks prior to treatment with either surgery or proton radiation, 18F-EF5 will be administered in the 
Department of Nuclear Medicine in the Hospital of the University of Pennsylvania (HUP) or in the Department 
of Radiation Oncology in the Perelman Center for Advanced Medicine.  Approximately 5mCi of 18F-EF5 will be 
administered as an IV bolus (for details of 18F-EF5 synthesis, see specific methods, below).  After the injection 
of 18F-EF5, subjects will be asked to remain in the Nuclear Medicine or Radiation Oncology waiting room 
during the free time before their PET/CT scan, where they may relax until they are required to go to the 
PET/CT scan room.  There is no bathroom restriction during this time.  The Scan will be performed at 180 
minutes (evaluation of hypoxia) following injection. Subjects will be positioned on the PET-CT imaging bed 
comfortably with their head secured in the head hold of the PET instrument.   
 
 
 
 
TIME (APPROXIMATELY) 
SCHEDULE OF EVENTS 
-30 minutes 
Transport to nuclear medicine facility 
 
 
-10 minutes 
Placement of one intravenous line 
0 minutes 
Injection of 18F-EF5 (≈ 5 mCi) 
1-179 minutes 
Free time 
180 minutes 
PET/CT Scan 
 
 
215 minutes 
Study completed 
 
 
 
Table 3: 18F-EF5 PET Protocol  
 
Expected Adverse Events Associated with radioactive 18F-EF5. 
The estimated radiation exposure from 5 mCi of 18F-EF5 is 2.5 mGy (see section 2.4, p. 10).  This is the 
equivalent of less than one year of exposure to natural background radiation (1 year exposure approximately 
3.6 mGy assuming quality factor of 1).  For comparison purposes, a bone scan is estimated to deliver an 
effective dose between 3.8 and 7.7 mGy (42).  A body CT scan is estimated to deliver 6-16 mGy (42, 43).  
Therefore, the amount of radiation to which patients will be exposed by 18F-EF5 PET scanning is well below 
that delivered by other standard radiological tests and is not expected to cause problems related to radiation 
exposure.  18F-EF5 and EF5 are identical from a chemical standpoint.  The amount of labeled drug will be less 
that 5 mg, compared with 1500 mg (for a 70 kg patient) of unlabeled drug.  Therefore no chemical toxicity can 
be expected for the small additional amount of labeled drug. 
 
Radiation Exposure Based on Pharmacokinetic Studies of 18F-EF5 in Human Subjects 
Potential radiation toxicities are limited by the short half-life of [18F] of 1.83 hours.  Clinical experience with 
other fluorine-18 labeled agents designed to image tumor hypoxia or other metabolic events confirms that the 
short half-life of [18F] results in no significant radiation toxicity. In order to determine more precisely the 
radiation exposure from [18F]-EF5, pharmacokinetic studies are currently underway.  The “worst case scenario” 
would be if the entire dose of [18F]-EF5 stayed within the body.  If there were uneven biodistribution, certain 
organs might get a relatively higher dose such as is the case with the thyroid with radioactive iodine.  For EF5, 
the major route of excretion is through the urinary bladder with substantial excretion via the gall bladder.  
Based on pharmacokinetic studies to date, bladder excretion is extremely consistent for each subject, with a 
typical rate of approximately 5% per hour.  Therefore, the radiation risk from [18F]-EF5 will be predicted to be 
nearly identical to that for the 18F-FDG dose used in a routine clinical PET scan.  The estimated dose to the 
subject based on data from [18F]-EF5 administration in human subjects is about 0.025 mSv/MBq.  This results 
in a radiation exposure of about 4 mSv for a standard subject getting 5 mCi, and is comparable to the annual 
background of about 3.6 mSv.  As mentioned above, organs that concentrate the radiotracer get a higher dose. 
Therefore, the urinary bladder wall is expected to receive about 5 times this dose (20 mSv), and the gall 
bladder wall receives about 2.5 times (10 mSv). 
 
Dose Rationale and Risk/Benefits 

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We have specified a dose range centered around 5 mCi (range: 2.5 – 7.5 mCi) since it is not possible to 
determine exactly how much [18F] labeled drug will be made prior to its synthesis and purification.  If an 
individual synthesis should produce less than 5 mCi, there is confidence that acceptable (although more noisy) 
data can be obtained with as little as 2.5 mCi.  Yields lower than 2.5 mCi will not be used. Conversely, it would 
be difficult to accurately subdivide the final sterile dose if it was somewhat higher than 5 mCi.  However, a dose 
greater than 7.5 mCi will be subdivided in order to administer a final subject dose of 5 mCi. 
 
As described above, the estimated radiation exposure from 5 mCi of [18F]-EF5 is 4 mSv based on the pre-
clinical studies of [18F]-EF5 dosimetry.  This is the equivalent of about one year of exposure to natural 
background radiation.  For comparison purposes, a bone scan is estimated to deliver an effective dose 
between 3.8 and 7.7 mSv (42).  A body CT scan is estimated to deliver 6-16 mSv (42, 43).  Therefore, the 
amount of radiation to which subjects will be exposed to by [18F]-EF5 PET scanning is within the range of that 
delivered by other standard radiological tests and is not predicted to result in unacceptable radiation exposure.   
[18F]-EF5 and EF5 are identical from a chemical standpoint.  The amount of labeled drug will be less than 5 
mg.   
 
PHARMACEUTICAL INFORMATION - [18F]-EF5  
The chemical properties and synthesis of [18F]-EF5 are described in detail in the INDs held by Varian 
Biosynergy Inc. and Stephen M. Hahn, MD. 
 
Availability of Study Drug 
[18F]-EF5 will be synthesized at the cyclotron facility of the University of Pennsylvania.  Dr. Richard Freifelder 
or his designate in the Department of Nuclear Medicine will maintain a complete log of each manufacture and 
disposition, including results of all SOPs.   
 
Dispensing of Study Drug 
Following the manufacture of [18F]-EF5 at the PENN cyclotron facilities, it is hand-carried to the Department of 
Nuclear Medicine in the Hospital of the University of Pennslvania or to the Department of Radiation Oncology 
in the Perelman Center for Advanced Medicine where the radioactivity is assessed.  It is anticipated that the 
activity will be in the range of 2.5-7.5 mCi.  For doses greater than 7.5 mCi, the study drug will be subdivided to 
ensure that the dose administered will be 5 mCi.  [18F]-EF5 will then be drawn into a sterile syringe for 
intravenous subject administration. 
 
Treatment Regimen 
[18F]-EF5 will be administered by a qualified user in the Department of Nuclear Medicine in the Hospital of the 
University of Pennsylvania or in the Department of Radiation Oncology in the Perelman Center for Advanced 
Medicine.  It will be administered as an IV bolus injection.  The dose will be approximately 5 mCi (acceptable 
range: 2.5-7.5 mCi).  
 
Destruction of Study Drug 
If the entire study drug dose is administered, the radioactive syringe will be disposed of into the radioactive 
waste in the Department of Nuclear Medicine or in the Department of Radiation Oncology in the Perelman 
Center for Advanced Medicine.  As the radioactive half-life of 18F is 1.83 hours, we anticipate that by the end of 
a working day, the radioactive syringe can be safely disposed of in the standard biologic waste.  In the event 
that the study drug is not administered or only partially administered, the radioactive syringe and its contents 
will be disposed of in the radioactive waste in the Department of Nuclear Medicine or in the Department of 
Radiation Oncology in the Perelman Center for Advanced Medicine.  It will be subsequently disposed of in the 
standard biologic waste upon sufficient decay of its radioactivity. 
 
 
 

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5 
STUDY PROCEDURES 
 
 
Pre-treat Day of 
F18-EF5 
PET/CT 
Prior to 
injection 
Weekly 
during 
RT 
Visit prior 
to surgery 
30 days 
post 
surg/RT1* 
Q3 months 
for 2 years, 
then q6 
months for 
years 3 - 5 
after 
surgery/RT 
Yearly 
(as long as 
the patient 
wishes to be 
followed) 
Tests and 
Observations 
 
 
 
 
 
 
 
History and PE 
X 
 
X 
X 
X 
X 
X 
ECOG PS 
X 
 
 
 
 
 
 
Biopsy 
X 
 
 
 
 
 
 
Urine 
Pregnancy Test 
 
X2 
 
 
 
 
 
 
Toxicity 
Assessment 
X 
 
X 
 
 
X 
 
Tumor 
Measurement 
X1 
 
 
X 
 
X 
 
18F-EF5 PET 
Scan (optional) 
X³ 
 
 
 
 
 
 
1- *Post radiation/surgery follow-up schedule defined for each cohort in Section 6. 
2- Urine pregnancy test is routinely performed prior to PET/CT scanning as departmental standard. 
3 – Subjects may participate in study with or without perrforming 18F EF5 PET scan.  This is a subject 
option.  
Post-treatment Evaluation and follow-up 
All subjects will be evaluated prior to initiation of treatment and weekly during the course of radiotherapy.  For 
patients receiving pre-operative radiation, a visit will occur prior to surgery.  This visit will involve an interval 
history and physical.  All patients will be seen for a first post-operative/post-radiation office visit with either the 
attending radiation oncologist or surgeon no more than 30 days following surgery/radiotherapy or discharge 
from the hospital, whichever comes later.  Pre-operative patients will be seen after surgery, weekly x 1 month, 
then every 2nd week x 1 month, then monthly for 3 months.  Post-operative patients will be seen one month 
after surgery and then in 3 months.  Follow up visits for pre-operative and post-operative patients will be with 
either the attending surgeon or radiation oncologist every 3 months for two years, and every 6 months 
thereafter for 3 years.  These office follow-up visits will consist of an interval history and physical and imaging 
studies as clinically indicated.  The wound complication endpoint will be scored at 4 months after surgery in the 
pre-operative group.  Post-operative patients will be scored for fibrosis, edema and joint stiffness within 2 years 
after after radiation.   
 
Assessment of Tumor Response   
Tumor Response (RECIST criteria): RECIST criteria will only be evaluated after radiation just prior to surgery 
in the pre-operative patients. Post-operative patients will not be evaluated since they undergo complete 
resection of STS.  
 
Target Lesions: 
– Complete Response (CR): Disappearance of all target lesions. 
– Partial Response (PR): At least a 30% decrease in the sum of the longest diameters of 
target lesion, taking as reference the baseline sum of the longest diameters. 

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– Progressive Disease (PD): At least a 20% increase in the LD of the target lesions, 
taking as reference the smallest sum of the LD recorded since the treatment started or 
the appearance any new lesion(s) 
– Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the treatment 
started. 
 
Non-Target Lesions: 
– Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker levels. 
– Incomplete Response/Stable Disease (SD):  Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker levels above normal limits. 
– Progressive Disease (PD):  Unequivocal progression of existing non-target lesions or 
any new lesion(s) 
 
Confirmation of Response (used only for studies with response as primary endpoint) 
– To assign a PR or CR, changes in tumor measurement must be confirmed by repeat 
assessments no less than 4 weeks after the criteria for response are first met. (Reflect 
this in your study procedures table in section 6) 
– To assign SD, measurements must have met the stable disease criteria at least once 
after study entry at “X” interval (as defined by protocol). 
 
Failure  
– Local failure is defined as: evidence of tumor growth in any direction beyond that 
present of the pre-treatment imaging studies or the appearance of tumor in tissues 
previously scored as sites of subclinical disease. The imaging studies are to be 
comparable in technical factors. 
– Marginal failure is defined as appearance of tumor growth at the margin of the target 
volume 
– Nodal Failure: Failure in regional lymph nodes. 
– Distant failure is defined as appearance of tumor at sites beyond regional nodal and 
marginal site. 
– Progression-Free Survival: duration measured from first day of treatment to first 
documented failure, death due to any cause or last patient contact alive. 
– Overall Survival: Duration measured from first day of treatment until death due to any 
cause or last patient contact alive. 
– Time to local failure, time to distant failure, PFS and OS will be calculated from first day 
of radiation in the pre-operative patients and calculated from day of surgery in the 
post-operative patients.  
 
PET scan imaging and analysis 
PET studies will be performed on a PET/CT scanner in the Department of Radiology in the Hospital of the 
University of Pennsylvania or in the Perelman Center for Advanced Medicine. PET scans will be processed 
with corrections for randoms, scatter, and attenuation before reconstruction.  The randoms are subtracted 
directly (on-line) using a delayed coincidence window.  The application of an accurate scatter correction 
method is necessary to achieve absolute quantification, and is particularly important for 3D PET.  We have 
developed a Single-Scatter-Simulation (SSS) algorithm for this purpose (44) which has been extended for TOF 
data.  The basic idea is to calculate from first principles the scatter distribution associated to an activity and 
scatter medium distribution, under the assumption that scatter is only due to single Compton scatter events.  
The assumption of single-event scatter is a good approximation for a system with good energy resolution, such 
as LYSO, particularly with a high energy threshold as used in the Gemini TF scanner.  In practice, we use an 
estimate of the activity distribution from the reconstructed image of total counts, and the distribution of the 

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scatter medium is obtained from the reconstructed transmission CT scan, which is also used for attenuation 
correction. 
 
For TOF reconstruction, we use the list-mode reconstruction implemented by Philips that is based upon a TOF 
list-mode maximum-likelihood algorithm which was originally developed in our laboratory at the University of 
Pennsylvania (45).  This algorithm models data corrections in the algorithm and uses consecutively ordered 
subsets to accelerate the reconstruction.  The Poisson statistics of the data are preserved by using the data in 
their original form (i.e., without binning) and incorporate the physical effects of PET imaging in the system 
model.  The TOF kernel is modeled as a one-dimensional Gaussian function along the LOR and is applied in 
both the forward-projection and back-projection operations.  We reconstruct patient studies using the protocol 
defined at the University of Pennsylvania that uses unrelaxed OSEM (λ=1) with 33 subsets and stops after 
three iterations for practical reconstruction time.  A fully 3D list-mode iterative reconstruction algorithm is 
computationally intensive and required specialize computer equipment and software development to 
implement in practice.  Using a 10-node (dual CPU) computer cluster, the image processing with this algorithm 
proceeds in parallel with data acquisition and is typically completed for clinical whole-body (multi-bed) studies 
10-30 minutes after the end of the acquisition, depending on the number of counts collected. 
 
The data corrections and 3D reconstruction that have been described help to improve the accuracy of 
quantification of the studies, in particular tumor contrast.  Nevertheless, we do not expect that full recovery of 
contrast of small tumors will be achieved.  Typically this is possible only if the tumor size is large compared to 
the spatial resolution.  For example, the contrast of a 2-cm tumor is only about 50% of its true value, assuming 
that the region-of-interest is equal to the size of the tumor.  Our image reconstruction algorithm has the 
capability of incorporating the measured point spread function into the system model so that we can recover 
the spatial resolution loss that is more significant as the distance from the center of the field-of-view increases. 
The resolution recovery technique will be further developed and validated for the tumor studies that will be 
performed for this project. 
 
Image registration of the PET images with other modalities (CT or MRI) will be performed using a mutual 
information algorithm developed at PENN and similar to the approach of Mattes (46).  Our algorithm allows 
non-rigid, as well as rigid registration, using a set of user-defined correspondence points as constraints.  For 
intra-patient comparisons between the PET scans and the MRI or CT, the fully automated rigid registration is 
expected to have sufficient accuracy. 
 
Tumor ROIs will be drawn with the help of MRI and/or CT images.  Tumor to normal tissue ratio will be 
determined in each voxel of the ROI. 
 
6 
STATISTICAL PLAN 
 
This is a study of proton therapy in extremity soft tissue sarcoma (STS). Patients will be stratified into pre- and 
post-operative cohorts. The trial will be conducted in two phases, first, a feasibility study and then, a phase II 
study to detect reduced complication rates. Since proton is a new treatment modality at PENN, the first proton 
trial conducted in each cancer site will be a feasibility study, in order to gain experience on both the logistics of 
proton planning, dosimetry, scheduling and delivery and patient safety issues. 
 
6.1  FEASBILITY STUDY.  
 
Design and Objectives: 
This feasibility trial is designed to establish feasibility and safety of proton therapy. Patients are 
stratified into pre-operative and post-operative groups with 12 patients in each stratum.  Patients 
with STS of the upper or lower extremity will be treated in the feasibility study.  These cohorts will 
be accrued, evaluated and advanced to the second phase independently.  Patients enrolled in the 

Protocol “Proton Radiotherapy for Extremity Soft Tissue Sarcoma” (PI: Stephen Hahn, MD) 
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feasibility study will continue to be followed for secondary endpoints, such as late toxicity and 
clinical efficacy.  
 
Pre-operative patients will receive 5-6 weeks of radiation.  Four to 12 weeks after completion of 
radiotherapy they will undergo surgery. In the feasibility study, pre-operative patients will be 
followed for a minimum of 90 days after start of radiation treatment or 30 days after surgery, 
whichever comes later to determine feasibility and safety (acute toxicity) before moving to the 
second phase of the study.  
 
Post-operative patients will receive 8 weeks of radiation.  Four weeks after completion of 
radiotherapy patients may receive chemotherapy, if clinically indicated.  Post-operative patients 
will be followed for a minimum of 90 days after start of radiation treatment, to determine feasibility 
and safety (acute toxicity) before moving to the second phase of the study.  Toxicities experienced 
during the post-radiation follow-up window will be carefully evaluated for relatedness to proton 
therapy or to surgery or chemotherapy.  
 
Endpoints 
 
Primary Endpoints:  
(i) Feasibility will be based on multiple radiation planning and treatment parameters. Should a 
patient experience one of the following events, treatment will be deemed infeasible: 
Patient cannot be given treatment because anatomy is such that a dosimetrically satisfactory 
treatment plan cannot be devised. For example, the dosimetry is unsatisfactory if <95% of target 
volume is covered by 95% of the dose. 
Patient is unable to tolerate 25% of treatments using proton radiotherapy, that is, up to 25% of 
treatments could be delivered using photons.  Reasons for missed treatments may include: unable 
to set patient up within acceptable limits of tolerance, patient unable to tolerate treatment position 
or immobilization for duration of treatment). 
Patient is unable to complete all of his/her treatments within 10 days of estimated date of 
treatment completion or requires a treatment break greater than 5 days. 
(ii) Acute toxicity is defined as any grade 3 or higher hematologic or non-hematologic toxicity that 
is probably or definitely related to radiotherapy (not surgery).  All toxicities observed within 90 
days from start of radiotherapy, will be graded by NCI CTC Version 4.0.  For pre-operative patients 
all toxicities observed within 90 days after start of radiation treatment or 30 days after surgery, 
whichever comes later, will be graded.  
 
Secondary Endpoints: 
(i) Late toxicity is defined as any grade 3 or higher hematologic or non-hematologic toxicity which 
occurs after 90 days from start of therapy.  Late toxicities will be graded according to the 
RTOG/EORTC late toxicity criteria.  The time frame for late toxicity is open-ended and late 
toxicities have been known to occur a year or more after therapy.  Follow-up for late toxicity will 
cease when a patient experiences disease progression, since 2nd line therapies may then be 
initiated.  
(ii) Wound complication is defined as a secondary operation under general or regional anesthesia 
for wound repair or wound management without second operation.  Wound management includes 
an invasive procedure without general or regional anesthesia, readmission for wound care such as 
iv antibiotics, or persistent deep packing for 120 days or longer.  Patients will be assessed for 
wound complications which develop within 4 months after surgery.  
(iii) Fibrosis and joint stiffness will be graded according to EORTC/RTOG late radiation toxicity 
criteria. Edema will be graded as 0= none, 1= mild, 2= moderate, 3= severe, 4= very severe, 
according to the criteria of Stern (Stern TN. Clinical examination: a textbook.  Year Book Medical 

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Publishers, 1964).  Patients will be assessed for fibrosis, joint stiffness and edema within 2 years 
of completion of radiotherapy.  
 
Clinical Efficacy is defined for pre-operative patients as overall response rate (CR + PR 
according to RECIST criteria) which is scored after radiation and before surgery.  
Progression-Free Survival is defined from first day of treatment to first documented 
failure, death due to any cause or last patient contact alive.  Overall Survival is defined 
from first day of treatment until death due to any cause or last patient contact alive.  
Time to local failure, time to distant failure, PFS and OS will be calculated from first day 
of radiation in the pre-operative patients and calculated from day of surgery in the post-
operative patients.  
 
Rules for Early Termination for Feasibility, Acute Toxicity and Wound Complication:  
Bayesian probability calculations will be employed to define rules of early termination and end of 
trial evaluation for feasibility and safety.  The tables below indicate termination rules after groups 
of 3 patients have been treated. Hundreds of patients with certain types of cancer have undergone 
radiation therapy with protons.  Thus, we will assume some “prior” feasibility and safety data for 
protons delivered at the standard radiation dose for our Bayesian calculations. We will assume 
prior information equivalent to that of 6 treated patients, which is commonly required to establish 
feasibility and safety in a standard 3+3 phase I trial design.  
 
Feasibility – conducted separately for each stratum 
We will assume a beta (5,1) prior, which is information equivalent to feasibility established in 5 of 6 
treated patients.  A feasibility rate > 90% is considered acceptable.  If the number of patients 
deemed feasible is less than or equal to the number in the table below then termination will be 
considered as it is highly unlikely that the feasibility rate is > 90%, as noted by the Bayesian 
posterior probabilities. 
 
Bayesian Rule for Feasibility 
 
Patients treated  
3 
6 
9 
12 
Patients who are feasible 
1 
4 
6 
9 
Posterior Prob[feasibility rate 
>90%] 
0.0
4 
0.0
9 
0.0
4 
0.0
8 
Action  
Terminate enrollment 
 
 
Acute Toxicity – conducted separately for each stratum * excludes wound complication * 
We will assume a beta (2,4) prior, which is information equivalent to unacceptable toxicity in 2 of 6 
treated patients. An acute toxicity rate < 33% is considered acceptable.  If the number of patients 
with unacceptable toxicity is greater than or equal to the number in the table below, then 
termination will be considered as it is likely that the toxicity rate is > 33%, as noted by the 
Bayesian posterior probabilities. 
 
Bayesian Rule for Acute Toxicity 
 
Patients treated  
3 
6 
9 
1
2 
Patients who experience acute 
toxicity 
2 
3 
4 
5 
Posterior Prob[acute toxicity 
rate >33%] 
0.7
5 
0.7
2 
0.7
0 
0.
6
8 
Action  
Terminate enrollment 
 

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Wound Complication – Pre-operative patients only 
We will assume a beta (2,4) prior, which is information equivalent to wound complication in 2 of 6 
treated patients. A wound complication rate >40% is considered unacceptable. If the number of 
patients with wound complications is greater than or equal to the number in the table below then 
termination will be considered as it is likely that the wound complication rate is >40%, as noted by 
the Bayesian posterior probabilities. 
 
Bayesian Rule for Wound complication 
 
Patients treated & have 4 mos followup 
3 
6 
9 
1
2 
Patients who experience wound 
complication 
3 
4 
6 
7 
Posterior Prob[wound complication rate 
>40%] 
0.83 
0.75 
0.85 
0.
8
0 
Action  
Terminate 
enrollment 
 
 
Statistical Analyses: (Separately by pre-operative and post-operative strata) 
 
Feasibility.  The feasibility rate and exact 90% CI will be computed.  The reasons why patients were 
not feasible will be tabulated.  At the end of the trial, a Bayesian probability will be computed, as 
shown in the table above. 
Acute toxicity. All toxicities as defined previously, will be graded by CTC Version 4.0 and 
tabulated.  At the end of the trial, a Bayesian probability will be computed, as shown in the table 
above. 
Late toxicity. All toxicities as defined previously, will be graded by EORTC/RTOG late toxicity 
criteria and tabulated.  
Wound complications, fibrosis, joint stiffness and edema will graded and tabulated.  These 
analyses will likely be performed in the phase II stage of the trial. 
Clinical Efficacy. The RECIST response rate (CR + PR based on RECIST) and 90% exact CI will be 
computed. Time to local recurrence, time to distant recurrence, PFS and OS will be estimated by 
Kaplan-Meier analysis. These analyses will likely be performed in the phase II stage of the trial. 
Estimation of Event Rates. The table below displays the 90% exact binomial confidence intervals 
based on 12 patients treated.  
 
No. of 
Event
s 
% 
90% exact 
CI 
No. of 
Events 
% 
90% exact 
CI 
0 
0.0 
17.5* 
7 
58.
3 
31.5 , 81.9 
1 
8.3 
.43 , 33.9 
8 
66.
7 
39.1 , 87.7 
2 
16.7 
3.0 , 43.8 
9 
75.
0 
47.2 , 92.8 
3 
25.0 
7.2 , 52.7 
10 
83.
3 
56.1 , 97.0 
4 
33.3 
12.3 , 60.9 
11 
91.
7 
66.1 , 99.6 
5 
41.7 
18.1 , 68.5 
12 
100
.0 
82.5* 

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6 
50.0 
24.5 , 75.5 
*  90% 1-sided CI 
 
6.2 
PHASE II STUDY 
 
Design and Objectives: 
This stratified phase II trial is designed to evaluate early complications (e.g., wound complication 
in pre-operative patients) and late complications (e.g., fibrosis, joint stiffness and edema in post-
operative patients).  Patients with STS of the lower extremity only will be treated in the phase II 
study.  Justification for enrolling lower extremity STS in phase II is that 80% of STS patients 
treated in the Department of Radiation Oncology have lower extremity STS and they are the 
subgroup who may benefit most from protons.  For example in the study by O’Sullivan et al 
(Lancet 359, 2002), in pre-operative patients, the wound complication rate from photon 
radiotherapy in patients with lower extremity STS was 43% (30 events in 70 patients) compared to 
5.5% (1 event in 18 patients) in upper extremity STS. 40 evaluable patients (including evaluable 
patients from the feasibility stage) will be enrolled in each stratum.  
 
Endpoints: 
Same endpoints as in Section 6.1:  Wound complication, Fibrosis and joint stiffness, Edema, Acute 
toxicity, Late toxicity and Clinical Efficacy.  
 
Evaluable for analysis: 
For pre-operative patients, patients must have a minimum of 4 months of follow-up post-surgery to 
be evaluable and included in the phase II analysis.  For post-operative patients, patients must have 
a minimum of 2 years of follow-up from the end of radiotherapy to be evaluable and included in the 
phase II analysis. 
 
Rules for Early Termination for Wound Complications: 
We will assume a beta (2,4) prior, which is information equivalent to wound complication in 2 of 6 
treated patients. A wound complication rate >40% is considered unacceptable. If the number of 
patients with wound complications is greater than or equal to the number in the table below then 
termination will be considered as it is likely that the wound complication rate is >40%, as noted by 
the Bayesian posterior probabilities. 
 
Bayesian Rule for Wound complication  
 
Patients treated & followed 4 
months 
1
5 
2
0 
2
5 
3
0 
3
5 
4
0 
Patients who experience wound 
complication 
 
8 
 
1
1 
 
1
3 
 
1
5 
 
1
7 
 
1
9 
Posterior Prob[wound 
complication toxicity rate >40%] 
 
0
.
7
6 
 
0
.
8
5 
 
0
.
8
2 
 
0.
8
1 
 
0.
7
9 
 
0.
7
8 
Action  
Terminate enrollment 
 
6.3 
STATISTICAL ANALYSES 
 
Pre-operative patients: Toxicity data will be graded and tabulated. A one-sample one-sided chi-square test will 
be performed to test the null hypothesis that the wound complication rate is 45% (same as photon). Patients 
must have a minimum of 4 months of follow-up after surgery to be evaluable for this analysis.  
 

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Post-operative patients: Toxicity data will be graded and tabulated. In the study by Davis et al 
(Radiother and Oncol 75, 2005), the grade 2+ fibrosis rate was 48%, joint stiffness 23% and edema 
23%. Since fibrosis is the most common post-operative toxicity, it is considered the primary 
endpoint and a one-sample one-sided chi-square test will be performed at the 5% significance 
level to test the null hypothesis of 50% (same as photon). Joint stiffness and edema are less 
frequent toxicities and will be treated as secondary endpoints. The null hypothesis is that the 
grade 2 or higher rate is 25% (same as photon) for these endpoints. Patients must have a minimum 
of 2 years of follow-up after surgery to be evaluable for this analysis.  
 
Acute toxicity (Late toxicity): Toxicities will graded and tabulated by stratum.  
 
Clinical Efficacy: For pre-operative patients, the RECIST response rate (CR + PR based on RECIST) and 90% 
exact CI will be computed. For each stratum, time to local recurrence, time to distant recurrence, PFS and OS 
will be estimated by Kaplan-Meier analysis.  
 
Exploratory Analyses of [18F]-EF5: 
The relationship between pre-treatment hypoxia as determined by F18-EF5 scanning and treatment 
outcome will be examined, stratified by pre- and post-operative cohorts.  The clinical outcomes are: 
RECIST response rate (pre-operative patients only), time to local recurrence, time to distant 
recurrence, PFS and OS.  We hypothesize that high 18F-EF5 signal of the primary tumor (e.g. high 
levels of hypoxia) will relate to poorer clinical outcome (lower response rate, shorter time to local 
recurrence, shorter time to distant recurrence, shorter PFS, and shorter OS) in this group of patients.  
We will examine the prognostic values of hypoxia, as measured by 18F-EF5, summarized from regions 
of the primary tumors.  These analyses will be stratified by pre- or post-operative cohorts.  Each subject 
will have summary statistics for hypoxia using 18F-EF5 PET available from the primary tumor for this 
analysis. The Kaplan-Meier method will be applied to estimate the distribution of time-to-event outcome 
variables for patients with 18F-EF signal above or below median of the summarized values.  The 
association between RECIST response and hypoxia (binary coding) will be assessed by chi-square 
test.  The association between time-to-event outcomes and hypoxia will be established by the Cox 
proportional hazards models.  Both binary and continuous summary measures of 18F-EF5 signal will be 
evaluated.  A binary indicator for a hypoxic tumor can be defined as 18F-EF5 signal above versus below 
median signal or based on other previously defined cut points.  The direction and magnitude of the 
association will be assessed by hazard ratio and its 95% confidence interval.  
 
6.4 
SAMPLE SIZE/POWER AND TRIAL DURATION. 
 
With 12 patients per year enrolled to each stratum and accounting for required follow-up time for feasibility and 
toxicities, this study should be active for 7 years.  Twelve pre-operative and 12 post-operative patients will be 
enrolled on the feasibility portion of the trial. If feasibility and safety are acceptable then 40 evaluable pre-
operative patients and 40 evaluable post-operative patients with STS of the lower extremity (each group 
includes evaluable patients from the feasibility stage) will be enrolled in the phase II portion of the trial. Up to 
50 pre-operative patients may need to be enrolled to yield 40 evaluable patients with lower extremity STS who 
undergo surgery and have 4 months of follow-up post-surgery. With 40 evaluable patients, there will be 84% 
power for a chi-square test at one-sided 5% type I error to test a grade 2 or higher wound complication rate of 
45% versus an alternative rate of 25%.  
 
Similarly, up to 50 post-operative patients may need to be enrolled to yield 40 evaluable patients with lower 
extremity STS who receive post-operative radiotherapy and remain on-study for 2 years from the end of 
radiotherapy. With 40 evaluable patients, there will be 83% power for a chi-square test at one-sided 5% type I 
error to test a grade 2 or higher fibrosis rate of 50% versus an alternative rate of 30%. In addition, there will be 
80% power for chi-square tests at one-sided 2.5% type I error to test grade 2 or higher joint stiffness and 

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edema, each with rates of 25% versus alternative rates of 9%. These secondary analyses will be tested at a 
2.5% significance level, to control the overall type I error. 
 
All correlative analyses of hypoxia and clinical outcome are exploratory. Results from this unique study will be 
used to estimate the magnitude of the associations for both RECIST response and time-to-event outcomes 
and will provide important guidance for future studies of the prognostic importance of hypoxia in STS patients. 
 
7 
SAFETY AND ADVERSE EVENTS 
 
The investigator or research staff will be responsible for detecting, documenting and reporting all events that 
meet the definition of an AE or SAE as defined in this protocol.   
 
Definition 
An adverse event (AE) is any unfavorable and unintended sign, symptom, sign (including abnormal 
laboratory findings), illness/disease (new or exacerbated) or experience that develops or worsens in 
severity temporally associated with the use of the investigational agent/device/procedure.  Intercurrent 
illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic procedures 
are considered to be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a Serious Adverse Event (SAE) 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
Radiation Effect 
Radiation side effects are typically divided into those that occur acutely (during radiation and up to 3 
months after radiation) and those that occur later (>3 months post-radiation).  Common acute radiation 
side effects include fatigue, skin irritation or erythema.  Typically, these side effects can be controlled with 
medication.  Late side effects that are unlikely to occur are paralysis or cardiac complications.  Another 
rare but serious late side effect is the development of second tumors. It is hoped that proton radiation will 
substantially reduce both acute and late side effects by reducing the amount of normal tissue that is 
irradiated. 
 
For acute radiation effect, through post treatment day 90 of treatment, CTCAE 4.0 will be employed.  
Late radiation effects will be evaluated using the RTOG/EORTC Late Radiation Morbidity Scoring 
System. 
 
Assessing and Recording Adverse Events 
All Adverse and Serious Adverse Events will be assessed using NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE 4.0) with the exception of late radiation effects as noted above.    
 
Reporting of Serious Adverse Events 
(a) IRB Notification by Investigator 
All events meeting the Penn IRB SOP for Unanticipated Events posing risks to subjects or others will 
be reported to the IRB as follows: 
 
Unanticipated problems are:  
(1) Unforeseen; and  
(2) indicate that participants are at increased risk of harm.  
 

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The IRB requires investigators to submit reports of the following problems within 10 working days with 
one exception. The one exception for prompt reporting within 10 days applies to death of a research 
participant as noted below. 
 
Adverse Event (regardless of whether the event is serious or non-serious, onsite or off-site) that occurs 
any time during or after the research study, which in the opinion of the principal investigator is both 
unexpected and related to research procedures. 
 
Note:  An event is “unexpected” when its specificity and severity are not accurately reflected in 
the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document, and (b) other 
relevant sources of information, such as product labeling and package inserts); An event is 
“related to the research procedures” if the event is deemed probably or definitely related. 
 
If the adverse event involved death as unforeseen and indicates participants or others are at increased 
risk of harm, report in three days. 
 
(b) Data and Safety Monitoring Committee (DSMC) Notification by Investigator 
All Serious Adverse Events (SAEs), regardless of grade, expectedness or attribution must be 
reported to the DSMC within 30 days.  Deaths that are possibly, probably or definitely related to 
the protocol treatment/experience must be reported within 24 hours.  SAEs should be reported 
to the DSMC for six months from the date the last subject was treated.   
 
(c) FDA Notification by Sponsor  
The study investigator shall notify the FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of the protocol 
agent/treatment/device as soon as possible but no later than 7 calendar days of knowledge of 
the event.   If all details of the event are not immediately know, a partial report should be sent to 
ensure compliance with reporting timeframes.  A follow-up report shall be submitted as soon as 
the relevant information is available.   
 
If a previous event that was not initially deemed reportable is later found to fit the criteria for 
reporting, the study sponsor will submit the event in a written report to the FDA as soon as 
possible, but no later than 15 calendar days from the day the determination is made. 
(d) Varian Biosynergy, Inc. 
All Unanticipated problems including Serious Adverse Events related to the study drug should 
be reported promptly to the Sponsor within 24 hours of discovery of the event. All other adverse 
events will be reported to Varian in an Annual Report at the Company’s Request. 
 
 
Stopping Rules  
(Please see Section 6 for “Stopping Rules”) 
 
8 
MEDICAL MONITOR 
 
Data Safety and 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 

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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 every six months 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 of the 
Cancer Center and the Associate Director for Clinical Research for consideration of appropriate 
administrative action, such as suspending accrual to the protocol. 
 
A Medical Monitor, Stephen Keefe, M.D., who is not directly involved in this trial and is not collaborating 
with the investigator in any other trials, has been selected for this trial.  The Medical Monitor will review 
adverse events, safety data, and activity data observed in the ongoing clinical trial.  The Medical Monitor 
may recommend reporting of adverse events and relevant safety data not previously reported, and may 
recommend suspension or termination of the trial.  The summary reports of all discussions of adverse 
events will be submitted to the Data and Safety Monitoring Committee (DSMC) on a bi-yearly basis or 
more frequently if appropriate. 
 
The Principal Investigator or his/her designee of the trial will present to the Medical Monitor all adverse 
events observed in-patients, any activity data obtained, and whether those data invoked any stopping 
criteria in the clinical protocol.  Adverse event reporting will follow the NCI guidelines.  Results of the data 
from toxicology or other animal studies that are relevant will be discussed.  Other information related to 
the safety and efficacy of the clinical study will be discussed.  This includes information of similar 
investigational materials used in different studies. 
 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see 
Section 11.2).  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events. 
 
The Medical Monitor will be Stephen Keefe, M.D. ( 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. 
Keefe’s background and experience in medical oncology, he is an appropriate Medical Monitor 
(MM) for this study.  In the role, he will review all AEs including grading, toxicity assignments, 
dose modifications, appropriateness of dose escalation 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 MM may recommend reporting of adverse 
events and relevant safety data not previously reported and may recommend suspension or 
termination of the trial.  The investigator will meet with the MM every three months.  Serious and 
unexpected issues will be handled on an ad hoc basis through calls or e-mail.  Documentation 
of MM activity will be maintained in the study specific Regulatory Binder.  Copies of an MM 
report requiring action on the part of the PI to protect subject safety or study integrity must be 
submitted to the DSMC within 10 business days.   
 
Protocol Deviations/Exceptions 

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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: 
 
Eligibility -  Deviations from established eligibility criteria will not be allowed.  If the investigator believes that a 
subject would truly benefit from the protocol therapy and there are no other viable options, then the protocol 
should be amended to reflect the change in restrictions.  There may be situations where the deviation from 
eligibility may not warrant a study amendment (e.g. a necessary test/procedure being a few days outside of the 
eligibility window, subject taking a concomitant medication within recent timeframe etc.).  These deviations 
must still be reviewed and approved in advance of enrolling the subject.    
 
The IRB must be notified of the planned deviation and a copy of all applicable amended study documents must 
be sent to the IRB.  The planned deviation must 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 must be given sufficient time to review the request, gather additional information as 
necessary and make a decision.  
 
Other Reportable - Deviations that affect the protocol treatment administration (i.e. dose administered, 
route/method of administration etc.), dose adjustment schema, stopping rules, modification to follow-up, 
removal of safety assessments/follow-up visits, accrual goal or any deviation that may affect  the study 
outcome analysis or study integrity must be approved by the IRB and reviewed by the DSMC.   
 
Non-Reportable - During the course of a study, there may be times when deviations are outside of the control 
of the investigator (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 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 notes or note/memo to file.  Notes/memos 
should be signed and dated.  
 
Reporting Deviations/Exceptions 
All deviations/exceptions will be reviewed and approved by the study Medical Monitor before being sent to the 
IRB and DSMC.  Reports to the IRB and DSMC will be done via the DSMC website www.ctsrmc.org.  
Reportable deviations must also be sent to the study Medical Monitor.   
 
9 
DATA HANDLING AND RECORD KEEPING 
 
All patients must have a signed Informed Consent Form and an On-study (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 patient ID at the time 
of study enrollment.  This 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 informed consent form and HIPAA authorization 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 study combined informed consent and HIPAA authorization form prior to study 
enrollment. 
• 
Each subject will be assigned a patient ID.  All research-related material (to include specimens for 
research) will be labeled with patient IDs only.  
• 
A list of the subject names with the associated patient IDs will be maintained in a locked cabinet and 
computer by the principal investigator and study coordinator. 
• 
All research subject records will be kept in a study chart. 
 
9.1  Data Entry 
All patients must have a signed Informed Consent Form and an On-study (confirmation 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. 
 
9.2  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 a signed subject authorization 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.   
 
9.2.1  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.).   
 
10  Records Retention 
 
10.1   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 whom 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. 

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11   STUDY MONITORING, AUDITING, AND INSPECTING 
 
11.1 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, “PROTON RADIOTHERAPY FOR EXTREMITY SOFT TISSUE 
SARCOMA” IS A TRIAL THAT IS SUBJECT TO OVERSIGHT OF THE UPCC THROUGH THE CLINICAL TRIALS SCIENTIFIC 
REVIEW AND MONITORING COMMITTEE (CTSRMC). THE CTSRMC ROLE IS 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 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. 
 
11.2 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 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 DSMC through the Director of Compliance 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. 
12  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.    

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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 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.  
13  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.  Any investigator involved with this study is 
obligated to provide the sponsor with complete test results  
 
14 REFERENCES 
 
1. 
Urano M, Verhey LJ, Goitein M, et al: Relative biological effectiveness of modulated proton 
beams in various murine tissues. Int J Radiat Oncol Biol Phys 10:509-14, 1984 
2. 
Gerweck LE, Kozin SV: Relative biological effectiveness of proton beams in clinical therapy. 
Radiother Oncol 50:135-42, 1999 
3. 
Tepper J, Verhey L, Goitein M, et al: In vivo determinations of RBE in a high energy modulated 
proton beam using normal tissue reactions and fractionated dose schedules. Int J Radiat Oncol 
Biol Phys 2:1115-22, 1977 
4. 
Paganetti H, Niemierko A, Ancukiewicz M, et al: Relative biological effectiveness (RBE) values 
for proton beam therapy. Int J Radiat Oncol Biol Phys 53:407-21, 2002 
5. 
Kozak KR, Kachnic LA, Adams J, et al: Dosimetric feasibility of hypofractionated proton 
radiotherapy for neoadjuvant pancreatic cancer treatment. Int J Radiat Oncol Biol Phys 
68:1557-66, 2007 
6. 
Lundkvist J, Ekman M, Ericsson SR, et al: Proton therapy of cancer: potential clinical 
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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor 
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