Conditions: Carcinoma, Squamous Cell of Head and Neck Oropharynx Squamous Cell Carcinoma
Keywords: Oropharynx Cancer OPSCC Nivolumab Adjuvant therapy De-Escalated Radiation Squamous cell carcinoma P16+ Head and Neck cancer Oropharynx Squamous Cell Carcinoma Carcinoma, Squamous Cell of Head and Neck Transoral surgery Radiotherapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
This clinical trial will evaluate a new combination of treatments for Oropharyngeal Squamous Cell cancers (OPSCC), and compare it to the current standard of care (concurrent, platinum-based chemoradiotherapy). Chemoradiotherapy is efficacious, but also associated with significant toxicities and is only suitable for patients with good performance status and without severe comorbidities. The purpose of this trial is to demonstrate equivalent oncologic outcome with fewer adverse effects and improved quality of life when compared to the standard of care.

Detailed description:
This study aims to enroll 135 patients (male and female, age 18+) who are newly diagnosed with resectable, squamous cell carcinoma or undifferentiated carcinoma of the oropharynx. Survival rate and treatment response of OPSCC varies based on HPV infection status and genotype; therefore, in this study, only patients who are HPV seropositive and have HPV type 16 will be enrolled. All patients will receive the same treatment, i.e. there is no active control group.

In this trial, patients will undergo transoral surgery followed by de-intensified adjuvant radiotherapy plus nivolumab. The radiotherapy will consist of 45 or 50 Gy (depending on tumor volume) in 25 daily fractions, 6 fractions per week. Nivolumab will be administered at a fixed dose of 240 mg over 30 minutes IV every 2 weeks during radiotherapy, and at 480 mg over 60 minutes IV every 4 weeks for 6 doses after radiotherapy. The first dose will be given prior to the first fraction of radiation (Day 1) on Day -3 (+/- 2 days), and continued every 2 weeks (+/- 2 days). Nivolumab will thus be given in weeks 2 and 4 of radiotherapy. Adjuvant nivolumab will then be given for a total of 6 additional doses after the completion of radiotherapy every 4 weeks (+/- 7 days), starting in the second or third week after the completion of radiotherapy. Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the subject tolerates the treatment. Relevant outcome measures include disease free survival (2 year post surgery); percutaneous gastronomy dependence (1-year postsurgery); acute and late toxicity; patient-reported Quality of Life measures, locoregional control and distant metastatic control.

Arms:
arm 1: RT of 45 or 50 Gy in 25 daily fractions, 6 fractions per week. Nivolumab will be administered at 240 mg every 2 weeks during radiotherapy, and at 480 mg every 4 weeks for 6 doses after radiotherapy.

Interventions: intervention 1: Nivolumab Injection intervention 2: Radiotherapy (RT)
Intervention descriptions: intervention 1: A fully human anti-programmed death 1 (PD-1) monoclonal antibody intervention 2: 45-50 Gy accelerated fractionation in 25 daily fractions, 6 fractions per week

Protocol document:
Prot_SAP_001.pdf: 
 
1 
Phase II Trial of Adjuvant De-Escalated Radiation + Concurrent and Adjuvant 
Nivolumab for Intermediate-High Risk P16+ Oropharynx Cancer 
 
STUDY CHAIR: 
Robert L. Ferris, M.D. Ph.D.  
STUDY CO-CHAIR: 
Adam Raben, M.D. 
MEDICAL ONCOLOGY CO-CHAIR: 
Lori Wirth, M.D. 
RADIATION THERAPY CO-CHAIR: 
D. Anthony Clump, II, M.D., Ph.D. 
SURGICAL CO-CHAIR: 
David Cognetti, M.D. 
STUDY STATISTICIAN: 
William Gooding, M.S. 
CORRELATIVES CO-CHAIR: 
Robert L. Ferris, M.D., Ph.D. 
Version Date: December 03, 2020 
 
 
  
Agents 
IND# 
Supply 
nivolumab 
141,230 
Investigational 
 
Study Co-Chair 
Robert L. Ferris, M.D., Ph.D. 
5115 Centre Avenue 
Hillman Cancer Center, Room 2.26b 
Pittsburgh, PA 15213 
Tel: 412-623-0327 
Fax: 412-623-4840 
Email: ferrisrl@upmc.edu 
Study Co-Chair 
Adam Raben, M.D. 
Helen F. Graham Cancer Center 
Suite 1109 
4701 Ogletown-Stanton Rd 
Newark, DE, 19713 
Phone: 302-623-4806 
Email: Araben@christianacare.org 
 
 


 
2 
 
Nivolumab will be administered at 240 mg IV q2 weeks during radiotherapy, and at 480 mg IV q4 weeks for 6 doses after RT. Radiotherapy 
to receive IMRT to 50 Gy/2 Gy per fraction/6 fxs per week, with the first dose of nivolumab delivered at day -3 ± 2 days prior to RT.  RT will 
be delivered daily for 4 days, with 2 fractions on day 5 per week. After 4 weeks, this will total 48Gy, with an additional day to reach 50Gy. 
 


 
3 
Eligibility Overview: 
Inclusion (AJCC 7th Edition): 
• 
P16+ squamous cell carcinoma of the oropharynx 
• 
Tobacco <10 pack years (pk-yr): T0-3 plus any one of the following: >N2b (> 5 LN’s +), N2c/N3, +ENE >1 mm,  or + 
margin (if approved by surgical chair)  OR 
• 
Tobacco >10 pk-yr: T0-3 plus any one of the following: any N2, N3, +ENE >1 mm, or + margin (if approved by surgical 
chair)  
• 
M0 
• 
Age >18, gender neutral 
• 
ECOG performance Status 0-1 
• 
Patients must have undergone gross surgical removal with transoral surgery + neck dissection for p16+ OPC 
• 
Patients undergoing tonsillectomy are eligible and do not require additional surgery if all gross disease removed 
• 
Adequate hematologic, renal and hepatic function for cisplatin 
Exclusion: 
• 
P16-negative 
• 
T4 primary 
• 
T4, or ≤N1 
• 
Gross residual disease after surgery 
• 
Female patient lactating or pregnant 
• 
Prior radiation or chemotherapy for head and neck cancer 
• 
Prior immunotherapy agents 
• 
Prior head and neck cancer treated < 5 years (surgery only) 
• 
Unstable cardiac disease 
• 
Patients with active/history of autoimmune, rheumatologic disease which may affect vital organ function or on 
immunosuppressive agents or systemic steroids for any medical condition 
• 
Uncontrolled undercurrent illness, such as CHF, active infection 
• 
Psychiatric illness or other social issues limiting compliance 
 


 
4 
TABLE OF CONTENTS 
Study Schema 
2 
Eligibility Overview 
3 
Table of Contents 
4 
List of Abbreviations and Definitions 
6 
1. Introduction 
9 
1.1 Study Disease 
9 
1.2 HPV Positive Oropharynx Tumors 
9 
1.3 Role of Surgery in Head and Neck Cancer 
10 
1.4 Postoperative Radiotherapy (PORT) with or without Cisplatin 
Chemotherapy 
13 
1.5 Role of IMRT and Lower Dose RT in Oropharynx Squamous Cell 
Carcinoma 
14 
1.6 Correlative Studies Background 
24 
1.7 Clinical Functional Outcomes 
25 
1.8 Functional Swallowing Outcomes 
25 
1.9 Patient-Reported Outcomes (PRO) 
25 
2. Objectives 
25 
2.1 Primary Objectives 
26 
2.2 Secondary Objectives 
26 
2.3 Laboratory Research Objectives 
26 
3. Eligibility Criteria 
26 
3.1 Inclusion Criteria 
26 
3.2 Exclusion Criteria 
27 
4. Registration Procedures  
28 
4.1 Required Information 
28 
4.2 Eligibility Verification 
29 
4.3 Participation in Modified Barium Swallow (MBS) Studies 
29 
5. Treatment Plan 
29 
5.1 Post-operative Management 
29 
5.2 Administration of Nivolumab 
34 
5.3 Adverse Event Reporting Requirements and Procedure 
39 
5.4 Dose Modifications 
41 
5.5 Supportive Care and Other Assessments 
42 
5.6 Duration of Therapy 
42 
 
 


 
5 
 
 
5.7 Duration of Follow-up 
42 
6. Measurement of Effect 
43 
6.1 Time to Progression 
43 
6.2 Methods of Measurement 
43 
7. Schedule of Assessments 
43 
8. Nivolumab Formulation and Procurement 
45 
9. Statistical Considerations 
46 
9.1 Objectives 
46 
9.2 Sample Size and Accrual Rate 
47 
9.3 Secondary Objectives 
48 
9.4 Data Safety Monitoring Plan 
48 
9.5 Gender and Ethnicity 
50 
9.6 Observer-Assessed Outcomes 
50 
9.7 Patient Reported Outcomes (PRO) 
51 
9.8 Exploratory Objectives 
52 
10. References 
52 
Appendix I Patient Reported Outcomes (PROs) 
58 
Appendix II Modified Barium Swallow Study Form 
59 
 
 
 


 
6 
LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ACE 
angiotensin converting enzyme 
AE 
adverse event 
AHNS 
American Head and Neck Society 
AIDS 
acquired immunodeficiency syndrome 
ALC 
absolute lymphocyte count 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
CMV 
cytomegalovirus 
CRT 
chemoradiotherapy 
CTEP-AERS 
Cancer Therapy Evaluation Program Adverse Event Reporting System 
CTV 
clinical target volume 
CVA 
cerebrovascular accident 
DFS 
disease-free survival 
DNA 
deoxyribonucleic acid 
DSMB 
data safety monitoring board 
DSMC 
data safety monitoring committee 
EBV 
Epstein-Barr virus 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ENE 
extranodal extension 
EORTC 
European Organisation for Research and Treatment of Cancer 
ERT 
external radiation therapy 
FR 
future risk 
GI 
gastrointestinal 
GTV 
gross tumor volume 
Gy 
gray (unit of ionizing radiation) 
HBV  
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HNC 
head and neck cancer 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papillomavirus 


 
7 
HR 
high risk 
IHC 
immunohistochemistry 
IMRT 
intensity modulated radiotherapy 
IR 
intermediate risk 
IRRC 
independent radiology review committee 
ITIM 
immunoreceptor tyrosine inhibitory motif 
ITSM 
immunoreceptor tyrosine-based switch motif 
IVRS 
interactive voice response system 
LRC 
locoregional control 
mAb 
monoclonal antibodies 
MBS 
modified barium swallow 
MDSC 
myeloid-derived suppressor cells 
MEL 
melanoma 
MHC 
major histocompatibility complex 
MLR 
mixed lymphocyte reaction 
MOA 
midline oral avoidance 
mPFS 
median progression-free survival 
NSCLC 
non-small cell lung cancer 
OAR 
organs at risk 
OPC 
oropharyngeal cancer 
OPSCC 
oropharyngeal squamous cell cancer 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PEG 
percutaneous gastronomy 
PFS 
progression-free survival 
PFSR 
progression-free survival rate 
PORT 
postoperative radiotherapy 
PRO 
patient-reported outcomes 
PS 
performance status 
PTV 
planning target volume 
PULA 
previously untreated, locally advanced 
QOL 
quality of life 
RT 
radiotherapy 


 
8 
RTOG 
Radiation Therapy Oncology Group 
SAE 
serious adverse event 
sAg 
surface antigen 
SLP 
speech language pathologist 
SOP 
standard operating procedure 
TIA 
transient ischemic attack 
TLM 
transoral laser CO2 microsurgery  
TME 
tumor microenvironment 
TORS 
transoral robotic surgery 
TOS 
transoral surgery 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
 


 
9 
1. 
Introduction 
1.1 
Study Disease 
Head and neck cancer remains a significant cause of morbidity worldwide, with approximately 
400,000 new cases per year. Squamous cell carcinoma is the most common histological type, 
accounting for >90% of head and neck tumors. At presentation, more than half of patients present 
with advanced locoregional disease.1 Ongoing advances in multidisciplinary management of this 
complex and multi-varied disease process are resulting in improved function, organ preservation, 
quality of life and survival.  Major developments include primary chemoradiotherapy (CRT) for 
unresectable disease with the goal of organ preservation, the addition of chemotherapy to adjuvant 
radiotherapy (RT) and improvement in surgical and radiation techniques.2 A consistent result of 
these aggressive multi-modality approaches is improvement in local-regional control but the impact 
on the development of metastases is variable. Despite these advances, 50% of all patients recur 
either locally or at distant sites (30%).2 A minority of patients will undergo successful surgical 
salvage of recurrent disease. While single institution series evaluating intensified CRT regimens 
suggest a shift in failure pattern to distant metastases, better control of local disease remains 
paramount to improve survival of patients with head and neck squamous cell carcinoma (HNSCC).2 
1.2 
HPV Positive Oropharynx Tumors 
The incidence of base of tongue and tonsillar carcinomas has been increasing over the past 
decade, especially in individuals under the age of 45.3 This change has been attributed to the 
increasing prevalence of human papillomavirus (HPV) infection in developed countries, the practice 
of oral sex and increasing number of sexual partners.3 Interestingly, patients with HPV-positive SCC 
have shown better overall survival and higher cure rates as compared to those with HPV-negative 
SCC.4 HPV is now recognized to play a role in the pathogenesis of HNSCC.5 Both molecular and 
epidemiologic studies demonstrate that approximately 60% of oropharynx cancers, specifically of 
the lingual and palatine tonsils, are HPV associated.5  
 
HPV16 driven Oropharyngeal Squamous Cell cancers (OPSCC) is now recognized as a rising global 
epidemic both in the USA and abroad, with expected peak in incidence by 2030.1 Patients who 
develop HPV16+ oropharyngeal cancer (OPC) tend to be younger, never or former smokers, and 
primarily male. Nearly 70% of reported OPC cases in the USA are HPV16+OPC.2 Current treatment 
standards are associated with a higher risk of significant debilitating short and long term side effects. 
The prognosis of HPV16+ OPSCC particularly with patients with < 10 pk-yr history of smoking is 
excellent, approaching 90% or better with a high probability of long-term survival, but with the optimal 
strategy yet to be defined. A retrospective analysis of RTOG 0129 survival outcomes after standard 
Cisplatin and 70 Gy ERT exposed three risk groups (FR, IR, HR based on HPV, smoking status and 
stage, setting the stage for new clinical risk-adaptive and de-escalation trials, (RTOG 1016, ECOG 
3311, NRG HN002). The current 7th edition AJCC staging system is outdated and does not reflect risk 
stratification based on HPV. New recommendations to re-classify staging for HPV16 + OPC have 
been proposed by an international collaborative group for the 8th edition of AJCC recognizing 
favorable outcomes in this group. Patients previously classified as stage II-IV would now be stage II 
(T1-T2N2 or T3N0-N2).3 I 
High-risk HPV genotypes (i.e. 16, 18, and 31) are known to be tumorigenic in human epithelial 
tissues. The E6 and E7 viral oncoproteins of high-risk HPV promote tumor progression by 
inactivating the TP53 and Rb tumor suppressor gene products, respectively.6 These tumors appear 
to be clinically and molecularly distinct from HPV-negative tumors. HPV-positive tumors are more 
likely to arise from the oropharynx, exhibit poor differentiation and basaloid morphologic features, 
and present at a lower T stage than HPV-negative primaries.5-9 
 
Recently, HPV-associated head and neck carcinoma, largely presenting in the oropharynx, has 


 
10 
been identified and appears to be rapidly increasing in incidence.8,10 In the US, some two-thirds of 
patients with OPSCC have HPV-associated tumors. Hence, in 2010 approximately 4200 squamous 
cancers of the oropharynx caused by tobacco and alcohol and 8400 new HPV-associated 
oropharynx cancer presented for treatment. HPV-associated OPSCC typically present as smaller 
primary tumors than those caused by substance abuse. Because HPV-associated OPSCC more 
frequently present in a younger population and seem particularly responsive to treatment with a 
better overall survival,11 attention has begun to focus reduction of treatment toxicity. In particular, 
attention has been focused on the development of late effects of CRT as the number of survivors 
have increased. While the organ-preservation CRT approach has become a standard of care,12,13 
there remain serious concerns about both short and long-term toxicity. Furthermore, the changing 
epidemiology of HPV-associated OPSCC has caused many to re-think this approach. Given the 
potential long-term sequelae of radiation therapy for a younger population,14 an alternative treatment 
paradigm is needed. The clearly better prognosis of this group of patients supports re-evaluation of 
adjuvant treatment intensity and, in particular, the prognostic and predictive role of traditional 
pathologic biomarkers obtained at surgery. 
 
Results from ECOG 2399 using induction chemotherapy with carboplatin and paclitaxel followed by 
CRT with Taxol/70Gy showed that HPV-positivity in OPC patients was associated with a 
significantly improved overall response to 2 cycles of paclitaxel/carboplatin induction chemotherapy 
(82% vs. 55%, p=0.01), as well as 2-yr PFS (85% vs. 50%, p=0.05) and overall survival (94% vs. 
58%p=0.004) following weekly paclitaxel/RT.15 Although acute toxicity was acceptable with this 
regimen, a substantial number of OPC patients have long-term consequences following CRT. In 
E2399, 49% of OPC patients had moderate to severe swallowing impairment 3 months following 
treatment, and 3% were still PEG dependent after 12 months. These results have generated interest 
in less toxic regimens for HPV-positive patients who experience substantial treatment side effects 
with contemporary CRT regimens.  
 
In this study, 64% of OPC patients had HPV-positive tumors, as measured in-situ hybridization for 
the HPV subtype 16. The presence of HPV deoxyribonucleic acid (DNA) correlated well with p16 
expression (kappa = 0.80; 95% CI, 0.73 to 0.87). Patients with HPV-positive tumors had significantly 
increased overall survival (OS) as well as PFS compared to patients with HPV-negative tumors. 
Furthermore, after adjusting for demographics, T stage, N stage, smoking, patients with HPV- 
positive OPC had a 58% reduction in the risk of death and a 51% reduction in risk of progression or 
death. Patients with HPV-negative tumors had a 25.1% reduction in OS at 3 (57.1% vs 82.4%) 
when compared to patients with HPV-positive tumors.16 Local-regional relapse at 3 years was 21% 
higher in patients with HPV-negative tumors: 35.1% (95% CI: 26.4 - 43.8) versus 13.6% (95% CI: 
8.9 - 18.3) for HPV-positive tumors (p < 0.001). These poor outcomes for HPV-negative patients 
occur despite the gradual trend toward increasing intensification of treatment with altered 
fractionation schema,17 concurrent chemoradiation, 18,19 multi-drug induction chemotherapy,20 and 
targeted molecular therapies.21 For patients with HPV-negative tumors altering the method of 
radiation delivery and the dosing and/or types of concurrent chemotherapy is not sufficient to 
improve oncologic outcomes. Because HPV-associated head and neck cancers more frequently 
present in a younger population and seem particularly responsive to treatment with a better overall 
survival,22 attention has focused on the subpopulation of > 10 pack-year smoking and N2-N3, whose 
prognosis is worse (60% - 70% 2-year progression-free survival (PFS)) as well as HPV-negative 
head and neck cancer (HNC) patients, whose clinical outcome has not improved despite 
intensification of standard chemotherapeutic agents and combinations. Thus, novel therapeutic 
approaches, such as immune modulation and blockade of suppressive immune cells and signals, 
are needed in clinical evaluation. 
1.3 
Role of Surgery in Head and Neck Cancer 
Our central hypothesis is that transoral surgery (TOS) is feasible and effective in low- to 
intermediate-risk, HPV+ OPSCC patients. We hypothesize that this permits pathologic-risk adjusted 


 
11 
reduction in adjuvant therapy and radiotherapy treatment planning benefits and may be associated 
with favorable functional and quality of life benefits without negatively impacting oncologic results. 
We will test this hypothesis in a single arm phase II design, to gather prospective data that will be 
essential to guide the design of a future, randomized phase III trial comparing the surgery/adjuvant 
therapy with standard non-surgical therapy. 
 
The current standard of care for primary nonsurgical treatment of locally advanced HNSCC is 
concurrent platinum-based CRT, which has been shown to significantly improve OS, PFS, and/or 
locoregional control compared with RT alone or the sequential administration of chemotherapy and 
RT.2 In a meta-analysis of 63 trials with nearly 11,000 patients with HNSCC, the addition of 
chemotherapy to RT resulted in an absolute survival improvement of 6% at 5 years.23 The results of 
this meta-analysis were confirmed in subsequent updated meta-analyses, the most recent of which 
included 93 randomized trials and 17,346 patients.15 Cisplatin CRT regimen is efficacious but also 
associated with significant toxicities and is suitable for patients with good performance status and 
without severe comorbidities.24 In addition to the 3-weekly schedule, a variety of other cisplatin 
schedules of administration have been employed (e.g. weekly).25 
 
The last twenty years have seen many advances in the management of HNSCC. The recognition 
that, through combined modality therapy, many advanced cancers could be controlled without a 
highly morbid operation (and without compromising the chance for cure) led to the development of 
new treatment schedules and the incorporation of new agents in the therapeutic armamentarium. 
These approaches were largely predicated on the assumption that normal tissue preservation would 
equate to functional preservation most notably for swallow function. Unfortunately, organ 
preservation does not always equate to functional preservation. These apparent therapeutic gains 
have been accompanied by significant early and late toxicity due to CRT.26 Chronic aspiration and 
dysphagia have been identified as important, but often underreported late toxicities of organ 
preservation regimens for HNSCC. Severe (grade 3-4) late laryngopharyngeal toxicity was reported 
in 43% of HNSCC survivors evaluated in a pooled analysis of 3 RTOG concurrent CRT trials. 
 
It is now clear that late swallowing injury is at least related to the dose of the radiotherapy and the 
use of concurrent chemotherapy. Both have been established as independent risk factors in several 
multivariate analyses.27-29 Dose correlation studies suggest that the threshold upon which late injury 
to the swallowing muscles such as the constrictor muscles occur in the range of 55-60 Gy when a 
large volume of the muscles are exposed to these doses of radiation. In addition, recent data show 
that most patients who develop severe refractory dysphagia years after radiotherapy for HNSCC 
have been treated with doses of 70 Gy or more.30 Hence, one strategy to reduce the risk of late 
swallowing injury would be to de-intensify the dose of radiation, particularly in patient populations 
with a favorable prognosis. Initial hypotheses that these young patients, with less morbidity, would 
tolerate treatment better and have less quality of life (QOL) impairment have been refuted; in fact, 
evidence suggests a greater acute QOL disadvantage in this cohort.31,32 Thus, attention has focused 
on the development of late effects from CRT as the number of survivors have increased.  
 
While the organ-preservation CRT approach has become a standard of care.12,13 there remain 
serious concerns about toxicity, both short and long-term. Furthermore, the changing epidemiology 
of head and neck cancer has caused many to re-think this approach.  Given the potential long-term 
sequelae of radiation therapy for a younger population14, an alternative treatment paradigm must be 
found, particularly for patients with oropharyngeal SCC. A common transoral route of exposure, 
incorporating minimally invasive techniques with transoral laser CO2 microsurgery (TLM) 33 and 
transoral robotic surgery (TORS)34,35 has emerged.36 
 
Role of transoral surgery (TOS) for OPSCC 
As HPV-associated OPSCC more frequently present in a younger population and seem particularly 
responsive to treatment with a better overall survival,11 attention has begun to focus on the reduction 


 
12 
of treatment toxicity. TORS dramatically limits the morbidity of surgical exposure and substantially 
reduces the acute and late effects of resection. It is important to recognize that the morbidity of past 
surgeries was a function of the injury that occurred with the required transcervical neck exposure. 
What is not clear is to what extent resection of important swallowing structures impact on this. The 
experience to date with TLM and TORS would suggest that resection can be safely performed for 
T1-2 oropharyngeal tumors without contributing to increased late swallowing complications as 
measured by dependence on percutaneous gastrostomy (PEG) tube. This is a particular attractive 
approach as HPV-associated OPSCC typically present as smaller primary tumors than those 
caused by substance abuse.37,38 
 
TOS for OPSCC using traditional headlight visualization, C02 laser-based TLM and more recently, 
robotic-assisted surgery, has been practiced at an increasing number of North American institutions. 
Case series suggest that excellent long-term function may be anticipated after resection. 
Indications, contraindications, standards of practice and outcome reporting are being defined. 
Surgical resection of OPSCC can be a curative single modality for appropriately selected Stage I-III 
tumors and for many Stage IV tumors when combined with standard adjuvant therapy. The adjuvant 
therapy that has been applied has been based on clinical studies evaluating adjuvant therapy for 
squamous cell carcinomas in multiple tumor sites.39,40 Clearly, patients who receive single modality 
transoral surgery have the functional advantage of swallowing preservation as a result of the ability 
to spare adjacent musculature critical to swallowing function. Whether this advantage is maintained 
with the addition of adjuvant radiation or chemoradiation remains unknown. Thus, the role of 
modern low-morbidity resection in the multidisciplinary management of Stage III-IV oropharynx 
cancer remains undefined.   
 
The Head and Neck Committees of the Radiation Therapy Oncology Group and the University of 
Pittsburgh Cancer Research Group (ECOG-ACRIN) have performed surgical trials in the recent 
past. Surgical interest in cooperative group activity remains high. For example, ECOG 4393 
represented a large study evaluating surgical margins, demonstrating the ability to perform 
surgical/adjuvant trials. While only a handful of institutions initially pursued transoral resection, it is 
now undertaken at an increasing number of academic medical centers increasing clinical 
investigation by qualified academically-oriented head and neck surgeons increasing the successful 
collection and storage of fresh, untreated tumor for scientific investigation. Numerous retrospective 
single-institution reports and a few important multicenter trials have generated significant 
enthusiasm for these transoral approaches in the multidisciplinary approach. In addition, while 
adjuvant therapy trials for oral cavity carcinoma have been published,41 little prospectively gathered 
data on postoperative therapy for p16+  OPSCC are available. 
 
HPV-positive SCC, which often presents with a small primary tumor, is particularly amenable to 
such an approach because the functional deficit resulting from their removal is low. Transoral 
resection of oropharyngeal cancers using the C02 laser or, more recently, robotic surgery, has been 
practiced at an increasing number of North American institutions. Furthermore, case series suggest 
that excellent long-term function may be anticipated after resection of early T1-T2 tumors. The da 
Vinci surgical robot (Intuitive corp., Sunnyvale, CA) is now FDA-cleared for the resection of T1-T2 
cancers of the oropharynx, and the machine is widely available. Robotic and laser transoral 
resection, while promising and increasingly utilized, should be investigated prospectively to design 
the most appropriate randomized phase II trial comparing this approach with CRT.  
 
Surgical resection of oropharynx cancer is a curative therapy and can be a single modality for 
patients with Stage I-III tumors. For many Stage IV patients with intermediate risk features, adjuvant 
radiation therapy has the advantage in that the RT dose is reduced (50-60 Gy) and may not require 
the addition of concurrent CT. Hence, surgical therapy has the potential to substantially diminish the 
application of high-dose radiation treatment as well as CRT for patients who are expected to do 
well. In those patients with more advanced disease, surgical resection in combination with post-


 
13 
operative CRT also has the potential to increase locoregional control. Clearly, patients who receive 
single modality transoral surgery have the functional advantage of swallowing preservation because 
of the ability to spare adjacent musculature critical to swallowing function. Whether this advantage is 
maintained with the addition of adjuvant radiation or CRT remains unknown. Thus, the role of 
modern low-morbidity resection in the multidisciplinary management of Stage III-IV oropharynx 
cancer remains undefined. 
 
In summary, the suggestion is that cases of HPV-associated OPSCC have a more favorable 
prognosis in part due the natural biology of the cancer and possibly greater radiosensitivity. In vitro 
analyses have demonstrated evidence to support that HPV infection can associated with increased 
intrinsic chemo-radiosensitivity,42,43 though it is recognized that there is no consensus on this issue. 
Nevertheless, there is compelling evidence both from the perspective of cancer cytotoxicity and 
normal tissue functional preservation (see above) to reduce the dose of postoperative radiotherapy 
in HPV-positive OPSCC to doses on the order of 55 Gy or less. 
1.4 
Postoperative Radiotherapy (PORT) with or without Cisplatin Chemotherapy 
Current postoperative radiotherapy (PORT) doses derive from a series of seminal investigations 
conducted at MD Anderson Cancer Center.40,44 The cumulative experiences from these randomized 
trials demonstrated that for SCC of all anatomic sites in the head and neck (32% of subjects with 
SCC of the oral cavity), the recommended PORT dose can be pathologically guided with high rates 
of local-regional disease control. While various risk stratification schema have been evaluated, the 
presence of a positive margin (not defined) and nodal ENE warrant at least 63 Gy.45 In the presence 
of any pathologic risk factors identified in the tumor specimen, an increased risk of local relapse was 
statistically identified if < 54 Gy was administered compared to 57.6 Gy40 (63% vs. 92%, p=.02). 
While the optimal postoperative dose for ENE and positive margins has not been established, 
several institutional reports have used doses typically in the range of 65-66 Gy or greater.41,46 
There is also indirect supportive evidence that a lower PORT dose may be sufficient when 
irradiating the pathologically involved neck. Investigators from the Netherlands (University Medical 
Center Groningen) demonstrated in a large retrospective review of over 800 patients (52% of 
subjects with SCC of the oral cavity) that postoperative irradiation of the pathologically involved 
cervical neck to only 56 Gy was associated with 85-93% 5-year regional control rates depending on 
whether only a single or multiple node were involved (Vergeer et al, personal communication).   
 
Neither of these clinical experiences distinguished the local or regional control rates by HPV status 
and potentially may have represented a predominantly HPV-negative study population based on the 
predominantly oral cavity SCC patients treated. Nevertheless, it demonstrates that high rates of 
cancer control may be seen in the pathologically involved site. For these reasons, the optimal 
postoperative radiation dose has yet to be determined. 
 
The necessity for PORT following surgery to a tumor bed that fails to demonstrate any adverse 
pathologic features is a controversial practice, rooted historically in the use of transcervical neck 
exposures and the early and seminal observations of Fletcher47 that was intended to also address 
the risk of tumor surgical seeding. The risk of local-regional relapse without adjuvant PORT for 
transcervical surgery would need to be on the order of 10%. In the setting of a transoral approach 
where no cervical fascial planes are disrupted, the evidence to date suggests that the risk of local 
relapse with either TLM or TORS for T1/T2 primary OPSCC is approximately 5%.48 
 
While concurrent chemotherapy, typically cisplatin, has been administered for the high-risk patient 
cohort following surgery, it is clear that the use of chemotherapy can also unnecessarily increase 
the risk of late swallowing complications.26-29 Retrospective cohorts of TORS followed by RT have 
reported on the risk of swallowing complications, but whether reduced dosage (50 Gy vs 60 Gy) 
should be used in designing the prospective, randomized phase III trial in comparison to CRT is 


 
14 
unknown. This proposal hypothesizes that reduced dose- RT may provide comparable 2-year PFS 
rates with the potential for reduced, late normal tissue injury for HPV+SCC.   
1.5 
Role of IMRT and Lower Dose RT in Oropharynx Squamous Cell Carcinoma 
A significant long-term toxicity in the irradiated oropharynx cancer patient is xerostomia caused by 
radiation delivered to the major salivary glands. Technologic advancements that now permit 
conformal fields using intensity modulated radiotherapy (IMRT) initially applied dose-constraints to 
reduce the volume of parotid gland parenchyma, and more recently, the contra-lateral 
submandibular gland exposed to high radiation doses. However, the salivary glands continue to 
receive lower radiation doses that can still result in long-term xerostomia, albeit of lower severity, 
despite the use of IMRT. This can still result in significant impairment based on patient reported 
quality of life measures. 
 
Dysphagia is the primary functional complication encountered after radiotherapy for oropharyngeal 
cancer. Impaired laryngopharyngeal physiology that results from neuromuscular fibrosis, 
independent of xerostomia, contributes to radiation-induced dysphagia. Even in the era of IMRT for 
oropharynx cancer, authors report rates of aspiration ≥1-year of 6% to 31% and g-tube dependence 
of 6% to 8%.28,49,50 Recent studies have demonstrated significant associations between swallowing 
outcomes and dose-volume coverage to key structures after IMRT including the anterior oral cavity, 
superior pharyngeal musculature, and inferior larynx/CP inlet. Dose-volume correlations have been 
observed for late objective endpoints of swallowing dysfunction such as nutritional dependence on a 
gastrostomy tube, measures of swallowing efficiency, aspiration, and swallowing-related QOL.49,51,52 
Pharyngeal dose to superior as well as inferior constrictor musculature is consistently found to relate 
to a variety of swallowing measures in numerous studies. Threshold pharyngeal doses as low as 50 
Gy to the inferior constrictors (V50)51 and as high as 65 Gy to the superior constrictors49,52 have been 
significantly associated with aspiration, stricture, and swallowing efficiency. In addition, mean 
pharyngeal dose is associated with QOL scores.52 As such, there exists supportive evidence that 
reductions in the prescribed RT dose to the pharynx and neck offer the potential to reduce the risk 
of both objective and patient-reported evidence of late RT-induced swallowing dysfunction. Based 
on these data, a dose threshold of at least 55 Gy to the superior pharyngeal musculature is felt to 
portend dysphagia. Moreover, IMRT did not historically use dose-limiting constraints with the 
primary goal of preserving swallowing function. These data also suggest early guidelines for dose-
constraints to dysphagia-specific organs-at-risk using IMRT that may further improve long-term 
functioning after treatment for HNSCC. 
Given the favorable prognosis that has been well described for the HPV-associated OPSCC patient, 
we hypothesize that the prescribed RT dose may be safely reduced following transoral surgical 
resection and pathologic risk stratification for the risk of relapse. On the other hand, patients with 
traditional high-risk pathologic features would be treated with current CRT to 66 Gy. Similarly, low-
risk patients could be observed. For the intermediate-risk patient, we hypothesize that the 
prescribed dose may be safely reduced from a standard intermediate-risk prescription of 60 Gy to 
50 Gy without compromise in local-regional control rates. Moreover, we expect a reduction in the 
development of both objective and patient-reported measures of late RT toxicities.   
 
Radiotherapy dose reduction has been studied in the recently completed E1308. This study 
prospectively examined the oncologic efficacy of reducing the RT dose to 54 Gy following a 
complete clinical response to induction CT. No pathologic evaluation of the primary site was 
required. The long-term results of this trial remain pending but early locoregional control (LRC) and 
disease-free survival (DFS) in complete responders, excluding T4 cancers and > 10 pk-yr tobacco 
exposure, are encouraging and comparable to standard dose radiation. Thus, the current 
hypothesis is predicated on transoral resection leaving a comparable, if not favorable, microscopic 
burden of residual cancer cells. Theoretical mathematical modeling of radiation response and 
cancer control in human solid tumors has been extensively reported and is based on the modeling 


 
15 
of reported local-regional control rates. Withers et al has evaluated the published literature and 
concluded that a dose of 50 Gy is associated with a 90% control rate for subclinical microscopic 
cancer. Evaluation of the clinical data has permitted mathematical modeling of the biologic effect of 
fractionated RT demonstrating that it may be modeled with linear quadratic equation, with most solid 
human tumors requiring an average of 3 Gy (D0) to reduce the surviving cells to 37% which reflects 
the intrinsic biology of the cell to the radiation and its repair response. Modeling suggests that a 
cytoreduction of 10-10 is required to achieve a 90% probability tumor control rate summarized by the 
D10 parameter that represents the relative dose that would be required to sterilize a tumor with 90% 
probability of tumor control. The D10 can be represented by: D10 = 2.3 x D0, where 2.3 is the natural 
logarithm of 10. Thus, the dose required would be: D10 = 2.3 x D0 = 2.3 x 3 = 6.9 Gy. 
 
The probability of achieving tumor control is influenced by the number of tumor cells present. While 
this is largely unknown and likely varies from patient to patient, it has been estimated that 109 cells 
may be present in a typical 4 cm tumor mass. Thus, the estimated modeled dose required would be: 
10 x 6.9 Gy = 69 Gy. 
 
For a tumor cytoreduced to microscopic burden, it is estimated that there may be 107 or less 
residual cancer cells.  Thus, it has been estimated that the radiation dose required to obtain a 90% 
likelihood of cure is: D8 = 8 x 6.9 Gy = 55.2 Gy 
 
This dose is consistent with the minimum dose (57.6 Gy) that has been found to be required in 
patients with pathologic evidence of risk for recurrence (intermediate-risk group). 
 
This proposal will randomize patients to an experimental arm of 50 Gy based on the hypothesis that 
HPV-associated cells will be more radiosensitive modeled by a decrease in the D0 of approximately 
10% (2.7 Gy instead of 3 Gy). 
 
Non-Surgical Risk Adaptive and De-escalation Trial Strategies for HPV+ OPC: 
While awaiting results of the completed RTOG 1016 de-escalation trial for HPV + OPC comparing 
Cisplatin to Cetuximab with standard radiation (70 Gy), the NRG is currently conducting a Phase II 
randomized trial of de-escalated radiation (60 Gy) +/- cisplatin chemotherapy for favorable risk OPC-
SCC, HPV16+, < 10 pack-yrs smoking. ECOG 1308, a phase II randomized risk-adaptive trial 
reported LRC > 95% at 2 years, in which patients demonstrating a complete clinical response at the 
primary site after induction Chemo-Biologic therapy, received substantial de-escalated radiotherapy 
(54 G) + Cetuximab, with no compromise in LRC or DFS.  
 
Surgical Risk Adaptive Strategies for HPV+OPC: 
Recent enthusiasm has emerged for the utilization of trans-oral surgery with neck dissection for HPV 
16+ OPC in which Stage I-II, favorable patients are observed rather than receive adjuvant therapy 
with few primary or reginal neck failures. (T1-2, N0-1).4 However, risk stratification to define 
intermediate and high-risk groups in the post- surgical setting for HPV+ OPC is unclear. The ECOG is 
currently conducting a randomized, risk adjusted treatment Intensity Trial (ECOG 3311) in which 
HPV16+ OPC, stage III-IV (cT1-2, N1-2b) undergo TORS followed by either observation (FR), IMRT 
alone to 50 or 60 Gy (IR) or for higher risk patients, IMRT 66 Gy + weekly Cisplatin, with a primary 
endpoint of PFS at 2 years. However, the doses in this trial for traditional IR and HR are equivalent or 
even higher than the doses currently employed in the Phase II NRG trial for definitive cases. Smoking 
status is not part of the randomization or associated with risk groups but is a stratification variable. 
Prior to HPV discovery, RTOG 9501, and the EORTC, based on two similar trials with extended 
follow-up > 10 years, re-defined high risk as either having + margins/ and or +ENE with marginal 
benefit to addition of cisplatin. Patients were not stratified or randomized based on smoking history. 
HPV as a causative factor in OPC was not known at that time. Subsequently, N2 lymph nodes stage 
was changed to intermediate risk (with no benefit to Cisplatin), forming the basis for RTOG 0920, 
stratified by HPV status, a randomized trial for intermediate risk patients to receive 60 Gy + /- 


 
16 
Cetuximab. This trial is accruing slowly and has not been completed and radiation doses for the HPV 
16+ patients are similar to the NRG HN 002 trial, with no de-escalation. For high risk HPV- patients, 
The RTOG 1216, is conducting a randomized three arm adjuvant trial to evaluate Docetaxel+/- 
Cetuximab, versus weekly Cisplatin, with ERT dose ranging from 60-66 Gy. This trial excludes many 
OPC patients even with HR features because of HPV 16+ is detected > 70% of cases. 
 
Commonly accepted high risks factors for recurrence in the adjuvant setting, such as positive 
margins, ENE, alone or combined with intermediate risk factors including multiple nodal involvement, 
LVI, +PNI, which have formed the basis of trials exploring the efficacy of concurrent chemotherapy, 
EGFR inhibitors or both, may not apply to HPV16 + OPC. Although recognized as a risk factor in the 
definitive setting (0129 trial), the impact of smoking history in the HPV+ patients after surgery is not 
clear and needs to be prospectively evaluated. A recent retrospective study of 201 patients with OPC 
that underwent surgery with/without adjuvant radiotherapy observed that for HPV 16+ cases, common 
risk factors described above were not independent predictors of survival, representing a different 
biological disease. New prognostic markers should therefore be incorporated into future trial design.5 
A more recent surgical series reported by Kharytaniuk et al at AHNS meeting in 2016, found no 
negative prognostic value impacting RFS with + ENE in HPV+ patients compared to HPV-. 
 
In summary, recognition of HPV16+ OPC as a distinct biological disease from HPV 16- SCC with 
more favorable outcomes has therefore led to clinical trial designs to de-escalate standard therapy 
(reduced dose and site of radiotherapy, more limited surgical resection, de-intensified chemotherapy 
and substitution with targeted therapeutics. Novel therapeutic opportunities now present themselves 
to better define IR and HR HPV+ in the adjuvant setting that has significant global implications. This 
has also led to investigations to identify possible biomarkers and genomic expression of antigens to 
utilize a more precision approach. This trial design evaluates the traditional intermediate and high-risk 
cohorts from ECOG 3311 which will close in the near future and investigates de-escalation of both radiation 
dose (50 Gy compared to 60-66 Gy), the need for chemotherapy in the setting of lower doses, and the emerging 
role and efficacy of concurrent and adjuvant PD-1 checkpoint inhibitor, Nivolumab.  This combination of RT plus 
anti-PD-1 immunotherapy has shown safety, without dose reduction, using pembrolizumab (Powell, Journal of 
Clinical Oncology 35, no. 15_suppl (May 2017) 6011-6011) or nivolumab (Gillison, ASTRO H&N Phoenix 2018, 
abstract accepted). 
 
Rationale for refining Risk Stratification based on Biomarkers 
The application of targeted therapies in the last decade has been limited primarily due to a lack of 
actionable therapeutic biomarkers. Currently, only Cetuximab has been approved as a targeted agent 
in HNSCC irrespective of HPV. However, response to Cetuximab does not correlate with EGFR 
expression/ amplification. ALK and ROS1, have been identified in the past as possible actionable 
targets, but in HNSCC, these appear to be rare. 
 
Large comprehensive genomic surveys of HNSCC have now demonstrated divergent genomic 
pathway mutations and drivers of HPV 16+ OPC from HPV 16-. HPV 16+, harbor few genomic 
alterations of P53 and/or CDKN2A, presumably due to activity of the HPVE6 and E7 viral 
oncoproteins.6 They also appear to display less genomic complexity as compared with HPV- disease. 
HPV+ lack focal RTK amplifications but do display a higher rate of focal PIK3CA amplification and 
mutation. PIK3CA alterations have been reported as therapeutic biomarkers in this patient population 
based on cell line and patient derived xenograft studies.14 HPV-associated HNSCCs also demonstrate 
enrichment for copy-number gains in TRAF3 and E2F1 and a lack of CCND1 amplification when 
compared with HPV-negative disease. HPV 16+ driven cancers display both mutations and fusions in 
the FGFR3 gene. 
 
Study rationale for addition of PD-1 targeted immune checkpoint inhibition 
Immunotherapy has now emerged as an alternative approach based on recent success in melanoma, 
lung and renal cell cancer. Checkpoint inhibitors and CTLA-4 inhibitors are being investigated in 
HNSCC in both the recurrent/metastatic setting with recently reported promising results (CheckMate 


 
17 
Trial NCT01860430, and NCT01935921) and in the definitive setting with CTLA-4 inhibitors 
(Ipilimumab). Pembrolizumab, a PD-1 blocker, was recently shown in a Phase I trial to have promising 
response outcomes in HPV+ recurrent HNSCC. 
 
The effects of standard of care therapy on immune response (CD4 (+), CD8(+) T cells, regulatory T 
cells(Treg) and myeloid-derived suppressor cells(MDSC) in HNSCC suggest an immunosuppressive 
effect. Standard Chemo-radiotherapy and radiotherapy to both sites of gross and elective risk nodal 
regions in HNSCC have been found to reduce circulating T cell responses and upregulate MDSCs. 
PD-1 expression on CD 4(+) T cells are up-regulated by 2.5-fold after CRT. PD-1 blockade resulted in 
in downregulation of MDSC, as well as TAM, CD47/SIRP pathway, and upregulated effector T cells 
and dendritic cells.7 Lower doses of radiotherapy without chemotherapy after surgery for HPV+ OPC 
may create an optimal microscopic tumor microenvironment that promotes neo-antigen expression 
and an abscopal effect without promoting a negative immunosuppressive environment. Combining 
this approach with PD-1 inhibition may lead to non-redundant immune response through several 
pathways that is additive and sustained.  
Programmed Cell Death-1 (PD-1; CD279) is a cell surface signaling molecule that delivers 
inhibitory signals that regulate the balance between T cell activation and tolerance by interacting 
with its ligands, PD-L1 (CD274; B7-H1) and PD-L2 (B7-DC/CD273). PD-1 is a 55 kD type I 
transmembrane protein that is a member of the CD28 family of T-cell regulatory receptors, 
which also includes CTLA-4, ICOS, and BTLA.1 PD-1 is primarily expressed on activated T 
cells, B cells, and myeloid cells.2 Its ligands, PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), 
have been shown to down-regulate T-cell activation upon binding to PD-1 in both murine and 
human systems.3,4 PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine 
inhibitory motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif (ITSM), 
that when phosphorylated, delivers a negative signal to the lymphocyte by the recruitment of SHP-
2 to the phosphorylated tyrosine residue in the ITSM in its cytoplasmic region.5,6 Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1-deficient mice. PD-1-deficient mice 
develop various autoimmune phenotypes, including dilated cardiomyopathy and a lupus-like 
syndrome with arthritis and nephritis.7-9 The emergence of these autoimmune phenotypes is 
dependent upon the genetic background of the mouse strain; many of these phenotypes emerge at 
different times and show variable penetrance. In addition to the phenotypes of null mutations, 
PD-1 inhibition by antibody-mediated blockade in several murine models has been found to play 
a role in the development of autoimmune diseases such as encephalomyelitis, graft-versus-
host disease, and type I diabetes.10-12  Taken together, these results suggest that PD-1 blockade 
has the potential to activate anti-self T-cell responses, but these responses are variable and 
dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied 
by a universal loss of tolerance to self-antigens. 
 
Preclinical animal models of tumors have shown that blockade of PD-1 by monoclonal antibodies 
(mAbs) can enhance the anti-tumor immune response and result in tumor rejection. This suggests 
that host mechanisms limit the antitumor response. 13-15,23-25  
 
In humans, PD-L1 is constitutively expressed on macrophage-lineage cells, activated T cells, 
lung, vascular endothelial cells, and placental syncytiotrophoblasts.53 Aberrant expression of PD-
L1 by tumor cells has been reported in a number of human malignancies. 26-29,54-56 PD-L1 
expressed by tumor cells has been shown to enhance apoptosis of activated tumor-specific T 
cells in vitro.30 Moreover, the expression of PD-L1 may protect the tumor cells from the induction of 
apoptosis by effector T cells.31 Retrospective analyses of several human tumor types suggest 
that tumor over-expression (as measured by immunohistochemistry) of PD-L1 may permit 
immune evasion by tumors. In renal cell carcinoma, high surface expression levels of PD-L1 on 
tumor cells are related to tumor aggressiveness. Patients with high tumor d/or lymphocyte PD-L1 
levels are 4.5 times more likely to die from their cancer than patients exhibiting low levels of PD-L1 
expression.32  


 
18 
 
PD-L1 and PD 1 expression may be virally mediated in HNSCC and represent a potential biomarker 
to blockage with checkpoint inhibitors.57 PD-L1 expression however is variable and not clearly 
understood. HPV- SCC have also been shown in RNA sequencing TCGA data to express PD-L1. It 
remains unclear, nor accepted as to the optimal method of PD-L1 measurement for patient 
stratification for future trials or whether PD-L1 expression predicts for response to checkpoint 
inhibitors. This has led to a search for other tumor biomarkers in addition to immune cell profiling to 
refine patient selection. Somatic gene alterations in HNSCC responsible for immune evasion, 
inflammation, and antigen presentation may play a role in response to checkpoint inhibition. PI3K 
expression in particular may be one such marker.58 Other investigations reported in metastatic solid 
tumors include possible association between checkpoint response and genomic instability due to 
mismatch repair deficiency leading to immune stimulation against epitopes,59 mutational burden and 
improved outcomes in melanoma and NSCLC with checkpoint inhibitors60 and the possible correlation 
of between neoantigen burden and response to immunotherapy. Neoantigen specific T-cell therapy 
that exposes epitopes derived from genetic aberrations, has demonstrated promising results when 
combined with checkpoint inhibition.61,62 Emerging evidence in pre-clinical and clinical studies strongly 
suggest that Radiotherapy, creates an abscopal effect by releasing tumor specific neoantigens, 
eliciting and immune response that combined with checkpoint inhibitors, results in a more robust and 
sustained T-cell immune response.63-65 Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that 
binds to PD-1. Blockade of the PD-1 pathway by nivolumab was studied using the mixed 
lymphocyte reaction (MLR). PD-1 blockade resulted in a reproducible enhancement of both 
proliferation and IFN-γ release in the MLR.33  The effect of nivolumab on antigen-specific recall 
response was investigated using a cytomegalovirus (CMV)-restimulation assay with human 
peripheral blood mononuclear cells (PBMCs), and was evaluated by ELISA. These data indicated 
that nivolumab, versus an isotype-matched control antibody, augmented IFN-g secretion from 
CMV-specific memory T cells in a dose-dependent manner. 
 
Clinical Efficacy of Nivolumab for R/M HNSCC 
The clinical efficacy of nivolumab in SCCHN has been established study CA209141 a randomized, 
open-label, Phase 3 trial that compared nivolumab, a fully human anti-programmed death 1 (PD-1) 
monoclonal antibody, to investigator’s choice (IC) of systemic therapy in patients with recurrent or 
metastatic SCCHN who progressed from a platinum containing therapy. At a preplanned interim 
analysis, the median OS was 7.5 months (95% CI 5.5 to 9.1) with nivolumab versus 5.1 months (95% 
CI, 4.0 to 6.0) with IC. There was a 30% reduction in the risk of death for patients on the nivolumab 
arm (hazard ratio 0.70; 97.73% CI 0.51 to 0.96; P=0.0101) over standard of care. In addition, the 
overall safety profile of nivolumab was favorable compared to standard of care. Clinical benefit seen in 
this chemotherapy pre-treated SCCHN suggests the potential clinical activity of nivolumab in earlier 
treatment settings. Two large, global randomized studies are investigating the combination of 
nivolumab with ipilimumab in the first-line recurrent/metastatic setting (CA209-714 and CA209-651).  
 
Rationale for Combining Nivolumab with Radiotherapy  
In addition to direct cytotoxic effects, radiotherapy may induce an immune effect important to tumor cell 
death.53 Preclinical data support synergy between checkpoint inhibitors and radiotherapy. Mouse 
models of poorly immunogenic tumors have demonstrated that concomitant administration of anti-
CTLA-4 antibodies and radiotherapy results in antitumor T cell responses both in the radiation field as 
well as outside of it (an abscopal effect). PD-1 blockade after completion of radiotherapy also has been 
shown to induce rejection of persistent tumors in mouse models. Combination PD-1 blockade and anti-
CD137 stimulation increased response to radiotherapy in a mouse model of triple negative breast 
cancer,56and PD-L1 blockade concomitant with radiotherapy improved survival in comparison to either 
therapy alone in mouse models of glioma.57 In human patients, case-reports support the existence of 
a clinically significant abscopal effect for patients with melanoma who have received ipilimumab prior to 
radiotherapy. These data support a hypothesis that radiotherapy-induced cell death may result in 
alterations in the tumor immune environment (via upregulation of MHC class I, ICAM-1, CD80) as well 


 
19 
as presentation of novel tumor and generation of anti-tumor immune responses.60 In addition to novel 
antigen presentation, recent in vivo data indicate that radiotherapy can induce increased PD-L1 
expression in tumors and thereby inhibit activation of cytotoxic CD8+ T cell responses, thus reducing 
the efficacy of radiotherapy. Concurrent administration of anti-PD1 antibodies improved response to 
radiotherapy and survival in mouse models whereas sequential therapy did not. These data support a 
hypothesis that checkpoint inhibitors administered prior to or concomitant with radiotherapy can induce 
clinically significant anti-tumor immune responses induced by “vaccination” to tumor-specific antigens 
exposed during radiation-induced cell death. Such a phenomenon may be particularly relevant to viral-
induced tumors, such as HPV-positive SCCHN and to highly genetically unstable tumors such as HPV-
negative SCCHN. 
 
Existing Data on Nivolumab in Combination with Radiotherapy  
Preliminary safety data are available from CA209-143, a study of nivolumab combined with 
radiotherapy and temozolomide in participants with newly-diagnosed Glioblastoma Multiforme (GBM). 
In September 2016, the interim analysis from Cohorts 1c and 1d in the study were reported64 which 
investigated the safety of nivolumab plus radiotherapy with or without temozolomide in 
methylated/unmethylated newly diagnosed GBM.  Fifty-three participants received nivolumab with 
radiation alone (n=53) or with radiation plus temozolomide (n=57). Most participants were still on 
treatment at data cutoff. Six participants in Cohort 1c discontinued treatment due to increased 
transaminases (n=3) and asthenia, fatigue, and hypotension (n=1 each). In Cohort 1d, 4 participants 
discontinued treatment due to increased ALT, increased lipase, herpes simplex virus (HSV) 
encephalitis, and acute kidney injury (n=1 each). Five participants died in each cohort. Causes of death 
included disease progression (n=4) and unknown (n=1) in Cohort 1c and disease progression (n=3), 
palliative care only due to HSV encephalitis and clinical decline (n=1), and unknown (n=1) in Cohort 
1d. The most common treatment-related serious adverse events (TRSAEs) and treatment-related 
adverse events (TRAEs) are reported below. These data suggest that nivolumab is well tolerated when 
given in combination with radiotherapy. No AEs attributable to combination of nivolumab with RT were 
identified. 
 
Summary of Nivolumab Clinical Activity in the Metastatic Setting 
The PK, clinical activity, and safety of nivolumab have been assessed in approximately 32 clinical 
studies sponsored by BMS or Ono Pharmaceutical Co., Ltd. (ONO): 11 Phase 1 studies, 13 Phase 2 
studies, and 8 Phase 3 studies. Approximately 7,600 subjects have received nivolumab in single- or 
multiple-dose Phase 1/2/3 studies or studies with nivolumab in combination with other therapeutics 
(ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies). 
 
In CA209003, the clinical activity of nivolumab was demonstrated in a variety of tumor types, 
including melanoma, RCC, and NSCLC. Clinical activity was noted across a range of doses 
(0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg). In CA209003, a total of 306 subjects with 
melanoma, RCC, and NSCLC have been evaluated for clinical activity. A response of either CR or 
PR, as determined by investigator assessed tumor evaluations based on RECIST 1.1 criteria 
has been reported at all dose levels. 
 
In NSCLC, the most active doses were 3 and 10 mg/kg. The overall response rate (ORR) of 
17% was reported with a 48-week PFS rate (PFSR) of 22% (95% CI: 15-30%), and a 24-month 
overall survival rate of 24% (95% CI: 16-32%). Only a single response (1/33) was reported at 1 
mg/kg. Durable responses were observed in both squamous and non-squamous subtypes. 
 
Historically, ORR of 5% to 10% and median PFS (mPFS) of 2 to 3 months has been reported 
with docetaxel treatment in previously-treated NSCLC subjects. A complete response (CR) or 
partial response (PR) was reported in 31% (95% CI: 22% - 41%) of the 107 response-evaluable 
subjects with melanoma treated with nivolumab monotherapy Q2W at doses ranging from 0.1 to 10 


 
20 
mg/kg in CA209-003. The responses were durable with a PFSR at 24 weeks of 38% (95% CI: 28 - 
47%) and OS at 24 months of 48% (95% CI: 38-57%). Of the 34 response evaluable RCC 
subjects in CA209-003, responses were reported in both the 1 mg/kg (5 of 18 subjects, 27 %) and 
10 mg/kg (5 of 16 subjects, 31%) treatment groups. PFSR at 24 weeks was 33% (95% CI: 14 
- 55%) in the 1 mg/kg and 37% (95% CI: 14 - 61%) in the 10 mg/kg nivolumab treatment groups. 
OS at 24 months was 51% (95% CI: 30 - 64%) and 44% (95% CI: 20 - 66) in the 1 mg/kg 
and 10 mg/kg groups, respectively.  
 
In CA209037, the ongoing Phase 3 study for subjects with previously-treated advanced 
melanoma of nivolumab (3 mg/kg administered by intravenous [IV] infusion every 2 weeks 
[Q2W]) vs investigator’s choice therapy, as of 30-Apr-2014, 120 nivolumab-treated and 47 
subjects in the investigator’s choice arm are available for determination of the ORR using 
RECIST 1.1 criteria. As determined by imaging plus clinical review by an Independent Radiology 
Review Committee (IRRC), the ORR for nivolumab vs the reference arm is 31.7% vs 10.6%, 
respectively. Four subjects in the nivolumab arm had a CR, whereas no subjects in the reference 
arm had a CR. Median progression-free survival was 4.7 months (95% CI: 2.3-6.5) vs 4.2 months 
(95% CI: 2.1 - 6.3) with a 6-month PFS rate of 48% (95% CI: 38 - 56) vs 34% (95% CI: 18 - 51) in 
the nivolumab (n = 122) vs reference arm (n = 60), respectively. In addition, recent clinical trial data 
in MEL (CA209066) and NSCLC (CA209017) has demonstrated OS benefit. In CA209066, a 
phase 3 study of 418 previously untreated metastatic melanoma patients without a BRAF 
mutation, 1- y e a r  overall survival was 72.9% (95% CI: 65.5 to 78.9) in the nivolumab group 
as compared to 42.1% (95% CI: 33.0 to 50.9) in the dacarbazine group (P<0.001). The median 
PFS was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard 
ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective 
response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 
9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with 
nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups 
defined by status regarding the programmed death ligand 1 (PD-L1). Additional supportive data for 
the clinical activity of nivolumab in advanced melanoma has been shown in a cohort of 107 
advanced melanoma subjects in an outpatient setting who enrolled between 2008 and 2012. In 107 
patients with advanced MEL treated with nivolumab, objective responses were observed in 
31% of patients. Median OS (62% with two to five prior systemic therapies) was 16.8 months, 
and 1- and 2-year survival rates were 62% and 43%, respectively. Median PFS (mPFS) was 3.7 
months (95% CI, 1.9 to 9.1 months), with 1- and 2-year PFS rates of 36% (95% CI, 27% to 46%) 
and 27% (95% CI, 17% to 36%), respectively. In CA209017, a phase 3 trial in 272 patients with 
metastatic squamous NSCLC with progression on or after platinum-based chemotherapy, 
subjects were randomized to nivolumab 3 mg/kg IV q2 week (n=135) or docetaxel (n=137) at 
75 mg/m2 every 3 weeks. Median OS was 9.2 months in the nivolumab group (95% CI: 7.3-13.3) 
vs 6.0 months in the docetaxel group (95% CI: 5.1-7.3) (HR of 0.59, P=0.00025). 
Summary of Nivolumab Safety in the Metastatic Setting 
In clinical trials, nivolumab has demonstrated an acceptable benefit-risk across multiple tumor 
types, including advanced melanoma, RCC, NSCLC, and some lymphomas. The two clinical trials 
that have contributed the most to the clinical experiences of nivolumab monotherapy are studies 
CA209003 and CA20937. Overall, the safety profile is quite similar between these two studies and 
is discussed further in the sections below. CA209003 is a completed Phase 1 open label, multiple 
dose escalation study in 306 subjects with select previously treated advanced solid tumors, 
including melanoma, RCC, NSCLC, colorectal cancer, and hormone-refractory prostate cancer. 
Subjects received nivolumab at doses of 0.1, 0.3, 1, 3, or 10 mg/kg intravenously every 2 weeks, up 
to a maximum of 2 years of total therapy. A total of 306 subjects were treated with nivolumab in the 
dose range of 0.1 - 10 mg/kg. No maximal tolerated dose was identified in CA209003. The incidence, 
severity and relationship of AEs were generally similar across dose levels and tumor types. 
Nivolumab related AEs of any grade occurred in 75.2% of subjects. Of the 306 treated subjects, 303 


 
21 
(99.0%) subjects have at least 1 reported AE regardless of causality. The most frequently 
reported AEs were fatigue (54.9%), decreased appetite (35.0%), diarrhea (34.3%), nausea 
(30.1%), and cough (29.4%). Treatment-related AEs were reported in 230 (75.2%) of the 306 
subjects. The most frequently reported treatment-related AEs were fatigue (28.1%), rash (14.7%), 
diarrhea (13.4%), and pruritus (10.5%). Most treatment-related AEs were low grade. Treatment-
related high grade (Grade 3-4) AEs were reported in 52 (17.0%) of subjects. The most common 
treatment-related high-grade AEs were fatigue (2.3%) and diarrhea (1%). Drug-related SAEs 
occurred in 11.5% of subjects. Grade 3-4 drug-related  SAEs  reported  in  at  least  2  subjects  
included:  diarrhea (3 subjects, 1.0%), pneumonitis (3 subjects, 1.0%), pneumonia (2 subjects, 
0.7%) and lipase increased (2 subjects, 0.7%). Select AE categories (events with a potential 
inflammatory mechanism requiring more frequent monitoring and/or unique intervention such as 
immunosuppressants and/or endocrine replacement therapy) include: GI AEs, pulmonary AEs, renal 
AEs, hepatic AEs, skin AEs, and endocrinopathies. In addition, select AEs include a category for 
infusion reactions are outlined below in the Table Treatment-related Select Adverse Events by 
Treatment - All CTC Grades Reported in at Least 10 Treated Subjects in CA209003). Each category is 
composed of a discrete set of preferred terms, including those of greatest clinical relevance. These 
select AEs are considered events of interest based on the mechanism of action and were 
previously referred to as immune-related AEs or immune-mediated AEs. Most high-grade events 
resolved following the treatment guidelines for the treatment of pulmonary events, GI events, hepatic 
events, renal events, and endocrine events, respectively. Overall, the safety profile at 3 mg/kg (n = 
54) was similar to safety profile across the dose ranges from 0.1 mg/kg to 10 mg/kg (n = 306). 
 
 


 
22 
Treatment-related Select Adverse Events by Treatment - All CTC Grades Reported  
in at Least 10 Treated Subjects in CA209003 
Preferred Term 
3mg/kg n=54 
Total (0.1 to 10 mg/kg) N=306 
 
Any Grade 
Grade 3-4 
Any Grade 
Grade 3-4 
Any Select AE 
23 (43) 
2 (4) 
140 (46) 
19 (6) 
Any Endocrinopathies 
4 (7) 
0 
29 (10) 
3 (1) 
Endocrinopathies Thyroid 
4 (7) 
0 
26 (9) 
2 (1) 
Blood TSH increased 
2 (4) 
0 
11 (4) 
1 (0.3) 
Hypothyroidism 
1 (2) 
0 
11 (4) 
1 (0.3) 
Any Skin AEs 
12 (22) 
0 
75 (25) 
1 (0.3) 
Rash 
5 (9) 
0 
45 (15) 
0 
Pruritus 
3 (6) 
0 
32 (11) 
1 (0.3) 
Any GI AE 
7 (13) 
0 
43 (14) 
3 (1) 
Diarrhea 
6 (11) 
0 
41 (13) 
3 (1) 
Any hepatic AE 
3 (6) 
2 (4) 
18 (6) 
4 (1) 
ALT increased 
1 (2) 
0 
11 (4) 
1 (0.3) 
Any Pulmonary AE 
2 (4) 
0 
17 (6) 
6 (2) 
Pneumonitis 
1 (2) 
0 
12 (4) 
4 (1) 
Other Select AE 
3 (6) 
0 
15 (5) 
2 (1) 
Infusion-related reaction 
3 (6) 
0 
12 (4) 
0 
Abbreviations: ALT: alanine aminotransferase, TSH: thyroid stimulating hormone. Source: MDX1106-03. 
Clinical data cut-off date: 18-Mar-2013. Total includes subjects who also received 0.1 mg/kg (n = 17), 0.3 
mg/kg (n = 18), 1 mg/kg (n = 86), and 10 mg/kg (n = 131) in addition to those illustrated at 3 mg/kg (n = 54). 
 
Treatment-related AEs leading to discontinuation were reported in 32 (10.5%) of the 306 nivolumab 
treated subjects on CA209003. The most frequent of these were pneumonitis (8 subjects; 2.6%) 
and colitis (3 subjects; 1.0%). There were 3 (1%) drug related deaths; each occurred after 
development of pneumonitis. CA209037 is an ongoing Phase 3, open-label study of nivolumab 
(3 mg/kg administered by intravenous [IV] infusion every 2 weeks [Q2W]) vs investigator’s 
choice therapy in subjects with previously-treated advanced melanoma. As of 30-Apr-2014, 268 
subjects have been treated with 3 mg/kg IV nivolumab in CA209037 with safety results as outlined 
below (source document interim CSR, DCN930081508) that are consistent with the Phase 1 
experience of CA209003.  
 
In CA209037, nivolumab related AEs of any grade occurred in 67.5% of subjects. Of the 268 
subjects treated with nivolumab, 255 (95.1%) subjects had at least 1 reported AE regardless of 
causality. The most frequently reported treatment-related AEs were fatigue (25.0%), pruritus 
(16.0%), diarrhea (11.2%), and nausea (9.3%). Most treatment-related AEs were low grade. 
Treatment -related high grade (Grade 3-4) AEs were reported in 24 (9.0%) of subjects. The most 
common treatment-related high-grade AEs were fatigue (0.7 %), anemia (0.7%), diarrhea (0.4%), and 
vomiting (0.4%). Drug-related SAEs occurred in 4.5% of subjects. Grade 3-4 drug-related SAEs 


 
23 
reported in at least 2 subjects included diarrhea (2 subjects, 0.7%). In addition, drug-related SAE 
of hyperglycemia occurred in 0.7%. 
 
Select AE categories (events with a potential inflammatory mechanism requiring more frequent 
monitoring and/or unique intervention such as immunosuppressants and/or endocrine replacement 
therapy) were: 
 
• Skin (29.1%) including pruritus (16.0%) and rash (9.3%) 
• GI (11.6%) including diarrhea (11.2%) and colitis (1.1%) 
• Endocrine (7.8%) including hypothyroidism (7.8%) and hyperthyroidism (1.9%) 
• Hepatic (4.5%) including AST increased (4.1%) and ALT increased (2.6%) 
• Pulmonary (2.2%) including pneumonitis (1.9%) 
• Hypersensitivity/infusion reaction (1.9%) 
• Renal (1.5%) including increased creatinine (0.7%), increased urea (0.4%), and 
• tubulointerstitial nephritis (0.4%) 
 
In general, these select AEs were considered by the investigator to be related to study drug, 
except for AEs in the hepatic and renal select AE categories. There were few high-grade select 
adverse events (n = 20), and most high-grade events (13 of 20) were subsequently resolved, 
including those for which immunosuppressive therapy was not initiated. Treatment-related  AEs  
leading to discontinuation were reported in 6 (2.2%) of the 268 nivolumab treated subjects in 
CA209037 including single events of colitis, pancreatitis, increased ALT, increased lipase, 
autoimmune neuropathy, and demyelination. In CA209037, one subject experienced drug-related 
grade 5 hypoxia, possibly pneumonitis, in the setting of lymphangitic spread and possible 
pneumonia. 
 
Taken together, these data from studies from CA209003 and CA209037 highlight the acceptable 
safety profile with similar trends in AEs in the 574 subjects treated with nivolumab in these 2 
studies. Additional details on the safety profile of nivolumab, including results from other 
clinical studies, are also available in the BMS-936558 (nivolumab) IB. 
Rationale For Immunotherapy In Viral-Associated Tumors 
As described above, the adaptive T cell response largely depends upon presentation of antigens by 
major histocompatibility complex (MHC) in the context of an immune-stimulatory environment. Viral 
proteins, mutated proteins (neoantigens), and spatio-temporally dysregulated self- proteins 
represent targets of the T cell response that have potential to result in tumor-cell clearance. As 
evidence, T cell responses to viral antigens in patients with Epstein-Barr virus (EBV)+ or polyoma 
virus+ tumors can be identified and T cells against tumor neoantigens and self-antigens have been 
widely reported in the literature. Further, overall survival of both gastric and Merkel cell carcinoma 
patients is prognostically associated with the presence of tumor infiltrating T cells, suggesting 
immunosurveillance of tumor growth is taking place. 
 
In Summary: 
Can radiotherapy doses be reduced over current standards in the adjuvant setting for HPV+ 
IR and HR patients, when combined with systemic therapy, and can immunotherapy replace 
cisplatin chemotherapy further reducing both acute and late toxicity and improving 
swallowing QOL? How does tobacco exposure affect risk stratification in the post-surgical 
setting of HPV+ OPC? 
 
 


 
24 
1.6 
 Correlative Studies Background 
TP53 Mutation and Prognosis 
TP53 mutation is frequent in HPV-negative HNSCC while it is rare in HPV-positive HNSCC. 
However, it is suggested that HPV-positive patients with mutated TP53 have a poorer prognosis 
when compared to HPV-positive patients with wild type TP5366. In addition, the location of mutations 
within TP53 can manifest as an abnormally truncated protein (nonsense mutation), disruption of 
DNA binding capacities (missense mutation), or without functional consequence (silent mutation)67 
found that 53.3% of HNSCC patients had TP53 mutations; functionally non-disruptive 33%, 
disruptive 20%, and wild type 47% (41). The patients with any p53 mutations associated with the 
worse overall survival compared to wild-type TP53 (HR to death, 1.4; 95% confidence interval 1.1-
1.8, p=0.009) while the association was stronger with functionally disruptive TP53 mutation (HR 1.7; 
1.3-2.4, p<0.001). Therefore, we hypothesize that the patients with HPV-positive and functionally 
disruptive TP53 mutations will have shorter time to disease progression and overall survival 
compared to patients with wild type TP53. In addition to TP53, a panel of 200 common cancer-
related genes will be sequenced in one assay which may yield novel prognostic and/or predictive 
biomarkers. 
 
Correlation of radiologic markers with pathologic nodal status 
Preoperative CT/MRI scans will be analyzed for nodal stage and prediction of ENE, and correlated 
with final pathologic nodal stage, presence and extent of ENE absent, microscopic or gross). 
HPV DNA measurement and alteration in serum and saliva  
HPV DNA and seropositivity to HPV antigens will also be measured quatitatively and qualitatively, 
before and after surgical and adjuvant treatment to measure stability and predictive ability over time 
in a prospective treated population. Baseline and posttreatment cytokines are potentially predictive 
of outcome. Furthermore, the association between serologic markers (detected in blood at baseline 
and two other timepoints, including cytokines, chemokines, growth factors, and angiogenic factors in 
blood and treatment efficacy will also be examined. DNA from buffy coat or PBMCs will be analyzed 
for quantitative and qualitative alterations in HPV DNA. These analyses will be performed under the 
direction of Robert L. Ferris, MD, PhD.  
Oral or serum HPV DNA level may correlate with PFS 
Given the ability to detect HPV DNA in salivary and serum specimens, we will perform an 
exploratory correlation between pre-treatment and post-treatment (1- and 2- year) HPV DNA, using 
QRT-PCR for HPV E6/E7. The data will be used to determine the feasibility and potential value of 
incorporating this potential biomarker into the future randomized phase III trial. 
 
Tumor antigen specific cellular immunity 
We and others have characterized the antigen specific cellular immune response to OPSCC, 
including HPV-, EGFR- and other antigens. PBL from pretreatment and post treatment patients will 
be correlated with disease recurrence, PFS, and OS. 
 
Quantification of HPV DNA and serology in serum and saliva 
Presence of HPV DNA and seropositivity has been reported in healthy individuals and HPV/p16+ 
OPSCC patients, in approximately 60-70% of patients’ serum and saliva. We collect blood and 
saliva from all patients for prediction of clinical response based on quantitative or qualitative 
alterations in these biomarkers in each specimen type after therapy and correlated with clinical 
outcome/response and Arm of adjuvant therapy. 
 
 


 
25 
1.7 
Clinical Functional Outcomes 
Clinical outcomes are those readily tracked by the clinical assessment team and trialist, most of 
which reflect assessments utilized in routine clinical practice.  
1.8 
Functional Swallowing Outcomes 
Swallowing is a complex biomechanical process involving 5 cranial nerves and over 25 muscles in 
the upper aerodigestive tract. Swallowing impairments can occur as the result of surgery alone, 
radiotherapy or CRT. Although there are many ways to report swallowing outcomes, the modified 
barium swallow (MBS) study remains the only measure that defines physiology and is predictive of 
adverse health effects (i.e., pneumonia). Although patient-reported outcomes provide an important, 
complementary perspective of swallowing abilities, they do not accurately reflect swallowing 
competency. Much of our knowledge of aspiration and physiologic impairment comes from data of 
laryngeal preservation trials that aggregate functional outcomes from multiple sites of HNSCC and 
show aspiration rates up to 40% in unselected cohorts, and in up to 80% of symptomatic patients 
when laryngopharyngeal function is impaired. These data based on findings from MBS studies 
confirm that when physiology is impaired, patients have high rates of aspiration, much of which is 
undetected by patient report because of a lack of sensory awareness. Hence, silent aspiration has 
been reported more than 50% of patients who aspirate.2,3,6 Data specific to patients with 
oropharyngeal primary tumors continue to demonstrate a high burden of dysphagia. In a population-
based analysis of over 8,000 HNSCC, patients with cancers of the oropharynx had the second-
highest prevalence of dysphagia.5 In addition, 31% of patients demonstrated elevated occurrences 
of aspiration relative to baseline >1 year after treatment, and 22% developed pneumonia in a trial of 
chemoIMRT that was designed to protect dysphagia-organs-at-risk using  dose-constraints for 
oropharyngeal cancer.6 Furthermore, aspiration based on MBS findings was significantly predictive 
of pneumonia in this trial of chemoIMRT for oropharyngeal cancer (p=0.017, Se 80%, Sp 60%), and 
silent aspiration was evident on MBS studies in 63% of patients who developed pneumonia. In 
addition, pharyngeal residue on MBS studies was significantly associated with the development of 
pneumonia after 7 chemoIMRT (p<0.01).6,7 These results offer compelling support for the 
examination of swallowing physiology (i.e., “airway protection” and “pharyngeal transit”) as these 
health-related endpoints cannot be obtained by PROs. Thus, we propose to evaluate swallowing 
using MBS studies as the primary objective functional measure of this trial. 
 
1.9 
Patient-Reported Outcomes (PRO) 
Patient-reported outcomes (PRO) will include head-and-neck specific symptoms (MDASI-HN), 
cancer and head and neck-specific quality of life (FACT-H&N), swallowing perception and 
performance (MDADI), voice outcomes (VHI-10), and overall health status (EQ-5D). Additionally, 
ability to return to employment will be assessed using a return to work instrument in use by RTOG.  
Head and neck-specific symptoms include issues of dry mouth, mucositis and mucosal sensitivity, 
shoulder and neck discomfort, and skin changes as well as swallowing and voice-related problems.  
It is well documented that head and neck cancer patients experience a profound, acute decrement 
in the level of general physical functioning and general cancer-specific QOL because of both 
surgery and adjuvant RT/CRT. Data regarding the late effects of treatment on disease-specific 
function is more limited; however, available studies indicate that a significant percentage of patients 
fail to return to baseline functioning. Patient-perception of swallowing performance has been shown 
to be associated with long-term swallowing related quality of life, and to remain depressed from 
baseline levels after treatment for oropharyngeal cancers.8 Voice-related changes that include 
alterations in resonance, pitch variation, loudness, and quality (i.e., hoarseness, raspiness, etc) 
more commonly result from treatments that affect the oropharynx, compared with articulatory 
changes that result from management of oral cavity cancers. 
 


 
26 
2. 
Objectives 
2.1 
Primary Objective 
The dual primary objectives of the study are (1) to  test the hypothesis that the proposed adjuvant 
de-escalation strategy (TORS + 50Gy RT + Nivolumab cancer) is equivalent (non-inferior) to current 
standard of care cisplatin chemotherapy + standard 60-66 Gy radiation, and (2) to demonstrate a 
reduction in the rate of PEG tube dependence at one year.  
 
Primary Hypotheses: We hypothesize that HPV + OPC is a distinct immunologic disease with a 
more favorable prognosis compared to HPV- OPC and represents a novel opportunity for de-
escalation strategies in the adjuvant setting in Intermediate-Risk p16+ OPC groups after trans-oral 
resection (TORS). Risk-Adaptive de-escalation through a combination of TORS surgical resection 
followed by de-escalated RT (50 Gy accelerated fractionation) and concurrent Nivolumab 
immunotherapy in HPV+ OPC patients will result in similar PFS compared to historical results of 
standard CRT studies (60-66 Gy +/- Cisplatin) in the adjuvant setting, typically recommended for 
Intermediate and High Risk patients (HPV-, >4 metastatic nodes, + extensive ENE, + margins), as 
well as improvement in secondary endpoints of reduced toxicity, and patient QOL measures. 
We further hypothesize that RT combined with concurrent and adjuvant Nivolumab will offer similar 
PFS outcomes to historical trials using cisplatin-based CRT through reduced tumor 
microenvironment immune suppression, enhanced systemic immune activation and response, and 
reduced toxicity by eliminating standard chemotherapy and allowing de-escalated RT. 
 
2.2 
Secondary Objectives 
• 
To estimate the following oncological outcomes: 
o LRC at 1 and 2 years 
o Acute toxicity at 1 and 6 months 
o Late toxicity profiles at 1 and 2 years 
o To determine patterns of failure (LRC vs Distant recurrence at 1, 2 years) 
o Evaluate pre-surgical and post swallowing function outcomes. 
o To determine QOL (PRO)  
o Evaluate the impact of current smoking, former smoking history < and > 10 pack years. 
• 
To assess and compare early and late toxicities associated with TOS and the different doses 
of adjuvant PORT. 
• 
To evaluate QOL, swallowing perception and performance, voice outcomes, and head and 
neck symptoms. 
2.3 
Laboratory Research Objectives 
Paraffin-embedded tumor block or 20 5-um sections will be sent to Dr. Ferris’s lab for translational 
biomarker studies: 
• 
To correlate tumor TP53 mutation and other associated mutation profiles with pathologic 
findings, with PFS and other outcome parameters in patients with resectable HPV-associated 
OPSCC after the above treatments. 
• 
To investigate the usefulness of biomarkers in predicting PFS and biomarkers, including tumor 
genomics, plasma cytokine/chemokines, cellular immunity to HPV, and oral HPV DNA  
 
3. 
Eligibility Criteria 
Each of the criteria that follows must be met for a patient to be considered eligible for this study. For 
each patient, an eligibility checklist must be completed and maintained in the patient’s chart. 
 


 
27 
NOTE: In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks 
later would be considered Day 28. 
3.1 
Inclusion Criteria 
 
• 
Age >/= 18 years. 
• 
ECOG performance status of 0 or 1. 
• 
Patients must have newly diagnosed, histologically or cytologically confirmed squamous cell 
carcinoma or undifferentiated carcinoma of the oropharynx. Patients must have been 
determined to have resectable oropharyngeal disease. Patients with primary tumor or nodal 
metastasis fixed to the carotid artery, skull base or cervical spine are not eligible. 
• 
Patients must have intermediate risk factors, as described below as determined by imaging 
studies (performed < 45 days prior to registration) and complete neck exam, from the skull 
base to the clavicles. The following imaging is required: CT scan of neck only with IV contrast 
or MRI. PET scan of HN and chest with IV contrasted CT correlation is encouraged prior to 
enrollment. 
o Intermediate risk features: 
 
Tobacco <10 pk-yr: T0-3 plus any one of the following: >N2b (> 5 LN’s +), 
N2c/N3, +ENE >1 mm,  or + margin (if approved by surgical chair) OR 
 
Tobacco >10 pk-yr: T0-3 plus any one of the following: any N2, N3, +ENE 
>1 mm, or + margin (if approved by surgical chair) 
• 
Patients must have no evidence of distant metastases (M0) 
• 
Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of 
invasive squamous cell carcinoma may have been obtained from the primary tumor or 
metastatic lymph node.  It is required that patients have a positive p16 IHC (as surrogate for 
HPV) status from either the primary tumor or metastatic lymph node. 
• 
Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression 
using immunohistochemistry (IHC) performed by a CLIA approved laboratory. 
• 
No prior radiation above the clavicles. 
• 
Patients with a history of a curatively treated malignancy must be disease-free for at least 
two years except for carcinoma in situ of cervix, differentiated thyroid cancer,  melanoma in-
situ (if fully resected), and/or non-melanomatous skin cancer, or clinically negligible in 
judgement of investigator. 
• 
Patients with the following within the last 6 months prior to registration must be evaluated by 
a cardiologist and/or neurologist prior to entry into the study.  
o Congestive heart failure > NYHA Class II 
o CVA / TIA 
o Unstable angina 
o Myocardial infarction (with or without ST elevation) 
• 
Patients must have acceptable renal and hepatic function within 4 weeks prior to registration 
as defined below: 
o Absolute neutrophil count ≥1,500/mm3 
o Platelets ≥ 100,000/mm3 
o Total bilirubin ≤ the upper limit of normal (ULN) 
o Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault 
formula: (140-age)*wt (kg)/([Cr]*72). For women the calculation should be multiplied 
by 0.85 
• 
Women must not be pregnant or breast-feeding. All females of childbearing potential must 
have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A 
female of childbearing potential is any woman, regardless of sexual orientation or whether 


 
28 
they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
o NOTE: Women of childbearing potential and sexually active males are strongly 
advised to use an accepted and effective method of contraception. 
• 
Patient without intercurrent illness likely to interfere with protocol therapy.  
• 
Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or 
uncontrolled hypertension within 30 days prior to registration. 
 
3.2 
Exclusion Criteria 
• 
Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair the 
ability of the subject to receive protocol therapy, or interfere with the interpretation of study 
results. 
• 
Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected 
to recur in the absence of an external trigger are permitted to enroll. 
• 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 
mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 
• 
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint 
pathways. 
• 
Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational 
therapy within 30 days of first administration of study treatment (subjects with prior radiation, 
cytotoxic or investigational products < 4 weeks prior to treatment might be eligible after 
discussion between investigator and sponsor, if toxicities from the prior treatment have been 
resolved to Grade 1 (NCI CTCAE version 4). 
• 
Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid (HCV antibody) indicating acute or chronic infection. Subjects who test 
positive for HCV antibody but negative for HCV ribonucleic acid are permitted to enroll. 
• 
Known history of testing positive for human immunodeficiency virus (HIV) and CD4 count < 
200 or known acquired immunodeficiency syndrome (AIDS). 
• 
Any Grade 4 laboratory abnormalities. 
• 
History of allergy to study drug components. 
• 
History of severe hypersensitivity reaction to any human monoclonal antibody. 
• 
Prisoners or subjects who are involuntarily incarcerated. 
• 
Subjects compulsorily detained for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness. 
 
4. 
Registration Procedures 
Patient must be registered within a maximum of 8 weeks following surgery. 
 
4.1 
Required Information 
 
Patient must be stratified/classified into one of the following risk categories: 


 
29 
 
• 
Tobacco <10 pk-yr: T0-3 plus any one of the following: >N2b (> 5 LN’s +), N2c/N3, 
+ENE >1 mm,  or + margin (if approved by surgical chair) OR 
• 
Tobacco >10 pk-yr: T0-3 plus any one of the following: any N2, N3, +ENE >1 mm, or + 
margin (if approved by surgical chair)  
 
Patients not categorized into the appropriate risk category will be considered ineligible for the study. 
 
4.2 
Eligibility Verification  
• 
Patients must meet all the eligibility requirements listed in Section 3.1. 
• 
Patients must provide a signed and dated, written informed consent form. 
• 
Treatment should start within ten working days after registration. 
• 
Submission of pathology materials for diagnostic review and classification is mandatory 
4.3 
Participation in Modified Barium Swallow (MBS) Studies 
 
The MBS studies are optional; however, they will be required at baseline and after treatment for 
patients from external sites that have declared participation in the MBS studies, and strongly 
encouraged from external sites that use the MBS study as standard-of-care for patients with 
swallowing dysfunction. 
 
5. 
Treatment Plan 
 
5.1 
Post-operative Management 
 
Postoperative Radiation Therapy 
Modality: Accelerator x-ray beams with nominal energy of at least 4 MV shall be used. Linear 
accelerators must be capable of delivering treatment using multi-leaf collimation.  
 
Intensity Modulated Radiation Therapy (IMRT) is mandatory for this study. (VMAT (Volumetric 
Modulated Arc Therapy is allowed if the site has been previously approved by the NRG-QARC) 
Guidelines developed by the NCI for the use of IMRT in clinical trials should be followed. (See IROC 
website, http://www.irocri.qarc.org). 
 
Calibration: All therapy units used for this protocol shall have their calibrations verified by the IROC 
Houston QA Center (RPC). 
 
CT Simulation:  CT simulation will be required in all patients.  A thermoplast mask shall be used for 
patient immobilization (shoulders along with head strongly encouraged, although an alternative 
method of ensuring reproducible shoulder position is acceptable) for both CT-simulation and for 
each daily treatment. A bite block is encouraged to immobilize the tongue base, as well as to 
separate the uninvolved palate when possible. IV contrast is not required in patients if appropriate 
pre-operative CT scans and/or MRI or PET are available for nodal site delineation. Slice thickness 
of ≤ 3mm is required.  The patient should be simulated and immobilized with the neck in a neutral 
position as best tolerated by the patient that will be reproducible daily.  Surface delineation of 
surgical scars with radio-opaque markers will also be required at the time of CT simulation. 
 


 
30 
Image Fusion:  Additional images of the patient in the treatment position such as with MRI and 18-
fluorodeoxyglucose PET will be permitted to facilitate the treatment planning process.  However, the 
primary image set for the treatment planning will be the CT image set. 
Organs at Risk (OAR) Delineation 
In general, the OARs that require delineation are dictated by the superior and inferior extent of the 
planning target volumes.  For example, if the superior extent of the target volume extends to the 
level of the C1 vertebral body, the brainstem at this level will need to be delineated.  
 
OARs that are suggested for delineation include the following if they lie within the superior and 
inferior extent of the planning target volumes: 
• 
spinal cord 
• 
brainstem 
• 
right and left middle and inner ears 
• 
right and left globe of the eye 
• 
right and left lacrimal gland 
• 
right and left optic nerves 
• 
optic chiasm 
• 
right and left lens 
• 
superior constrictor muscle 
• 
middle constrictor muscle 
• 
inferior constrictor muscle 
• 
cricopharyngeus muscle 
• 
esophagus 
• 
endolarynx:  
o This volume will consist of the tissues medial and contained within the laryngeal 
cartilage and will include the endolaryngeal structures from the level of the tip of the 
suprahyoid epiglottis to the inferior extent of the cricoid cartilage that does not overlap 
with any adjacent Planning Target Volume (PTV). This OAR will be gapped from the 
adjacent PTV by 5-15 mm. Where the adjacent PTV is to be prescribed 50 Gy, the 
endolarynx will be gaped from the PTV by 5 mm 
• 
right and left parotid glands 
• 
right and left submandibular glands 
• 
skin 
• 
midline oral avoidance (MOA) 
o This midline avoidance structure will include the portion of the oral cavity and 
oropharynx that is not included in the planning target volume. The avoidance structure 
will be delineated such that there is a gap between the avoidance structure and the 
adjacent PTV that may range from 5-15 mm. Where the adjacent PTV is to be 
prescribed 50 Gy, the MOA will be gaped from the PTV by 5 mm.   
• 
mandible 
 
Additional OARs that may be contoured but not required include  
• 
right and left temporal-mandibular joint 
• 
right and left thyroid gland 
• 
right and left brachial plexus 
• 
laryngeal cartilage 
• 
hyoid bone 
• 
thyroid gland 
 
Planning OARs 


 
31 
For critical neurologic OARs such as the brainstem, spinal cord, chiasm and optic nerves, a 
systematic margin of 2 mm may be added to generate additional planning OAR volumes (PRVs). 
 
To avoid the potential under-dosing of the CTV-N50 volumes where they overlap with the deep 
parotid lobes, a planning parotid volume may be delineated that represents the non-overlap portion of 
the parotid glands. This planning OAR will be referred to as “parotid-PTV.” 
 
Target Volumes Delineation and Definitions: The definition of volumes will be in accordance with 
ICRU Reports #50 and #62. Target volume nomenclature shall include the following:  
 
• 
Gross Tumor Volume (GTV) is defined as all known areas of pre-operative gross disease 
determined from CT, MRI, clinical information, and endoscopic findings. Grossly involved 
lymph nodes are defined as any lymph node ≥1cm or nodes with a necrotic center or that have 
abnormal FDG uptake on PET. It is strongly encouraged that the radiation oncologist outlines 
the radiographic extent of the primary tumor and neck nodes along with neuro-radiologist. 
Whenever possible, it is recommended that diagnostic images be fused to the planning CT 
scan image dataset to more accurately determine the GTV. The gross tumor at the primary 
site will designated as GTV-P, and clinically involved gross lymph nodes are designated GTV-
N. 
 
• 
Clinical Target Volume (CTV) is defined as all areas that may have subclinical carcinoma 
based on assessment of the preoperative imaging, intraoperative findings by the surgeon and 
the final pathologic evaluation.  Where there are potential discordant findings especially 
between the final pathology and the intraoperative findings typically with regards to the extent 
of the primary tumor, communication between the radiation oncologist and the surgeon is 
required for a consensus to be reached regarding the original extent of the primary carcinoma. 
 
• 
Planning Target Volume (PTV) will provide a margin around the CTVs to compensate for 
variabilities in daily treatment set up, patient positioning, and internal organ motion. A 
minimum of 3 mm and a maximum of 5 mm around the CTVs is required in all directions to 
define each respective PTV (i.e. PTV-P50, PTV-N50)The extent of the PTV margin is 
influenced by the set-up reproducibility at each institution. Daily IGRT is encouraged (ROI C1-
2) to reduce setup variability. 
 
Guidelines for Target Volume Delineation 
• 
CTV-P50:  CTV-P50 will represent the primary invasive tumor base. As the surgery will be 
transoral, the need to comprehensively treat the surrounding normal tissues that would 
otherwise be at risk for tumor seeding is not a major consideration.  The primary factor 
influencing the delineation of the CTV-P50 volume should be influenced by the intra-operative 
assessment of the invasive base of the tumor.  These findings should be compared to the 
preoperative imaging to reconcile any discrepancy.  CTV-P50 should not include the 
preoperative intra-luminal extent of the primary tumor that did not invade the oropharyngeal 
mucosa.  This volume shall include a 3-5 mm margin of uncertainty around the estimated 
extent of the invasive tumor base that is deemed at risk. 
 
• 
CTV-N50:  CTV-N50 will represent the dissected cervical nodal volume found to have nodal 
metastases.  This nodal volume will include the peripheral extent of the sternocleidomastoid 
muscle laterally and medially, will include a portion of the levator scapulae and the scalene 
muscles. 
 


 
32 
• 
CTV-N45:  CTV-N45 will represent the either dissected cervical nodal volumes found not to 
have nodal metastases or the undissected contralateral cervical neck when it is treated.  This 
nodal volume will include the peripheral extent of the sternocleidomastoid muscle laterally and 
medially, will include a portion of the levator scapulae and the scalene muscles.  Anteriorly, the 
posterior aspect of the submandibular gland and the medial pterygoid muscle will be the 
anterior boundary of level II nodal region. 
 
For the ipsilateral dissected neck, CTV-N50 should be extended to nodal volumes adjacent to 
pathologically involved nodal volumes.  For example, if the neck dissection reveals nodal 
metastases in level II, the adjacent level I and level V should be included in CTV-N50.  This nodal 
volume will include the peripheral extent of the sternocleidomastoid muscle laterally and medially, 
will include a portion of the levator scapulae and the scalene muscles. 
 
Indications for inclusion of the lateral retropharyngeal lymph nodes include the presence of 
ipsilateral level II nodal metastases or primary tumor extension to involve the posterior pharyngeal 
mucosa or suspected to be at risk due to involvement of the posterior tonsil pillar mucosa.  The 
ipsilateral lateral retropharyngeal lymph nodes lie medial to the internal carotid artery and are 
predominantly located at the level of C1 vertebral body and occasionally at the C2 vertebral body 
level. The medial retropharyngeal lymph nodes are not to be delineated. 
 
The contralateral retropharyngeal lymph nodes will be delineated as part of CTV-N45 when there 
are clinical/pathologic findings of ipsilateral retropharyngeal lymph node metastases. 
 
For the contralateral undissected neck, CTV-N45, the nodal volume should include the contralateral 
level II, III and IV nodal regions beginning at the level of the posterior digastric muscle.  This nodal 
volume will include the peripheral extent of the sternocleidomastoid muscle laterally and medially, 
will include a portion of the levator scapulae and the scalene muscles. 
 
Ipsilateral neck will be permitted, i.e. omitting the contralateral CTV-N45when the mucosal invasive 
base of the tumor is > 1 cm from the midline mucosa as judged at the time of the surgery.  For base 
of tongue cancers, the primary tumor adverse pathologic features including the positive surgical 
margins should not be present on the medial tumor specimen.  For base of tongue cancers, the 
primary tumor should also not demonstrate a deep invading tumor front at the time of the surgery.  
The distance from the midline mucosa will require documentation including the mucosal surface that 
is involved when the contralateral CTV-N50 is omitted.  Omitting the contralateral neck CTV-N50 is 
not permitted for N2c tumors and where clinical/pathologic findings of ipsilateral retropharyngeal 
lymph node metastases. 
 
IMRT Prescription and Treatment Planning: The prescription dose will be administered to the 
PTV50 at 2.0 Gy per fx delivered 6 fractions/week. PTV 45 Gy will be delivered concurrently using 
SIB.   Treatment breaks, if necessary, should not exceed 5 treatment days and the reason(s) for the 
break must be clearly recorded in the treatment record. Any treatment break(s) exceeding two (2) 
treatment days for reasons other than toxicity/illness will be considered a protocol deviation. The 
reason for the missed treatment or treatments must be clearly indicated in the copy of the patient’s 
treatment record. 
• 
P50 and PTV-N50: will be prescribed 50 Gy in 25 daily fractions, 6 fractions per week. 
• 
PTV-N45: will be prescribed 45 Gy in 25 daily fractions, 6 fractions per week with SIB 
Tissue Heterogeneity: The dose calculation shall consider the effect of tissue heterogeneities. The 
method used for tissue heterogeneity calculations shall be reported. The dose prescription is to be 
based on a dose distribution corrected for heterogeneities.  
 


 
33 
No specific beam arrangements will be specified. Commonly, a co-planar beam arrangement is 
used.   
 
Treatment Planning Objectives: The treatment plan(s) used for each patient will be based on an 
analysis of the volumetric dose, including dose-volume histogram (DVH) analyses of the PTVs and 
critical normal structures. Inverse optimization algorithms will be used to achieve at least 95% of the 
volume of the specified PTVs is covered by the prescribed isodose surface while meeting the dose 
limitations to the delineated OARs. 
Priority 
Structure Name 
Treatment Planning Objective 
Coverage 
Volume 
OAR Maximum Dose 
Constraint (Gy) 
OAR Partial Volume 
Dose Constraint 
Volume 
Dose (Gy) 
1 
PTVs 
D95 = 
prescription 
dose 
 
 
 
 
1 
spinal cord 
 
1 cc 
45 Gy 
 
 
1 
brainstem 
 
1 cc 
54 Gy 
 
 
1 
R and L optic 
nerve 
 
0.1 cc 
45 Gy 
 
 
1 
optic chiasm 
 
0.1 cc 
45 Gy 
 
 
 
 
 
 
 
 
 
2 
R and L optic 
nerve PRV 
 
0.1 cc 
50 Gy 
 
 
2 
R or L parotids 
 
 
 
50% 
< 20 Gy 
2 
R and L parotids 
combined 
 
 
 
mean 
< 26 Gy 
2 
midline oral 
avoidance 
 
5 cc 
45 Gy 
50% 
< 35 Gy 
2 
endolarynx 
 
1 cc 
50 Gy 
50% 
< 30 Gy 
2 
cricopharyngeus 
 
1 cc 
50 Gy 
50% 
< 30 Gy 
2 
esophagus 
 
1 cc 
45 Gy 
 
 
2 
R and L middle 
and inner ear 
 
0.1 cc 
45 Gy 
 
 
2 
R and L optic 
globe 
 
1 cc 
50 Gy 
 
 
2 
R and L lacrimal 
gland 
 
1 cc 
40 Gy 
 
 
2 
R and L lens 
 
1 cc 
30 Gy 
 
 
2 
mandible 
 
1 cc 
60 Gy 
 
 
2 
skin 
 
5 cc 
60 Gy 
 
 
3 
submandibular 
gland 
contralateral to 
the side of the 
neck dissection* 
 
 
 
50% 
< 35 Gy 
*when the contralateral level I nodal group is not part of CTV-N50 
For treatment planning purposes, the dosimetric constraints that will be used for each phase of the 
IMRT treatment planning will be modified by a proportion that reflects the maximum dose for that 
phase to the total prescription dose.   


 
34 
 
Definitions of Dosimetric Variation - Minor Variation/Major Variation: To avoid a minor 
variation: no more than 3% volume of the PTV will receive greater than 108% of the prescribed 
dose, and no tissue (target or non-target) shall receive more than 110% of the prescribed dose. In 
addition, no more than 5% volume of any PTV shall receive less than 95% of the prescribed PTV 
dose, and no more than 1% of the PTV volume receives less than 93% of the prescribed dose. 
Reported doses for PTVs shall include the prescription dose, maximum point dose for each PTV, % 
PTV receiving 110%, 108% and 95% and 93% dose. Also, the mean dose must be reported.  
 
Repeat Simulation and Planning: There are circumstances where it may be appropriate to repeat 
a patient’s simulation. Examples may be when there is excessive weight loss and either the 
thermoplast mask is no longer tight or the patient’s external contour no longer matches the original 
contour due to weight loss. The original PTVs should continue to be treated to the original volume. 
 
Definitions of Deviations in Protocol Performance 
 
Dose:  
• 
Minor deviation: The delivered dose to the prescription volume differs from protocol 
specification by more than 5% but less than 10%. 
• 
Major deviation: The delivered dose to the prescription volume differs from protocol 
specification by more than 10%.  
Dose Uniformity:  
• 
Minor deviation: More than 3% of the PTV receives more than 108% of the prescription dose 
or more than 1% of the PTV receives less than 93% of the prescription dose.  
• 
Major deviation: More than 5% of the PTV receives more than 115% of the prescription dose.  
 
Volume:  
• 
Minor deviation: Margins for PTV less than specified, or field(s) excessively large.  
• 
Major deviation: GTV (or corrected GTV if not appropriately drawn) not included within the 
95% dose volume. 
 
Treatment Breaks:  
More than two missed treatment days for any reason other than a toxicity is considered a deviation.  
• 
Minor deviation: 3-5 days.  
• 
Major deviation: > 5 days  
 
Evaluation After Completion of Concurrent Therapy  
Patients will be re-evaluated after the completion of treatment to assess clinical and radiographic 
response by complete head and neck exam and imaging studies. 
 
Patients with persistent disease will be evaluated and where indicated undergo appropriate surgical 
resection.  
 
5.2 
Administration of Nivolumab 
 
Nivolumab will be administered at a fixed dose of 240 mg over 30 minutes IV every 2 weeks during 
radiotherapy, and at 480 mg over 60 minutes IV every 4 weeks for 6 doses after radiotherapy. The 
first dose will be given prior to the first fraction of radiation (Day 1) on Day -5 (+/- 2 days) and 
continued every 2 weeks (+/- 2 days). Nivolumab will thus be given in weeks 2 and 4 of radiotherapy. 


 
35 
Adjuvant nivolumab will then be given for a total of 6 additional doses after the completion of 
radiotherapy every 4 weeks (+/- 7 days), starting in the second or third week after the completion of 
radiotherapy. 
 
There are no recommended premedications for nivolumab. 
 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the subject 
tolerates the treatment. 
 
Dose delay criteria apply for all drug-related AEs. Treatment delay up to 6 weeks for nivolumab from 
the last dose are allowable (any dose delays greater than these will require approval from the medical 
co-chair).  
 
Radiation therapy should not be delayed. 
 
Dosing modifications: 
There will be no dose modifications allowed for the management of toxicities of individual 
subjects. 
 
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed. 
 
Nivolumab should be delayed for the following: 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, except for fatigue and laboratory 
abnormalities 
• 
Any Grade ≥ 3 skin drug-related AE 
• 
Any Grade ≥ 3 drug-related laboratory abnormality with the following exceptions for 
lymphopenia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total 
bilirubin or asymptomatic amylase or lipase: 
o Grade 3 lymphopenia does not require a dose delay 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade 2 toxicity 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥ 3 toxicity 
o Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. The 
Medical Co-chair should be consulted for such Grade ≥ 3 amylase or lipase 
abnormalities. 
• 
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
 
Nivolumab Dose Discontinuation Due to Drug-Related AE(s) 
Treatment with nivolumab should be permanently discontinued for any of the following: 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
• 
Any Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction, 
regardless of duration; 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory abnormalities: 
• 
Any Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires discontinuation. 


 
36 
• 
Any Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 
• 
Any Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation. 
o Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation 
 
AST or ALT > 5 -10x ULN for > 2 weeks 
 
AST or ALT > 10x ULN 
 
Total bilirubin > 5 x ULN 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events, which do not require discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 
week of onset. The Medical Co-chair should be consulted for Grade 4 amylase or 
lipase abnormalities 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
• 
AST or ALT more than 5 times the upper limit of normal (ULN) or total bilirubin more than 3 
times the ULN, for any duration of time 
• 
Grade 3 adrenal insufficiency regardless of whether adequately controlled with physiologic 
hormone replacement 
• 
Grade 3 myocarditis 
• 
Requirement for 10 mg per day or greater of prednisone or equivalent for management of 
immune-related adverse reactions for more than 12 weeks 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing. 
 
Criteria to Resume Nivolumab Dosing 
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to Grade ≤ 1 
or baseline, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue. 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity. 
• 
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters should have treatment permanently discontinued. 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the Medical Co-chair. 
• 
Subjects who received systemic corticosteroids for management of any drug-related toxicity 
must be off corticosteroids or have tapered down to an equivalent dose of prednisone ≤ 10 
mg/day. 
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment. 
• 
Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires 
treatment discontinuation, with exceptions as noted above. 


 
37 
 
Nivolumab Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to 
occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours as an SAE if criteria are met. Infusion reactions should be graded according 
to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE, Version 
4.0) guidelines. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
 
Treatment Recommendations for Nivolumab Infusion Reactions 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not indicated) 
• 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes 
before additional nivolumab administrations. 
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤ 24 
hours) 
• 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as 
appropriate. If the infusion is interrupted, then restart the infusion at 50% of the 
original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
subject closely. If symptoms recur, then no further nivolumab will be administered at 
that visit. Administer diphenhydramine 50 mg IV and remain at bedside and monitor 
the subject until resolution of symptoms. The amount of study drug infused must be 
recorded on the electronic case report form (eCRF). 
• 
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325-1000 mg should 
be administered >30 minutes before nivolumab  infusion. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used. 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [e.g., renal impairment, 
pulmonary infiltrates]. Grade 4: Life threatening; pressor or ventilatory support indicated). 
• 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms. 
 


 
38 
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine 
or corticosteroids). 
 


 
39 
Duration of Nivolumab 
Nivolumab will be given for a total of 9 doses, as detailed above, or until progressive disease, 
unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first. For all 
subjects, global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time is allowed, if necessary. 
 
5.3 
Adverse Event Reporting Requirements and Procedure 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part of every clinical trial, 
are done to ensure the safety of the patients enrolled, as well as those who will enroll in future 
studies using similar agents. 
 
• 
Routine reporting:  Adverse events are reported in a routine manner at scheduled times 
during the trial using UPMC coordinating center (for external sites).   
• 
Expedited reporting:  In addition to routine reporting, certain adverse events must be 
reported in an expedited manner for timelier monitoring of patient safety and care. The 
following sections provide information and instructions regarding expedited adverse event 
reporting. 
 
Definitions 
• 
Adverse Event (AE): Any untoward medical occurrence associated with the use of a drug in 
humans, whether considered drug related. Therefore, an AE can be ANY unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether considered related to the medicinal 
product. 
 
• 
Life-threatening adverse event or life-threatening suspected adverse reaction: An 
adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
• 
Serious adverse event or serious suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
• 
Suspected adverse reaction: Any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies less certainty about causality than adverse 
reaction, which means any adverse event caused by a drug.  


 
40 
 
Adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset 
of all suspected adverse reactions where there is reason to conclude that the drug caused the 
event. 
 
• 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event 
or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. "Unexpected," as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
 
• 
Attribution:  An assessment of the relationship between the adverse event and the protocol 
treatment, using the following categories. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse Events provides a descriptive 
terminology that is to be utilized for AE reporting.  A grade (severity) is provided for each AE 
term. 
 
• 
Expectedness:  Any adverse event, the type or severity of which is consistent with the current 
investigator’s brochure, product label, and/or the protocol document. 
 
Reporting Procedure 
 
Internal Reporting Requirements: All events meeting the definition of a serious adverse event 
should be reported according to the internal departmental SAE checklist and SAE form. Copies 
should be sent to: 
1. 
Investigator  
2. 
crssafetysubmissions@upmc.edu 
3. 
Local Institutional Review Board when reporting requirements are met. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 
24 hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on the internal 
departmental SAE form.   
SAE Email Address:  Worldwide.Safety@BMS.com 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 


 
41 
SAE Facsimile Number:  +1 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to BMS using the 
same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include as applicable the following information that is available at the time of report within 
the Sections of the departmental SAE form: 
 
• 
CTCAE term(s) and grade(s)  
• 
current status of study drug 
• 
all interventions to address the AE (testing and result, treatment and response) 
• 
hospitalization and/or discharge dates 
• 
event relationship to study drug 
 
Follow-up Reports: Additional information may be added to a previously submitted report by adding to 
the original departmental SAE form and submitting it as follow-up or creating supplemental summary 
information and submitting it as follow-up with the original departmental SAE form. 
Reporting adverse events to the responsible IRB: In accordance with applicable policies of the 
University of Pittsburgh Institutional Review Board (IRB), the Investigator will report, to the IRB, any 
observed or volunteered adverse event that is determined to be 1) associated with the investigational 
drug or study treatment(s); 2) serious; and 3) unexpected. Adverse event reports will be submitted to 
the IRB in accordance with the respective IRB procedures. 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later than 
10 calendar days following the sponsor-investigator’s receipt of the respective information. Adverse 
events which are 1) associated with the investigational drug or study treatment(s); 2) fatal or life-
threatening; and 3) unexpected will be reported to the IRB within 24 hours of the Sponsor-
Investigator’s receipt of the respective information. 
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the relevant 
information is available. If the results of the Investigator’s follow-up investigation show that an adverse 
event that was initially determined to not require reporting to the IRB does, in fact, meet the 
requirements for reporting; the Investigator will report the adverse event to the IRB as soon as 
possible, but in no event later than 10 calendar days, after the determination was made. 
 
5.4 
Dose Modifications 
All toxicity grades below are described using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of 
the CTCAE version 4.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). 
 
The use of colony stimulating factors (G-CSF, GM-CSF), and amifostine are explicitly discouraged. 
Erythropoietin stimulating agents, such as erythropoietin, and darbepoetin, are prohibited. 


 
42 
5.5 
Supportive care and Other Assessments 
Patient Reported Outcomes (PROs) 
Quality of Life (QOL) assessments will be performed at baseline, end of treatment, and at 3, 6, 12, 
and 24 months after completion of treatment. If an additional tumor assessment is done prior to 3 
years from study entry, one final QOL assessment is requested. QOL will continue to be collected 
for all patients post recurrence. 
Paper questionnaires will be completed by the patient, and then data from the questionnaire should 
be provided within 7 days of completion. The original copy needs to be kept in the study subject’s 
research binder.  
 
Rehabilitation 
It is strongly encouraged that all patients be referred for an assessment by a certified physical 
therapist after the completion of concurrent therapy. Components of the evaluation should include: 
neck shoulder and jaw range of motion, general conditioning level, the degree of treatment related 
fatigue, and postural issues. Patients with significant levels of deconditioning, postural 
abnormalities, or decrease in range of motion may require physical therapy. Occupational therapy 
may be needed in patients with extreme degrees of dysfunction. Patients with lymphedema should 
be referred for lymphedema therapy which should include: education, manual lymph drainage and 
the use of compression garments.  
 
Speech and Language Pathology 
Swallowing assessment and therapy is considered a critical component of care for all head and 
neck cancer patients. An MBS study will be required at baseline and after treatment as standard-of-
care for patients with swallowing dysfunction.  Assessments should be done by a trained Speech-
Language Pathologists (SLP). The SLP should be consulted during treatment planning and should 
provide routine follow-up throughout the trajectory of the patient’s treatment and recovery. The 
treating physician should communicate with the SLP to coordinate care in those patients found to 
have significant swallowing abnormalities. Critical component of the swallowing evaluation should 
include: 1) identification of any swallowing abnormalities, 2) recommendations for further testing, 3) 
formation of a treatment plan, 4) dietary recommendations, and 5) clear identifications of patients at 
risk for aspiration. Patients should be referred immediately for evaluation if any of the following 
“trigger symptoms” are identified: coughing or clearing the throat before, during or after eating, 
inability to control food, liquids or saliva in the oral cavity, complaint of difficulty swallowing or food 
“sticking” in the throat, nasal regurgitation of food, or pocketing of food in the cheek. 
 
All supportive measures consistent with optimal patient care will be given throughout the study. 
5.6 
Duration of Therapy  
• 
Patients will receive protocol therapy unless: 
• 
Treatment is interrupted for 4 consecutive weeks; patient’s protocol treatment will be 
discontinued  
• 
Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient's health, protocol treatment should be discontinued  
• 
Patient develops unacceptable toxicity; then the patient will discontinue protocol therapy  
• 
Patients may withdraw consent and withdraw from the study at any time for any reason 
5.7 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy early, will be 
followed for response until progression, even if non-protocol therapy is initiated, and for survival for 
5 years from the date of registration. 


 
43 
6. 
Measurement of Effect 
6.1 
Time to Progression  
This interval will be measured from the date of entry on the study to the appearance of new 
metastatic lesions or objective tumor progression. 
6.2 
Methods of Measurement  
Imaging based evaluation is preferred to evaluation by clinical examination. The same imaging 
modality must be used throughout the disease evaluation. 
 
CT and MRI: CT and magnetic resonance imaging (MRI) are the best currently available and most 
reproducible methods for measuring target lesions.  
 
Chest X-Ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by an aerated lung. However, CT is preferable. 
Tumor Markers: Tumor markers alone cannot be used to assess response.  
 
Clinical Examination: Clinically detected lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color 
photography, including a ruler to estimate size of the lesion, is recommended. Photographs should 
be retained at the institution. 
 
Cytology and Histology: Cytologic confirmation of the neoplastic nature of any effusion that 
appears or worsens during treatment is required when the measurable tumor has met response or 
stable disease criteria. 
 
Ultrasound: Ultrasound may be used only as an alternative to clinical measurements for superficial 
palpable lymph nodes, subcutaneous lesions, and thyroid nodules. 
7. 
Schedule of Assessments 
 
NOTE: There is a window of ±1 week available for scheduling treatment and/or procedures at the 
discretion of the Investigator/Sub-investigator. This applies also if a course is missed or a subject's 
treatment and/or testing day(s) need to be rescheduled due to the subject’s inability to comply with the 
study calendar (i.e., hospitalizations, business, vacation plans, travel from long distances for study 
treatment, in advance of the scheduled date to allow ready access to the result(s), reduce financial 
burden on the subject [i.e. non-UPMC insurance coverage] or reduce travel inconvenience, illness, 
transportation issues, holidays, family emergencies, etc.). 
 
 


 
44 
 
Screening1 
Day -5 ± -2 
Adjuvant 
Nivolumab 
EOT10 
LTFU 
Medical history, 
physical exam,  
vital signs  
X 
X 
X 
X 
 
Height  
X 
 
 
 
 
Weight  
X 
X 
X 
X 
 
ECOG performance 
status  
X 
X 
X 
X 
 
CBC w/diff, platelets 
X1 
X 
X 
X 
 
Amylase, lipase  
X 
 
X 
 
 
TSH  
X7 
 
X 
 
 
Serum chemistry 
X1 
X 
X 
X 
 
Serum pregnancy 
test 
X1 
 
 
 
 
QOL questionnaires 
X 
 
 
X 
X9 
Adverse event 
evaluation  
X 
X 
X 
X 
 
Disease evaluation 
by clinical methods2 
X 
 
X2 
X2 
X2 
CT scan/MRI2 
X 
 
X2 
X2 
X2 
SLP consult with 
MBS3 
X 
 
 
X 
X3 
Tumor tissue 
X 
 
 
 
 
Blood and saliva 
biomarkers8 
 
X 
X 
X 
X 
IMRT 
 
 
 
 
 
Nivolumab5,6 
 
X 
X 
 
 
1Pre-study laboratory assessments should be done ≤ 4 weeks before registration. 
2Disease evaluation by clinical methods and a CT and/or MRI to assess all measurable or non-measurable 
sites of disease will be obtained at screening (≤ 4 weeks before registration), symptomatically during IMRT, 
every 3 months during adjuvant nivolumab treatment starting from end of radiation therapy, every 6 months for 
3 years, and annually for 2 more years to confirm standard of care assessments. 
3SLP = speech language pathologist; MBS = modified barium swallow; Required for participation at screening 
and 6 and 24 months after treatment, and if MBS is performed as standard of care. 
4All labs may be completed within 7 days of surgery. 
5Nivolumab 240mg IV every two weeks 
6Nivolumab 480mg every 4 weeks for 6 doses. 
7TSH to be drawn for baseline status. Is not an eligibility criterion  
8Blood biomarkers will be drawn at screening, week 0: Day -3 (± 2 Days), every 4 Weeks (post Week 4) x 24 
Weeks (± 7 Days), EOT.  For LTFU: Every 3 Months x 24 Months then every 6 Months x 3-5 Years from 
completion of radiation therapy 
a. Serum Cytokines/Chemokines 
b. HPV DNA (blood & saliva) 
c. Tumor antigen specific cellular immunity 
d. Lymphocyte Markers 
9 QOL’s will be collected for LTFU at 3, 6, 12, 24 months from completion of radiation therapy  


 
45 
10 EOT should coincide with 6 month CT scan post radiation therapy. 
8. 
Nivolumab Formulation and Procurement 
 
Product 
Description / Class 
and Dosage Form 
Potency 
IP/Non-IMP 
Blinding 
Packaging 
Storage 
Conditions 
(per label) 
BMS-936558-01 
(Nivolumab) Solution 
for Injection* 
100 mg  
(10 mg/mL) 
IP 
Open Label 
10 mL per 
vial (5 or 10 
vials/carton) 
Store at 2° - 8 °C. 
Protect from light 
and freezing. 
*May be labeled as either “BMS-936558-01” or “Nivolumab” 
 
Investigational Product 
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. The 
investigational product should be stored in a secure area according to local regulations. It is the 
responsibility of the investigator to ensure that investigational product is only dispensed to study 
subjects. The investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. In this protocol, the investigational product is nivolumab. 
 
Storage and Dispensing 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately. 
 
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets). 
 
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5% dextrose 
injection) will not be supplied by the sponsor and should be purchased locally if permitted by 
local regulations. 
 
Please refer to the current version of the Investigator Brochure and/or pharmacy reference sheets for 
complete storage, handling, dispensing, and infusion information for nivolumab. 
 
Nivolumab is to be administered as an IV infusion. At the end of the infusion, flush the line with a 
sufficient quantity of dextrose or normal saline. 
 
Selection and Timing of Dose for Each Subject 
Dosing modifications: 
There will be no dose modifications allowed for the management of toxicities of individual 
subjects. 


 
46 
Dosing window: 
Subjects may be dosed no less than 12 days between doses. A dose given more than 3 days after 
the intended dose date will be considered a delay. A maximum delay of 6 weeks between doses is 
allowed. 
 
Treatment Compliance 
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF. 
 
Destruction of Study Drug 
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes must be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxic agents or biologics). 
 
On-site destruction is allowed provided the following minimal standards are met: 
• 
On-site disposal practices must not expose humans to risks from the drug. 
• 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• 
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s standard operating procedures (SOPs) and a copy provided to BMS upon 
request. 
• 
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented. 
• 
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period. 
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug. 
 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
9. 
Statistical Considerations 
The purpose of this phase II trial of p16+ OPSCC patients that will undergo transoral surgery 
followed by de-intensified adjuvant radiotherapy plus nivolumab is to demonstrate equivalent 
oncologic outcome with fewer adverse effects and improved quality of life when compared to the 
standard of care 
9.1 
Objectives 
The dual primary objectives of this phase II study are (1)   test the hypothesis that the proposed 
adjuvant de-escalation strategy (TORS + 50Gy RT + Nivolumab cancer) has equivalent (non-
inferior) 2-year PFS.  PFS is survival without local, regional or distant disease progression; patients 
who do not progress or die while disease – free will be censored and (2) to demonstrate a reduction 
in the rate of PEG tube dependence at one year.  
 


 
47 
Secondary objectives include estimating recurrence patterns, assessing quality of life (QOL) and 
swallowing function before and after treatment and evaluating toxicity.  
 
With improved outcomes for p16+ oropharyngeal cancers treatment de-escalation is a critical and 
topical subject for a controlled clinical.  This trial tests the hypothesis that de-escalating treatment of 
intermediate risk p16+ oropharyngeal cancer patients benefits them by providing equivalent oncologic 
outcome with superior quality of life.    
 
The first hypothesis to be tested is that oncologic outcome following de-escalation is clinically equivalent 
to conventional standard systemic therapy with transoral robotic surgery (TORS) plus adjuvant cisplatin 
and 60-66 Gy radiation.  The definition of non-inferiority is clearly within a desired clinical window of 
equivalence, defined as 2-year PFS, not less than 10% lower than expected under standard-of-care. 
Therefore, the design is to establish the non-inferiority of the experimental therapy (TORS + Nivolumab 
+ 50 Gy radiation). The second hypothesis to be tested is de-escalation is warranted, by virtue of a 
clinically meaningful improvement in quality of life as measured by reduced G tube patency. 
  
The decision to select a single arm trial is based on the following:  A two arm randomized non-
inferiority trial would be prohibitively expensive, infeasible (approximately 600 patients would be 
needed) and delay results for five years.  This single-arm trial is feasible and is powered to produce 
a definitive result in 3 years from 1st accrual. The comparison is a to large-well characterized 
contemporaneous subset of the ECOG 3311 trial with similar pathologic features as we propose in 
our new trial, that received cisplatin and standard dose radiotherapy in Arm D of ECOG 
3311.  Patients recruited to ECOG 3311 are expected to be similar to our patients at the University 
of Pittsburgh, a large tertiary-care academic medical center, in part since we were the #1 largest 
accrue in the US to ECOG 3311 (Dr. Ferris is PI of that trial as well).   
9.2 
Sample Size and Accrual Rate  
Approximately 135 eligible subjects will be enrolled in this multicenter clinical trial that will be 
conducted at approximately 25 UPMC sites and up to 5 external sites in North America.  
 
The first primary objective is to demonstrate that TORS with de-escalation RT (50Gy) and Nivolumab 
is equivalent (not inferior) to the standard of care of chemotherapy + standard 60-66 Gy radiation. The 
first primary endpoint is probability of progression free survival where an event is any type of disease 
progression or recurrence (local, regional or distant). In this definition deaths from other cancers, 
other non-cancer causes or treatment related deaths are censored. The historical control for the study 
is based part upon the results of Huang 9 in which the probability of 3 year OS was approximately 
65%  for high risk  (Group III,T4 or N3, age < 70) HPV+  patients treated with chemoradiation and that 
3 year OS is an approximation of two year PFS. Since there is not an ideal, published cohort to use, 
the trial is designed to investigate whether TORS with 50 Gy RT + Nivolumab is not inferior to 
standard of care chemotherapy + standard 60-66 Gy radiation. 
  
We plan to devote 2 years of accrual and one year of additional follow-up.  We assume that the 
experimental arm is not inferior to the standard if the 2-year PFS is not less than 55%, 10% less than 
the assumed standard. Thus 55% 2-year TTP for de-escalation RT + Nivolumab is considered not 
inferior to the 65% 2-year PFS for Cisplatin + 60-66 Gy RT.  
 
Using a one-tailed exponential test (using he maximum likelihood estimator for the hazard rate of the 
exponential distribution) at α = .10, 135 patients will provide 90% power to reject the null hypothesis 
that the experimental arm is inferior (less than 55% 2-year PFS) when the underlying 2-year PFS is 
65%. 
  
The second primary objective is to demonstrate reduction in feeding tube dependence. We will 
compare 1-year PEG tube dependence for patients who have not progressed to the SOC. Based on 


 
48 
unpublished results from RTOG 0234 for 84 patients treated with RT + cisplatin + cetuximab, 67 
(80%) did not have disease progression at one year.  Of these, 11 (16%) were dependent upon a 
feeding tube one year after the start of treatment.  Assuming a 15% PEG tube SOC rate, we wish to 
demonstrate a 50% improvement or to 7.5% due to the proposed de-escalation regimen.  We assume 
the same 1 year non-progression rate of 80% which suggests 80% of 135 or 108 patients will be 
candidates for a feeding tube at one year. A one tailed exact binomial test with 108 patients at alpha = 
.06 will have 80% power to detect a reduction in 1 year PEG tube rate from 15% to 7.5%.  Using the 
Bonferroni inequality, the type I error for testing both primary hypotheses is 16% with 135 patients.   
 
Thus, we require accrual of 45 patients/yr for 3 years (135 total) with one year of additional follow-up. 
9.3 
Secondary Objectives 
Secondary endpoints include toxicity, recurrence patterns, overall survival, swallowing function, and 
patient-reported outcomes. 
Toxicity. For each arm, all treated patients will be evaluated by CTCAE version 4.0. Descriptive 
statistics will be provided by grade and type of toxicity.). The proportion of radiation-attributable 
grade III/IV toxicities will be estimated with 95% confidence intervals.  These confidence intervals 
will be informally compared to published rates for standard of care radiation. In addition, frequencies 
of  toxicity by grade  in each arm will be compared with the Jonckheere-Terstra test 
 
Recurrence Patterns Kaplan-Meier estimates with confidence intervals will be prepared for local, 
regional and distant recurrence.   In addition, cumulative incidence functions will be estimated for 
local, regional and distant recurrence as well as death in the absence of disease progression.  
Gray’s test will be applied to test differences in cumulative incidence patterns between treatment 
arms. 
 
Overall Survival. Overall survival will be determined as the time from registration onto the study until 
death from any cause. Patients who were alive at the time of analysis will be censored at the date 
last known alive.  Kaplan-Meier estimates will be calculated, along with their corresponding 95% 
confidence intervals. The median, 1-year, and 2-year survival rates will be estimated. Only eligible 
and treated patients will be analyzed for overall survival (by arm). 
Swallowing Function and Voice. Descriptive statistics will be provided  with confidence intervals  for 
swallowing function, evaluated using the MBS ratings, PSS-HN normalcy of diet scale, and the 
validated survey MDADI instrument. Longitudinal analysis will be performed on each of these 
measures. All eligible and treated patients (on both steps) will be analyzed for PSS-HN diet scale, 
MDADI, and VHI-10.  The MBS analysis will be performed on eligible and treated patients only if 
accrued at vetted participating centers.    
Quality of Life. The primary variable of interest in the QOL analysis is the individual change in the 
FACT-H&N total score from baseline (prior to TOS) to 6 months post-RT.  The within-patient change 
in FACT_H&N score will be calculated and tested with the signed rank test or Friedman’s’ test for 
more than 2 sequential observations per patient.   
 
9.4 
Data Safety Monitoring Plan 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, clinical 
research associates, data managers, and clinic staff meet regularly in disease center Data Safety 
Monitoring Boards (DSMB) to review and discuss study data to include, but not limited to, the 
following: 
 
• 
serious adverse events 
• 
subject safety issues 
• 
recruitment issues 


 
49 
• 
accrual 
• 
protocol deviations 
• 
unanticipated problems 
• 
breaches of confidentiality 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria Version 4.0. All study treatment associated adverse events that are serious, 
at least possibly related and unexpected will be reported to the IRB.  Any modifications necessary to 
ensure subject safety and decisions to continue or close the trial to accrual are also discussed during 
these meetings. If any literature becomes available which changes the risk/benefit ratio or suggests 
that conducting the trial is no longer ethical, the IRB will be notified in the form of an Unanticipated 
Problem submission and the study may be terminated.  
 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem submission. 
The summaries of these meetings are forwarded to the UPMC Hillman Cancer Center Data Safety 
Monitoring Committee (DSMC) which also meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC 
progress reports, to include a summary of all serious adverse events and modifications, and approval 
will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed bi-annually. 
 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center DSMB have 
the authority to suspend accrual or further investigate treatment on any trial based on information 
discussed at these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records.  
 
Safety Monitoring 
 
Adverse events are graded per CTCAE version 4. The primary endpoint for evaluating safety is dose-
limiting toxicity (DLT). The period of observation for a DLT is from day -3 (first dose of nivolumab) 
through to 4 weeks after the completion of radiotherapy. A DLT is defined as: 
1. Any ≥ grade 3 adverse event that is related to nivolumab that does not resolve to 
grade 1 or less within 28 days;  
2. A delay in radiotherapy of > 2 weeks due to toxicity related to nivolumab; 
3. Inability to complete radiotherapy due to toxicity related to nivolumab; 
Patient safety will be monitored continuously using Bayesian methods. The presence or absence of a 
treatment-related DLT as defined above will be tabulated and used to compute the posterior probability 
of an excessive DLT rate. A 25% DLT is expected and acceptable; a 40% DLT rate is considered 
excessive.  If the posterior probability is .80 or greater, that 40% or more of treated subjects experience 
a treatment related DLT, the study will be suspended pending review by the DSMC. This posterior 
probability will be calculated from the study’s accumulating data and a weakly informative prior 


 
50 
distribution. If π denotes a random variable representing the proportion of subjects who will experience 
a treatment related DLT, we assume π has a prior beta distribution with parameters a = .75 and b = 
2.25, which is consistent with an expected DLT rate of 25%.  
Selected values of the posterior distribution PP (π ≥ .40 | DLTs and prior) are shown in the table below. 
Also shown are the binomial probabilities of suspending the study for the observed count of DLT’s. 
Number of subjects observed to have treatment-related DLTs needed to suspend the study 
 
Subjects Treatment-Related DLTs PP (π > 25%)* Pr (X ≥ r|p = 0.25) 
5 
4 
.937 
.087 
10 
6 
.805 
.166 
20 
11 
.857 
.128 
30 
15 
.812 
.175 
40 
20 
.861 
.130 
50 
24 
.836 
.156 
60 
28 
.815 
.178 
70 
33 
.858 
.136 
80 
37 
.842 
.152 
90 
41 
.828 
.166 
100 
45 
.816 
.179 
110 
49 
.805 
.190 
120 
54 
.843 
.153 
130 
58 
.834 
.162 
 
*π is the DLT rate. The minimum acceptable upper bound of a treatment-related DLT is 25%. PP (π > 
25%) is the posterior probability that the RLT rate exceeds this 25% upper bound. This posterior 
probability of an DLT is calculated from the prior distribution, the number of subjects treated and the 
observed number of treatment-related RLTs.  The table above presents the minimum number of 
subjects experiencing treatment-related DLTs (i.e., those DLTs judged to be possibly, probably, or 
related to Nivolumab) that would dictate suspension of the trial in accordance with the stopping rule. 
9.5 
Gender and Ethnicity 
The total accrual goal will be 135 patients without regard to all ethnic groups  
 
9.6 
Observer-Assessed Outcomes 
Performance Status (PS):  Performance status will be assessed using the ECOG performance 
status scale and must be 0-1 at baseline for study eligibility.  Changes in ECOG PS will be tracked 
at all PRO endpoints. 
 
Weight Loss: The degree of weight loss may contribute to fatigue, weakness and deconditioning. 
Weight loss during therapy will be documented as well as post-treatment weight changes.  
 
Tracheostomy and Enteral Feeding Tube Status: The presence of either assistive device will be 
tracked prospectively at all PRO time points. 
 
Charlson Comorbidity Index: Comorbidity will be documented by chart abstraction at baseline. 
 
Head and Neck Cancer Specific Performance Status: The Performance Status Scale (PSS-HN)68 is 
a clinician-rated instrument consisting of 3 questions: normalcy of diet, public eating, and 
understandability of speech.  The PSS-HN has been psychometrically validated and recommended 
by the National Comprehensive Cancer Network for measurement of swallowing and speech 


 
51 
performance in patients with head and neck cancer.  It is not a PRO; it can be completed quickly by 
the trialist without adding to patient burden. 
Swallowing Endpoint:  Swallowing outcomes will be measured as a secondary endpoint of this trial 
using modified barium swallow (MBS) studies according the assessment schedule. A standardized 
contrast medium (Varibar® thin liquid and pudding contrast, Bracco Diagnostics, Inc. Princeton, NJ) 
and digitally record MBS studies (30 frames/second) must be used. Three swallowing outcomes will 
be rated by the SLP conducting the MBS study and reported by research staff: 1) laryngeal 
penetration (yes, no); 2) aspiration (no, sensate, silent), and 3) pharyngeal residue (no, < 50%, > 
50%). These have been selected as universal items generally reported by swallowing clinicians that 
have been shown to significantly predict pneumonia in patients with oropharyngeal cancers. 
Prevalence of these dysphagia endpoints will be estimated at each time point.  
9.7 
Patient Reported Outcomes (PRO) 
 
Quality of Life: Quality of life will be assessed using the Functional Assessment of Cancer Therapy 
– Head and Neck Cancer (FACT-H&N). The FACT-H&N (version 4)17 consists of a cancer-specific 
questionnaire, FACT-G, in addition to 12 H&N cancer-specific items (the HN subscale). FACT-G is a 
27-item measure that assesses general cancer quality of life [Cella, 1993; Cella, 1997]. The FACT-
G contains 4 subscales: physical, social/family, emotional, and functional well-being. Individuals are 
asked to indicate how true 27 statements are for them, using the past 7 days as the timeframe. 
Responses range from not at all (0), to very much (4) on a 5-point scale. Psychometric properties of 
the FACT-G have been examined in a variety of oncology populations with alpha coefficients 
ranging from .65 to .89 [Cella, 1997]. After reverse coding selected items in the physical and 
emotional subscales, items are summed to provide total subscale scores, which will be used in our 
analyses. Using this scoring, higher values reflect better quality of life. 45. The full FACT-H&N 
provides a summary score for overall head and neck cancer related QOL and has been used 
frequently in clinical trials. 
 
Head and Neck Symptom Burden: The MD Anderson Symptom Inventory-Head & Neck (MDASI-
HN12) measures treatment related symptom burden in head and neck cancer patients. The MDASI 
measures both severity and burden of symptoms and their effect on patients’ daily activities, using a 
numeric rating scale of 0-10.  This instrument includes 13 core symptoms and 9 head and neck 
specific items. The instrument was validated in a cohort of more than 200 patients. The coefficient 
alpha was highly reliable. The MDASI takes less than 5 minutes for patients to complete. 12,13,69,70 
 
Swallowing and Voice: Data regarding swallowing perception and performance and voice 
outcomes will be obtained from the MD Anderson Dysphagia Inventory (MDADI) 71 and Voice 
Handicap Index-10 (VHI-10).   
The MDADI measures swallowing-related quality of life (QOL) in patients with swallowing 
dysfunction in a 20 – item written questionnaire.  It evaluates the patient’s physical (P), emotional 
(E) and functional (F) perceptions of swallowing dysfunction. This instrument has been 
psychometrically validated in head and neck cancer patients.   
 
The VHI-10 23is a patient self-assessment instrument that quantifies patients’ perception of their 
voice handicap.  It evaluates patient’s physical (P), emotional (E), and functional (F) perceptions of 
voice and has shown to be highly reliable for internal consistency and test-retest stability.  The VHI-
10 utilizes a 10-item questionnaire in which the patient circles the response that most accurately 
reflects his or her own experience on a linear scale (from “never” to “always”). 
Return to Work: Return to work will be tracked prospectively following treatment. While this data is 
patient reported, it does not generate a score requiring psychometric validation.  It has been judged 
to have face validity and is brief and practical for use in a clinical trial.  


 
52 
9.8 
Exploratory Objectives 
Prognostic Biomarkers.  Biomarkers of outcome include laboratory values determined at baseline 
from patient tissue and serum samples, clinical stage, and smoking history, expressed as pack 
years. Prognostic biomarkers will be assessed for prognostic impact with proportional hazards 
regression.  Predictive biomarkers will be assessed by a proportional hazards regression model that 
adds 2nd order interaction with treatment arm.  All hypotheses for prognosis and prediction will be 
simultaneously adjusted for false discovery by the method of Benjamini and Hochberg. Positive 
claims will be limited to those with a 10% expected false discovery rate.  
10. 
References 
 
1. 
Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple 
primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. The 
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2. 
Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. The New England journal 
of medicine 2001;345:1890-900. 
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Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the 
U.S. population ages 20-44 years. Cancer 2005;103:1843-9. 
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Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human 
papillomavirus and a subset of head and neck cancers. Journal of the National Cancer Institute 
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5. 
Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and 
neck squamous cell carcinomas worldwide: a systematic review. Cancer epidemiology, biomarkers & 
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American Society of Preventive Oncology 2005;14:467-75. 
6. 
Gillison ML. Human papillomavirus-associated head and neck cancer is a distinct 
epidemiologic, clinical, and molecular entity. Seminars in oncology 2004;31:744-54. 
7. 
D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and 
oropharyngeal cancer. The New England journal of medicine 2007;356:1944-56. 
8. 
Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human 
papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2008;26:612-9. 
9. 
Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: the 
International Agency for Research on Cancer multicenter study. Journal of the National Cancer 
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10. 
Fakhry C, Westra W, Li A, et al. Prognostic significance of human papillomavirus (HPV) tumor 
status for patients with head and neck squamous cell carcinoma (HNSCC) in a prospective, multi-
center phase II clinical trial.  2007 ASCO Annual Meeting Proceedings; 2007; Chicago, IL: Part 1. p. 
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58 
Appendix I Patient Reported Outcomes (PROs)  
 
EQ5D 5L Health Questionnaire 
Functional Assessment of Cancer Therapy – Head and Neck Cancer (FACT-HN) 
MD Anderson Symptom Inventory-Head & Neck (MDASI-HN) 
MD Anderson Dysphagia Inventory (MDADI) 
VHI-10 
 
 
 
VHI-10.pdf
FACT-HN.pdf
MDADI.pdf
MDASI-HN.pdf
EQ5D 5L Health Questionnaire.pdf


 
59 
Appendix II: Modified Barium Swallow Study Form 
 
 
                      Modified Barium Swallow Study Form 
 
Phase II Trial of Adjuvant De-Escalated Radiation + Concurrent and Adjuvant Nivolumab for 
Intermediate-High Risk P16+ Oropharynx Cancer 
INSTRUCTIONS: To be filled out by the speech pathologist after the modified barium swallow 
study. Dates are recorded as mm-dd-yyyy unless otherwise specified. 
MBS PROTOCOL: 
All MBS studies must follow a standard protocol as outlined below.  
Additional bolus presentations or swallowing strategies may be tested after completing bolus 
trials in the study protocol, at the discretion of the clinician conducting the MBS study.   
Studies will be done in lateral and AP views with focus fixed on the soft palate superiorly, 
cricopharyngeus inferiorly, lips anteriorly, and cervical spine posteriorly. 
Video-recordings will require time code imprints accurate to 0.01 seconds (30 frames/second).  
Video-recordings between 15-30 frames/second will be accepted as long as the recording rate is 
clearly documented in advance.  Video-recordings below 15 frames/second will not be accepted. 
Studies must be recorded in AVI or MPEG format.  All centers must use the Kay Digital 
Swallowing Workstation for the studies; or alternatively, can convert files to AVI of MPEG format. 
Centers must use Varibar products. Consistencies and quantities are listed below.  Liquids must 
be administered first to avoid confounding the results from remaining residue in the pharynx after 
solid consistencies. 
A dime must be taped to the subject’s chin during the swallowing study.  The circular shape of the 
dime minimizes the impact of head rotation and the known diameter of the dime allows for 
calibration of pixels per cm and thus calculation of distances and areas on the lateral view of the 
x-ray. 
Lateral view: 
• 
5mL thin (2 trials, tsp). Instruction to the patient: please hold this in your mouth until asked 
to swallow. 
• 
20mL thin (1 trial). Instruction to the patient: please try to take the whole amount and hold 
it in your mouth until I ask you to swallow. Self-administration is optimal, but clinician 
administration is acceptable. 
• 
5mL pudding (1 trial tsp). Instruction: swallow when you are ready. 
• 
1/2 cookie or cracker, barium coated - coated with 3 ml (1/2 tsp) of Varibar pudding (1 
trial). Instruction to the patient: chew this up and swallow when you feel comfortable and ready to 
swallow. 
A-P view: 
10mL thin (1 trial). Instruction: slightly raise your chin (neutral position, not tucked or extended), 
hold this in your mouth until asked to 
RATING RULES: 
Rate MBS outcomes below on the basis of bolus trials in the University of Pittsburgh protocol.  Do 
not rate based on additional bolus trials that are administered outside of the protocol or based on 
bolus trials in which a swallow strategy/posture was tested.  Please select a SUMMARY RATING 
based on the highest level of impairment you observe on any bolus trial in the protocol. 
MBS 


 
60 
 
                      Modified Barium Swallow Study Form 
 
Phase II Trial of Adjuvant De-Escalated Radiation + Concurrent and Adjuvant Nivolumab for 
Intermediate-High Risk P16+ Oropharynx Cancer 
1 DATE OF MBS  _____-_____-_____ 
2 
□TIME OF MBS 
1. 
Baseline  
2. 
After surgery (before adjuvant therapy)  
3. 
Six months after treatment 
4. 
Twenty-four months after treatment 
Outcome 
Variables 
Definition 
Scoring Rules 
(Rate the worst of 
impairment across all 
bolus trials in the MBS 
protocol) 
Rating 
3 LARYNGEAL 
PENETRATION 
PENETRATION: Bolus 
enters the larynx but 
does not pass below 
the TVFs 
Select “1” if 
LARYNGEAL 
PENETRATION 
occurred on any bolus 
in the protocol. 
□  No penetration 
(0) 
□  Penetration (1) 
4 ASPIRATION 
ASPIRATION: Bolus 
enters the larynx and 
passes  below the 
TVFs. 
SENSATE: attempts to 
eject aspirate from 
airway (e.g., cough, 
throat clear) 
SILENT: no effort to 
eject aspirate from 
airway (no cough, 
throat clear)  
Select the highest level 
of aspiration that 
occurred during the 
protocol. 
Select “1” if SENSATE 
ASPIRATION ocurred 
on any bolus in the 
protocol, but silent 
aspiration NEVER 
occurred. 
Select “2” if SILENT 
ASPIRATION occurred 
on any bolus in the 
protocol.  
□  No aspiration 
(0) 
□  Yes, sensate (1) 
□  Yes, silent (2) 
5 PHARYNGEAL 
RESIDUE 
RESIDUE: bolus 
remaining on or within 
the pharynx at the 
conclusion of the initial 
swallow.  The 
conclusion of the initial 
swallow is when the 
hyoid bone returns to 
rest.  If the patient 
spontaneously 
swallows several times 
to clear the bolus, 
residue is rated after 
the 1st swallow 
attempt. 
Rate the highest level 
of residue that 
occurred during the 
protocol.   
Select “0” is no residue 
or only pharyngeal 
coating occurred during 
the protocol. 
Select “1” if pharyngeal 
residue of <50% of the 
original bolus remained 
in the pharynx on any 
bolus in the protocol. 
Select “2” if pharyngeal 
residue of half or more 
of the original bolus 
□  No residue (0) 
□  <50% 
pharyngeal residue 
(1) 
□  ≥ 50% 
pharyngeal residue 
(2) 
MBS 


 
61 
 
                      Modified Barium Swallow Study Form 
 
Phase II Trial of Adjuvant De-Escalated Radiation + Concurrent and Adjuvant Nivolumab for 
Intermediate-High Risk P16+ Oropharynx Cancer 
remained in the 
pharynx on any bolus 
in the protocol. 
PERSON COMPLETING FORM:  
NOTE: This form is for reference only. The MBS information for each registered patient will be 
entered directly into the UPMC database.  
 
MBS