A Phase II Study of Hypofractionated Pre-Operative Radiation Therapy for Localized, Resectable Soft Tissue Sarcoma of the Extremity and Superficial Trunk
Phase: PHASE2
Conditions: Resectable Soft Tissue Sarcoma, Stage I Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8, Stage IA Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8, Stage IB Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8, Stage II Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8
Sponsor: Mayo Clinic

 
 
 
 
 
MC1973 / 19-011871 
 
 
A Phase II Study of Hypofractionated Pre-Operative Radiation 
Therapy for Localized, Resectable Soft Tissue Sarcoma of the 
Extremity or Superficial Trunk 
 
 
NCT04562480 
 
 
Document Date: 04/17/2024 

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Mayo Clinic: Department of Radiation Oncology 
 
 
MC1973: A Phase II Study of Hypofractionated Pre-Operative Radiation Therapy for 
Localized, Resectable Soft Tissue Sarcoma of the Extremity and Superficial Trunk 
 
 
Study Chair: 
Safia Ahmed, M.D. 
Mayo Clinic 
Department of Radiation Oncology 
5777 E. Mayo Blvd 
Phoenix, AZ, 85054 
Study Co-Investigators: 
Ivy Petersen, M.D. 
Matthew T. Houdek, M.D. 
Peter S. Rose, M.D. 
Brittany L. Siontis, M.D. 
James L. Leenstra, M.D. 
Michael Rutenberg, M.D., Ph.D. 
Meng Welliver, M.D., Ph.D. 
 
Statisticians: 
Maddy Dorr, M.S.√ 
Study Contributor(s): 
Yeoniee Kim, B.S. √ 
√Study contributor(s) not responsible for patient care 
 
 
 
Document History 
 
Version 1 
5/20/2020 
Version 2 
10/16/2020 
Version 3 
12/09/2020 
Version 4 
01/22/2021 
Version 5 
03/30/2021 
Version 6 
03/04/2022 

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Version 7 
7/18/2022 
Version 8 
2/20/2023 
Version 9 
5/4/2023 
Version 10 
7/20/2023 
Version 11 
9/05/2023 
Version 12 
1/04/2024 
Version 13 
4/17/2024 
 
 
Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility, test schedule, 
treatment delays/interruptions/ 
adjustments, dose modifications, 
forms completion/ submission, & 
adverse events 
 
Radiation Oncology Study Team Contacts listed on the 
consent form 
Protocol document, consent form 
and regulatory issues 
Yeoniee Kim. B.S. 
E-mail: kim.yeoniee@mayo.edu 
Statisticians 
Maddy Dorr, M.S. 
E-mail: dorr.madeline@mayo.edu 

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Table of Contents 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Study Schema ................................................................................................................................................ 4 
List of Abbreviations ..................................................................................................................................... 5 
1.0 
Background and Rationale ............................................................................................................ 6 
2.0 
Goals ............................................................................................................................................. 8 
3.0 
Patient Eligibility ........................................................................................................................... 8 
4.0 
Test Schedule .............................................................................................................................. 11 
5.0 
Stratification Factors OR Grouping Factor .................................................................................. 11 
6.0 
Registration/Procedures ............................................................................................................... 11 
7.0 
Protocol Treatment ...................................................................................................................... 11 
8.0 
Dosage Modification Based on Adverse Events .......................................................................... 19 
9.0 
Ancillary Treatment/Supportive Care.......................................................................................... 19 
10.0 
Adverse Event (AE) Monitoring and Reporting .......................................................................... 19 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................. 25 
12.0 
Descriptive Factors ...................................................................................................................... 25 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................. 26 
14.0 
Body Fluid Biospecimens ............................................................................................................ 27 
15.0 
Drug Information ......................................................................................................................... 27 
16.0 
Statistical Considerations and Methodology ............................................................................... 27 
17.0 
Pathology Considerations/Tissue Biospecimens ......................................................................... 34 
18.0 
Records and Data Collection Procedures .................................................................................... 34 
19.0 
Budget ......................................................................................................................................... 34 
20.0 
References ................................................................................................................................... 35 
Appendix I ECOG Performance Status ....................................................................................................... 37 
Appendix II  PROMIS…………………………………………………………………………………….48 
Appendix III  TESS……………………………………………………………………………………...49 
 
Appendix IV  Joint Stiffness Assessment…………………………………………………………………72 
 
 
     Appendix V Regional Alopecia Assessment………………………………………………………………73 
 
 
     Appendix VI  Surgical Wound Complication Asessment……………………………………………….…7

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Study Schema 
 
 
Localized, resectable soft tissue 
sarcoma of the extremity/limb girdle 
or superficial trunk 
↓ 
Pre-operative radiation therapy 
Dose: 42.75 Gy in 15 fractions 
↓ 
Definitive surgical resection 
(3-6 weeks interval between 
radiation therapy and definitive 
surgery) 
↓ 
Event Monitoring 

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List of Abbreviations 
 
 
AE 
Adverse Event/Adverse Experience 
BID 
Twice daily 
cGy 
centiGray 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Target Volume 
DSMB 
Data and Safety Monitoring Board 
DVH 
Dose Volume Histogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ER / ES 
Electronic Record and Electronic Signature 
Gy 
Gray 
GTV 
Gross Tumor Volume 
ICRU 
International Commission on Radiation Units and Measurements 
IMPT 
Intensity Modulated Proton Therapy 
IMRT 
Intensity Modulated Radiotherapy 
IND / IDE 
Investigational Drugs and Devices 
IRB 
Institutional Review Board 
ITV 
Internal Target Volume 
LFR5 
Local Failure Rate at 5 years 
MCCC 
Mayo Clinic Cancer Center 
MRI 
Magnetic Resonance Imaging 
PROMISE 
Patient-Reported Outcomes Measurement Information System 
PS 
Performance Status 
PTV 
Planning Target Volume 
RBE 
Relative Biological Effectiveness 
RT 
Radiation Therapy 
SOC 
System Organ Class 
TESS 
Toronto Extremity Salvage Score 
UPIRTSO 
Unanticipated Problems Involving Risks To Subjects or Others 
VMAT 
Volumetric Modulated Arc Therapy 
3DCRT 
3D Conformal Radiation Therapy 

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1.0 
Background and Rationale 
Approximately 12,000 patients are diagnosed with soft tissue sarcomas annually in the 
United States, accounting for 1% of all adult malignancies.1 Given the rarity, diversity (> 
60 different histologies), and treatment complexity associated with soft tissue sarcomas, 
patients routinely undergo treatment at specialty centers. Historically, extremity soft 
tissue sarcomas were treated with amputation. Advances in radiation therapy and surgical 
techniques, however, have made radiation therapy plus limb-salvage surgery the standard 
treatment for most localized, extremity soft tissue sarcomas.2-5 Superficial trunk soft 
tissue sarcomas are treated in a similar fashion. With this multi-modal treatment 
approach, the 5 year local recurrence rate for extremity and superficial trunk soft tissue 
sarcomas is ≤10%.6 
 
Radiation therapy can be administered preoperatively, intraoperatively, postoperatively, 
or as a combination of the aforementioned.2,3,7 Preoperative radiation therapy is 
associated with a higher acute wound complication rate compared to postoperative 
radiation therapy.6 O’Sullivan et. al. reported a 35% acute wound complication rate with 
preoperative radiation therapy compared to a 17% rate with postoperative radiation.6 
Acute wound complication was defined as a major wound issue requiring an invasive 
intervention (i.e., second surgery or hospitalization for wound care) within 3 months of 
surgery.6 Several other reports document similar acute wound complication rates.8-12 
Many centers in the Unites States and abroad favor pre-operative radiation therapy due to 
the lower total radiation dose administered (50 Gray (Gy) versus 60-66 Gy) and smaller 
treatment volume compared to postoperative radiation therapy. These aspects are thought 
to contribute to the lower irreversible, long-term toxicity rates seen with preoperative 
radiation therapy.13,14 Davis et. al. reported more frequent rates of fibrosis (48.2% versus 
31.5%), edema (23.2% versus 15.1%), and joint stiffness (23.2% versus 17.8%) with 
postoperative radiation therapy compared to preoperative radiation therapy.14 Higher 
rates of irreversible, long-term toxicities adversely affect patient function.13,14 Lastly, 
preoperative radiation therapy optimizes the chances of obtaining a margin-negative 
resection and may decrease the potential for metastatic cell spread at time of surgery.6,8,15 
The radiation therapy course for soft tissue sarcomas is certainly long, with total number 
of fractions ranging from 25 fractions (preoperative treatment) to 33 fractions 
(postoperative treatment). Given the financial and time commitments associated with the 
radiation treatment length, there are potential benefits for patients by reducing the 
number of daily fractions administered. Shorter treatment duration can translate to 
reduced costs and improved patient experiences due to reduced travel times, decreased 
time off work and away from family, and lessened financial demands associated with 
pursuing treatment at a specialty center. Additionally, a shorter radiation course may lead 
to higher limb preservation rates and improved survival in minority groups as outcomes 
are known to be inferior in African American and Latino populations compared to the 
Caucasian population.16,17 
 
One method to shorten radiation treatment length is to administer a hypofractionated 
treatment course. Hypofractionated radiation therapy administers the total radiation dose 

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as larger daily doses compared to conventionally fractionated therapy. This effectively 
reduces the overall treatment duration by weeks. Hypofractionated radiation therapy is 
proven to be a more convenient and lower cost option for early stage breast and prostate 
cancers, without compromising oncologic outcomes or increasing the likelihood of 
treatment-related side effects.18-20 For example, Whelan et. al. demonstrated the efficacy 
of a hypofractionated postoperative treatment course (42.56 Gy in 16 fractions) for early 
stage breast cancer compared to conventionally fractionated treatment (50 Gy in 25 
fractions).20 At 10 years, the local recurrence rate was 6.7% for conventionally 
fractionated radiation therapy versus 6.7% for hypofractionated radiation therapy.20 
Additionally, there was no difference in overall survival or cosmetic outcomes between 
the two treatment arms.20 
Hypofractionated radiation therapy has been studied to a more limited degree in soft 
tissue sarcomas. In Poland, a study of hypofractionated preoperative radiation therapy 
(25 Gy in 5 fractions) was conducted in 272 patients from 2006 to 2011.21 This study 
yielded a higher local failure rate: 19%, with a median follow up of 35 months.21 Of note, 
the biologic effective dose is 34.27 Gy10 with this regimen compared to 43.83 Gy10 with 
conventional fractionation, suggesting a higher biologic effective dose is needed with 
hypofractionation to achieve optimal outcomes. Another preoperative hypofractionated 
study from University of California Los Angeles studied 28 Gy in 8 fractions (biologic 
effective dose of 32.63 Gy ) 22 The local failure rate at 3 years was 11%.22 Again, these 
10 . 
results suggest a higher total radiation dose is needed for efficacy when utilizing a 
hypofractionated radiation treatment course in soft tissue sarcomas. 
We propose conducting a single arm, prospective study to evaluate the efficacy and 
safety of a preoperative hypofractionated course, 42.75 Gy in 15 fractions, for localized, 
extremity and superficial trunk soft tissue sarcomas. The biologic equivalent dose of this 
regimen is 45.20 Gy10, similar to 43.83 Gy10 associated with conventionally fractionated 
50 Gy in 25 fractions. The primary aim of the study is to determine acute wound 
complications rates, as defined by O’Sullivan et. al.6 Secondary aims will analyze local 
failure rate, disease-free survival, overall survival, patterns of relapse, late toxicities, and 
quality of life/patient-reported outcomes. We hypothesize a 15 fraction hypofractionated 
radiation therapy course will be associated with equivalent short-term toxicity rates and 
oncologic outcomes as compared to historical standards. 

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2.0 
Goals 
 
2.1 
Primary Objective 
2.1.1 To report the major acute wound complication rate associated with 
hypofractionated preoperative radiation therapy, 42.75 Gy in 15 fractions. 
See section 11.1 for definition of major acute wound complications. 
2.2 
Secondary Objectives 
2.2.1 To report the 5-year local failure rate associated with hypofractionated 
preoperative radiation therapy, 42.75 Gy in 15 fractions. 
2.2.2 To report the 5-year disease-free survival rate associated with 
hypofractionated preoperative radiation therapy, 42.75 Gy in 15 fractions. 
2.2.3 To report the 5-year overall survival rate associated with hypofractionated 
preoperative radiation therapy, 42.75 Gy in 15 fractions. 
2.2.4 To report long-term toxicity rates associated with hypofractionated 
preoperative radiation therapy, 42.75 Gy in 15 fractions. 
2.2.5  To describe patterns of relapse associated with hypofractionated 
preoperative radiation therapy, 42.75 Gy in 15 fractions. 
2.2.6  To describe patient reported outcomes/quality-of-life outcomes with 
hypofractionated preoperative radiation therapy, 42.75 Gy in 15 fractions. 
 
 
3.0 
Patient Eligibility 
 
The patient must meet all selection criteria as specified in Section 3.1 and be agreeable 
to adhere to the follow-up evaluations and schedule. Written informed consent must be 
obtained from the patient prior to enrollment and prior to any trial-specific evaluations. 
3.1 
Inclusion Criteria 
3.1.1 Males and females age ≥ 18 years. 
 
3.1.2 Newly diagnosed, histological confirmation of soft tissue sarcoma of the 
extremities (including limb girdle) or superficial trunk that present as 
either – 
 
• Deemed a candidate for complete macroscopic resection of the 
primary sarcoma. 
 
OR 

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• Having had non-oncologic excisional procedure with positive or 
uncertain resection margins and still be eligible if the evaluating 
sarcoma surgeon recommends oncologic re-resection of the surgical 
bed to obtain negative margins after a course of preoperative radiation 
therapy. 
3.1.3 No evidence of nodal or distant metastases as determined by clinical 
examination on any form of imaging. 
3.1.4 Eastern Cooperative oncology Group (ECOG) Performance Status (PS) ≤ 
3 (Appendix I). 
3.1.5 Life expectancy greater than 6 months. 
3.1.6 Patients capable of childbearing must agree to use adequate contraception. 
3.1.7 Ability to complete questionnaire(s) by themselves or with assistance. 
3.1.8 Ability to provide written informed consent. 
3.1.9 Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
 
3.2 
Exclusion Criteria 
3.2.1 Previous radiation therapy to the site of the sarcoma or area surrounding it 
such that it would be encompassed by the radiation field needed to treat 
the current sarcoma. In other words, treatment on this trial would require 
re-irradiation of tissues. 
3.2.2 Patients with nodal or distant metastases. 
3.2.3 Rhabdomyosarcoma, soft tissue osteosarcoma, soft tissue Ewing sarcoma, 
and benign histologies. 
3.2.4 Any of the following: 
• Pregnant women 
• Nursing women 
• Men or women of childbearing potential who are unwilling to 
employ adequate contraception 

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4.0 
Test Schedule 
 
Pre-treatment/ 
Baseline 
 
≤30 days 
prior to 
registration 
Hypo- 
fractionated 
RT 
42.75 Gy in 15 
fractions 
Post-RT 
Assessment 
 
(+/- 5 days) 
Pre- 
Operative 
Assessment 
Within 2 
weeks of 
surgery9 
Post- 
Operative 
Assessment 
4-8 weeks 
Post-Surgery6,9 
Years 1 & 2 
Post-Surgery 
Assessment 
Every 6Months 
Post- 
Surgery7,8,9(+/- 
8 weeks) 
Years 3-5 
Post-Surgery 
Assessment 
Annually Post- 
Surgery7,8,9 
(+/- 8 weeks) 
History, physical 
exam7, ECOG 
status 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Pathology review 1 
X 
 
 
 
X 
 
 
Primary site MRI 2, 
5 
X 
 
 
X 
 
X 
X 
PET/CT or CT 
Chest5, 
X 
 
 
X 
 
X 
X 
Pregnancy test 3 
X 
 
 
 
 
 
 
AE Acute 
Assessment (See 
section 10.0) 
 
X 
 
 
X 
 
X 
 
 
 
Hypofractionated 
RT 
 
X 
 
 
 
 
 
CTCAE v5.0 
Solicited Late 
Toxicity 
Assessment (See 
section 10.0) 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Wound 
Complication 
Assessment 
(Appendix 
VI/Section 11.0) 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Regional Alopecia 
Assessment 
(Appendix V) 
X 
 
X 
X 
 
 
 
Joint Stiffness 
Assessment 
(Appendix IV) 
X 
 
X 
X 
 
X 
X 
PROMISE-10a 
X 
 
 
X 
 
X4 
 
TESSb 
X 
 
 
X 
 
X4 
 
1. Pathology review includes histopathologic diagnosis of soft tissue sarcoma and grade, where applicable. 
2. CT is acceptable if MRI is not advisable. 
3.  For women of childbearing potential only. Must be done ≤7 days prior to beginning radiation treatment. Tubal 
ligation and IUD in place are exceptions. 
4. Obtained at 12, 18, and 24 months. 
5. Within 60 days of enrollment 
6.  Follow Up timepoints may be evaluated outside the anticipated window as deemed appropriate by Stand of Care 
Radiation Oncology and Orthopedic Surgery follow up schedule 
a. Patient-Reported Outcomes Measurement Information System 
b. Toronto Extremity Salvage Score 
7.  Assessments may be completed by NP/PA in person or by virtual and/or phone visit if patient is unable to return 
to study site. 
8. Per physician discretion 
9. If patient develops any type of disease progression or is unwilling to return to the institution, patients will move to yearly survival 
follow up. No additional assessments will need to be done. 
 

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5.0 
Grouping Factors 
 
5.1 Anatomical Sites of Tumor: Proximal lower extremity (includes knee) versus rest. 
Note: As of July 19, 2023, there are no restrictions on number of patients enrolled per 
anatomical sites of tumor. 

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6.0 
Registration Procedures 
Patients will be registered by completing the registration through PTrax, and eligibility 
case report forms (CRFs) stored in MedidataRave. 
 
6.1 
Prior to patient enrollment, the investigator should ensure that all of the following 
requirements are met: 
6.1.1 The patient meets all inclusion criteria and exclusion criteria apply. 
6.1.2 The patient and investigator have signed and dated all applicable consent 
forms. 
6.1.3 All baseline assessments and examinations have been performed. 
6.1.4 All registration CRFs have been completed, signed, and dated. 
6.1.5 Protocol treatment must begin within 2 weeks of registration. 
 
 
7.0 
Protocol Treatment 
7.1 
Radiation Therapy 
All patients enrolled on this trial will receive radiation therapy as detailed below. 
 
7.1.1 Simulation 
 
7.1.1.1 Patient Positioning and Immobilization 
The patient may be treated in any appropriate, stable position. No 
specific immobilization is mandated. However, reproducible setup 
is critical and the use of standard immobilization devices for the 
extremity and/or truck is strongly encouraged. 
Bolus should not be used unless: 
a. The tumor involves cutaneous structures, 
b. The tumor is very superficial such that adequate target dose 
(<90% prescription dose to the planning target volume (PTV)) 
cannot be delivered without it, 
c. Or, the surgeon indicates the biopsy scar and/or skin will not be 
resected. 
 
7.1.1.2 Image Acquisition 
Computed tomography (CT) imaging obtained during simulation 
will be the primary imaging modality for target delineation and 

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treatment planning. CT simulation imaging will be obtained per 
institutional policies and procedures. 
 
Diagnostic or treatment position Magnetic Resonance Imaging 
(MRI) may be used to aid with target delineation and treatment 
planning at the discretion of the treating radiation oncologist. 
Similarly, use of intravenous contrast, breath hold techniques, and 
acquisition of 4D imaging sets are at the discretion of the treating 
radiation oncologist. 
 
7.1.2 Target Volume Definitions 
 
Treatment planning will be based on the following definitions. 
 
7.1.2.1 GTV 
Gross tumor volume (GTV) is the volume of all known disease 
based on CT simulation imaging and physical exam. If MRI is 
used for target delineation, GTV is best delineated on T1 contrast 
sequences. 
 
If there has been prior surgical violation of the sarcoma (for 
example, a non-oncologic partial or positive-margin excision), the 
GTV may be extended to include the initial region of gross tumor 
as well as any disturbed tissues. In most cases, an open biopsy 
scar should not be included in the GTV as standard of care is for 
the incision to be resected. In the unusual situation where an open 
biopsy scar will not be resected, this should be confirmed with the 
surgeon and included in the GTV. 
7.1.2.2 CTV 
Clinical target volume (CTV) includes the GTV and sites of 
potential occult tumor involvement. A 2.0-4.0 cm longitudinal and 
1.0-1.5 cm radial expansion from GTV will be used to generate the 
CTV. The expansions should follow natural planes of spread for 
sarcomas, while respecting intact bone and compartment 
boundaries. If MRI is used for target delineation, the CTV should 
also include physician-determined suspicious peri-tumoral edema 
seen on T2 sequence images. In patients who received neoadjuvant 
chemotherapy and experienced a reduction in tumor volume with 
chemotherapy, the pre-chemotherapy extent of the tumor in soft 
tissues should be included in the CTV. 
 
7.1.2.3 PTV 
A geometric margin of 5-10 mm will be used to create PTV. Daily 
image guidance is required. 

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7.1.2.4 Proton Therapy 
 
7.1.2.4.1 
GTV is the same for protons and photons 
 
7.1.2.4.2 
CTV is the same for protons and photons 
 
7.1.2.4.3 
PTV is not the same as photons due to differences in 
beam penetration with movement and set up 
uncertainty. PTV varies with each individual field and 
requires additional adjustments based on set up error for 
the involved body site. In general, adjustment margins 
are usually 2-7 mm and will follow institutional policies 
and procedures. 
 
7.1.3 Organs at Risk Contouring Definitions 
Only organs at risk relevant to the treatment field within 2 cm superior and 
inferior to the PTV edge should be contoured. 
7.1.3.1 Bone avoid (only applicable for extremity tumors) 
The bone immediately adjacent to the gross tumor is contoured as 
bone avoid. The bone avoid structure will extend 2 cm superior 
and inferior to the PTV edge. 
7.1.3.2 Soft tissue avoid (only applicable for extremity tumors) 
The soft tissue surrounding the PTV and extending 2 cm superior 
and inferior to the PTV edge is defined as soft tissue avoid. To 
create the soft tissue avoid structure, an intermediate structure is 
first created defined as PTV + a 2.0 cm geometric expansion. 
Then, the body only contour is subtracted from the PTV+2.0 cm 
intermediate structure and limited to 2 cm superior and inferior to 
the PTV edge. This final soft tissue avoid structure is cropped out 
of bone avoid and volumes <1cm3 are erased (Figure 1). 
 
 
Figure 1. Example of the soft tissue avoid structure in axial plane. PTV is 
in magenta, soft tissue avoid is in light green, and bone avoid is in orange. 

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7.1.4 Radiation Therapy Planning 
 
7.1.4.1 Dose definition 
Photon dose will be specified in centigray (cGy). For proton 
therapy, the absorbed dose is specified in centigray equivalents 
(CGE), which is the same as ICRU 78 DRBE using a standard RBE 
of 1.10 with respect to water. 
 
7.1.4.2 Target Dose 
The radiation dose prescribed to the PTV will be 4275 cGy in 15 
daily fractions over 3 weeks. Treatment will be delivered once 
daily, except on weekends and holidays. Twice daily (BID) 
treatments are not allowed. 
 
7.1.4.3 Treatment Planning 
The treatment technique and modality are at the discretion of the 
treating radiation oncologist. The patient may be treated using 
conventional 3D radiotherapy (3DCRT); Intensity Modulated 
Radiotherapy (IMRT), rotational IMRT techniques such as 
Volumetric Arc Radiation Therapy (VMAT), or proton therapy 
(3D or Intensity Modulated Proton Therapy (IMPT)). 
 
The dose will be prescribed to the treatment isocenter, which 
serves as the ICRU reference point. Appropriate beam modality 
and energy should be selected for the size and depth of the tumor, 
tissue, and site to be treated. Every attempt should be made to use 
techniques (i.e., 3DRT, IMRT, VMAT, etc.) and modalities (i.e., 

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electrons, photons, protons) which avoid unnecessary irradiation of 
critical normal tissues. 
 
7.1.4.4 Target Dose Requirements and Uniformity 
Table 1.0 lists dose volume histogram (DVH) requirements for 
CTV and PTV. If DVH requirements cannot be met, an 
explanation must be submitted to the study co-chairs (S. K. 
Ahmed, M.D. or I.A. Petersen, M.D.). 
Table 1.0 – DVH requirements for CTV and PTV 
 
Structure 
DVH 
Endpoint 
Requirement 
Priority 
DVH 
Endpoint 
Requirement Priority 
CTV_4275 
D95%[%] 
≥ 100% 
2 
D95%[%] 
≥ 95% 
1 
 
 
 
 
CV95%[cc] 
<0.5cc 
1 
 
V110% 
 
Report  
 
 
PTV_4275 
D95%[%] 
≥ 99% 
2 
D95%[%] 
≥ 95% 
1 
 
 
 
 
CV95%[cc] 
<0.5 cc 
1 
 
V110% 
 
Report  
 
 
7.1.4.4.1 Minor Deviation Definition 
a) PTV_4275 D95% <95% but ≥ 90% 
AND / OR 
b)  >20% but ≤ 25% of PTV_4275 receives ≥110% of 
prescription dose 
 
7.1.4.4.2 Major Deviation Definition 
a) PTV_4275 D95% <90% 
AND / OR 
b) >25% of PTV_4275 receives ≥110% of prescription 
dose 
AND / OR 
c) Dose to the priority 1 organs at risk is more than the 
recommended limit (Table 2.0) 

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7.1.4.5 Organs at Risk Dose Constraints 
 
Normal tissue dose constraints are listed in Table 2.0. Every effort 
should be made to avoid treating the full circumference of any 
extremity. There is no special requirement for skin dose limit. 
However, full prescription dose to skin over areas commonly 
traumatized (e.g., elbow, knee, shin) should be avoided unless in 
the PTV. 
While every effort should be made to deliver prescription doses to 
the PTV as specified while adhering to normal tissue constraints, it 
is recognized that certain anatomical factors may prevent this. As 
such, if normal tissue constraints are unachievable, the patient will 
be taken off the trial and treated with standard pre-operative RT to 
50 Gy in 25 fractions meeting standardly accepted constraints for 
that fractionation schedule. 
 
Table 2.0 –Organs at Risk Dose Constraints 
 
Organ at Risk 
Dose Constraints 
Priority 
Bone avoid 
Mean < 32 Gy 
V35Gy < 64% 
V35Gy < 40% 
1 
1 
2 
Soft tissue avoid 
Mean < 26 Gy 
V18Gy <50% 
2 
1 
Joint (only major joints: 
hip/knee/shoulder) 
V42.56Gy <50% 
2 
Anus 
Max 
V42.75Gy (%) 
V40.6Gy (%) 
Report 
Report 
Report 
Genitalia 
Max 
Mean <26 Gy 
Report 
1 

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Testis (if fertility preservation 
desired) 
V1Gy ≤ 60% 
V1Gy ≤ 50% 
1 
2 
Ovaries (if fertility 
preservation desired) 
V4.8Gy ≤ 60% 
V1Gy ≤ 50% 
1 
2 
Lungs 
V18Gy≤ 20% 
1 
Brachial plexus 
Max < 48 Gy 
1 
Heart 
Mean < 10 Gy 
1 
Esophagus 
Mean <26 Gy 
1 
Liver 
Mean <26 Gy 
1 
Stomach 
Max ≤38 Gy 
1 
Small Bowel 
Max ≤ 45 Gy; if in PTV 
V42.75Gy <20 cc 
V26.5Gy <100 cc 
V39Gy <60 cc 
21 
2 
1 
Large Bowel 
Max < 45 Gy; if in PTV 
V42.75Gy (%) 
V40.6Gy (%) 
V42.75Gy (cc) <50 cc 
2Report 
Report 
2 
Kidney 
V11.8 Gy < 10% for total 
kidney volume 
V11.8Gy <33% for each 
kidney 
V5Gy for each kidney 
1 
 
 
2 
 
 
Report 
Spinal Cord 
Max 
Report 

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V39Gy <0.1% 
2 
Bladder 
Max 
V42.75Gy <50% 
V30Gy <60% 
Report 
2 
2 
7.1.5 Radiation Therapy Delivery 
Radiation therapy will be delivered using a linear accelerator or proton 
gantry. Patients will be set up according to the instructions from CT 
simulation and treatment planning. Image guidance procedures will be 
determined at the discretion of the treating radiation oncologist. 
 
7.1.6 Treatment Delays 
There will be no planned rests or breaks from treatment. Once radiation 
therapy has been initiated, treatment will not be interrupted except for 
severe illness or unplanned emergencies. The reason for any interruptions 
greater than three days should be recorded and submitted to the study 
Chair (S.K. Ahmed, M.D.). When treatment interruptions or delays occur, 
the total number of fractions or cumulative dose should not be modified. 
 
7.1.7 Special Considerations 
 
7.1.7.1 Tumor motion 
Acquisition of 4D imaging sets, use of breath hold techniques, or 
treatment delivery via phase gating for tumors with internal motion 
are at the discretion of the treating radiation oncologist. In these 
cases, an internal target volume (ITV) will be delineated per 
standard institutional policies and procedures. 
 
7.1.7.2 Nodal Radiation 
For tumors with no evidence of nodal involvement, the draining 
regional lymph nodes should not be irradiated. Tumors with nodal 
involvement are excluded on this trial. 
7.1.8 Quality Assurance 
All target volumes and final treatment plans must be submitted for review 
and approval by a study co-chair (S. K. Ahmed, M.D. or I.A. Petersen, 
M.D.). 
 
7.1.9 Intraoperative and Postoperative Radiation Therapy 
Use of intraoperative and postoperative radiation therapy is discouraged. If 
intraoperative or postoperative radiation therapy is deemed to be of benefit 
for a high-risk case, contact a study co-chair (S. K. Ahmed, M.D. or I.A. 
Petersen, M.D.). 

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7.2 
Surgery 
Patients will undergo oncologic resection ideally 3-4 weeks after completion of 
preoperative radiation therapy per institutional standards. If surgery is not feasible 
during this ideal period, it must be performed within 6 weeks (± 1 week) of 
completing preoperative radiation therapy. Acute wound complications will be 
recorded as detailed in section 11.1. 
 
7.3 
Chemotherapy 
The use of chemotherapy will be at the discretion of the multidisciplinary team 
and medical oncology consultant involved in the case. Chemotherapy will not be 
used concurrently with radiation therapy on this study. In cases where 
chemotherapy is used either neo-adjuvantly or adjuvantly, the agents used and 
number of cycles/doses of chemotherapy will be documented. 
 
7.4 
Patient reported questionnaires 
All patients will complete Patient-Reported Outcomes Measurement Information 
System (PROMIS) and Toronto Extremity Salvage Score (TESS) questionnaires 
at baseline, post-radiotherapy, and post-surgery time-points as detailed in section 
4.0. 
 
8.0 
Dosage Modifications Based on Adverse Events 
N/A 
 
 
9.0 
Ancillary Treatment/Supportive Care 
9.1 Permitted Supportive Therapy 
 
All supportive therapies for optimal medical care are allowed during the study period 
at the discretion of the provider within the parameters of the protocol. Examples 
include skin care, physical therapy and rehabilitation, occupational therapy, anti- 
emetics, anti-diarrheals, prophylaxis for constipation, anti-inflammatories, anti- 
pyretics, intravenous fluids, and appetite enhancers. 
 
9.2 Non-permitted Supportive Therapy 
 
No investigational agents are permitted. 
 
 
10.0 Adverse Event (AE) Monitoring and Reporting 

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10.1 
Definitions 
Adverse Event- An untoward or undesirable experience associated with the use of 
a medical product (i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event – Any grade 4 or 5 adverse event as defined by CTCAE 
v5.0. Adverse events are classified as serious or non-serious. Serious 
problems/events can be well defined and include in general: 
• Death 
• Life threatening adverse experience where emergent lifesaving 
treatment is necessary. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO)- Any 
unanticipated problem or adverse event that meets the following three criteria: 
 
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for 
the subject or others (including individuals who are not research subjects). These 
include: (1) death; (2) life threatening adverse experience; (3) hospitalization - 
inpatient, new, or prolonged; (4) disability/incapacity - persistent or significant; (5) 
birth defect/anomaly; (6) breach of confidentiality and (7) other problems, events, 
or new information (i.e. publications, DSMB reports, interim findings, product 
labeling change) that in the opinion of the local investigator may adversely affect 
the rights, safety, or welfare of the subjects or others, or substantially compromise 
the research data, 
AND 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event 
is "unanticipated" when it was unforeseeable at the time of its occurrence. A 
problem or event is "unanticipated" when it occurs at an increased frequency or at 
an increased severity than expected, 
AND 
Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
Preexisting Condition- A preexisting condition is one that is present at the start of 
the study. A preexisting condition should be recorded as an adverse event if the 
frequency, intensity, or the character of the condition worsens during the study 
period. At screening, any clinically significant abnormality should be recorded as a 
preexisting condition. At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event. 
10.2 
Recording Adverse Events 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 

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(CTCAE) version 5.0 will be utilized for AE reporting unless as otherwise stated 
in the table below. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
10.2.1 Adverse event monitoring and reporting is a routine part of every clinical 
trial. First, identify and grade the severity of the event using the CTCAE 
version 5.0. Next, determine whether the event is expected or unexpected 
and if the adverse event is related to the medical treatment or procedure. 
With this information, determine whether the event must be reported as an 
expedited report (see Section 10.3). 
10.2.2 Assessment of Attribution 
Only G4 or G5 adverse events will require an attribution. Any change in 
the grade of an adverse event within the list of monitored AEs will be 
recorded and considered to be related to treatment. Any new adverse not 
listed occurring within the radiated area or in close proximity will be 
graded and attribution defined by the study PI. 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal 
relationship between the treatment and the adverse event. 
 
10.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated 
action necessary to protect the study participant and then complete the Study 
Adverse Event Worksheet and log. The sponsor-investigator will evaluate the 
event and determine the necessary follow-up and reporting required. 
a. Serious Adverse Events will be reported as part of regular adverse event 
reporting mechanisms via the data capture system and logged for review 
reporting. 
10.3.1 Investigator Reporting: Notifying the Mayo IRB 
The IRB requirements reflect the guidance documents released by the 
Office of Human Research Protections (OHRP), and the Food and Drug 
Administration (FDA) in early 2007 and are respectively entitled 
“Guidance on Reviewing and Reporting Unanticipated Problems 
Involving Risks to Subjects or Others and Adverse Events” and “Guidance 
for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting – 
Improving Human Subject Protection.” 
10.3.1.1 
According to Mayo IRB Policy any serious adverse event 
(SAE) which the Principal Investigator has determined to 
be a UPIRTSO must be reported to the Mayo IRB as soon 

MC1973 
23 
 
as possible but no later than 5 working days after the 
investigator first learns of the problem/event. 
10.3.1.2 
Non-UPIRTSO – the investigator reports problems or 
events that do NOT meet criteria of an UPIRTSO in 
summary format at the time of the next continuing review. 
The investigator monitors the severity and frequency of 
subsequent non-UPIRTSOs. 
Consider the following information to collect when developing any forms 
for documentation of adverse events. 
Example 
Information collected on the adverse event worksheet (and entered in the 
research database): 
• Subject’s name: 
• Medical record number: 
• Disease/histology (if applicable): 
• The date the adverse event occurred: 
• Description of the adverse event: 
• Relationship of the adverse event to the research (drug, procedure, 
or intervention): 
• If the adverse event was expected: 
• The severity of the adverse event: (use a table to define severity 
scale 1-5) 
• If any intervention was necessary: 
• Resolution: (was the incident resolved spontaneously, or after 
discontinuing treatment) 
• Date of Resolution: 
The investigator will review all adverse event reports to determine if 
specific reports need to be made to the IRB and FDA. The investigator 
will sign and date the adverse event report when it is reviewed. For this 
protocol, only directly related SAEs/UPIRTSOs will be reported to the 
IRB. 
10.4 
Solicited toxicities to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated based on the schedule of events using 
the CTCAE v5.0 grading unless otherwise stated in the table below.  This 
regimen has established safety, based on this article 
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00638-
6/fulltext so the focus is on solicited toxicities and not any adverse event after 
radiation therapy is completed. 
 
ACUTE TOXICITIES – Upper Proximal Extremity 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Baseline 
During RT & Preoperative 
Assessment 

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General disorders 
and administration 
site conditions 
 
Fatigue 
 
X 
 
X 
 
 
Skin and 
subcutaneous tissue 
disorders 
Dermatitis 
Radiation 
 
X 
 
X 
 
Hyperpigmentation 
 
X 
 
X 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain 
 
X 
 
X 
 
 
LATE TOXICITIES – Upper Proximal Extremity 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Post-Surgery & Follow Up 
Skin and 
subcutaneous tissue 
disorders 
 
Hyperpigmentation1 
 
X 
Vascular 
Lymphedema2 
X 
General disorders and 
administration site 
conditions 
 
Localized edema1 
 
X 
 
Musculoskeletal and 
connective tissue 
disorders 
Fibrosis deep connective 
tissue1 
X 
Joint range of motion 
decreased2 
X 
Osteonecrosis1 
X 

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25 
 
 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain1 
 
X 
Injury, poisoning and 
procedural 
complications 
 
Fracture1 
 
X 
Gastrointestinal 
Disorders 1 
Esophageal fistula 
X 
Respiratory, thoracic 
and mediastinal 
disorders 
 
Pneumonitis1 
 
X 
1 Specific to radiation / surgery treatment area 
2 Specific to ipsilateral extremity / region 
 
 
 
ACUTE TOXICITIES – Upper Distal Extremity (includes elbow) 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Baseline 
During RT & Preoperative 
Assessment 
General disorders 
and administration 
site conditions 
 
Fatigue 
 
X 
 
X 
 
 
Skin and 
subcutaneous tissue 
disorders 
Dermatitis 
Radiation 
 
X 
 
X 
 
Hyperpigmentation 
 
X 
 
X 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain 
 
X 
 
X 

MC1973 
26 
 
 
LATE TOXICITIES – Upper Distal Extremity (includes elbow) 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Post-Surgery & Follow Up 
Skin and 
subcutaneous tissue 
disorders 
 
Hyperpigmentation1 
 
X 
Vascular 
Lymphedema2 
X 
General disorders and 
administration site 
conditions 
 
Localized edema1 
 
X 
 
Musculoskeletal and 
connective tissue 
disorders 
Fibrosis deep connective 
tissue1 
X 
Joint range of motion 
decreased2 
X 
Osteonecrosis1 
X 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain1 
 
X 
Injury, poisoning and 
procedural 
complications 
 
Fracture1 
 
X 
1 Specific to radiation / surgery treatment area 
2 Specific to ipsilateral extremity / region 
 
ACUTE TOXICITIES – Lower Proximal Extremity (includes knee) 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Baseline 
During RT & Preoperative 
Assessment 
General disorders 
and administration 
site conditions 
 
Fatigue 
 
X 
 
X 

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27 
 
 
 
 
Skin and 
subcutaneous tissue 
disorders 
Dermatitis 
Radiation 
 
X 
 
X 
 
Hyperpigmentation 
 
X 
 
X 
 
Gastrointestinal 
disorders 
Diarrhea 
X 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Renal and urinary 
disorders 
Dysuria 
X 
X 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain 
 
X 
 
X 
 
 
LATE TOXICITIES – Lower Proximal Extremity (includes knee) 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Post-Surgery & Follow Up 
Skin and 
subcutaneous tissue 
disorders 
 
Hyperpigmentation1 
 
X 
Vascular 
Lymphedema2 
X 
General disorders and 
administration site 
conditions 
 
Localized edema1 
 
X 
 
Fibrosis deep connective 
tissue1 
X 

MC1973 
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Musculoskeletal and 
connective tissue 
disorders 
Joint range of motion 
decreased2 
X 
Osteonecrosis1 
X 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain1 
 
X 
Injury, poisoning and 
procedural 
complications 
 
Fracture1 
 
X 
Gastrointestinal 
Disorders 1 
Anal fistula 
X 
Colonic fistula 
X 
Duodenal fistula 
X 
Ileal fistula 
X 
Jejunal fistula 
X 
Rectal fistula 
X 
Anal ulcer 
X 
Colonic ulcer 
X 
Duodenal ulcer 
X 
Ileal ulcer 
X 
Jejunal ulcer 
X 
Rectal ulcer 
X 
Small intestine ulcer 
X 
Anal stenosis 
X 
Colonic stenosis 
X 
Duodenal stenosis 
X 

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Ileal stenosis 
X 
Jejunal stenosis 
X 
Rectal stenosis 
X 
Small intestine stenosis 
X 
Rectal perforation 
X 
Small intestine 
perforation 
X 
Colonic perforation 
X 
Duodenal perforation 
X 
Ileal perforation 
X 
Jejunal perforation 
X 
Enterovesical fistula 
X 
Renal and urinary 
disorders1 
Urinary fistula 
X 
Bladder perforation 
X 
1 Specific to radiation / surgery treatment area 
2 Specific to ipsilateral extremity / region 
 
 
 
 
 
 
 
 
ACUTE TOXICITIES – Lower Distal Extremity 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Baseline 
During RT & Preoperative 
Assessment 

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General disorders 
and administration 
site conditions 
 
Fatigue 
 
X 
 
X 
 
 
Skin and 
subcutaneous tissue 
disorders 
Dermatitis 
Radiation 
 
X 
 
X 
 
Hyperpigmentation 
 
X 
 
X 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain 
 
X 
 
X 
1 Per study definition 
 
 
 
LATE TOXICITIES – Lower Distal Extremity 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Post-Surgery & Follow Up 
Skin and 
subcutaneous tissue 
disorders 
 
Hyperpigmentation1 
 
X 
Vascular 
Lymphedema2 
X 
General disorders and 
administration site 
conditions 
 
Localized edema1 
 
X 
 
Musculoskeletal and 
connective tissue 
disorders 
Fibrosis deep connective 
tissue1 
X 
Joint range of motion 
decreased2 
X 
Osteonecrosis1 
X 

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Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain1 
 
X 
Injury, poisoning and 
procedural 
complications 
 
Fracture1 
 
X 
1 Specific to radiation / surgery treatment area 
2 Specific to ipsilateral extremity / region 
 
 
 
ACUTE TOXICITIES – Superficial Trunk 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Baseline 
During RT & Preoperative 
Assessment 
General disorders 
and administration 
site conditions 
 
Fatigue 
 
X 
 
X 
 
 
Skin and 
subcutaneous tissue 
disorders 
Dermatitis 
Radiation 
 
X 
 
X 
 
Hyperpigmentation 
 
X 
 
X 
 
Gastrointestinal 
disorders 
Diarrhea 
X 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Renal and urinary 
disorders 
Dysuria 
X 
X 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain 
 
X 
 
X 

MC1973 
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LATE TOXICITIES 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event / 
Symptoms 
Post-Surgery & Follow Up 
Skin and 
subcutaneous tissue 
disorders 
 
Hyperpigmentation1 
 
X 
General disorders and 
administration site 
conditions 
Localized edema1 
X 
Lymphedema 
X 
 
Musculoskeletal and 
connective tissue 
disorders 
Fibrosis deep connective 
tissue1 
X 
Joint range of motion 
decreased2 
X 
Osteonecrosis1 
X 
Neoplasm benign, 
malignant and 
unspecified 
 
Tumor pain1 
 
X 
Injury, poisoning and 
procedural 
complications 
 
Fracture1 
 
X 
Gastrointestinal 
Disorders 1 
Anal fistula 
X 
Colonic fistula 
X 
Duodenal fistula 
X 
Esophageal fistula 
X 
Gastric fistula 
X 
Ileal fistula 
X 
Jejunal fistula 
X 

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Rectal fistula 
X 
Anal ulcer 
X 
Colonic ulcer 
X 
Duodenal ulcer 
X 
Gastric ulcer 
X 
Ileal ulcer 
X 
Jejunal ulcer 
X 
Rectal ulcer 
X 
Small intestine ulcer 
X 
Anal stenosis 
X 
Colonic stenosis 
X 
Duodenal stenosis 
X 
Gastric stenosis 
X 
Ileal stenosis 
X 
Jejunal stenosis 
X 
Rectal stenosis 
X 
Small intestine stenosis 
X 
Rectal perforation 
X 
Small intestine 
perforation 
X 
Colonic perforation 
X 
Duodenal perforation 
X 
Gastric perforation 
X 
Ileal perforation 
X 

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Jejunal perforation 
X 
Enterovesical fistula 
X 
Renal and urinary 
disorders1 
Urinary fistula 
X 
Bladder perforation 
X 
Respiratory, thoracic 
and mediastinal 
disorders 
 
Pneumonitis1 
 
X 
1 Specific to radiation / surgery treatment area 
2 Specific to ipsilateral extremity / region 
 
 
10.5 
Submit via appropriate reporting mechanisms the following AEs experienced by a 
patient through the course of Radiation Therapy and not specified in Section 10.4: 
10.5.1 Grade 3, 4, and 5 AEs regardless of attribution to the study treatment or 
procedure. 
10.5.2 Grade 5 AEs (Death) 
10.5.2.1  Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure 
10.522 Any death more than 30 days after the patients last study treatment 
or procedure that is felt to be at least possibly treatment related 
must also be submitted as a Grade 5 AE, with a CTCAE type and 
attribution assigned. 
10.6 
Monitoring and Auditing 
The investigator will permit study-related monitoring, audits, and inspections by 
the IRB, the sponsor, and government regulatory agencies, of all study related 
documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). Participation as an investigator in this study implies acceptance 
of potential inspection by government regulatory authorities and applicable 
compliance offices. 
10.6.1 Medical Monitoring 

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It is the responsibility of the Principal Investigator to oversee the safety of 
the study at his/her site. This safety monitoring will include careful 
assessment and appropriate reporting of adverse events as noted above, as 
well as the construction and implementation of a site data and safety- 
monitoring plan (see section 10.5 “Monitoring and Auditing”). Medical 
monitoring will include a regular assessment of the number and type of 
serious adverse events. Any serious adverse events will be followed up by 
the sentinel event reporting procedure. 
10.6.2 Internal Data and Safety Monitoring Board 
The trial will be reviewed by the Cancer Center Auditing area on a bi- 
annual or yearly basis dependent on random study selection to assess 
accrual, adverse events, and any endpoint problems. Any safety issues 
requiring protocol changes will be communicated through protocol 
amendments. 
 
 
11.0 
Treatment Evaluation/Measurement of Effect 
11.1 
Development of a surgical wound complication: Secondary unplanned operation 
under general or regional anesthesia for wound repair (e.g., debridement, 
operative drainage, or secondary wound closure including rotationplasty, free 
flaps or skin grafts); or wound management without secondary operation 
including invasive procedures (e.g., aspiration of seroma or readmission for 
wound care such as intravenous antibiotics or persistent deep packing for 120 
days or longer). 
11.2 
Local recurrence free survival: Any radiographic or pathologic evidence of 
recurrent disease inside the CTV and/or beyond the CTV to within a 3 cm 
distance from the edge of the CTV. Ideally assessed by radiographic imaging in 
comparison to the treatment fields in order to determine site of recurrence. 
 
 
12.0 
Descriptive Factors 
12.1 
ECOG Performance Status: 0 versus 1 versus 2 versus 3. 
12.2 
Sex: Male versus female. 
12.3 
Age: 18-30 versus 31-50 versus 51-70 versus ≥70. 
12.4 
Tumor Size: <5 cm versus 5-10 cm versus 11-15 cm versus >15 cm. 

MC1973 
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12.5 
Anatomic location: Proximal upper extremity versus distal upper extremity 
(including elbow) versus proximal lower extremity (including knee) versus distal 
lower extremity versus superficial trunk. 
 
12.6 
Lesion presentation: de novo (biopsy only) versus status post inadvertent 
excision. 
12.7 
Histology: Undifferentiated pleomorphic sarcoma versus liposarcoma versus 
leiomyosarcoma versus myxofibrosarcoma versus other histology. 
12.8 
Tumor depth: Superficial and deep to fascia versus deep to fascia versus 
superficial to fascia. 
 
12.9 
Radiation Treatment Modality: 3D conformal versus IMRT versus proton therapy. 
12.10 Neoadjuvant chemotherapy: Yes versus no. 
12.11 Margin status: R0 vs R1 vs R2. 
12.12 Surgical closure: Primary closure versus skin graft versus flap. 
 
 
13.0 
Treatment / Follow-up Decision at Evaluation of Patient 
As per standard of care, throughout the study, investigators can prescribe any 
medications/treatments that have been deemed necessary for the well-being and over all 
treatment of the patient. 
13.1 
A patient is deemed ineligible if after registration, it is determined that at the time 
of registration, the patient did not satisfy each and every eligibility criteria for 
study entry. The patient will go off study. 
• If the patient received MR for radiotherapy planning, all data up until the 
point of confirmation of ineligibility must be submitted. 
• If the patient never received radiation therapy, on-study material must be 
submitted. No additional follow up is necessary. 
13.2 
Those patients who will not receive any radiation treatment or who will receive 
radiation treatment elsewhere will go off study. 
13.3 
Inevaluable Patients 
If a patient fails to complete radiation therapy for reasons other than toxicity, the 
patient will be regarded as inevaluable and will be replaced. 
13.4 
Patients with a Major Deviation 
A patient is deemed a major violation if: 
a) PTV_4275 D95% <90% 
AND / OR 

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b) >25% of PTV_4275 receives ≥110% of prescription dose 
AND / OR 
c) Dose to the organs at risk is more than the recommended limit (Table 2.0) 
These patients will be flagged but included in the primary endpoint analysis. 
Separate sensitivity analysis will also be performed between the patients with 
major violation vs no major violation on major wound complication rate. 

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14.0 
Body Fluid Biospecimens 
N/A 
 
 
15.0 
Drug Information 
N/A 
 
 
16.0 
Statistical Considerations and Methodology 
16.1 
Overview 
This phase II single arm study will utilize a non-inferiority design approach to 
assess the rate of major wound complications associated with hypofractionated 
preoperative radiation therapy of 42.75 Gy in 15 fractions for localized, resectable 
soft tissue sarcoma of the extremity and superficial trunk compared to conventional 
fractionation of 50 Gy in 25 fractions. 
16.1.1 Primary Endpoint 
The primary endpoint of this trial is the proportion of patients who 
experience major wound complications within 120 days of surgical 
resection of soft tissue sarcoma of the extremity and superficial trunk 
following preoperative radiation therapy of 42.75 Gy in 15 fractions. Major 
wound complication is defined as secondary unplanned operation under 
general or regional anesthesia for wound repair (e.g.,debridement, operative 
drainage, or secondary wound closure including rotationplasty, free flaps or 
skin grafts); or wound management without secondary operation including 
invasive procedures (e.g., aspiration of seroma or readmission for wound 
care such as intravenous antibiotics or persistent deep packing for 120 days 
or longer). All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for the primary 
endpoint. 
 
 
16.2 Statistical Design 
The non-inferiority one-sample test was utilized from PASS software for this 
design (Non-Inferiority of One Proportion using the Z-Test with S(P0) in PASS 
16.0.4). A sample size of 108 evaluable patients achieves 80% power (1-sided 
significance level of 10%) to detect a non-inferiority margin of 10%, assuming that 
any major wound complication rate of 45% or above is inferior as compared to the 
current standard of care complication rate of 35%.6 We hypothesize that the 
proposed hypofractionated preoperative radiation therapy of 42.75 Gy in 15 
fractions is not inferior to the conventional fractionation of 50 Gy in 25 fractions 

MC1973 
39 
 
by showing the complication rate is < 45% for the proposed treatment (non- 
inferiority margin of 10%). 
 
16.2.1 Decision Rule 
After the first 108 eligible patients have completed 120 days post-treatment, 
we’ll do the final analysis of the data, and if the Z-test is significant at the 
10% significance level, we’ll conclude that hypofractionated preoperative 
radiation therapy of 42.75 Gy in 15 fractions is not inferior to conventional 
fractionation of 50 Gy in 25 fractions and can be tested further in larger 
studies. 
 
16.2.2 Sample Size 
This study is expected to need to accrue 108 evaluable patients unless the 
study is closed early for excessive toxicity. We anticipate approximately 
10% lost to follow-up due to 120 day endpoint, therefore we anticipate 
accruing an additional 12 patients to account for ineligibility, cancellation, 
or other reasons, making the overall sample size of 120 patients. 
 
16.2.3 Accrual Rate and Study Duration 
The expected accrual rate is about 4 patients per month. With this accrual 
rate, we expect to finish accrual within about 30 months of study activation, 
assuming we accrue 120 total patients. The final analysis can begin as soon 
as the last patient has been observed for 4 months post treatment, or at 
approximately 3 years after the study opens to accrual. 
 
16.2.4 Power and Significance Level 
Assuming that the number of major wound complications is binomially 
distributed, the significance level is 0.1 i.e. there is 10% chance of finding 
hypofractionated preoperative radiation therapy to be effective when it truly 
is not. The probability of declaring that the proposed radiation therapy 
warrants further studies (i.e., statistical power) is 80.01%, if the true acute 
wound complication is <45%. 
 
16.2.5 Other Considerations 
Adverse events, quality/duration of response, and patterns of treatment 
failure observed in this study, as well as scientific discoveries or changes in 
standard care will be taken into account in any decision to terminate the 
study. 
 
16.3 
Analysis Plan 

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The analysis for this trial will commence at planned time points (see 16.2.3) and at 
the time the patients have become evaluable for the primary endpoint. The 
Statistician and Study Chair will make the decision, in accord with CCS Standard 
Operating Procedures, availability of data for secondary endpoints (e.g., disease 
free survival, overall survival), and the level of data maturity. It is anticipated that 
the earliest date in which the results will be made available via manuscript, abstract, 
or presentation format is when last patient has been followed for at least 6 months. 
 
Note: Both primary and secondary outcomes will be compared between anatomical 
sites (proximal lower limb (includes knee) vs rest). The comparison between groups 
will be exploratory in nature. 
 
16.3.1 Primary Outcome Analysis 
 
16.3.1.1 Definition: The primary endpoint of this trial is the proportion of 
patients who experience major wound complications within 120 
days of surgical resection of soft tissue sarcoma following 
preoperative radiation therapy. All patients meeting the eligibility 
criteria who have signed a consent form and have begun treatment 
will be evaluable for the major wound complication rate. 
 
16.3.1.2 Estimation: The proportion of major wound complications will be 
estimated by the number of patients who experience the major 
wound complications within 120 days following surgery divided 
by the total number of evaluable patients. 95% confidence 
intervals using normal approximation to binomial wound 
complication proportion will be calculated. 
 
16.3.1.3 Over Accrual: If more than the target number of patients are 
accrued, the additional patients will not be used to evaluate the 
stopping rule or used in any decision making process; however, 
they will be included in final endpoint estimates and confidence 
intervals. 
 
16.3.2 Secondary Outcome Analysis 
16.3.2.1 Local failure is defined any radiographic or pathologic evidence 
of recurrent disease inside the CTV and/ or to within 3 cm from 
the edge of the CTV. In the absence of censored patients prior to 
5 years, local failure rate at 5 years (LFR5) will be equal to the 
binomial proportion. LFR5 will be evaluated by the number of 
patients free of local failure/recurrence at 5 year divided by the 
total number of evaluable patients. Exact binomial 95% 

MC1973 
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confidence interval for the point estimate will be provided. In the 
case of censoring prior to 5 years, LFR5 will be estimated using 
the Kaplan-Meier method. 
16.3.2.2 Disease-Free Survival is defined as the time from registration date 
to the earliest date of documentation of either, local recurrence, 
regional recurrence, distant recurrence, or death due to any cause, 
censoring patients who are alive and local recurrence free at the 
date of last know clinical assessment. The distribution of disease- 
free survival will be estimated using method of Kaplan-Meier. 
16.3.2.3 Overall Survival is defined as the time from registration date to 
death due to any cause, censoring patients alive at the date of last 
contact. The distribution of overall survival will be estimated 
using method of Kaplan-Meier. 
16.3.2.4 Late toxicity is defined as toxicity occurs any time between 3 
months and 24 months after completion of hypofractionated 
preoperative radiation therapy. The rate of ≥ grade 2 late 
toxicities will be estimated by the number of patients with a ≥ 
grade 2 late  toxicity divided by the total number of evaluable 
patients. Exact binomial 95% confidence intervals for the true 
rate of ≥ grade 2 toxicity events will be calculated. 
16.3.2.5 Pattern of relapse will be evaluated by number of patients with 
patterns of tumor recurrence such as local recurrence, marginal 
recurrence, regional recurrence, distant metastasis, and second 
primary tumor divided by the total number of evaluable patients. 
Exact binomial 95% confidence interval for the point estimate 
will be provided. 
16.3.2.5.1 Local tumor recurrence is defined as any tumor 
recurrence inside the CTV. 
16.3.2.5.2 Marginal tumor recurrence is defined as any tumor 
recurrence beyond the CTV to within a 3 cm distance from the 
edge of the CTV. 
16.3.2.5.3 Distant tumor recurrence is defined as any tumor that 
develops distantly from the primary site of sarcoma. 

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16.3.2.5.4 Second primary tumor is defined as any different 
histology of sarcoma or any other type of malignancy inside or 
outside the radiation field. 
16.3.2.6 Adverse Events: All eligible patients that have initiated treatment 
will be considered evaluable for assessing adverse event rate(s). 
The maximum grade for each type of adverse event will be 
recorded for each patient, and frequency tables will be reviewed 
to determine patterns. Additionally, the relationship of the 
adverse event(s) to the study treatment will be taken into 
consideration. Late toxicities (as defined in sections 16.3.2.4) 
will be summarized separately. 
16.3.2.7 Quality of Life Measurements – PROMIS-10: Results from the 
ten-item PROMIS questionnaire will be used to evaluate physical 
health and mental health, separately. Changes in raw score from 
baseline to 24-months post-surgery will be assessed, in each of 
the physical and mental health domains. The Wilcoxon signed- 
rank test will be utilized to assess changes in raw PROMIS 
scores. Mean change, along with standard deviation will be 
reported. 
A scoring table to compare this patient population to global 
means may be utilized for various timepoints. However, because 
this scoring table is prepared for a fixed set of items, it can only 
be used when an examinee responds to all of the items in the set. 
This, along with all other analyses, including graphical 
representations and comparisons between other timepoints or 
subgroups of patients may be performed, but will be considered 
exploratory. 
16.3.2.8 Quality of Life Measurements – TESS: Results from the 
Toronto Extremity Salvage Score (TESS) questionnaire will be 
used to evaluate functional outcomes. The TESS specifically 
measures performance of activities of daily living, and is 
separated into upper and lower extremity versions (29 and 30 
questions, respectively). 
Patients will fill out the appropriate version, and point totals will 
be summed. Mean change from baseline to 24 months post- 
surgery, along with standard deviation will be reported by 
version. The Wilcoxon signed-rank test will be used to assess 
changes in TESS scores within questionnaires. All other 
analyses, including graphical representations, GEE model 
creation, and comparisons between different timepoints or 
subgroups of patients may be performed, but will be considered 
exploratory. 

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16.4 Data Safety and Monitoring 
16.4.1 Safety Review: The principal investigator(s) and the study statistician will review 
the study monthly to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least biannually, based on reports provided by the MCCC 
Statistical Office. 
16.4.2 Adverse Event Stopping Rules: The stopping rule specified below is based on 
the knowledge available at study development. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening 
to accrual or (2) at any time during the conduct of the trial and in consideration 
of newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may choose to suspend 
accrual because of unexpected adverse event profiles that have not crossed the 
specified rule below. 
Accrual may be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to Radiation Therapy (i.e., an 
adverse event with attribute specified as “possible”, “probable”, or “definite”) 
that satisfy one of the following: 
• If 8 or more of the first 20 patients (or 40% or more of all patients after 
10 are accrued) experience a Grade 3+ AE. 
• If 4 or more experience a Grade 5 AE at any time. 
After consideration by the study team (Study Chair, statistician, etc.), a 
decision will be made as to whether accrual can be resumed. In addition, we 
will review grade 4 and 5 adverse events deemed “unrelated” or “unlikely to be 
related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
 
16.5 
Subset Analyses for Minorities 
16.5.1 Study Availability 
This study will be available to all eligible patients, regardless of gender, 
race or ethnic origin. 
16.5.2 Statistical Analysis by Subset 
There is no information currently available regarding differential effects of 
this radiation treatment in subsets defined by race, gender, or ethnicity, 
and there is no reason to expect such differences to exist. Therefore, 
although the planned analyses will look for differences in treatment effect 
based on racial groupings, the sample size is not increased in order to 
provide additional power for subset analyses. 

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16.5.3 Regional Population 
The geographical region served by MCCC has a population which 
includes approximately 10% minorities. Expected sizes of racial by gender 
subsets are shown in the following table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
3 
6 
Not Hispanic or Latino 
57 
57 
114 
Ethnic Category: Total of all subjects* 
60 
60 
120 
Racial Category 
American Indian or Alaskan Native 
2 
1 
3 
Asian 
1 
2 
3 
Black or African American 
2 
2 
4 
Native Hawaiian or other Pacific 
Islander 
1 
1 
2 
White 
54 
54 
108 
Racial Category: Total of all subjects* 
60 
60 
120 
 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection strategies.) 
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 

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17.0 
Pathology Considerations/Tissue Biospecimens 
N/A 
 
 
18.0 
Records and Data Collection Procedures 
18.1 
Data Collection and Processing 
All data will be entered into electronic case report forms (eCRF’s) through the 
Medidata Rave system. Case report forms will be automatically rolled out based 
on a predetermined, and visit based schedule to improve study staff workflow and 
data quality. Data will be exported nightly to a secure FTP for analysis and 
reporting. 
18.2 
Data Security and Confidentiality 
The Medidata Rave database access model is role based and fully auditable at the 
study, form, and field levels. Data will be de-identified whenever possible and 
the ability to update will be limited to necessary staff. Access will be managed by 
the Mayo CTMS Service and Solution Center, under a controlled and monitored 
access request system. Medidata’s platform specifically supports Electronic 
Record and Electronic Signature (ER/ES) requirements, including US 21 CFR 
part 11. 
18.3 
Data Quality Assurance 
Each eCRF will contain edit checks and custom functions to ensure the highest 
possible data quality. Only necessary eCRF’s will be available for data entry to 
reduce the possibility of erroneous entry. 
 
The edit checks and custom functions on the eCRF’s will trigger queries 
requesting the attention of appropriate study staff. The fields will be marked in 
pink to allow study staff to quickly identify the data fields that require attention or 
actions. Additionally, secure email notifications will be sent for adverse event 
tracking and monitoring. 
 
 
19.0 
Budget 
 
19.1 
Costs charged to patient: Routine clinical care 
 
19.2 
Tests to be research funded: None 

MC1973 
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20.0 
References 
1. 
Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the 
extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation 
therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 
1982;196:305-15. 
2. 
Pisters PW, Harrison LB, Leung DH, 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. 
3. 
Yang JC, Chang AE, Baker AR, 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. 
Barkley HT, Jr., Martin RG, Romsdahl MM, Lindberg R, Zagars GK. Treatment of soft 
tissue sarcomas by preoperative irradiation and conservative surgical resection. Int J Radiat 
Oncol Biol Phys 1988;14:693-9. 
5. 
Lindberg RD, Martin RG, Romsdahl MM, Barkley HT, Jr. Conservative surgery and 
postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 1981;47:2391-7. 
6. 
O'Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative 
radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235-41. 
7. 
Beane JD, Yang JC, White D, Steinberg SM, Rosenberg SA, Rudloff U. Efficacy of 
adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year 
follow-up of a randomized prospective trial. Ann Surg Oncol 2014;21:2484-9. 
8. 
Cannon CP, Ballo MT, Zagars GK, et al. Complications of combined modality treatment 
of primary lower extremity soft-tissue sarcomas. Cancer 2006;107:2455-61. 
9. 
DeLaney TF, Spiro IJ, Suit HD, et al. Neoadjuvant chemotherapy and radiotherapy for 
large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2003;56:1117-27. 
10. 
Moore J, Isler M, Barry J, Mottard S. Major wound complication risk factors following 
soft tissue sarcoma resection. Eur J Surg Oncol 2014;40:1671-6. 
11. 
Wang D, Zhang Q, Eisenberg BL, et al. Significant Reduction of Late Toxicities in 
Patients With Extremity Sarcoma Treated With Image-Guided Radiation Therapy to a Reduced 
Target Volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial. J Clin Oncol 
2015;33:2231-8. 
12. 
Scharschmidt T, Chen Y, Wand D, Chi Y, Kayton M, J S. ARST1321: Pazopanib 
neoadjuvant trial in non-rhabdomysarcoma soft tissue sarcomas: A report of major wound 
complications. J Clin Oncol 2019;37. 
13. 
Davis AM, O'Sullivan B, Bell RS, et al. Function and health status outcomes in a 
randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue 
sarcoma. J Clin Oncol 2002;20:4472-7. 
14. 
Davis AM, O'Sullivan B, Turcotte R, et al. Late radiation morbidity following 
randomization to preoperative versus postoperative radiotherapy in extremity soft tissue 
sarcoma. Radiother Oncol 2005;75:48-53. 
15. 
Davis AM, Sennik S, Griffin AM, et al. Predictors of functional outcomes following limb 
salvage surgery for lower-extremity soft tissue sarcoma. J Surg Oncol 2000;73:206-11. 
16. 
Haas RL, Delaney TF, O'Sullivan B, et al. Radiotherapy for management of extremity 
soft tissue sarcomas: why, when, and where? Int J Radiat Oncol Biol Phys 2012;84:572-80. 

MC1973 
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17. 
Haas RL, Miah AB, LePechoux C, et al. Preoperative radiotherapy for extremity soft 
tissue sarcoma; past, present and future perspectives on dose fractionation regimens and 
combined modality strategies. Radiother Oncol 2016;119:14-21. 
18. 
Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high- 
dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, 
non-inferiority, phase 3 CHHiP trial. Lancet Oncol 2016;17:1047-60. 
19. 
Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy 
(START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year 
follow-up results of two randomised controlled trials. Lancet Oncol 2013;14:1086-94. 
20. 
Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation 
therapy for breast cancer. N Engl J Med 2010;362:513-20. 
21. 
Kosela-Paterczyk H, Szacht M, Morysinski T, et al. Preoperative hypofractionated 
radiotherapy in the treatment of localized soft tissue sarcomas. Eur J Surg Oncol 2014;40:1641- 
7. 
22. 
Pennington JD, Eilber FC, Eilber FR, et al. Long-term Outcomes With Ifosfamide-based 
Hypofractionated Preoperative Chemoradiotherapy for Extremity Soft Tissue Sarcomas. Am J 
Clin Oncol 2018;41:1154-61. 

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Appendix I 
ECOG Performance Status 
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To 
duplicate the scale, please cite the reference above and credit the Eastern Cooperative Oncology 
Group, Robert Comis M.D., Group Chair. 
 
From http://www.ecog.org/general/perf_stat.html 

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Appendix II – PROMIS-10 
 
 
 

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Appendix III- TESS 
 

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M C 1 9 7 3
 7 1
 
 
A p p e n dix I V 
J oi nt Stiff n ess Ass ess m e nt 
(S p e cifi c t o i p sil at e r al e xtr e mit y/r e gi o n) 
 
 
 
M C:   
 
P ati e nt N a m e:    
 
 
 
D at e of A s s e s s m e nt:   
 
N a m e of A s s e s s or:   
 
 
 
W a s J oi nt Stiff n e s s Pr e s e nt:  Y e s/ N o ( cir cl e o n e) 
 
If y es, J oi nt Aff ect e d: 
 U p p er pr o xi m al e xtr e mit y 
 U p p er di st al e xtr e mit y (i n cl u d e s el b o w) 
 L o w er pr o xi m al e xtr e mit y (i n cl u d e s k n e e) 
 L o w er di st al e xtr e mit y 
 S u p erfici al tr u nk 
Gr a d e: 
 
 
 
 
Attri b uti o n t o R T: 
 D efi nit e  
 P o s si bl e 
 Pr o b a bl e 
 U nli k el y  
 U nr el at e d 
Attri b uti o n t o S ur g er y: 
 D efi nit e  
 P o s si bl e 
 Pr o b a bl e 
 U nli k el y  
 U nr el at e d 
 1- Mil d stiff n e s s; sli g ht R O M l o s s  
 2 - M o d er at e stiff n e s s; p ai n, R O M loss  
 3 - S e v er e stiff n e s s, p ai n, R O M l o s s  
 4 - N e cr o si s; c o m pl et e fi x ati o n  

M C 1 9 7 3
 7 2
 
 
A p p e n di x V 
 
R e gi o n al Al o p e ci a A s s e s s m e nt 
 
 
M C:   
 
 
P ati e nt N a m e:    
 
 
 
D at e of A s s e s s m e nt:   
 
N a m e of A s s e s s or:   
 
 
W as R e gi o n al Al o p eci a Pr es e nt:  Y es/ N o 
If y es, R e gi o n Aff ect e d: 
 U p p er pr o xi m al e xtr e mit y 
 U p p er di st al e xtr e mit y (i n cl u d e s el b o w) 
 L o w er pr o xi m al e xtr e mit y (i n cl u d e s k n e e) 
 L o w er di st al e xtr e mit y 
 S u p erfici al tr u nk 
Gr a d e: 
 
 
 
 
Attri b uti o n t o R T: 
 D efi nit e  
 P o s si bl e 
 Pr o b a bl e 
 U nli k el y  
 U nr el at e d 
 1 - H air l o s s of < 5 0 % of n or m al f or t h at i n di vi d u al t h at i s n ot o b vi o u s on 
cl o s e i n s p e cti o n  
 2 -  H air l o s s of > 5 0 % n or m al f or t h at i n di vi d u al t h at i s r e a dil y a p p ar e nt to 
ot h er s  

M C 1 9 7 3
 7 3
 
 
A p p e n dix VI 
S ur gic al W o u n d C o m plic ati o n Ass ess m e nt 
 
 
 
M C:   
 
P ati e nt N a m e:   
 
 
N a m e of A s s e s s or:   
 
 
 
 
 
S ur gic al w o u n d c o m plic ati o n:  Y es/ N o 
If y es, 
S ur gic al w o u n d st art d at e:    
  
S ur gic al w o u n d e n d d at e:    
 
D at e n otifi e d of s ur gic al w o u n d c o m plic ati o n:   
 
 
S ur gic al w o u n d c o m plic ati o n cl assific ati o n: 
 W o u n d m a n a g e m e nt vi a s ec o n d ar y u n pl a n n e d o p er ati o n u n d er a n est h esi a 
 W o u n d m a n a g e m e nt vi a i n v asi v e pr oc e d ur es ot h er t h a n o p er ati o n 
 
S ur gic al w o u n d c o m plic ati o n pr oc e d ur e p erf or m e d: