Feasibility Study of Temporally Feathered Radiation Therapy (TFRT) for Head and Neck Squamous Cell Carcinoma: Means of Toxicity Reduction
Phase: NA
Conditions: Head and Neck Cancer
Sponsor: Case Comprehensive Cancer Center

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STUDY NUMBER:  CASE 4318  
 
ClinicalTrials.gov NCT #:  03768856 
 
Version Date: 5/8/2020 
 
STUDY TITLE:  Feasibility Study of Temporally Feathered Radiation Therapy (TFRT) 
for Head and Neck Squamous Cell Carcinoma: Means of Toxicity Reduction 
 
 
 
 
PRINCIPAL INVESTIGATOR:  Shlomo Koyfman, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
Cleveland Clinic 
 
 
 
10201 Carnegie Ave, Desk CA-50 
 
Cleveland, OH 44195 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co-INVESTIGATOR: 
 
Jacob Scott, MD, DPhil 
Department of Translational Hematology and Oncology 
Research 
Desk NE-6 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH 44195 
 
 
 
 
 
 
 
 
 
 
 
 
Peng Qi, PhD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
Cleveland Clinic 
 
 
 
10201 Carnegie Ave, Desk CA-50 
 
Cleveland, OH 44195 
  
 
 
 

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Jeremy Donaghue, MS 
Department of Radiation Oncology 
Cleveland Clinic – Fairview Hospital 
18200 Lorain Ave 
Cleveland, OH 44111 
 
 
 
 
 
 
 
Neil Woody 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
Cleveland Clinic 
 
 
 
10201 Carnegie Ave, Desk CA-50 
 
Cleveland, OH 44195 
 
 
 
 
 
 
 
 
 
 
 
Eric Murray, CMD  
Department of Radiation Oncology 
 
 
 
 
Cleveland Clinic 
 
 
 
10201 Carnegie Ave, Desk CA-50 
 
Cleveland, OH 44195 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shireen Parsai, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
Cleveland Clinic 
 
 
 
 
 
 
 
10201 Carnegie Ave, Desk CA-50 
 
 
 
 
 
Cleveland, OH 44195 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICIAN:  
 
Chandana Reddy,   
Cleveland Clinic 
 
 
 
10201 Carnegie Ave, Desk CA-50 
 
Cleveland, OH 44195 
 
 
 
 
 
 
 
 
 
 
 

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SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
 
SUPPORT/FUNDING: 
 
Research Program Committees Grant 
 
 

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SUMMARY OF CHANGES 
 
Protocol 
Date 
Section 
Change 
10/10/18 
6.5.1 
Target Volumes updated to include extra CTV_and PTV_6300 
 
6.8 
Compliance criteria table updated to include PTV_6300 
 
11.0 
List of Patient Reported Outcomes Questionnaires updated 
 
Appendix 
III 
Treatment subplan updated from days Mon-Fri to treatments A-E 
12/7/18 
Title 
Page 
Clinicaltrials.gov NCT number added 
 
Title 
Page 
Protocol date updated 
 
Title 
Page 
Shireen Parsai changed from Study Coordinator to Co-Investigator 
 
Title 
Page 
Study Coordinator last name and email change 
 
4.1.1 
“Oral cavity” removed from eligibility criteria 
 
6.6.2 
Clarification of treatment plan documents required in Mosaiq 
 
9.2 
“Height” removed from required assessments in study calendar 
 
Appendix 
II 
“Missed fractions should NOT be added to the end of the treatment 
schedule”  removed 
12/28/18 
Footer 
 Version date change to reflect previous amendment 
4/10/19 
Title 
Page 
Study coordinator name and contact info changed. 
4/10/19 
7.1.3 
Clarification on AE’s that are to be reported in the database.  
5/8/20 
Title 
Page, 
7.3.1 
PI changed from Dr. Joshi to Dr. Koyfman, additional study staff 
updated 

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STUDY SCHEMA 
 
x 
 

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PROTOCOL SUMMARY 
 
Protocol Number/Title 
CASE4318 Feasibility Study of Temporally Feathered 
Radiation Therapy (TFRT) for Head and Neck Squamous 
Cell Carcinoma: Means of Toxicity Reduction 
Study Phase 
Feasibility 
Brief Background/Rationale 
 
 
 
Intensity‐modulated radiation therapy (IMRT) has allowed 
for optimization of three‐dimensional spatial radiation dose 
distributions permitting target coverage while reducing 
normal 
tissue 
toxicity. 
However, 
acute 
and 
late 
radiation‐induced normal tissue toxicity is a major 
contributor to patients’ quality of life and often a 
dose‐limiting factor in the definitive treatment of cancer 
with radiation therapy. We propose the next logical step in 
the 
evolution 
of 
IMRT 
incorporates 
canonical 
radiobiological 
principles, 
optimizing 
the 
temporal 
dimension through which radiation therapy is delivered to 
further reduce radiation‐induced toxicity by increased time 
for normal tissue recovery. This new technique of radiation 
planning and delivery is termed Temporally Feathered 
Radiation Therapy (TFRT). TFRT has been previously 
modeled in silico and has demonstrated potential to reduce 
normal tissue toxicity. Given that TFRT is dependent on 
normal tissue recovery, a dynamic normal tissue 
complication probability (NTCP) model is used to ascertain 
the potential benefits of TFRT as compared to conventional 
IMRT planning. In this study, we will examine the 
feasibility of generating and delivering TFRT plans in the 
modern clinical workflow. Importantly, the radiation dose 
to the target volume is not altered and therefore this 
technique of radiation planning only examines techniques 
to reduce toxicity. All radiation prescription doses used in 
this study are determined as per current standards of care. 
Primary Objective  
Primary Endpoints  
Feasibility of TFRT planning and delivery defined as 
patient starting radiation within 15 days of CT simulation. 
Secondary Objective(s) 
Secondary Endpoints 
(1) 
Estimate acute grade 3-5 toxicity (within 90 
days after RT)  
(2) 
Patient-reported outcomes of toxicity during and 
after TFRT. 
(3) 
Compliance with plan delivery 
Exploratory Objective(s) 
Exploratory Endpoints (s) 
 
Compare doses to organs at risk delivered by 
TFRT compared to conventional IMRT plans on a 
per patient basis 

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Correlative Objective(s) 
 
Correlative Endpoint(s) 
N/A 
Sample Size 
5 patients 
Patients age >18 years, male and female  
Disease sites/Conditions 
with ICD 10 codes 
C01 Base of Tongue 
C05 Palate (soft) 
C09 Tonsil 
C10 Oropharynx 
C10 Epiglottis 
C11 Nasopharynx 
C11 Pharyngeal Wall 
C12-C13 Hypopharynx 
C13 AE Fold 
C14 Pharynx (NOS) 
C32 True Vocal Cord 
C32 Glottis 
C32 Larynx 
C32 Supraglottic 
C44 Squamous Cell Cancer 
Interventions 
Temporally Feathered Radiation Therapy (TFRT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ABBREVIATIONS  
 
 
 
 
CCCC Case Comprehensive Cancer Center 
CRF 
Case Report Form 
DCRU Dahm’s Clinical Research Unit 
DSTC 
Data Safety and Toxicity Committee 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRMC Protocol Review and Monitoring Committee 
SOC 
Standard of Care 
CCF 
Cleveland Clinic Foundation 
UH 
University Hospitals 
TFRT 
Temporally Feathered Radiation Therapy 
IMRT 
Intensity Modulated Radiation Therapy 
OAR 
Organ At Risk 
dS 
Standard fractional dose 
dL 
Low fractional dose 
dH 
High fractional dose 
NTCP 
Normal tissue complication probability 

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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background  
1.2  
Description of Temporally Feathered Radiation Therapy 
1.3  
Rationale   
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
2.3 
Exploratory Objectives(s) 
2.4 
Correlative Objective(s) 
 
3.0 
STUDY DESIGN 
3.1 
Study design 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview  
6.2  
Dose Specifications  
6.3 
Technical Factors 
6.4 
Localization, Simulation, Immobilization 
6.5 
Target Volumes 
6.6 
Treatment Planning, Assessment, and Delivery 
 
7.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
7.1 
Definitions 
7.2 
Serious Adverse Event Report Form 
7.2 
Reporting Procedures for Serious Adverse Event  
7.3 
Serious Adverse Events and OnCore®    
7.4 
Data Safety Toxicity Committee 
7.5 
Data and Safety Monitoring Plan 
 
8.0 
EXPLORATORY/CORRELATIVE  
8.1  
Dosimetric Comparison 
 
9.0 
STUDY PARAMETERS AND CALENDAR 

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9.1 
Study Parameters 
9.2 
Calendar 
 
10.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
10.1 
Data Reporting 
10.2 
Regulatory Considerations  
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
REFERENCES 
 
  
APPENDICES  
 
 
 
APPENDIX 1  
 
Karnofsky Performance Status Criteria 
 
 
APPENDIX 2 
Therapist Treatment Delivery Timeout 
 
 
APPENDIX 3 
Safety Summary Tables for Treatment Plan Documentation 
 
APPENDIX 4 
Patient Reported Outcome Questionnaires 
 
APPENDIX 5 
Radiation Oncology SAE Report Form 
 
 
 

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1.0 
Introduction  
 
1.1 
Background of Study Disease  
 
In 2017, the incidence of new cases of head and malignancies, including the oral cavity 
and pharynx was estimated to be about 1.7 million with about 600,000 deaths 
worldwide.1 These cancers have been historically treated with a surgical approach; 
however given the morbidity of surgery, the standard has shifted to definitive non-
surgical organ sparing approaches including radiotherapy with or without concurrent 
chemotherapy.2 Conventional techniques of radiotherapy and chemotherapy resulted in 
high rates of late effects, such as dysphagia, radionecrosis, and xerostomia. With the 
advancement of radiotherapy techniques through the years, specifically the adoption of 
intensity-modulated radiotherapy (IMRT) coupled with image guidance, the practitioner 
now has greater control over the physical distribution of dose over the target volume and 
nearby surrounding structures. This has led to decreased late toxicity rates. In a recent 
study of patients receiving definitive radiotherapy with or without chemotherapy for 
HPV-related oropharynx cancer, the cumulative incidence of severe late toxicity at 2-
years after completing treatment was 2.3%, whereas 42% of patients experienced grade 3 
or higher acute toxicity.2 The most common grade 3 or greater acute toxicity was 
dysphagia (24%), followed by mucositis (17%), and dermatitis (8%). For those who 
required feeding tube placement, the median duration of acute feeding tube use was 1.7 
months. Of the patients followed greater than one year without local failure, 24% 
experienced grade 2 xerostomia. Notably, in historic trials, higher rates of toxicity have 
also been recorded with concurrent chemotherapy and radiotherapy.3-7 Quality of life also 
declines following therapy. Though most patients recover global quality of life by 12 
months, deterioration in physical functioning, fatigue, xerostomia, and sticky saliva 
persist beyond 12 months in head and neck cancer survivors.8,9 In this study we aim to 
further decrease acute and late toxicities associated with radiotherapy. We examine a new 
technique termed temporally feathered radiation therapy (TFRT), through which the dose 
delivered to the target volume remains unchanged while the fractional dose delivered to 
the surrounding organs at risk is altered.  
 
 
The biologic basis of dose and fractionation arises from the four pillars of 
radiobiology: (i) repair of sub-lethal damage, (ii) reassortment of cells within the cell 
cycle, (iii) repopulation, and (iv) reoxygenation.10 Recovery from radiation-induced 
toxicity is primarily dependent on sub-lethal damage repair and repopulation. For this 
reason, fractionated radiotherapy still predominates in the clinic. As a low fractional dose 
of radiation is delivered daily, consistent insult is delivered to tumor cells while allowing 
time for normal tissue recovery between fractions. Despite this, as discussed above, 
toxicity still manifests mid-way or toward the end of most treatment courses acutely and 
late toxicities remain dose-limiting. Attention has been turned to techniques to widen the 
therapeutic ratio between tumor control probability (TCP) and normal tissue complication 
probability (NTCP). This had been achieved previously by pharmaceuticals such as 
radiosenstizers and radioprotectants, until the advent of intensity modulated radiation 
therapy (IMRT), which now is one of the greatest contributors to reduced toxicity 
associated with radiotherapy.2,11,12 The implementation of IMRT into clinical practice 

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took nearly 50 years from when Dr. Birkhoff solved the inverse problem of IMRT in the 
1940s, until Dr. Brahme illustrated the IMRT principles in 1988, and ultimately when the 
Peacock planning system was used to treat the first patient with IMRT in the mid-
1990s.13-17 
 
As an extension of IMRT, other researchers namely Dr. Unkelbach have 
examined the role of altering both the fractional dose delivered to the target as well as the 
organs at risk to continue to widen the therapeutic ratio.18-22 Temporally feathered 
radiation therapy takes a different approach to reducing toxicity, without altering target 
volume coverage or dosing. Temporally feathered radiation therapy optimizes not only 
the physical distributions of dose, but also the time through which radiation therapy is 
delivered with the goal of allowing increased time for normal tissue recovery between 
fractional doses. Preclinical data demonstrating the potential benefit of TFRT are 
discussed below (section 1.2.1).23  
 
1.2  
Temporally Feathered Radiation Therapy 
 
1.2.1  Preclinical Data  
 
Temporally feathered radiation therapy is designed for targets within close proximity to 
multiple organs at risk. The foundation of this planning technique is the rotation of 
radiation dose to the nearby organs at risk on a daily basis, and hence the term 
“feathering”. Radiation dose feathering is a technique that has been long used for creating 
a uniform distribution of dose across radiation field junctions at which hot or cold spots 
may occur. In TFRT planning, the physical dose is deliberately feathered among the 
neighboring organs at risk unevenly. Temporally feathered radiation plans are composed 
of 5 isocurative subplans which are scheduled to be delivered once per week as illustrated 
in Figure 1. Each of these subplans delivers a therapeutic dose of radiation therapy to the 
target, however one organ at risk is chosen to be deprioritized per subplan and therefore 
receive a slightly higher fractional dose (dH) as compared to the standard fractional dose 
(dS) delivered by conventional planning. dH is defined as a measure of dose distributed 
over a deprioritized organ. The following is true: dH > dS > dL. Resultantly, each OAR 
which received a slightly higher fractional dose once weekly, followed by slightly lower 
fractional dose the remaining four fractions of that week as reflected in the other four 
subplans. The hypothesis is that if dH is delivered to an organ at risk once weekly 
followed by four dL (lower fractional dose), there is increased time for normal tissue 
recovery. 
 
 

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Figure 1. Schematic representation of Temporally Feathered Radiation Therapy. 
The target volume (black pentagon) is surrounded by 5 organs at risk (circles). Five 
individual radiation plans are created for each day of the week whereby a  higher 
fractional dose, dH, is delivered to the OAR of interest (grey) and the remaining four 
OARs receive a lower fractional dose, dL.  
 
 
In silico simulations, TFRT demonstrated potential for reduced normal tissue 
toxicity compared to conventionally planned IMRT as demonstrated in Figure 2.23 The 
sequencing of high and low fractional doses delivered to OARs by TFRT plans suggested 
increased normal tissue recovery, and hence less overall radiation-induced toxicity 
compared to conventionally planned IMRT. The simulations were conducted using the 
following dynamic normal tissue complication probability model (equation 1) which 
accounts for normal tissue recovery in response to radiation therapy.23  
 
                                                          (1) 
 
The organ-specific parameter µ > 0 represents the recovery rate of radiation-induced 
damage. N(t) < N(0) represents the level of normal tissue damage by radiotherapy, 
considering that normal tissue at homeostasis with a 1% turnover rate would be denoted 
as N(0) = 0.99. Small values of N(t) relate to severe damage. The effect of radiation is 
included by the loss term δ(ti ) RT(d) N(t)(1-N(t)) where δ(ti) is a characteristic function 
equal to 1 at the time of irradiation ti, and zero in other case. The magnitude of toxicity 
reduction by TFRT planning was found to depend on corresponding standard fractional 
dose of IMRT and organ-specific recovery rate of sub-lethal radiation-induced damage.  
 
 
 
 
 
 
 
 
 
 
 

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Figure 2. Comparison of conventionally fractionated IMRT and TFRT with respect 
to the standard fractional dose (ds) and organ-specific recovery rate (µ). (a) Overall 
potential benefit (OBPTF) and (b) maximum potential benefit (MAXTF) of TFRT over 
conventional planned IMRT. (I-III) Top panels represent the single cases marked by stars 
in (a). The x- and y-axes represent ∆L = dS − dL and ∆H = dH − dS, respectively. Bottom 
panels show time-evolution of OAR toxicity included by the IMRT and TFRT plans 
corresponding to the location marked by diamonds in the top panels.  
 
Further dosimetric evaluations were conducted with IMRT head and neck cases 
that were replanned with TFRT technique. As illustrated in figure 3, the TFRT plans were 
achievable while maintaining the dose delivered the planning target volume.  

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Figure 3. Proof of principle of Temporally Feathered Radiation Therapy. Panel A 
illustrates changes in OAR toxicity and NTCP over time for varying OAR recovery rates. 
Panel B demonstrates a dose volume histogram for the target in a TFRT plan (red) 
compared to conventionally planned IMRT (black). Panel C demonstrates axial images of 
a head and neck plan with superimposed isodose lines for conventionally planned IMRT, 
a TFRT plan with dH delivered to the OAR, and a TFRT plan with dL delivered to the 
OAR (left to right).   
 
 
1.2.2 Clinical Data 
 
There are no available clinical research data to date on temporally feathered radiation 
therapy.  
 
1.3 
Rationale  
 
Given prior preclinical data suggesting the potential for reduced normal tissue toxicity 
with TFRT, we will now evaluate the feasibility of treatment planning and delivery in 
current clinical workflow. Subsequent studies will be powered for toxicity outcomes. 
Patients with head and neck malignancies were chosen, as the current standard of care 
requires conventionally fractionated radiation therapy over 7 weeks. Due to the anatomy 

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of the region, the target volume often is surrounded by multiple organs at risk. Therefore, 
head and neck malignancies are a prime example in which temporally feathered radiation 
therapy may decrease normal tissue toxicity.  
 
2.0  
Objectives 
2.1 
Primary Objective  
 
To determine feasibility of TFRT planning and delivery for head and neck 
squamous cell carcinoma defined as patient starting radiation within 15 days of 
simulation. 
 
2.2 
Secondary Objective(s) 
 
(1) 
Estimate grade 3-5 acute toxicity (within 90 days after RT)  
(2) 
Patient-reported outcomes (PRO) of toxicity during and after TFRT. 
(3) 
Compliance with plan delivery 
 
3.0 
Study Design 
 
3.1  
Study design including dose escalation / cohorts  
 
This study is planned as a single arm feasibility trial to demonstrate clinical delivery of 
TFRT plans. Five patients will be accrued as a single cohort. 
 
3.2 
Number of Subjects 
 
Five patients will be enrolled in this trial. 
 
3.3 
Replacement of Subjects  
 
Subjects who come off of study for reasons unrelated to treatment course may be 
replaced.  
 
3.4  
Expected Duration of Treatment and Subject Participation 
 
Treatment will last for a duration of 7 weeks and patients will be followed for a total of 3 
months following treatment completion.  
 
4.0 
Subject Selection 
Each of the criteria in the sections that follow must be met in order for a subject to be 
considered eligible for this study. Eligibility criteria must be met to confirm a subject’s 
eligibility.  
 
4.1 
Inclusion Criteria 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment:  
 

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
 
4.1.1 Subjects must have histologically or cytologically confirmed squamous cell 
carcinoma arising from a primary head and neck site (oropharynx, larynx/ 
hypopharynx, nasopharynx). TX-4, NX-3, MX-0 stages are permitted.  
 

 
4.1.2 Subjects must be eligible for definitive radiation therapy (70Gy in 35 
fractions) with or without chemotherapy.   

 
4.1.3 Age ≥18 years.  
 

 
4.1.4 Karnofsky Performance status ≥80 [See Appendix 1].  
 

 
4.1.5 Subjects must have the ability to understand and the willingness to sign a 
written informed consent document. 
 
4.2 
Exclusion Criteria 
The presence of any of the following will exclude a subject from study enrollment. 
 

 
 4.2.1 Subjects receiving any other investigational agents.  
 

 
4.2.2 Postoperative radiotherapy is not permitted. 
 

 
4.2.3 History of prior head and neck radiation therapy.  
 

 
4.2.4 Subjects with uncontrolled inter-current illness including, but not limited to 
ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements.  
 

 
4.2.5 Pregnant or breastfeeding women are excluded from this study because 
radiation therapy has the potential for teratogenic or abortifacient effects. 
Because there is an unknown, but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with radiation therapy, breastfeeding 
should be discontinued if the mother is treated with radiation therapy. These 
potential risks may also apply to other agents used in this study.  
 

 
4.2.6 The patient cannot have distant metastatic disease (or M1 disease by AJCC 
8th edition). 
 
 
4.3 
Inclusion of Women and Minorities  
Men, women and members of all races and ethnic groups are eligible for this trial. 
 
5.0 
Registration 
All subjects who have been consented are to be registered in the OnCore® Database. For 
those subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded. 
 

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All subjects will be registered through Cleveland Clinic and will be provided a study 
number by contacting the study coordinator listed on the cover page.  
 
 
 
6.0  
Radiation Treatment Plan 
 
6.1 
Radiation Treatment Regimen Overview 
Protocol treatment must begin within 15 days after simulation.  
 
Patients will receive temporally feathered radiation therapy as part of their definitive 
course of radiation therapy with indications as per standard of care for patients with head 
and neck malignancies.  
 
No investigational agents or investigational therapies may be administered with the intent 
to treat the subject's malignancy. 
 
6.2 Dose Specifications 
 
6.2.1 Dose Fractionation 
Patients must be eligible to receive 70 Gy in 35 fractions to the primary target 
(PTV_7000) and to receive 56 Gy in 35 fractions to the elective volume (PTV_5600). 
The doses are prescribed at the edge of the PTV. Treatment will be delivered once daily 
from Monday to Friday over 7 weeks. Missed treatments can be compensated for by 
treating on the Saturday or Sunday of that week, or adding to the end of treatment.  
 
6.3 Technical Factors 
 
6.3.1 Treatment Planning and Delivery  
The IMRT plan can be delivered with step-and-shoot, sliding window, or 
volumetric modulated arc therapy (VMAT) techniques on a linear 
accelerator with equipped with multileaf collimator (MLC). Any MV 
photon beam energies will be allowed.   
 
6.3.2 Image Guidance for IGRT 
Daily image guidance should be achieved using kilovoltage (KV) cone-
beam CT (CBCT) images. 
 
6.4 Localization, Simulation, and Immobilization 
 
6.4.1 Patients must have an immobilization device (Aquaplast mask) at the time 
of CT simulation. It is strongly encouraged that the immobilization device 
should limit motion in the head and neck region as well as the shoulders. 
Bite blocks may be used for maintaining tongue position. 
 

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6.4.2 IV contrast should be used with the treatment planning CT unless the 
patient has a contraindication. The treatment planning CT will be acquired 
in the treatment position with the immobilization device. CT slice 
thickness should be ≤ 0.3 cm. 
 
6.5 Target Volumes 
 
 
6.5.1  Definition of Target Volumes 
In addition to the planning CT, additional imaging (e.g. PET/CT, MRI) 
can be fused with the planning CT to guide target delineation. Standard 
volume definitions were borrowed from consensus from RTOG 1016 
protocol  
 
Gross Tumor Volume (GTV): The GTV represents the clinical or 
radiographic areas grossly involved with tumor and will be designated as 
GTV_7000. Involved nodes must be included in the GTV and are defined 
as those greater than 1 cm in short axis, nodes with central necrosis or 
those with PET avidity deemed to be positive.  
Clinical Target Volume (CTV): The CTV represents the area at risk for 
microscopic disease spread, respecting natural barriers of disease spread. 
Two CTVs must be created. CTV_7000 will encompass possible local 
subclinical infiltration at the primary site. CTV_7000 is created by a 0.25-
0.5 cm expansion of GTV_7000. CTV_5600 will encompass the clinically 
uninvolved nodal regions considered to be at high risk for microscopic 
spread. An optional CTV_6300 may be designated at the physician’s 
discretion in regions felt to be at especially high risk for recurrence.  
 
Planning Target Volumes (PTV): The PTV represents the volume to which 
radiation dose will be prescribed, delivered, and evaluated. The PTV 
accounts for interfraction set-up variability. Two PTVs will be generated. 
A PTV_7000 will be created from the CTV_7000 and a PTV_5600 will be 
created from the CTV_5600. An option PTV_6300 may also be 
designated as above. The PTV is created by an isotropic expansion of 
0.25cm-0.5 cm on the CTV. The PTV should not extend beyond the skin 
surface. If the skin is considered to be at high risk, bolus material should 
be placed over this portion of the PTV. 
 
6.5.2  Definition of Normal Tissues/ Organs at Risk (OARs): All normal tissues 
are evaluated as the regions not overlapping with the PTV and are 
summarized in Table 1. 
Spinal cord: The cranial border of the spinal cord is at the craniocervical 
junction (the top of C1 vertebral body). The inferior border is at 
approximately T3-T4 (i.e., just below the lowest slice that has PTV on it). 
A Planning Risk Volume (PRV) of the cord should be created by 
expanding the cord with a uniform margin of 5 mm.   
 

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Brainstem: The cranial border of the brainstem is approximately at the 
level of the top of the posterior clinoid. The inferior border is at the 
craniocervical junction. The brainstem and spinal cord are contiguous 
structures. A PRV of 3 mm should be delineated around the brainstem also 
as a separate structure.  
 
Lips and Oral Cavity: Delineation of lips is self-explanatory. The oral 
cavity is delineated as the anterior ½-2/3 of the oral tongue/ floor of 
mouth, buccal mucosa, and palate. 
 
Parotid Glands: Each parotid gland is drawn as an individual structure 
based on CT anatomy. The superficial and deep lobes should be included.  
 
Submandibular Glands: Each submandibular gland is drawn as an 
individual structure based on CT anatomy. 
 
OARpharynx: This structure encompasses the posterior pharyngeal wall 
and adjacent constrictor muscles, extending cranially from the level of the 
pterygoid plates to the level of the esophagus. 
 
Esophagus: The cervical esophagus is defined on CT anatomy. The 
superior border is at the bottom of the pharynx (cricopharyngeal inlet) and 
the inferior border is at the thoracic inlet.  
 
Supraglottis: The supraglottis is drawn separate from the larynx, cranially 
including the epiglottis. This structure is contiguous with the glottic larynx 
caudally. 
 
Larynx: The larynx only encompasses the glottic larynx.  
 
Glottic/Supraglottic Larynx (GSL): The GSL includes a fusion of the 
supraglottic larynx and the glottic larynx.  
 
Table 1: Normal Tissues/Organs at Risk to be Delineated 
 
OAR Standard Name 
Description 
SPINAL_CORD 
Spinal cord 
SPINAL_CORD_PRV5 
Planning risk volume of 5 mm around spinal 
cord  
BRAINSTEM 
Brainstem 
BRAINSTEM_PRV3 
Planning risk volume of 3 mm around 
brainstem 
LIPS 
Lips 
ORAL_CAVITY 
Oral cavity 
PAROTID_R 
Right parotid gland 
PAROTID_R_PTV 
Right parotid gland, nonoverlapping with PTV 

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PAROTID_L 
Left parotid gland 
PAROTID_L_PTV 
Left parotid gland, nonoverlapping with PTV 
SUBMANDIBULAR_R 
Right submandibular gland 
SUBMANDIBULAR_L 
Left submandibular gland 
OAR_PHARYNX 
OAR pharynx 
OAR_PHARYNX_PTV 
OAR pharynx, nonoverlapping with PTV 
ESOPHAGUS 
Esophagus 
SUPRAGLOTTIS 
Supraglottis 
LARYNX 
Glottic larynx 
GSL 
Supraglottic and glottic larynx 
 
6.5.3 In cases of anatomical changes (i.e. due to weight loss), an adaptive replan 
is permitted with repeat CT simulation at the discretion of the treating 
physician in order to recreate an immobilization mask and adjust the 
planning volumes.   
6.5.4 Any OAR involved by tumor will not need to be deliberately avoided.  
However, they should still be contoured.  
 
6.6 Treatment Planning, Assessment and Delivery 
 
6.6.1 Planning Temporally Feathered Radiation Therapy: The treating physician 
will designate up to 5 organs at risk (OARs) to be feathered based on 
proximity to target, prior to treatment planning. As shown in Figure 1, 5 
subplans (designated as plan A, plan B, plan C, plan D, and plan E) will 
be generated, with each deprioritizing one of the 5 OARs. The plans are 
considered to be isocurative based on meeting standard guidelines for 
PTV coverage as described in 6.2.2.  
 For each of these subplans, a single OAR is deprioritized such 
that it receives a higher dose (dH) while the remaining 4 OARs 
receive a lower dose (dL) than the standard fractional dose (dS) 
delivered in a conventional IMRT plan. 
 The daily dose delivered to the PTV is still 2 Gy. 
 The OARs that may be feathered include, but are not limited 
to, the following: oral cavity, each submandibular gland, each 
parotid 
gland, 
OARpharynx, 
supraglottis, 
larynx, 
and 
esophagus.  
 A standard IMRT plan must also be generated. If the patient 
cannot be started on the TFRT plan within 15 days of 
simluation, the standard IMRT plan should be delivered 
instead.  
 Note: If the patient’s start date for radiation therapy is delayed 
for medical reasons (eg dental extractions) not related to the 
timing of TFRT planning, TFRT planning can still be 
continued as planned. Delays in radiation start date must be 
designated whether directly attributable to TFRT planning. 

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Refer to appendix III on correct procedures for resumption of 
treatment schedule after a missed fraction.  
 
6.6.2 Assessing Temporally Feathered Radiation Therapy: The treatment plan 
documents signed by the physician will be stored in Mosaiq. The 
treatment plan documents must include the treatment fields, the isodose 
lines, and DVH composite plan (labeled as COMPOSITE). Appendix III 
lists all of the components necessary in the approved treatment plan 
document. 
 
Each subplan must be assessed individually in addition to the composite 
plan.  
1. Assessment of the composite plan: The composite plan and DVH must 
be generated from the cumulative dose delivered by each of the 5 
temporally feathered subplans. The composite plan must meet the 
compliance criteria as in 6.8. 
2. Assessment of each subplan: dH is defined as a measure of dose 
distributed over a deprioritized organ. The max point dose for dH must 
comply with:0.03 cc of the deprioritized organ cannot exceed >10% of 
the prescription dose. The dose delivered to each PTV must meet the 
compliance criteria as in 6.8. 
 
6.6.3 Delivery of Temporally Feathered Radiation Therapy: The patient should 
start radiation treatment within 15 days of CT simulation. If the patient is 
unable to be started on TFRT treatment plan within 15 days of the date of 
CT simulation, the patient must start radiation therapy using the standard 
IMRT plan previously created (and not TFRT plan) so as not to delay 
treatment schedule.  
 
The treatment plan can be started on any day of the week, as long as at 
least 2 consecutive fractions are delivered before the weekend.  
 
Specific IMRT QA should be performed for each subplan to ensure plan 
integrity.   
 
 
 
Two therapists must be present for the delivery of TFRT. The therapists 
should continue with standard time out procedures with an additional 
verification that the correct subplan is selected for treatment according to 
the day of the week as in Appendix II. It is strongly encouraged that the 
attending physician or physicist to be present at the first 5 fractions of 
TFRT delivery. 
 
6.7 Doses to critical structures for the composite plan 
All dose constraints to critical structures include the volume of the critical 
structure outside of the planning target volume. Standard dose constraints were 
adapted from RTOG 1016 protocol (NCT01302834). 

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Spinal cord: 0.03 cc of the PRV should not exceed ≥50 Gy. 0.03 cc of the 
spinal cord should not exceed ≥45 Gy.  
 
Brainstem: 0.03 cc of the brainstem should not exceed 60 Gy. 0.03 cc of 
the PRV brainstem should not exceed 63 Gy.  
 
Lips: Reduce dose as much as possible, with goal of mean dose <20 Gy. 
 
Oral Cavity: Reduce dose as much as possible, with goal of mean dose 
<30 Gy for the uninvolved oral cavity. Hot spots >60 Gy should be 
avoided as possible within the uninvolved oral cavity.  
 
Parotid Glands: Each parotid gland should be optimized separately, with a 
goal of mean dose <26 Gy. 
 
Contralateral Submandibular Glands: If contralateral nodal level IB is not 
targeted, goal is to reduce mean contralateral submandibular to <39 Gy. 
 
OARpharynx: Reduce the dose as much as possible with goal mean dose 
<45 Gy. 
 
Esophagus: Reduce the dose as much as possible, with goal mean dose 
<30 Gy. 
 
Supraglottis: Reduce the dose as much as possible, with goal mean dose 
<45 Gy. 
 
Larynx: Reduce the dose as much as possible, with goal mean dose <45 
Gy. 
 
GSL:  Reduce the dose as much as possible, with goal mean dose <45 Gy. 
 
6.8 Compliance Criteria 
Treatment breaks and reasons must be indicated in the treatment record. Treatment 
breaks should not exceed 5 consecutive treatment days or 10 days total. 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Total RT dose to 
PTV_7000 (to 95% 
of the PTV) 
70 Gy 
None 
none 
Minimum 
dose 
(“cold spot” within 
PTV_7000, 
not 
including 
portion 
near (<8 mm skin) 
66.5 Gy (equals 
95% prescribed 
dose) 
<66.5 but >63 Gy 
≤63 Gy 

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defined for a point 
that is 0.03 cc in 
size 
Maximum 
dose 
(“hot spot” >1 cc) 
within PTV_7000 
≤77 Gy 
>77 Gy but ≤82 Gy 
>82 Gy 
 
 
 
 
Total RT dose to 
PTV_5600 (to 95% 
of the PTV) 
56 Gy 
≥45 but <56 Gy 
<45 Gy 
Total RT dose to 
PTV_6300 (to 95% 
of the PTV) 
63 Gy 
 
Required when 
applicable 
≥52 but <63 Gy 
<52 Gy 
Total RT dose to 
spinal 
cord 
PRV 
(0.03 cc) 
≤50 Gy 
≥50 Gy but ≤52 Gy 
>52 Gy 
 
6.9 Radiation Therapy Adverse Event Reporting 
Adverse event reporting will occur according to section 7. 
 
6.10 
General Concomitant Medications and Supportive Care Guidelines 
 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, cytokines, antibiotics, antiemetics, etc when appropriate. 
 
6.11 
Criteria for Removal from Study 
In the absence of treatment delays due to adverse events, treatment will continue until 
completion of treatment or one of the following criteria applies: 
 
• Disease progression, 
 
• Inter-current illness that prevents further administration of treatment, 
 
• The investigator considers it, for safety reasons, to be in the best interest of the subject.  
 
• Subject decision to withdraw from treatment (partial consent) or from the study (full 
consent), 
 
• Pregnancy during the course of the study for a child-bearing participant 
 
 
 
6.12 
Duration of Follow Up 
Subjects will be followed for toxicity for 3 months after treatment has been completed/ 
discontinued or until death, whichever occurs first.  

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7.0 
Adverse Events and Potential Risks  
 
Note: Only serious adverse events as defined above will be reported. Standard head and 
neck radiotherapy engenders significant acute toxicity and may be associated with grade 
3-5 acute toxicity.  These may be associated with pain, dysphagia, mucositis, weight loss, 
feeding tube use, narcotic use, hospitalizations, dehydration, infections, dermatitis, 
laryngeal edema.  These are routine expected side effects from radiation and should not 
be affected by the method of planning used in this study.  
 
7.1 
Definitions  
 
7.1.1 
Adverse Event   
An adverse event (AE) is any unfavorable or unintended event, physical or 
psychological, associated with a research study, which causes harm or injury to a 
research participant as a result of the participant’s involvement in a research study. The 
event can include abnormal laboratory findings, symptoms, or disease associated with the 
research study. The event does not necessarily have to have a causal relationship with the 
research, any risk associated with the research, the research intervention, or the research 
assessments.  
 
Adverse events may be the result of the interventions and interactions used in the 
research; the collection of identifiable private information in the research; an underlying 
disease, disorder, or condition of the subject; and/or other circumstances unrelated to the 
research or any underlying disease, disorder, or condition of the subject.  
 
7.1.2   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that 
results in any of the following outcomes:  
 Results in death.  
 Is a life-threatening adverse experience. The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk 
of death at the time of the event.  It does not refer to an adverse event which 
hypothetically might have caused death if it were more severe.  
 Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.  Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 

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However it should be noted that invasive treatment during any hospitalization 
may fulfill the criteria of “medically important” and as such may be reportable as 
a serious adverse event dependant on clinical judgment.  In addition where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.  
 Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal 
life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a 
serious adverse experience when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples 
of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood disease or disorders, or 
convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
7.1.3 Adverse Event Evaluation  
The investigator or designee is responsible for ensuring that all adverse events (both 
serious and non-serious) observed by the clinical team or reported by the subject which 
occur after the subject has signed the informed consent are fully recorded in the subject’s 
medical records. Source documentation must be available to support all adverse events.  
 
For the purposes of data collection, only non-serious adverse events that are possibly, 
probably or definitely related to protocol treatment will be reported in the database. 
Serious adverse events of any attribution will be reported in the database.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, 
result in a delay or dose modification of study treatment, or judged relevant by the 
investigator), should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the 
following for all adverse events (both serious and non-serious): 
 Event term (as per CTCAE) 
 Description of the event 
 Date of onset and resolution 
 Expectedness of the toxicity 
 Grade of toxicity 
 Attribution of relatedness to the treatment- (this must be assigned by an 
investigator, sub-investigator, or treating physician) 
 Action taken as a result of the event, including but not limited to; no changes, 

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dose interrupted, reduced, discontinued, etc. or action taken with regard to the 
event 
 Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the 
prescribed course of radiotherapy.  Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the prescribed course of radiotherapy. 
 Probable – The AE is likely related to the prescribe course of radiotherapy. 
 Possible – The AE may be related to the prescribed course of radiotherapy. 
 Unlikely – The AE is doubtfully related to the prescribed course of 
radiotherapy. 
 Unrelated – The AE is clearly NOT related to the prescribed course of 
radiotherapy. 
 
There is no attrition allowed for the prescribed course of radiotherapy depending on 
response to therapy.  
 
7.2  
SAE Report Form 
 
SAE’s related to radiation therapy only will be recorded into OnCore and reported to IRB 
according to local IRB policies and procedures.  
 
SAEs related to agent therapy will be recorded on the Radiation Oncology SAE Report 
Form [Appendix V].  
 
7.3  
Reporting Procedures for Serious Adverse Events 
For the purposes of safety reporting, all adverse events will be reported that occur from 
the day of registration through 90 days after the completion of the prescribed course of 
therapy. Adverse events, both serious and non-serious, and deaths that occur during this 
period will be recorded in the source documents. All SAEs should be monitored until 
they are resolved or are clearly determined to be due to a subject’s stable or chronic 
condition or intercurrent illness(es). Related AEs will be followed until resolution to 
baseline or grade 1 or stabilization.  

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7.3.1 SAE Reporting Requirements 
 Participating investigators (all sites) must report all serious adverse events to the 
Lead Site Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of 
discovery or notification of the event. The participating investigator must also 
provide follow-up information on the SAE until final resolution.  
o Lead Site PI: Shlomo Koyfman, koyfmas@ccf.org Fax: 216-445-1068. 
Protocol coordinator can be contacted if applicable.  
 The Lead Site Principal Investigator will review the SAE and report the event to 
IRB as applicable. 
 It is the Principal Investigator’s responsibility to ensure that ALL serious adverse 
events that occur on the study are reported to the Data Safety Toxicity Committee. 
 
Institutional Review Board Reporting Requirements: 
 Investigative sites will report adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events.  
 
7.4  
SAEs and OnCore 
 All SAEs will be entered into OnCore.   
 A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded 
into Oncore. 
 
7.5  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial 
(internal or external) are reported to the Case Comprehensive Cancer Center’s Data and 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
sponsor and/or other regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as 
per CCCC Data and Safety Monitoring Plan. 
  
7.6 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI guidelines.  
 
8.0 
EXPLORATORY ENDPOINTS 
 
8.1 
Dosimetric Comparison of TFRT and Conventional IMRT 
Dosimetric parameters including the mean dose, maximum dose, and minimum dose to 
the organs at risk will be analyzed among the subplans, composite TFRT plan, and 
conventional IMRT plan.  
 
8.1.1 Background  
Using the dynamic NTCP model, the greatest difference between dH and dL theoretically 
will create the biggest reduction in normal tissue complication probability. To further 

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understand the appropriate prioritization parameters dosimetric endpoints will be 
compared.  
 
8.1.2   Rationale for Analysis 
The dosimetric parameters will be reported in a descriptive pattern to detail the planning 
parameters used to optimize temporally feathered radiation therapy plans.  
 
 
9.0  
STUDY PARAMETERS AND CALENDAR  
 
9.1 
Study Parameters 
 
9.1.1 Screening Evaluation  
Evaluations including that needed to establish diagnosis, will be used to determine the 
eligibility of each subject for study inclusion. All evaluations must be completed < 40 
days prior to administration of protocol therapy.  
 
9.1.2 Treatment Period 
Patients will be evaluated in consultation, at which time information will be gathered 
regarding trial eligibility. Subsequently, patients will undergo CT simulation, initiation of 
radiation delivery, and weekly on-treatment visits. Follow-up visits will occur 2 weeks, 4 
weeks, and 3 months post completion of treatment. At the indicated visits below, toxicity 
will be assessed by way of CTCAE criteria and patient-reported quality of life 
questionnaires.  
 
9.2 
Calendar  
At the scheduled visits below the patients will undergo evaluation of toxicity with 
physician-assigned grade as per CTCAE V4 as well as patient reported outcome 
measures using EORTC QLQ-C30, EORTC QLQ-HN35 and Xerostomia Questionnaire 
(XQ) as demonstrated in Appendix IV.  
A visit window of +/- 4 days is allowed for the visits while the patient is undergoing 
treatment. A visit window of +/- 7 days is allowed for the visits 2 and 4 weeks after 
completing treatment. A visit window of +/- 28 days is allowed for the 3 month post-
treatment.  
 
Study Days 
Wk 1 of RT 
(+/- 4 days) 
Wk 4 of RT 
(+/- 4 days) 
Wk 7 of RT 
(+/- 4 days) 
2 Wks post-
RT 
 (+/- 7 days) 
4 wks post 
RT 
(+/- 7 days) 
3 mos post 
RT 
(+/- 28 days) 
REQUIRED 
ASSESSMENTS 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
Vitals (blood 
pressure, pulse, 
respiratory rate, 
and temperature) 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
PRO Assessment 
X 
X 
X 
X 
X 
X 

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Karnofsky PS 
X 
X 
X 
X 
X 
X 
 
10.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
10.1 
Data Reporting  
The Overture Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management. 
Overture is a Clinical Trials Management System housed on secure servers maintained at 
Case Western Reserve University. Access to data through Overture is restricted by user 
accounts and assigned roles. Once logged into the Overture system with a user ID and 
password, Overture defines roles for each user which limits access to appropriate data. 
User information and password can be obtained by contacting the Overture Administrator 
at OnCore-registration@case.edu. 
 
Overture is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification. This study will utilize electronic 
Case Report Form completion in the Overture database. A calendar of events and 
required forms are available in Overture 
 
10.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 
10.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and be allowed time to consider the 
information provided.  
The original, signed written Informed Consent Form must be kept with the Research 
Chart in conformance with the institution’s standard operating procedures. A copy of the 
signed written Informed Consent Form must be given to the subject. Additionally, 
documentation of the consenting process should be located in the research chart. 
10.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to 
subject’s medical information that includes all hospital records relevant to the study, 
including subjects’ medical history.  

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10.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted.  
 
10.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonization (ICH), and any 
applicable regulatory requirements.  For multi-center studies, participating sites must 
inform the sponsor-investigator of pending audits.  
 
11.0  STATISTICAL CONSIDERATIONS 
 
This study is designed as a feasibility study, with the goal of accruing 5 patients over the 
course of one year from trial opening. The primary objective is to determine the 
feasibility of TFRT planning and delivery in a modern clinical workflow. Feasibility is 
defined as a patient starting radiotherapy within 15 days of simulation. The TFRT 
technique will be deemed feasible if 3/5 patients meet the above criteria.  
 
Descriptive statistics will be applied. Secondary endpoints include estimates of (1) acute 
grade 3-5 toxicity as per CTCAE version 4, (2) estimates of patient-reported outcomes 
during and after TFRT delivery using EORTC QLQ-H&N35, EORTC QLQ-C30, and 
Xerostomia Questionnaire (XO) and (3) compliance with plan delivery.  
 
The patient-reported outcomes (PROs) from the above questionnaires will be collected at 
week 1 (baseline), week 4, and week 7 of treatment, as well as 2 weeks, 4 weeks, and 3 
months post completion of treatment radiation. Descriptive associations between PROs 
and CTCAE toxicity criteria will be reported.  

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Spatiotemporal fractionation schemes for liver stereotactic body radiotherapy. 
Radiotherapy and oncology : journal of the European Society for Therapeutic 
Radiology and Oncology. 2017;125(2):357-364. 
22. 
Unkelbach J, Papp D. The emergence of nonuniform spatiotemporal fractionation 
schemes within the standard BED model. Medical physics. 2015;42(5):2234-
2241. 
23. 
López Alfonso JC, Parsai S, Joshi N, et al. Temporally feathered intensity 
modulated radiation therapy: a planning technique to reduce normal tissue 
toxicity. Medical physics. 2018. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX I 
 
KARNOFSKY PERFORMANCE STATUS CRITERIA 
 
 
Percent 
Description 
 
100 
 
Normal, no complaints, no 
evidence of disease. 
 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work.  
 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
 
50 
Requires considerable 
assistance and frequent 
medical care. 
 
40 
 
Disabled, requires special care 
and assistance. 
 
30 
 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
 
20 
Very sick, hospitalization 
indicated. Death not imminent.  
 
10 
Moribund, fatal processes 
progressing rapidly. 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX II 
 
Therapist Treatment Delivery Timeout 
 
 
Two therapists must be present for the treatment timeout.  
 
1. Current practices of verifying patient and treatment site must occur. 
 
2. The treatment navigator in Mosaiq must be used to confirm the 
treatment plan fraction delivered the day before and determine the 
next appropriate fraction. Fractions will be delivered in a pattern of 
Plan A – Plan B – Plan C – Plan D – Plan E. For example, if plan B 
was delivered the day prior (i.e. on a Wednesday) then plan C must be 
delivered next for the next fraction (i.e. Thursday). In this example, 
Plan D would be delivered on Friday and Plan E would be delivered 
on Monday. 
 In the event the patient misses a planned treatment fraction, the 
therapist must notify Eric Murray, CMD, Peng Qi, PhD, and 
Shlomo Koyfman, MD. The determination can then be made in 
how to update the patient data in Mosaiq. Treatments should be 
resumed as soon as possible. The patient should resume therapy 
following the same pattern previously used A-B-C-D-E. Two 
fractions can never be delivered in the same day.  
 No overrides are allowed to occur without the presence of a 
physicist. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX III 

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Safety Summary Tables for Treatment Plan Documentation 
 
The following tables must be completed and printed in the treatment plan.  
 
Treatment 
Subplan 
Fractional 
dose 
deprioritized 
OAR (dH), a 
(cGy) 
Fractional 
dose 
deprioritized 
OAR (dH), b 
(cGy) 
Fractional 
dose 
deprioritized 
OAR (dH), c 
(cGy) 
Fractional 
dose 
deprioritized 
OAR (dH), d 
(cGy) 
Fractional 
dose 
deprioritized 
OAR (dH), e 
(cGy) 
PTV_7000 
coverage 
(%) 
PTV_5600 
coverage 
(%) 
A  
 
 
 
 
 
 
 
B  
 
 
 
 
 
 
 
C  
 
 
 
 
 
 
 
D  
 
 
 
 
 
 
 
E  
 
 
 
 
 
 
 
 
Treatment 
Subplan 
Diff in dose 
between TFRT 
subplan and 
conventional 
IMRT plan for 
deprioritized 
OAR, a (cGy) 
Diff in dose 
between TFRT 
subplan and 
conventional 
IMRT plan for 
deprioritized 
OAR, b (cGy) 
Diff in dose 
between TFRT 
subplan and 
conventional 
IMRT plan for 
deprioritized 
OAR, c (cGy) 
Diff in dose 
between TFRT 
subplan and 
conventional 
IMRT plan for 
deprioritized 
OAR, d (cGy) 
Diff in dose 
between TFRT 
subplan and 
conventional 
IMRT plan for 
deprioritized 
OAR, e (cGy) 
A  
 
 
 
 
 
B  
 
 
 
 
 
C  
 
 
 
 
 
D  
 
 
 
 
 
E  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX IV 
 

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Patient Reported Outcome Questionnaires 
(clickable files) 
 

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APPENDIX V 
 
Radiation Oncology SAE Report Form 
 
 
 
Event Date: ___________ 
Event End Date: ___________  
Initial Report Date: ___________ 
 
Follow Up Report Date: __________________ 
 
 
Death Date: ______________  
 
 
Event: ____________  
 
 
 
 
Grade: _____ 
 
Start of treatment date: _/__/__ 
 
 
 
End of treatment date: __/__/__ 
 
Date of most recent treatment: __/__/__ 
 
Radiation Intervention 
 
 
Type of Radiation: 
 
 
Total Dose (to date): 
 
 
Date of last treatment: 
 
 
Schedule: 
 
 
Number of fractions: 
 
 
Number of elapsed days: 
 
 
Action taken with Radiation  
 
 
 
Event Narrative: 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
____________________________________________________ 
 
Treating Physician Comments:  
_______________________________________________________________________________________
_______________________________________________________________________________________
 
Study Number (PRMC): 
 
ID Number: 
 
Patient Initials: __________ 

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_______________________________________________________________________________________
_________________________ 
 
 
PI Comments:  
_______________________________________________________________________________________
_______________________________________________________________________________________
_______________________________________________________________________________________
_______________________________________________________________________________________
_______________________________________________________________________________________
_______________________________________________________________________________________ 
 
Protocol Attribution:  
 
 Not related 
 Not likely related 
 Possibly related 
 Probably related 
 Definitely related 
 
Relationship to Radiation: 
 
 
 
 
 Not related  
 
 
 
 
 Not likely related 
 
 
 
 
 Possibly related 
 
 
 
 
 Probably related 
 
 
 
 
 Definitely related 
 
 
 
 
 
If event is unrelated or unlikely related, please state what event is likely related to (disease, etc): 
_______________________________________________________________________________________ 
  
Expected:   
 Yes 
 No 
 
 
Outcome:  
 
 Resolved completely     
 Resolved with sequelae    
 Not yet recovered     
 Fatal 
 Unknown 
 
 
 
Investigator Signature: _________________________________________       Date: ________________ 
 
 
 
Nurse Signature:     ____________________________________________         Date: ________________