Clinical trial NCT03067610
Conditions: Head and Neck Cancer Carcinoma, Squamous Cell Neoplasms, Oral Neoplasms, Pharyngeal
Sponsor: University of Texas Southwestern Medical Center
Start date: 2017-01-20; Completion date: 2021-03-09
Enrollment: 72 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel)

Detailed description:
This study aims to significantly improve the acute and late morbidity of patients with oropharyngeal and laryngeal squamous cell carcinoma both by tailoring the elective irradiation only to regions with a legitimate risk of recurrence (\> 5%) and by lowering the elective dose to 40 Gy. Level IB will not be electively treated unless it is involved with pathologic or suspicious lymphadenopathy. Level V will not be treated unless two or more ipsilateral nodal levels are involved (or level V itself has pathologic or suspicious adenopathy). Levels III and IV will only be irradiated if the immediately proximal level contains pathologic lymphadenopathy (i.e. level III irradiated if level II is positive; level IV irradiated if level III is positive). We anticipate that this approach should dramatically improve the acute and late complication profile.

Arms: arm 1: Intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel)
Interventions: intervention 1: Intensity Modulated Radiation Therapy intervention 2: chemotherapy
Intervention descriptions: intervention 1: The radiotherapy plan wil be delivered in 2 sequential courses. The first course involves 20 fractions of 2 Gy per fraction to the entire volume (gross disease and elective). The second course involves 15 fractions (thus, total of 35 fractions), at either 2 Gy (gross disease) or 1.6 Gy (microscopic disease and suspicious node) per fraction. intervention 2: chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel) per physician discretion

Protocol documents:
Prot_SAP_000.pdf: 
 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
 
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 052016-044 
INFIELD: A Prospective Phase II Study of Involved Field Elective Volume De-Intensification for 
Oropharyngeal and Laryngeal Squamous Cell Carcinoma treated with Intensity Modulated 
Radiation Therapy 
 
Principal Investigator:  
 
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 
 
Sub-Investigator(s): 
 
Local Sub-Investigators 
 
 
 
 
 
 
Department of Medical Oncology 
 
Saad Khan, MD 
Randall Hughes, MD 
 
Department of Radiology 
 
 
 
 
 
William Moore, MD 
                                                    Rathan Subramaniam, MD 
 
 
 
 
 
 
 
 
 
National Sub-Investigators 
 
 
 
 
 
Rush University Medical Center 
 
 
 
 
 
 
 
 
 
Neilayan Sen, MD 
 
 
 
 
500 S. Paulina St, Ground Floor 
 
 
 
 
Chicago, IL 60612 
 
 
 
Biostatistician: 
 
Chul Ahn, PhD 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
Dallas, TX 75390 
 
 
 
 
chul.ahn@utsouthwestern.edu 
 
 
 
 
214-648-9418 
 
Study Drug/Treatment:             IFRT 
 
Funding Source:  
Departmental 
 
Initial version: 
1.0  
 
Amended: 
 
 
Version 2 
9/28/16 
Version 3 
9/28/16 
Version 4 
2/21/17 
Verion 5 
4/24/18 
Version 6 
5/16/2019 


 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
 
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 
 
Version 7 
2/18/2021 
 
 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
 
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 #__________7___________________ 
 
STU 052016-044 
INFIELD: A Prospective Phase II Study of Involved Field Elective Volume De-Intensification for 
Oropharyngeal and Laryngeal Squamous Cell Carcinoma treated with Intensity Modulated 
Radiation Therapy 
 
 
Principal Investigator (PI) Name: __David J. Sher MD, MPH___________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS (EXAMPLES) ......................................... Error! Bookmark not defined. 
STUDY SCHEMA ............................................................................................................................. 3 
STUDY SUMMARY .......................................................................................................................... 4 
1.0 
BACKGROUND AND RATIONALE .................................... Error! Bookmark not defined. 
1.1 
Disease Background........................................................................................................ 5 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 5 
1.3 
Other Agents .................................................................................................................... 6 
1.4 
Rationale .......................................................................................................................... 6 
1.5 
Correlative Studies .......................................................................................................... 9 
2.0 
STUDY OBJECTIVES ......................................................... Error! Bookmark not defined. 
2.1 
Primary Objectives ........................................................................................................... 9 
2.2 
Secondary Objectives ...................................................................................................... 9 
2.3 
Exploratory Objectives ................................................................................................... 10 
2.4 
Endpoints ....................................................................................................................... 10 
3.0 
Subject ELIGIBILITY .......................................................... Error! Bookmark not defined. 
3.1 
Inclusion Criteria .............................................................. Error! Bookmark not defined. 
3.2 
Exclusion Criteria ........................................................................................................... 11 
4.0 
TREATMENT PLAN ............................................................ Error! Bookmark not defined. 
4.1 
Treatment Dosage and Administration ............................ Error! Bookmark not defined. 
4.2 
Toxicities and Dosing Delays/Dose Modifications ........... Error! Bookmark not defined. 
4.3 
Concomitant Medications/Treatments ........................................................................... 21 
4.4 
Other Modalities or Procedures ....................................... Error! Bookmark not defined. 
4.5 
Duration of Therapy ......................................................... Error! Bookmark not defined. 
4.6 
Duration of Follow Up ...................................................... Error! Bookmark not defined. 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
ii 
4.7 
Removal of Subjects from Protocol Therapy ................... Error! Bookmark not defined. 
4.8 
Subject Replacement....................................................... Error! Bookmark not defined. 
5.0 
STUDY PROCEDURES ....................................................... Error! Bookmark not defined. 
5.1 
Screening/Baseline Procedures ...................................... Error! Bookmark not defined. 
5.2 
Procedures During Treatment ....................................................................................... 23 
5.3 
Follow-up Procedures ...................................................... Error! Bookmark not defined. 
5.4 
Time and Events Table .................................................... Error! Bookmark not defined. 
5.5 
Removal of Subjects from Study ..................................... Error! Bookmark not defined. 
6.0 
Measurement of Effect ....................................................... Error! Bookmark not defined. 
6.1 
Antitumor Effect- Solid Tumors ........................................ Error! Bookmark not defined. 
6.2 
Safety/tolerability ............................................................. Error! Bookmark not defined. 
7.0 
ADVERSE EVENTS ............................................................ Error! Bookmark not defined. 
7.1 
Experimental Therapy...................................................... Error! Bookmark not defined. 
7.2 
Adverse Event Monitoring ............................................................................................. 28 
7.3 
Steps to Determine If an Adverse Event Requires Expedited ReportingError! Bookmark not 
defined. 
7.4 
Unblinding Procedures .................................................... Error! Bookmark not defined. 
7.5 
Stopping Rules ................................................................ Error! Bookmark not defined. 
8.0 
DRUG INFORMATION ........................................................ Error! Bookmark not defined. 
8.1 
Cisplatin ......................................................................................................................... 33 
8.2 
Cetuximab ...................................................................................................................... 34 
8.3 
Paclitaxel ....................................................................................................................... 34 
8.4 
Carboplatin .................................................................................................................... 36 
9.0 
CORRELATIVES/SPECIAL STUDIES ............................... Error! Bookmark not defined. 
9.1 
Specimen Banking ......................................................................................................... 37 
10.0 
STATISTICAL CONSIDERATIONS ................................ Error! Bookmark not defined. 
10.1 
Study Design/Study Endpoints ...................................................................................... 37 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
iii 
10.2 
Sample Size and Accrual ................................................ Error! Bookmark not defined. 
10.3 
Data Analyses Plans........................................................ Error! Bookmark not defined. 
11.0 
STUDY MANAGEMENT .................................................. Error! Bookmark not defined. 
11.1 
Conflict of Interest ............................................................ Error! Bookmark not defined. 
11.2 
Institutional Review Board (IRB) Approval and Consent . Error! Bookmark not defined. 
11.3 
Required Documentation (for multi-site studies) ............. Error! Bookmark not defined. 
11.4 
Registration/Randomization Procedures ......................... Error! Bookmark not defined. 
11.5 
Data Management and Monitoring/Auditing .................... Error! Bookmark not defined. 
11.6 
Adherence to the Protocol ............................................... Error! Bookmark not defined. 
11.7 
Amendments to the Protocol ........................................... Error! Bookmark not defined. 
11.8 
Record Retention ............................................................. Error! Bookmark not defined. 
11.9 
Obligations of Investigators ............................................. Error! Bookmark not defined. 
12.0 
REFERENCES ................................................................. Error! Bookmark not defined. 
13.0 
APPENDICES .................................................................. Error! Bookmark not defined. 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
1 
LIST OF ABBREVIATIONS (EXAMPLES) 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ASCO 
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 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IDE 
Investigational Device Exemption 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IV (or iv) 
Intravenously 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
2 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 
STUDY SCHEMA 
STUDY SUMMARY 
Title 
Full title of protocol 
Short Title 
Shortened title(match this to title used it ClinicalTrials.gov) 
Protocol Number 
The standard protocol number used to identify this study 
Phase 
Clinical study phase (e.g., Phase 1, 2, 3 or 4) 
Methodology 
Design attributes such as single blind, double blind or open label; 
randomized, placebo or active placebo control; cross-over design, etc. 
Study Duration 
Estimated duration for the main protocol (e.g., from start of screening to 
last subject processed and finishing the study) 
Study Center(s) 
Single-center or multi-center; if multi-center, note number of projected 
centers to be involved 
Objectives 
Brief statement of primary study objectives 
Number of Subjects 
Number of subjects projected for the entire study (e.g., not for simply one 
site, rather for all sites combined) 
Diagnosis and Main 
Inclusion Criteria 
Note the main clinical disease state under study and the key inclusion 
criteria (i.e. not the entire list that will appear later in the protocol, rather 
only the key inclusion criteria) 
Study Product(s), Dose, 
Route, Regimen 
Study drug name(s) (generic name, though can also state marketed 
name if name-brand used in the study) and/or description of non-drug 
therapy (i.e., radiation, surgery, etc.);include dose, route and regimen 
Duration of administration 
Total duration of drug product administration (including any open-label 
lead-in, if applicable) 
Reference therapy 
Note if there is a standard reference therapy against which the study 
product is being compared, or if the reference is a placebo 
Statistical Methodology 
A very brief description of the main elements of the statistical 
methodology to be used in the study (as few lines as possible) 
 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
3 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiotherapy or chemoradiotherapy 
Follow for 2 years following 
treatment, including disease 
recurrence and patient-reported 
outcome results 
Neck CT at 6, 9, 12, 18, and 24 
months, or when clinically 
indicated 
PET-CT at 10-12 weeks following 
treatment 
Patient registration 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
4 
STUDY SUMMARY 
Title 
INFIELD: A Prospective Phase II Study of Involved Field Elective 
Volume De-Intensification for Oropharyngeal and Laryngeal 
Squamous Cell Carcinoma treated with Intensity Modulated 
Radiation Therapy 
 
Short Title 
INFIELD: A Prospective Phase II Study of Involved Field Elective 
Volume De-escalation  
Protocol Number 
STU 052016-044 
Phase 
Phase 2 
Methodology 
Prospective study 
Study Duration 
2 years to accrue plus additional 2 years of follow-up 
Study Center(s) 
Multi-center 
Objectives 
To determine the risks and quality-of-life-benefits of using a tailored 
strategy of elective volume de-intensification.  
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 
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 
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 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  
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
5 
 
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.  
 
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. Fields that eliminate or minimize elective irradiation are termed “involved-field.” In this 
study, we aim to improve acute and long-term toxicity of IMRT for OPC and LXC by delivering a 
conservative form of involved-field radiotherapy, using a lower dose while also sparing tissue with 
an established, very low risk of occult microscopic disease.  
 
1.2 
Study Agent(s) 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-
hematologic acute grade 3-5 toxicity, and 39.1% of patients developed acute grade 3-5 
mucositis/stomatitis (6) . 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) 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
6 
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 stage I and II disease will be treated with radiotherapy alone. Patients with 
stage III (T1-2 N1) may be treated with radiotherapy alone or concurrent chemoradiotherapy. 
Patients with 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(7, 8). 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 (9). There were no elective volume failures 
in a 71-patient retrospective study of oropharyngeal cancer from UCSF (54 Gy in 33 fractions) 
(10). In a carefully-performed patterns-of-failure study from Ghent University Hospital, there were 
no solitary elective nodal failures (out of 140, with the majority oropharynx [35%] or larynx [28%]) 
in the primarily irradiated neck, in which the elective neck received 56 Gy in 35 fractions (11).  


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
7 
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 (12).  
 
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 (13).Studer et al. described the 
patterns-of-failure in 202 head and neck cancer patients (70% OPC and LXC) treated with IMRT 
(14) . 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 (15). 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)(16). With 
longer follow-up, the authors found no difference in local control but significant improvements in 
grade 3 dysphagia at 6 months and borderline improvement at 2 years (p=0.065) (ESTRO, 2014, 
OC-0058).  
 
 
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 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. 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
8 
 
 
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 
recurrences and only one out-of-field failure, which occurred simultaneous to an in-field 
recurrence.  
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
9 
 
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%). 
 
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 if levels II-IV contain minimal disease.  
 
7. Occult disease in level IV is extremely rare 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. 
 
 
Given these observations, this study aims to significantly improve the acute and late 
morbidity of patients with oropharyngeal and laryngeal squamous cell carcinoma both by tailoring 
the elective irradiation only to regions with a legitimate risk of recurrence (> 5%) and by lowering 
the elective dose to 40 Gy. Level IB will not be electively treated unless it is involved with 
pathologic or suspicious lymphadenopathy. Level V will not be treated unless two or more 
ipsilateral nodal levels are involved (or level V itself has pathologic or suspicious adenopathy). 
Levels III and IV will only be irradiated if the immediately proximal level contains pathologic 
lymphadenopathy (i.e. level III irradiated if level II is positive; level IV irradiated if level III is 
positive). We anticipate that this approach should dramatically improve the acute and late 
complication profile.  
 
1.5 
Correlative Studies 
NA 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To determine the risk of solitary elective volume recurrence following elective 
volume and dose de-escalation. 
 
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 
To determine patient-reported outcomes (PRO) following treatment with elective 
volume and dose de-escalation. 
 
2.2.2 
To describe the rates of grade 3 and 4 acute and late toxicities following elective 
volume and dose de-escalation. 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
10 
2.2.3 
To estimate the rates gastrostomy dependence at 3, 6, 12 and 24 months 
following treatment. 
 
2.2.4 
To characterize patient utilities following treatment with elective volume and dose 
de-escalation.  
 
2.2.5 
To determine 2-year overall and progression-free survival following elective 
volume and dose de-escalation.  
 
2.2.6 
To describe the patterns-of-failure following elective volume and dose de-
escalation.  
 
2.3 
Exploratory Objectives 
NA 
 
2.4 
Endpoints 
 
2.4.1 
Primary endpoint: 2-year crude risk of solitary elective volume recurrence 
(SEVR). 
 
2.4.2 
Secondary endpoints: 
 
2.4.2.1 Patient-reported outcomes: Difference in PRO measures between 
baseline and 1, 3, 6, 12, and 24 months following treatment: 
 
2.4.2.1.1  
EORTC QLQ-C30 Summary score 
2.4.2.1.2  
EORTC QLQ-C30 Physical and role functioning subscales 
 
2.4.2.1.3 
EORTC HN35 Dry mouth and sticky saliva subscales 
2.4.2.1.4 
MDADI global, emotional, functional and physical subscales 
2.4.2.1.5 
EQ-5D global score (0-100) 
 
2.4.2.2 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.  
 
 
2.4.2.3 Prevalence of gastrostomy-dependence at 3, 6, 12 and 24 months from 
the end of treatment. 
 
2.4.2.4 Average patient utilities (derived from EQ-5D) at baseline, 3, 6, 12 and 
24 months from the end of treatment. 
 
 
 
 
2.4.2.5 Overall survival probability at 2 years from the start of treatment 
 
 
 
2.4.2.6 Progression-free survival probability at 2 years from the start of treatment 
 
2.4.2.7 Cumulative incidence of locoregional recurrence at 2 years, with death 
as a competing risk 
 
 
2.4.2.8 Cumulative incidence of distant metastasis at 2 years, with death and 
prior locoregional failure as competing risks 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
11 
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 or 
larynx. 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. Patients may undergo a diagnostic 
tonsillectomy, and diagnostic lymph node excision (< 2 nodes) is also allowable. 
 
3.1.3 
Clinical stage I-IVB (AJCC, 7th edition); stages I-II glottic cancer are excluded 
 
3.1.4 
Age ≥ 18 years. 
 
3.1.5 
ECOG Performance Status 0-2  
 
3.1.6 
Adequate organ and marrow function as defined below: 
- leukocytes 
 
≥ 3,000/mcL 
- absolute neutrophil count ≥ 1,500/mcL 
- platelets  
 
≥ 100,000/mcl 
- total bilirubin 
 
within normal institutional limits 
- AST(SGOT)/ALT(SPGT) ≤ 2.5 X institutional upper limit of normal 
 
 
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. 
 
3.1.6.1 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 pregnancy test within 2 weeks before registration for women of 
childbearing potential. 
 
3.1.9 
Neck CT and/or neck MRI, and whole body PET-CT. 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Distant metastasis or adenopathy below the clavicles. 
 
3.2.2 
Inability to undergo PET-CT. 
 
3.2.3 
Stage I and II glottic carcinoma. 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
12 
 
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 and larynx, 
except for synchronous well-differentiated thyroid cancer; in the latter case, 
surgery may occur before or after INFIELD 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 
 
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 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 immunosuppression, including HIV, and organ or stem cell transplant, 
or an autoimmune condition previously treated with immunosuppressive therapy. 
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 
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.  
 
The radiotherapy plan wil be delivered in 2 sequential courses. The first course involves 20 
fractions of 2 Gy per fraction to the entire volume (gross disease and elective). The second 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
13 
course involves 15 fractions (thus, total of 35 fractions), at either 2 Gy (gross disease) or 1.6 Gy 
(microscopic disease and suspicious node) per fraction.  
 
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 
 
 
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. 
 
 
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 pPTV64; note this volume receives 40 Gy 
in the first 20 fractions, and then 1.6 Gy per fraction.  
 
 
A lower dose primary clinical target volume (pCTV2) will be designed by 
expanding the pGTV by typically 5-10 mm and deleting contours in 
structures that are a natural barrier to spread. The specific width here is 
reliant on physician discretion. The pCTV2 is then expanded by 5-8 mm 
to create pPTV40. 
 
 
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 > 1.0 cm for other nodal stations 
 
The node shows central necrosis or heterogeneous 
enhancement  
 
Lymph nodes whose max SUV is greater than mean liver SUV 
may be considered “involved” at the discretion of the treating 
physician. (32) 
 
 
 
 
A node is “suspicious” if it doesn’t meet the above criteria, but: 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
14 
 
The combined diameter of the lymph node is 17 mm or more 
(15), OR 
 
Max SUV is greater than mean liver SUV(32) 
 
Lymph nodes whose max SUV is greater than mean blood pool 
may be considered “suspicious” at the discretion of the treating 
physician. (32) 
 
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)  
 
Contouring and dosing schemes are as followed:  
 
 
 
4.1.1.5.1 Any involved node receives 70 Gy (nPTV70). The 
elective CTV must include this node plus 5 mm expansion to 
account for microscopic extranodal extension. 
  
  
4.1.1.5.2 Any suspicious node receives  64 Gy (nPTV64). In the 
first course, the node is treated to 40 Gy in 2 Gy fractions, then 
1.6 Gy per fraction for 15 fractions. The station containing that 
node is treated in the elective CTV. The elective CTV must 
include this node plus 5 mm expansion to account for 
microscopic extranodal extension. 
 
 
4.1.1.5.3 For oropharynx primaries, level II is treated bilaterally 
(except in early-stage tonsil cancer, see Section 4.1.1.6.3). For 
either side of the neck, if level II does not contain an involved 
node then levels III-IV are not treated. If level III does not contain 
an involved node, then level IV is not treated. Level V is only 
treated if 2 levels of the neck are involved. When level IV and 
level V are treated, the entire level is included.  
 
 
4.1.1.5.4 For larynx primaries, levels II-III are treated bilaterally. 
For either side of the neck, if level III does not contain an 
involved node, then level IV is not treated. Level V is only treated 
if 2 levels of the neck are involved. When level IV and level V are 
treated, the entire level is included. 
 
 
4.1.1.5.5 A suspicious node does not lead to treatment of the 
next elective station. 
 
 
4.1.1.5.6 Level IB is never treated unless it includes an involved 
or suspicious node, or there is oral cavity extension of the 
oropharynx primary tumor. 
 
 
4.1.1.5.7 If level II has an involved node, then upper level II 
(above the subdiagstric node) is treated to 40 Gy (nCTV40) 
because of poor salvage rates. If level II does not have an 
involved node, then its cranial border is the subdigastric node. 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
15 
 
4.1.1.5.8 Larynx cancer with subglottic extension should have 
level IV and level VI included in the nCTV40. 
 
 
4.1.1.5.9 For oropharynx cancer, ipsilateral retropharyngeal 
nodes are included (i.e. in the CTV40) if level II includes an 
involved lymph node, or there is an involved or suspicious lymph 
node in the retropharyngeal station. For larynx cancer, ipsilateral 
retropharyngeal lymph nodes are never included unless there 
are involved or suspicious lymph nodes in the retropharyngeal 
station. For both oropharyngeal and laryngeal cancer, if there is 
an involved retropharyngeal node, then elective retropharyngeal 
nodes on both side of the neck are treated to 40 Gy (i.e. included 
in the nCTV40). 
 
 
4.1.1.5.10 The PTV64 and PTV40 may be reduced to 1 mm if it 
is abutting an organ-at-risk.  
 
 
4.1.1.5.11 A node that is biopsied and positive should be treated 
as an involved node. A node that is biopsied and negative may 
be treated as a negative node, regardless of imaging findings.  
  
 
4.1.1.5.12 The ipsilateral and contralateral retropharyngeal 
nodes may be included in nCTV40 if there is soft palate invasion.  
 
 
 
 
All elective nodal CTV’s are expanded by 5 mm, except 3 mm medially.  
 
 
All PTV’s are trimmed by 3 mm inside skin to arrive at the final structure, 
unless there is skin involvement, in which case bolus placement may be 
used to ensure adequate skin dose. 
 
4.1.1.6 Contours under special conditions 
 
 
4.1.1.6.1 If the patient underwent a diagnostic tonsillectomy with 
a pathologically positive result, the tonsillar fossa should be 
contoured as psCTV. The psCTV is then expanded by 5 mm to 
create the psPTV40 (margins 2 mm or more) or psPTV64 
(margins less than 2 mm). The PTV is trimmed by 3 mm inside 
skin to arrive at the final structure. 
 
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 nsPTV40 (no ECE) or nsPTV64 
(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 
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 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
16 
nodes, may receive ipsilateral radiotherapy only after discussion 
with Principal Investigator Dr. Sher. 
 
 
4.1.1.6.5 Patients requiring an emergent tracheostomy will have 
levels IV and VI covered, and the tracheostomy site should be 
included in the 40 Gy (pCTV40). The tracheostomy site may be 
included in the 64 Gy volume (pCTV1) at the discretion of the 
treating physician.  
 
 
4.1.1.6.6 If a suspicious node is seen in a level below an 
untreated level, the intervening level is included in the 40 Gy 
volume. For example, if level 4 includes a suspicious node but 
level 3 was not otherwise being treated, level 3 should be 
included in the 40 Gy volume.  
 
  
 
 
4.1.1.7 Dose prescription 
 
Structure 
Description 
1st course 
dose (20 
fractions) 
2nd course dose 
(15 fractions) 
Total dose 
(35 fractions) 
Primary 
tumor 
Gross primary 
disease 
40 Gy 
30 Gy 
70 Gy 
Elective 
primary  
volume 
Microscopic 
disease around 
primary tumor  
40 Gy 
24 Gy 
64 Gy 
Involved 
lymph 
nodes 
Gross nodal 
disease 
40 Gy 
30 Gy 
70 Gy 
Suspicious 
lymph 
nodes 
Lymph nodes of 
possible 
malignant 
potential  
40 Gy 
24 Gy 
64 Gy 
Elective 
lymph 
nodes 
Regions of 
microscopic 
nodal disease 
40 Gy 
0 Gy 
40 Gy 
Prescribed volumes under special conditions 
Tonsil 
resection 
bed, high-
risk 
Resected 
tonsillar fossa 
with close or 
positive margins  
40 Gy 
24 Gy 
64 Gy 
Tonsil 
resection 
bed, low-
risk 
Resected 
tonsillar fossa 
with negative 
margins  
40 Gy 
0 Gy 
40 Gy 
Lymph 
node 
excision 
bed, high-
risk 
Resected lymph 
node bed with 
ECE 
40 Gy 
24 Gy 
64 Gy 
Lymph 
node 
excision 
bed, low-
risk 
Resected lymph 
node bed 
without ECE 
40 Gy 
0 Gy 
40 Gy 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
17 
 
 
The radiation treatment will be delivered in two courses. 
 
Course 1: All PTV’s receive 40 Gy in 2 Gy fractions.  
 
Course 2: All PTV70 structures (primary and nodes) will then receive 30 Gy in 15 
fractions. All PTV64 structures (primary CTV and suspicious nodes) will then 
receive 24 Gy in 15 fractions.  
 
Summary of prescription doses (expansions for setup error are described in 
4.1.1.4 and 4.1.1.5) 
 
Summary of elective nodal volumes (descriptions are described in 4.1.1.4 and 
4.1.1.5) [Note: RP = retropharyngeal] 
 
Any lymph node station containing an involved or suspicious node will be 
included in the 40 Gy volume. The table below describes the treatment levels if 
that lymph node station is radiologically benign (i.e. no involved or suspicious 
lymph nodes) 
 
Station 
Oropharynx 
Larynx 
Note 
I 
Only if oral cavity 
extension of primary 
tumor 
NEVER 
 
II 
ALWAYS 
ALWAYS 
Cranial border is 
subdiagstric 
node if neck 
does not have an 
involved node; 
otherwise, cranial 
border is jugular 
foramen 
 
Lateralized tonsil 
cancers may 
undergo 
ipsilateral RT per 
4.1.1.6.3 and 
4.1.1.6.4     
III 
Only if level II includes an 
involved node 
ALWAYS 
 
IV 
Only if level III includes 
an involved node 
Only if level III includes 
an involved node, there is 
subglottic extension, or 
emergency tracheostomy 
 
V 
Only if 2 levels of the 
neck include involved 
nodes 
Only if 2 levels of the 
neck include involved 
nodes 
Both Va and Vb 
are included in 
the volume 
VI 
NEVER 
Subglottic extension, or 
emergency tracheostomy 
 
RP 
Only if level II includes an 
involved node 
NEVER 
If there is an 
involved RP 
node, bilateral 
RP stations are 
treated 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
18 
 
 
4.1.1.8  Treatment planning 
 
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). 
 
4.1.8.1 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.  
 
4.1.8.2 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 
 
 
pCTV64 
Not applicable 
 
 
pCTV40 
Not applicable 
 
 
niGTV70 
Not applicable 
 
 
nsGTV64 
Not applicable 
 
 
nCTV40 
Not applicable  
 
 
PTV70 
95% of PTV70 
covered by 70 Gy 
None 
 
< 95% 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
19 
 
99% of PTV70 
covered by 66.5 
Gy 
 
Max hot spot < 75 
Gy 
 
97% of PTV70 
covered by 66.5 Gy 
 
Max hot spot < 77 
Gy 
 
< 97% 
 
 
> 77 Gy 
PTV64 
95% of PTV64 
covered by 64 Gy 
 
99% of PTV64 
covered by 60.8 
Gy 
93% of PTV64 
covered by 64 Gy 
 
97% of PTV64  
covered by 60.8 Gy 
< 93% 
 
 
< 97% 
PTV40 
95% of PTV40 
covered by 40 Gy 
 
99% of PTV40 
covered by 38 Gy  
93% of PTV40 
covered by 40Gy 
 
97% of PTV40 
covered by 38 Gy  
< 93% 
 
 
< 97% 
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 
CL_parotid 
Contralateral parotid (defined by site of tumor) 
IL_parotid 
Ipsilateral parotid 
IL_sup_parotid 
Ipsilateral superficial parotid 
CL_SMG 
Contralateral submandibular gland 
IL_SMG 
Ipsilateral submandibular gland 
OC 
Oral cavity 
Constrictors 
Pharyngeal constrictors 
PACS 
Post-arytenoid and cricoid space 
Cerv_esoph 
Cervical esophagus 
Larynx 
Larynx 
Ipsi_mass 
Ipsilateral masseter 
CL_mass 
Contralateral masseter 
Mandible 
Mandible 
R_plexus 
Right brachial plexus 
L_plexus 
Left brachial plexus 
 
R_cerebellum 
Right cerebellum 
L_cerebellum 
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 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
20 
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.   
 
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, and so there is no 
reason to expect that the effective elective dose would be meaningfully different among 
them; because the side effect profiles are so different, it is important to allow investigator 
discretion for each individual patient.  
 
 
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 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
21 
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 
 
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. 
4.2 
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 
 
4.3 
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. 
4.4 
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) 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
22 
 
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”. 
 
4.5 
Duration of Follow Up 
 
Patients will be followed for 2 years from the completion of treatment. 
4.6 
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 treatment discontinuation 
and the date of discontinuation. The subject should be followed-up per protocol.  
 
4.7 
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: 
5.1.1 
Informed Consent 
5.1.2 
Medical history 
    Complete medical and surgical history  
5.1.3 
Demographics 
    Age, gender, race, ethnicity 
5.1.4 
Review subject eligibility criteria 
5.1.5 
Review previous and concomitant medications 
5.1.6 
Physical exam including vital signs, height and weight 
                             Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 
Performance status 
                             Performance status evaluated prior to study entry according to Appendix B. 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
23 
5.1.8 
Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for 
Adverse Event monitoring and reporting. 
5.1.9 Hematology 
5.1.10 Blood and urine draw for correlative studies 
                             See Section 9.0 for details. 
5.1.11 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, 
potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin. 
5.1.12 Pregnancy test (for females of child bearing potential) 
 
 
   See section 3.1.6.1 for definition.  
5.1.13 Dental evaluation (if patient not edentulous) 
5.1.14 Tumor assessment 
Patients must have dedicated neck imaging (neck CT with intravenous contrast 
if not contraindicated; otherwise neck MRI with or without contrast if not 
contraindicated; otherwise neck CT with contrast), and whole body PET-CT.  
5.1.15 Completion of PRO instruments (before treatment) 
 
EORTC QLQ-30 
 
EORTC HN35 
 
MDADI 
 
EQ-5D  
5.2 
Procedures During Treatment 
5.2.1 
During each week of radiotherapy  
    Physical exam, vital signs by radiation oncologist 
    Assessment of performance status 
    Adverse event assessment 
5.2.2 
During each week of chemotherapy 
 
Standard procedures per local treating facility 
 
 
 
 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
24 
5.3 
Time and Events Table  
 
5.3.1 
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 
Dental evaluation 
X 
CBC with differential, platelets 
X 
Serum chemistries 
X 
Dedicated neck imaging 
X (within 60 days of registration) 
Whole body PET-CT 
X (within 30 days of registration) 
Serum pregnancy test (if applicable) 
X 
Adverse event assessment 
X 
Patient reported outcome assessment 
 
EORTC QLQ-C30 
 
EORTC HN35 
 
MDADI 
 
EQ-5D 
X (before treatment) 
 
 
  
5.3.2 
Assessments during treatment 
 
Assessments 
Time points 
 
Weekly during treatment 
History and physical with weight and 
vital signs 
X 
Performance Status 
X 
CBC with differential and platelets 
X (if receiving systemic therapy) 
Creatinine, ALT and AST, total 
bilirubin, alkaline phosphatase 
X (if receiving systemic therapy) 
Adverse event assessment 
X 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
25 
5.3.3 
Assessments following treatment 
 
Assessments 
Time Points (after treatment) 
History and physical with weight and 
vital signs 
X (1, 3, 6, 9, 12, 18, 24 months) 
Performance Status 
X (1, 3, 6, 9, 12, 18, 24 months) 
Adverse event assessment 
X (1, 3, 6, 9, 12, 18, 24 months) 
PET-CT 
X (3 months) 
Dedicated neck imaging (CT or MRI) 
X (6, 12, 18, 24 months) 
Patient reported outcomes 
 
EORTC QLQ-C30 
 
EORTC HN35 
 
MDADI 
 
EQ-5D 
 
 
X (1, 3, 6, 12, 24 months) 
 
  
                 5.4    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: 
5.4.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.4.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.4.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject demonstrates disease progression (unless continued treatment with 
study drug/treatment is deemed appropriate at the discretion of the investigator); 
5.4.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.4.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.4.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.4.8 
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; 
5.4.9 
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  
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
26 
 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect 
Because this protocol is treating known regions of cancer with standard-of-care radiotherapy 
doses, treatment response is not an endpoint of this study. 
 
Rather, the secondary endpoints involve assessments of locoregional and distant recurrence, 
which will be defined in this section. 
 
6.1.1 
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 64. 
 
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 40.    
 
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 64 for a suspicious lymph node).  
 
Elective volume regional recurrence (EVRR). Regional recurrence that is not an IFRR and > 50% 
of the recurrent disease is within the 95% isodose line of the PTV 40.   
 
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. 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
27 
6.1.2     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.     
6.1.3 
Solitary elective volume regional recurrence (SEVR) 
Solitary elective volume regional recurrence (SEVR) is the development of an 
EVLR, EVRR, or OFRR in the absence of prior or synchronous LR, IFRR, IFRR 
or DM.  
 
6.1.4 
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. 
6.1.5 
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 
For the most recent safety update (in drug studies), please refer to the current 
Investigator’s Brochure or Study Agent Prescribing Information. 
7.1.1 
Contraindications 
There are no special contraindications for this study beyond typical 
contraindications to radiation therapy or chemotherapy (when indicated). 
7.1.2 
Special Warnings and Precautions for Use 
 
 
None 
7.1.3 
Interaction with other medications 
 
 
None 
 
7.1.4 
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 Adverse Event Monitoring 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
28 
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 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. 
 
[Inserted from Adverse Event Definitions and Reporting Section – Appendix II of 
the SCC DSMC Plan] 
7.2.1 
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, imaging finding or clinically significant 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  


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
29 
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0. 
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 
 
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 hospitalization1,2 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 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 >24 hour inpatient admission to the hospital 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. 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
30 
7.2.2 
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); 
                                               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 treatmen 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 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 treatment. 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 (if applicable); 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
31 
 
the drug package insert (if applicable); 
 
the current Investigator’s Brochure (if applicable) 
 
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. 
 
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.  
 
 
 
Telephone reports to: 
 
Sandra Morones, 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 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
32 
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 
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 
 
NA 
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 patients were followed for 2 years. 
If the conditional power is less than 50%, the trial will be discontinued. 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
33 
8.0 
DRUG/TREATMENT INFORMATION 
8.1 
Cisplatin  
 
 
Other names for the drug(s): Platinol 
 
 
Classification - type of agent: cytotoxic chemotherapy  
 
 
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: Reconstituted solution of cisplatin is stable for 20  
hours when stored at 27°C and should be protected from light if not used within 6 
hours. The vials and injection should not be refrigerated. Cisplatin has been shown to 
react with aluminum needles, producing a black precipitate within 30 minutes. 
 
 
Protocol dose: Bolus or weekly 
 
 
Preparation: Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of 
mannitol, and hydrochloric acid for pH adjustment. One vial is reconstituted with 10 
ml of sterile water. The pH range will be 3.5 to 4.5. Cisplatin injection also is available 
from the manufacturer in aqueous solution, each ml containing 1 mg cisplatin and 9 
mg NaCl and HCL or NaOH to adjust pH. 
 
 
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 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
34 
8.1.1 
Return and Retention of Study Drug 
N/A 
 
8.2 
 Cetuximab 
 
 
Other names for the drug(s): Erbitux 
 
 
Classification - type of agent: biologic  
 
 
Mode of action: Unknown. Binds to the EGFR receptor (epidermal growth factor 
receptor) 
 
 
Storage and stability: Reconstituted solution of cisplatin is stable for 20  
hours when stored at 27°C and should be protected from light if not used within 6 
hours. The vials and injection should not be refrigerated. Cisplatin has been shown to 
react with aluminum needles, producing a black precipitate within 30 minutes. 
 
 
Protocol dose: Loading and then weekly 
 
 
Preparation: Cetuximab must not be administered as an iv push or bolus. Cetuximab 
must be administered with the use of a low protein binding 0.22-micrometer in-line 
filter. Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of 
cetuximab at a concentration of 2 mg/mL in phosphate buffered saline. The solution 
should be clear and colorless and may contain a small amount of easily visible white 
amorphous cetuximab particulates. DO NOT SHAKE OR DILUTE. Cetuximab can be 
administered via infusion pump or syringe pump. 
 
 
Route of administration for this study: Intravenous 
 
 
Incompatibilities: It should not be mixed with any other compounds. 
 
 
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 
8.2.1 
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 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
35 
 
 
Storage and stability: All solutions of paclitaxel exhibit a slight haziness directly 
proportional to the concentration of drug and the time elapsed after preparation, 
although when prepared as described above, solutions of paclitaxel (0.3-1.2 mg/ml) 
are physically and chemically stable for 27 hours. Paclitaxel vials should be stored 
between 2°-25°C (36°-77°F). 
 
 
Protocol dose: Weekly 
 
 
Preparation: Paclitaxel is a sterile solution concentrate, 6 mg/ml in 5 ml vials (30 
mg/vial); 100 mg/16.7ml vial; or 300 mg/50 ml vial, in polyoxyethylated castor oil 
(Cremophor EL) 50% and dehydrated alcohol, USP, 50%. Improved solubility 
requires a mixed solvent system with further dilutions of either 0.9% sodium chloride 
or 5% dextrose in water. The contents of the vial must be diluted just prior to clinical 
use. Paclitaxel, at the appropriate dose, will be diluted in 1000 ml of D5W, USP, in 
5% polyolefin containers due to leaching of diethylhexphthalate (DEHP) plasticizer 
from polyvinyl chloride (PVC) bags and intravenous tubing by the Cremophor vehicle 
in which paclitaxel is solubilized. Each bag/bottle should be prepared immediately 
before administration. Note: Formation of a small number of fibers in solution 
(acceptable limits established by the USP Particular Matter Test for LVP’s) have 
been observed after preparation of paclitaxel. Therefore, in-line filtration is necessary 
for administration of paclitaxel solutions. In-line filtration should be accomplished by 
incorporating a hydrophilic, microporous filter of pore size not greater than 0.22 
microns (e.g.: Millex-GV Millipore Products) into the i.v. fluid pathway distal to the 
infusion pump. Although particulate formation does not indicate loss of drug potency, 
solutions exhibiting excessive particulate matter formation should not be used. 
 
 
Route of administration for this study: Intravenous 
 
 
Incompatibilities: Avoid the use of PVC bags and infusion sets due to leaching of 
DEHP (plasticizer). Prior administration of cisplatin may increase myelosuppression 
because of reduced clearance of paclitaxel. Ketoconazole, verapamil, diltiazem, 
quinidine, dexamethasone, teniposide, etoposide, vincristine, and cyclosporine may 
inhibit paclitaxel metabolism, based on in vitro data. 
 
 
Availability: Commercially available 
 
 
Side effects:  
o 
Hematologic: neutropenia, leukopenia, thrombocytopenia, anemia  
o 
Gastrointestinal: nausea/vomiting, diarrhea, mucositis  
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  
 
 
Nursing implications: N/A 
8.3.1 
Return and Retention of Study Drug 
N/A 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
36 
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: Store the unopened vials at controlled room temperature 15° - 
30°C (59°-86°F). Protect unopened vials from light. Solutions for infusion should be 
discarded 8 hours after preparation. 
 
 
Protocol dose: Weekly  
 
 
Preparation: Add 5, 15, or 45 ml sterile water, normal saline, or 5% dextrose to the 
50, 150, or 450 mg vial, respectively. The resulting solution contains 10 mg/ml. The 
desired dose is further diluted, usually in 5% dextrose. 
 
 
Route of administration for this study: Intravenous 
 
 
Incompatibilities: General: Needles or intravenous administration sets containing 
aluminum parts that may come in contact with paraplatin should not be used for the 
preparation or administration of the drug. Aluminum can react with carboplatin 
causing precipitate formation and loss of potency. 
 
 
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).  
o 
Other: Pain, asthenia.  
 
Miscellaneous: moderate–severe hypersensitivity reactions, flushing, 
rash, dyspnea, fatigue  
 
 
Nursing implications: N/A 
8.4.1 
Return and Retention of Study Drug 
N/A 
 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
37 
9.0 
CORRELATIVES/SPECIAL STUDIES 
9.1 
Specimen Banking 
Subject samples collected for this study (blood, urine and biopsy tissue) will be retained 
at UT Southwestern according to approved UTSW protocol 11210: Tissue Procurement 
and Outcome Collection for Radiotherapy Treated Patients.  
 
Collaborating institutions will be encouraged to collect the same specimens per local 
institutional protocols, but that will not be paid for by UTSW or this study.  
 
If funding ultimately becomes available, we will perform genomic studies on these 
specimens to assess their ability to predict survival, local, and distant recurrence.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available: 
 
Diagnosis  
 
Collection time in relation to study treatment 
 
Clinical outcome – if available 
 
Demographic data 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
 
10.1.1 Primary endpoint: 2-year crude risk of solitary elective volume recurrence 
(SEVR). 
 
10.1.2 Secondary endpoints: 
 
10.1.2.1 
Patient-reported outcomes: Difference in PRO measures between 
baseline and 1, 3, 6, 12, and 24 months following treatment: 
 
10.1.2.1.1   
EORTC QLQ-C30 Summary score 
10.1.2.1.2   
EORTC QLQ-C30 Physical and role functioning 
subscales 
 
10.1.2.1.3  
EORTC HN35 Dry mouth and sticky saliva 
subscales 
10.1.2.1.4  
MDADI global, emotional, functional and 
physical subscales 
10.1.2.1.5  
EQ-5D global score (0-100) 
 
10.1.2.2 
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.  
 
 
 
10.1.2.3 
Prevalence of gastrostomy-dependence at 3, 6, 12 and 24 months 
from the end of treatment. 
 
10.1.2.4 
Average patient utilities (derived from EQ-5D) at baseline, 3, 6, 12 
and 24 months from the end of treatment. 
 
 
10.1.2.5 
Overall survival probability at 2 years from the start of treatment 
 
10.1.2.6 
Progression-free survival probability at 2 years from the start of 
treatment 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
38 
 
10.1.2.7 
Cumulative incidence of locoregional recurrence at 2 years, with 
death as a competing risk 
 
 
10.1.2.8 
Cumulative incidence of distant metastasis at 2 years, with death 
and prior locoregional failure as competing risks 
 
10.2 
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 were followed for 2 years. 
If the conditional power is less than 50%, the trial will be discontinued. 
 
10.3 
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 
number. 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 0.5. These results 
assume a baseline risk of 0.03 and that the actual difference is 0.0  
 
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. Thus, the 
only patients who need to be replaced are those who are lost to follow-up so there is no 
2-year endpoint. With the conservative assumption of 10% loss to follow-up, the final 
sample size will be 67 patients.  
 
10.4 
Data Analyses 
10.3.1 Primary endpoint (SEVR) 
 
The crude risk of 2-year solitary elective volume recurrence will be calculated among all 
patients who are followed for at least 2 years. Patients who die before 2 years without an 
SEVR will be included in the denominator. A binomial 95% confidence interval will be 
calculated.  
 
10.3.1.1 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 
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 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
39 
 
OPC versus larynx site 
 
10.3.2 Secondary endpoints 
 
10.3.2.1 Patient reported outcomes 
 
Each of the patient reported outcomes are single numeric scores that are 
collected at baseline, 1, 3, 6, 12, and 24 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).   
 
10.3.2.2 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.  
 
10.3.2.3 Gastrostomy dependence 
 
The prevalence of gastrostomy use at 3, 6, 12 and 24 months will be described. 
Predictors of gastrostomy-dependence will be determined using multivariable 
logistic regression.  
 
10.3.2.4 Patient utilities 
 
The average patient utilities (derived from EQ-5D) at baseline, 3, 6, 12 and 24 
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 grade2-3 xerostomia and grade 2-3 
dysphagia, to produce an estimate of the utility decrement from this toxicity.  
 
10.3.2.5 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.  
 
10.3.6 Progression-free survival  
 
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. 
 
10.3.7 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. A 
comparison of these endpoints will be performed using Gray’s test.  


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
40 
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 
 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: this is required if {institution} 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/Randomization Procedures 
All subjects must be registered with through RedCap before enrollment to study. Prior to 
registration, eligibility criteria must be confirmed with the Study Coordinator. To register a 
subject, call (214) 648-1821 Monday through Friday, 9:00AM-5:00PM.  
 
Research staff from all participating sites will have online access to UTSW REDCap, and 
all patients will be registered electronically through REDCap. All subjects consenting to 
participate in any aspect of the trial must be registered on REDCap before initiating 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
41 
protocol activities. 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.  
 
Following registration, research staff from CRO will review all relevant data to ensure 
eligibility criteria have been met.   
 
The first number of the subject’s ID will refer to the treatment site. The ordering is: 
 
01: UTSW 
02: Rush 
 
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-
001-001. The third patient consented and second enrolled at Rush will have the number 
02-003-002.  
 
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 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 SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project 
 
Other institutions participating in this trial as sub-sites will be expected to enter data into 
REDCap and upload de-identified source materials when instructed by the Simmons 
Cancer Center study team to facilitate remote source to case report form verification.  
 
In order to facilitate remote source to case report form verification, the Simmons 
Comprehensive Cancer Center study team will require other institutions participating in 
this trial as sub-sites to enter data into the selected EDC system and upload selected de-
identified source materials when instructed  
 
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 and/or the CRO 
Multi-Center IIT Monitor. This review 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.   
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
42 
For further information, refer to the UTSW SCCC IIT Management Manual. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs 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 SCCC 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.  
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.  
11.6.1 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 
 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. 
11.6.2 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. 
11.6.3 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 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
43 
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). 
 
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. 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
44 
 
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. 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
45 
12.0 
REFERENCES 
1. Nguyen-Tan PF, Zhang Q, Ang KK, Weber RS, Rosenthal DI, Soulieres D, et al. Randomized 
phase III trial to test accelerated versus standard fractionation in combination with concurrent 
cisplatin for head and neck carcinomas in the radiation therapy oncology group 0129 trial: Long-
term report of efficacy and toxicity. J Clin Oncol. 2014 Dec 1;32(34):3858-66.  
 
2. Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, et al. Randomized 
phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage 
III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 2014 Sep 20;32(27):2940-50.  
 
3. Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, et al. Long-term results 
of RTOG 91-11: A comparison of three nonsurgical treatment strategies to preserve the larynx in 
patients with locally advanced larynx cancer. J Clin Oncol. 2013 Mar 1;31(7):845-52.  
 
4. Lefebvre JL, Pointreau Y, Rolland F, Alfonsi M, Baudoux A, Sire C, et al. Induction 
chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: 
The TREMPLIN randomized phase II study. J Clin Oncol. 2013 Mar 1;31(7):853-9.  
 
5. Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al. Parotid-sparing 
intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): A 
phase 3 multicentre randomised controlled trial. Lancet Oncol. 2011 Feb;12(2):127-36.  
 
6. Nguyen-Tan PF, Zhang Q, Ang KK, Weber RS, Rosenthal DI, Soulieres D, et al. Randomized 
phase III trial to test accelerated versus standard fractionation in combination with concurrent 
cisplatin for head and neck carcinomas in the radiation therapy oncology group 0129 trial: Long-
term report of efficacy and toxicity. J Clin Oncol. 2014 Dec 1;32(34):3858-67.  
 
7. Sher DJ, Thotakura V, Balboni TA, Norris CM, Haddad RI, Posner MR, et al. Treatment of 
oropharyngeal squamous cell carcinoma with IMRT: Patterns of failure after concurrent 
chemoradiotherapy and sequential therapy. Ann Oncol. 2012 Sep;23(9):2391-8.  
 
8. Dandekar V, Morgan T, Turian J, Fidler MJ, Showel J, Nielsen T, 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 Oncol. 2014 May;50(5):520-6.  
 
9. Garden AS, Dong L, Morrison WH, Stugis EM, Glisson BS, Frank SJ, et al. Patterns of disease 
recurrence following treatment of oropharyngeal cancer with intensity modulated radiation 
therapy. Int J Radiat Oncol Biol Phys. 2013 Mar 15;85(4):941-7.  
 
10. Huang K, Xia P, Chuang C, Weinberg V, Glastonbury CM, Eisele DW, et al. Intensity-
modulated chemoradiation for treatment of stage III and IV oropharyngeal carcinoma: The 
university of california-san francisco experience. Cancer. 2008 Aug 1;113(3):497-507.  
 
11. 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. Int J Radiat Oncol Biol Phys. 2011 
Feb 1;79(2):450-8.  
 
12. Bedi M, Firat S, Semenenko VA, Schultz C, Tripp P, Byhardt R, et al. Elective lymph node 
irradiation with intensity-modulated radiotherapy: Is conventional dose fractionation necessary? 
Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):e87-92.  
 
13. 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. Radiother 
Oncol. 2009 Dec;93(3):498-502.  
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
46 
14. Studer G, Huber GF, Holz E, Glanzmann C. Less may be more: Nodal treatment in neck 
positive head neck cancer patients. Eur Arch Otorhinolaryngol. 2015 Apr 29.  
 
15. 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. Int J Radiat 
Oncol Biol Phys. 2016 Mar 15;94(4):766-74.  
 
16. Nuyts S, Lambrecht M, Duprez F, Daisne JF, Van Gestel D, Van den Weyngaert D, 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. Radiother Oncol. 2013 Nov;109(2):323-9.  
 
17. Sanguineti G, Pai S, Agbahiwe H, Ricchetti F, Westra W, Sormani MP, 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 Oncol. 2014 May;53(5):662-8.  
 
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. Laryngoscope. 2006 
Jul;116(7):1148-52.  
 
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. Ann 
Otol Rhinol Laryngol. 2001 Oct;110(10):982-4.  
 
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. J 
Otolaryngol. 2006 Apr;35(2):108-11.  
 
21. Tam M, Riaz N, Kannarunimit D, Pena AP, Schupak KD, Gelblum DY, et al. Sparing bilateral 
neck level IB in oropharyngeal carcinoma and xerostomia outcomes. Am J Clin Oncol. 2015 
Aug;38(4):343-7.  
 
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. Int J 
Radiat Oncol Biol Phys. 2016 Mar 15;94(4):775-82.  
 
23. Naiboglu B, Karapinar U, Agrawal A, Schuller DE, Ozer E. When to manage level V in head 
and neck carcinoma? Laryngoscope. 2011 Mar;121(3):545-7.  
 
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. 2003 Feb;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 Otolaryngol. 2013 Feb;133(2):218-24.  
 
26. Mohindra P, Urban E, Pagan JD, Geye HM, Patel VB, Bayliss RA, 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. 2016 Apr;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? Clin 
Otolaryngol. 2008 Oct;33(5):450-7.  
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
47 
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. Braz J Otorhinolaryngol. 2012 Oct;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 Oncol. 
2006 Jan;42(1):102-7.  
 
30. Villaflor VM, Melotek JM, Karrison TG, Brisson RJ, Blair EA, Portugal L, et al. Response-
adapted volume de-escalation (RAVD) in locally advanced head and neck cancer. Ann Oncol. 
2016 Feb 15.  
 
31. Sadick M, Weiss C, Piniol R, Frey S, Hoermann K, Schoenberg SO, et al. 18F-
fluorodeoxyglucose uptake level-based lymph node staging in oropharyngeal squamous cell 
cancer--role of molecular marker expression on diagnostic outcome. Oncol Res Treat. 2015;38(1-
2):16-22. 
 
32. Marcus C, Ciarallo A, Tahari AK, Mena E, Koch W, Wahl RL, et al. Head and neck PET/CT: 
Therapy response interpretation criteria (hopkins criteria)-interreader reliability, accuracy, and 
survival outcomes. J Nucl Med. 2014 Sep;55(9):1411-6.  
 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
48 
13.0 
APPENDICES 
 
Appendix A: AJCC Staging 
 
PRIMARY 
Oropharynx 
T1 Tumor 2 cm or less in greatest dimension 
 
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 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
49 
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. 
 
NODE 
 
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 
 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
50 
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). 
 
 
 
 
 
 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
51 
Appendix C (EORTC QLQ-30) 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
52 
 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
53 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
54 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
55 
Appendix D (EORTC HN-35) 
 
 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
56 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
57 
Appendix E: MDADI 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
58 
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  
 
 
 
            ❑ 
 
 
Patient ID: _______________ 
Date: ___/___/____ 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
59 
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  
 
 
 
❑ 
 
 


STU 052016-044 
________________________________________________________________________ 
STU052016-044, Sher, FormA-ResearchProtocol, Mod_25, 03-15-21 (1) 
60 
We would like to know how good or bad your health is 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 
 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 =