INRT- AIR: A Prospective Phase II Study of Involved Nodal Radiation Therapy Using Artificial Intelligence-Based Radiomics for Head and Neck Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: University of Texas Southwestern Medical Center

 
STU2019-0711, Sher, FormA-ResearchProtocol, Mod_11, 08-25-20 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
 
 
STU 2019 – 0711 
INRT- AIR: A Prospective Phase II Study of Involved Nodal Radiation Therapy using 
Artificial Intelligence-Based Radiomics for Head and Neck Squamous Cell Carcinoma 
 
Principal Investigator:  
David J. Sher, MD, MPH 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5801 Forest Park Rd 
 
 
 
 
Dallas, TX 75390  
 
 
 
 
214-645-7607 
 
 
 
 
214-645-7624 
 
 
 
 
david.sher@utsouthwestern.edu 
 
Co-Principal Investigators or Lead Sub-Investigator(s): 
 
 
 
 
 
 
 
 
 
Jing Wang, PhD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
Randall Hughes, MD 
Department of Medical Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biostatistician: 
 
Chul Ahn, PhD 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
Dallas, TX 75390 
 
 
 
 
chul.ahn@utsouthwestern.edu 
 
 
 
 
214-648-9418 
 
 
 
 
Chul.Ahn@UTSouthwestern.edu 
 
Study Drug/Treatment:             Intensity modulated radiation therapy (IMRT) with or without 
chemotherapy 
 
Funding Source:  
Departmental 
 
Initial version: 
1.0  March 13, 2019 
 
 
 
UT Southwestern Medical Center (UTSW) 
Radiation Oncology Clinical Research Office 
 
 
 
 
 
2280 Inwood Rd  
Dallas, Texas 75390-9303 
 
Version 2 
1/30/2020 

 
STU2019-0711, Sher, FormA-ResearchProtocol, Mod_11, 08-25-20 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
Amendment/Version #________version 2_____________________ 
 
STU 2019 – 0711 
 
INRT- AIR: A Prospective Phase II Study of Involved Nodal Radiation Therapy using Artificial 
Intelligence-Based Radiomics for Head and Neck Squamous Cell Carcioma 
 
 
Principal Investigator (PI) Name:______David Sher, MD MPH_______________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 

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                                                           TABLE OF CONTENTS 
LIST OF ABBREVIATIONS (EXAMPLES) ..................................................................................... 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE .................................................................................... 4 
1.1 
Disease Background........................................................................................................ 4 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities ................. 4 
1.3 
Other Agents .................................................................................................................... 5 
1.4 
Rationale .......................................................................................................................... 5 
1.5 
Correlative Studies .......................................................... Error! Bookmark not defined. 
2.0 
STUDY OBJECTIVES ....................................................................................................... 12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives .................................................................................................... 12 
2.3 
Exploratory Objectives ..................................................... Error! Bookmark not defined. 
2.4 
Endpoints ....................................................................................................................... 13 
3.0 
Subject ELIGIBILITY ........................................................................................................ 13 
3.1 
Inclusion Criteria ............................................................................................................ 13 
3.2 
Exclusion Criteria ........................................................................................................... 14 
4.0 
TREATMENT PLAN .......................................................................................................... 15 
4.1 
Treatment Dosage and Administration .......................................................................... 15 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 21 
4.3 
Concomitant Medications/Treatments ........................................................................... 22 
4.4 
Other Modalities or Procedures ..................................................................................... 22 
4.5 
Duration of Therapy ....................................................................................................... 22 
4.6 
Duration of Follow Up .................................................................................................... 22 
4.7 
Removal of Subjects from Protocol Therapy ................................................................. 22 

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4.8 
Subject Replacement..................................................................................................... 23 
5.0 
STUDY PROCEDURES ..................................................................................................... 23 
5.1 
Screening/Baseline Procedures .................................................................................... 23 
5.2 
Procedures During Treatment ....................................................................................... 24 
5.3 
Follow-up Procedures .................................................................................................... 24 
5.4 
Time and Events Table .................................................................................................. 25 
5.5 
Removal of Subjects from Study ................................................................................... 26 
6.0 
Measurement of Effect ..................................................................................................... 26 
6.1 
Antitumor Effect- Solid Tumors ...................................................................................... 26 
6.2 
Safety/tolerability ........................................................................................................... 28 
7.0 
ADVERSE EVENTS .......................................................................................................... 28 
7.1 
Experimental Therapy (i.e. chemoradiotherapy) ........................................................... 28 
7.2 
Adverse Event Monitoring ............................................................................................. 28 
7.3 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the SCCC 
DSMC and/or HRPP ................................................................................................................... 31 
7.3.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center (SCCC) Data 
Safety Monitoring Committee (DSMC) ....................................................................................... 31 
7.4 
Unblinding Procedures .................................................................................................. 33 
7.5 
Stopping Rules .............................................................................................................. 33 
8.0 
DRUG INFORMATION ...................................................................................................... 33 
8.1 
Cisplatin ......................................................................................................................... 33 
8.2 
Cetuximab ...................................................................................................................... 34 
8.3 
Paclitaxel ....................................................................................................................... 35 
8.4 
Carboplatin .................................................................................................................... 36 
9.0 
CORRELATIVES/SPECIAL STUDIES .............................................................................. 37 
10.0 
STATISTICAL CONSIDERATIONS .................................................................................. 37 
10.1 
Study Design/Study Endpoints ...................................................................................... 37 

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10.2 
Sample Size and Accrual .............................................................................................. 38 
10.3 
Data Analyses Plans...................................................................................................... 38 
11.0 
STUDY MANAGEMENT .................................................................................................... 40 
11.1 
Conflict of Interest .......................................................................................................... 40 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 40 
11.3 
Required Documentation (for multi-site studies) ........................................................... 40 
11.4 
Registration Procedures ................................................................................................ 41 
11.5 
Data Management and Monitoring/Auditing .................................................................. 41 
11.6 
Adherence to the Protocol ............................................................................................. 42 
11.7 
Amendments to the Protocol ......................................................................................... 43 
11.8 
Record Retention ........................................................................................................... 43 
11.9 
Obligations of Investigators ........................................................................................... 44 
12.0 
REFERENCES ................................................................................................................... 44 
13.0 
APPENDICES .................................................................................................................... 47 

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LIST OF ABBREVIATIONS (EXAMPLES) 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
ASCO 
Absolute Lymphocyte Count 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DM 
Distant metastasis 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EVLR 
Elective volume local recurrence 
EVRR 
Elective volume regional recurrence 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
HPV 
Human papillomavirus 
HRPP 
Human Research Protections Program 
IF-EVRR 
In-field elective volume regional recurrence 
IF-LR 
In-field local recurrence 
IF-RR 
In-field regional recurrence 
IHC 
Immunohistochemistry 
IMRT 
Intensity modulated radiation therapy 
IND 
Investigational New Drug 
IV (or iv) 
Intravenously 
LR 
Local recurrence 
LXC 
Laryngeal carcinoma 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
OF-EVRR 
Out of field elective volume regional recurrence 
OF-LR 
Out of field local recurrence 
OPC 
Oropharyngeal carcinoma 
ORR 
Overall Response Rate 
OS 
Overall Survival 
pCR 
Pathologic Complete Response 

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PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Regional recurrence 
RT 
Radiotherapy 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SOF-EVRR 
Solitary out of field elective volume regional recurrence 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
Involved Nodal Radiotherapy (INRT),  
+/- concurrent chemotherapy  
Neck CT and follow-up at 
months 6, 12, 18, 24 and 36 
PET-CT at 3 months and ENT 
evaluation 
Patient registration 

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STUDY SUMMARY 
Title 
INRT- AIR: A Prospective Phase II Study of Involved Nodal Radiation 
Therapy using Artificial Intelligence-Based Radiomics for Head and 
Neck Squamous Cell Carcinoma 
 
Short Title 
INRT-AIR: A Prospective Phase II Study of Involved Nodal Radiation 
Therapy   
Protocol Number 
STU 2019 -0711 
Phase 
Phase 2 
Methodology 
Prospective, single-arm study 
Study Duration 
3 years to accrue plus additional 3 years of follow-up 
Study Center(s) 
Multi-center 
Objectives 
To determine the oncologic efficacy and quality-of-life-benefits of 
involved nodal radiotherapy 
Number of Subjects 
67.  
Diagnosis and Main 
Inclusion Criteria 
Stage I-IVB oropharyngeal squamous cell carcinoma, treated with 
definitive radiotherapy or chemoradiotherapy. 
Stage I-IVB laryngeal squamous cell carcinoma, excluding glottis T1-2 
carcinoma 
Stage I-IVB hypopharyngeal squamous cell carcinoma 
Study Product(s), Dose, 
Route, Regimen 
Intensity modulated radiation therapy (IMRT) with or without 
chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-
paclitaxel) 
Duration of administration 
 6.5-7 weeks of radiotherapy or chemoradiotherapy 
Reference therapy 
N/A 
Statistical Methodology 
A sample size of 60 achieves a 90% power to detect a non-inferiority 
difference of -0.1 for solitary elective nodal failure using a one-sided exact 
test with a significance level (alpha) of 0.05 following INRT. These results 
assume a baseline risk of 0.03 and that the actual difference is 0.0. After 
accounting for 10% loss to follow-up, a total of 67 patients will be 
enrolled.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
Oropharyngeal (OPC) and laryngeal cancer (LXC) are the most common sites of head 
and neck cancer disease treated with primary radiotherapy (RT) or chemoradiotherapy (CRT). 
For example, in the two most recent large RTOG randomized trials involving primary CRT, these 
two disease sites comprised 86% and 93% of the entire cohort of RTOG 0129 and 0522, 
respectively.1,2 
 
 Outcomes following radiotherapy depend strongly on disease site. Patients with OPC are 
now dichotomized into human papillomavirus (HPV)-related disease (HPV-positive), and HPV-
negative disease. The outcomes are dramatically improved in patients with virally-mediated 
cancer, with 8-year overall survival (OS), progression-free survival (PFS), locoregional recurrence 
(LRR) and distant metastasis (DM) risks of  70.9%, 64%, 19.5% and 10.3% versus 30.2%, 
23.3%, 52.4% and 16.1% for HPV-positive versus HPV-negative, respectively.  
 
The survival outcomes for patients with laryngeal cancer have remained roughly stable 
over the years. In RTOG 9111, definitive CRT using conventional radiotherapy led to 5-year OS, 
LRR and DM of 55.1%, 32.3%, and13.6%, respectively.3  In a more recent study (also using 
conventional radiotherapy), induction chemotherapy plus CRT for LXC led to a crude risk of 
locoregional and distant failure of 20% and 8.3% at a median follow-up of only 36 months, 
suggesting similar rates of disease success over time.4   
 
Radiotherapy has evolved dramatically over the past 20 years, such that now intensity 
modulated radiation therapy (IMRT) is the standard-of-care. IMRT allows the physician to contour 
(i.e. target) regions for specific doses of radiotherapy, while also specifying normal structures 
(termed organs-at-risk, OAR) that should be avoided. The use of IMRT has been shown to 
reduce xerostomia in randomized trials.5 However, IMRT still targets the same lymph node 
regions as conventional 2D radiotherapy, despite our ability to tailor the radiotherapy volume and 
dose to specific areas.  
 
We have recently completed a phase II study of dose and volume de-escalation for 
patients with OPC and LXC called INFIELD, enrolling more than 70 patients. In this study, the 
elective neck was treated to 40 Gray (Gy) (rather than the typical 56-60 Gy), and nodal levels 
were entired spared radiotherapy if more than 1 echleon away from malignant lymphadenopathy. 
Thus far there have been no elective nodal recurrences.  
 
It is notable that the majority of disease sites treated with radiotherapy no longer receive 
elective/prophylactic radiotherapy to clinically-negative areas, including lung, pancreas, and 
lymphoma. Indeed, as will be discussed, these disease sites now employ involved nodal 
radiotherapy, or INRT, focusing on involved lymphadenopathy. In this study, we aim to improve 
acute and long-term toxicity of IMRT for OPC, LXC and hypopharyngeal cancer (HPX) by 
delivering INRT. 
 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
 
Radiotherapy and chemoradiotherapy are established treatments for oropharyngeal 
squamous cell carcinoma. This study is evaluating a radiation dose paradigm that should be 
equally or more tolerable – in both the short- and long-term – than the established outcomes. The 
dose to known gross disease is the same as in these studies, but the dose to the areas with 
potential microscopic disease, termed elective volumes, will be lowered or eliminated.  
 
The allowed chemotherapy regimens are standard agents that have been used in 
prospective phase II and III studies and are considered feasible treatments according to the 
NCCN guidelines.  
 
To provide a rough estimate of acute and late toxicities, in the control arm of RTOG 0129 
(conventional radiotherapy plus bolus cisplatin), 73.7% of patients experienced a non-

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hematologic acute grade 3-5 toxicity, and 39.1% of patients developed acute grade 3-5 
mucositis/stomatitis.1 A total of 9.4% of patients developed febrile neutropenia. However, only 
3.7% of patients were diagnosed with late (i.e. after 90 days from the start of RT) 
mucositis/stomatitis. Thirty-six percent of patients experienced any late grade 3-5 toxicity, the 
majority of which were esophageal (8%), “other” (8%), or salivary gland (4%). 
  
1.3 
Other Agents 
 
Patients with AJCC v7 stage I and II disease will be treated with radiotherapy alone. 
Patients with AJCC v7 stage III (T1-2 N1) may be treated with radiotherapy alone or concurrent 
chemoradiotherapy. Patients with AJCC v7 stage III (T3N0-1) and IVA-B cancers will be treated 
with concurrent chemoradiotherapy. 
 
The specific systemic therapy agent will be left to the physician. The four allowed 
chemotherapy regimens are bolus cisplatin,weekly cisplatin, cetuximab (weekly, including 1 week 
before treatment), and carboplatin-paclitaxel (weekly, over the course of treatment).  
 
1.4 
Rationale 
 
Before proceeding with the rationale section, it is critical to note that radiotherapy targets 
two basic types of treatment volumes: gross disease and microscopic disease. Gross disease, 
termed gross tumor volume (GTV) receives the highest dose level, and microscopic disease, 
termed clinical target volume (CTV) receives a lower dose level. Frequently (but not always) there 
are several CTV dose levels, depending on the risk of microscopic disease. The critical organs-
at-risk (salivary glands, oral cavity, pharyngeal constrictors, larynx and esophagus) almost always 
abut areas that may harbor microscopic disease but are relatively distant (1 cm or more) from 
GTV. In practical terms, this means that the dose to structures crucial to long-term quality-of-life 
are determined by the elective, CTV, dose rather than the radiation to the known gross disease.  
 
When we think about reducing the intensity of treatment to the CTV, we aim to minimize 
the subsequent risk of solitary elective recurrence (i.e. first and only failure). That is, the risk of 
recurrence in an elective region before any other treatment failure, either local or distant. A 
patient who has an elective recurrence synchronous with (or after) an in-field or distant 
recurrence was not harmed by the less intense elective treatment, because the disease would 
have recurred anyway.  
 
There are thus three key questions in considering how to manage elective volume 
irradiation. First and second, how frequent are solitary elective recurrences and at what elective 
dose are these outcomes achieved? Thirdly, what is the risk of any microscopic disease in the 
first place?  
 
Frequency of solitary elective recurrences, and required dose 
 
 
With respect to the patterns-of-recurrence and required elective dose, although RTOG 
0129 did not describe the patterns-of-failure relative to the irradiation field, many other studies 
have shown that the vast majority of recurrences occur within the high-dose zone. In a 
retrospective study from Dana-Farber Cancer Institute, the risk of recurrence within the elective 
volume (56-63 Gy) was 1%, and results were very similar from Dandekar et al, which showed 
only a 2% elective failure risk in regions treated to 54-56 Gy.6,7 In a very large study from MD 
Anderson (776 oropharyngeal cancer patients), only 7 patients (< 1% of total) failed outside of the 
high-dose zone, with the low-dose irradiated to 50 Gy.8 There were no elective volume failures in 
a 71-patient retrospective study of oropharyngeal cancer from UCSF (54 Gy in 33 fractions).9 In a 
carefully-performed patterns-of-failure study from Ghent University Hospital, there were no 

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solitary elective nodal failures (out of 285, with the majority oropharynx [35%], larynx [28%], or 
hypopharynx [21%]) in the primarily irradiated neck, in which the elective neck received 56 Gy in 
35 fractions.10  Bedi et al described 69 patients treated with 50 Gy in 35 fractions to the low-risk 
elective neck, with no recurrences at a median 2.5 years of follow-up.11  
 
In a very large study (376 patients, 70% OPC and 16% LXC) from Belgium, although 
11.1% (41 patients) developed a regional recurrence, only 11 patients (3% of total) developed a 
solitary regional recurrence. Moreover, only 2 patients (<1% of total) developed a solitary elective 
regional recurrence in an area that received between 46-50 Gy.12 Studer et al. described the 
patterns-of-failure in 202 head and neck cancer patients (91% OPC, LXC or HPX) treated with 
IMRT.13 In this series, 99 patients underwent prophylactic neck dissection after RT, and 29 nodes 
were still positive; 28 out of these 29 (96.5%) were only positive in gross disease. Out of the 103 
patients who did not receive a prophylactic neck dissection, 27 (26%) patients developed an 
isolated nodal relapse. However, out of these 27 patients, only 1 (4%) occurred in the elective 
PTV. Importantly, salvage surgery was performed in 24 of these individuals (89%) and was 
successful in 21/24 (88% of attempted surgeries, 78% of all recurrences), despite nearly all of 
these recurrences reflecting in-field failures.  
 
Similarly, there were only 6 solitary elective recurrences out of 264 (50% OPC, 37% LC) 
patients treated to 50 Gy in 34 fractions in van den Bosch et al.14 Importantly, this latter paper 
evaluated almost 1200 lymph nodes, and found that elective nodal recurrence always occurred 
in a previously visualized (presumed benign) lymph node. Thus, the nodes at-risk appear to 
be visible at diagnosis. Moreover, the risk of recurrence in these radiologically-negative nodes 
was only 0.4% (at 2 years) if the summed diameter of the lymph node was less than 17 mm. In 
summary, it seems clear that solitary elective recurrences are very rare, if a radiologically-clear 
region has microscopic disease, 50 Gy is nearly always sufficient to sterilize it.  
 
In fact, the drive to lower the elective dose even further led to a Belgian randomized 
controlled trial comparing 50 Gy with 40 Gy to the elective neck, with 100 patients in either arm. A 
preliminary study showed significantly improved dosimetry in the dose to the swallowing 
structures, with significantly less grade 3 dysphagia at 3 months (2% vs 11%, p=0.03).15 With 
longer follow-up, the authors found no difference in regional control but significant 
improvements in grade 3 dysphagia at 6 months and borderline improvement at 2 years 
(p=0.065).16 
  
 
 
Risk of disease in level IB (submandibular nodes) 
 
 
The second issue is the probability of any microscopic disease in a given lymph node 
level, because if that risk is sufficiently low, no irradiation is required at all. Although the original 
IMRT experience treated all lymph node stations in the neck to parallel older irradiation 
techniques, there is now a substantial volume of pathologic and radiotherapeutic data supporting 
a very low risk of occult disease in radiologically-negative regions. Several surgical series have 
shown a low risk of disease in ipsilateral level IB in oropharyngeal cancer. For example, 
Sanguineti et al showed that out of 91 patients with resected, HPV-positive oropharyngeal cancer 
with a lymph node 10 mm or smaller in level IB, the risk of level IB pathologic involvement was 
2.5%.17 In a surgical series of 104 oropharyngeal patients who underwent neck dissections, there 
were no occult metastases to level IB.18  
 
Parallel surgical studies in larynx cancer confirm similar patterns of disease. dos Santos 
et al performed 100 consecutive dissections for patients with T3-4 or N1-N2c disease, and only 2 
(2%) patients had level I involvement.19 Mercante et al dissected 150 patients with larynx and 
hypopharynx cancer, finding no patients with level IB disease. 20 
 
Primary radiation-based series also show a very low risk of microscopic disease in level 
IB. Tam et al reported on 125 node-positive OPSCC patients from Memorial Sloan-Kettering 
Cancer Center treated with bilateral submandibular sparing radiotherapy, including 26% T3-4 
disease and 76% N2b or N2c, finding no submandibular recurrences .21 In a very large patterns-
of-failure study, Kjems study excluded level IB in the IMRT for all oropharyngeal and laryngeal 
cancers (unless it was clearly involved or the oral cavity was involved), and there was only 1 
oropharyngeal patient (out of 469) and no larynx patients (out of 253) with a level IB recurrence 

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when it wasn’t initially included in the field.22 Thus excluding level IB from the treatment field is 
extremely reasonable in the absence of overt involvement or oral cavity extension. 
 
 
Risk of disease in level V (posterior neck nodes) 
 
 
The risk of level V disease is similarly low, and in fact, it is often not dissected in 
oropharyngeal cancer. The absolute risk of level V disease in Sanguineti et al was only 2.6%.17  
Naiboglu et al. reported on the nodal pathology of 107 patients (43 oropharynx, 16 larynx) who 
underwent level V neck dissection.23 Although level V was involved in 13 patients (12.1%), it was 
only positive when nodes in levels II-IV were positive. Similarly, Spriano et al dissected 346 
clinically N0 necks in patients with larynx cancer, and only 10 out of 604 (1.6%) level V nodes 
were involved.24 In a node dissection study including 72 OPC and LXC patients, only 1 patient 
had a positive level V (1.4%) node without other nodes also being involved.25  
 
Mohindra et al reported on a series of 35 patients with oropharyngeal cancer treated with 
radiotherapy in which level V was spared ipsilaterally, and there were no recurrences in this 
echelon.26 In the Kjems study, in which level V in OPC or LXC was only included if obviously 
involved, there were no level V recurrences.22 
 
The preponderance of extant data thus supports sparing level V as well if that side has a 
low burden of nodal disease. Thus we would only treat level V if the patient has 2 or more 
involved nodes on a given side.   
 
 
Risk of disease in level IV (low neck nodes) 
 
Level IV lymph nodes start at the cricoid and extend inferiorly into the supraclavicular  
fossa. Although they are nearly always included in the typical irradiation field, the surgical data 
actually suggests the risk is very low if the (superior) level III is uninvolved. For example, 
Sanguineti et al showed that the risk of occult level IV disease was just over 2.5% when level III 
lymph nodes were 8 mm or less.17 This estimate was supported by an oropharyngeal cancer 
surgical series from Lim et al, in which there were only 3 occult level IV metastases out of 104 
necks, and all three occurred in combination with level III metastases.18 In a similar report from 
Lodder et al from Erasmus Medical Center, there was only 1 skip metastasis to level IV alone out 
of 92 oropharyngeal neck dissections.27 Chone et al performed a prospective study of results 
from laryngeal cancer neck dissections, finding that while 25% of 54 necks had level IV disease, 
they only were positive if level II or III was positive.28 Similarly, Lim et al reported on 72 clinically 
N0 neck dissections, finding that only 3.5% of all necks contained level IV disease, all of which 
were ipsilateral, and there were skip metastases to level IV in only 2 necks (1.4% of all necks).29 
As perhaps the best evidence that sparing level IV is oncologically sound, Kjem et al routinely 
spared level IV if level III was not clinically involved in OPC and LXC, and there were no solitary 
level IV recurrences.22  
 
 
University of Chicago experience 
 
 
As one final supporting example to motivate this study, investigators at the University of 
Chicago performed a prospective phase II study titled RAVD (response-adapted volume de-
escalation), in which all patients received 2 cycles of induction chemotherapy,  and good 
responders (50% or greater) received treatment just to the gross disease, without elective 
irradiation.30 It’s notable that the investigators used a large margin on gross disease (1.5 cm), 
presumably encompassing neighboring microscopic disease, but this group received no 
intentional elective irradiation. Patients without a good response received 45 Gy to the first 
uninvolved nodal echelon and then a boost to 75 Gy to gross disease plus 1.5 cm. No other 
elective nodal stations were irradiated. Of the 93 patients, 71 had OPC, and 7 had LXC. Much of 
the neck was still spared, even in poor responders. Since the majority (72%) of patients had 
ipsilateral disease, most patients did not receive contralateral levels III and IV irradiation, and 
several presumably did not receive any contralateral RT at all. Despite this somewhat radical 
change in treatment fields, there were no solitary nodal failures. There were 13 locoregional 

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recurrences and only one out-of-field failure, which occurred simultaneous to an in-field 
recurrence.  
 
 
Hypopharynx cancer 
 
 
The hypopharynx has non-trivial differences in regional spread, especially with respect to 
the retropharyngeal nodes, level V and level VI. One challenge is that hypopharyngeal cancer is 
typically treated with non-surgical therapy, and therefore we have fewer pathologic data on which 
we can establish typical patterns-of-spread. 
 
 
Retropharyngeal nodes 
 
 
There are a handful of studies that have identified the risk of occult retropharyngeal 
disease in hypopharynx cancer. Yoshimoto et al31 performed retropharyngeal dissections in 366 
patients, finding involved nodes in 54 (14.8%); risk was highest for tumors involving the posterior 
pharyngeal wall (37.3%), especially contralaterally. Importantly, however, only 9 positive nodes 
were undetectable on preoperative imaging, meaning a false-negative risk of only 2% (without 
PET imaging). In another large surgical series, Wu et al dissected 218 hypopharyngeal patients, 
finding an overall pathologic retropharyngeal involvement risk of 17%;32 pharyngeal wall tumors 
had the highest risk (36.4%), and it was significantly lower for piriform sinus cancer (11.2%). 
Node number and size were strongly correlated with involvement. Finally, in Kjems et al, the 
authors only treated the retropharyngeal nodes if the posterior wall was involved, and out of 112 
hypopharynx patients, there was only ONE retropharyngeal failure, and that patient 
retrospectively had pharyngeal wall involvement. These results are reassuring that sparing the 
contralateral RP nodes for non-pharygeal wall tumors is reasonable in patients without any 
evidence of nodal disease on imaging.  
 
 
Level VI  
 
 
There are unfortunately few data that characterize the risk of pathologic involvement of 
level VI in hypopharynx cancer. For example, Chung et al found that out of 68 hypopharynx 
patients who underwent level VI dissection, it was positive in nearly 28% of them, most 
prominently in individuals with pyriform sinus involvement (23.1%) and posterior pharyngeal wall 
(50%).33 That same institution looked more carefully at 68 pyriform sinus patients, confirming a 
non-trivial risk of level VI involvement (16.2%), but the risk of contralateral disease was very low 
for lateralized tumors (5.2%).34  
 
 
Level V 
 
 
Level V  is classically considered a primary draining zone for hypopharyngeal cancer, 
although the pathologic studies are surprisingly spare. Chung also reported on level V 
involvement in his series, finding that 11 patients (out of 68,16%) had involved nodes, but none 
contralaterally.33 In a retrospective cohort of patients 174 patients with hypopharynx cancer who 
underwent bilateral lymph node dissection, ipsilateral level V was involved in 32 patients (18% of 
total), but there was no ipsilateral (0/34) or contralateral (0/21) level V involvement for clinical 
N0.35 Therefore, sparing the contralateral level V appears to be an oncologically sound approach 
provided that side is otherwise negative. 
 
 
 
Summary points 
 
1. Many organs-at-risk border elective treatment volumes rather than gross disease. 
 
2. Solitary elective volume failures are extremely rare (0-5%). 
 

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3. 50 Gy to the elective regions is sufficient to sterilize microscopic disease and may 
even be too high, as randomized data suggest 40 Gy may be adequate. 
 
4. Failures in elective nodal regions occur in previously identified, radiologically-
negative, lymph nodes, as opposed to tissue without any prior evidence of a “benign” 
node. 
 
5. Occult disease in level IB is extremely rare. 
 
6. Occult disease in level V is extremely rare (in oropharynx and larynx cancer) if levels 
II-IV contain minimal disease.  
 
7. Occult disease in level IV is extremely rare in larynx and hypopharynx cancer if level 
III is uninvolved, and in general, as shown by the University of Chicago study, skip 
metastases (i.e. level III is involved without prior level II involvement) are very 
unusual. 
 
8. For hypopharynx cancer, contralateral retropharyngeal, level V and level VI disease 
is very uncommon in a clinically negative neck, unless the pharyngeal wall is 
involved.  
 
 
 
INFIELD  
 
 
Given these preliminary data, we performed a prospective phase II study of elective 
volume and dose de-escalation, called INFIELD (clinicaltrials.gov identifier NCT 03067610), from 
January 2017 through November 2018. Patients with oropharyngeal and laryngeal cancer were 
enrolled, with the nodal CTV dose lowered to 40 Gy, with the elective volumes reduced 
substantially, determined by the expected patterns-of-spread for these disease sites. Over 70 
patients were enrolled, and thus far there have been no solitary elective failures, either in 
the 40 Gy volume or in regions that were not treated. Therefore, thus far this study has met 
its primary endpoint and the paradigm is considered a success. Although follow-up is 
relatively short, the fact is that untreated cancer would be expected to recur quickly, and 
that has not been seen. Patient reported outcomes appear very favorable, although we 
have not formally analyzed them. The next natural question is whether any elective nodal 
dose is required.  
 
 
 
 
INVOLVED NODAL RADIOTHERAPY 
 
 
The INFIELD protocol implemented an approach in radiotherapy called involved-field 
radiotherapy (IFRT). In contrast to conventional head and neck radiotherapy, in which the 
majority of the neck receives an elective/prophylactic dose of radiotherapy, with IFRT, only lymph 
node basins perceived to be at a significantly higher risk of occult disease are irradiated. The 
transition to from large-field radiotherapy to progressively smaller-field radiation treatment has 
been most pronounced in lymphoma, in which the current radiotherapy fields have moved even 
smaller than IFRT to involved-site radiotherapy (ISRT) or involved nodal radiotherapy (INRT); the 
difference between these two is relatively trivial. In INRT, only the involved lymph nodes are 
irradiated, not a more general volume to treat microscopic disease. In lung cancer as well, only 
the involved nodes are treated, and mediastinal nodal stations are not electively irradiated.  
 
The potential benefit of INRT in head and neck cancer is profound, as significantly less 
dose is delivered to normal tissue. Below is a comparison of the INFIELD regimen with the INRT 
regimen, highlighting the significant difference in intermediate (40-60 Gy) and low dose radiation 
(< 40 Gy) (Figure 1). 
 

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INFIELD 
Involved nodal radiotherapy (INRT) 
Figure 1.The RED color reflect 70 Gy; YELLOW 60 Gy; BLUE 40 Gy, and WHITE 20 Gy.  
While the volumes receiving 70 Gy are comparable, 
  the volume receiving 40 Gy and no dose are much less with INRT. 
 
 
 
IDENTIFYING SUSPICIOUS LYMPH NODES FOR INRT TREATMENT 
 
Inherent in this treatment paradigm is the required confidence in the definition of a “negative” 
lymph node that does not require treatment. We have therefore created an algorithm that is 
extremely sensitive for detecting occult nodal disease. We will use three distinct criteria for the 
nodal target delineation: 
 
1. PET-CT results. The INFIELD study used the “Hopkins criteria” to define a lymph node as 
suspicious, in which the lymph node is compared to the neighboring jugular vein. Prior work 
has repeatedly shown that this approach yields a negative predictive value (NPV) over 90%, 
if not over 95%.36,37 The multi-institutional ACRIN 6685 study has further confirmed this 
result, and it has further shown a NPV over 95% if the lymph node SUV max is less than 
3.5.38 Therefore, our criteria to treat a node as involved or suspicious if it meets the Hopkins 
criteria or has an SUV over 3 is very conservative. 
 
2. Neck CT results (on CT simulation). Tradiational anatomic criteria for involvement include a 
short-axis length of 1.5 cm for level II nodes, 1 cm for levels 3-5 nodes, and 8 mm for 
retropharyngeal nodes. In this study, we will treat any node whose cross-sectional diameter 
in any dimension is 17 mm or greater, or if ANY sized retropharyngeal or level VI node is 
seen (level VI for hypopharynx patients only). Moreover, any degree of contrast enhancement 
will mandate treatment. Finally, any identified node, regardless of what it looks like, may be 
treated as suspicious if it is in the same level as an involved node. 
 
3. Our department has created the Medical Artificial Intelligence and Automation Lab (MAIA), 
whose mission is to innovate, develop, and apply artificial intelligence (AI) technologies to 
solve medical problems. Under Dr. Jing Wang’s direction, investigators have developed a 
published, multi-objective artificial intelligence radiomics (AIR) model using CT and PET-CT 
to predict outcomes following radiotherapy.39,40 
 
For this protocol, Dr. Wang (co-I in this project) has performed a retrospective analysis of 129 
patients who underwent surgery for oropharynx and larynx cancer, with a total of 543 
harvested nodes (413 benign/130 malignant). The location of each node was anatomically 
mapped according to preoperative imaging and the operative/pathology report. The goal of 
this study was to use their established AI process to develop a tool that can further facilitate 
the identification of malignant lymph nodes. 
 

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Seventy percent of this set was used for AI training, and the remaining 30% was used for 
validation. Dr. Wang has developed this algorithm to optimize the sensitivity and reduce 
false-negatives.  The results were superb, as the model achieved an area under the curve 
(AUC) of 0.98, with a sensitivity of 95%, specifity of 85%, and negative predictive value of 
98%: 
 
 
 
 
 
4. Therefore, for this study, involved nodes (receiving 70 Gy) will be identified using the 
previously established INFIELD criteria and suspicious nodes (receiving ~66 Gy) will be 
identified if any criteria from PET, CT or AIR are met to indicate potential involvement. Based 
on the established sensitivity and negative predictive value of PET and CT (in sum, greater 
than 95%), we believe that those two modalities alone would be sufficient for this study. 
However, to be especially cautious and conservative, we will employ the AIR model to further 
improve the negative predictive value.  
 
 
 
TRANSORAL RESECTION 
 
The current NCCN guidelines specify that patients with clinical T1 or T2 disease without adverse 
features (specifically, positive margins, pT3/4, PNI or LVI) can be treated with transoral resection 

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(TOR) alone without adjuvant radiotherapy, provided there are no indications for neck treatment, 
such as extranodal extension.41 This approach has been borne out by retrospective data, with a 
local failure risk less than 3% following surgery alone in a large, recent analysis by the Mayo 
Clinic as well as in a prospective series from University of Pennsylvania.42,43 In addition, sparing 
the primary site alone for low-risk disease was shown to be viable in a recently published 
retrospective study of 40 patients.44 
 
This clinical approach has already been implemented in some tertiary care centers as their 
standard-of-care. For example, Sinha et al. from Washington University in St. Louis reported on 
92 patients with resected T1-2 disease treated with TOR alone to the primary site (i.e. no 
radiotherapy to the primary), finding an absolute local recurrence risk of only 3%, and a 5 year 
locoregional-free survival of 94%.45  
 
Therefore, in this study, at physician and patient discretion, patients with small-volume 
oropharyngeal cancer (clinical T1-2) may undergo TOR without neck dissection prior to 
radiotherapy or chemoradiotherapy. If the pathologic results would support surgery alone as 
definitive therapy alone for this primary lesion (i.e. no LVI, no PNI, and negative margin [> 1 mm, 
or initially negative but < 1 mm with subsequent re-resection]), the primary will be avoided by the 
radiation treatment; otherwise, the primary resection bed receives standard postoperative dose 
and volume. The neck is then treated with radiotherapy/chemoradiotherapy per protocol.   
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To determine the risk of solitary elective volume recurrence following elective 
volume reduction using INRT. 
 
2.1.1.1 Definition: solitary means that the recurrence occurred without a 
preceding or synchronous in-field or distant recurrence 
2.2 
Secondary Objectives           
 
 
2.2.1  
Comparison of SEVR risks by p16 status and anatomic site 
 
2.2.2 
To determine patient-reported outcomes (PRO) following treatment with INRT. 
 
2.2.3 
To describe the rates of grade 3 and 4 acute and late toxicities following 
treatment with INRT. 
 
2.2.4 
To estimate the rates gastrostomy dependence at 3, 6, 12 and 24 months 
following treatment with INRT. 
 
2.2.5 
To characterize patient utilities following treatment with INRT.  
 
2.2.6 
To determine 2-year overall and progression-free survival following treatment 
with INRT.  
 
2.2.7 
To describe the patterns-of-failure following INRT. 
 
  
 
 

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2.3 
Endpoints 
 
2.4.1 
Primary endpoint: 2-year crude risk of solitary elective volume recurrence 
(SEVR) following INRT. 
 
2.4.2 
Secondary endpoints:  
 
2.4.2.1       Comparison of SEVR risks by p16 status and anatomic site. 
 
2.4.2.2 
Patient-reported outcomes: Difference in PRO measures between 
baseline and 1, 3, 6, 12, 18 and 24, and 36 months following 
treatment: 
 
o 
EORTC QLQ-C30 Summary score 
o 
EORTC QLQ-C30 Physical and role functioning subscales 
o 
EORTC HN35 Dry mouth and sticky saliva subscales 
o 
MDADI global, emotional, functional and physical subscales 
o 
EQ-5D global score (0-100) 
 
2.4.2.3 
Rate of grade 3-5 acute (start of treatment through 90 days from the 
completion of treatment) and late (after 90 days from the completion 
of treatment) adverse events, according to NCI’s CTCAE v4.0 
toxicity criteria.  
 
 
 
2.4.2.4 
Prevalence of gastrostomy-dependence at 3, 6, 12 and 24 months 
from the end of treatment. 
 
2.4.2.5 
Average patient utilities (derived from EQ-5D) at baseline, 3, 6, 12, 
18, 24 and 36 months from the end of treatment. 
 
 
2.4.2.6 
Overall survival probability at 2 years from the start of treatment 
 
2.4.2.7 
Progression-free survival probability at 2 years from the start of 
treatment 
 
2.4.2.8 
Cumulative incidence of locoregional recurrence at 2 years, with 
death as a competing risk 
 
 
2.4.2.9 
Cumulative incidence of distant metastasis at 2 years, with death 
and prior locoregional failure as competing risks 
 
3.0 
Subject ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
 
3.1.1 
Pathologically-proven diagnosis of squamous cell carcinoma of the oropharynx, 
larynx, or hypopharynx. Squamous cell carcinoma of unknown primary is not 
allowed.  
 
3.1.2 
Patients must have clinically or radiographically evident measureable disease at 
the primary site and/or nodal stations. Diagnostic lymph node excision (< 2 
nodes) is also allowable. 

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3.1.3 
Patients may undergo a diagnostic or therapeutic transoral resection for a T1-2 
tonsil or base of tongue cancer. 
 
3.1.4 
Clinical stage I-IVB (AJCC, 7th edition); stages I-II glottic cancer are excluded 
 
3.1.5 
Age ≥ 18 years. 
 
3.1.6 
ECOG Performance Status 0-2  
 
3.1.7 
Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for 90 days following 
completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
3.1.7.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
3.1.8 
Negative serum or urine pregnancy test within 2 weeks before registration for 
women of childbearing potential. 
 
3.1.9 
Neck CT and/or neck MRI, and PET-CT (at least skull-to-thigh). 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Distant metastasis. 
 
3.2.2 
Inability to undergo PET-CT. 
 
3.2.3 
Stage I and II glottic carcinoma. 
 
3.2.4 
Gross total excision of both the primary and nodal disease. 
 
3.2.5 
Synchronous non-skin cancer primaries outside of the oropharynx, larynx, and 
hypopharynx except for low- and intermediate-risk prostate cancer and 
synchronous well-differentiated thyroid cancer; in the latter case, surgery may 
occur before or after treatment, provided all other eligibility criteria are met . 
 
3.2.6 
Prior invasive malignancy  with an expected disease-free interval of less than  3 
years. 
 
3.2.7 
Prior systemic chemotherapy for the study cancer; prior chemotherapy for a 
remote cancer is allowable 
 

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3.2.8 
Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation fields.  
 
3.2.9 
Subjects may not be receiving any other investigational agents. 
 
3.2.10 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to the chemotherapy agents in this study (if necessary).  
 
3.2.11 Uncontrolled intercurrent 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, in the opinion of the 
investigator, would limit compliance with study requirements 
 
3.2.12 Subjects must not be pregnant or nursing due to the potential for congenital 
abnormalities and the potential of this regimen to harm nursing infants. 
 
3.2.13 History of severe immunosuppression, including HIV, and organ or autologous or 
allogeneic stem cell transplant. 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
The overall treatment approach (RT with or without systemic therapy) is defined by the AJCC 7 
stage and described as follows: 
 
• 
AJCC stage IVA, IVB or T3N0-1 stage III: radiotherapy with concurrent systemic therapy 
• 
AJCC stage III (T1-2 N1): radiotherapy with concurrent systemic therapy OR accelerated 
radiotherapy alone (6 fractions per week) 
• 
AJCC stage II: radiotherapy alone OR accelerated radiotherapy alone (6 fractions per 
week) 
• 
AJCC stage I: radiotherapy alone (5 fractions per week)   
 
There is controversy on how to manage T1-2 N1 head and neck cancer and either 
chemoradiotherapy or accelerated radiotherapy are viable approaches. It will be up to physician 
discretion as to which paradigm is applied to a given patient. The difference in the effective 
elective dose is expected to be trivial between these approaches.  
 
This treatment will consist of one course of 35 fractions, with 2 Gy per fraction delivered to gross 
disease, 1.9 Gy per fraction delivered to suspicious nodes, and 1.8 Gy per fraction delivered to 
the primary site.  
 
4.1.1 
Radiation Therapy  
 
4.1.1.2 CT simulation 
 
 
Patients will be simulated in a thermoplastic mask extending from the 
scalp through upper chest (e.g. “5 point mask”).  
 
 
IV contrast is recommended but not mandatory. 
 
4.1.1.3 Primary tumor delineation and targeting 
 

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The primary gross tumor volume (pGTV) will be contoured on the 
planning CT, using radiographic and clinical information to define its 
extent.  
 
 
The pGTV will be expanded by 5 mm to create the pPTV70.   
 
 
For patients with T1N0 OPSCC, pGTV plus 5 mm will create the 
pPTV66. 
 
4.1.1.4 Primary elective volume delineation and targeting. 
 
• 
INRT 
o 
The creation of the primary clinical target volume 
(pCTV1), which is the primary elective volume, is a multi-
step process. First, the pGTV will be expanded by 5-8 
mm. Then any contours in structures that are a natural 
barrier to spread (e.g. bone) will be deleted. The pCTV1 
is then expanded by 5-8 mm to create pPTV63. For 
hypopharynx and larynx patients, the entire hypopharynx 
and larynx may be included in the pCTV1 per physician 
discretion (such contouring is the current institutional 
standard). For tonsil tumors, the soft palate and/or 
ipsilateral base of tongue may be included in the pCTV1 
per physician discretion. 
 
 
 
 
4.1.1.5 Nodal tumor delineation and targeting. 
 
Visible lymph nodes will be categorized as benign, suspicious, or 
involved. By definition, a node is “involved” if it meets any of the following 
criteria: 
 
• 
Max SUV is greater than 3.0 (31) 
• 
The short-axis diameter is > 1.5 cm (level II), > 0.8 cm 
(retropharyngeal nodes or level VI), or > 1.0 cm for other nodal 
stations 
• 
The node shows central necrosis or ring enhancement 
• 
 
 
 
 
A node is “suspicious” if it doesn’t meet the above criteria, but: 
 
• 
The combined diameter of the lymph node is 17 mm (in any 
dimension) or more OR 
• 
The node has a rounded appearance or irregular borders  
• 
FDG uptake is greater than the adjvacent blood pool, OR 
• 
AIR defines the lymph node as involved/suspicious, OR 
• 
A retropharyngeal node is identified 
• 
A level VI node is identified in a tumor with hypopharyngeal 
involvement  
 
 
 
 
A node is “potentially suspicious” if: 
• 
It is in the same station as an involved node but doesn’t meet 
any of the above criteria. OR 
• 
It is in the same or adjacent station as a suspicious node 
and exhibits heterogeneous enhancement.  
 

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The nodal gross tumor volume (niGTV or nsGTV for involved or 
suspicious nodes) will be contoured on the planning CT, using 
radiographic and clinical information to define its extent. The nodes will 
be expanded by 5 mm to create the PTVs.  
 
Lymph node stations will be contoured according to RTOG consensus 
guidelines (description and atlas included at 
https://www.rtog.org/CoreLab/ContouringAtlases/HNAtlases.aspx)  
 
All involved nodes are treated to 70 Gy, with a 5 mm expansion to 
create the PTV70.  
 
Only involved and suspicious nodes must be treated. The dose for 
suspicious nodes is 66.5 Gy (1.9 Gy/fraction). The PTV66.5 is 
created by expanding the GTV by 5 mm, although it can be trimmed 
to 1 mm if abutting an organ-at-risk. 
 
Potentially suspicious nodes may be treated to 66.5 Gy at the 
discretion of the physician.  
 
Level IB lymph nodes are treated differently than other regions. All 
involved IB lymph nodes nodes are treated to 70 Gy. 
 
Level IB lymph nodes on the same side as an involved node: 
 
• 
Suspicious nodes are diagnosed by size or PET-CT 
characteristics; AI may be used at investigator discretion 
 
Level IB lymph nodes on the same side as a negative-neck (i.e. no 
involved nodes): 
 
• 
Suspicious nodes may be diagnosed by size or PET-CT 
characteristics; AI may be used at investigator discretion. It is 
acceptable not to include any suspicious IB nodes in an 
otherwise negative neck. 
 
 
4.1.1.6 Contours under special conditions 
 
 
4.1.1.6.1 Patients who have undergone a transoral resection 
may or may not receive adjuvant radiotherapy to the primary site. 
Patients with a final positive margin will receive 66.5 Gy to the 
resection bed. Patients with an initial margin > 1 mm, or initially 1 
mm margin with subsequent negative margins, AND without 
LVI/PNI, will not receive radiation to the primary site. All other 
patients will receive 63 Gy to the resection bed.  
 
4.1.1.6.2 If the patient underwent a diagnostic lymph node 
excision, the resection “bed” (where the previous lymph node(s) 
was) should be contoured as nsCTV. The nsCTV is then 
expanded by 5 mm to create nsPTV63 (no ECE) or nsPTV66.5 
(ECE). The PTV is trimmed by 3 mm inside skin to arrive at the 
final structure. 
 
 
4.1.1.6.3 Patients with T1-2 N0-1 tonsillar cancer without soft 
palate extension and base of tongue extension should receive 

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ipsilateral radiotherapy if there is no radiographic evidence of 
extracapsular extension and no involved nodes on the 
contralateral side.  
 
 
4.1.1.6.4 Patients with T1-2 N2a-b tonsillar cancer without soft 
palate extension and base of tongue extension, without 
radiographic evidence of ECE, and without contralateral involved 
nodes, may receive ipsilateral radiotherapy only after discussion 
with Principal Investigator Dr. Sher. 
 
 
4.1.1.6.5 Patients requiring a tracheostomy should  have the 
tracheostomy site included in the 63 Gy volume (pCTV1). 
 
 
4.1.1.7 Dose prescription  
 
 
 
The radiation treatment will be delivered in one course. 
 
Single course: All PTV’s receive prescribed dose.  
 
Summary of prescription doses (expansions for setup error are described in 
4.1.1.4 and 4.1.1.5) 
 
 
 
 
Structure 
Description 
Total dose (35 fractions) 
Primary 
tumor 
Gross primary disease 
70 Gy 
Elective 
primary  
volume 
Microscopic disease around 
primary tumor  
63 Gy 
Involved 
lymph nodes 
Gross nodal disease 
70 Gy 
Suspicious 
lymph nodes 
Lymph nodes of possible 
malignant potential  
66.5 Gy 
Elective 
lymph nodes 
Regions of microscopic 
nodal disease 
(0 Gy) 
Prescribed volumes under special conditions 
Primary 
resection 
bed, high-
risk 
Positive margins  
66.5 Gy 
Primary 
resection 
bed, 
intermediate-
risk 
T3-4,LVI,PNI, close margins  
63 Gy 
Primary 
resection 
bed, low-risk 
T1-2, no LVI, no PNI, initial 
margins > 1 mm or = 1 mm 
with an additional negative 
margin. 
0 Gy 
Lymph node 
excision 
bed, low-risk 
Resected lymph node bed 
without ECE 
63 Gy 
 
 
 
 
4.1.1.8  Treatment planning 

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Radiotherapy must be delivered using intensity modulated radiation therapy 
(IMRT). The IMRT may be implemented using any delivery platform, including 
volumetric modulated arc therapy (VMAT), step and shoot IMRT, or helical 
tomotherapy (HT). 
 
4.1.1.8.1 Coverage constraints 
 
All plans must be normalized such that 95% of the volume of 
each PTV is covered by the prescription dose.  
 
At least 99% of the volume of each PTV should receive 95% of 
the dose (i.e. V95 > 99%). 
 
The dose should not exceed 77 Gy anywhere in the plan.  
 
4.1.1.9.2 OAR constraints 
 
MANDATORY:  
Spinal cord: maximum point dose 45 Gy  
Spinal cord + 5 mm: maximum point dose < 54 Gy 
Brainstem: maximum point dose 54 Gy 
Brainstem + 5 mm: maximum point dose 60 Gy 
 
RECOMMENDED:  
Contralateral parotid: mean < 15 Gy 
Contralateral submandibular gland: mean < 30 Gy 
Cochlea: maximum < 40 Gy, mean < 20 Gy 
Oral cavity (must be 5 mm from PTV: mean < 20 Gy 
Constrictors (should exclude PTV from structure): mean < 20 Gy 
Post-arytenoid and cricoid space: mean < 10 Gy 
Cervical esophagus: mean < 10 Gy 
Ipsilateral superficial parotid: mean < 18 Gy 
Larynx (glottic larynx up to hyoid): mean < 20 Gy 
Ipsilateral masseter: mean < 20 Gy 
Contralateral masseter: mean < 15 Gy 
Brachial plexus: max 60 Gy unless in PTV70, where max 66 Gy 
Mandible: maximum point dose < 71 Gy, preferably < 66 Gy. 
Cerebellum: maximum dose < 45 Gy, mean < 15 Gy  
Temporal lobe: maximum dose < 40 Gy. mean < 5 Gy 
 
The standard names for these structures and compliance criteria are below. 
 
 
 
 
Name 
Per protocol 
Variation 
acceptable 
Variation 
unacceptable 
pGTV 
Not applicable 
 
 
pCTV63 
Not applicable 
 
 
niGTV70 
Not applicable 
 
 
nsGTV66.5 
Not applicable 
 
 
PTV70 
95% of PTV70 
covered by 70 Gy 
 
99% of PTV70 
covered by 66.5 
Gy 
None 
 
 
97% of PTV70 
covered by 66.5 Gy 
 
< 95% 
 
 
< 97% 
 
 

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Max hot spot < 75 
Gy 
Max hot spot < 77 
Gy 
> 77 Gy 
PTV66.5  
95% of PTV66.5  
covered by 66.5 
Gy 
93% of PTV66.5  
covered by 66.5 Gy 
< 93% 
 
PTV63  
95% of PTV63 
covered by 63 Gy 
93% of PTV63 
covered by 63 Gy 
< 93% 
 
Cord 
< 45 Gy 
< 50 Gy 
> 50 Gy 
Exp_Cord (Cord+5 
mm) 
< 54 Gy 
< 56 Gy 
> 56 Gy 
Brainstem 
< 54 Gy 
< 57 Gy 
> 57 
Exp_Brainstem 
< 60 Gy 
None 
None 
OARS 
Description 
See Section 4.1.9.2 for constraints 
Parotid_CL 
Contralateral parotid (defined by site of tumor) 
Parotid_IL 
Ipsilateral parotid 
Parotid_Sup_IL 
Ipsilateral superficial parotid 
SMG_IL 
Contralateral submandibular gland 
SMG_CL 
Ipsilateral submandibular gland 
Cavity_Oral 
Oral cavity 
PACS 
Post-arytenoid and cricoid space 
Cerv_esoph 
Cervical esophagus 
Larynx 
Larynx 
Mass_IL 
Ipsilateral masseter 
Mass_CL 
Contralateral masseter 
Mandible 
Mandible 
Plexus_R 
Right brachial plexus 
Plexus_L 
Left brachial plexus 
 
Cerebellum_R 
Right cerebellum 
Cerebellum_L 
Left cerebellum 
 
 
4.1.1.9 Treatment fractionation 
 
Patients receiving chemotherapy will receive one fraction per day, 5 days per 
week, for 35 fractions. Patients receiving cetuximab may be treated with 6 
fractions per week, since the original randomized study showing cetuximab leads 
to a survival benefit allowed this fractionation. Patients who miss more than 1 
planned treatment should make up the missed day(s) with a second daily fraction 
more than 6 hours apart. 
 
Patients receiving conventional radiotherapy alone will receive one fraction per 
day, 5 days per week, for 35 fractions (33 fractions if T1). Patients who miss 
more than 1 planned treatment should make up the missed day(s) with a second 
daily fraction more than 6 hours apart.  
 
Patients treated with accelerated radiotherapy with receive 6 fractions per week, 
for 35 fractions. The second daily fraction should be 6 hours or more after the 
first fraction. Patients who miss more than 1 planned treatment should make up 
the missed day(s) with a second daily fraction more than 6 hours apart (BID 
treatment). Patients may also receive a BID treatment to make up for a 4 day 
week (e.g. holiday).    
 

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Patient with a total treatment time 1-5 days beyond prescribed is an acceptable 
variation, and more than 5 days break is an unacceptable variation. The reasons 
for treatment break must be documented.  
 
 
4.1.1.10 
Treatment delivery 
 
Daily CBCT (cone-beam CT) or megavoltage CT must be used for patient set-up. 
 
 
4.1.1.11 
Re-planning  
 
If a patient loses a significant amount of weight on treatment, or the tumor 
contour changes substantially, repeat CT simulation and planning is allowed. 
However, the gross tumor volume may not be reduced due to tumor shrinkage. 
The original extent of disease must be included in the replanned GTV.  
 
4.1.1.12 
Documentation and quality assurance 
 
 
Every CT simulation scan with target and normal structures, as well as the 
radiation treatment plan, will be reviewed by Principal Investigator Dr. David Sher 
within 3 fractions of the initiation of treatment. 
 
4.1.2 Drug therapy 
 
Concurrent systemic therapy will be implemented per Section 4.1 . The specific agent is at 
physician discretion, choosing between cisplatin (bolus or weekly), cetuximab, and 
carboplatin-paclitaxel. All of these regimens are NCCN-endorsed. Although not preferred, 
weekly chemotherapy may start during week 2 of radiotherapy if the plan is still to deliver 
a total of 6 cycles, which is our institutional standard.  
 
 
4.1.2.1 Systemic therapy regimens 
 
4.1.2.1.1 Bolus cisplatin (every 3 weeks) 
 
4.1.2.1.2 Weekly cisplatin  
 
4.1.2.1.3 Weekly cetuximab 
 
4.1.2.1.4 Weekly carboplatin and paclitaxel 
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table in Section 5.4. Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
4.2.1 
Radiation therapy 
 
The dose constraints for radiation therapy are described in 4.1.1.9. No alterations in 
treatment doses are allowable per protocol.  
 
4.2.2 
Systemic therapy 
 

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The dose modifications for each systemic agent should be performed per the standard-
of-care at each local treating facility. Each regimen is considered a national standard-of-
care per NCCN guidelines. 
 
4.3 
Concomitant Medications/Treatments 
Supportive medications may be given at any point during the treatment course at the 
discretion of the treating physicians.  These medications include: 
 
• 
Anti-emetics 
• 
Non-opiate and opiate pain medications 
• 
Antidiarrheals 
• 
Nutritional supplementation 
• 
Anti-depressants 
 
 
 
The use of anti-oxidant vitamins is prohibited. 
4.4 
Other Modalities or Procedures 
 
Gastrostomy tubes are optional for patients on this study.  
 
Physicians should attempt to avoid gastrostomy if patients are receiving radiotherapy 
alone OR ipsilateral radiotherapy (with or without concurrent systemic therapy). 
 
However, gastrostomy tubes are strongly recommended in the following scenarios: 
 
• 
More than 10% body weight loss prior to diagnosis (prophylactic) 
• 
Treatment with chemoradiotherapy and BMI < 25 (prophylactic) 
• 
More than 10% body weight loss on treatment (reactive) 
 
The gastrostomy tube should be removed after patients maintain a stable or increasing 
weight for 2 weeks without enteral supplementation. 
4.5 
Duration of Therapy 
Protocol therapy will end under the following conditions: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Subject  decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the subject  
unacceptable for further treatment in the judgment of the investigator”. 
4.6 
Duration of Follow Up 
 
Patients will be followed for 3 years from the completion of treatment. 
4.7 
Removal of Subjects from Protocol Therapy 
Subjects  will be removed from therapy when any of the criteria listed in Section 5.5 
apply. Notify the Principal Investigator, and document the reason for study removal and 
the date the subject  was removed in the Case Report Form. The subject should be 
followed-up per protocol.  

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4.8 
Subject Replacement 
Subjects may be replaced in the study if they do not complete radiotherapy. Because this 
treatment is less intensive than conventional radiotherapy, we do not feel that treatment 
non-compliance is a risk of the protocol therapy. However, inadequate receipt of 
treatment may lead to a spuriously high recurrence rate, and therefore these patients 
may be replaced.   Patient replacement must be verified through review of the case by 
Principal Investigator Dr. Sher.   
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 30 days prior to registration unless 
otherwise stated. The screening procedures include: 
 
Informed Consent 
 
Medical history 
  Complete medical and surgical history  
 
Demographics 
 
Age, gender, race, ethnicity 
 
Review subject eligibility criteria 
 
Review previous and concomitant medications 
 
Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, blood pressure), height, weight 
 
Performance status 
Performance status evaluated prior to study entry according to Appendix B. 
 
Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for Adverse Event 
monitoring and reporting. 
 
Pregnancy test (for females of child bearing potential) 
  See section 3.1.7.1 for definition.  
 Tumor assessment 
 
  Patients must have dedicated neck imaging (neck CT with intravenous contrast    
                                          is preferred, although neck MRI with or without contrast, or CT without contrast           
                                          are acceptable), and PET-CT (at least skull to mid-thigh).  
 Completion of PRO instruments (before start of radiation            
treatment) 
 
EORTC QLQ-30 
 
EORTC HN35 

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MDADI 
 
EQ-5D  
5.2 
Procedures During Treatment 
 
During each week of radiotherapy  
• Vital sign 
• Physical exam, radiation oncologist 
• Assessment of performance status 
 
5.3 
Follow-up Procedures 
 
Patients will be seen by the treating radiation oncologist at 1 month (+/- 1 week) and 11-
14 weeks from the completion of treatment. More frequent visits are encouraged if the 
patient requires additional help with recovery and rehabilitation.  
 
Restaging PET-CT must be performed between 11-14 weeks from the completion of 
treatment. The patient must see an otolaryngologist after the PET-CT to decide on post-
treatment neck dissection per the surgeon’s judgement.  
 
Patients will then be seen every 3 months from the end of treatment (+/- 2 weeks) for the 
first year, and then at least every 6 months (+/-2 weeks) until the 36 month mark. 
Subsequent and intervening follow-up visits will be made per physician preference.  
 
Dedicated neck imaging will be performed at 6, 12, 18, 24 months and 36 months 
following treatment, to minimize the risk of missing occult residual disease. Clinical 
follow-up and management of these findings will proceed according to physician 
judgement.  
 
 

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25 
 
5.4 
Time and Events Table  
 
5.4.1 
Pre-treatment assessments 
  
 
Assessments 
Time Points 
 
<30 days prior to  registration 
Histological or Cytological Confirmation of 
Tissue Diagnosis 
At any point prior to registration 
History and physical with weight and Vital 
Signs 
 
X 
Performance Status 
X 
Dedicated neck imaging 
X (prior to registration) 
PET-CT (at least skull to thigh) 
X (within 2 months of registration) 
Serum or urine pregnancy test (if applicable) 
X 
Adverse event assessment 
X (baseline) 
Patient reported outcome assessment 
• 
EORTC QLQ-C30 
• 
EORTC HN35 
• 
MDADI 
• 
EQ-5D 
X (before first radiation treatment) 
 
5.4.2 
Assessments during treatment 
 
  
Assessments 
Time points 
 
Weekly during radiation treatment 
History and physical with weight and 
vital signs 
X 
Performance Status 
X 
Adverse event assessment 
X (during last week of treatment)** 
** Since adverse events are almost always cumulative, it is more efficient and accurate to wait until the last week (+ 2 weeks) to 
identify and score on-treatment adverse events. 
 
5.4.3.  Assessments following treatment 
 
Assessments 
Time Points (after treatment) 
History and physical with weight and 
vital signs 
X (1, 3†, 6, 9, 12, 18, 24, 30, 36 months)* 
Performance Status 
X (1, 3†, 6, 9, 12, 18, 24, 30, 36 months)* 
Adverse event assessment 
X (1, 3†, 6, 9, 12, 18, 24, 30, 36 months)* 

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PET-CT 
X (11-14 weeks) 
Otolaryngology consult 
Within 1 month of PET-CT completion 
Dedicated neck imaging (CT or MRI) 
X (6, 12, 18, 24, and 36 months) 
Patient reported outcomes 
• 
EORTC QLQ-C30 
• 
EORTC HN35 
• 
MDADI 
• 
EQ-5D 
 
 
X (1, 3, 6, 12, 18, 24, and 36 months)  
  † Visit should take place between 11 and 14 weeks from the completion of treatment.    
  * 1 month (+/- 1 week), 11-14 weeks, and subsequent follow up visits (+/- 2 weeks) are dated   
  from the completion of treatment. 
 
5.5 
Removal of Subjects from Study 
Subjects  can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject  demonstrates disease progression (unless continued treatment with 
local and/or systemic therapy is deemed appropriate at the discretion of the 
investigator); 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.7 
Subject  becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented and 
approved by the Data Monitoring Committee. 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect- Solid Tumors 
 
Because this protocol is treating known regions of cancer with standard-of-care 
radiotherapy doses, treatment response is not an endpoint of this study. 
 

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Rather, the secondary endpoints involve assessments of locoregional and distant 
recurrence, which will be defined in this section. 
 
Definitions 
 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with radiotherapy. 
 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with radiotherapy. 
 
Local recurrence (LR). Biopsy-proven cancer originating from the primary tumor 
(i.e. base of tongue, tonsil, soft palate, pharyngeal wall, or larynx). 
 
In-field local recurrence (IFLR). Local recurrence in which the > 50% of the 
recurrent disease is within the 95% isodose line of the PTV 70. 
 
Elective volume local recurrence (EVLR). Local recurrence that is not an IFLR 
AND > 50% of the recurrent disease is within the 95% isodose line of the PTV 
63/PTV62.5.    
 
Out-of-field local recurrence (OFLR). Local recurrence that is not an IFLR or 
EVLR 
 
Regional recurrence (RR). Biopsy-proven cancer in a lymph node basin above 
the clavicles. 
 
In-field regional recurrence (IFRR). Regional recurrence in which > 50% of the 
recurrence disease is within the 95% isodose line of the PTV 70 (or PTV 66 for a 
suspicious lymph node).  
 
Elective volume regional recurrence (EVRR). Regional recurrence that is not an 
IFRR but would have been in a standard elective neck. 
 
Out-of-field regional recurrence (OFRR). Regional recurrence that is not a IFRR 
or EVRR. 
 
Distant metastasis (DM). Recurrent cancer below the clavicles. Biopsy is strongly 
recommended but not mandated. If biopsy is not obtained, the initiation of anti-
cancer therapy is assumed to indicate metastasis, with the date of scan 
prompting therapy serving as the date of metastasis.   
 
 
Definition of progression 
Local and regional progression require biopsy confirmation, which will be used as 
the date of progression. 
 
Biopsy confirmation of metastatic disease is strongly preferred, but otherwise 
consensus clinical opinion based on radiologic and clinical findings is acceptable.     
 
 
Solitary elective volume regional recurrence (SEVR) 
Solitary elective volume regional recurrence (SEVR) is the development of an 
EVRR, or OFRR in the absence of prior or synchronous LR, IFRR, IFRR or DM.  

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Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression (LR, RR, or DM) or death. 
 
Overall survival 
Overall survival (PFS) is defined as the duration of time from start of treatment to 
time of progression (LR, RR, or DM) or death. 
 
6.2 
Safety/tolerability 
 
 Analyses will be performed for all subjects having received at least one dose of study 
radiotherapy. The study will use the CTCAE version 4.0 for reporting of non-hematologic 
adverse events (http://ctep.cancer.gov/reporting/ctc.html). 
7.0 
ADVERSE EVENTS 
7.1 
Experimental Therapy (i.e. chemoradiotherapy) 
 
Contraindications 
 
There are no special contraindications for this study beyond typical 
contraindications to radiation therapy or chemotherapy (when indicated). 
 
Special Warnings and Precautions for Use 
 
 
 
None 
 
Interaction with other medications 
 
 
 
None 
 
Adverse Reactions 
 
Head and neck radiotherapy and chemoradiotherapy are associated with many 
acute and late side effects. Since this study is a de-intensified version of RT and 
CRT, by definition the treatment-related morbidities will either be the same or 
better than conventional treatment, include acute mucositis, dermatitis, pain and 
dysphagia, and late dysphagia, xerostomia, and soft tissue injury.  
 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. All adverse events after radiation 
treatment will be captured at the time of radiation oncology follow-up. Additionally, certain 
adverse events must be reported in an expedited manner to allow for optimal monitoring 
of subject  safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the adverse 

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29 
 
event return to baseline;  
➢ any abnormal laboratory values have returned to baseline;  
➢ there is a satisfactory explanation other than the study drug for the changes 
observed; or 
➢ death. 
 
 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporarily 
associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research.   
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Adverse Events will be reported as indicated by the appropriate following table (see 
below).    
 
 
 
Acute Adverse Events 
Adverse events occurring in the time period from the signing of the informed consent, 
through 90 days post treatment will be known as acute adverse events.  All acute 
adverse events will be assessed and reported as per below.   
 
 
 
Late Adverse Events  
 
Adverse effects occurring in the time period from the end of acute monitoring, to 36 
months post treatment, will be defined as late adverse events. These events will include 
all adverse events reported directly to a member of the study team and will be captured, 
assessed, graded and reported as appropriate.  
 
In addition, the study team will review encounters in the following select specialty 
categories relevant to study endpoints: radiation oncology, medical oncology, and 
otolaryngology. The queried encounters will be limited in scope based on categorization of 
events; namely, encounters that related to any head and neck or gastrointestinal event or 
problem. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 
specified in the protocol. Adverse events not specifically defined in the NCI CTCAE will 
be scored on the Adverse Event log according to the general guidelines provided by the 
NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 

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Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring 
for adverse and serious adverse events would be a serious adverse event, even if the 
event observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE 
truly fits this definition and NOT for hospitalizations associated with less serious events. 
For example: a hospital visit where a patient is admitted for observation or minor 
treatment (e.g. hydration) and released in less than 24 hours. Furthermore, 
hospitalization for pharmacokinetic sampling is not an AE and therefore is not to be 
reported either as a routine AE or in an expedited report. 
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 

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31 
 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.3 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the 
SCCC DSMC and/or HRPP 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment (alternatively, to the end of the acute adverse events reporting period as 
defined in section 7.2.1). Any event that occurs more than 30 days after the last dose of 
treatment (alternatively, during the late adverse event period as defined in section 7.2.1) 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
• 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities  
section of this protocol 
7.3.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer 
Center (SCCC) Data Safety Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for 
which the SCCC is the DSMC of record require reporting to the DSMC 
regardless of whether IRB reporting is required. All SAEs/UPIRSOs occurring 
during the protocol-specified monitoring period should be submitted to the SCCC 
DSMC within 5 business days of the PI or delegated study team members 
awareness of the event(s). In addition, for participating centers other than UTSW, 
local IRB guidance should be followed for local reporting of serious adverse 
events. 

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32 
 
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC 
DSMC Coordinator.  Hardcopies or electronic versions of the eIRB Reportable 
Event report; FDA Form #3500A forms, or other sponsor forms, if applicable; 
and/or any other supporting documentation available should be submitted to the 
DSMC Coordinator.  The DSMC Coordinator forwards the information onto the 
DSMC Chairman who determines if immediate action is required.  Follow-up eIRB 
reports, and all subsequent SAE/UPIRSO documentation that is available are also 
submitted to the DSMC Chair who determines if further action is required. (See 
Appendix III of the SCCC DSMC Plan for a template Serious Adverse Event Form 
which may be utilized when a sponsor form is unavailable and SAE submission to 
the eIRB is not required). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW 
Simmons Comprehensive Cancer Center, the DOT Manager or lead coordinator 
ensures that all participating sites are notified of the event and resulting action, 
according to FDA guidance for expedited reporting. DSMC Chairperson reviews 
all SAEs/UPIRSOs upon receipt from the DSMC Coordinator.  The DSMC 
Chairperson determines whether action is required and either takes action 
immediately, convenes a special DSMC session (physical or electronic), or 
defers the action until a regularly scheduled DSMC meeting. 
 
 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP/IRB 
 
UTSW reportable event guidance applies to all research conducted by or on 
behalf of UT Southwestern, its affiliates, and investigators, sites, or institutions 
relying on the UT Southwestern IRB. Additional reporting requirements apply for 
research relying on a non-UT Southwestern IRB. 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, 
outcomes, etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
Telephone reports to: 
 
Sarmistha Sen, Clinical Research Manager 
214-645-1477 
Written reports to: 
 
Department of Radiation Oncology 
Clinical Research Office 
The University of Texas Southwestern Medical Center 
Attention:  Sarmistha Sen, Project Manager 
2201 Inwood Road 
Dallas, Texas  75390-9303 
FAX #: 214-648-5923 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 

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33 
 
subject’s underlying condition or not expected as a risk of the study; 
therefore, not included in the investigator’s brochure, protocol, or informed 
consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized.  Note: According to OHRP, if the adverse 
event is serious, it would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device 
effects (UADEs) and death or serious injury related to a humanitarian use device 
(HUD).  
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of 
PI awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single 
IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf 
of UT Southwestern or its affiliates are responsible for submitting LOCAL 
UPIRSOs to the UT Southwestern IRB within 5 working days of PI awareness. 
Investigators must report to their relying IRB according to the relying IRB’s policy. 
In addition, the external IRB’s responses or determinations on these local events 
must be submitted to the UT Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, 
summarized, and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-
administration/irb/assets/policies-combined.pdf 
7.4 
Unblinding Procedures 
N/A 
7.5 
Stopping Rules 
 
Conditional power (CP) is the probability that the final study result will be statistically 
significant, given the data observed thus far and a specific assumption about the pattern 
of the data to be observed in the remainder of the study, such as assuming the original 
design effect, or the effect estimated from the current data, or under the null hypothesis. 
Conditional power will be computed when the first 30 INRT patients were followed for 2 
years. If the conditional power is less than 50%, the trial will be discontinued. 
 
8.0 
DRUG INFORMATION 
8.1 
Cisplatin  
 
• 
Other names for the drug(s): Platinol 
 
• 
Classification - type of agent: cytotoxic chemotherapy  

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34 
 
 
• 
Mode of action: The dominant mode of action of cisplatin appears to be inhibition of 
the incorporation of DNA precursors, although protein and RNA synthesis are also 
inhibited. Although this drug seems to act as an alkylating agent, there are data to 
indicate that its mode and sites of action are different from those of nitrogen mustard 
and the standard alkylating agents. 
 
• 
Storage and stability: Please refer to the cisplatin prescribing information for storage 
and stability of the cisplatin commercial product. 
 
• 
Protocol dose: Bolus or weekly 
 
Preparation: Please refer to the cisplatin prescribing information for storage and 
stability of the cisplatin commercial product. 
 
• 
Route of administration for this study: Intravenous 
 
• 
Incompatibilities: Cisplatin may interact with metal aluminium to form a black 
precipitate of platinum. All aluminium-containing IV sets, needles, catheters and 
syringes should be avoided. There is a total loss of cisplatin in 30 minutes at room 
temperature when mixed with metoclopramide and sodium metabisulphite in 
concentrations equivalent to those that would be found on mixing with a commercial 
formulation of metoclopramide. Cisplatin and sodium bisulphite have been known to 
react chemically. Such antioxidants might inactivate cisplatin before administration if 
they are present in intravenous fluids. 
 
• 
Availability: Commercially available 
 
• 
Side effects: Human toxicity includes nausea, vomiting, renal toxicity (with an 
elevation of BUN and creatinine and impairment of endogenous creatinine clearance, 
as well as renal tubular damage, which appears to be transient), ototoxicity (with 
hearing loss that initially is in the high-frequency range, as well as tinnitus), and 
hyperuricemia. Much more severe and prolonged toxicity has been observed in 
patients with abnormal or obstructed urinary excretorytracts. Myelosuppression, often 
with delayed erythrosuppression, is expected. Please see the package insert for a 
comprehensive list of adverse events. 
 
• 
Nursing implications: N/A 
 
Return and Retention of Study Drug 
N/A 
 
8.2 
 Cetuximab 
 
• 
Other names for the drug(s): Erbitux 
 
• 
Classification - type of agent: epidermal growth factor  receptor inhibitor monoclonal 
antibody.  
 
• 
Mode of action: Binding to the EGFR blocks phosphorylation and activation of 
receptor-associated kinases, resulting in inhibition of cell growth, induction of 
apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth 
factor production. 

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• 
Storage and stability: Please refer to the cetuximab prescribing information for 
storage and stability of the cetuximab commercial product. 
 
• 
Protocol dose: Loading and then weekly 
 
• 
Preparation: Please refer to the cetuximab prescribing information for the specific 
preparation of the cetuximab commercial product  
 
• 
Route of administration for this study: Intravenous 
 
• 
Incompatibilities:  Please refer to the cetuximab prescribing information for information 
about incompatibilities of the cetuximab commercial product 
 
• 
Availability: Commercially available 
 
• 
Side effects: Cetuximab may be associated with significant toxicities, most commonly 
fatigue, skin rash/folliculitis and paronychia, and gastrointestinal effects, nausea and 
diarrhea. Hypomagnesia is common. Of greatest concern is the potential for an 
allergic reaction, possibly anaphylaxis. Please see the package insert for a 
comprehensive list of adverse events. 
 
• 
Nursing implications: N/A 
 
Return and Retention of Study Drug 
N/A 
8.3 
Paclitaxel 
 
• 
Other names for the drug(s): Taxol 
 
• 
Classification - type of agent: cytotoxic chemotherapy  
 
• 
Mode of action: Microtubule inhibitor 
 
• 
Storage and stability: Please refer to the paclitaxel prescribing information for storage 
and stability of the paclitaxel commercial product. 
 
• 
Protocol dose: Weekly 
 
• 
Preparation: Please refer to the paclitaxel prescribing information for storage and 
stability of the paclitaxel commercial product. 
 
• 
Route of administration for this study: Intravenous 
 
• 
Incompatibilities: Please refer to the paclitaxel prescribing information for information 
about incompatibilities of the paclitaxel commercial product. 
 
• 
Availability: Commercially available 
 
• 
Side effects:  
o 
Hematologic: neutropenia, leukopenia, thrombocytopenia, anemia  
o 
Gastrointestinal: nausea/vomiting, diarrhea, mucositis  

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36 
 
o 
Hepatic: elevated liver function tests  
o 
Cardiac: heart block, bradycardia  
o 
Neurologic: peripheral neuropathy, arthralgia/myalgia  
o 
Dermatologic: alopecia, onycholysis  
o 
Reproductive: Infertility; may be teratogen  
o 
Miscellaneous: moderate–severe hypersensitivity reactions, flushing, rash, 
dyspnea, fatigue  
 
Please refer to the paclitaxel prescribing information for information about 
adverse events of the paclitaxel commercial product. 
 
• 
Nursing implications: N/A 
 
Return and Retention of Study Drug 
N/A 
 
8.4 
Carboplatin 
 
• 
Other names for the drug(s): Paraplatin 
 
• 
Classification - type of agent: cytotoxic chemotherapy  
 
• 
Mode of action: Second generation tetravalent organic platinum compound. Like 
cisplatin, carboplatin produces predominantly interstrand DNA crosslinks rather than 
DNA-protein crosslinks. Cell-cycle nonspecific. 
 
• 
Storage and stability: Please refer to the carboplatin prescribing information for 
storage and stability of the carboplatin commercial product  
 
• 
Protocol dose: Weekly  
 
• 
Preparation: Please refer to the carboplatin prescribing information for the specific 
preparation of the carboplatin commercial product 
 
• 
Route of administration for this study: Intravenous 
• 
Incompatibilities: Please refer to the carboplatin prescribing information 
for  information about incompatibilities of the carboplatin commercial 
product. 
 
• 
Availability: Commercially available 
 
• 
Side effects:  
o 
Hematologic: Thrombocytopenia, neutropenia, leukopenia, more pronounced 
in patients with compromised renal function and heavily pretreated patients; 
may be cumulative.  
o 
Gastrointestinal: Nausea and vomiting (less severe than with cisplatin), 
treatable with moderate doses of antiemetics.  
o 
Dermatologic: Rash, urticaria.  
o 
Hepatic: Abnormal liver function tests, usually reversible with standard 
doses.  
o 
Neurologic: Rarely peripheral neuropathy.  
o 
Renal: Elevations in serum creatinine, BUN; electrolyte loss (Na, Mg, K, Ca).  

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o 
Other: Pain, asthenia.  
• 
Miscellaneous: moderate–severe hypersensitivity reactions, flushing, 
rash, dyspnea, fatigue  
 
Please refer to the carboplatin prescribing information for information about 
adverse events of the carboplatin commercial product." 
 
• 
Nursing implications: N/A 
 
Return and Retention of Study Drug 
N/A 
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
 
 
NA 
 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
 Primary endpoint: 2-year crude risk of solitary elective volume recurrence 
(SEVR). 
 Secondary endpoints:  
10.1.2.1 Comparison of SEVR risks by p16 status and anatomic site. 
10.1.2.2 Patient-reported outcomes: Difference in PRO measures 
between baseline and 1, 3, 6, 12, 18, 24 and 36 months 
following treatment: 
10.1.2.3.1          EORTC QLQ-C30 Summary score 
10.1.2.3.2   
EORTC QLQ-C30 Physical and role functioning 
subscales 
 
10.1.2.3.3  
EORTC HN35 Dry mouth and sticky saliva 
subscales 
10.1.2.3.4  
MDADI global, emotional, functional and 
physical subscales 
10.1.2.3.5  
EQ-5D global score (0-100) 
 
10.1.2.4 
Rate of grade 3-5 acute (start of treatment through 90 days 
from the completion of treatment) and late (after 90 days 
from the completion of treatment) adverse events, according 
to NCI’s CTCAE v4.0 toxicity criteria.  
 
 
 
10.1.2.5 
Prevalence of gastrostomy-dependence at 3, 6, 12, 18, 24 
and 36 months from the end of treatment. 
 
10.1.2.6 
Average patient utilities (derived from EQ-5D) at baseline, 3, 
6, 12, 18, 24, and 36 months from the end of treatment. 
 
 
10.1.2.7 
Overall survival probability at 2 years from the start of 
treatment 
 

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10.1.2.8 
Progression-free survival probability at 2 years from the start 
of treatment 
 
10.1.2.9 
Cumulative incidence of locoregional recurrence at 2 years, 
with death as a competing risk 
 
 
10.1.2.10 
Cumulative incidence of distant metastasis at 2 years, with 
death and prior locoregional failure as competing risks 
 
10.1.3 Stopping rule 
 
Conditional power (CP) is the probability that the final study result will be statistically 
significant, given the data observed thus far and a specific assumption about the pattern 
of the data to be observed in the remainder of the study, such as assuming the original 
design effect, or the effect estimated from the current data, or under the null hypothesis. 
Conditional power will be computed when the first 30 patients are followed for 2 years. If 
the conditional power is less than 50%, the trial will be discontinued. 
 
10.2 
Sample Size and Accrual 
 
The primary hypothesis is that the risk of elective or out-of-field failure (i.e. in largely 
unirradiated tissue) is less than 10% more than the baseline risk. As a general rule, the 
10% threshold is used as a reason to irradiate a given region, which is why we chose this 
level. A sample size of 60 achieves a 90% power to detect a non-inferiority difference of -
0.1 using a one-sided exact test with a significance level (alpha) of 0.05. These results 
assume a baseline risk of 0.03 and that the actual difference is 0.0. The power of the 
study was computed using the sample size software PASS16.  
 
Note that patients who develop recurrent disease that is not SEVR are not censored, 
since those patients would not have benefitted from dose to the elective regions (since 
they failed elsewhere, regardless). The same logic holds for patients who die.  
 
With the conservative assumption of 10% loss to follow-up, the final sample size will be  
67 patients.  
 
10.3 
Data Analyses Plans 
 
10.3.1 Primary endpoint (SEVR in INRT patients) 
 
The crude risk of 2-year solitary elective volume recurrence will be calculated among 
patients who are followed for at least 2 years. Patients who die before 2 years without an 
SEVR will be included in the denominator, as are patients who developed a recurrence 
that is not a SEVR. A binomial 95% confidence interval will be calculated.  
 
10.3.2 Secondary endpoints 
 
10.3.2.1. Comparison of SEVR risks by p16 status and anatomic site 
 
Given the recognized difference in locoregional recurrence risk and survival 
between patients with p16-positive oropharyngeal cancer with p16-negative 
oropharyngeal cancer, we will perform several analyses on the risk of SEVR as a 
function of p16 status, as well as by anatomic site of origin. These comparisons 
will be important to confirm that the risk of solitary elective recurrence does not 

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39 
 
vary by histology or disease site. In addition to using SEVR as the endpoint, we 
will also include any elective volume recurrence as the outcome. These 
comparisons will include: 
 
• 
p16-positive versus p16-negative OPC 
• 
p16-positive, minimal smokers (< 10 pack-year) versus p16-positive 
smokers and p16-negative OPC 
• 
OPC versus larynx/hypopharynx site 
 
 
10.3.2.2 Patient reported outcomes 
 
Each of the patient reported outcomes are single numeric scores that are 
collected at baseline, 1, 3, 6, 12, 18, 24 and 36 months from treatment. Patients 
with disease recurrence will be excluded. The changes in these outcomes from 
baseline to these timepoints will be analyzed using generalized estimated 
equations (GEE).   
 
 
10.3.2.3 Toxicity 
 
Only adverse events assessed to be definitely, probably, or possibly related to 
protocol treatment will be considered. The rates of all Grade 3-5 adverse events, 
and death during or within 30 days of discontinuation of protocol treatment will be 
characterized. Predictors of high-grade acute and late toxicity will be determined 
using multivariable logistic regression.  
 
 
10.3.2.4 Gastrostomy dependence 
 
The prevalence of gastrostomy use at 3, 6, 12, 18, 24 and 36 months will be 
described. Predictors of gastrostomy-dependence will be determined using GEE.  
 
 
 
10.3.2.5 Patient utilities 
 
The average patient utilities (derived from EQ-5D) at baseline, 3, 6, 12, 18, 24 
and 36 months from the end of treatment will be described. Changes in patient 
utility will be analyzed using generalized estimated equations (GEE). These 
models will be used to estimate the beta coefficient for grade 2-3 xerostomia and 
grade 2-3 dysphagia, to produce an estimate of the utility decrement from this 
toxicity.  
 
 
 
10.3.2.6 Overall survival 
 
Overall survival outcomes will be estimated using the Kaplan-Meier approach. 
The Cox proportional hazard regression model will be used to determine hazard 
ratios and 95% confidence intervals for key covariates of interest, including age, 
T and N stage, and smoking status. Overall survival will be calculated from the 
initiation of treatment. 
 
 
 
10.3.2.7 Progression-free survival  
 

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Progression-free survival outcomes will be estimated using the Kaplan-Meier 
approach. The Cox proportional hazard regression model will be used to 
determine hazard ratios and 95% confidence intervals for key covariates of 
interest, including age, T and N stage, and smoking status. Progression-free 
survival will be calculated from the initiation of treatment. 
 
10.3.2.8 Locoregional recurrence and distant metastasis 
 
The cumulative incidence of locoregional and distant failure will be estimated 
using cumulative incidence statistics, with death serving as the competing risk.  
 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject  and by the person who conducted the 
informed consent discussion. 
11.3 
Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following documentation must be 
provided to the Research Office.  
 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list or Federal wide Assurance letter 
• 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 

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41 
 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: this is required if _ENREF_131 holds the IND. Otherwise, the affiliate 
Investigator’s signature on the protocol is sufficient to ensure compliance) 
• 
A copy of the IRB-approved consent form 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Executed clinical research contract 
11.4 
Registration Procedures 
Prior to registration, eligibility criteria must be confirmed with the research study 
coordinator and the enrolling physian. Signature of the eligibility checklist signifies 
enrollment to the study. 
 
Research staff will have online access to UTSW REDCap, and all patients will be 
registered  electronically through REDCap. The eligibility checklist and confirming 
documentation will be entered electronically through the system.  
 
All research data will be recorded and entered into Case Report Forms using REDCap 
(when applicable).  
 
 
                          The first number of the subject’s ID will refer to the treatment site. The ordering is: 
 
01: UTSW 
 
We will use this system in the future event of collaboration with other departments.  
 
New subjects will receive a secondary number beginning with 001 upon study consent 
such that the first subject consented is numbered 001, the second subject consented 
receives the number 002, etc. Upon confirmation of eligibility and enrollment as per the 
afore-mentioned instructions, the subject will be assigned a tertiary number in the order 
of enrollment.  
 
For example, the first patient consented and enrolled at UTSW will have the number 01-
001-101.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration/randomization code 
according to the numbering schema outlined above, which should then be entered as the 
patient study id in Velos upon updating the status to enrolled. 
 
The numbering schema should clearly identify the site number; the sequential number of 
the subject enrolled as well as the status of the subjects enrolled so that the number of 
subjects consented versus the number of subjects actually enrolled may be easily 
identified. 
  
11.5 
Data Management and Monitoring/Auditing 
REDCap is the UTSW SCC institutional choice for the electronic data capture of case 
report forms for this and all SCC Investigator Initiated Trials. REDCap will be used for 
electronic case report forms in accordance with Simmons Cancer Center requirements. 
 
Other institutions participating in this trial in the future as sub-sites will be expected to 
enter data into REDCap and upload de-identified source materials when instructed by the 

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42 
 
Simmons Cancer Center study team to facilitate remote source to case report form 
verification.  
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT, which includes 
but is not limited to accuracy of case report forms, protocol compliance, timeless and 
accuracy of Velos entries and AE/SAE management and reporting. Documentation of trial 
monitoring will be maintained along with other protocol related documents and will be 
reviewed during internal audit.   
 
For further information, refer to the UTSW SCCC IIT Management Manual. 
 
The UTSW Simmons Cancer Center (SCC) Data Safety Monitoring Committee (DSMC) 
is responsible for monitoring data quality and patient safety for all UTSW SCC clinical 
trials.  As part of that responsibility, the DSMC reviews all local serious adverse events 
and unanticipated problems in real time as they are reported and reviews adverse events 
on a quarterly basis.  The quality assurance activity for the Clinical Research Office 
provides for periodic auditing of clinical research documents to ensure data integrity and 
regulatory compliance.  A copy of the DSMC plan is available upon request. 
 
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as part 
of the DSMC to conduct regular audits based on the level of risk. Audit findings are 
reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of 
investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles.  
 
The Department of Radiation Oncology Clinical Research Office, UTSW, meets monthly 
to review adverse events for this protocol observed within the institution as well as all 
participating sites with evaluations that include attribution.  This information is forwarded 
to the SCC-DSMC as a resource for its determinations. 
 
The Radiation Oncology Clinical Research Office (CRO) reports serious adverse events 
(SAEs) to Radiation Oncology Safety Assurance Committee (ROSAC) monthly. The 
principal investigator and study coordinator will review the SAEs on a real time basis via 
email or meeting.  These SAEs are also reported to the University of Texas Southwestern 
Medical Center (UTSW) IRB per IRB guidelines and SCC DSMC.   
 
All clinical trials are reviewed on monthly basis for enrollment. A summary of adverse 
events will also be reviewed at the time of SAEs review during the monthly ROSAC 
meeting.   For investigator-initiated trials, all SAEs are monitored – both local and at 
affiliated institutions.   
11.6 
Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
• intentional on part of the investigator; or 

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43 
 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
➢ Reporting requirement: Exceptions are non-emergency deviations that require prospective 
IRB approval before being implemented. Call the IRB if your request is 
urgent. If IRB approval is not obtained beforehand, this constitutes a major 
deviation. 
 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
• avoid immediate apparent harm, or 
• protect the life or physical well-being of subjects or others 
➢ Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within 5 working days of occurrence. 
 Major Deviations (also called violations): include any departure from IRB-
approved research that: 
• 
Harmed or placed subject(s) or others at risk of harm (i.e., did or has the 
potential to negatively affect the safety, rights, or welfare of subjects or 
others), or 
• 
Affect data quality (e.g., the completeness, accuracy, reliability, or validity of 
the data) or the science of the research (e.g., the primary outcome/endpoint of 
the study) 
➢ Reporting requirement: Major deviations must be promptly reported to  
the IRB within 5 working days of PI awareness. 
 
 11.6.4   Minor Deviations: include any departure from IRB-approved research that: 
• 
Did not harm or place subject(s) or others at risk of harm (i.e., did not or did 
not have the potential to negatively affect the safety, rights, or welfare of 
subjects or others), or 
• 
Did not affect data quality (e.g., the completeness, accuracy, reliability, or 
validity of the data) or the science of the research (e.g., the primary 
outcome/endpoint of the study) 
➢ Reporting requirement: Minor deviations should be tracked and 
summarized in the progress report at the next IRB continuing review. 
11.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 

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44 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
11.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.0 
REFERENCES 
 
1. 
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2. 
Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated 
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Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of 
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Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either 
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Mar 1 2013;31(7):853-859. 
5. 
Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus 
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6. 
Sher DJ, Thotakura V, Balboni TA, et al. Treatment of oropharyngeal squamous cell carcinoma 
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7. 
Dandekar V, Morgan T, Turian J, et al. Patterns-of-failure after helical tomotherapy-based 
chemoradiotherapy for head and neck cancer: implications for CTV margin, elective nodal dose 
and bilateral parotid sparing. Oral oncology. May 2014;50(5):520-526. 
8. 
Garden AS, Dong L, Morrison WH, et al. Patterns of disease recurrence following treatment of 
oropharyngeal cancer with intensity modulated radiation therapy. International journal of radiation 
oncology, biology, physics. Mar 15 2013;85(4):941-947. 
9. 
Huang K, Xia P, Chuang C, et al. Intensity-modulated chemoradiation for treatment of stage III 
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Aug 1 2008;113(3):497-507. 
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Duprez F, Bonte K, De Neve W, Boterberg T, De Gersem W, Madani I. Regional relapse after 
intensity-modulated radiotherapy for head-and-neck cancer. International journal of radiation 
oncology, biology, physics. Feb 1 2011;79(2):450-458. 
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Bedi M, Firat S, Semenenko VA, et al. Elective lymph node irradiation with intensity-modulated 
radiotherapy: is conventional dose fractionation necessary? International journal of radiation 
oncology, biology, physics. May 1 2012;83(1):e87-92. 
12. 
Lambrecht M, Dirix P, Van den Bogaert W, Nuyts S. Incidence of isolated regional recurrence 
after definitive (chemo-) radiotherapy for head and neck squamous cell carcinoma. Radiotherapy 
and oncology : journal of the European Society for Therapeutic Radiology and Oncology. Dec 
2009;93(3):498-502. 
13. 
Studer G, Huber GF, Holz E, Glanzmann C. Less may be more: nodal treatment in neck positive 
head neck cancer patients. European archives of oto-rhino-laryngology : official journal of the 
European Federation of Oto-Rhino-Laryngological Societies. Jun 2016;273(6):1549-1556. 
14. 
van den Bosch S, Dijkema T, Verhoef LC, Zwijnenburg EM, Janssens GO, Kaanders JH. 
Patterns of Recurrence in Electively Irradiated Lymph Node Regions After Definitive Accelerated 
Intensity Modulated Radiation Therapy for Head and Neck Squamous Cell Carcinoma. 
International journal of radiation oncology, biology, physics. Mar 15 2016;94(4):766-774. 
15. 
Nuyts S, Lambrecht M, Duprez F, et al. Reduction of the dose to the elective neck in head and 
neck squamous cell carcinoma, a randomized clinical trial using intensity modulated radiotherapy 
(IMRT). Dosimetrical analysis and effect on acute toxicity. Radiotherapy and oncology : journal of 
the European Society for Therapeutic Radiology and Oncology. Nov 2013;109(2):323-329. 
16. 
Nevens D, Duprez F, Daisne JF, et al. Reduction of the dose of radiotherapy to the elective neck 
in head and neck squamous cell carcinoma; a randomized clinical trial. Effect on late toxicity and 
tumor control. Radiotherapy and oncology : journal of the European Society for Therapeutic 
Radiology and Oncology. Feb 2017;122(2):171-177. 

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17. 
Sanguineti G, Pai S, Agbahiwe H, et al. HPV-related oropharyngeal carcinoma with Overt Level II 
and/or III metastases at presentation: The risk of subclinical disease in ipsilateral levels IB, IV and 
V. Acta oncologica. May 2014;53(5):662-668. 
18. 
Lim YC, Koo BS, Lee JS, Lim JY, Choi EC. Distributions of cervical lymph node metastases in 
oropharyngeal carcinoma: therapeutic implications for the N0 neck. The Laryngoscope. Jul 
2006;116(7):1148-1152. 
19. 
dos Santos CR, Goncalves Filho J, Magrin J, Johnson LF, Ferlito A, Kowalski LP. Involvement of 
level I neck lymph nodes in advanced squamous carcinoma of the larynx. The Annals of otology, 
rhinology, and laryngology. Oct 2001;110(10):982-984. 
20. 
Mercante G, Bacciu A, Oretti G, Ferri T. Involvement of level I neck lymph nodes and 
submandibular gland in laryngeal and/or hypopharyngeal squamous cell carcinoma. The Journal 
of otolaryngology. Apr 2006;35(2):108-111. 
21. 
Tam M, Riaz N, Kannarunimit D, et al. Sparing bilateral neck level IB in oropharyngeal carcinoma 
and xerostomia outcomes. American journal of clinical oncology. Aug 2015;38(4):343-347. 
22. 
Kjems J, Gothelf AB, Hakansson K, Specht L, Kristensen CA, Friborg J. Elective Nodal Irradiation 
and Patterns of Failure in Head and Neck Cancer After Primary Radiation Therapy. International 
journal of radiation oncology, biology, physics. Mar 15 2016;94(4):775-782. 
23. 
Naiboglu B, Karapinar U, Agrawal A, Schuller DE, Ozer E. When to manage level V in head and 
neck carcinoma? The Laryngoscope. Mar 2011;121(3):545-547. 
24. 
Spriano G, Piantanida R, Pellini R, Muscatello L. Elective treatment of the neck in squamous cell 
carcinoma of the larynx: clinical experience. Head & neck. Feb 2003;25(2):97-102. 
25. 
Kainuma K, Yano T, Kitoh R, Naito T, Usami S. Prevalence of level V metastasis in head and 
neck squamous cell carcinoma. Acta oto-laryngologica. Feb 2013;133(2):218-224. 
26. 
Mohindra P, Urban E, Pagan JD, et al. Selective omission of level V nodal coverage for patients 
with oropharyngeal cancer: Clinical validation of intensity-modulated radiotherapy experience and 
dosimetric significance. Head & neck. Apr 2016;38(4):499-505. 
27. 
Lodder WL, Sewnaik A, den Bakker MA, Meeuwis CA, Kerrebijn JD. Selective neck dissection for 
N0 and N1 oral cavity and oropharyngeal cancer: are skip metastases a real danger? Clinical 
otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-
Laryngology & Cervico-Facial Surgery. Oct 2008;33(5):450-457. 
28. 
Chone CT, Kohler HF, Magalhaes R, Navarro M, Altemani A, Crespo AN. Levels II and III neck 
dissection for larynx cancer with N0 neck. Brazilian journal of otorhinolaryngology. Oct 
2012;78(5):59-63. 
29. 
Lim YC, Choi EC, Lee JS, Koo BS, Song MH, Shin HA. Is dissection of level IV absolutely 
necessary in elective lateral neck dissection for clinically N0 laryngeal carcinoma? Oral oncology. 
Jan 2006;42(1):102-107. 
30. 
Villaflor VM, Melotek JM, Karrison TG, et al. Response-adapted volume de-escalation (RAVD) in 
locally advanced head and neck cancer. Annals of oncology : official journal of the European 
Society for Medical Oncology. May 2016;27(5):908-913. 
31. 
Yoshimoto S, Kawabata K. Retropharyngeal node dissection during total pharyngolaryngectomy 
for hypopharyngeal cancer. Auris, nasus, larynx. Jun 2005;32(2):163-167. 
32. 
Wu Z, Deng XY, Zeng RF, et al. Analysis of risk factors for retropharyngeal lymph node 
metastasis in carcinoma of the hypopharynx. Head & neck. Sep 2013;35(9):1274-1277. 
33. 
Chung EJ, Kim GW, Cho BK, Park HS, Rho YS. Pattern of lymph node metastasis in 
hypopharyngeal squamous cell carcinoma and indications for level VI lymph node dissection. 
Head & neck. Apr 2016;38 Suppl 1:E1969-1973. 
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Chung EJ, Lee SH, Baek SH, Park IS, Cho SJ, Rho YS. Pattern of cervical lymph node 
metastasis in medial wall pyriform sinus carcinoma. The Laryngoscope. Apr 2014;124(4):882-
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Amar A, Dedivitis RA, Rapoport A, Quarteiro AL. Indication of elective contralateral neck 
dissection in squamous cell carcinoma of the hypopharynx. Brazilian journal of 
otorhinolaryngology. Jul-Aug 2009;75(4):493-496. 
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Marcus C, Ciarallo A, Tahari AK, et al. Head and neck PET/CT: therapy response interpretation 
criteria (Hopkins Criteria)-interreader reliability, accuracy, and survival outcomes. Journal of 
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Kendi AT, Brandon D, Switchenko J, et al. Head and neck PET/CT therapy response 
interpretation criteria (Hopkins criteria) - external validation study. American journal of nuclear 
medicine and molecular imaging. 2017;7(4):174-180. 
38. 
Lowe VJ, Duan F, Subramaniam RM, et al. Multicenter Trial of [(18)F]fluorodeoxyglucose 
Positron Emission Tomography/Computed Tomography Staging of Head and Neck Cancer and 
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13.0  APPENDICES 
 
Appendix A: AJCC Staging, 7th Edition 
 
PRIMARY 
Oropharynx 
T1 Tumor 2 cm or less in greatest dimension 
 

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T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension 
 
T3 Tumor more than 4 cm in greatest dimension or extension to lingual surface of epiglottis 
 
T4a Moderately advanced local disease 
Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible* 
 
T4b Very advanced local disease 
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or\ skull base or encases 
carotid artery *Note: Mucosal extension to lingual surface of epiglottis from primary tumors of the base of 
the tongue and vallecula does not constitute invasion of larynx. 
 
Larynx 
 
Supraglottis 
T1 Tumor limited to one subsite of supraglottis with normal vocal cord mobility 
 
T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside 
the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation 
of the larynx 
 
T3 Tumor limited to larynx with vocal cord fixation and/or invades any of the following:\ postcricoid area, 
pre-epiglottic tissues, paraglottic space, and/or inner cortex of thyroid cartilage 
 
T4a Moderately advanced local disease Tumor invades through the thyroid cartilage and/or invades 
tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep extrinsic muscle of the 
tongue, strap muscles, thyroid, or esophagus) 
 
T4b Very advanced local disease 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures 
 
Glottis 
T1 Tumor limited to the vocal cord(s) [may involve anterior or posterior commissure] with normal mobility 
T1a Tumor limited to one vocal cord 
T1b Tumor involves both vocal cords 
T2 Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility 
T3 Tumor limited to the larynx with vocal cord fixation, and/or invasion of paraglottic space, and/or inner 
cortex of the thyroid cartilage 
T4a Moderately advanced local disease 
Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx 
(e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, 
or esophagus) 
T4b Very advanced local disease 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures. 
 
Subglottis 
T1 Tumor limited to the subglottis 
T2 Tumor extends to vocal cord(s) with normal or impaired mobility 
T3 Tumor limited to larynx with vocal cord fixation 
T4a Moderately advanced local disease 
Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx\ (e.g., trachea, soft 
tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus) 
T4b Very advanced local disease 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures. 
 
Hypopharynx 

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T1  Tumor limited to one subsite of hypopharynx and/or 2 cm or smaller in greatest dimension 
T2 Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures larger than 2 
cm but not larger than 4 cm in greatest dimension without fixation of hemilarynx 
T3 Tumor larger than 4 cm in greatest dimension or with fixation of hemilarynx or extension to 
esophageal mucosa 
T4a Moderately advanced local disease: Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid 
gland, esophageal muscle, or central compartment soft tissue (Central compartment soft tissue includes 
prelaryngeal strap muscles and subcutaneous fat.) 
T4b Very advanced local disease 
 
NODE (p16+ oropharynx will be reported per AJCC 7 criteria) 
 
NX Regional lymph nodes cannot be assessed 
N0 No regional lymph node metastasis 
N1 Metastasis in a single ipsilateral node, 3 cm or less in greatest dimension 
N2 Metastasis in a single ipsilateral node, more than 3 cm, but not more than 6 cm in greatest dimension, 
or in multiple ipsilateral lymph nodes, none greater than 6 cm in greatest dimension, or bilateral or 
contralateral nodes, none more than 6 cm in greatest dimension 
N2a Metastasis in a single ipsilateral node more than 3 cm, but not more than 6 cm in greatest dimension 
N2b Metastasis in multiple ipsilateral nodes, none more than 6 cm in greatest dimension 
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension 
N3 Metastases in a lymph node, more than 6 cm in greatest dimension 
 
STAGE GROUPING 
 
Stage 0  
Tis, N0, M0  
 
Stage I  
T1, N0, M0  
 
Stage II  
T2, N0, M0  
 
Stage III  
T3, N0, M0 
T1-3, N1, M0 
 
Stage IVA  
T4a, N0-1, M0 
Any T, N2, M0 
 
Stage IVA  
T4a, N0-2, M0 
T1-3, N2, MO 
 
Stage IVB 
T4b, Any N, MO 
Any T, N3, M0 
 

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Appendix B – ECOG Performance Scale 
 
 
ECOG PERFORMANCE SCALE 
 
0  
Fully active, able to carry on all predisease activities without restriction (Karnofsky 90-100). 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry work of a light or 
sedentary nature. For example, light housework, office work (Karnofsky 70-80). 
 
2  
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours (Karnofsky 50- 60). 
 
3  
Capable of only limited self-care, confined to bed or chair 50% or more of waking hours 
(Karnofsky 30-40). 
 
4  
Completely disabled. Cannot carry on self-care. Totally confined to bed or (Karnofsky 10-20). 
 
5 
Death (Karnofsky 0). 
 

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Appendix C (EORTC QLQ-30) 

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Appendix D (EORTC HN-35) 
 
 

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AAppendix E:Appendix E MDADI 
Appendix E: MDADI 

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 Appendix F: EQ-5D 
 
Under each heading, please check the ONE box that best describes your health TODAY 
 
MOBILITY 
I have no problems walking   
 
 
 
 
❑ 
I have slight problems walking  
 
 
 
 
❑ 
I have moderate problems walking 
  
 
 
 
❑ 
I have severe problems walking 
  
 
 
 
❑ 
I am unable to walk 
 
 
 
 
 
 
❑ 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
❑ 
I have slight problems washing or dressing myself   
 
❑ 
I have moderate problems washing or dressing myself  
 
❑ 
I have severe problems washing or dressing myself  
 
❑ 
I am unable to wash or dress myself  
 
 
 
❑ 
 
USUAL ACTIVITIES (e.g. work, study, housework,  
family or leisure activities) 
I have no problems doing my usual activities  
 
 
❑ 
I have slight problems doing my usual activities  
 
 
❑ 
I have moderate problems doing my usual activities  
 
❑ 
I have severe problems doing my usual activities  
 
 
❑ 
I am unable to do my usual activities  
 
 
 
❑ 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
❑ 
I have slight pain or discomfort  
 
 
 
 
❑ 
I have moderate pain or discomfort   
 
 
 
❑ 
I have severe pain or discomfort  
 
 
 
 
❑ 
I have extreme pain or discomfort  
 
 
 
 
❑ 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
❑ 
I am slightly anxious or depressed   
 
 
 
❑ 
I am moderately anxious or depressed  
 
 
 
❑ 
I am severely anxious or depressed   
 
 
 
❑ 
I am extremely anxious or depressed  
 
 
 
❑ 
 

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        We would like to know how good or bad your health is TODAY. 
 
This scale is numbered from 0 to 100. 
 
100 means the best health you can imagine. 
 
0 means the worst health you can imagine. 
 
Mark an X on the scale to indicate how your health is TODAY. 
 
 
YOUR HEALTH TODAY = 
 
 
 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
The best health        
 you can imagine 
The worst health       
 you can imagine 
 
Patient’s initials       _________________ 
 
 
Today’s Date           _________________ 
 
 

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INRT-AIR Educational Handout 
 
In the past, the normal-appearing lymph nodes in the neck (that may be cancerous) 
were treated with a dose that was only 20% less than the dose given to the actual tumor. 
This research study, INRT-AIR, targets the cancerous lymph nodes and delivers radiation 
only to those specific areas. We are identifying each small lymph node that may have 
microscopic cancer using neck CT scan, PET-CT scan and artificial intelligence, so we can 
focus the treatment to areas at risk for recurrence but dramatically spare radiation to your 
normal tissues. 
 
We believe this new treatment approach should significantly improve your 
tolerance of radiation therapy, as well as minimize the long-term side effects such as: dry 
mouth, swallowing problems, and skin tightness. The risk of the study is the possibility that 
a small cancerous lymph node is not fully treated, although we estimate that likelihood to 
be quite low.  
 
Example 
 
In standard radiation, both sides of the neck are treated with radiation to kill these 
microscopic cells. In this study, we only treat the known cancerous lymph nodes and any 
small lymph nodes we believe may have microscopic cancer in them. 
 
 Standard Radiation 
    
        INRT-AIR (this trial)  
 
 
KEY 
 = Full Radiation Dose 
 = Lower Radiation Dose 
 
= Cancerous lymph nodes 
 
= Small lymph nodes  
(May have microscopic cancer 
cells in them)