Image Guided Radiotherapy for the Treatment of Musculoskeletal Tumors: A Phase II Prospective Evaluation of Radiation-related Treatment Effects
Phase: PHASE2
Conditions: Sarcoma, Ewing's, Rhabdomyosarcoma, Soft Tissue Sarcoma, Musculoskeletal Tumors
Sponsor: St. Jude Children's Research Hospital

Official Study Title: Image Guided Radiotherapy for the Treatment of Musculoskeletal Tumors: A 
phase II Prospective Evaluation of Radiation-related Treatment Effects 
 
CTG Number: NCT00186992 
 
Document Date: 07/13/2023 

Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
 
SJCRH 
RT-SARC
June 3, 2002 (Resubmitted: 12-19-2002) (IRB Approved: January 7, 2003)
Activated: January 9, 2003
Revision 0.1 March 27, 2003 (HIPAA) (IRB Approved: April 7, 2003)
Amendment 1.0, September 15, 2003 (IRB Approved: November 11, 2003)
Revision 1.1, November 17, 2003 (IRB Approved: November 21, 2003)
Revision 1.2, June 29, 2004 (IRB Approved: July 12, 2004)
Amendment 2.0, March 21, 2005 (IRB Approved: May 24, 2005)
Revision 2.1, November 22, 2006 (IRB Approved: December 7, 2006)
Amendment 3.0, December 26, 2007 (IRB Approved: February 26, 2008)
Revision 3.1, May 6, 2009 (IRB Approved: June 10, 2009)
Revision 3.2, October 19, 2009 (IRB Approved: October 23, 2009)
Activated: October 26, 2009
Amendment 4.0, April 20, 2012 (IRB Approved: July 13, 2012)
Revision 4.1, August 21, 2012 (IRB Approved: September 7, 2012)
Activated: September 10, 2012
Revision 4.2: September 24, 2012 (IRB Approved: December 7, 2012)
Activated: December 19, 2012
Amendment 5.0, May 16, 2013; Resubmitted to IRB July 2, 2013; (IRB Approved: July 3, 2013)
Activated: July 10, 2013
Revision 5.1, September 15, 2015; (IRB Approved: September 22, 2015)
Activated: September 24, 2015
Revision 5.2 June 9, 2023, (IRB approved:          )      Activated:
Image Guided Radiotherapy for the Treatment of Musculoskeletal Tumors: 
A phase II Prospective Evaluation of Radiation-related Treatment Effects
Principal Investigator 
Matthew Krasin, MD1
Co-Investigators
Thomas Merchant, DO, PhD1 
Chia-ho Hua1 
Andrew Davidoff, MD2
Michael Neel, MD2 
Alberto Pappo, MD3 
Mary Elizabeth McCarville, MD7 
Gene Reddick, PhD7
Barry Shulkin, M.D.7 
Shengjie Wu, MS5 
Catherine Billups, MS5 
Kirsten Ness, PhD6
External Co-Investigators
Angela Davey, PhD
Marianne Aznar, PhD
The University of Manchester
St. Jude Children's Research Hospital 
262 Danny Thomas Place
Memphis, Tennessee 38105-2794
Telephone: (901) 595-3300
Department of: 1Radiation Oncology, 2Surgery, 3Oncology,
4Rehabilitation Services, 5Biostatistics, 6Epidemiology & Cancer Control 7Diagnostic Imaging
Contents of this document may not be extracted without permission from the Principal Investigator.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
 
1.0
OBJECTIVES ........................................................................................................................1
1.1 Primary Objectives...........................................................................................................1
1.2 Secondary Objectives......................................................................................................1
1.3 Exploratory Objectives .................................................................................................................2
2.0
BACKGROUND.....................................................................................................................2
2.1 Issue in the Radiotherapeutic Management of Pediatric Sarcomas.................................2
2.2 Image Guided Radiotherapy............................................................................................3
2.3 Tumor Control..................................................................................................................5
2.4 Radiation-Related Tissue Toxicities.................................................................................6
2.5 Outline of Study ...............................................................................................................6
2.6 Image Guided Radiotherapy for Pediatric Sarcomas.......................................................8
2.7 Radiation Related Tissue Effects.....................................................................................10
3.0
DRUG INFORMATION – not applicable................................................................................13
4.0
PATIENT ELIGIBILITY ..........................................................................................................13
5.0
TREATMENT PLAN ..............................................................................................................14
5.1 Overview..........................................................................................................................14
6.0
RADIATION THERAPY.........................................................................................................15
6.1 Equipment .......................................................................................................................15
6.2 Techniques......................................................................................................................15
6.3 Radiotherapy Volume and Dose......................................................................................15
6.4 Immobilization and Patient Positioning ............................................................................20
6.5 Simulation and Treatment Planning.................................................................................20
6.6 Treatment Delivery ..........................................................................................................21
6.7 Treatment Related Effects of Radiation...........................................................................21
7.0
PRETREATMENT EVALUATIONS .......................................................................................21
7.1 Physical Function.............................................................................................................21
7.2 Diagnostic Imaging ..........................................................................................................22
8.0
EVALUATIONS DURING THE FOLLOW-UP PERIOD .........................................................24
9.0
TOXICITY MONITORING......................................................................................................24
9.1 Reporting to the IRB ........................................................................................................24
10.0
CRITERIA FOR RESPONSE, TREATMENT FAILURE AND SITES OF
FAILURE ...............................................................................................................................25
11.0
DATA ACQUISITION AND QUALITY ASSURANCE MONITORING ....................................26
12.0
STATISTICAL CONSIDERATIONS.......................................................................................27
13.0
OFF STUDY CRITERIA.........................................................................................................32
14.0
DATA SAFETY MONITORING..............................................................................................33
15.0
OBTAINING CONSENT ........................................................................................................33
APPENDICES .......................................................................................................................34
REFERENCES......................................................................................................................39
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 1
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
1.0
Objectives 
Primary Objective
1.1
To estimate local control rates with image guided radiation therapy as defined in 
this study for patients with primary musculoskeletal tumors (MST).
1.1.1
Prospectively establish a baseline estimate of local control for patients 
with 
MST 
(Ewing’s 
sarcoma 
family 
of 
tumors 
(ESFT), 
rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma soft tissue 
sarcoma (STS)) treated with image guided radiation therapy.
1.1.2
Demonstrate that the increased level of conformality afforded by image 
guided radiation therapy does not reduce its efficacy relative to 
previously utilized non-image guided radiation therapy techniques in 
patients with Ewing’s sarcoma family of tumors, resected soft tissue 
sarcomas, and group III rhabdomyosarcomas.
1.1.3
Assess local and regional patterns of failure for patients with MST 
treated with image guided radiation therapy relative to their targeted 
volumes.
1.1.4
Provide a long term (>5 year) estimate of local disease control for 
patients with MST (Ewing’s sarcoma family of tumors (ESFT), 
rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma soft tissue 
sarcoma (STS) treated with image guided radiation therapy.
Secondary Objectives
1.2
Establish a quantitative baseline estimate of radiation dose-related changes in 
normal 
tissues 
using 
novel 
objective 
measures 
of 
somatic 
change, 
musculoskeletal function, tissue biochemistry and physiology.
1.2.1
Investigate the dose and volume relationship for the developing physis 
and cortical bone using physical measures and imaging evaluations 
including:
1.2.1.1
Prospectively 
investigate 
whether 
an 
age 
based 
radiotherapeutic threshold of dose and volume that will 
induce premature physis closure and alter long bone length 
can be quantitatively identified.
1.2.1.2
Quantitatively explore the impact of radiation on cortical 
bone thinning and long bone curvature.
1.2.1.3
Relate radiation dose and volume to late (10+ year) 
alterations in bone integrity
1.2.2
Describe the severity and time course of radiation-induced changes in 
the 
soft 
tissues 
and 
adjacent 
organs, 
including 
muscle 
and 
subcutaneous tissues.
1.2.2.1
Delineate sequential changes in muscular volume, muscle 
function and organ function (delineated by imaging and 
measures of physical function) following image guided 
radiation for specific muscular groups.
1.2.2.2
Correlate the temporal changes in muscular volume and 
function with changes in vascularity and metabolism defined 
by imaging studies.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 2
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Exploratory Objectives
1.3
Correlate changes in quantitative scales assessing quality of life (QOL) and 
function with range of motion and dosimetric parameters.
2.0
Background
We will use the terminology musculoskeletal tumors (MST) to describe bone and soft 
tissue tumors that will be eligible for this protocol. MST includes Ewing’s sarcoma family 
of tumors (ESFT), rhabdomyosarcoma (RMS), small round blue cell tumors that can only 
be classified as undifferentiated sarcoma, the soft-tissue tumors whose histiotypes are 
more commonly found in adults and classified as non-rhabdomyosarcoma soft-tissue 
sarcoma or soft-tissue sarcoma (STS), osteosarcoma (OS) and other localized tumors of 
the musculoskeletal tissues requiring focal therapy.
2.1
Issues in the Radiotherapeutic Management of Pediatric Sarcomas
The delivery of radiotherapy to pediatric patients with sarcomas is complicated, 
as one must balance the appropriate dose and volume of treatment needed for 
local control with radiotherapy’s potential effects on developing tissues. These 
goals are often at odds with one another as critical structures are closely related 
geometrically to targets, and radiation tolerances of structures are not fully 
defined; as radiation techniques advance toward greater conformity of the high 
dose region to the target, lower heterogeneous doses are distributed more 
broadly in adjacent tissues (1,2).
The local control rates for Ewing’s family sarcoma, rhabdomyosarcoma, and non- 
rhabdomyosarcoma soft tissue sarcoma are defined using conventional radiation 
therapy techniques prior to the conformal radiation therapy era (3-10). These 
techniques often deliver relatively high radiation doses to normal tissue not 
considered at risk for harboring microscopic or gross tumor. Image guided 
techniques may allow sparing of these normal tissues. Brachytherapy has also 
been utilized as a form of adjuvant radiotherapy in these tumor types, most 
commonly for non-rhabdomyosarcoma soft tissue sarcoma (11). Retrospective 
reviews of brachytherapy in pediatric patients appear to result in favorable local 
control rates but prospective data to confirm the benefit of this modality is needed
(12). The addition of imaging with CT scans to assist in targeting and planning of 
brachytherapy cases should enhance the delivery of this local modality. We will 
test the hypothesis that treatment of pediatric sarcomas with image guided 
radiotherapy techniques will maintain at least the current levels of local tumor 
control achieved with conventional techniques, while studying the impact of 3- 
dimensional, image-guided radiation techniques to potentially decrease radiation- 
related normal tissue effects.
Patients treated on the RT-SARC protocol currently have local disease control 
outcomes at 2 years of 89% for patients with rhabdomyosarcoma (13), 94% for 
patients with soft-tissue sarcomas (14) and 95% for patients with Ewing’s family 
tumors (unpublished data). These data begin to form the basis for local outcome 
measures with a well defined clinical cohort of patients receiving standardized, 
focal, limited-volume radiation therapy. Additional patient numbers and follow-up 
will help this cohort become the benchmark for future prospective focal radiation 
therapy studies measuring local disease control. Long term local control 
estimates obtained with 10+ year follow-up (or follow-up into adulthood 18 years 
of age}) will establish this as a reference dataset for future trials and 
comparisons.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 3
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Treatment related effects secondary to radiation therapy, both during and 
following treatment, have been a major area of concern relative to the use of 
therapeutic radiation in children and adolescents. The period of growth during 
the childhood and adolescent years is primarily responsible for the specific group 
of radiation related effects seen in children. These effects have often been 
ascribed to radiation by relating the site of the effect relative to the site of 
radiation treatment. Most historic information on treatment related effects of 
radiation is empiric and based on little data. Even in the adult radiation oncology 
community (where patient numbers are much greater than in pediatrics) definite 
normal tissue tolerances to radiation are not known (15). Data regarding 
treatment related effects of radiation on the pediatric patient are very limited and 
only correlate prescription doses of radiation with basic measurable endpoints 
(e.g. sitting and standing height or comparisons with normal populations) (16- 
20)). Prospective data in the pediatric population is noticeably absent. In the era 
of image guided radiation therapy, true analysis of the effects of radiation at a 
specific dose delivered to a specific volume may now be conducted. A 
prospective study in localized pediatric brain tumors conducted at St. Jude (RT- 
1) has made significant contributions to the understanding of these radiation 
dose and volume related effects (21,22). Within this study we propose to 
establish the needed baseline data to relate image guided radiotherapeutic 
parameters to functional and imaging measures of tissue function. This body of 
data will then allow meaningful comparisons with new treatment techniques and 
modalities.
Preliminary analyses from this clinical trial have yielded measures of normal 
tissue function (either structural, biochemical or functional) that appear to be well 
correlated with treatment dosimetry and clinical variables (23). As this dataset 
matures, additional patient cases accrued and more specific imaging 
implemented we anticipate to further refining the relationship of individual 
dosimetric features to quantifiable outcomes for normal tissue response. The 
additional numbers of cases and further specificity of imaging will add strength to 
our ability to correlate these outcomes.
Late effects of radiation continue to accumulate over time. Long term risks to 
bone integrity and strength result in fracture, altered bone growth or shape. 
Changes in soft tissue and organ function also continue to occur and evolve. 
Their cumulative effect on quality of life is frequently described relative to 
radiation therapy yet quality estimates do not exist in the context of well-defined 
dosimetry. Amendment 4.0 will focus on extending the long term follow-up of 
these patients as the protocol nears complete accrual. We will collect 5+ 
additional years of follow-up on the long-term survivors of this trial out to 
adulthood to better define and describe these effects. Imaging requirements will 
be reduced across the trial to transition this study towards a focus on long-term 
effect of therapy.
2.2
Image Guided Radiotherapy
Image guided radiotherapy defines a group of radiotherapy treatment techniques 
that deliver high doses (the prescription dose) of radiation to a specific volume, 
usually delineated by CT scan or MRI. 
Relatively lower doses may be 
incidentally delivered to surrounding normal tissues. Radiation therapy may be 
described as image-guided when four criteria are met: (1) three-dimensional 
imaging data (CT or MR) are acquired with the patient in the treatment position or 
brachytherapy catheters are in place, (2) imaging data are used to delineate and 
reconstruct a gross target volume, clinical target volume, planning target volume,
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 4
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
and normal or critical structures in 3-dimensions; (3) radiation beams can be 
freely oriented in 3-dimensions for both the planning and delivery process, and 
structures traversed by the beam can be visualized with the eye of the beam; for 
brachytherapy planning the activity of sources to be implanted can be freely 
manipulated to achieve the desired dose distribution; (4) the distribution of dose 
relative to the target volume or any structure is computable on a point by point 
basis in 3-dimensional space. Image guided radiotherapy for the purposes of this 
study include three different delivery systems outlined below. The general 
differences in each technique and the potential benefits and limitations are noted.
2.2.1
Conformal radiotherapy
The delivery of 3D-conformal radiotherapy (3D-CRT) allows specific 
targeting of tumor volumes based on imaging studies obtained in the 
treatment position. This method of external beam radiotherapy delivery 
utilizes multiple fields or portals delivered daily with shaping of each 
beam aperture to the tumor volume. Beam modifiers such as wedges 
are utilized to “conform” and homogenize dose to the tumor volume. 
Conformal radiotherapy excels when target volumes are convex and 
critical structures do not invaginate target volumes. 
Conformal 
radiotherapy has been aggressively studied in the adult radiation 
oncology setting in disease sites including head and neck cancer, lung 
cancer and prostate cancer. Available data demonstrate a decrease in 
toxicity despite escalating doses to the target volume (23-30). St. Jude 
has the largest pediatric experience using conformal radiotherapy to treat 
focal brain tumors in the RT-1 study (31). Current data in this group of 
patients demonstrates both its safety and efficacy in the CNS setting.
2.2.2
Intensity Modulated Radiotherapy
Intensity modulated radiotherapy or IMRT is another external beam 
radiotherapy delivery method that requires imaging in the treatment 
position and delineation of target volumes and critical structures. Dose is 
delivered to the target with multiple small fields that do not encompass 
the entire target volume, but summate to deliver the prescribed dose per 
fraction. IMRT differs from conformal radiotherapy in the following ways:
1) an increase in the complexity and time required for planning and 
delivery of treatment; 2) an increase in quality assurance work prior to 
treatment delivery; 3) an increase in dose heterogeneity within the target 
volume with inherent intralesional areas of relatively high dose; 4) the 
difference that both subclinical (microscopic) and clinical (gross) target 
volumes are treated concurrently (rather than sequentially, as in 
conventional or in 3-D CRT) resulting in daily fraction sizes that may be 
higher than 200 cGy in some cases; and 5) the ability to treat concave 
targets while sparing critical structures that invaginate the target volume. 
The last difference holds promise for increased normal tissue sparing 
and the potential for reduction in late toxicities. Data from adult series of 
patients treated with IMRT is becoming available demonstrating its 
potential for reduction in treatment toxicities when applied to brain 
tumors, head and neck cancer, lung cancer and prostate cancer 
(1,30,32,33).
2.2.3
Brachytherapy
Brachytherapy is a method of delivering irradiation to a tumor or tumor 
bed by placing radioactive sources within or adjacent to the target
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 5
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
volume. This is usually performed at the time of a surgical resection 
under direct vision. Planning of the dose to be delivered to the target 
volume is accomplished after surgery and may utilize CT or MRI imaging 
studies. In following the model of image-guided radiotherapy, target 
volumes and critical structures are outlined. The appropriate radioactive 
source strengths are determined by prospective planning of the dose to 
be delivered to the target volume and critical structures. Unlike the 
external beam modalities outlined above, brachytherapy (using low dose 
rate techniques) is delivered continuously over a period of two to five 
days, usually while the patient is admitted to the hospital. High dose rate 
brachytherapy (delivered in moderate 3-5 Gy fractions) will also be used 
as indicated. Benefits of the high dose rate technique are multiple and 
include: 1) the ability to better shape dose to the target and away from 
normal tissue, 2) reduced radiation exposure to family members and staff 
and 3) delivery of therapy as an outpatient reducing the hassle and cost 
associated with inpatient hospitalization. 
Experience with both 
modalities in patients with sarcomas is limited to smaller pediatric series 
and moderate sized adult trials. We have had experience with this 
modality in the pediatric setting as a single adjuvant modality and as a 
boost dose to external beam radiotherapy. Late toxicity data is not as 
well studied as compared to conformal radiotherapy or IMRT (34-36).
2.3
Tumor Control
Establishing long-term tumor control for pediatric musculoskeletal tumors 
necessitates a multi-disciplinary treatment approach. Treatment entails local and 
systemic therapy in specific sequences established through extensive clinical 
trials. Irradiation is frequently used to treat local or regional tumor. The 
sequencing of local control measures is typically derived from the tumor type, 
extent, and anatomic location; radiation therapy may be used post-operatively, 
pre-operatively, or as the sole local therapy. Similar factors determine whether 
irradiation is given following and/or concurrently with chemotherapy. Gross tumor 
or microscopic residual disease following surgery can often be effectively treated 
with local radiotherapy, as can disease that includes regional nodal involvement. 
Additionally, many sarcomas are infiltrative tumors with tissue beyond the 
resected volume at risk for harboring microscopic disease, even in the setting of 
apparently negative histologic margins. Clinical trials have established the 
benefits of local/regional radiotherapy including limb preservation, the avoidance 
of disfiguring surgery, increased local tumor control obviating a second surgery, 
and increased disease control that often relates to improvement in overall 
survival (3-7,9-12,34-36).
Local radiotherapy has several requirements to allow the highest chance of 
success. These are as follows: 1) adequate definition of the target volume 
including the gross tumor or tumor bed (gross tumor volume or GTV), and tissues 
at risk for microscopic disease (clinical target volume or CTV); 2) establishment 
of adequate immobilization of the target (external beam) with an appropriate 
planning target volume (PTV) to account for organ motion and daily set-up 
variability; 3) delivery of an adequate dose of radiation to the target volume 
through appropriate planning and treatment techniques. 
Deviation from 
adequate volume definition may risk local failure and overall survival. Tissue 
definitions and quantitative parameters defining radiation volume parameters 
have varied from 2-dimensionally derived margins of 2 cm to as much as 5 cm 
Volume 
recommendations 
have 
only 
recently 
included 
image-guided 
radiotherapy treatment planning techniques that include CT-based treatment 
planning  with  delineation  of  a  three-dimensional  target  volume  (40).
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 6
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Modifications in quantitative margins have been interposed when natural barriers 
to tumor spread such as bone or joint-spaces, and sometimes fascial planes 
define tumor extent. If one utilizes image-guided radiotherapy for the treatment 
of sarcomas, the volume of tissue requiring high radiation doses usually 
decreases compared to traditional two-dimensional treatment techniques. 
Reduction in the high dose volume has potential implications for reduction of 
radiation-related toxicity, but a potential increased risk of local failure. A major 
prospective study of image-guided radiotherapy is needed to assess its benefits 
and ensure that the rates of local control for MST are at least maintained.
2.4
Radiation-Related Tissue Toxicities
Delivery of appropriate radiation dose to the target volume is the first priority in 
therapy for sarcoma patients. In addition, avoidance of surrounding critical 
structures is needed to minimize significant late toxicity. While doses required for 
tumor control are relatively well established, the tolerances of normal tissues in 
the pediatric population are only estimates. Treatment related side effects for 
patients with sarcomas treated with radiation therapy include decrease in bone 
growth, soft tissue fibrosis, muscle hypoplasia, and the “seminal” microvascular 
changes, which appear to underlie or enhance somatic effects. Radiation-related 
toxicities may be modified or enhanced by interaction with other treatment 
modalities, 
including 
surgery 
and 
chemotherapy. 
Radiation 
therapy’s 
contribution to late somatic changes is related to the dose and volume of 
radiation and the volume and anatomic location of intervening or adjacent normal 
tissues. Image guided radiotherapy is ideally suited for the measurement of 
radiation dose and volume effects on critical normal tissues. Prospective serial 
evaluations of specific musculoskeletal and vascular functions and their 
correlation with three-dimensional radiotherapy dosimetry and patient host 
factors can be uniquely studied in the context of the current clinical trial, allowing 
quantitative estimates of the relationships amongst radiation dose, volume and 
musculoskeletal toxicities.
2.5
Outline of Study
This trial is a therapeutic phase II study evaluating local disease control utilizing 
image guided radiotherapy (3D-CRT, IMRT and/or brachytherapy) to deliver local 
irradiation to the prospectively defined target volume. CT- and MRI- based 
treatment planning will be conducted for each patient to treat the GTV, CTV and 
PTV defined by imaging and/or surgical findings. Treatment plans for an 
individual patient will deliver the appropriate prescribed dose to the target volume 
while striving to minimize dose to specific critical structures. High gradients of 
dose fall-off outside the target volume and modest levels of heterogeneity across 
the target volume will help minimize unwanted high dose effects on adjacent 
normal tissues. 
With this amendment, we will continue to accrue new 
participants to the study until we reach 210 enrollments. In addition we will 
extend the follow-up for all patients that were enrolled on the trial out to 10+ 
years (10 years of follow-up or 18 years of age, whichever is greater) and focus 
on the long-term local control estimates and radiation dose toxicities. Patients 
currently in follow up will be offered participation in this amended trial. 
Participants who are currently off trial due to completing the study requirements 
are eligible to re-enroll on amendment 4.0. Due to the need for re-enrollment, 
we will accrue approximately 280 patients to this study. The increase in number 
will have no effect on statistical outcomes.
Follow-up for this study occurs over a planned 10+ years or until adulthood (18 
years of age – whichever is longer) from the start of radiation therapy.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 7
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
2.5.1
Primary Objectives
Patients with MST will have their target volumes (GTV, CTV and PTV) 
defined on planning imaging studies with anatomic and geometric 
margins defined in section 6.3. Target definitions are consistent with 
active national protocol guidelines when available. Radiation doses are 
prescribed relative to the PTV and are also consistent with available 
national protocol guidelines. Local tumor control will be evaluated by 
clinical exam and imaging studies as defined in section 10.1. Local 
control rates with image guided radiation therapy will be compared with 
expected rates of control using traditional techniques for patients with 
Ewing’s sarcoma, resected soft tissue sarcoma and clinical group III 
rhabdomyosarcoma. 
Patients with rhabdomyosarcoma and non- 
rhabdomyosarcoma soft tissue sarcoma will have further reductions (by 
5mm) in their clinical target volume (CTV) margins to remain consistent 
with national protocols. This group of patients will be monitored 
separately as well as together with the prior group of patients with RMS 
and STS for rates of local failure. This plan is outlined in statistical 
section 12.1. Local control and local/regional patterns of failure will be 
determined relative to the GTV, CTV, PTV, the volume irradiated to the 
prescription dose as noted in section 10.6 and primary site imaging 
parameters. The center or apparent origin of the recurrence will be 
considered when assigning a pattern of failure (appendix A).
2.5.2
Secondary Objectives
Radiation related toxicities as determined by clinical evaluation, 
laboratory studies, and imaging will be correlated with the radiation dose 
and volume delivered to defined normal tissues. 
Prospective 
assessment of normal tissue function will be done prior to, during and 
following radiation therapy.
2.5.2.1
Treatment Effects on Bone
Quantification of radiation effects on bone growth will be made 
by determining physical alterations in (1) overall standing and, 
where appropriate, sitting height, (2) specific bone length, (3) 
relative bone length for paired bones, (4) alterations in bone 
curvature and cortical bone thickness, and (5) reductions in 
bone density. Assessment of bone length will be correlated 
with (1) radiation dose and volume, (2) premature epiphysis 
closure or partial closure and (3) bone age. Bony effects will 
be assessed by physical examination, MRI and CT bone 
densitometry.
2.5.2.2
Treatment Effects on Muscle, End Organs and SoftTissue
Muscle, organ specific and soft tissue treatment effects will be 
measured by changes in function; alterations in both MR 
imaging-based signal via multi slice dynamic contrast 
enhanced MR (DCE MR), multi slice arterial-spin labeled MR 
(as appropriate), and PET 18F-Fluorodeoxyglucose uptake (by 
objective – standard uptake values or SUV’s and subjective 
means) in muscle and soft tissue will be quantified. , 
Functional and quantitative scales, quantitative MRI data, and
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 8
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
PET imaging will be obtained during the study. Changes or 
assessments will be correlated with radiation dose and the 
volume subtended by the specific soft tissue or bone included.
2.5.2.3
Treatment Effects on the Vasculature
The changes in microvasculature caused by radiation are well 
recognized and will be measured by both DCE MR and 
arterial-spin labeled MR when feasible. Correlations between 
vascular measurements, the measurable endpoints of bone 
growth, muscle atrophy and soft tissue fibrosis and the three- 
dimensional radiation dosimetry will be evaluated in the 
context of this trial.
2.6
Image Guided Radiotherapy for Pediatric Sarcomas
The implementation of image-guided radiotherapy to treat pediatric sarcomas 
entails several distinct components. To utilize either 3D-CRT or IMRT, the region 
to be treated must be immobilized in a position to allow access of treatment 
beams while ensuring immobilization of the patient during each fraction of 
treatment and reproducibility of positioning each day of treatment. CT and MRI 
datasets are obtained in the immobilized position in the axial plane. Datasets are 
transferred to a treatment-planning computer and co-registered. Target volumes 
(GTV, CTV, PTV) as well as normal tissues are contoured on the computer 
based imaging datasets. These contoured structures are thus rendered in three- 
dimensions for planning purposes. Treatment beams are virtually positioned and 
shaped from any orientation attempting to avoid entering or exiting critical 
structures. The relative weights and shapes of beams are either “forward” 
planned based on experience (3D-CRT), or “inversely” planned using inverse 
planning algorithms (IMRT). The doses delivered to the target volumes and 
critical structures are calculated. Treatment plans are evaluated based on 
delivery of the prescribed dose to the target volume while limiting dose to critical 
structures. Treatment is then delivered on a daily basis in conventional fractions 
(1.8-2.0 Gy/fx) to the prescription dose.
Image guided brachytherapy follows a similar treatment planning process with 
inherent exceptions. Non-radioactive catheters or applicators for radioactive 
sources are placed under direct vision, typically in the operating suite at the time 
of tumor resection. CT imaging is obtained following catheter placement for 
volumetric treatment planning. Target volumes and critical structures are 
contoured on axial images following transfer of the dataset to a treatment- 
planning computer. Source type (usually seeds or ribbons of 125I or 192Ir), 
strengths, and positions along the catheters or applicators are varied to create a 
treatment plan with appropriate dosimetric coverage of the target volume.
2.6.1
Volume of Treatment for Pediatric Sarcomas
Definition of the appropriate treatment volume for pediatric sarcomas is 
critical to both maintain current levels of local tumor control yet avoid 
treating so much surrounding normal tissue to cause excessive late 
treatment toxicities. Volumes of treatment are specific for each 
histological type and will be addressed as such.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 9
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
2.6.1.1
Treatment Volume and Dose in Ewing’s family of Sarcomas
The appropriate radiotherapeutic volume of treatment for 
Ewing’s sarcoma was originally felt to be the entire medullary 
cavity of the involved bone (9,41,42). This question was tested 
prospectively in POG study 8346 where whole bone radiation 
to 39.6 Gy followed by treatment field reductions and delivery 
of an additional 16.2 Gy was compared with treatment to the 
initial tumor with a 2 cm margin to a dose of 55.8 Gy. No 
difference in local control was seen between the techniques 
and the majority of local failures were in the irradiated volume
(10). Patients treated on a St. Jude Ewing’s sarcoma protocol 
received radiation to the pre-radiation therapy tumor volume 
with a 3 cm margin; in only one instance was local failure 
marginal 
to 
the 
targeted 
region. 
(8). 
Patients 
with 
extraosseous Ewing’s sarcoma treated on the IRS I, II and III 
studies showed a local control rate of 89% when complete 
response to chemotherapy was followed by irradiation with 
margins of 2 cm beyond the primary tumor or tumor bed (4). 
Local treatment volumes to the initial bone and pre-radiation 
therapy soft tissue volume appear to be effective in controlling 
Ewing’s sarcoma family of tumors locally. Limiting margins of 
normal adjacent tissue at risk for microscopic disease could 
reduce the risk of treatment related toxicities. Anatomically 
constrained margins of 1 cm (defined as the CTV) around MRI 
defined target volumes will be evaluated. 
The dose of 
radiation therapy delivery to the primary tumor site has varied 
by institution and clinical study. Dose reduction based on 
imaging or histologic response has met with limited success in 
achieving rates of local tumor control equivalent to surgical 
resection (8,64). Doses of radiation therapy in the range of 
5040 cGy for patients with microscopic residual disease and 
5580 cGy for patients with gross residual disease appear to 
achieve local tumor control rates in excess of 80% (64,65). 
Patients with gross residual disease and initial tumor volumes 
of 8cm or greater have local failure rates of 40% or greater. 
Delivery of an adequate dose of radiation therapy prior to the 
IGRT era has been limited by dose constraints of surrounding 
normal 
tissues. 
IGRT 
techniques 
including 
intensity 
modulated radiation therapy allow delivery of therapeutic 
doses of irradiation while protecting adjacent normal tissues. 
Patients with unresected or incompletely resected ESFT will 
receive 6480 cGy delivered to gross disease.
2.6.1.2
Treatment Volume and Dose in Rhabdomyosarcoma and 
Small Round Blue Cell Undifferentiated Sarcoma
Rhabdomyosarcoma has been approached with systematic 
radiotherapy in the vast majority of patients treated in the 
United States. 
Treatment has primarily been delivered 
according 
to 
guidelines 
within 
the 
serial 
Intergroup 
Rhabdomyosarcoma Studies. On these studies, local control 
rates have been well defined with a low incidence of marginal 
failure. Local control rates have ranged from 75% to 85% (6- 
7,35).  Radiotherapeutic margins have included a treatment
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 10
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
volume of 2 cm around the gross tumor volume or tumor bed. 
Doses recommended have been protocol specific and varied 
by the degree of prior surgery. Experience from the IRS 
studies and other institutional series demonstrates that 
microscopic residual tumor in the tumor bed (margin negative 
or margin positive surgery) is almost systematically controlled 
with radiotherapy doses in the range of 3600 to 4140 cGy 
(7,35,43). Gross disease has been controlled in >80% of 
cases with doses of 5040 cGy (5,6).
2.6.1.3
Treatment Volume and Dose in Soft Tissue Sarcoma 
(excluding RMS and EOE)
Soft tissue sarcoma (STS) is frequently managed with 
radiation therapy (either brachytherapy or external beam 
radiotherapy) following surgical resection. Local control rates 
have been high with either modality alone or in combination. 
Traditional views on the appropriate margin of normal tissue to 
include when treating STS have ranged from a 2-5 cm margin 
to the entire muscle compartment. Larger field irradiation (>5 
cm margin) is supported by older series with less precise 
imaging (44-45). A University of Chicago retrospective series 
utilizing external beam radiotherapy suggests a clinical margin 
below 5 cm may compromise local control (46). Conventional 
target volume definitions do not directly translate to 
conformally defined target volumes using the paradigm of 
GTV, CTV and PTV. Brachytherapy techniques, where tissues 
at risk are rigorously defined intra-operatively, document 
control rates for adult STS of 89% with margins of 2 cm 
beyond the surgically defined tumor bed (11-12). Benefits to 
minimizing treatment volume in STS are most critical as doses 
required for local tumor control are high and may be 
associated with significant late somatic effects. Experience 
from randomized studies of external beam radiotherapy and 
brachytherapy, as well as retrospective institutional series 
demonstrate that microscopic residual tumor in the tumor bed 
(margin negative or margin positive surgery) may be controlled 
with external beam radiotherapy doses in the range of 6300 – 
6660 cGy or low dose rate brachytherapy doses of 4200-4500 
cGy (3-4,11-12,45-48). Gross disease has been treated with 
doses of 7000 cGy or more with relatively poor long-term 
control (7).
2.7
Radiation Related Tissue Effects
Models and Mechanisms for Radiation Effects
Radiation-related normal tissue effects are the result of complex interactions 
involving somatic or visceral cell types and the surrounding cellular matrix. 
Tissues may have individual response profiles to radiation, but respond 
differently in vivo where they interact with other regionally affected and 
unaffected tissues. Adverse responses in vivo may be ameliorated where 
adjacent tissues provide the necessary environment for repair of acute and late
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 11
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
effects. Conversely, surrounding tissues may promote a cascade of events that 
further enhance regional tissue injuries. Direct effects of radiotherapy are seen 
on growing individual tissues that result in the depopulation of specific cells 
necessary for growth. Such a direct effect may be responsible for changes in the 
bony physes resulting in decreased or asymmetric long bone growth. The time 
of apparent “acute” or “late” effects of treatment relate to the rapidity of 
depopulation of the respective tissues, based most often on the timeframe of 
stem cell turnover. Indirect or regional tissue effects may occur in several 
theoretical ways. When multiple tissue-related injuries occur in a given region, 
the effect upon an individual tissue often reflects both tissue-specific stem cell 
depopulation and disruption of the regional support structure (microvascular 
injury, regional inflammation) further injuring normal tissues. Whether by direct 
or indirect effect, the complex normal tissue response to radiation is only 
beginning to be understood, and this complexity is greater in pediatric patients 
with developing normal tissues.
2.7.1
Bone Growth
Changes in growing bone are clinically evident following radiotherapy at 
doses below tumoricidal levels. The exact mechanism is not fully 
understood but likely involves depopulation of chondrocytes located in 
the epiphysis of long bones and below the periosteum in flat bones. The 
effects of radiation on the process of bone growth appear to have a dose 
and spatial or volume based component. Clinically evident effects are 
seen in children treated with conventional techniques to doses above 20 
Gy, particularly in prepubertal patients (10,46-50). Kyphosis, lordosis 
and scoliosis are also seen following radiation to doses above 30-36 Gy. 
These curvatures may be secondary to inhomogeneous irradiation of the 
spine (i.e. non-uniform effects on the paired vertebral epiphyseal 
centers) and/or changes in the adjacent muscle secondarily affecting 
spinal growth. Full understanding of changes in bony growth are 
hampered by the retrospective nature of earlier studies, often relying on 
available plain films and measurements of sitting and standing height; 
these endpoints are correlated with retrospective estimates of dose 
delivered to the physis. Rarely is pretreatment bone age known for 
these patients. Assessments of bone densitometry are rarely obtained at 
the treated site using QCT. Understanding the direct biochemical 
alteration initiated by radiation therapy and its geometric relation to 
dosimetry for the first time may provide insight to a mechanism for injury. 
The patient will be used as their own control for this quantitative 
assessment. Adequate assessment of radiation bone growth effects 
requires prospective baseline and serial clinical and imaging evaluations 
correlated with clinical factors including other therapies (surgery and 
chemotherapy) and age of the patient at the time of treatment. When 
correlated with specific radiation dosimetric parameters, recognition of 
other impacting factors may lead to a greater understanding of the 
etiology of bony growth changes following radiation and potentially 
increase the likelihood of ameliorating such effects in the future.
2.7.2
Muscle, Adjacent Organs, and Soft Tissue
The pathophysiology of radiation-related changes in muscle, organs and 
soft tissue are poorly understood. The clinical manifestations of 
treatment to doses ranging from 50-60 Gy range from fibrosis to atrophy, 
and often result in diminished physical function (51). Anecdotal 
experiences in young children suggest doses at or below 20 Gy are
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 12
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
associated with readily discernible soft tissue alterations. Correlations 
have been evaluated in patients treated for breast cancer using breast 
conservation surgery followed by breast irradiation. Relationships have 
been established between radiation parameters (dose delivered to the 
intact breast and the volume receiving high dose radiation) and clinical 
cosmetic scores (52). Measurement of tissue compliance has also been 
used as an objective documentation of superficial fibrosis. Though not 
specific for a given tissue type, this technique appears to be a simple, 
method for determining changes in soft tissue compliance consistent with 
subjective grading of fibrosis (53). Evaluations of the available data 
suggest that the variability of site contains as much error as the ability to 
measure fibrosis. We will discontinue collecting tissue compliance with 
this amendment (amendment 5.0) and report the outcomes for the 
available data.
Muscle atrophy is a clinically evident phenomenon seen following 
radiotherapy to the soft tissues. (54). Treatment results in decreased 
development of major muscle groups in some patients. Correlations with 
radiotherapy dose and volume have been poorly defined, but this 
treatment effect appears to occur following large volume radiotherapy 
delivered to higher doses. The resultant functional effects of decreased 
strength and mobility are not documented. Incorporation of validated 
functional scales and assessments of quality of life related to function will 
provide needed data on the long term effects of specific dosimetric 
parameters. Relation of the outcome measures to radiation dosimetry 
through mathematical models will further our understanding of these 
effects and how they may be avoided in the future. Elucidation, through 
prospective evaluation, of possible factors affecting the formation of 
fibrosis, muscle atrophy and functional changes may allow improved 
treatment approaches with reduction of these effects in the future.
The study of basic functional changes, determined from standard 
imaging, clinical testing or functional scales, in individual irradiated 
organs is key to defining normal tissue tolerances as we move forward 
with increasingly conformal radiation modalities and techniques. We will 
continue to collect information about these toxicities and related them to 
dosimetry and clinical characteristics as patient numbers and organ 
exposure allow.
2.7.3
Vascular Changes
Tissue microvasculature and some macrovasculature are affected by 
radiation. Radiation induced endothelial cell proliferation and endothelial 
cell loss may result in thrombosis of capillaries and arterioles (17). 
Larger vessel injury has been reported in patients irradiated for 
parasellar central nervous system tumors (Moyamoya syndrome) (55), 
but has not been documented in the irradiation of other larger vessels. 
Radiation induced vascular changes may not be the primary 
pathophysiologic event responsible for late tissue effects, but in 
conjunction with direct visceral and somatic effects of radiation may 
further promote late treatment events.
Radiation related tissue effects on the musculoskeletal system among 
pediatric patients have been mostly anecdotal in nature. The available 
studies with specific musculoskeletal measurements evaluate a limited 
number of variables retrospectively and lack correlation with volumetric
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 13
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
dosimetry utilized in image-guided radiation therapy, required for 
accurately assessing radiation related treatment effects. Historic data 
reported in the literature lacks paired datasets with measurements of the 
contralateral untreated side, serial studies to adequately delineate the 
time course of treatment related effects and specifically designed 
imaging studies to assess effects on the musculoskeletal system. Within 
the context of this study these variables will be assessed in a prospective 
manner to establish a baseline for radiation related treatment effects with 
image-guided radiation therapy. From this protocol we hope to generate 
objective functions to describe the probability and/or severity of the 
above listed treatment effects based on radiotherapeutic dose, volume 
and pretreatment clinical factors. This paradigm has been established at 
St. Jude in the RT-1 protocol for localized pediatric brain tumors. 
Specific subjective and objective measurements are listed in table 2.7 
below.
Table 2.7
Measurement
Evaluation
Objective
Subjective
Clinical
Physical Examination
Sitting/standing height
Musculoskeletal/Radiation CTC
PT/OT
Functional Evaluation
Measurements of tissue bulk
Strength
Range of motion
Bone length (when available) 
Specific functional scales:
DASH
Upper extremity function
TESS
Lower extremity function
U. of Wash. QOL
H&N function
Diagnostic Imaging
Standard of care imaging
qCT Densitometry
Treated bone density
Bone strength
3.0
Drug Information – Drug therapy is given on concomitant 
chemotherapy protocols or a best clinical management plan.
4.0
Patient Eligibility
4.1
Age  25 years (new enrollments only). No age limit on participants who 
reconsent or reenroll.
4.2
Musculoskeletal tumor involving the primary site of origin requiring curative 
definitive, pre-operative or post-operative irradiation to that primary site.
4.3
No prior therapeutic irradiation at the primary site except for emergent radiation 
to the primary site lasting 1 week or less (5 treatment days) that can be 
dosimetrically accounted for in the analysis.
4.4
Negative serum or urine -HCG for females of child bearing age (not applicable 
for reconsents and reenrolled females)
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 14
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
4.5
Patients will be stratified into 2 groups for evaluation of secondary objective 
endpoints based on the absence or presence of metastatic disease.
Patients may enter this study in specific clinical situations often defined by 
multimodality protocols that include the use of radiation therapy, including 
irradiation alone or combined with surgery (following surgical resection that may 
be macroscopically complete or incomplete, with positive or negative histologic 
margins) and/or chemotherapy (following neoadjuvant chemotherapy or 
combined with post-irradiation adjuvant chemotherapy). Patients requiring 
regional nodal irradiation and/or metastatic site irradiation are allowed as long as 
the primary site requires radiation. Patients with recurrent tumors or second 
malignant neoplasms are allowed on this study if the current primary tumor site 
requiring irradiation has not previously been irradiated. The treatment plan 
detailed in this study will allow most patients to be concurrently enrolled on 
institutional and COG studies.
Patients enrolled prior to amendment 4.0, who are still in active participation will 
be reconsented to the current version of the protocol (4.0). Patients off-study 
due to completion will be reenrolled on protocol version 4.0 to complete the 7/8 
year, 10/11 year and adulthood (18 years of age) requirements. All patients will 
now follow the same follow-up schedule and procedures as outlined in Table 8.1.
5.0
Treatment Plan
5.1
Overview
Eligible patients will be accessioned at the time of irradiation and undergo a pre- 
radiotherapy evaluation, treatment planning, image-guided radiotherapy delivery 
and intra- and post-irradiation evaluations. Imaging studies obtained for other 
clinical protocols or routine clinical management may be accepted for use prior 
to, during or following radiation therapy on this study. Table B1 (appendix B) 
indicates which studies are considered “standard of care” and which are for 
research purposes only.
Table 5.1
Treatment Planning and Evaluation Schedule for All Patients
Evaluation Schedule
Pre-IGRT1
week 1
week 2
week 3
week 4
week 5
week 6
week 7
Clinical
Physical Examination
X
X2
X
X
X
X
X
X
Physical / Occupational Therapy
Functional Evaluation
X
X1
-
-
-
-
X3
-
1 Pre-IGRT includes the interval of time 4 weeks prior to the initiation of treatment. Studies for determination of 
metastatic disease do not need to be repeated if done at diagnosis. Note for patients receiving brachytherapy 
only, functional evaluation, MRI and PET imaging will follow catheter removal during week 1 in place of Pre- 
IGRT imaging
2Sitting and standing height only need to be obtained prior to radiation therapy as tolerated by patient. No 
measurements of height are recorded during irradiation
3 At or following the completion of radiation therapy
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 15
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
6.0
Radiation Therapy
6.1
Equipment for treatment delivery 
External beam
6.1.1
Megavoltage linear accelerators utilizing 6MV to 21MV photon energies 
as well as 4 MeV through 21 MeV electron energies
6.1.2
Multileaf collimator or cerrobend block shaped fields
6.1.3
Immobilization devices for daily positioning for treatment 
Brachytherapy
6.1.4
Interstitial catheters, custom molds or intracavitary applicators
6.1.5
Iodine-125 or Iridium-192 low dose rate or high dose rate sources
6.2
Techniques for radiation therapy treatment 
External beam
6.2.1
Multiple static field conformal techniques with single or multiple field 
segments
6.2.2
Weekly portal imaging
6.2.3
All fields treated daily 
Brachytherapy
6.2.4
Low dose rate or high dose rate source loadings with equal weight or 
variable weight sources
6.2.5
Transverse or longitudinal interstitial catheter placement
6.2.6
Low dose rate source loading for interstitial brachytherapy on the fifth 
post-operative day or later
6.3
Radiotherapy Volume and Dose
The gross tumor volume (GTV), clinical target volume (CTV), and planning target 
volume (PTV) will be delineated for each patient on a treatment planning imaging 
study (CT with or without MRI) prior to planning treatment. The larger PTV (PTV- 
1) should be treated first followed by the smaller PTV (PTV-2). The appropriate 
margins for these volumes are outlined as follows:
6.3.1
Ewing’s family of tumors
6.3.1.1
Definitive radiotherapy (no surgical resection)
GTV1 – Visible gross tumor consisting of bone initially 
involved with tumor and soft tissue contiguous with the initial 
tumor prior to radiotherapy (usually post-chemotherapy) 
defined by physical exam and imaging studies.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 16
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
CTV1 – This target volume consists of GTV1 with a 1.0 cm 
anatomic margin of tissue, respecting anatomic barriers that 
limit tumor spread.
PTV1 – CTV1 with a treatment site and immobilization 
device specific margin for target motion and daily treatment 
set-up variation, usually 5 - 10mm.
PTV2 - GTV1 with a treatment site and immobilization device 
specific margin for target motion and daily treatment set-up 
variation, usually 5 - 10mm.
6.3.1.2
Post-operative radiotherapy (following surgical resection)
GTV1 – The surgical tumor bed consisting of the margin of 
bone initially involved with tumor and soft tissue contiguous 
with the tumor prior to surgical resection as defined by 
physical exam, imaging studies, operative notes, and 
pathology reports.
CTV1 – This target volume consists of GTV1 with a 1 cm 
anatomic margin of tissue, respecting anatomic barriers that 
limit tumor spread.
PTV1 – CTV1 with a treatment site and immobilization 
device specific margin for target motion and daily treatment 
set-up variation, usually 5 - 10mm.
6.3.1.3
Brachytherapy (limited to use in soft tissue Ewing’s family of 
tumors)
GTV1b – The surgical tumor bed defined by intraoperative 
examination and preoperative imaging studies
CTV1b – This target volume consists of GTV1 with a 1 cm 
lateral margin and a 2 cm proximal and distal margin relative 
to the long axis of the tumor for interstitial approaches. For 
intracavitary and surface brachytherapy applications a 
margin appropriate for the tumor site and presentation, 
usually 1-2 cm is recommended.
No PTV exists for brachytherapy procedures.
6.3.2
Rhabdomyosarcoma and small round blue cell undifferentiated sarcoma
6.3.2.1
Definitive radiotherapy (no surgical resection)
GTV1 – Visible gross tumor including initially involved soft 
tissue prior to biopsy or therapy as defined by physical exam 
and imaging studies.
CTV1 – This target volume consists of GTV1 with a 1 cm 
anatomic margin of tissue, respecting anatomic barriers of
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 17
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
tumor spread, and regional areas of nodal involvement 
warranting irradiation.
PTV1 – This volume includes the CTV1 with a treatment site 
and immobilization device specific margin for target motion 
and daily treatment set-up variation, usually 5 - 10mm.
PTV2 – This volume includes the GTV1 with a treatment site 
and immobilization device specific margin for target motion 
and daily treatment set-up variation, usually 5 - 10mm.
6.3.2.2
Post-operative radiotherapy (following surgical resection)
GTV1 – The post-operative tumor bed consisting of the 
initially involved soft tissue contiguous with the initial tumor 
prior to any therapy as defined by physical exam and 
imaging studies.
CTV1 – This target volume consists of GTV1 with a 1 cm 
anatomic margin of tissue, respecting anatomic barriers of 
tumor spread, and regional areas of nodal involvement 
warranting irradiation.
PTV1 – This volume includes the CTV1 with a treatment site 
and immobilization device specific margin for target motion 
and daily treatment set-up variation, usually 5 - 10mm.
6.3.2.3
Brachytherapy
GTV1b – The surgical tumor be defined by intraoperative 
examination and preoperative imaging studies CTV1b – This 
target volume consists of GTV1 with a 1 cm lateral margin 
and a 1 cm proximal and distal margin relative to the long 
axis of the tumor for interstitial approaches. For intracavitary 
and surface brachytherapy applications a margin appropriate 
for the tumor site and presentation, usually 1-2 cm is 
recommended.
No PTV exists for brachytherapy procedures.
6.3.3
Non-rhabdomyosarcoma soft tissue sarcoma (STS)
6.3.3.1
Definitive radiotherapy (no surgical resection) or pre- 
operative radiotherapy*
GTV1 – Visible gross tumor including initially involved soft 
tissue prior to biopsy or therapy as defined by physical exam 
and imaging studies.
CTV1 – This target volume consists of GTV1 with a 1.5 cm 
anatomic margin of tissue, respecting anatomic barriers of 
tumor spread.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 18
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
PTV1 – The CTV1 with a treatment site and immobilization 
device specific margin for target motion and daily treatment 
set-up variation, usually 5 - 10mm.
6.3.3.2
Post-operative radiotherapy (following surgical resection)
GTV1 – The post-operative tumor bed consisting of the 
initially involved soft tissue contiguous with the initial tumor 
prior to any therapy as defined by physical exam and 
imaging studies.
CTV1 – This target volume consists of GTV1 with a 1.5 cm 
anatomic margin of tissue, respecting anatomic barriers of 
tumor spread.
PTV1 – This volume includes the CTV1 with a treatment site 
and immobilization device specific margin for target motion 
and daily treatment set-up variation, usually 5 - 10mm.
6.3.3.3
Brachytherapy
GTV1b – The surgical tumor be defined by intraoperative 
examination and preoperative imaging studies
CTV1b – This target volume consists of GTV1 with a 1 cm 
lateral margin and a 1.5 cm proximal and distal margin 
relative to the long axis of the tumor for interstitial 
approaches. For intracavitary and surface brachytherapy 
applications a margin appropriate for the tumor site and 
presentation, usually 1-2 cm is recommended.
No PTV exists for brachytherapy procedures.
6.3.4
Other musculoskeletal tumors
6.3.4.1
Patients receiving radiotherapy for osteosarcoma will receive 
radiotherapy according to the volumetric and dosimetric 
guidelines given for Ewing’s sarcoma given in section 6.3.1 
and table 6.3.1. Patients receiving radiotherapy for other 
musculoskeletal tumors will receive radiotherapy according 
to the volumetric and dosimetric guidelines given for soft 
tissue sarcomas given in section 6.3.3 and table 6.3.3.
The radiation dose will be prescribed to the ICRU reference point, with 
the target volume minimum and maximum doses being recorded.
Total radiation doses recommended are disease specific and are 
designed to be consistent with current and proposed institutional and 
national protocols.
Table 6.3.1
Ewing’s sarcoma family of tumors*
Volume Dose
Cumulative Dose
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 19
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Definitive radiotherapy
Primary tumor <8cm
PTV1 (GTV1 + CTV1)
4500 cGy
4500 cGy
PTV2 (GTV2)
1080 cGy
5580 cGy
Primary tumor ≥ 8cm
PTV1 (GTV1 + CTV1)
4500 cGy
4500 cGy
PTV2 (GTV2)
1980 cGy
6480 cGy
Post-operative radiotherapy
PTV1 (GTV1 + CTV1)
5040 cGy
5040 cGy
Post-operative brachytherapy and 
External beam radiotherapy
CTV1b (brachytherapy)
1500 – 2500 cGy
1500 – 2000 cGy
PTV1 (GTV1 + CTV1 + CTV1b)
4500 cGy
6000 – 7000 cGy
Table 6.3.2
Rhabdomyosarcoma and undifferentiated sarcoma**
Volume Dose
Cumulative Dose
Definitive radiotherapy
PTV1 (GTV1 + CTV1)
3600 cGy
3600 cGy
PTV2 (GTV2)
900 – 1440 cGy
4500 – 5040 cGy
Post-operative radiotherapy
PTV1 (GTV1 + CTV1)
3600 cGy
3600 cGy
Post-operative brachytherapy
CTV1b (brachytherapy)
2100 cGy (7 fxn BID)
2100 cGy
Table 6.3.3
Soft tissue sarcoma*
Volume Dose
Cumulative Dose
Definitive radiotherapy
PTV1 (GTV1 + CTV1)
6600 – 7000 cGy
6600 – 7000 cGy
Pre-operative radiotherapy
PTV1 (GTV1 + CTV1)
4500 - 5580 cGy
4500 - 5580 cGy
Post-operative radiotherapy
PTV1 (GTV1 + CTV1)
5580 - 6300 cGy
5580 - 6300 cGy
Post-operative brachytherapy and external beam 
radiotherapy
CTV1b (brachytherapy HDR)
1350 cGy (3 fxn BID)
1350 cGy
PTV1 (GTV1 + CTV1 + CTV1b)
4500 – 5040 cGy
5850 – 6390 cGy
Post-operative brachytherapy
CTV1b (brachytherapy)
3400 cGy (10 fxn BID)
3400 cGy
* Patients receiving radiotherapy for osteosarcoma and other musculoskeletal tumors will receive radiotherapy 
according to the volumetric and dosimetric guidelines given for Ewing’s sarcoma and soft tissue sarcomas 
respectively.
** RMS dose based on tumor group and stage at diagnosis and immediately prior to radiation defined in section 6.3.2
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 20
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
The daily radiation fraction size will be 1.8 Gy once daily, with the exception of 
cases treated with intensity modulation where the microscopic and gross tumor 
volumes are treated concurrently. In this situation the microscopic tumor daily 
dose shall be no less than 170 cGy per day.
Brachytherapy cases will be treated with high dose rate techniques where the 
prescription isosurface will cover the tumor bed (CTV1b) and be delivered at 300- 
340 cGy per fraction delivered BID.
6.4
Immobilization and Patient Positioning
Positioning of the patient for daily radiotherapy will be disease site and patient 
specific. Devices such as alpha-cradles, aquaplast and vac-lock treatment bags 
will be utilized to ensure daily reproducibility of set-up between 5-8 mm. 
Isocenter marks will be made on the patient and immobilization device; treatment 
table position and source to skin distance (SSD) will be noted for each patient 
and used daily for patient set-up.
6.5
Simulation and Treatment Planning
Simulation will consist of orthogonal simulation radiographs and CT scan in the 
treatment position or CT simulation on a CT simulator. These CT images and 
other imaging modalities (MRI) are transferred to a treatment-planning computer 
and undergo co-registration (image fusion) to define the treatment planning study 
set. Outlines of normal tissues and target volumes are created on axial, sagittal 
coronal, or any arbitrary plane within the study set. All targets and structures 
must define a three dimensional polygon and follow the target volume 
conventions previously (GTV, CTV and PTV) or describe a specific normal tissue 
structure. Normal tissues contoured may include (but are not limited to) the 
epiphysis, physis, metaphysis, cortical bone including long or flat bone, and 
individual muscle groups.
Treatment plans will be generated by a cooperative effort between medical 
physics and the responsible radiation oncologist. Brachytherapy catheter 
placement will follow the guidelines described by MSKCC (11). The most 
appropriate set of treatment beams, dose constraints or source activities will be 
evaluated for three-dimensional conformal, IMRT and brachytherapy treatment 
plans respectively. Plans will be evaluated subjectively by review of isodose 
distributions and objectively by review of dose-volume histograms. The most 
appropriate plan will be selected by weighing the benefits and complexities of 
target coverage, normal tissue sparing, dose heterogeneity and complexity of 
delivery. Guidelines for these parameters are as follows:
6.5.1
Target coverage – 95% of the PTV should be covered by 95% of the 
prescribed dose (note PTV excludes the contained CTV, i.e. PTV-CTV). 
In the case of brachytherapy treatment plans 100% of the CTV must 
receive 95% of the prescribed dose.
6.5.2
Normal tissue doses – Normal tissues should be treated to as low a dose 
as possible while maintaining adequate target coverage. Exceptions to 
mandating complete target coverage should be made in the case of 
critical structures such as spinal cord (limited to 4500-5000 cGy), large 
volumes of bowel (limited to 4500 cGy), excessive volume of lung, etc.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 21
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
6.5.3
Dose heterogeneity – For 3-D conformal and IMRT treatment plans no 
more than 15% of the combined GTV, CTV and PTV volume may 
exceed 115% of the prescribed dose. For brachytherapy plans dose 
heterogeneity is anticipated and dose to 5% of the target volume (CTV) 
will be recorded.
6.5.4
Treatment plan complexity – As treatment plans allow more conformal 
delivery of radiation to complex target volumes, delivery times and 
delivery complexity will increase. No objective criteria exist for judging 
treatment plan complexity, but a less complex plan may be preferable if 
consistent and reliable delivery is better achieved.
6.6
Treatment Delivery
Following completion of treatment planning, the patient will return and undergo 
verification of position and individual treatment beams. After correct localization 
of the patient on the treatment couch, radiation therapy will commence. All fields 
are treated daily at the prescribed dose and fractionation scheme outlined in 
tables 6.3.1, 6.3.2, and 6.3.3. Localization images are obtained weekly or more 
often for accuracy of patient positioning. For brachytherapy treatments, following 
treatment planning, radioactive sources are ordered and catheter placement is 
again verified, either clinically or radiographically if indicated.
6.7
Treatment Related Effects of Radiation
6.7.1
Radiotherapy related treatment effects are both location- and time- 
dependent and clearly related to the dose delivered to specific organs or 
structures. Effects are divided into acute reactions, early delayed 
reactions and late reactions divided by arbitrary time periods indicated 
below.
6.7.2
Acute reactions (during radiotherapy): Hair loss, errythema of skin, 
desquamation, edema of soft tissues,
6.7.3
Subacute reactions (6 weeks to 3 months after irradiation): Soft tissue 
edema
6.7.4
Late reactions (more than 3 months after irradiation): Fibrosis of soft 
tissues including muscle, injury to muscle or bone, including changes in 
bone growth, and changes in tissue vascularity.
7.0
Pretreatment Evaluations
Pretreatment evaluations consist of examinations of physical function, and imaging 
studies. These studies will also be obtained during and following completion of delivery 
of radiation (table 5.1, 7.1). Imaging studies obtained pretreatment and during the follow- 
up period are designed to concur with national and institutional studies.
7.1
Evaluations of Physical Function
Analytic evaluations of physical function will be obtained in conjunction with the 
departments of physical and occupational therapy as well as consultation with 
orthopedic surgery. Evaluations will be made post surgery and prior to irradiation 
for patients undergoing external beam radiotherapy.  For patients who will
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 22
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
receive brachytherapy with or without external beam irradiation an additional 
evaluation will be obtained prior to surgery. General information regarding height 
(sitting and standing), weight, and limb length or muscle bulk will be obtained, as 
relevant. 
All evaluations use quantitative subjective scales or absolute 
measurements and include the contralateral unirradiated side if relevant. 
Assessments are sequential in nature to develop data regarding the time course 
of specific treatment related effects. Specific instruments of physical function are 
included in appendix C. The scope of such evaluations will include information 
regarding range of motion, muscle tone and strength specific to the muscle 
groups and joints to be irradiated.
7.2
Diagnostic Imaging
7.2.1
Magnetic Resonance Imaging
Magnetic resonance imaging beyond the standard of care (RTSARC 
MRI) will no longer be used in the trial in new patients or those currently 
on study. The section below will be left in place as a reference for the 
patient data collected prior to this amendment.
Magnetic resonance imaging (MR) will be used for all patients enrolled 
on study unless implanted metallic objects preclude its use in which case 
a diagnostic CT study will be used. The specific MRI sequences 
required for this protocol are outlined in appendix D and are appended 
on to the site specific MR imaging protocol. Dynamic contrast enhanced 
MR (DCE-MR) has been applied to evaluate tumor response and 
necrosis in patients with osteosarcoma. This technique delineates rate 
of contrast leakage for specified regions of tissue, which provides 
imaging based objective measurements of microvascular changes in 
both adjacent normal tissue and intact tumor (if present). Arterial spin 
labeling also evaluated vascular flow and density in sites were it is 
applicable. Both DCE-MR and arterial spin labeling MR will be applied 
when feasible though certain anatomic sites such and chest wall may not 
be imaged with these techniques due to the effects of motion and 
technical limitations of the sequence
Anatomic measurements of the primary tumor, muscle volume, bone 
length, cortical thickness and physis closure will be made with multi-slice 
axial coronal and sagital imaging acquired with the typical clinical 
sequences (e.g T1 fat saturation VIBE, Flash,or MPR Rage techniques). 
Tumor measurements will be made using a unidimensional maximal 
diameter. All measurements, including those of bone length, volume, 
muscle volume and quantitative MR parameters will be obtained 
following post imaging processing of MR datasets at the time of analysis.
7.2.2
Positron Emission Tomography (PET)
PET imaging beyond the standard of care will no longer be used in this 
trial in new patients or those currently on study. The section below will 
be left in place as a reference for the patient data collected prior to this 
amendment.
PET scans will be obtained of the whole body following administration of 
18F-Fluorodeoxyglucose (FDG) per standard imaging protocols. PET- 
FDG evaluates glucose uptake (and most often its metabolism) into 
tissues. This form of functional imaging is becoming more prevalent and
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 23
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
its application to pediatric oncology is promising. Currently, little data 
exist regarding the application of PET to pediatric patients with 
musculoskeletal tumors. Following surgical resection PET may better 
define the region at high risk for residual disease prior to radiation. In 
intact tumors PET obtained serially before and after radiation may define 
functional radiotherapeutic response and its clinical significance.
Normal tissue imaging with PET has usually occurred in the brain when 
functional neuro-imaging studies are desired. Extracranial assessment 
of normal (non-tumor) tissues is not well studied. PET-FDG may provide 
information about normal tissue metabolism following radiation.
A PET-FDG requires the administration of radioactive labeled glucose. 
The amount of radiation given for one PET scan is about one-third of the 
yearly limit for radiation workers (physicians, nurses, scientists) over the 
course of one year. Four PET scans are scheduled during this study. 
These imaging studies are encouraged but optional. The PET-FDG 
studies are optional; the patient or their guardian may decline any or all 
PET imaging studies.
7.2.3
QCT Bone Densitometry
Bone densitometry will be obtained using QCT at years 7 or 8, 10 or 11 
of follow-up and at age 18 (if year 10 is earlier). This study may be 
performed at the same time as a QCT obtained to document / investigate 
bone loss due to systemic therapy. The entire treated bone or bone 
adjacent the treatment site will be identified and imaged in its entirety. 
This will allow assessment of bone density within and outside the high 
dose radiation regions (hypothesized to alter bone density). Correlations 
will be made between bone density and radiation dose. There may be 
limits of applying the QCT technique to whole bone imaging outside of 
long bones. Complex bony structures such as the face may have limited 
applicability of this technique, while adjacent bones such as vertebral 
bodies would be more appropriate. In these cases the P.I. will review the 
patient’s initial dosimetry from their radiation therapy treatment plan and 
consult with Dr. Kaste or her designee regarding the use of QCT.
The axial images of the entire bone will also be utilized to assess bone 
growth over the 10-year follow-up period and into adulthood (18 years of 
age) compared with the initial study MR and / or CT simulation study. 
Models of long-term bone growth will be generated based on this data.
QCT studies inherently deliver a small dose to the patient in order to 
obtain density information regarding the bone. Typical QCT studies 
would image one or more lumbar vertebral bodies or a portion of a long 
bone, but not the entire bone. For this study we are requiring the entire 
bone to be imaged to fully study the effects of radiation on these bones, 
including understanding its effect on growth, correlation with risk of 
fracture due to decreased bone density, as well as overall bone health. 
This could entail imaging the radius, a vertebral body, rib or tibia. All of 
the sites would have potentially different effective radiation exposures for 
the patient. Though there is some clinical benefit to this procedure, we 
obtained radiation phantom base dose estimates (in conjunction with Dr. 
Chia-ho Hua, Radiation Oncology Physics faculty and Dr. Sam Brady, 
Diagnostic Imaging Physics) for a number of possible scenarios in order 
to better assess the risk-benefit ratio to the patient. This information is
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 25
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
A reportable event entry into TRACKS should follow within 48 hours. Serious, 
unanticipated, and related or possibly related events must be reported within 10 
working days. At the same time, the investigator will notify the study sponsor 
(NIH or pharmaceutical company), cooperative group, and/or the FDA, as 
appropriate. To report adverse events in gene therapy trials, investigators should 
use specific RAC forms found at 
http://www4.od.nih.gov/oba/RAC/Adverse_Event_Template.doc .
The principal investigator is responsible for reviewing the aggregate toxicity 
reports and reporting to the IRB if the frequency or severity of serious toxicities 
exceed those expected as defined in the protocol or based on clinical experience 
or the published literature. Any proposed changes in the consent form or 
research procedures resulting from the report are to be prepared by the study 
team and submitted with the report to the IRB for approval.
The following definitions apply:
A serious event refers to any event in which the outcome is fatal or life- 
threatening, results in permanent disability, causes inpatient hospitalization or 
prolongs existing inpatient hospitalization, or is a congenital anomaly, cancer, or 
overdose.
An unanticipated adverse event refers to those not identified in their nature, 
severity, or frequency in the current risk documents (e.g., investigator’s 
brochure), or consistent with the investigational plan.
The following are considered reportable: Any injuries, serious event or other 
unanticipated adverse events involving risk to participants or others which occur 
at a frequency above that considered acceptable by the investigators and the 
IRB. (FDA) As described in 4.3 above, the OHSP Director or designee performs 
the initial review of unanticipated problems or serious adverse event reports.
Internal reports of events that are unanticipated, serious, and related or possibly 
related to study interventions or procedures are then forwarded to the IRB Chair 
or designee and if necessary, referred to the full IRB. Based on the frequency 
and seriousness of adverse events, the IRB Chair or Committee may deem it 
necessary to suspend or terminate a research study or studies.
10.0
Criteria for Response, Treatment Failure and Sites of Failure
Response to local therapy will be evaluated by history, physical exam and imaging 
studies as indicated in table 8.1. Additional evaluations will be at the discretion of the 
treating physicians as warranted by the clinical situation. Response will be determined 
serially prior to radiation therapy and at each follow-up evaluation. The designation of 
response is measured relative to initial imaging and physical examination for the current 
course of treatment (i.e. imaging at diagnosis or imaging at recurrence prompting 
treatment on this study).
10.1
Local Failure – Tumor recurrence or progressive disease by imaging or biopsy 
that falls within the original clinical target volume (CTV) is classified as a local 
failure counting as an event against tumor control. This can be accomplished by 
comparing the location of the recurrence by image fusion or direct measurement 
with the image guided radiotherapy target volumes. Patients that have a positive 
biopsy at the primary tumor site will be classified as a local failure only if the 
positive biopsy results in a change in therapy or change in patient status
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 26
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
(additional local or systemic therapy). Treatment failures are classified according 
to the location of the recurrent tumor relative to the targeted volumes (PTV, CTV 
and GTV) diagrammed in appendix A.
10.2
Complete Response – Disappearance of all primary and regional tumor as 
defined by physical examination and imaging. Patients undergoing complete 
resection prior to radiation or patients with no visible tumor on baseline imaging 
prior to radiation are considered a complete response at the time of irradiation.
10.3
Partial Response – More than 50% reduction in the unidimensional maximal 
diameter of the tumor compared with the baseline evaluation.
10.4
Stable Disease – Less than 50% reduction in the unidimensional maximal 
diameter of the tumor compared with the baseline evaluation.
10.5
Progressive Disease – More than 25 % increase in the unidimensional maximal 
diameter of the tumor compared with the baseline evaluation. In patients that 
have undergone complete resection prior to radiation, progressive disease is the 
appearance of any new local disease. Appearance of new regional or metastatic 
disease or a 25% increase in regional or metastatic disease will be classified as 
regional or metastatic progression. Any positive biopsy of a known metastatic 
disease site that results in a change in therapy or change in patient status (e.g. 
additional local or systemic therapy) will be classified as disease progression
11.0
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY
11.1
Enrollment on Study
Confirm subject eligibility as defined in Section 4.0 Patient Eligibility. Complete 
and sign the ‘Patient Eligibility Checklist.’ Be sure that all required values and 
dates are filled in.
Fax the completed Checklist to the Central Protocol and Data Monitoring Office 
(CPDMO) at 
 Follow with a phone call to 
 to 
ensure that the fax has been received. Eligibility will be reviewed, a patient- 
specific consent form will be generated, and the consent, protocol, and protocol 
standard order set will be delivered to the area designated on the Checklist. The 
signed consent form must be faxed to the CPDMO in order to complete the 
enrollment.
The CPDMO is staffed 7:30 am-6:00 pm CST, Monday through Friday (excluding 
holidays) and 9:00 am to 1:00 pm on Saturday. The office is staffed 9:00 am to 
3:00 pm CST all weekday holidays except Christmas. A staff member is 
available by pager Saturday afternoons, Sundays and on Christmas Day for 
SJCRH enrollments.
11.2
Data Collection
Case report forms (CRFs) will be completed and reviewed by the SJCRH data 
manager for accuracy and completeness. Data will then be entered into a secure 
CRIS database.
11.3
Study Monitoring
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 27
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Source document verification of eligibility and informed consent for 100% of St. 
Jude participants will be performed by the Eligibility Coordinators within 10 
working days of completion of enrollment.
The Clinical Research Monitor will perform monitoring of applicable essential 
regulatory documentation. Also, reviewing for the timeliness of serious adverse 
event reporting (type, grade, attribution, duration, timeliness and 
appropriateness) for selected study participants semi-annually and track accrual 
continuously. The monitor will verify those data points relating to the primary 
study objective for a certain number of study enrollees as specified in the 
Moderate Risk monitoring plan checklist for this study. Protocol compliance 
monitoring will include participant status, safety assessments, eligibility, the 
informed consent process, participant protocol status, off-study, and off-therapy 
criteria. The Monitor will generate a formal report which is shared with the 
Principal Investigator (PI), study team and the Internal Monitoring Committee 
(IMC).
Monitoring may be conducted more frequently if deemed necessary by the 
CPDMO or the IMC.
Continuing reviews by the IRB and CT-SRC will occur at least annually. In 
addition, SAE reports in TRACKS (Total Research and Knowledge System) are 
reviewed in a timely manner by the IRB/ OHSP.
11.4
Confidentiality
Study numbers will be used in place of an identifier such as a medical record 
number. No research participant names will be recorded on the data collection 
forms. The list containing the study number and the medical record number will 
be maintained in a locked file and will be destroyed after all data have been 
analyzed.
The medical records of study participants may be reviewed by the St. Jude IRB, 
FDA, clinical research monitors, etc.
12.0
Statistical Considerations
12.1
To estimate the rates of local failure and tumor progression
The primary objective is to estimate the local control and patterns of failure for 
patients with primary musculoskeletal tumors including the Ewing’s sarcoma 
family of tumors (ESFT), rhabdomyosarcoma (RMS) and non- 
rhabdomyosarcoma soft tissue sarcoma (STS) treated with image guided three- 
dimensional conformal radiation therapy. Different tumor types are accessioned 
to this study and their local failure rates differ significantly. To account for these 
differences, three groups of patients will be selected for local failure analysis 
based on the expected accrual of these patients to this study (Appendix E).
These groups are defined by histology, site and degree of surgical resection and 
are selected to allow meaningful comparison with targeted rates of local control. 
Target local control rates for these specific treatment groups are established and 
listed in appendix E based on selected literature (3, 5-6, 9-12, 64,65). A lower 
limit to the local control rate is given to define a threshold below which the 
paradigm for treatment described in this protocol is deemed unacceptable.
Analysis of local control will be undertaken for a treatment group at each event
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 28
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
counted as a local failure, when each treatment group has completed accrual and 
has been followed for five years, and at intervals specified below. The accrual of 
patients in five years in the study for all tumor types is projected in Table 12.1.1 
below. For the local control analysis, projections for accrual for the specific 
treatment groups are listed in Table 12.1.2 below. For nonsequential tests, if the 
actual final accruals are different from the projected accruals, then for Group III 
RMS or for the Resected or Small ESFT (target 85%), the lower limit to the local 
control rate is 60%, 70%, 72%, or 73.3%, respectively, for the final accrual of 15, 
20, 25, or 30 patients. For the Resected STS (target rate 90%), the lower limit 
73.3%, 75%, 76%, or 80%, respectively, for the final accrual of 15, 20, 25, or 30 
patients. For the Large ESFT (target rate 55%), the lower limit 33.3%, 35%, 36%, 
or 40%, respectively, for the final accrual of 15, 20, 25, or 30 patients. A 
sequential safety-monitoring plan is given in Table 12.1.3 in terms of minimum 
number for the number of patients locally controlled corresponding to the number 
of patients accrued within a treatment group during the study, assuming the final 
accrual is 30 patients in each treatment group. The minimum number is 
calculated for each of the four treatment groups (Group III RMS, Resected STS, 
and Resected / Small ESFT, and Large ESFT), respectively. For each of the four 
treatment groups, when the number of patients accrued during the study reaches 
5, 10, 15, 20, 25, or 30, the number of patients with local tumor control will be 
reviewed and must not be less than the corresponding minimum number (Table 
12.1.3). If fewer patients than targeted are controlled locally, then the rate of 
local control is considered be too low for that treatment group and the study for 
that treatment group will be stopped for investigating the reasons. At any event 
counted as a local failure during study, the local control rate for that treatment 
group will be determined. If the local control rate is lower than targeted, then 
accrual to that treatment group will be halted and the reasons investigated. If the 
number of patients accrued is other than 5, 10, 20, 25, or 30, the assistance of 
the statistician (J.W..) may be requested by the PI (M.K.) to calculate the new 
minimum number of patients locally controlled according to the actual number of 
patients accrued. In the above monitoring scheme, the number of patients locally 
controlled is counted disregarding the timing (since initiation of radiation therapy) 
of events (local failures) as this calculation is based on a target rate of local 
control at 2 years that is identical at 5 years. These target rates are expected 
estimates of local control and not actual local control rates based directly on 
historic data. We will use the survival model with competing risk (e.g., patient 
death) (57) to estimate the rates of local failure and tumor progression (defined in 
10.1-10.6) for each tumor group. One-hundred evaluable patients will be 
required based on the projected accruals in table 12.1.1 below. We expect to 
enroll a total of 110 patients based on our current accrual to generate 100 
evaluable patients for analysis.
Table 12.1.1 
Projected Accruals
RMS
STS
ESFT
W/o Metastases
18
26
26
W & w/o Metastases
29
26
37
Table 12.1.2
Accrual in Groups for Local Control Analysis
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 29
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Group III 
RMS
Resected 
STS
Resected ESFT 
or
Small (<8cm) 
ESFT
Large (≥8cm) ESFT
W/o Metastases
17
24
15
3
W & w/o 
Metastases
28
24
18
12
Table 12.1.3
Safety Monitoring Plan: Minimum number of patients locally controlled per patients enrolled in 
each treatment group*
Minimum Expected Number of Patients with Local Tumor Control
Number of 
Patients Enrolled 
in a Treatment 
Group
Group III 
RMS
Resected 
STS
Resected ESFT 
or
Small (<8cm) 
ESFT
Large (≥8cm) ESFT
5
3
3
3
10
7
7
7
1
15
10
11
10
3
20
13
15
13
4
25
16
19
16
7
30
19
22
19
11
*For each of the three treatment groups, when the number of patients accrued during the 
study reaches 5, 10, 15, 20, 25, or 30, if the number of patients locally controlled is equal to or 
less than the corresponding minimum number, then the rate of local control is considered be 
too low for that treatment group and the study for that group will be stopped for investigating 
reasons.
The Second Phase Accrual: The original plan of accrual of 110 patients has been 
completed (September 2007), and additional accrual of patients is planned for 
this study as the second phase of accrual. The numbers of patients anticipated 
for the four treatment groups for the second phase accrual are shown in Table
12.1.4. These numbers are estimated based on the accrual of an additional 100 
patients with the same distribution of disease (histology, size and use of surgery) 
as the initial 110 patient cases. For the groups of ESFT-small/resected and 
ESFT-large, the treatments in the second phase are exactly the same as that in 
the first phase, so the patients in the second phase will be taking together with 
those in the first phase for safety monitoring according to the plan in Table
12.1.3. The treatments for the groups of Group III RMS and Resected STS will 
be changed such that the irradiation margin will be decreased from 2cm to 1.5cm 
for the Group III RMS, and be decreased from 1.5cm to 1.0cm for the Resected 
STS. Since the patients in the second phase in these two groups may be at 
higher risk for local failure than those in the first phase (due to clinical treatment 
margin reduction), these patients will be monitored separately from, as well as 
together with, the patients from the first phase. The monitoring plans for these 
two groups are given in Table 12.1.5. For each group, the accrual of patients will 
be held if the stopping rule is activated by any one of the two monitoring plans for 
the group.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 30
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Table 12.1.4
The Second Phase Accrual in Groups for Local Control Analysis
Group III 
RMS
Resected 
STS
Resected ESFT 
or
Small (<8cm) 
ESFT
Large (≥8cm) ESFT
W & w/o 
Metastases
35
35
13
12
For Group III RMS or for the Resected or Small ESFT (target 85%), the 5% lower 
limit for non-sequential tests for the local control rate is 26 (74.3%) or 50 (76.9%), 
respectively, for the final accrual of 35 or 65 patients. For the Resected STS 
(target rate 90%), the 5% lower limit is 28 (80.0%) or 54 (83.1%), respectively, for 
the final accrual of 35 or 65 patients. From the sample sizes of the fixed sample 
test design, we derived the sequential boundaries in Table 12.1.5 for monitoring 
the local control rates.
Table 12.1.5
The Second Phase Safety Monitoring Plan: Minimum number of patients locally controlled per 
patients enrolled in each treatment group*
Minimum Expected Number of Patients with Local Tumor Control
Number of
Patients Enrolled
Group III RMS
Resected STS
in a Treatment
Two Phases
Two Phases
Group
2nd Phase Only
Together
2nd Phase Only
Together
5
2
2
10
5
6
15
9
10
20
12
14
25
16
18
30
20
22
35
25
27
40
28
31
45
32
35
50
36
39
55
40
44
60
44
48
65
49
53
*For the second phase accrual for each of the two treatment groups, the local controls will be 
monitored simultaneously in two ways: 1) alone: when the number of patients accrued from 
the second phase accrual reaches 5, 10, 15, 20, 25, or 35, if the number of patients locally 
controlled is equal to or less than the corresponding minimum number, then the rate of local 
control is considered be too low for that treatment group and the study for that group will be 
stopped for investigating reasons; 2) together with patients accrued in the first phase: during 
the second phase accrual, if the number of all patients accrued so far from the two phases 
reaches 40, 45, 50, 55, 60, or 65 and if the number of patients locally controlled is equal to or 
less than the corresponding minimum number, then the rate of local control is considered be 
too low for that treatment group and the study for that group will be stopped for investigating 
reasons.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 31
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
12.2
Assessment of Treatment Related Effects
12.2.1
Assessment of Changes in Bone
Changes in bone assessed by physical evaluation, quality of life 
measures, QCT and MRI (or CT) will be correlated with radiotherapeutic 
parameters including dose, and volume. Changes over time will be 
assessed by serial evaluations of patient height, bone length and 
imaging evaluations of physis closure when feasible. Assessment will be 
made relative to the untreated contralateral side or another normal site 
within the patient when available.
12.2.2
Assessment of Changes in Muscle
Assessment of muscular development by physical functional scales, 
assessments of function and QOL, and volumetric changes determined 
by MRI (or CT) will be correlated with radiotherapeutic parameters and 
vascular changes assessed by DCE-MR and arterial spin labeling MR. 
Assessment will be made relative to the untreated contralateral side 
when available. PET-FDG imaging will be used to evaluate the level of 
glucose metabolism in treated muscle groups both compared to the 
untreated contralateral side and serially over time. Functional scales 
(DASH, TESS, and U. of Wash. QOL) will be obtained at 2 time points 
(84 and 120 months). These assessments will be analyzed relative to 
normative population scores.
12.2.3 Assessment of Changes in Soft Tissue
The surrounding connective tissue (soft tissue) will be serially evaluated 
by the treating radiation oncologist and physical therapist using a site- 
specific physical evaluation. MRI of the primary site will be conducted 
serially for imaging related correlates of late soft tissue effects. We will 
investigate both acute and late changes noted in soft tissue relative to 
radiotherapeutic parameters including dose, and volume.
12.2.4
Assessment of Changes in Microvasculature
Microvasculature within and outside the treated volume will be assessed 
sequentially during and following radiation therapy utilizing DCE-MR and 
arterial spin labeling MR. 
The relationships between measured 
parameters and radiotherapeutic parameters will be assessed.
12.3
Data Management
All clinical, functional, and imaging datasets will be maintained under the control 
of the protocol PI (M.K.) in a relational database. Full imaging datasets in 
electronic form will be maintained in a database that is readily accessible for 
determination of completeness and for analysis. Portions of this study may be 
analyzed and reported prior to the completion of the study with the permission of 
the P.I. Data may be collected or processed in “batches” (i.e. not in real time to 
facilitate efficiency and consistency). We anticipate reporting primary outcomes 
for patients prior to accrual of the total of 210 patients.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 32
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
12.4
Dose Effects Model for Radiation Therapy
The major difference between the IGRT and conventional RT is the difference of 
their dose distributions, i.e., the IGRT irradiates a smaller volume to with high 
doses and a larger volume to with low doses compared to the conventional RT. In 
this study we will use a statistical model, the dose effects model, to investigate the 
correlation between dose distribution and the acute and late treatment effects in
11.2. The dose effects model was first proposed in St. Jude protocol RT-1, and 
has been successfully used for assessing RT dose effects on neuropsychological 
deficits for brain tumor patients. In this model, the integral effect of radiation is a 
sum of effects of lower dose to higher dose weighted by the volumes of brain 
receiving those doses. Mathematically, the dose effects model is
I
Eintegral = R Vi
i 1
Edosei  ,
where R is the total amount of radiation on the tumor, Vi is the volume that 
receiving ith dose (i.e., dosage at the ith interval) and Edose-i is a parameter 
representing the effect of the ith dose. R and Vi are known and depend on the 
patient; Edose-i s are unknown parameters of the population and are to be 
estimated. For example, if we divide the range of dose into 5 intervals: (0%, 20%), 
(20%, 40%), (40%, 60%), (60%, 80%), (80%, 100%) and for a specific patient, 
R=60.0 Gy is the total dose received, then V1=42%, V2=27%, V3=18%, V4=8%, 
V5=5% are volumes receiving dose from those intervals. It follows that 
V1+V2+V3+V4+V5=100%. The parameters Edose-i=1,.., 5 are, respectively, the 
effects of dose in those five intervals. If each patient receives a same total 
dosage, i.e., R is the same for each patient, we will use another dose effects 
model which is more direct,
I
Eintegral =  Ri
i 1
*
dosei
For example, if each patient receives 60 Gy, we can assume the range of dosage 
is divided into, e.g., 3 intervals: (0Gy, 20Gy), (20Gy, 40Gy), (40Gy, 60Gy). 
R1=5.1Gy, R2=8.6Gy, R3=10.5Gy, where Ri is the total of dosage received from
the ith dose interval.
*
dosei is the effect of the ith dose interval and a parameter
to be estimated. The dose effect model will be imbedded as part of covariates into 
regression models for analyses. As the time since RT exposure is the most 
important covariate variable in the regression models, Eintegral will be used as a 
coefficient of the time since RT exposure to estimate the slope of longitudinal 
change of a response variable (e.g., muscular development by physical functional 
scales and volumetric changes determined by MRI). 
Additional clinical 
pretreatment and treatment related variables will be evaluated in analysis of 
radiation related treatment effects. These variables will include bone age, patient 
age and other pretreatment clinical variables that may be collected and analyzed 
for their additional effects. Radiosensitizing chemotherapy administered as 
adjuvant therapy for musculoskeletal tumors (including, but not limited to, 
Adriamycin, Actinomycin-D, topotecan and irinotecan) will also be evaluated as a 
treatment related variable for regional tissue effects. It is anticipated that the 
cumulative chemotherapeutic dose prior to radiation, the schedule of drug delivery 
and the temporal relation of drug delivery to the initiation of radiation may be a 
clinical factor in treatment related effects.
13.0
Off Study Criteria
E
E
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 33
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
13.1
Criteria for Removal from Protocol Therapy or Protocol Evaluations 
Patients may be taken off protocol for any of the following reasons:
13.1.1
Parent or patient request
13.1.2
Physician’s discretion based on patient’s ability to comply with protocol 
therapy or follow-up
13.1.3
Patient meets off study criteria (section 13.3)
13.1.4
Completion of study requirements
13.1.5
Recurrence or progression of local or metastatic disease following 
radiotherapy
13.2
Criteria for Removal from Follow-up
13.2.1
Parent or patient request
13.2.2
Patient meets off study criteria (section 13.3)
13.3
Off Study Criteria
13.3.1
Death
13.3.2
Recurrence or progression of local or metastatic disease following 
radiotherapy
13.3.3
Entry into another study not compatible with this protocol
14.0
Data Safety Monitoring Committee
RT-SARC will not be referred to the DSMB at St. Jude Children’s Research Hospital 
because it does not fit any category for DSMB review. The safety in terms of efficacy of 
local control for this protocol will be monitored by the protocol PI (M.K.) according to the 
plan listed in Table 12.1.2.
15.0
Obtaining Informed Consent and Informed Assent
The process of obtaining informed consent will follow institutional guidelines. Informed 
consent will be obtained by the attending physician or his designee in the presence of at 
least one witness. Verbal assent will be obtained from patients 7 to less than 14 years 
old and written assent from patients 14 to less than18 years old.
15.1 Consent at Age of Majority
The age of majority in the state of Tennessee is 18 years old. Research participants 
must be consented at the next clinic visit after their 18th birthday.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 35
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Appendix B
Comparison of “standard of care” vs. “research only” tests
A study that is utilized in the standard care of managing a patient (even if it is also used for 
research purposes) it is indicated with an “S”. Those studies with are for research purposes only 
are indicated with an “R”
Table B1
Treatment Planning and Evaluation Schedule
Evaluation Schedule
Pre-IGRT  week 1
week 2
week 3
week 4
week 5
week
6
week 7
Clinical
Physical Examination
S
S
S
S
S
S
S
S 
Physical / Occupational Therapy
Functional Evaluation
S
S
-
-
-
-
S/R
-
Diagnostic Imaging 
Standard of care imaging
Table B2
Evaluation following initiation of Radiation Therapy
Evaluation
Months after Initiation of Radiation Therapy*
- 
PT/OT
Functional Evaluation
S/R S/R S/R S/R S/R S/R S/R S/R S/R S/R S/R 
Functional Scales
-
-
-
-
-
-
-
-
-
S/R S/R
S/R
Diagnostic Imaging 
Standard of care imaging
Bone Densitometry
-
-
-
-
-
-
-
-
-
R R  or
R
3
6
9
12
18
24
36
48
60 84/96 120/132 18 yrs.
Clinical
Physical Examination
S
S
S
S
S
S
S
S
S
S
S
S
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 36
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Appendix C.
Functional assessment instruments are electronic documents entered directly into the participants 
electronic medical record by the treating physical therapist.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 37
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Appendix D
Local control will be estimated for the patient groups indicated below.
Tumor groups are defined as follows: 
Rhabdomyosarcoma (RMS)
Group III patients (biopsy or partial resection) followed by definitive radiation
Soft Tissue Sarcoma (STS)
Surgery consisting of a wide local excision (negative or positive margins) 
followed by radiation
Small or Resected Ewing’s Sarcoma Family of Tumors (ESFT)
Surgery consisting of a wide local excision (negative or positive margins) 
followed by radiation for any primary site of disease
or
Definitive radiation therapy for any small primary site of disease (<8cm in 
greatest dimension at diagnosis)
Large Ewing’s Sarcoma Family of Tumors (ESFT)
Definitive radiation therapy for any large primary site of disease (≥8cm in greatest 
dimension at diagnosis)
Defined 5 Year Local Control Rates for Evaluable Patient Groups 
Amend 2.0
Group III RMS
Resected STS
Resected ESFT or 
Small ESFT
Large ESFT
Target Local Control Rate
85%
90%
85%
55%
Lower Limit LC Rate
71.4%
75%
66.7%
35%
Projected accrual (n)
28
24
18
12
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 38
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
Appendix E.
qCT exposure estimates obtained for relative risk analysis.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 39
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
References
1.
Intensity Modulated Radiation Therapy Collaborative Working Group. Intensity-Modulated 
radiotherapy: Current status and issues of interest. Int J Radiat Oncol Biol Phys 
2001;51:880-914.
2.
Emami B, Purdy JA, Manolis J, Barest G, Cheng E, Coia L et al. Three-dimensional 
treatment planning for lung cancer. Int J Radiat Oncol Biol Phys 1991;21:217-27.
3.
Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL et al. Randomized 
prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue 
sarcomas of the extremity. J Clin Oncol 1998;16:197-203.
4.
Spunt SL, Poquette CA, Hurt YS, Cain AM, Rao BN, Merchant TE et al. Prognostic factors 
for children and adolescents with surgically resected nonrhabdomyosarcoma soft tissue 
sarcoma: An analysis of 121 patients treated at St. Jude Children's Research Hospital. J 
Clin Oncol 1999;17:3697-705.
5.
Wharam MD, Hanfelt JJ, Tefft MC, Johnston J, Ensign LG, Breneman J et al. Radiation 
therapy for rhabdomyosarcoma: local failure risk for clinical group III patients on Intergroup 
Rhabdomyosarcoma Study II. Int J Radiat Oncol Biol Phys 1997;38:797-804.
6.
Donaldson SS, Meza J, Breneman JC, Crist WM, Laurie F, Qualman SJ et al. Results from 
the IRS-IV randomized trial of hyperfractionated radiotherapy in children with 
rhabdomyosarcoma - a report from the IRSG. Int J Radiat Oncol Biol Phys 2001;51:718-28.
7.
Smith LM, Anderson JR, Qualman SJ, Crist WM, Paidas CN, Teot LA et al. Which patients 
with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A 
report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin 
Oncol 2001;19:4058-64.
8.
Arai Y, Kun LE, Brooks MT, Fairclough DL, Fontanesi J, Meyer WH et al. Ewing's sarcoma: 
local tumor control and patterns of failure following limited-volume radiation therapy. Int J 
Radiat Oncol Biol Phys 1991;21:1501-8.
9.
Dunst J, Sauer R, Burgers JMV, Hawliczek R, Kurten R, Winkelmann W et al. Radiation 
therapy as local treatment in Ewing's sarcoma. Results of the Cooperative Ewing's 
Sarcoma Studies CESS 81 and CESS 86. Cancer 1991;67:2818-25.
10.
Donaldson SS, Torrey M, Link MP, Glicksman A, Gilula L, Laurie F et al. A multidisciplinary 
study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Int J 
Radiat Oncol Biol Phys 1998;42:125-35.
11.
Pisters PWT, Harrison LB, Leung DHY, Woodruff JM, Casper ES, Brennan MF. Long-term 
results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J 
Clin Oncol 1996;14:859-68.
12.
Merchant TE, Parsh N, Del Valle PL, Coffey DH, Rodriguez Galindo C, Jenkins JJ et al. 
Brachytherapy for pediatric soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 2000;46:427- 
32.
13.
Hua C., Merchant T.E., Spunt S.L., Krasin M.J. Early Results of a Prospective Study 
Delivering Limited Margin Radiotherapy for Pediatric Patients With Rhabdomyosarcoma 
International journal of radiation oncology, biology, physics (volume 69 issue 3 Page S37), 
2007
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 40
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
14
Krasin M.J., Merchant T.E., Spunt; S.L. Davidoff A.M, Navid F., Wu S., Xiong X., Hua C., 
Kun L.E.. Early Results of a Prospective Study Delivering Limited Margin Radiotherapy for 
Pediatric Non-Rhabdo-Soft Tissue Sarcomas (NRSTS) and Aggressive Fibromatoses (AF) 
International journal of radiation oncology, biology, physics(volume 66 issue 3 Page S112), 
2006
15.
Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE et al. Tolerance of normal 
tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-22.
16.
Bolek T, Marcus R, Mendenhall NP, Scarborough MT, Graham-Pole J. Local control and 
functional results after twice-daily radiotherapy for Ewing's sarcoma of the extremities. Int J 
Radiat Oncol Biol Phys 2002;35:687-92.
17.
Denys D, Kaste SC, Kun LE, Chaudhary MA, Bowman LC, Robbins KT. The effects of 
radiation on craniofacial skeletal growth; a quantitative study. Int J Pediatric Oto Rhino 
Laryngology 1998;45:7-13.
18.
Li C, Wilson PB, Levine E, Barber J, Stewart AL, Kumar S. TGF-Beta 1 levels in pre- 
treatment plasma identify breast cancer patients at risk of developing post-radiotherapy 
fibrosis. Int J Cancer (Pred.Oncol.) 1999;84:155-9.
19.
Quarmby S, Kumar P, Kumar S. Radiation-induced normal tissue injury: Role of adhesion 
molecules in leukocyte-endothelial cell interactions. Int J Cancer 1999;82:385-95.
20.
Marks SC, Popoff SN. Bone cell biology: The regulation of development, structure, and 
function of the skeleton. Am J Anatomy 1988;183:1-44.
21.
Merchant TE, Goloubeva O, Pritchard D.L, Gaber MW, Xiong X, Danish RK et al. Radiation 
Dose-Volume effects on growth hormone secretion. Int J.Radiat Oncol Biol Phys 
2002;52:1264-70.
22.
Merchant TE, Kiehna E.N., Miles MAZJ, Xiong X, Mulhern RK. Acute effects of irradiation 
on cognition: changes in attention on a computerized continuous performance test during 
radiotherapy in pediatric patients with localized primary brain tumors. Int J Radiat Oncol 
Biol Phys 2002;53:1271-8.
23.
Sim S, Rosenzweig KE, Schindelheim R, Ng KK, Leibel SA. Induction chemotherapy plus 
three-dimensional conformal radiation therapy in the definitive treatment of locally 
advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2001;51:660-5.
24.
Bradley JD, Ieumwananonthachai N, Purdy JA, Wasserman TH, Lockett MA, Graham MV 
et al. Gross tumor volume, critical prognostic factor in patients treated with three- 
dimensional conformal radiation therapy for non-small-cell lung carcinoma. Int J Radiat 
Oncol Biol Phys 2002;52:49-57.
25.
Krasin MJ, Xiong X, Reddick WE, Ogg RJ, Hoffer FA, McCarville B, Kaste SC, Spunt SS, 
Navid F, Davidoff AM, Zhang L, Kun LE, Merchant TE. A Model Predicting Radiation- 
Induced Quantitative Changes in the Magnetic Resonance Signal Characteristics in the 
Muscle of Children Over Time. Magn Reson Imaging. 2006 Dec;24(10):1319-24
26.
Michalski JM, Purdy JA, Winter K, Roach III M, Vijayakumar S, Sandler HM et al. 
Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 
3DOG/RTOG 9406. Int J Radiat Oncol Biol Phys 2000;46:391-402.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 41
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
27.
Boersma LJ, van den Brink M, Bruce AM, Shouman T, Gras L, Te Velde A et al. Estimation 
of the incidence of late bladder and rectum complications after high-dose (70-78 Gy) 
conformal radiotherapy for prostate cancer, using dose-volume histograms. Int J Radiat 
Oncol Biol Phys 1998;41:83-92.
28.
Storey MR, Pollack A, Zagars G, Smith L, Antolak J, Rosen I. Complications from 
radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial. 
Int J Radiat Oncol Biol Phys 2000;48:635-42.
29.
Pommier P, Ginestet C, Sunyach M-P, Zrounba P, Poupart M, Ceruse P et al. Conformal 
radiotherapy for paranasal sinus and nasal cavity tumors: three-dimensional treatment 
planning and preliminary results in 40 patients. Int J Radiat Oncol Biol Phys 2000;48:485- 
93.
30.
Dawson LA, Anzai Y, Marsh L, Martel MK, Paulino A, Ship JA et al. Patterns of local- 
regional recurrence following parotid-sparing conformal and segmental intensity-modulated 
radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2000;46:1117-26.
31.
Merchant TE, Zhu Y, Thompson SJ, Sontag MR, Heideman RL, Kun LE. Preliminary 
results from a Phase II trial of conformal radiation therapy for pediatric patients with 
localized low-grade astrocytoma and ependymoma. Int J Radiat Oncol Biol Phys 
2002;52:325-32.
32.
Sultanem K, Shu H-K, Xia P, Akazawa C, Quivey JM, Verhey LJ et al. Three-dimensional 
intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: The 
University of California-San Francisco experience. Int J Radiat Oncol Biol Phys 
2000;48:711-22.
33.
Teh BS, Mai W-Y, Uhl BM, Augspurger ME, Grant III WH, Lu HH et al. Intensity-modulated 
radiation therapy (IMRT) for prostate cancer with the use of a rectal balloon for prostate 
immobilization: Acute toxicity and dose-volume analysis. Int J Radiat Oncol Biol Phys 
2001;49:705-12.
34.
Tepper JE, Suit HD. Radiation therapy alone for sarcoma of soft tissue. Cancer
1985;56:475-9.
35.
Wolden SL, Anderson JR, Crist WM, Breneman JC, Wharam Jr, Wiener ES et al. 
Indications for radiotherapy and chemotherapy after complete resection in 
rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J 
Clin Oncol 1999;17:3468-75.
36.
Hoffmann C, Ahrens S, Dunst J, Hillmann A, Winkelmann W, Craft A et al. Pelvic Ewing 
Sarcoma. A retrospective analysis of 241 cases. Cancer 1999;85:869-77.
37.
Nag S, M.D., Tippin D, M.D., Ph.D., Ruymann FB, M.D. Long-Term Morbidity in Children 
Treated With Fractionated High-Dose-Rate Brachytherapy for Soft Tissue Sarcomas. 
Journal of Pediatric Hematology/Oncology, Vol. 25, No. 6, June 2003
38.
Laskar S, Bahl G, Ann Muckaden M, Puri A, Agarwal MG, Patil N, Shrivastava SK, 
Dinshaw KA. Interstitial brachytherapy for childhood soft tissue sarcoma.Pediatr Blood 
Cancer. 2007 Oct 15;49(5):649-55.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 42
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
39.
Pohar S, Haq R, Liu L, Koniarczyk M, Hahn S, Damron T, Aronowitz JN. Adjuvant high- 
dose-rate and low-dose-rate brachytherapy with external beam radiation in soft tissue 
sarcoma: a comparison of outcomes.Brachytherapy. 2007 Jan-Mar;6(1):53-7.
40.
Merchant TE. Conformal therapy for pediatric sarcomas. Seminars in Radiation Oncology
1997;7:236-45.
41.
Carrie C, Mascard E, Gomez F, Habrand J-L, Alapetite C, Oberlin O et al. Nonmetastatic 
pelvic Ewing Sarcoma: Report of the French Society of Pediatric Oncology. Med Pediatr 
Oncol 1999;33:444-9.
42.
Craft AW, Cotterill SJ, Bullimore JA, Pearson D, on behalf of the United Kingdom Children's 
Cancer Study Group (UKCCSG) and the Medical Research Council Bone Sarcoma 
Working Party. Long-term results from the First UKCCSG Ewing's Tumour Study (ET-1). 
Eur J Cancer 1997;33:1061-9.
43.
Regine WF, Fontanesi J, Kumar P, Ayers D, Bowman LC, Pappo AS et al. Local tumor 
control in rhabdomyosarcoma following low-dose irradiation: comparison of Group II and 
select Group III patients. Int J Radiat Oncol Biol Phys 1995;31:485-91.
44.
LePechoux C, LeDeley M-C, Delaloge S, Lartigau E, Levy-Piedbois C, Bonvalot S et al. 
Postoperative radiotherapy in the management of adult soft tissue sarcoma of the 
extremities: results with two different total dose, fractionation, and overall treatment time 
schedules. Int J Radiat Oncol Biol Phys 1999;44:879-86.
45.
Lindberg RD, Martin RG, Romsdahl MM, Barkley JrHT. Conservative surgery and 
postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 1981;47:2391- 
7.
46.
Mundt AJ, Awan A, Sibley GS, Simon M, Rubin SJ, Samuels B et al. Conservative surgery 
and adjuvant radiation therapy in the management of adult soft tissue sarcoma of the 
extremities: clinical and radiobiological results. Int J Radiat Oncol Biol Phys 1995;32:977- 
85.
47.
Fleming JB, Berman RS, Cheng S-C, Chen NP, Hunt KK, Feig BWRPM et al. Long-term 
outcome of patients with American Joint Committee on cancer stage IIB extremity soft 
tissue sarcomas. J Clin Oncol 1999;17:2772-80.
48.
Silber JH, Littman PS, Meadows AT. Stature loss following skeletal irradiation for childhood 
cancer. J Clin Oncol 1990;8:304-12.
49.
Eifel PJ, Donaldson SS, Thomas PRM. Response of growing bone to irradiation: A 
proposed late effects scoring system. Int J Radiat Oncol Biol Phys 1995;31:1301-7.
50.
Willman KY, Cox RS, Donaldson SS. Radiation induced height impairment in pediatric 
Hodgkin's Disease. Int J Radiat Oncol Biol Phys 1994;28:85-92.
51.
Gillette EL, Mahler PA, Powers BE, Gillette SM, Vujaskovic Z. Late radiation injury to 
muscle and peripheral nerves. Int J Radiat Oncol Biol Phys 1995;31:1309-18.
52.
Johansen J, Taagehoj F, Christensen T, Overgaard J, Overgaard M. Quantitative magnetic 
resonance for assessment of radiation fibrosis after post-mastectomy radiotherapy. British 
J of Radiology 1994;67:1238-42.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 43
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
53.
Marinus J, Niel CGJH, De Bie RA, Wiggenraad RGJ, Schoppink EM, Beukema LH. 
Measuring radiation fibrosis: The interobserver reliability of two methods of determining the 
degree of radiation fibrosis. Int J Radiat Oncol Biol Phys 2000;47:1209-17.
54. Raney RB, Asmar L, Newton Jr WA, Bagwell C, Breneman JC, Crist W et al. Ewing's 
sarcoma of soft tissues in childhood: A report from the Intergroup Rhabdomyosarcoma 
Study, 1972 to 1991. J Clin Oncol 1997;15:574-82.
55.
Rajakulasingham K, Cerullo L, Raimondi A. Childhood moyamoya syndrome - 
postirradiation pathogenesis. Child Brain 1979;5:467-75.
56.
Chen Y, Rubin P, Williams J, Hernady E, Smudzin T, Okunieff P. Circulating IL-6 as a 
predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys 2001;49:641-8.
57.
Anscher MS, Marks LB, Shafman TD, Clough R, Huang H, Tisch A et al. Using plasma 
transforming growth factor Beta-1 during radiotherapy to select patients for dose escalation. 
J Clin Oncol 2001;19:3758-65.
58.
Anscher MS, Kong F-M, Andrews K, Clough R, Marks LB, Bentel G et al. Plasma 
transforming growth factor ß1 as a predictor of radiation pneumonitis. Int J Radiat Oncol 
Biol Phys 1998;41:1029-35.
59.
Wickremesekera JA, Chen W, Cannan RJ, Stubbs RS. Serum proinflammatory cytokine 
response in patients with advanced liver tumors following selective internal radiation 
therapy (SIRT) with 90YTTRIUM microspheres. Int J Radiat Oncol Biol Phys 2002;49:1015- 
21.
60.
Canney PA, Dean S. Transforming growth factor beta: a promoter of late connective tissue 
injury following radiotherapy? Br J Radiol 1990;63:620-3.
61.
Martin M, Lefaix J-L, Delanian S. TGF-ß1 and radiation fibrosis: A master switch and a 
specific therapeutic target? Int J Radiat Oncol Biol Phys 2000;47:277-90.
62.
Herskind C, Bamberg M, Rodemann HP. The role of cytokines in the development of 
normal-tissue reactions after radiotherapy. Strahlenther Onkol 1998;174:12-5.
63.
Fine JP, and Gray RJ. A proportional hazards model for the subdistribution of a competing 
risk. J American Statistical Association 1999;94:496-509.
64.
Krasin MJ, Rodriguez-Galindo C, Davidoff AM, Billups CA, Fuller CE, Neel MD, Kun LE, 
Merchant TM. Efficacy of combined surgery and irradiation for localized Ewing’s sarcoma 
family of tumors. Pediatr Blood Cancer 43:229-236, 2004.
65.
Krasin MJ, Rodriguez-Galindo C, Billups CA, Davidoff AM, Neel MD, Merchant TE, Kun LE. 
Definitive irradiation in the multidisciplinary management of Ewing Sarcoma family of 
tumors in pediatric patients: Outcome and prognostic factors. Int J Radiat Oncol Biol Phys 
60, No. 3:830-838, 2004.
66.
Krasin M, Spalding A, Navid F, Hoth K, Hua C, Merchant T, Wu S. Tumor and Systemic 
Cytokine Response in Patients with Pediatric Sarcomas Treated with Limited Margin 
3DCRT and IMRT. I.J.Radiation Oncology, Biology, Physics 78[3S], S592. 2010.
Ref Type: Abstract
67.
Zhang L, Yang M, Bi N, Ji W, Wu C, Tan W, Zhao L, Yu D, Lin D, Wang L. Association of 
TGF-beta1 and XPD polymorphisms with severe acute radiation-induced esophageal
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023

RTSARC - 44
Rev 5.2, dated: 6/9/2023 
Protocol document date: 6/9/2023
toxicity in locally advanced lung cancer patients treated with radiotherapy. Radiother.Oncol. 
2010 Oct;97(1):19-25
68.
Langsenlehner T, Renner W, Gerger A, Hofmann G, Thurner EM, Kapp KS, Langsenlehner
U. Association between single nucleotide polymorphisms in the gene for XRCC1 and 
radiation-induced late toxicity in prostate cancer patients. Radiother.Oncol. 2011 
Mar;98(3):387-93
69.
Krasin MJ, Xiaoping X, Shengjie W, Merchant TE. The effects of external beam irradiation 
on the growth of flat bones in children: Modeling a dose-volume effect. Int J.Radiat Oncol 
Biol Phys 2005 Aug 1;62(5):1458-62
70.
Krasin MJ, Hoth KA, Hua C, Gray JM, Wu S, Xiong X. Incidence and correlates of radiation 
dermatitis in children and adolescents receiving radiation therapy for the treatment of 
paediatric sarcomas. Clin.Oncol.(R.Coll.Radiol) 2009 Dec;21(10):781-5
71.
Krasin MJ, Constine LS, Friedman DL, Marks LB. Radiation-related treatment effects 
across the age spectrum: differences and similarities or what the old and young can learn 
from each other. Semin.Radiat.Oncol. 2010 Jan;20(1):21-9. PMCID:PMC2843498
72.
Krasin M, Wiese K, Spunt S, Hua C, Daw N, Navid F, Davidoff A, McGregor L, Merchant T, 
Kun L, et al. Jaw Dysfunction Related To Pterygoid and Masseter Muscle Dosimetry After 
Radiation Therapy in Children and Young Adults with Head and Neck Sarcomas. 
I.J.Radiation Oncology, Biology, Physics Forthcoming.
St. Jude Children's Research Hospital
IRB NUMBER: RTSARC
IRB APPROVAL DATE: 07/13/2023