Phase II Trial of Surgery Followed by Risk-Directed Post-Operative Adjuvant Therapy for HPV-Related Oropharynx Squamous Cell Carcinoma: "The Minimalist Trial (MINT)"
Phase: PHASE2
Conditions: HPV Related Oropharyngeal Squamous Cell Carcinoma
Sponsor: Washington University School of Medicine

Version 2/27/2023 
 1 of 57 
 
 
Phase II Trial of Surgery followed by Risk-Directed Post-Operative Adjuvant 
Therapy for HPV-Related Oropharynx Squamous Cell Carcinoma: 
  
“The Minimalist Trial (MINT)” 
 
HRPO #: 201808045 
Version date: 02/27/2023 
 
PRINCIPAL INVESTIGATOR 
Douglas Adkins, M.D. 
Washington University School of Medicine 
Campus Box 8056, 660 South Euclid Ave. 
St Louis, MO 63110 
Office Phone: 314-747-8475 
dadkins@wustl.edu  
 
Sub-Investigators 
 
 
Modality 
Wade Thorstad, M.D.  
 
Radiation Oncology 
Ryan Jackson, M.D. 
 
 
ENT 
Jason Rich, M.D. 
 
 
ENT 
Peter Oppelt, M.D. 
 
 
Medical Oncology 
Randall Paniello, M.D.  
 
ENT 
Patrik Pipkorn, M.D. 
 
 
ENT 
Hiram Gay, M.D.  
    
 
Radiation Oncology 
Esther Lu, PhD  
 
 
Biostatistics 
Rebecca Chernock, M.D. 
 
Pathology 
Mena Mansour  
 
 
Pathology 
Sid Puram, M.D., PhD  
 
ENT  
Craig Buchman, MD 
 
 
ENT  
 
Study Drugs: 
 
Cisplatin 
                                           
ClinicalTrials.gov #: NCT03621696 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless law or 
regulations require such disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them 

Version 2/27/2023 
 2 of 57 
Phase II Trial of Surgery followed by Risk-Directed Post-Operative Adjuvant 
Therapy for HPV-Related Oropharynx Squamous Cell Carcinoma:  
 
“The Minimalist Trial (MINT)” 
 
 Protocol Revision History 
 
Initial Approval 
 
 
 
07/25/2018 
Amendment #1 
 
 
 
01/23/2019 
Amendment #2 
 
 
 
07/16/2019 
Amendment #3 
 
 
 
08/12/2019 
Amendment #4 
 
 
 
10/30/2019 
Amendment #5 
 
 
 
06/04/2020 
Amendment #6 
 
 
 
10/07/2020 
Amendment #7 
 
 
 
09/14/2021 
Amendment #8 
 
 
 
02/27/2023 
 

Version 2/27/2023 
 3 of 57 
Phase II Trial of Surgery followed by Risk-Directed Post-Operative Adjuvant Therapy for HPV-Related Oropharynx 
Squamous Cell Carcinoma:  
 
“The Minimalist Trial (MINT)” 
 
 
MINT SCHEMA 
 

Version 2/27/2023 
 4 of 57 
TABLE OF CONTENTS 
 
1.0 
INTRODUCTION AND BACKGROUND ....................................................................6 
1.1 Introduction ...............................................................................................................6 
1.2 Outcomes of HPV-related OPSCC after Surgery and Adjuvant Therapy ...................7 
1.3 Acute and Long Term Toxicities of Surgery and Adjuvant Therapy for HPV-related 
OPSCC 
8 
1.4 Steps Already Taken to Reduce Treatment-Related AE in Patients with HPV-related 
OPSCC 
9 
1.5 HPV-Related OPSCC is More Radiosensitive than HPV-Unrelated OPSCC ...........10 
1.6 Selection of Appropriate Candidates with HPV-Related OPSCC for ........................11 
1.7 Current Trials of De-intensification Therapy in HPV-related OPSCC .......................13 
1.8 Rationale for 42 Gy IMRT + Chemotherapy for HPV-related OPSCC ......................14 
1.9 “The MINT Trial” ......................................................................................................16 
2.0 
STUDY ENDPOINTS AND OBJECTIVES ...............................................................17 
2.1 Primary Objective ....................................................................................................17 
2.2 Secondary Objectives..............................................................................................17 
2.3 Exploratory Objectives .............................................................................................18 
3.0 
PATIENT ELIGIBILITY ............................................................................................18 
3.1 Inclusion Criteria ......................................................................................................18 
3.2 Exclusion Criteria ....................................................................................................18 
3.3 Inclusion of Women and Minorities ..........................................................................19 
4.0 
REGISTRATION PROCEDURES............................................................................19 
4.1 Confirmation of Patient Eligibility .............................................................................19 
4.2 Patient Registration in the Siteman Cancer Center OnCore Database ....................19 
4.3 Assignment of UPN .................................................................................................19 
5.0 
TREATMENT PLAN AND SCHEDULED ASSESSMENTS ......................................20 
5.1 Baseline Assessment ..............................................................................................20 
5.2 Standard of Care Surgery ........................................................................................21 
5.3 Interim Assessment .................................................................................................21 
5.4 Postoperative Adjuvant Chemotherapy ...................................................................22 
5.5 POART ....................................................................................................................24 
5.6 Follow-Up Assessments after Adjuvant Therapy .....................................................29 
5.7 Evaluations for Toxicity and Disease Relapse .........................................................31 
5.8 General Concomitant Medication and Supportive Care Guidelines..........................31 
5.9 Women of Childbearing Potential ............................................................................31 
5.10 Duration of Therapy .................................................................................................31 
6.0 
PHARMACEUTICAL INFORMATION ......................................................................32 
6.1 Cisplatin (CDDP, Platinol-AQ®) ...............................................................................32 
7.0 
DOSE MODIFICATIONS .........................................................................................33 
7.1 Cisplatin Dose Modifications (Arm 3 only) ...............................................................33 
7.2 Radiation Dose Modifications ..................................................................................34 
8.0 
CORRELATIVE STUDIES .......................................................................................34 
8.1 Tumor Acquisition Protocol ......................................................................................34 
8.2 Quality of Life Assessments ....................................................................................35 
9.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................35 
9.1 Definitions ...............................................................................................................35 
9.2 Reporting to the Human Research Protection Office (HRPO) at Washington 
University 37 
9.3 Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University ..............................................................................................................38 

Version 2/27/2023 
 5 of 57 
9.4 Timeframe for Reporting Required Events ...............................................................38 
10.0 
STATISTICAL CONSIDERATIONS .........................................................................38 
10.1 Study Design ...........................................................................................................38 
10.2 Sample Size Calculation ..........................................................................................38 
10.3 Accrual ....................................................................................................................39 
10.4 Statistical Analyses .................................................................................................39 
11.0 
DATA SUBMISSION SCHEDULE ...........................................................................40 
12.0 
DATA AND SAFETY MONITORING .......................................................................41 
13.0 
REFERENCES ........................................................................................................43 
14.0 
STUDY CALENDARS .............................................................................................45 
14.1 Baseline and Treatment Calendar ...........................................................................45 
14.2 Follow-up Calendar .................................................................................................47 
APPENDIX 1: ECOG Performance Status ..........................................................................48 
APPENDIX 2: Comorbidity Index.........................................................................................49 
APPENDIX 3: FACT-H&N (Version 4) .................................................................................50 
APPENDIX 4: M.D. Anderson Dysphagia Inventory ............................................................53 
APPENDIX 5: University of Michigan Xerostomia Index ......................................................54 
APPENDIX 6: Scale of Subjective Total Taste Acuity ..........................................................54 
APPENDIX 7: Neck Dissection Impairment Index ...............................................................56 
APPENDIX 8: Performance Status Scale for Head & Neck Cancer Patients – PSS-HN ......57 
 
 

Version 2/27/2023 
 6 of 57 
1.0 
INTRODUCTION AND BACKGROUND 
 
1.1 
Introduction 
 
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common 
cancer. HNSCC originates in the squamous cell mucosa of the oropharynx (OP), 
oral cavity, larynx and hypopharynx. OPSCC is one of the most common subtypes 
of HNSCC and the incidence of OPSCC has risen significantly over the last 
decade.1 Last year, 16,000 new cases of OPSCC were diagnosed in the USA. 
Previously, the primary cause of OPSCC was smoking; however, currently the 
majority of cases (>90%) are due to the Human Papilloma Virus (HPV).2 HPV-
related OPSCC is expected to comprise the majority of HNSCCs by 2030.1 
 
HPV-related OPSCC has a better prognosis compared to smoking-induced HPV-
unrelated disease. Only 10-15% of patients with HPV-related OPSCC develop 
disease relapse after initial therapy compared to 40-60% of patients with HPV-
unrelated disease. Also, patients with HPV-related OPSCC are younger and 
healthier than patients with HPV-unrelated disease and thus deaths due to non-
OPSCC causes are much lower in HPV-related OPSCC. As a result, the 5 year 
overall survival (OS) of patients with HPV-related OPSCC is 70-90% compared to 
30% for HPV-unrelated disease (Figure)3: 
 
                                        Overall survival by p16 staining (p16+ is a surrogate marker of HPV) 
 
The current standard of care therapy for HPV-related and HPV-unrelated OPSCC 
is the same, even though the chances for cure and OS are far better with the former 
diagnosis. Treatment options include surgery and adjuvant radiation-based 
therapy or definitive chemoradiation therapy (DCRT). Both options result in intense 
and frequent acute toxicity and long-term morbidity that impair quality of life (QOL). 
The current focus for HPV-related OPSCC is to investigate less intense therapy 
with the goal to reduce treatment-related toxicity while maintaining the low relapse 
risk. The focus for HPV-unrelated disease is to investigate more intense therapy 

Version 2/27/2023 
 7 of 57 
to reduce relapse risk.  
 
This protocol will evaluate two less intense post-operative adjuvant radiation-
based therapy approaches in patients with HPV-related OPSCC who have a low 
(Arm 1) or very low (Arm 2) risk for disease relapse. A standard, intense post-
operative CRT pathway will be reserved for patients with a high risk for disease 
relapse (Arm 3).    
 
1.2 
Outcomes of HPV-related OPSCC after Surgery and Adjuvant 
Therapy  
 
Washington University has published a large body of data on outcomes of patients 
with HPV-related OPSCC treated with primary surgery and post-operative 
adjuvant radiation therapy (POART) or chemoradiation therapy (POACRT). In a 
retrospective report of 84 patients treated with transoral laser microsurgery (TLM) 
(median follow-up: 53 months), OS at 2 and 5 years was 94% and 88%, 
respectively.4 The risk of recurrence was 7%. Most of these patients had small 
primary tumors (T1-2:74%). OS was adversely impacted by advanced T stage (T3-
4) and positive margins. In a retrospective report of 204 patients treated with TLM, 
the OS at three years was 86% and the relapse risk was 13%.3 Advanced T stage 
(T3-4) and positive margin were adverse prognostic factors (Figures):  
 
 
 
 
 

Version 2/27/2023 
 8 of 57 
Other reports identified that five or more pathologic positive neck nodes was 
also an adverse prognostic factor (Figure)5: 
 
 
 
 
Seventeen percent of patients with OPSCC have five or more positive neck nodes, 
but even these patients had a favorable five year disease-specific survival (DSS) 
of 80%.6 
 
1.3 
Acute and Long Term Toxicities of Surgery and Adjuvant Therapy for 
HPV-related OPSCC 
 
The treatment-related toxicity burden experienced by patients with HPV-related 
OPSCC is substantial. Adverse events (AEs) due to surgery with modern trans-
oral techniques usually resolve after 3-4 weeks. Swallowing function after TLM and 
adjuvant therapy was good at two years in 93% of patients with T1-3 disease but 
in only 40% of patients with T4 base of tongue (BOT) disease.4 Shoulder 
dysfunction due to injury of cranial nerve XI is frequent but temporary in most 
cases, except those patients with bulky, infiltrative neck nodal disease.  
 
In contrast to surgery, the toxicity of POACRT is much more significant. Acute AEs 
include mucositis, dysgeusia, dry mouth, weight loss, fatigue, renal dysfunction, 
myelosuppression, tinnitus, and high frequency hearing loss. Chronic AEs include 
xerostomia, dysgeusia, dental caries, difficulty swallowing, pain, hearing loss, 
carotid artery atherosclerosis, and fatigue. These AEs impair global patient-
reported quality of life (PRQOL), and social, functional, physical, and emotional 
domains.     
 
 
 

Version 2/27/2023 
 9 of 57 
1.4 
Steps Already Taken to Reduce Treatment-Related AE in Patients 
with HPV-related OPSCC   
 
The goal of primary surgery is to remove all gross disease at the primary tumor 
site and remove the involved and at risk neck nodes, to result in a state of 
microscopic disease. Nearly all cases can be performed by trans-oral procedures 
(TLM or TORS), which are much mess morbid compared to open surgical 
techniques. The vast majority of patients with HPV-related OPSCC do not need to 
undergo 
reconstruction 
procedures 
and 
their 
associated 
morbidities. 
Reconstruction procedures using free- or pedicle-flaps are usually only required 
for management of bulky or infiltrative tumors (T4 or N3).  
 
The goal of POART is to eliminate microscopic tumor in at risk zones that may 
have been left behind after surgery. A series of studies in patients with OPSCC 
showed that changes in radiation technique, doses, and port volumes can be 
safely performed without loss of efficacy and resulted in improvement in PRQOL 
and reduction in toxicity. The shift from 3D CRT to IMRT resulted in a reduction in 
grade 3 acute (mucositis, dysphagia, and pain) and delayed (xerostomia and 
dysphagia) toxicities.7 Elimination of POART to the primary tumor site resulted in 
a risk of local recurrence of 3% in patients with T1-2 disease compared to 17% in 
patients with T3-4 disease.6 Rates of temporary percutaneous endoscopic 
gastrostomy (PEG) tube requirements were 6% with no primary bed radiation vs 
41% with primary bed radiation. These data support elimination of radiation to the 
primary tumor bed in patients with T1-2 disease. In HPV-related OPSCC, no 
difference in local-regional recurrence-free survival occurred between post-
operative adjuvant IMRT doses of 60 Gy compared to 66Gy (98.5% vs 98.1% at 2 
years, respectively).8  
 
 
 
In OPSCC patients with a clinically uninvolved contralateral neck, eliminating 
coverage of POART to the contralateral high level II neck and retropharyngeal 
nodes was associated with a minimal risk for failure in these regions and an 
improved PRQOL.9 

Version 2/27/2023 
 10 of 57 
 
 
 
 
 
1.5 
HPV-Related OPSCC is More Radiosensitive than HPV-Unrelated 
OPSCC 
 
The molecular basis of the favorable outcomes of HPV-related OPSCC treated 
with CRT has not been clearly determined. One report did find that HPV positive 
HNSCC cell lines were more radiosensitive than HPV negative HNSCC cell lines.10 
 
 
 
The increased radiosensitivity of HPV positive HNSCC cell lines was not due to 
increased apoptosis or cell cycle arrest in G1 a result of the effect of the E6 viral 
protein on wtp53. Impaired DNA double strand break repair capacity was found to 
be the likely basis for the increased radiosensitivity of HPV positive HNSCC cell 
lines. 
 

Version 2/27/2023 
 11 of 57 
 
 
Additional pre-clinical data support the increased radiosensitivity of HPV positive 
OPSCC cell lines.11 Also, HPV positive cell lines appear to retain some p53 
function as shown by the ability of cisplatin or radiation to induce the p53 target 
gene GADD45.12 In HPV positive cell lines, cisplatin repressed E6 expression and 
induced p21, p53, and BAX expression resulting in induction of apoptosis.13  
 
Clinical data support that HPV-related OPSCC is more radiosensitive than HPV-
unrelated OPSCC. The rate of tumor regression during week one of IMRT was 
greater in HPV-related OPSCC than HPV-unrelated OPSCC (33% difference in 
gross tumor volume [GTV] p< 0.001 and the average absolute change in GTV was 
-22.9 cc/week vs -5.9 cc/week, respectively p< 0.001).14 
 
1.6 
Selection of Appropriate Candidates with HPV-Related OPSCC for          
De-Intensification of CRT? 
 
Recognition that patients with AJCC/UICC 7th edition stage III/IV HPV-related 
OPSCC had a substantially better prognosis than those with stage III/IV HPV-
unrelated OPSCC resulted in development and implementation of a new staging 
system specific to HPV-related OPSCC. The new staging system correlated 
prognosis for each stage better than the old staging system.   
 
Investigators at Princess Margaret Cancer Centre showed that the AJCC/UICC 
TNM 7th edition clinical staging system distinguished OS prognosis among the 
different stages of HPV-unrelated OPSCC, but it did not do so for HPV-related 
OPSCC.15  Five year OS for HPV-unrelated OPSCC was 70% (stage I), 58% 
(stage II), 50% (stage III), and 30% (stage IV). Five year OS for HPV-related 
OPSCC was 88% (stage I), 78% (stage II), 71% (stage III), and 74% (stage IV). 
This group performed recursive partitioning analysis (RPA) on a large internal 
dataset and divided HPV-related OPSCC into three groups: I (59%; T1-3 N0-2b), 
II (16%; T1-3 N2c), and III (26%; T4 N3) with 5 year OS of 82%, 76%, and 54%, 
respectively. 
             

Version 2/27/2023 
 12 of 57 
 
 
 
Weaknesses of the Princess Margaret report included data from a single institution 
and lack of validation in a separate cohort. The International Collaboration on 
Oropharyngeal cancer Network for Staging (ICON-S) report addressed these 
weaknesses by performing a multicenter validation study using clinical (not 
pathologic) staging methods.16 T stages remained similar except that T4a and T4b 
were bundled into T4 based on the same OS between these T4 subsets. Clinical 
N stages were divided into N1 (ipsilateral neck nodes), N2 (bilateral or contralateral 
neck nodes), and N3 (> 6 cm neck node). The proposed ICON-S clinical 
classification was stage I (T1-2, N0-1), stage II (T1-2N2 or T3N0-2), stage III (T4 
or N3), and stage IV (metastatic). An exploratory analysis showed that lower neck 
nodal involvement had a significant adverse impact on OS in stage III but no effect 
in stages I-II. Also, OS was similar for patients with < 5 neck nodes and > 5 neck 
nodes, across all stages.  
 
 
 
 
 
 
 

Version 2/27/2023 
 13 of 57 
The tables below summarize the new AJCC 8th edition clinical and pathologic 
staging systems for HPV-related OPSCC: 
 
 
 
 
 
 
 
 
 
 
The ICON-S clinical staging system determined that stages I-II HPV-related 
OPSCC had excellent prognoses (5 year OS > 80%) with current therapy and 
would be appropriate candidates for trials evaluating de-intensification of current 
CRT. ICON-S stages I and II represented 83% of patients in this analysis. Patients 
with ICON-S stage III disease (17% of all patients) had a poorer prognosis (5 year 
OS 60%), and would not be appropriate candidates for trials evaluating de-
intensification of current therapy. 
 
1.7 
Current Trials of De-intensification Therapy in HPV-related OPSCC  
 
Nine trials evaluating strategies to de-intensify CRT in patients with HPV-related 

Version 2/27/2023 
 14 of 57 
OPSCC are either ongoing or recently completed with results awaiting maturation 
of data. Five of these trials use the surgical platform and four use the definitive 
radiation platform. The lowest dose of once daily radiation being investigated in all 
current trials of de-intensification is 50 Gy, with one exception. The Mayo Clinic 
trials are evaluating 30-36 Gy RT; however, RT is delivered in an accelerated 
scheme, which is known to be more toxic than once daily radiation schemes. Note 
that risk stratification factors vary in each of these trials, making comparisons 
challenging. 
 
Surgery Trials: ECOG 3311 is a phase III trial that treats post-operative patients 
who have intermediate risk (IR) features with POART 50 vs 60 Gy to the primary 
tumor site and bilateral neck nodes. Chemotherapy is not given to these patients. 
The PATHOS trial also compares POART 50 Gy vs 60 Gy in patients with IR 
disease. The DART phase III trial (Mayo Cinic) compares arm 1: 30 Gy in 150 cGy 
bid x 12 doses (IR) or 36 Gy in 180 cGy bid x 12 doses (HR: ECE) + docetaxel 2 
doses vs arm 2: 60 GY in 200 cGy doses, both with weekly cisplatin x 7. The SIRS 
phase II trial (Mt Sinai) uses POART 50 Gy, but is limited to patients with T1-2 IR 
disease. MC 1273 phase II trial (Mayo Clinic) used POART 36 Gy (180 cGY bid) 
+ docetaxel (2 doses).  
 
Definitive Radiation Trials: NRG HN002 is a phase III trial that compares definitive 
RT 60 Gy in 6 weeks + weekly cisplatin x 6 vs accelerated definitive RT 60 Gy in 
5 weeks (6 doses per week). This trial does not include patients with T4, N2c or 
N3 disease, or patients with > 10 pack-year history of smoking. RTOG 1016 is a 
phase III trial comparing accelerated definitive RT 70 Gy over 6 weeks (with 2 
fractions one day per week) + HDB cisplatin x 2 vs cetuximab x 8. ECOG 1308 
was a phase II trial in which all patients were treated with induction chemotherapy 
followed by definitive RT 54 Gy + cetuximab (if complete response to induction 
chemotherapy) or RT 69.3 Gy + cetuximab (if not complete response to induction 
chemotherapy). A single arm phase II trial (University of California) treated patients 
with two cycles of induction paclitaxel and carboplatin followed by either 54 Gy 
IMRT + paclitaxel (CR or PR) or 60 Gy IMRT + paclitaxel (< PR).17  
 
The results of these trials (except ECOG 1308 and the University of California 
trials) are not available yet, as many are still accruing and none have mature follow-
up. 
 
1.8 
Rationale for 42 Gy IMRT + Chemotherapy for HPV-related OPSCC 
 
Normal Tissue Complication Probability (NTCP) due to radiation therapy is an 
important concept related to the likelihood and severity of acute and long term 
toxicity in an attempt to cure malignancy with a radiation therapy approach.  When 
other modalities are used, NTCP can be extended to account for the overall 
complication probability due to the sum of all treatment modalities involved.  It is 
anecdotally evident that lower dose and/or lower volume of radiation correlate with 
less toxicity, but it was not until the advent of 3D radiation therapy technology that 

Version 2/27/2023 
 15 of 57 
NTCP could be quantified. The Quantitative Analysis of Normal Tissue Effects in 
the Clinic (QUANTEC) study18 summarized the latest understanding of organ 
specific dose/volume/outcome data.   
 
Based on QUANTEC, there is much to be gained by reducing radiation therapy 
dose to 42 Gy for HPV related OPSCC.  The organs related to swallowing function 
include the pharyngeal constrictors, larynx, and esophagus.  For the pharyngeal 
constrictors, a mean radiation dose of less than 50 Gy reduces the risk of 
symptomatic dysphagia and aspiration to less than 20%.  For the larynx, a mean 
dose of < 50 Gy reduces the risk of aspiration to less than 30%, and the risk of 
laryngeal edema is less than 20% with a mean dose of less than 44 Gy.  For the 
esophagus, if the volume receiving 50 Gy is less than 40%, the risk of grade 2 or 
above toxicity is no more than 30%.  The increase in NTCP with dose has an 
exponential component. Therefore at doses above 50 Gy, the risk of damage 
increases exponentially with rising dose.  However, the reduction in NTCP also 
has an exponential component, meaning that a dose of 42 Gy would significantly 
reduce normal tissue risk relative to 50 Gy in the QUANTEC data above, and 
relative to the 60 Gy standard dose for OPSCC in the postoperative setting.   
 
Like HPV-related OPSCC, anal canal SCC is also caused by HPV. Anal SCC is 
treated 
non-operatively 
with 
CRT. 
Radiation 
therapy 
and 
concurrent 
chemotherapy (5-FU and Mitomycin C) is the standard of care treatment for non-
metastatic anal canal SCC. The treatment plan for T2N0 disease is 42 Gy elective 
nodal and 50.4 Gy anal tumor planning target volumes (PTV) in 28 fractions and 
for T3-4N0-3 disease is 45 Gy elective nodal, 50.4 Gy for < 3 cm or 54 Gy for > 3 
cm metastatic nodal and 54 Gy anal tumor in 30 fractions. Use of IMRT reduced 
acute GI and GU mucosal toxicity compared to non-conformal radiation.19  
 
In anal SCC, mitomycin C and 5-FU are the standard chemotherapy agents given 
with RT. In OPSCC, cisplatin is the standard agent given with RT. Mitomycin C 
has not been tested in HPV-related OPSCC. However, cisplatin and 5-FU was 
compared to mitomycin C and 5-FU with RT in anal SCC20. The OS was not 
different between the two regimens. The rates of distant metastasis were not 
significantly different between the two groups (15% with mitomycin C and 19% with 
cisplatin). In anal SCC, the total dose of cisplatin given during RT is 150 mg/m2; 
whereas, in HPV-related OPSCC, the total dose of cisplatin given during RT is 300 
mg/m2.  
 
The studies of CRT in anal SCC showed that a radiation dose of only 42 Gy 
and a total cisplatin dose of only 150 mg/m2 were effective in eliminating 
microscopic disease in most patients. Is it possible that a dose of only 42 Gy 
would also eliminate microscopic disease in patients with HPV-related OPSCC?  
 
The optimal platform to test this question is in patients who undergo surgery to 
resect all gross disease at the primary tumor site and neck nodes. Many of these 
patients still have microscopic disease at the primary tumor site or in neck nodes 

Version 2/27/2023 
 16 of 57 
and thus all patients are treated with adjuvant therapy to reduce the risk of disease 
recurrence. The standard radiation dose used in this setting is 60 Gy, and most of 
these patients also receive concurrent cisplatin 100 mg/m2/dose for up to three 
doses. Based on studies in anal SCC, 42 Gy of RT should eliminate microscopic 
disease in most patients with OPSCC who have undergone complete resection of 
all gross disease. Studies in anal SCC used a total cisplatin dose of 150 mg/m2; 
however, these patients were managed non-operatively and thus all patients had 
gross disease when CRT was initiated. For this reason, a total dose of cisplatin 
lower than 150 mg/m2 seems reasonable to explore in patients with OPSCC who 
have undergone complete resection of all gross disease. In HNSCC, 5-FU has not 
been shown to add benefit to RT. 
 
De-intensification of adjuvant therapy by reduction in radiation dose from 60 Gy to 
42 Gy and in the total cisplatin dose from 300 to 100 mg/m2 should result in a 
substantial reduction in acute toxicity and improvement in QOL, but this is only 
acceptable if there is not an increased risk of disease relapse.    
 
1.9 
“The MINT Trial”  
 
The overarching goal of the MINT trial is to reduce treatment-related toxicity while 
maintaining efficacy. Patients with HPV-related OPSCC will undergo resection of 
the primary tumor site and involved/at risk regional neck nodes. Based on the 
clinical and pathologic staging and the details of the pathology report, patients will 
be assigned to one of three adjuvant treatments: 
• Arm 1 (extracapsular extension (ECE) or positive margin but not clinical or 
pathologic T4 or clinical N3 disease) will be treated with POAmCRT (42 Gy 
RT + cisplatin 1 dose) 
• Arm 2 (no ECE, no positive margins, and not clinical or pathologic T4 or 
clinical N3 disease) will be treated with POAmRT (42 Gy RT, no cisplatin) 
• Arm 3 (clinical or pathologic T4 or clinical N3 disease) will be treated with 
POART (60 Gy RT). If there is pathologic evidence of ECE or positive 
margin, 3 cycles of cisplatin will be given concurrently with POART (60Gy). 
 
Intermediate risk patients will be assigned to Arm 1 where they will be treated with 
de-intensified CRT: 42 Gy of RT (vs 60 Gy) and cisplatin 1 dose (vs 3). Reduction 
in treatment-related toxicity is expected in Arm 1. 
 
Low risk patients will be assigned to Arm 2 where they will be treated with de-
intensified RT: 42 Gy (vs 60 Gy) and no cisplatin at all. Reduction in treatment-
related toxicity is expected in Arm 2. 
 
High risk patients will be assigned to Arm 3 where they will be treated with standard 
intensive therapy, so reduction in treatment-related toxicity is not expected in this 
group.  
 

Version 2/27/2023 
 17 of 57 
Mucosal damage is the key mediator of most of the acute toxicity for POART and 
POACRT. The primary endpoint for the MINT trial is weight loss, a reliable, easily 
measured and practical surrogate marker of mucosal toxicity. Historical data 
showed that the percent weight loss during POACRT in patients with HPV-
related OPSCC was 7.39%. The primary hypothesis of this trial is that the 
percent weight loss of patients in Arm 1 during POAmCRT will be 3.7% (50% 
reduction).  
 
Secondary endpoints of mucosal toxicity to be determined include the proportion 
of patients who had PEG tubes placed, who experienced a doubling of the serum 
creatinine from baseline (a surrogate of dehydration and/or cisplatin toxicity), and 
who remained on narcotics at 6 weeks after POAmCRT. The secondary 
hypothesis for this trial is the proportion of patients with the composite endpoint of 
PEG tube placement/doubling of the serum creatinine/requirement for narcotics at 
6 weeks after POAmCRT will be reduced from the historical control of 72.6% to 
36.3% (50% reduction). Similar endpoints will be monitored for Arm 2, although 
the number of patients in this arm is expected to be small based on historical data. 
As such, we will not develop formal hypothesis testing for Arm 2, but will report the 
toxicity data in descriptive form. 
 
Patients (and clinicians) will not accept an increased risk of disease recurrence 
even with a significant reduction in toxicity with de-intensified therapy.21 To address 
this concern, we will establish rates of disease recurrence for Arm 1 that will be 
unacceptable. Our historical control data showed that the absolute risk of disease 
recurrence in patients with the characteristics of Arm 1 was 10% and that 89% of 
these recurrence events occurred by 24 months after completion of therapy. The 
upper threshold for disease recurrence in Arm 1 will be 20% by 24 months after 
completion of therapy. In Arms 2 and 3, we will report the proportion of patients 
with disease recurrence, but will not develop formal hypotheses testing because 
Arm 2 patients will be too few in number and Arm 3 patients will receive standard 
POACRT.     
 
 
2.0 
STUDY ENDPOINTS AND OBJECTIVES 
 
2.1 
Primary Objective 
 
1. To determine the percent weight loss in patients during POAmCRT (Arm 1) 
starting at Day 1 and ending on the last day of RT.  
 
2.2 
Secondary Objectives 
 
1. To evaluate the narcotics administration of patients 6 weeks after POAmCRT 
(Arm 1).  
2. To determine the disease recurrence rate at 24 months post-treatment in each 
arm. 

Version 2/27/2023 
 18 of 57 
3. To determine progression free survival (PFS) and overall survival (OS) for each 
arm. 
4. To evaluate the proportion of PEG tube placements in each arm. 
5. To determine the serum creatinine changes in patients receiving POAmCRT 
(Arm 1). 
 
 
2.3 
Exploratory Objectives 
 
1. To document the measures of Quality of Life (QOL) at baseline, during 
treatment, and through one year after completion of treatment in each arm. 
 
 
3.0 
PATIENT ELIGIBILITY 
 
3.1 
Inclusion Criteria  
 
1. Histologically or cytologically confirmed HPV-related stages I-III OPSCC (8th 
edition of AJCC/UICC Staging Manual) or HPV-related neck node with 
unknown primary. HPV-related may be defined by p16 IHC stain and/or HPV-
ISH or PCR using standard definitions of positive and negative test results.  
cT1N0 and cT2N0 excluded. 
2. Primary tumor that will be resected via a transoral oral approach (conventional 
surgery, transoral laser microsurgery, transoral robotic surgery) 
3. ECOG PS 0-2. 
4. Normal organ and marrow function defined as: 
a. Creatinine clearance > 50 cc/min.  
b. ANC > 1,000/mcL. 
c. Platelet count >100,000/mcL. 
5. At least 18 years of age. 
6. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control, abstinence) prior to 
study entry and for the duration of participation.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she must 
inform her treating physician immediately. 
7. Patient (or legally authorized representative) must be able to understand and 
willing to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
1. cT1N0 or cT2N0 staging. 
2. Prior curative therapy for HNSCC. 
3. Patient must not have known distant metastatic disease at presentation.  
4. History of prior invasive malignancy diagnosed within 2 years prior to study 
enrollment; exceptions are malignancies with a low risk of metastasis or death 
(e.g., expected 5-year OS > 90%) that were treated with an expected curative 
outcome, such as squamous cell carcinoma of the skin, in-situ carcinoma of 

Version 2/27/2023 
 19 of 57 
the cervix uteri, non-melanomatous skin cancer, carcinoma in situ of the breast, 
or incidental histological finding of prostate cancer (TNM stage of T1a or T1b). 
5. Receiving any other investigational agents. 
6. Uncontrolled serious inter-current illness or serious psychiatric illness/social 
situations that would limit compliance with study requirements. 
7. Pregnant and/or breastfeeding.  A negative serum or urine pregnancy test is 
required at screening for all female patients of childbearing potential. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for 
this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the 
Siteman Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study 
team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore 
database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  
All data will be recorded with this identification number on the appropriate CRFs. 
 

Version 2/27/2023 
 20 of 57 
5.0 
TREATMENT PLAN AND SCHEDULED ASSESSMENTS 
 
Patients with HPV-related OPSCC will undergo resection of the primary tumor site and 
involved/at risk regional neck nodes. Based on the clinical and pathologic staging and the 
details of the pathology report, patients will be assigned to one of three adjuvant 
treatments. Arm 1 (ECE or positive margin but not clinical or pathologic T4 or clinical N3 
disease) will be treated with POAmCRT (42 Gy RT + cisplatin 1 dose). Arm 2 (no ECE, 
no positive margins, and not clinical or pathologic T4 or clinical N3 disease) will be treated 
with POAmRT (42 Gy RT, no cisplatin). Arm 3 (clinical or pathologic T4 or clinical N3 
disease) will be treated with POART (60 Gy RT). If there is pathologic evidence of ECE 
or positive margin, 3 cycles of cisplatin will be given concurrently with POART (60Gy).  
 
Please note that because weight loss is the primary endpoint, a specific scale must be 
chosen at each facility.  It is the responsibility of the research coordinator to ensure that 
the same scale is used for all patients at that facility.  Patient weight will be assessed with 
clothes on (no outer layers such as jackets) and shoes off. 
 
5.1 
Baseline Assessment 
 
The baseline assessment will include the following tests or procedures and must 
occur within 35 days (PET scan within 42 days) of enrollment: 
 
1. Clinical examination to document extent of primary tumor by laryngoscopy 
performed in the office or in the operating room (depending on the ease of 
the exam and the primary tumor site) and palpable involved regional neck 
nodes. 
2. Documentation of site of primary tumor (HPV-related oropharynx or CUP), 
location and level of clinically involved neck nodes (right or left neck, Level 
I-V), T stage (1-4), N stage (0-3), and overall clinical stage (I-III by AJCC 
Cancer Staging Manual Eighth Edition). 
3. Documentation of demographic information, including gender (M/F), age 
(years), height (cm), weight (Kg), and BSA (m2).  
4. Documentation of baseline patient symptoms using NCI-CTCAE version 
4.0. 
5. Documentation of ECOG performance status (Appendix 1). 
6. Completion of QOL questionnaires (Appendices 3, 4, 5, 6, and 7). 
7. Documentation of Comorbidity Index (Appendix 2). 
8. Laboratory evaluations: CBC, CMP, magnesium, PT/PTT, serum 
pregnancy test if patient is a female of childbearing potential. 
9. CT scan of the neck (IV contrast preferred) to document and measure the 
extent of the primary tumor size and involved regional neck nodes.  
10. FDG-PET/CT scan (whole body) to document and measure the FDG avidity 
at the primary tumor site and at the involved regional neck nodes. 
11. OPTIONAL: Speech and swallowing assessment including a modified 
barium swallow (MBS) study and the Performance Status Scale for Head 
and Neck Cancer (PSS-HN) questionnaire (Appendix 8). 

Version 2/27/2023 
 21 of 57 
5.2 
Standard of Care Surgery 
 
Patients will undergo a typical preoperative workup in preparation for surgery, 
including routine lab work, electrocardiogram, and a preoperative assessment by 
anesthesiology.  Patients will undergo surgical resection of the primary tumor via 
a transoral approach, including conventional transoral surgery, transoral laser 
microsurgery (TLM), or transoral robotic surgery (TORS). The choice of surgical 
technique will be based on surgeon preference, tumor characteristics, and tumor 
site. Margin status will be assessed intra-operatively on frozen section and 
confirmed on permanent section.  
 
At the time of transoral resection, patients will also undergo surgical management 
of cervical lymph nodes via a conventional selective neck dissection.  For 
oropharyngeal tumors, this most often includes dissection of Levels II-IV. If the 
tumor approaches within one centimeter of midline, the patient will undergo 
bilateral neck dissections.   
 
The 
pathology 
report 
documents 
margin 
status, 
perineural 
invasion, 
lymphovascular invasion, and extracapsular extension (ECE). Margins will be 
considered positive if gross or microscopic disease is present at the margins based 
on the surgical pathologist’s judgement. ECE will be defined as tumor extending 
beyond the lymph node capsule into the surrounding soft tissue (AJCC 8th Edition 
Staging Manual). ECE will be measured when possible; however, extensive ECE 
or soft tissue metastases may preclude this measurement. 
 
5.3 
Interim Assessment 
 
The interim assessment will include the following tests or procedures and should 
occur within 14-42 days of surgery: 
 
1. Clinical examination. 
2. Documentation of key data from the pathology report: T (1-4) and N (0-3) stage, 
ECE status (+/-) and extent of ECE (mm), margin status (+/-).  
3. Arm assignment (based on pathology data) 
4. Documentation of patient symptoms using NCI-CTCAE version 4.0; please 
note that AEs considered at least possibly related to surgery need not be 
recorded. 
5. Documentation of ECOG performance status. 
6. Completion of QOL questionnaires. 
7. Documentation of Comorbidity Index. 
8. Laboratory evaluations: CBC, BMP, magnesium, PT/PTT. 
9. OPTIONAL: Speech and swallowing assessment including MBS and PSS-HN 
questionnaire. 
 
 
 
 

Version 2/27/2023 
 22 of 57 
5.4 
Postoperative Adjuvant Chemotherapy 
 
5.4.1 ARM 1 ONLY - Cisplatin (one dose) + 21 doses of RT 
 
The dose of cisplatin will be given on the same day as one of the initial 5 
doses of POART (refer to Section 5.5 for RT dosing). 
 
Recommended procedures for cisplatin therapy are as follows: 
 
1. Antiemetic premedication prior to cisplatin: palonosetron 0.25 mg  
IVPB, dexamethasone 10 mg IVPB and aprepitant 150 mg IVPB. 
2. Hydration consisting of 1L IVF NS (10 meq KCL/L + 8 meq MgSO4/L) 
over 60 minutes before and after cisplatin on the day of dosing.  2L IVF 
NS over 60 minutes on each of the two days following cisplatin dosing. 
3. Administration of cisplatin (100 mg/m2 IVPB over 60 minutes) on one 
day only during one of the first 5 doses of radiation. 
4. Physical examination will be performed on the day of cisplatin 
administration and on day 22 (+/- 2) and 36 (+/- 2) after starting radiation 
therapy. 
5. Weight (kg) will be collected weekly during radiation.  
6. Documentation of ECOG performance status will be done on the day of 
cisplatin administration and on days 22 (+/- 2) and 36 (+/- 2) after starting 
radiation therapy. 
7. Documentation of patient symptoms using NCI-CTCAE version 4.0 will 
be done on the day of cisplatin administration and on days 22 (+/- 2) and 
36 (+/- 2) after starting radiation therapy. 
8. CBC, BMP and magnesium on the day of cisplatin administration and 
on days 22 (+/- 2) and 36 (+/- 2) after starting radiation therapy. 
9. Patient to complete QOL questionnaire prior to starting radiation (-7/+0) 
and during the fourth week of radiation (radiation doses 16-21) and 36 
(+/- 2) days after starting radiation therapy. 
10. OPTIONAL: Patient to receive speech and swallowing assessments 
prior to starting radiation* and during the fourth week of radiation 
(radiation doses 16-21) and 2 weeks after completing radiation therapy. 
*Modified barium swallow not needed within one week prior to starting 
radiation. 
 
5.4.2 ARM 2: No Cisplatin. 21 doses of RT only. 
 
Refer to Section 5.5 for RT dosing instructions. 
 
1. Physical examination and weight (kg) will be performed on the first day 
of radiation therapy and on days 22 (+/- 2) and 36 (+/- 2) after starting 
radiation therapy. 
2. Weight (kg) will be collected weekly during radiation.  

Version 2/27/2023 
 23 of 57 
3. Documentation of ECOG performance status will be done on the first 
day of radiation therapy and on days 22 (+/- 2) and 36 (+/- 2) after 
starting radiation therapy.  
4. Documentation of patient symptoms using NCI-CTCAE version 4.0 will 
be done on the first day of radiation therapy and on days 22 (+/- 2) and 
36 (+/- 2) after starting radiation therapy. 
5. CBC, BMP and magnesium on the first day of radiation therapy and on 
days 22 (+/- 2) and 36 (+/- 2) after starting radiation therapy. 
6. Patient to complete QOL questionnaire prior to starting radiation (-7/+0) 
and during the fourth week of radiation (radiation doses 16-21), and 36 
(+/- 2) days after starting radiation therapy. 
7. OPTIONAL: Patient to receive speech and swallowing assessments 
prior to starting radiation* and during the fourth week of radiation 
(radiation doses 16-21) and 36 days after starting radiation therapy. 
*Modified barium swallow not needed within one week prior to starting 
radiation. 
 
5.4.3 ARM 3 ONLY – Thirty doses of RT (+ 3 doses of Cisplatin if 
positive margins or ECE) 
 
If the patient has positive margins or ECE, they will receive Cisplatin with 
the 30 doses of RT. The first dose of cisplatin will be given on one of the 
days during the initial 5 days of POART, the second cisplatin dose on the 
day of radiation dose 16  (+/- 5 days), and the third cisplatin dose on the 
day of radiation dose 26 (+/- 5 days). 
 
Recommended procedures for Arm 3 are as follows: 
 
1. Physical examination will be performed on each day of cisplatin 
administration (radiation dose 1, 16 (+/- 5) and 26 (+/- 5)). 
2. Documentation of ECOG performance status will be done on each day 
of cisplatin administration (radiation dose 1, 16 (+/- 5) and 26 (+/- 5)). 
3. Documentation of patient symptoms using NCI-CTCAE version 4.0 will 
be done on each day of cisplatin administration (radiation dose 1, 16 (+/- 
5) and 26 (+/- 5)). 
4. Patient to complete QOL questionnaire prior (-7/+0) to starting radiation, 
during the fourth week of radiation (radiation doses 16-20) and during 
the last week of radiation (radiation doses 26-30). 
5. OPTIONAL: Patient to receive speech and swallowing assessment prior 
(within one week) to starting radiation*, during the fourth week of 
radiation (radiation doses 16-20) and during the last week of radiation 
(radiation doses 26-30). *Modified barium swallow not needed within 
one week prior to starting radiation. 
 
Recommended procedures for cisplatin therapy (on Arm 3) are as follows: 
 
1. Antiemetics premedication prior to each dose of cisplatin: palonosetron 

Version 2/27/2023 
 24 of 57 
0.25 mg IVPB, dexamethasone 10 mg IVPB and aprepitant 150 mg 
IVPB. 
2. Hydration consisting of 1L IVF NS (10 meq KCL/L + 8 meq MgSO4/L) 
over 60 minutes before and after cisplatin on the day of dosing.  2L IVF 
NS over 60 minutes on each of the two days following cisplatin dosing. 
3. Administration of cisplatin (100 mg/m2 IVPB over 60 minutes) on days 
1, 22 (+/- 5), and 36 (+/- 5). 
4. Weight (kg) will be collected weekly during radiation.  
5. CBC, BMP and magnesium on each day of cisplatin administration 
(radiation dose 1, 16 (+/- 5) and 26 (+/- 5)). 
 
5.5 
POART 
 
It is recommended that radiation therapy begin within 28 to 49 days (and no later 
than 56 days) after the surgical resection.  Intensity modulated radiation therapy 
(IMRT) or intensity modulated proton therapy (IMPT) is to be used exclusively for 
this study. IMRT or IMPT will be delivered once per day Monday through Friday 
per routine clinical practice in Arm 3. In Arms 1 and 2, one BID treatment will be 
given during the course of therapy. If patient logistics prohibit the one BID 
treatment, once daily treatments throughout will be acceptable. The total dose to 
the postoperative tumor bed will be: 
• Arm 1: 4200 cGy in 21 fractions of 200 cGy each over 4 weeks 
• Arm 2: 4200 cGy in 21 fractions of 200 cGy each over 4 weeks 
• Arm 3: 6000 cGY in 30 fractions of 200 cGy each over 6 weeks 
 
Additional regions in the ipsilateral and contralateral neck at risk for microscopic 
disease in the cervical lymph nodes will receive: 
• Arm 1: 3780 cGy in 21 fractions of 180 cGy each 
• Arm 2: 3780 cGy in 21 fractions of 180 cGy each 
• Arm 3: 5200 cGy in 30 fractions of 173 cGy each 
 
5.5.1 CT Simulation 
 
As per routine practice, computed tomography (CT) will be the primary 
image platform for targeting and treatment planning.  Prior to the scan, the 
patient will be given IV contrast according to institutional protocols (provided 
the patient has normal renal function and no allergies to contrast).  The 
patient will be positioned supine on the CT simulator table (head toward the 
gantry). The head will be placed on standard or customized headrest so as 
to have the neck slightly extended.  Alternatively, a custom head/shoulder 
mold may be used for immobilization. An immobilization mask will then be 
fashioned. A CT dataset will be acquired from the top of the head through 
5 cm below the clavicular heads with no more than 5 mm axial slices.  Three 
localization marks will be drawn and wired on the patient’s immobilization 
mask at the angle of the mandible bilaterally and midline. These marks will 
serve to establish an internal reference from which an isocenter is placed 

Version 2/27/2023 
 25 of 57 
midline, midplane, at the level of the angle of the mandible.   
 
5.5.2 Virtual Simulation and Contouring 
 
The CT scan will be exported to a commercially available virtual simulation 
software package.  Guidelines for delineating each lymph node level will be 
based on the international consensus for delineation of head and neck 
lymph nodes (http://www.rtog.org/hnatlas/main.html). These guidelines 
were derived in part from Washington University School of Medicine 
institutional data and are consistent with routine clinical practice at 
Washington University.   
 
Arms 1 and 2: An example case of a T3N2BM0 (AJCC 7th edition), stage 
IVA tonsil cancer is outlined in the table below. Current treatment guidelines 
for this case including dose levels are represented with CTV1 and CTV2.  
 
CTV1 
CTV2 
[GTVp + GTVn] + 1.0 to 1.5 cm 
minimum concentric margin 
excluding bone and air with aid of 
preop imaging with/without fusion 
IN (II-V) + BRPLN +  
CN (IIb-IV) 
Exclusive of CTV1. 
Dose 42 Gy/21 fx 
Dose 37.8 Gy/21 fx 
 
Key: GTVp = GTV primary tumor; GTVn = GTV nodal tumor; IN = ipsilateral neck; CN = 
contralateral neck; roman numbers relate to the level system of naming lymph node 
regions; BRPLN = bilateral retropharyngeal lymph nodes).  
 
Arm 3: An example case of a T4N2M0 (AJCC 7th edition), stage IVA tonsil 
cancer is outlined in the table below.  Current treatment guidelines for this 
case including dose levels are represented with CTV1 and CTV2.  
 
CTV1 
CTV2 
[GTVp + GTVn] + 1.0 
to 1.5 cm minimum 
concentric margin 
excluding bone and 
air with aid of preop 
imaging with/without 
fusion 
IN (II-V) + BRPLN + 
CN (IIb-IV) Exclusive 
of CTV1. 
Dose 60 Gy/30 fx 
Dose 52 Gy/30 fx 
 
Key: GTVp = GTV primary tumor; GTVn = GTV nodal tumor; IN = ipsilateral neck; CN = 
contralateral neck; roman numbers relate to the level system of naming lymph node 
regions; BRPLN = bilateral retropharyngeal lymph nodes).  
 
Normal structure and treatment volume contours will be delineated in a 
manner consistent with routine clinical practice. 
 

Version 2/27/2023 
 26 of 57 
5.5.3 IMRT and/or IMPT Optimization 
 
The image and contour data will be exported to the Varian Eclipse platform 
where IMRT or IMPT optimization will be performed.  
 
5.5.4 Treatment Field Arrangement 
 
The Varian System employs up to ten co-planar fields with static or dynamic 
multileaf collimation. The treatment planning system calculates the 
optimized collimator leaf delivery pattern that most closely approximates the 
prescribed constraints and prescription goals. 
 
5.5.5 Dose, Energy and Prescription Parameters 
 
Arms 1 and 2: External beam radiation with 6 MV photons will be delivered 
in 200 cGy daily fractions (Monday through Friday), 21 fractions over 4 
weeks to a total dose of 4200 cGy. 
   
Prescription Coverage Goals 
99% of clinical treatment volumes should receive at least 95% of the 
respective prescription dose (i.e. 99% of PTV 4200 should be covered by 
3990 cGy and 99% of PTV 3780 covered by 3591 cGy). 
 
No more than 5% of the volume “Skin” should receive more than the 
prescription dose (42 Gy) and hotspots must be within the PTV.   
 
Arm 3: External beam radiation with 6 MV photons will be delivered in 200 
cGy daily fractions (Monday through Friday), 30 fractions over 6 weeks to a 
total dose of 6000 cGy. 
   
Prescription Coverage Goals 
99% of clinical treatment volumes should receive at least 93% of the 
respective prescription dose (i.e. 99% of PTV 6000 should be covered by 
5700 cGy, and 99% of PTV 5200 covered by 4940 cGy). 
 
No more than 5% of the volume “Skin” should receive more than the 
prescription dose (60 Gy) and hotspots must be within the PTV.   
 
5.5.6 Normal Structure Dose Limit Guidelines 
 
Arms 1 and 2: Dose limit guidelines for normal structures are as follows: 
Structure 
Volume 
Dose 
Guideline 
(Gy) 
Dose Mean 
(Gy) 
Critical Structures 
 
 
 
Spinal Cord + 8 mm 
1 cc 
42 
 
Spinal Cord 
0.1 cc 
40 
 

Version 2/27/2023 
 27 of 57 
Brainstem 
1% 
40 
 
 
0.1 cc 
40 
 
Brain 
1% 
40 
 
 
5 cc 
45 
 
Optic nerve* 
1% 
40 
 
 
0.1 cc 
42 
 
Optic chiasm 
1% 
40 
 
 
0.1 cc 
42 
 
Eye* 
 
 
45 
Normal Structures 
 
 
 
Retina* 
1% 
40 
25 
Lens* 
 
 
2 
Oral cavity 
 
 
35 
Larynx 
 
 
42 
Mandible 
5% 
45 
 
Skin 
5% 
45 
 
Partial esoph 
2 cc 
40 
 
Middle Ear* 
 
 
45 
Parotid glands* 
20 cc 
20 
26 
*Paired structures. Dose constraints apply to one such structure and are equivalent for the 
contralateral side. 
 
Priority for Above Dose Constraints 
1. Critical Structures 
2. PTV Prescription Goals 
3. Salivary Glands 
4. Other Structures 
 
Arm 3: Dose limit guidelines for normal structures are as follows: 
Structure 
Volume 
Dose 
Guideline 
(Gy) 
Dose Mean 
(Gy) 
Critical Structures 
 
 
 
Spinal Cord + 8 mm 
1 cc 
50 
 
Spinal Cord 
0.1 cc 
45 
 
Brainstem 
1% 
60 
 
 
0.1 cc 
60 
 
Brain 
1% 
60 
 
 
5 cc 
65 
 
Optic nerve* 
1% 
60 
 
 
0.1 cc 
60 
 
Optic chiasm 
1% 
60 
 
 
0.1 cc 
60 
 
Eye* 
 
 
45 
Normal Structures 
 
 
 
Retina* 
1% 
50 
35 
Lens* 
 
 
2 
Oral cavity 
 
 
35 

Version 2/27/2023 
 28 of 57 
Larynx 
 
 
45 
Mandible 
5% 
73.5 
 
Skin 
5% 
70 
 
Partial esoph 
2 cc 
54 
 
Middle Ear* 
 
 
45 
Parotid glands* 
20 cc 
20 
26 
*Paired structures. Dose constraints apply to one such structure and are equivalent for the 
contralateral side. 
 
Priority for Above Dose Constraints 
1. Critical Structures 
2. PTV Prescription Goals 
3. Salivary Glands 
4. Other Structures 
 
5.5.7 Treatment Plan Evaluation 
 
The plan will be reviewed by the treating physician prior to treatment in order 
to ensure that all parameters have been met.  Isodose curves and dose 
volume histograms (DVH) will be analyzed. 
 
Arms 1 and 2: Criteria for plan evaluation will include: 
• Isodose Curves: 
The 95% isodose line must be generally conformal to the PTV with 
visually acceptable tumor coverage and visually acceptable critical 
structure avoidance. 
The 110% isodose line must not include any critical structure 
volumes. 
The 4200 cGy isodose line must not encroach on the “Spinal cord + 
5 mm”. 
The 2600 cGy isodose line should spare parotid glands when 
possible. 
 
• Dose Volume Histograms (DVHs): 
No more than 20% of any PTV should exceed 110% of the 
prescribed dose. 
DVH from PTVs must meet all prescription parameters. 
Normal structure DVHs should meet constraint parameters as listed 
above. 
 
Arm 3: Criteria for plan evaluation will include: 
• Isodose Curves: 
The 95% isodose line must be generally conformal to the PTV with 
visually acceptable tumor coverage and visually acceptable critical 
structure avoidance. 
The 110% isodose line must not include any critical structure 
volumes. 

Version 2/27/2023 
 29 of 57 
The 4200 cGy isodose line must not encroach on the “Spinal cord + 
5 mm”. 
The 2600 cGy isodose line should spare parotid glands when 
possible. 
 
• Dose Volume Histograms (DVHs): 
No more than 20% of any PTV should exceed 110% of the 
prescribed dose. 
DVH from PTVs must meet all prescription parameters. 
Normal structure DVHs should meet constraint parameters as listed 
above. 
 
5.5.8 Daily Radiation Treatment 
 
Arms 1 and 2: Patients will receive external beam radiation treatment 
delivered by a Varian linear accelerator once a day, five days a week, for 4 
to 4 1/5 weeks as per routine clinical practice. 
 
Arm 3: Patients will receive external beam radiation treatment delivered by 
a Varian linear accelerator once a day, five days a week, for 6 weeks as per 
routine clinical practice.  
 
5.5.9  Quality Assurance 
 
Treatment plan physics review and QA are required for each patient in 
accordance with current institutional standards for IMRT. 
 
Daily set-up error will be minimized by the following clinically approved and 
commercially available patient setup techniques: immobilization mask, 
standard skin/mask alignment marks, and daily on-board imaging.  
 
Per routine practice, daily cone beam CT scans will be acquired and 
compared with planning CT overlay. 
 
These setup scans will be performed immediately prior to each treatment 
and the appropriate shifts will be made at that time.  
 
5.6 
Follow-Up Assessments after Adjuvant Therapy 
 
Follow-up assessments will be planned at the following time points; actual follow 
up times may vary due to patient logistics and compliance: 
• 6 weeks (+/- 1 week) following completion of adjuvant therapy 
• 4 months (+/- 2 weeks) following completion of adjuvant therapy 
• 6, 12, 18, 24, 30, 36, 48, and 60 months (+/- 6 weeks) following completion 
of adjuvant therapy 
• annually thereafter for 5 years (total follow-up 10 years) 

Version 2/27/2023 
 30 of 57 
Patients with disease progression will only be followed for survival and will not stay 
on the above follow-up schedule. Their follow-up schedules will then be at the 
discretion of the investigator. 
 
5.6.1 Six Week (+/- 1 week) Assessment 
 
1. Physical examination and weight (kg). 
2. Serum creatinine (BMP). 
3. Documentation of ECOG performance status. 
4. Documentation of narcotic and PEG tube usage. 
5. Documentation of patient symptoms using NCI-CTCAE version 4.0. 
6. Completion of QOL questionnaires 
7. CT Neck. 
8. OPTIONAL: Speech and swallowing assessment 
 
5.6.2 Four Month (+/- 2 weeks) Assessment  
 
1. Physical examination and weight (kg). 
2. Documentation of ECOG performance status. 
3. Documentation of narcotic and PEG tube usage. 
4. Completion of QOL questionnaires. 
5. OPTIONAL: Speech and swallowing assessment 
 
5.6.3 Six to Sixty Month (+/- 6 weeks) Assessments 
 
1. Physical examination and weight (kg). 
2. Documentation of ECOG performance status. 
3. Documentation of narcotic and PEG tube usage. 
4. Completion of QOL questionnaires (to occur at 6, 12 and 24 month visits 
only). 
5. CT scan of neck and chest (IV contrast preferred) to be done at 6, 12, 
18, 24, and 36 months (+/- 6 weeks) following completion of therapy. 
CXR (PA and Lateral) may be substituted for CT chest if unable to obtain 
the latter. 
6. OPTIONAL: Speech and swallowing assessment (to occur at 6, 12, and 
24 month visits only). These will include MBS at 6 months post-adjuvant 
therapy, PSS-HN questionnaires at 6, 12, and 24 months, and Fiberoptic 
Endoscopic Evaluation of Swallowing (FEES) as clinically indicated. 
 
5.6.4 Annual Assessments Subsequently 
 
1. Physical examination and weight (kg). 
2. Documentation of ECOG performance status. 
 
 
 

Version 2/27/2023 
 31 of 57 
5.7 
Evaluations for Toxicity and Disease Relapse 
 
All patients who receive any study treatment (starting point of “study treatment” is  
first dose of post-operative RT) are evaluable for toxicity. Patients are evaluated 
from first day of study treatment until five years after the conclusion of treatment, 
or death. 
 
All patients who undergo surgery are evaluable for disease relapse. 
 
5.8 
General Concomitant Medication and Supportive Care Guidelines 
 
Primary prophylaxis with G-CSF or Neulasta is not permitted; however it can be 
used in a non-prophylactic setting following neutropenia.  Use of erythropoietin is 
not permitted. 
 
5.9 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women 
with amenorrhea, women with irregular cycles, women using a contraceptive 
method that precludes withdrawal bleeding, and women who have had a tubal 
ligation) are required to have a negative serum pregnancy test within 35 days of 
enrollment.   
 
Female and male patients (along with their female partners) are required to use 
two forms of acceptable contraception, including one barrier method, during 
participation in the study and for 1 month following the last day of study treatment.  
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum 
pregnancy test.  If it is confirmed that the patient is not pregnant, the patient may 
resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during 
therapy or within 1 month after the last day of study treatment, the investigator 
must be notified in order to facilitate outcome follow-up. 
 
5.10 Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to 
the patient’s health and/or the patient no longer wishes to continue protocol 
therapy, the protocol therapy should be discontinued and the reason(s) for 
discontinuation documented in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
for the duration of surgery and RT +/- cisplatin until one of the following criteria 
applies: 

Version 2/27/2023 
 32 of 57 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe 
or permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
6.0 
PHARMACEUTICAL INFORMATION 
 
6.1 
Cisplatin (CDDP, Platinol-AQ®) 
 
6.1.1 Cisplatin Description 
 
Molecular formula: PtCl2H6N2 
Molecular weight: 300.1. 
 
6.1.2 Clinical Pharmacology 
 
The mechanism of action of cisplatin has not been clearly elucidated. 
However the most likely mechanism of antitumor action of this drug resides 
in its ability to inhibit DNA synthesis, and to a lesser degree, RNA and 
protein synthesis. It has also been shown that Cisplatin binds to DNA and 
produces inter-strand cross-links. Also cisplatin is not phase-sensitive and 
its cytotoxicity is similar in all phases of the cell cycle. Additional information 
can be found in the package insert. 
 
6.1.3 Supplier 
 
Cisplatin is commercially available as 1 mg/mL in both 50 mL multiple dose 
vial and 100 mL multiple dose vial. 
 
6.1.4 Dosage Form and Preparation 
 
The stability of cisplatin in solution is dependent upon the chloride ion 
concentration present in the diluent. Cisplatin should be diluted into an IV 
solution containing NaCL at a minimum chloride ion concentration of 0.040 

Version 2/27/2023 
 33 of 57 
mol/L (0.2% NaCL). Needles, syringes, catheters and IV administrations 
sets containing aluminum must be avoided during preparation and 
administration due to cisplatin-aluminum reaction causing precipitation and 
loss of potency. Mannitol 12.5 to 25 gm may be added per institutional 
guidelines. 
 
6.1.5 Storage and Stability 
 
The dry, unopened vials should be stored at room temperature (15° -25° C). 
The unopened container should be protected from light and stored in the 
carton until contents are used. Do not refrigerate. Cisplatin remaining in the 
amber vial following initial entry is stable for 28 days protected from light or 
for 7 days under fluorescent room light. 
 
6.1.6 Administration 
 
Patients will receive cisplatin via IV infusion over 60 minutes.  Adequate 
hydration must be maintained during and after administration as described 
in the treatment section. It is recommended that all patients should be 
premedicated with antiemetics. 
 
7.0 
DOSE MODIFICATIONS 
 
At each of the scheduled visits noted in the study calendar, an assessment of adverse 
events (AEs) will be made by the treating physician with toxicity grading using the NCI 
CTCAE version 4. Patients without AEs will continue on study treatment as planned. 
Patients who develop grade 1-2 or selected grade 3 (nausea/vomiting/fatigue) AEs will 
be supported symptomatically and encouraged to continue on study treatment as 
planned. Modifications in their therapy may be necessary and will be detailed below.  
Management of specific AEs is noted below. 
 
7.1 
Cisplatin Dose Modifications (Arm 3 only) 
  
7.1.1 Ototoxicity 
 
Grade 3-4 hearing loss/tinnitus is an indication to consider discontinuation 
of the drug. 
 
7.1.2 Kidney Impairment 
 
Calculated 
Creatinine 
Clearance 
Percent Dose to Give 
≥ 50 mL/min 100% 

Version 2/27/2023 
 34 of 57 
< 50 mL/min 
0% (withhold treatment for this dose and repeat serum 
creatinine weekly after additional hydration), then for next 
chemotherapy dose: 
If CrCl was already < 50 mL/min 
and is now:  
The percent dose 
to give is:  
> 40 but < 50 
50% 
< 40 
0% 
Please note that dose reduction percentage is calculated by taking off 
from the original dose and not the previous dose. 
 
7.1.3 Neutropenia/Thrombocytopenia 
 
Nadir of last 
course 
ANC/Platelets (Day 1 of each cycle) 
ANC < 500 
Plts < 60,000 
ANC 500-749 
Plts 60,000-99,000 
ANC ≥ 750 
Plts > 99,000 
ANC > 500  
Plts > 30,000 
Hold cisplatin 
50% cisplatin 
100% cisplatin 
ANC < 500 
Plts < 30,000 
 Hold cisplatin 
Hold cisplatin 
50% cisplatin 
 
7.1.4 Other Grade 2-4 Non-Hematologic AEs 
 
At the discretion of the treating physician, clinical judgement may be used 
to hold doses of cisplatin if current or interim toxicities are felt to significantly 
increase the risk of serious toxicity with administration of that dose of 
cisplatin. 
 
7.2 
Radiation Dose Modifications 
 
There are no planned dose modifications or delays for radiation therapy.  Delays 
are allowed at the discretion of the treating physician. 
 
8.0 
CORRELATIVE STUDIES 
 
8.1 
Tumor Acquisition Protocol 
 
All patients will be strongly encouraged to participate on this companion protocol 
(HRPO #201102323) for future correlative studies. Tumor samples will be 
collected in the operating room by trained research personnel, processed and 
stored according to established protocols. 
 
Correlative studies may be conducted to further determine potential molecular 
markers of risk in HPV-positive oropharyngeal cancer. These studies may include 
DNA sequencing for mutational analysis and copy number variations. HPV viral 
load and integration versus episomal status may also be assessed. 
 

Version 2/27/2023 
 35 of 57 
Additionally, gene expression studies, including expression of viral genes, may be 
conducted on all samples and correlated with other tumor characteristics and 
outcomes. Future studies may also include the creation of PDX models as well as 
immunohistochemistry.  
 
8.2 
Quality of Life Assessments 
 
QOL will be assessed using the FACT-H&N (Appendix 3), MD Anderson 
Dysphagia Inventory (Appendix 4), University of Michigan Xerostomia Index 
(Appendix 5), Scale of Subjective Total Taste Acuity (Appendix 6), and Neck 
Dissection Impairment Index (Appendix 7) at the following time points: 
• Baseline (before the start of any treatment) 
• Interim assessment (14-42 days post-surgery) 
• Day 1 of radiation (-7/+0 days) 
• Day 22 after the start of radiation (Arm 1 & 2 +/- 2 days; Arm 3 +/- 5 days) 
• Day 36 after the start of radiation (Arm 1 & 2 +/- 2 days; Arm 3 +/- 5 days) 
• 6 weeks after the completion of adjuvant therapy (+/- 1 week) 
• 4 months after the completion of adjuvant therapy (+/- 2 weeks) 
• 6 months after the completion of adjuvant therapy (+/- 6 weeks) 
• 12 months after the completion of adjuvant therapy (+/- 6 weeks) 
• 24 months after the completion of adjuvant therapy (+/- 6 weeks) 
 
9.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require 
reporting as outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all 
events meeting the definition of unanticipated problem or serious noncompliance be 
reported as outlined in Section 9.2. 
 
9.1 
Definitions 
 
9.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject 
including any abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for all toxicity reporting.  A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the 
definitions for the terms listed that should be used are those provided by the 
Department of Health and Human Services’ Office for Human Research 

Version 2/27/2023 
 36 of 57 
Protections (OHRP).  A copy of this guidance can be found on OHRP’s 
website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
9.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results 
in any of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
9.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which 
is not consistent with the current investigator brochure (or risk information, 
if an IB is not required or available). 
 
9.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view 
of the investigator) at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
 
9.1.5 Unanticipated Problems 
 
Definition: 
 
• 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; 
• 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 

Version 2/27/2023 
 37 of 57 
• 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. 
 
9.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies 
that govern human subjects research or failure to follow the determinations 
of the IRB.  Noncompliance may occur due to lack of knowledge or due to 
deliberate choice to ignore regulations, institutional policies, or 
determinations of the IRB. 
 
9.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in 
substantial harm to subjects or others, or that materially compromises the 
rights or welfare of participants. 
 
9.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under 
the research team’s control. Exceptions apply only to a single participant or 
a singular situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
9.2 
Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which 
occur at WU, any BJH or SLCH institution, or that impacts participants or 
the conduct of the study. 
• Noncompliance with federal regulations or the requirements or 
determinations of the IRB. 
• Receipt of new information that may impact the willingness of participants 
to participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the 
occurrence of the event or notification to the PI of the event.  The death of a 
research participant that qualifies as a reportable event should be reported within 
1 working day of the occurrence of the event or notification to the PI of the event. 
 
 

Version 2/27/2023 
 38 of 57 
9.3 
Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at 
WU or any BJH or SLCH institution that has been reported to and acknowledged 
by HRPO as reportable.  (Unanticipated problems reported to HRPO and 
withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to a QASMC auditor. 
 
9.4 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked through the 6 weeks post-end of adjuvant therapy 
visit.  For the purposes of this protocol, adverse events related to the standard of 
care surgery will not be collected and documented on CRFs.  
 
10.0 STATISTICAL CONSIDERATIONS 
 
10.1 Study Design 
 
This is a three-arm non-randomized Phase II trial. All the enrolled patients will 
undergo resection of the primary tumor site and involved/at risk regional neck 
nodes. Patients will be assigned to one of three adjuvant treatments based on the 
clinical and pathologic staging and the details of the pathology report. 90%, 5%, 
and 5% of the patients are expected to be in Arm 1, 2, and 3, respectively. The 
overarching goal is to reduce treatment-related toxicity while maintaining efficacy. 
Weight loss is a reliable, easily measured and practical surrogate marker of 
mucosal toxicity. Therefore, the primary objective is to determine the percent 
weight loss of patients during POAmCRT in Arm 1. The secondary objectives are 
to evaluate the proportion of PEG tube placements, determine the serum 
creatinine changes in patients receiving POAmCRT, evaluate the narcotics 
administration of patients 6 weeks after POAmCRT, document the measures of 
Quality of Life (QOL) at baseline/during treatment/one year after completion of 
treatment on all arms, determine the disease recurrence free survival (RFS) at 24 
months post-treatment in each arm, and determine progression free survival (PFS) 
and overall survival (OS). 
 
10.2 Sample Size Calculation 
 
The primary endpoint is percent weight loss from Day 1 of treatment to last day of 
RT. The sample size calculation is based on the primary endpoint only. Our 
historical data showed that the mean and standard deviation of percent weight loss 
during POACRT in patients with HPV-related OPSCC are 7.39% and 5.46%, 
respectively. The primary hypothesis of this trial is that the percent weight loss of 
patients in Arm 1 during POAmCRT will be 3.7% (50% reduction). Twenty patients 

Version 2/27/2023 
 39 of 57 
will have 80% power to detect the percent weight loss difference if assuming the 
standard deviation of 5.46% using a two-sided one-group t test at the type I error 
of 5%. We will enroll 24 patients in Arm 1 accounting for 15% drop-out22.  We 
estimate that 14 patients will be enrolled in Arm 2 and 6 patients will be enrolled in 
Arm 3 for a total of 40 patients. 
 
In December 2019, we reached the 40 patient enrollment mark. However, Arm 1 
had enrolled only 13 of the target of 20 patients at that time.  In June 2020, we plan 
to increase enrollment to reach 7 additional patients on Arm 1, or 20 additional 
patients onto any arm, whichever comes first. 
 
10.3 Accrual 
 
We perform surgery in 60-80 patients per year at Washington University with 
similar characteristics and estimate approximately 30-40 patients/year may be 
eligible for and will participate in this trial. We anticipate enrollment of 
approximately 2-3 patients per month.  
 
10.4 Statistical Analyses 
 
10.4.1 Patient Disposition 
 
The number of patients discontinued, the reasons for discontinuation, and 
the amount of therapy administered will be summarized by patient and by 
reason for discontinuation by arm. 
 
10.4.2 Protocol Deviations 
 
All significant deviations will be summarized by patient and by type of 
deviation. 
 
10.4.3 Demographics and Baseline Characteristics 
 
Subject demographic and clinical characteristics will be summarized to 
characterize the population. Descriptive summaries will include means, 
standard deviations, medians, ranges for continuous variables and 
frequency and percentage for categorical variables. They are presented by 
total and each arm, respectively. 
 
10.4.4 Endpoint Analysis 
 
The primary endpoint is percent weight loss. Weight (kg) will be collected 
weekly during radiation within each arm. The percent weight loss from the 
baseline is calculated at any post-baseline. The generalized estimating 
equation (GEE) model with identity link function will be used to analyze this 
percent weight loss data, in which the correlation among the repeated 
measures from the same patient need be considered. The autoregressive 

Version 2/27/2023 
 40 of 57 
of first order as working correlation structure will be used. The GEE model 
includes baseline weight and time points. The p-value is estimated to 
assess whether the percentages of weight loss across all time points are 
different. Least square means for percent weight loss at each time point and 
mean differences between any time points will be estimated,  and their 
standard errors will be calculated within the use of GEE sandwich method 
when accounting for within-patient correlation. 
 
The secondary endpoints include proportion of PEG tube placements for all 
enrolled patients, the serum creatinine changes in patients receiving 
POAmCRT, proportion of the narcotics administration of patients 6 weeks 
after POAmCRT,and RFS. Proportions of PEG tube placements for all 
enrolled patients and the narcotics administration of patients 6 weeks after 
POAmCRT and their associated 95% confidence intervals will be calculated 
assuming a binomial distribution23. The serum creatinine is measured at the 
baseline and six weeks after POAmCRT. The paired t-test will be 
considered to test the change.  
 
Disease recurrence rate at 24 months post-treatment (DRR-24) in each arm 
is calculated for each arm. The proportion and 95% CI from binomial 
distribution will be shown for Arm 1. If 95% upper CI is smaller than 20%, 
then the risk of disease recurrence is deemed as acceptable. If 95% lower 
CI is larger than 20%, then the risk of disease recurrence is deemed as 
unacceptable. Given our small sample size, there are some uncertainties. 
Therefore, we do not test the hypothesis about (DRR-24) but provide a 
preliminary data for planning future studies.   
 
PFS will be calculated from the date of surgery to the date of progression, 
death of any cause, or last known date alive.  OS will be calculated from the 
date of surgery to the date of death or last known date alive.  PFS and OS 
will be evaluated using Kaplan Myer. 
 
The exploratory endpoint includes the measures of Quality of Life (QOL). 
QOL are measured at baseline/during treatment/one year after completion 
of treatment on all arms. Similarly, the GEE model will be used to analyze 
the longitudinal QOL data.   
 
Data on the toxicity in each arm will be collected for each subject, including 
frequency, type, and severity of adverse events. All analyses were 
conducted using SAS (SAS Institute, Cary, NC) at the two-sided 5% 
significance level. 
 
11.0 DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to 
the schedule listed in this section. 

Version 2/27/2023 
 41 of 57 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Surgery Form 
Time of surgery 
QOLs Forms 
Baseline 
Interim assessment 
Day 1 of RT (-7/+0) 
Day 22 after start of RT (Arm 1 & 2 +/- 2 days; Arm 3 +/- 5 
days) 
Day 36 after start of RT (Arm 1 & 2 +/- 2 days; Arm 3 +/- 5 
days) 
6 weeks after completion of adjuvant therapy 
4 months after completion of adjuvant therapy 
6 months after completion of adjuvant therapy 
12 months after completion of adjuvant therapy 
24 months after completion of adjuvant therapy 
Toxicity Form 
Continuous 
Weight Form 
Baseline, weekly during treatment, and at each follow-up 
visit 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Narcotics Form 
PEG Form 
6 weeks, 4 months, 6 months, 12 months, 18 months, 24 
months, 30 months, 36 months, and 48 months after the 
completion of adjuvant therapy 
RECIST Form 
Baseline, 6 weeks after completion of adjuvant therapy, and 
6 months after completion of adjuvant therapy 
 
 
12.0 DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring 
Plan, the Principal Investigator will provide a Data and Safety Monitoring (DSM) report to 
the Washington University Quality Assurance and Safety Monitoring Committee 
(QASMC) semi-annually beginning six months after accrual has opened (if at least five 
patients have been enrolled) or one year after accrual has opened (if fewer than five 
patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide 
a semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data 
coordinator name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO 
approval/revision, date of HRPO expiration, date of most recent QA audit, study 
status, and phase of study 
• History of study including summary of substantive amendments; summary of 
accrual suspensions including start/stop dates and reason; and summary of 
protocol exceptions, error, or breach of confidentiality including start/stop dates 
and reason 
• Study-wide target accrual and study-wide actual accrual 

Version 2/27/2023 
 42 of 57 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants 
who have met each objective 
• Measures of efficacy  
• Early stopping rules with supporting data and list the number of participants 
who have met the early stopping rules 
• Summary of toxicities separated by cohorts  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the 
study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient 
Coordinator becomes aware of an adverse event, the AE will be reported to the HRPO 
and QASMC according to institutional guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Version 2/27/2023 
 43 of 57 
13.0 REFERENCES 
 
1. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human 
papillomavirus-related and -unrelated oral squamous cell carcinomas in the United 
States. J Clin Oncol. 2008;26(4):612-619. 
2. Allen CT, Lewis JS, El-Mofty SK, Haughey BH, Nussenbaum B. Human 
papillomavirus 
and 
oropharynx 
cancer: 
biology, 
detection 
and 
clinical 
implications. Laryngoscope. 2010;120(9):1756-1772. 
3. Haughey BH, Hinni ML, Salassa JR, et al. Transoral laser microsurgery as primary 
treatment for advanced-stage oropharyngeal cancer: a United States multicenter 
study. Head Neck. 2011;33(12):1683-1694. 
4. Rich JT, Milov S, Lewis JS, Thorstad WL, Adkins DR, Haughey BH. Transoral laser 
microsurgery (TLM) +/- adjuvant therapy for advanced stage oropharyngeal cancer: 
outcomes and prognostic factors. Laryngoscope. 2009;119(9):1709-1719. 
5. Zenga J, Haughey BH, Jackson RS, et al. Outcomes of surgically treated human 
papillomavirus-related 
oropharyngeal 
squamous 
cell 
carcinoma 
with 
N3 
disease. Laryngoscope. 2016. 
6. Sinha P, Pipkorn P, Thorstad WL, Gay HA, Haughey BH. Does elimination of planned 
postoperative radiation to the primary bed in p16-positive, transorally-resected 
oropharyngeal 
carcinoma 
associate 
with 
poorer 
outcomes? Oral 
Oncol. 2016;61:127-134. 
7. Al-Mamgani A, van Rooij P, Verduijn GM, Mehilal R, Kerrebijn JD, Levendag PC. The 
impact of treatment modality and radiation technique on outcomes and toxicity of 
patients 
with 
locally 
advanced 
oropharyngeal 
cancer. Laryngoscope. 2013;123(2):386-393. 
8. Chin RI, Spencer CR, DeWees T, et al. Reevaluation of postoperative radiation dose 
in the management of human papillomavirus-positive oropharyngeal cancer. Head 
Neck. 2016;38(11):1643-1649. 
9. Spencer CR, Gay HA, Haughey BH, et al. Eliminating radiotherapy to the contralateral 
retropharyngeal and high level II lymph nodes in head and neck squamous cell 
carcinoma is safe and improves quality of life. Cancer. 2014;120(24):3994-4002. 
10. Rieckmann T, Tribius S, Grob TJ, et al. HNSCC cell lines positive for HPV and p16 
possess higher cellular radiosensitivity due to an impaired DSB repair 
capacity. Radiother Oncol. 2013;107(2):242-246. 
11. Pang E, Delic NC, Hong A, Zhang M, Rose BR, Lyons JG. Radiosensitization of 
oropharyngeal squamous cell carcinoma cells by human papillomavirus 16 
oncoprotein E6∗I. Int J Radiat Oncol Biol Phys. 2011;79(3):860-865. 
12. Butz K, Whitaker N, Denk C, Ullmann A, Geisen C, Hoppe-Seyler F. Induction of the 
p53-target 
gene 
GADD45 
in 
HPV-positive 
cancer 
cells. Oncogene. 1999;18(14):2381-2386. 
13. Butz K, Geisen C, Ullmann A, Spitkovsky D, Hoppe-Seyler F. Cellular responses of 
HPV-positive cancer cells to genotoxic anti-cancer agents: repression of E6/E7-
oncogene expression and induction of apoptosis. Int J Cancer. 1996;68(4):506-513. 
14. Chen AM, Li J, Beckett LA, et al. Differential response rates to irradiation among 
patients with human papillomavirus positive and negative oropharyngeal 
cancer. Laryngoscope. 2013;123(1):152-157. 

Version 2/27/2023 
 44 of 57 
15. Huang SH, Xu W, Waldron J, et al. Refining American Joint Committee on 
Cancer/Union for International Cancer Control TNM stage and prognostic groups for 
human 
papillomavirus-related 
oropharyngeal 
carcinomas. J 
Clin 
Oncol. 2015;33(8):836-845. 
16. O'Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system 
for HPV-related oropharyngeal cancer by the International Collaboration on 
Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort 
study. Lancet Oncol. 2016;17(4):440-451. 
17. Chen AM, Felix C, Wang PC, et al. Reduced-dose radiotherapy for human 
papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, 
phase 2 study. Lancet Oncol. 2017;18(6):803-811. 
18. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue complication in probability 
models in the clinic.  Int J Radiat Oncol Biol Phys. 2010;76(3):S10-19. 
19. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-
painted intensity modulated radiation therapy in combination with 5-fluorouracil and 
mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J 
Radiat Oncol Biol Phys. 2013;86(1):27-33. 
20. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, Mitomycin, and Radiotherapy 
vs Fluorouracil, Cisplatin and Radiotherapy for carcinoma of the anal canal. JAMA. 
2008;299(16):1914-21. 
21. Brotherston DC, Poon I, Le T, et al. Patient preferences for oropharyngeal cancer 
treatment de-escalation. Head Neck. 2013;35(2):151-159. 
22. Fleiss JL, Levin B, Paik MC. Statistical methods for rates and proportions. Third 
Edition. 2003. John Wiley & Sons. New York. 
23. Newcombe RG. Two-sided Confidence Intervals for the Single Proportion: 
Comparison of Seven Methods. Stat Med. 1998;17:857-72. 

Version 2/27/2023 
 45 of 57 
14.0 STUDY CALENDARS 
14.1 Baseline and Treatment Calendar 
1. Assessment of primary tumor site will be done by laryngoscopy performed in the office or operating room.  
2. In women of childbearing potential only. 
3. FACT H&N, M.D. Anderson Dysphagia Inventory, University of Michigan Xerostomia Index, Scale of Subjective Total Taste Acuity, and Neck Dissection  
    Impairment Index. 
4. Baseline assessments must take place no more than 35 days prior to enrollment, with the exception of PET scans (within 42 days).                   
5. See Section 5.2. 
6. Arms 1 and 2: Once daily M-F, with one BID treatment each week for 4200 cGy in 21 fractions. Arm 3: Once daily M-F for 6000 cGy in 30 fractions 
7. To be given during initial 5 doses of POART.  See Section 5.4.1 for fluids and premedications. On Arm 3, cisplatin will only be given to patients with 
pathologic evidence of positive margins or ECE (see section 1.9). 
 
Baseline4 
Surgery 
Interim Assessment 
(14 to 42 days  
post-surgery) 
Post-operative Adjuvant Chemotherapy/Radiation 
D1 
D2212 
D3612 
Informed consent 
X 
 
 
 
 
 
Laryngoscopy1 
X 
 
 
 
 
 
PE w/ECOG PS 
X 
 
X 
X 
X 
X 
Weight 
X 
 
 
X8---------------------------------------------------X8 
Comorbidity index 
X 
 
X 
 
CBC 
X 
 
X 
X 
X 
X 
CMP + magnesium 
X 
 
 
 
 
 
BMP + magnesium 
 
 
X 
X 
X 
X 
PT/PTT 
X 
 
X 
 
 
 
Pregnancy test2 
X 
 
 
 
 
 
Neck CT w/contrast 
X 
 
 
 
 
 
FDG-PET/CT 
X 
 
 
 
 
 
QOLs3 
X 
 
X 
X13 
X 
X 
OPTIONAL:  
Speech & Swallow Study10 
X 
 
X 
X11 
X 
X9 
Surgery5 
 
X5 
 
 
 
 
Rad Tx Planning 
 
 
X 
 
 
 
IMRT or IMPT6 
 
 
 
X-----------------------------------------------------------------------------------X9 
Arms 1 & 3: Cisplatin7 
 
 
 
X7 
X9 
X9 
AE assessment 
X 
 
X 
X 
X 
X 
Documentation of narcotic 
usage 
 
 
 
X 
X 
X 

Version 2/27/2023 
 46 of 57 
8. Collect weight weekly during Radiation. 
9. Arm 3 only. 
10. Modified barium swallow and the Performance Status Scale for Head and Neck Cancer (PSS-HN) questionnaire. 
11. Modified barium swallow NOT needed on this day. 
12. Arm 1 & 2 +/- 2 days; Arm 3 +/- 5 days 
13. -7/+0 days 

 
 
Version 2/27/23 
 47 of 57 
14.2 Follow-up Calendar 
 
 
Short Term Follow-up 
Long-Term Follow-Up 
Months post-end of CRT3 
Annually Thereafter5 
6 weeks post-
end of tx 
(+/- 1 week) 
4 months post 
end of tx 
(+/- 2 weeks) 
6 
12 
18 
24 
30 
36 
48 
PE w/ECOG PS + Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMP  
X 
 
 
 
 
 
 
 
 
Neck CT w/contrast  
X 
 
X 
X 
X 
X 
 
X 
 
 
Chest CT w/contrast2 
 
X 
X 
X 
X 
 
X 
 
 
QOLs                              
X 
X 
X 
X 
 
X 
 
 
 
 
OPTIONAL: 
Speech & Swallow Assessment 
X 
X 
X 
X4 
 
X4 
 
 
 
 
Documentation of narcotic usage 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Documentation of PEG tube usage 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE assessment 
X 
 
 
 
 
 
 
 
 
 
1. FACT H&N, M.D. Anderson Dysphagia Inventory, University of Michigan Xerostomia Index, Scale of Subjective Total Taste Acuity, and Neck Dissection  
    Impairment Index. 
2. Chest x-ray (PA and Lateral) may be substituted for chest CT if it is unable to be obtained (i.e. insurance issues) 
3. +/- 6 week window 
4. Modified barium swallow not required 
5. For 5 years (total of 10 years of follow-up) 
 
 
 

 
 
Version 2/27/23 
 48 of 57 
 
APPENDIX 1: ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 
 
 
 
 

 
 
Version 2/27/23 
 49 of 57 
APPENDIX 2: Comorbidity Index 
 
http://otooutcomes.wustl.edu/Research/Research-Focus/Cancer/Comorbidity-
Calculator 
 
If a patient has Grade 2 events in more than one system, their overall score will be Grade 
3 

 
 
Version 2/27/23 
 50 of 57 
  
APPENDIX 3: FACT-H&N (Version 4) 
 
Below is a list of statements that other people with your illness have said are important. Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy  
0 
1 
2 
3 
4 
GP2 
I have nausea  
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble meeting the 
needs of my family  
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain  
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment  
0 
1 
2 
3 
4 
GP6 
I feel ill  
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends  
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family  
0 
1 
2 
3 
4 
GS3 
I get support from my friends  
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness  
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my illness  
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support)  
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 

 
 
Version 2/27/23 
 51 of 57 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad  
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness  
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness  
0 
1 
2 
3 
4 
GE4 
I feel nervous  
0 
1 
2 
3 
4 
GE5 
I worry about dying  
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse  
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home)   
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling  
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life  
0 
1 
2 
3 
4 
GF4 
I have accepted my illness  
0 
1 
2 
3 
4 
GF5 
I am sleeping well  
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun  
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now  
0 
1 
2 
3 
4 
 
 
 

 
 
Version 2/27/23 
 52 of 57 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
H&N1 
I am able to eat the foods that I like 
0 
1 
2 
3 
4 
H&N2 
My mouth is dry 
0 
1 
2 
3 
4 
H&N3 
I have trouble breathing 
0 
1 
2 
3 
4 
H&N4 
My voice has its usual quality and strength 
0 
1 
2 
3 
4 
H&N5 
I am able to eat as much food as I want 
0 
1 
2 
3 
4 
H&N6 
I am unhappy with how my face and neck look 
0 
1 
2 
3 
4 
H&N7 
I can swallow naturally and easily 
0 
1 
2 
3 
4 
H&N8 
I smoke cigarettes or other tobacco products 
0 
1 
2 
3 
4 
H&N9 
I drink alcohol (e.g. beer, wine, etc.) 
0 
1 
2 
3 
4 
H&N 
10 
I am able to communicate with others 
0 
1 
2 
3 
4 
H&N 
11 
I can eat solid foods 
0 
1 
2 
3 
4 
H&N 
12 
I have pain in my mouth, throat or neck 
0 
1 
2 
3 
4 
 
 
 
 

 
 
Version 2/27/23 
 53 of 57 
APPENDIX 4: M.D. Anderson Dysphagia Inventory 
 
This questionnaire asks for your views about your swallowing ability.  This information will help 
us understand how you feel about swallowing. 
 
The following statements have been made by people who have problems with their swallowing.  
Some of these statements may apply to you. 
 
Please read each statement and mark the response which best reflects your experience IN 
THE PAST WEEK. 
 
 
 
 
 
 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
My swallowing ability limits my day to day 
activities. 
         
         
         
         
         
I am embarrassed by my eating habits. 
         
         
         
         
         
People have difficulty cooking for me. 
         
         
         
         
         
Swallowing is more difficult at the end of the 
day. 
         
         
         
         
         
I do not feel self-conscious when I eat. 
         
         
         
         
         
I am upset by my swallowing problem. 
         
         
         
         
         
Swallowing takes great effort. 
         
         
         
         
         
I do not go out because of my swallowing 
problem. 
         
         
         
         
         
My swallowing difficulty has caused me to lose 
income. 
         
         
         
         
         
It takes me longer to eat because of my 
swallowing problem. 
         
         
         
         
         
People ask me, “Why can’t you eat that?” 
         
         
         
         
         
Other people are irritated by my eating problem. 
         
         
         
         
         
I cough when I try to drink liquids. 
         
         
         
         
         
My swallowing problems limit my social and 
personal life. 
         
         
         
         
         
I feel free to go out to eat with my friends, 
neighbors, and relatives. 
       
       
        
        
        
I limit my food intake because of my 
swallowing difficulty. 
       
        
         
       
       
I cannot maintain my weight because of my 
swallowing problem. 
         
         
         
         
         
I have low self-esteem because of my 
swallowing problem. 
         
         
         
         
         
I feel that I am swallowing a huge amount of 
food. 
         
         
         
         
         
I feel excluded because of my eating habits. 
         
         
         
         
         

 
 
Version 2/27/23 
 54 of 57 
 
APPENDIX 5: University of Michigan Xerostomia Index 
 
Please mark the appropriate answer.  
 
1. Rate your difficulty in talking due to dryness 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO  
Dry  Mouth 
 
 
 
 
 
 
 
 
 
Extreme Dry 
Mouth 
 
2. Rate your difficulty in chewing due to dryness 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO  
Dry  Mouth 
 
 
 
 
 
 
 
 
 
Extreme Dry 
Mouth 
 
3. Rate your difficulty in swallowing solid food due to dryness 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO  
Dry  Mouth 
 
 
 
 
 
 
 
 
 
Extreme Dry 
Mouth 
 
4. Rate the frequency of your sleeping problems due to dryness 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO  
Dry  Mouth 
 
 
 
 
 
 
 
 
 
Extreme Dry 
Mouth 
 
5. Rate your mouth or throat dryness when eating food 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO  
Dry  Mouth 
 
 
 
 
 
 
 
 
 
Extreme Dry 
Mouth 
 
6. Rate your mouth or throat dryness while not eating 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO  
Dry  Mouth 
 
 
 
 
 
 
 
 
 
Extreme Dry 
Mouth 
 
7. Rate the frequency of sipping liquids to aid swallowing food 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO  
Dry  Mouth 
 
 
 
 
 
 
 
 
 
Extreme Dry 
Mouth 
 
8. Rate the frequency of sipping liquids for oral comfort when not eating 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO  
Dry  Mouth 
 
 
 
 
 
 
 
 
 
Extreme Dry 
Mouth 
 
 
 
 
 
 
 
 
 
APPENDIX 6: Scale of Subjective Total Taste Acuity 

 
 
Version 2/27/23 
 55 of 57 
 
Please circle the appropriate answer (Only ONE answer). 
 
Symptom 
Grade 
Same taste acuity as before treatment  
0 
Mild loss of taste acuity, but not inconvenient 
in daily life  
1 
Moderate loss of taste acuity, and sometimes 
inconvenient in daily life  
2 
Severe loss of taste acuity, and frequently 
inconvenient in daily life  
3 
Almost complete or complete loss of taste 
acuity  
4 
 
 
 

 
 
Version 2/27/23 
 56 of 57 
 
APPENDIX 7: Neck Dissection Impairment Index 
 
As a result of the cancer TREATMENT OF YOUR NECK, how much have you been bothered 
by the following over the past 4 WEEKS?  Please mark the appropriate answer. 
 
Not 
At All 
A Little 
Bit 
A 
Moderate 
Amount 
Quite 
A Bit 
A Lot 
1. Are you bothered by neck or shoulder 
pain or discomfort? 
 
 
 
 
 
2. Are you bothered by neck or shoulder 
stiffness? 
 
 
 
 
 
3. Are you bothered by difficulty with self-
care activities because of you neck or 
shoulder (for example, combing hair, 
dressing, bathing, etc?) 
 
 
 
 
 
4. Have you been limited in your ability to 
lift light objects because of your shoulder 
or neck? 
 
 
 
 
 
5. Have you been limited in your ability to 
lift heavy objects because of your 
shoulder or neck? 
 
 
 
 
 
6. Have you been limited in your ability to 
reach above for objects because of your 
shoulder or neck (for example, from 
shelves, tables or counters)? 
7. Are you bothered by your overall activity 
level because of your shoulder or neck? 
 
 
 
 
 
8. Has the treatment of your neck affected 
your participation in social activities? 
 
 
 
 
 
9. Have you been limited in your ability to 
do leisure or recreational activities 
because of your neck or shoulder? 
 
 
 
 
 
10. Have you been limited in your ability to 
do work (including work at home) 
because of neck or shoulder discomfort or 
pain?  
 
 
 
 
 
 
 
 

 
 
Version 2/27/23 
 57 of 57 
APPENDIX 8: Performance Status Scale for Head & Neck Cancer Patients – PSS-
HN