The Sinai Robotic Surgery Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma (SCCA)
Phase: NA
Conditions: Human Papilloma Virus, Oropharyngeal Squamous Cell Carcinoma
Sponsor: Icahn School of Medicine at Mount Sinai

The Sinai Robotic Surgery Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma
(SCCA) (SIRS TRIAL)
Dr. Raymond Chai
NCT02072148
Document Date: 2-14-2022

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The Sinai Robotic Surgery Trial in HPV Positive 
Oropharyngeal SCCA
SIRS Trial
Principal Investigator: Raymond Chai, MD
Mount Sinai School of Medicine
One Gustave. L. Levy Place,
New York, NY-10029
Raymond.Chai@mountsinai.org
(212) 844-8560
Funding Sponsor: Icahn School of Medicine at Mount Sinai
IND Sponsor: Not applicable
Version: 25.0
Version Date: 2.7.2022
Effective Date: 2/14/2022
End Date:2/7/2023

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Investigators/Study Staff
Raymond Chai, MD
Principal Investigator 
Otolaryngology
212-844-8560
Raymond.Chai@mountsinai.org
Krzysztof Misiukiewicz, MD
Co- Investigator
Medical Oncology Chairman
212-659-5567
kryzstof.misiukiwiecz@mssm.edu
Eric Genden, MD
Co-Investigator
Chairman, Surgical Oncology
212-241-7063
eric.genden@mountsinai.org
Vishal Gupta, MD 
Co-Investigator
Chairman, Radiation Oncology
212-241-7818
vishal.gupta@mountsinai.org
Richard Bakst, MD
Co-Investigator
Radiation Oncology
212-241-3545
richard.bakst@mountsinai.org
Sonam Sharma, MD
Co-Investigator
Radiation Oncology
212-241-3545
sonam.sharma@mountsinai.org
Marshall Posner, MD
MSSM Medical Oncology
212-241-0288
marshall.posner@mssm.edu
Bruce Culliney, MD
Co-Investigator
MSSM Medical Oncology
212-844-8280
bruce.culliney@mountsinai.org
Marita Teng, MD
Co-Investigator
Otolaryngology
212-241-9410
marita.teng@mssm.edu
William Westra, MD
Co-Investigator
Anatomic Pathology
212-241-6133
William.westra@mountsinai.org
Seunghee Kim-Schulze, PhD
Co-Investigator
Immune Monitoring, Biorepository
212-659-8264
seunghee.kim-schulze@mssm.edu
Nicholas Rohs, MD
Mohemmed Khan, MD
Co-Investigator
Co-Investigator
212 367 0137
212-844-8775
nicholas.rohs2@mountsinai.org
mohemmed.khan@mountsinai.org
Scott Roof, MD
Jerry Liu, MD
Co-Investigator
Co-Investigator
347- 461-3389
212-844-8409
Scott.Roof@mountsinai.org
jerry.liu@mountsinai.org
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Table of Contents
INVESTIGATORS/STUDY STAFF…………………………………………………………………............................2
1.0INTRODUCTION
1.1
Primary Objectives....................................................................................................................................4
1.2
Secondary Objectives................................................................................................................................4
1.3
Treatment Schema.....................................................................................................................................5
2.0
       BACKGROUND
2.1
       HPV – Related Oropharynx Cancer……………………………………………………………………...6
2.2
Transoral Surgery and HPV Related Oropharyngeal Cancer………………………………………….…6 
2.3    
      Rationale for Single Modality Treatment of Early stage HPV related OPSCC…………………………..9
2.4               Histological Requirements………………………………………………………………………………...9
2.5             Correlative Studies Background…………………………………………………………………….……..10
3.0
PARTICIPANT SELECTION .......................................................................................................................11
3.1
Inclusion Criteria.....................................................................................................................................11
3.2
Exclusion Criteria.................................................................................................................................12
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations ...........................................13
4.0
REGISTRATION PROCEDURES................................................................................................................13
4.1
General Guidelines..................................................................................................................................14
4.2
Registration Process..............................................................................................................................14
5.0
TREATMENT PLAN ....................................................................................................................................14
5.1
Chemoradiotherapy .............................................................................................................................19
5.2
Salvage Protocol……….. .......................................................................................................................18
6.0
STUDY PARTICIPATION ………........................................................................................................18
6.1
Duration of Follow Up ............................................................................................................................20
6.2
Criteria for Removal from Study ............................................................................................................20
7.0
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS......................................20
7.1
Anticipated Toxicities .............................................................................................................................20
7.2
Dose Modifications/Delays.....................................................................................................................21
8.0
DRUG FORMULATION AND ADMINISTRATION .................................................................................24
9. 0
CORRELATIVE/SPECIAL STUDIES..........................................................................................................24
9.1               Probable Laboratory Correlative Studies..................................................................................................22
9.2
       Specific Study Plans................................................................................................................................24
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9.3
       Blood and Tissue Collection and Preparation.........................................................................................25
10.0
STUDY CALENDAR (History, Exam and Lab)...........................................................................................27
11.0
MEASUREMENT OF EFFECT....................................................................................................................29
12.0        ASSESSMENT OF QUALITY OF LIFE AND PATIENT REPORTED SYMPTOMS .............................29
13.0
ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................31
13.1
Definitions...............................................................................................................................................31
13.2
Procedures for AE and SAE Recording and Reporting ..........................................................................33
13.3
Reporting Requirements..........................................................................................................................34
13.4
Reporting to the Study Center.................................................................................................................34
13.5
Reporting to the Institutional Review Board (IRB) ................................................................................35
13.6
Reporting to Hospital Risk Management................................................................................................35
13.7
Monitoring of Adverse Events and Period of Observation.....................................................................35
14.0
DATA AND SAFETY MONITORING ........................................................................................................35
14.1
Data Reporting ........................................................................................................................................35
14.2
Safety Meetings.......................................................................................................................................36
15.0
REGULATORY CONSIDERATIONS .........................................................................................................38
15.1
Protocol Review and Amendments.........................................................................................................38
15.2
Informed Consent....................................................................................................................................38
15.3
Ethics and Good Clinical Practice (GCP) ...............................................................................................38
15.4
Study Documentation..............................................................................................................................39
15.5
Records Retention ...................................................................................................................................39
15.6
Multi-center Guidelines...........................................................................................................................39
16.0
STATISTICAL CONSIDERATIONS ...........................................................................................................39
16.1
Study Design/Endpoints..........................................................................................................................39
16.2
Sample Size/Accrual Rate.......................................................................................................................40
16.3
Stratification Factors ...............................................................................................................................41
16.4  
Analysis of Primary Endpoints ...............................................................................................................41
16.5
Analysis of Secondary Endpoints ...........................................................................................................41
17.0
PUBLICATION PLAN..................................................................................................................................42
18.0
REFERENCES...............................................................................................................................................43
19.0
APPENDICES................................................................................................................................................47
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1.0 INTRODUCTION
Study Design
Non-randomized Phase II de-escalation clinical trial to establish recurrence rates, site of recurrence,  
survival and quality of life outcomes for early T-stage HPV positive oropharyngeal SCCA treated with 
upfront surgery and reduced dose radiotherapy.  Eligible, consented and registered patients will undergo 
transoral robotic surgery and selective neck dissection. After pathologic evaluation, patients with early 
stage disease as defined below will be placed into surveillance protocol as outlined or assigned to 
adjuvant therapy, depending on risk factors. Patients with intermediate risk factors will receive 
postoperative radiotherapy alone (5000 cGy).  Patients with poor prognostic features will receive 
concurrent chemoradiotherapy (5600 cGy) with weekly cisplatin.  Patients taken off study (based on 
Section 9.2 “Criteria from Removal of Study”) will be followed for survival until the study ends.  Any 
adverse events occurring thereafter in these patients will not be considered related to the study and will 
not be tracked or reported. 
1.1
Primary Objectives
1.1.1
To determine the rate of local regional control (LRC) at 5 years in patients with early and intermediate 
stage HPV related oropharynx cancer treated with surgery alone.
1.1.2
To determine the rate of progression free survival (PFS) at 5 years in patients with early and 
intermediate stage HPV related oropharynx cancer treated with surgery alone. 
1.1.3
To determine overall survival (OS) at 5 years in patients with early and intermediate stage HPV 
related oropharynx cancer treated with surgery alone. 
1.1.4
To determine the rate of local regional control (LRC) at 3 years in patients with HPV related 
oropharynx cancer treated with a de-intensified adjuvant protocol.
1.1.5
To determine the rate of progression free survival (PFS) at 3 years in patients with HPV related 
oropharynx cancer treated with a de-intensified adjuvant protocol.
1.1.6
To determine overall survival (OS) at 3 years in patients with HPV related oropharynx cancer treated 
with a de-intensified adjuvant protocol.
1.1.7
To determine the rate of PFS (Ultimate Disease Control – UDC) and of OAS after secondary therapy 
for patients treated with surgery only who have local regional relapse at 5 years
1.1.8
To determine the rate of PFS (UDC) and OAS after secondary therapy for patients who relapse with 
distant disease after surgery only
1.1.9
To quantify the quality of life of patients treated with this protocol at 3 years
1.2
Secondary Objectives
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1.2.1
To determine the rate of local-regional control (LRC) over 5 years in patients with  HPV related 
oropharynx cancer treated with a de-intensified adjuvant protocol.
1.2.2
To determine the rate of progression free survival (PFS) over 5 years in patients with HPV related 
oropharynx cancer treated with a de-intensified adjuvant protocol.
1.2.3
To determine the rate of Overall Survival (OS) at 5 years in patients with HPV related oropharynx 
cancer treated with a de-intensified adjuvant protocol.
1.2.4
To discover potential biomarkers predictive of local regional and distant failure.
1.2.5
To establish a tumor tissue, germline DNA and plasma bank for future studies of the protocol selected 
and treated populations.
1.2.6
To quantify the quality of life of patients treated with this protocol at 5 years
1.3
Treatment Schema
Surveillance
TORS 
ChemoXRT
5600 cGy 
PATH
XRT
5000 cGy 
Consent and
Registration
1.
HPV 16+ and p16+
2.
< 3 Nodes,
3.
No ECS, Matted
Nodes, N3 , >Level 3
4.
No T4
5.
Non-Smokers
Group I
Favorable Prognostic 
Features:
T1-T2, N1-N2b
No ECS, LVI, PNI, >Level 3
Group IIIB 
Incomplete surgical resection
with +surgical margins 
>1mm ECS or matted nodes
Group II
Intermediate Prognostic 
Features:
N2B distinct, LVI, PNI
≤1 mm ECS, Margin
Group IIIA
>3+ nodes
+Supraclavicular nodes
+Contralateral nodes
(no ECS >1mm) 
ChemoXRT
5000 cGy 
2  BACKGROUND
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2.1
HPV – Related Oropharynx Cancer
The demographics and excellent prognosis of HPV related oropharyngeal squamous cell cancer (HPVOPC) 
has called into question the rational for aggressive concurrent chemoradiotherapy for intermediate stage HPV 
related oropharyngeal SCCA. Epidemiologic evidence has revealed a significant increase in the incidence of 
oropharynx cancer (OPC) in North America and Europe. Molecular studies of oropharyngeal tumors have 
revealed that this increase is due to an increase in the incidence of tumors which contain Human Papillomavirus 
(HPV), most specifically HPV16 and for which there is direct evidence that HPV16 is the molecular cause 
mechanistically driving the development and viability of the cancer cells. HPV-related oropharynx cancer 
(HPVOPC) now accounts for almost 60% of OPC seen in the USA and an increasing fraction of these 
malignancies in Europe 1-3.  
Based on the existing data from clinical trials and patient material through retrospective analysis, it is now 
understood that there are two dominant carcinogenic and biologic pathways where oropharynx cancer 
develops: Environmentally related OPC (EROPC), caused principally by smoking and alcohol, and HPV 
related OPC (HPVOPC).  The relative paucity of genetic changes in HPV-positive head and neck cancer is in 
sharp contrast to what is observed in HPV-negative head and neck cancer and is mechanistically related to the 
direct effects of viral proteins in inactivating regulators of key cellular processes4-7. In the typical EROPC, 
mutations and deletions of p53 have very frequently been demonstrated. In contrast, HPVOPC do not contain 
p53 mutations. Similarly, p16 in the Rb pathway of cell growth is frequently mutated, deleted or silenced in 
EROPC but is often up-regulated in HPVOPC as a consequence of viral alterations in Rb function. Up 
regulation of p16 can be seen in up to 20% of non-HPV related cancers including other sites in the head and 
neck, however, p16 appears to be up-regulated in >95% of HPVOPC making it a good screening tool8.
Studies in unselected patients suggest that patients with HPVOPC have a better prognosis than patients with 
HPV-negative, predominantly environmentally related OPC (EROPC) 9-11.  In one retrospective study of 
radiotherapy as sole therapy from Denmark, p16 was used as a surrogate for HPV. In this randomized study 
of a radiation sensitizer, the control arm of radiotherapy only was analyzed for p16 expression. There was 62% 
5-year survival among p16+ patients compared to 26% in p16- patients. LRC was 58% vs. 28%, respectively
(Figure 1). A significant fraction of p16+ tumors were not of oropharyngeal origin 12.
A second trial, Licitra et al retrospectively evaluated surgery in the HPV positive and negative cases. Surgery 
alone was effective therapy for a small group of patients.  Patients who underwent surgery as a single modality 
were spared the long term consequences of radiation. However, selection criteria for surgery alone was not 
well explained13.
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Licitra et al, JCO  2006
Figure 2: Surgery and HPV in Oropharynx Cancer
Recently, results of retrospective analyses of survival and HPV status were reported from two International 
Phase III trials comparing chemoradiotherapy (CRT) regimens in locally advanced HNC. In both trials there 
were insufficient patient numbers to report a treatment effect; however the impact of HPV on survival, 
regardless of therapeutic assignment, was highly significant 8,14. The RTOG (R) 01-29 has the most extensive 
data and retrospectively analyzed on 323 out of 433 OPC cases.  In RTOG 01-29, patients were randomized 
between CRT with accelerated fractionation with cisplatin versus regular fractionation and cisplatin. The 
overall survival (OS) and progression free survival (PFS) at three years were 82%and 74% in HPVOPC 
compared to 57% and 43% for EROPC, respectively. A careful analysis of failure and death revealed a LRF 
rate of 14% versus 35% for HPVOPC versus EROPC and a second primary tumor rate of 6% versus 15% 
respectively. Non-cancer deaths also occurred in 9% and 19% respectively. All these data support a better 
outcome for HPVOPC, much of which is found in improved LRC, some of which is explained by less co-
morbidity.
2.2
Transoral Surgery and HPV Related Oropharynx Cancer
Robotic surgery has been widely applied in the medical field and the FDA has approved several 
applications including: laparoscopic surgery (2000),  prostate surgery (2001),  thorascopic surgery (2001),  
mitral valve surgery (2002). More recently, investigators began exploring the feasibility of transoral robotic 
surgery in the oropharynx.  Hockstein et al. studied the use of the robot in an airway mannequin and determined 
that it was feasible to access both the oropharynx and the larynx using the Da Vinci robot and both the 5 mm 
and 8mm instrument arms.15 In a subsequent report, the same group demonstrated that several surgical 
procedures including a tongue base resection and several laryngeal procedures were technically feasible using 
the Da Vinci robot system.16  Hockstein further demonstrated that effective hemostasis of the extensive 
pharyngeal vasculature was achievable using a combination of cautery and robotically applied hemoclips to 
control the lingual artery.17
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These pre-clinical studies conducted by Hockstein and the University of Pennsylvania group led the way for 
several preliminary clinical cohort studies.  O’Malley et al. described the first series of TORS tongue base 
resections for squamous cell carcinoma.18 In this report, he outlined the surgical technique and advantages and 
disadvantages of the multiple retraction systems used during transoral tongue base surgery. All three patients 
were eating a full diet within 6 weeks. Weinstein et al. subsequently reported the use of the robot for 
supraglottic surgery with a series of 3 patients undergoing robotic supraglottic laryngectomy.19 Solares et al. 
followed shortly thereafter with a report of a supraglottic laryngectomy performed using a CO2 laser.20  The 
University of Pennsylvania group also reported the first series of TORS cases for radical tonsillectomy on 27 
patients.21 The technical aspects of the surgery were described to allow for negative margin resection of tonsil 
malignancies while protecting the internal carotid artery in the parapharyngeal space. In this early series, all 
patients had gastrostomy tubes inserted prophylactically and one patient had planned tracheostomy. An 
additional patient had unexpected tracheostomy following exacerbation of pre-existing obstructive sleep 
apnea.  The surgical complication rate was 19% including one mucosal hemorrhage requiring a return to the 
operating room, one tracheostomy, two patients developed trismus, and one patient developed hypernasality 
requiring an outpatient procedure for correction. Genden et al. and the Mount Sinai group published their 
institutional experience with their first 20 transoral robotic surgery cases.22  Two cases were aborted due to 
inadequate access and the remaining 18 cases consisted of 7 tonsil lesions, 4 tongue base lesions, 4 supraglottic 
lesions, 2 parapharyngeal lesions and 1 palate lesion.  Patients did not require prophylactic gastrostomy tubes, 
and oral diet was achieved on 1.4 days after surgery on average.  Patients were discharged on average 1.7 days 
after surgery.23 These investigations lead to FDA approval of transoral robotic surgery in 2009.
Functional Outcomes 
Proponents of transoral robotics surgery for oropharynx cancer contend that it offers improved 
functional outcomes when compared to non-surgical treatment with radiation therapy with or without 
chemotherapy.  Many of the functional limitations incurred by chemoradiotherapy are related to long term 
toxicities.  A recent retrospective analysis of three RTOG trials suggested that the rate of severe late toxicities 
in patients receiving chemoradiotherapy is 43% for all subjects, and 35% for patients with oropharyngeal 
cancer.24 This group defined late toxicities as grade 3 or 4 pharyngeal/laryngeal toxicity, feeding tube 
dependence at 2 or more years from treatment, and/or treatment related death (grade 5 toxicity).  Another 
prospective study of 104 patients (72 oropharyngeal cancers) found that 26.4% of patients are feeding tube 
dependent at one year, and 13.8% were tracheotomy dependent (although less commonly for oropharyngeal 
cancers).25  These numbers are considerably better in modern practice, and only 5-12% of patients remain PEG 
dependent in more recent studies. In patients undergoing TORS and selective neck dissection, pathologic data 
can provide staging information that may allow for tailoring treatment to the individual and obviate the need 
for unnecessary toxic adjuvant treatments.  Additionally, patients with unfavorable pathologic criteria are 
identified and more intense adjuvant therapy may be applied more appropriately.
Several studies report favorable swallowing outcomes using TORS for resection of oropharyngeal 
cancers.21,22,26-29  Genden et al. reported all patients (n=20) tolerated an oral diet at a mean 1.4 days after surgery 
without any patients requiring gastrostomy tubes, in patients who did not receive adjuvant CCRT.22  Iseli et al. 
performed TORS on 54 patients, and 83% of their patients were tolerating a diet within 14 days, 17% required 
a feeding tube at 12 months follow-up, and 5.6% of patients demonstrated signs or symptoms of aspiration.29  
Moore et al. performed TORS on 45 patients, and 82% of patients were tolerating an oral diet by the first post-
operative visit.  Seventeen percent of patients required a feeding tube, but none required assistance with feeding 
at one year follow-up.28 Hurtuk et al also described an early return to oral diet with all 54 patients in their study 
tolerating oral diet on the day of surgery.27  They reported, 20% of their patients requiring feeding tubes mainly 
during adjuvant therapy. In these studies, tracheostomy rates varied from 0-31% of patients requiring 
temporary tracheostomy tubes, more commonly for supraglottic or laryngeal malignancies.21,22,28,29  However, 
the majority of patients were decannulated within two weeks and no patients required tracheotomy tubes at 
one year follow-up.
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Quality of Life
Patient reported quality of life may be the next most important outcome besides survival and in many 
instances patients are willing to trade-off a longer life for a better quality of life.  Treatment for cancer often 
entails some negative effects on quality of life during the treatment period which may improve over time.  
Leonhardt et al. prospectively administered the Performance Status Scale, a disease-specific questionnaire, 
and the SF-8, a generic questionnaire, to 34 patients with TORS surgery and followed these patients for a 
year.30   They observed that the swallowing domains in the PSS, eating and diet, suffered and experienced 
significant decreases which returned to normal at the 1 year time point.  The speech domain, however, was 
significantly reduced at both the 6 month and the 1 year time-points.  They also noted that patients who had 
TORS with chemoradiation had significantly lower swallowing scores compared to those without.  Genden et 
al. performed a case-control study to compare quality of life for patients undergoing TORS compared to those 
undergoing primary chemoradiotherapy. In the swallowing domains, eating and diet, TORS patients had 
significantly better scores immediately post-treatment (72 vs. 43; p=0.008 and 43 vs. 25; p=0.01).31  While 
TORS patients had a return to baseline in all domains at 12 months, patients who had chemoradiotherapy did 
not have a return to baseline in the diet domain. 
Oncologic Outcomes 
The retrospective oncologic outcomes from TORS surgery for oropharyngeal cancer are slowly 
emerging, and early outcomes are promising.  Recent studies have reported local failure rates which varied 
between 0-3% with median follow-up rates ranging from 18 months to two years.26,31-33 Regional recurrence 
rates in the same studies varied between 2-8%, while distant disease was identified in 1-9% of patients.26,31-33  
Eighteen month overall survival was 90% in one study31, and two-year overall survival was 82% and 80.6% 
in two other studies.26,32  While many investigations include large proportions of HPV+ oropharyngeal 
malignancies, Cohen et. al. stratified survival by HPV status and there were no differences with an overall 
survival of 81% in the HPV+ group and 80% in the HPV-.  Two year disease-specific survival rates were 90% 
and 92.6%, respectively .26,32  Meanwhile 18 month recurrence free survival rates were 78% and  two year 
rates were 79% and 86.3% respectively.26,32,33  These early figures compared favorably to existing reports of 
oropharyngeal cancer treated with chemoradiotherapy.34-38 While patients who receive concurrent 
chemoradiotherapy can be stratified based on HPV and smoking status into a de-intensification or 
intensification regimens, staging information regarding their disease is lost.  Furthermore, patients treated non-
surgically require high-dose radiation to definitively treat the primary tumor and metastatic cervical nodes.   
There is definitive evidence that radiation effects on critical structures such as the pharyngeal constrictors are 
dose dependent and reduced dosage may reduce the risk of chronic dysphagia, feeding tube dependence, and 
aspiration risk.39-42  By physically removing tumor, one can theoretically offer a lower or dose or entirely 
eliminate primary radiation reserving it for salvage and confer better swallowing and QOL outcomes. 
Following the data published by Ang et al. demonstrating that survival and local regional control is 
better amongst HPV positive patients, new studies are underway to evaluate the role of de-intensification of 
therapy.43  The Easter Cooperative Oncology Group (ECOG) and the Radiation Therapy Oncology Group 
(RTOG) both have studies investigating de-intensified therapy.  The former group is investigating the role of 
induction therapy with dose-reduced radiation while the latter group is conducting a phase III randomized  
controlled trial comparing standard chemoradiation with cisplatin to radiation and cetuximab in HPV positive 
patients. 
In addition, more recent data has prompted changes in the AJCC staging system for HPV related 
oropharyngeal squamous cell carcinoma.44 This data has indicated that the prognostic impact of the number of 
cervical lymph nodes appears less important than previously realized. This has prompted the addition of a 
cutoff group of >6 nodes (as proposed in the new AJCC staging system, see SIRS Groups IIIA,IIIB) for a 
marker for more advanced disease, thereby warranting the addition of chemotherapy. In addition, this proposed 
staging system which will be implemented in 2018 has now been validated by analysis of additional 
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cohorts.45,46 Additional data indicates a low rate of contralateral node failure in this population further 
supporting an upfront surgical approach in order to spare patients uncessesary adjuvant radiation.47
Amidst these trials there is a clear need to study the use of surgery alone to replace radiation for local 
regional control, reserving “salvage” chemoradiotherapy for local regional failure and sparing a large fraction 
of patients the morbidity and mortality of radiotherapy. 
2.3
Rationale for Single Modality Treatment of Early stage HPV related OPSCC 
In general, patients with HPVOPC are young and will live for prolonged periods. They are at high risk for 
long-term toxicity and mortality from therapy24. While the long-term consequences of chemotherapy for head 
and neck cancer are relatively constrained, high-dose radiotherapy (RT) and chemoradiotherapy substantially 
impact on local tissues and organ function and result in a significant rate of late mortality and morbidity in 
patients48-51. Studies are now being designed to reduce the impact of RT and CRT for patients. 
There are currently few trials examining the role of de-escalation using surgery alone in early T-stage HPV 
related disease or reduced radiotherapy in intermediate risk patients.  New surgical techniques have broadened 
the range of patients capable of achieving a complete resection and the functional outcomes in such patients. 
Furthermore, the sensitivity of HPVOPC to chemotherapy and radiotherapy raise the possibility that delayed 
or salvage treatment in early stage patients would be highly effective, would result in similar survival outcomes 
and could be applied to a much smaller population then current standards call for. Looked at from a different 
perspective, the need for post-operative radiotherapy in this younger, HPV+ and more functional population 
have not been validated in clinical trials to date. 
2.4
Histological Requirements
Patient selection for the SIRS trial will include squamous cell carcinomas of head and neck classified as 
oropharynx that are both positive for HPV16 or any high risk HPV subtype (i.e. 18, 33, 35, etc.) by PCR and 
p16 positive1,52. Tissue for confirmation of p16 status and confirmatory HPV-PCR and will be required and 
analyzed at a central laboratory. Although p16 has been found to be a potential independent risk factor for 
prognosis, and a negative p16 is highly predictive of a negative HPV test, about 20% of HNC tumors are p16 
positive independent of HPV presence. Because the biologic behavior of this population may be heterogeneous 
and is less well understood, p16- or p16+ HPV- patients will be excluded from the trial. Similarly, 90% of 
HPV positive oropharynx cancer is HPV16+, and the behavior of other serotypes is unknown. Hence this study 
will be limited to HPV16+ cancers, and cancers from high risk HPV subtypes will be analyzed in a separate 
group. Testing for p16 will be performed and/or reviewed in the central laboratory.
In addition, smoking has been shown to be a prognostic factor in HPVOPC53. In the SIRS trial, patients with 
a history of > 20 pack years and recent (within 5 years) tobacco abuse will be excluded, as this is a known 
negative prognostic factor and the role of adjuvant therapy in smoking related HPVOPC is currently being 
examined in other investigations.
2.5
Correlative Studies Background
It is still not well understood as to what biological factors influence the growth and response to treatment of 
HPVOPC tumors.  Current research strongly suggests that there are multiple pathways that may account for 
the difference in growth and treatment response between HPVOPC and non-HPVOPC tumors.  Furthermore, 
there are several mechanisms reported in the literature that may account for differences in survival within the 
HPVOPC subset of patients.  The advantage of surgical trials in this arena is the availability of high quality 
tissue specimens for analysis.
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This study will collect blood and tumor samples in order to further quantify such mechanisms.  Studies will 
be performed on samples in order to analyze expression of p16, p53, cMET in tumor, and HPV copy number 
among others. Serial blood samples will be collected to measure sequential serum anti-HPV antibody titers to 
HPV16 proteins, cytokines, HGF and quantification of circulating tumor cells, MDSC, and other immune 
function cells.  Additionally, studies will be performed to quantify tumor EGFR copy number and Bcl-xL 
expression, in order to further study the relationship between these proteins and survival of HPVOPC patients.  
Finally, HPV related signaling pathways will be analyzed using such markers as NFĸβ and STAT3 in tissues 
or a high throughput screening system. Antibodies the HPV16 early antigens are elevated in HPVOPC and 
may prove to be a useful biomarker for assessing risk of recurrence and  response to therapy54.
Kumar, et. al. reported that low EGFR and high p16 expression are markers of good response to treatment 55.  
Other studies have also shown HPV copy number to be linked to better response to treatment and improved 
OS7.  p16 will be measured as a marker for HPV status, as it is a cyclin-dependent kinase inhibitor, which acts 
to inhibit pRb phosphorylation, thus blocking cell cycle progression.  The inactivation of pRb by HPV leads 
to overexpression of p16, making it a good marker for HPV status.  Additionally, high EGFR expression, low 
p53, as well as high Bcl-xL (an antiapoptotic protein) expression are factors that may indicate poor response 
to treatment and poor outcomes.  This study will seek to analyze these factors, as well as proteins that are often 
mutated in cell signaling pathways, such as cMET, in order to further correlate these proteins with treatment 
response.
3.0
PARTICIPANT SELECTION
All patients will be evaluated and consented in the multidisciplinary head and neck cancer clinic where 
eligibility criteria, entry and disease parameters will be evaluated and documented. Subjects who enroll on this 
study must be diagnosed with HPV related squamous cell carcinoma in the oropharynx, and must not have 
received any prior chemotherapy, radiotherapy or surgery for their cancer. Potential participants will be 
screened based on their past medical history, the results of their radiological scans, blood work, as well as a 
number of other required studies that will determine their eligibility.  To be screened and consented on this 
study subjects must have had a biopsy and must display clinical features that are consistent with p16 positivity 
(i.e., no history of smoking/alcohol, age range, etc.). To be assigned to a group and participate in the 
experimental portion of the trial, surgery must be performed at MSSM, tumor tissue must be available, and 
both p16 and HPV status must be assessed and proven to be positive for HPV 16 or any high risk HPV subtype 
(i.e., 18, 33, 35, etc.) by PCR and p16 positive by IHC.
3.1
Inclusion Criteria
Participants must meet the following criteria to be eligible to participate in the study. Patients may be 
screened and consented if they display clinical features that are consistent with p16 positivity, but not yet 
tested for p16 by IHC and for HPV by PCR and if they meet the other eligibility criteria. They will enter the 
experimental post-surgical portion of the study if they have surgery performed at MSSM and surgical 
specimens or biopsies proven to be both p16+ on IHC testing and HPV+ on PCR testing:
3.1.1 
Participants must have histologically or cytologically confirmed and identified resectable primary 
squamous cell carcinoma of the oropharynx that is HPV 16 positive or positive for any high risk HPV 
subtype (i.e., 18, 33, 35, etc.) as determined by PCR at the central laboratory.  Patients must have p16+ 
status as determined by IHC performed or reviewed at the central laboratory. Both p16 and HPV status 
must be determined prior to post-surgical adjuvant treatment assignment. Tissue from the primary site 
must be available for biomarker studies after surgery. Patients with an unknown primary site may be 
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12
enrolled  if the primary site is identified as a result of the definitive surgical intervention and meets 
criteria in 3.1.2 and 3.1.1 with confirmation of p16 positivity.
3.1.2
Stage 1, 2, 3 or early and intermediate stage IVa (T1N0-2B, T2N0-2B) (Level 2, non-matted) disease 
without evidence of distant metastases or extracapsular extension. Primary site must be lateralized for a 
functional dissection. 
3.1.3  Age > 18 years.
3.1.4
No previous surgery, radiation therapy or chemotherapy for SCCHN  (other than biopsy 
or tonsillectomy) is allowed at time of study entry.
3.1.5
ECOG performance status of 0 or 1. 
3.1.6
No active alcohol addiction (as assessed by medical caregiver).
3.1.7
No active tobacco use ( ≥1cigarette or cigarette-equivalent per day within the 
last 5 years) and no cumulative smoking history of >20 pack years
3.1.7.1    1 
cigar 
= 
4 
cigarette-equivalent 
exposure 
(http://www.smoking2.nes.scot.nhs.uk/module4/working-out-cigarette-
equivalents.html)
3.1.8  Ability to understand and the willingness to sign a written informed consent document.
3.1.9
Participants must have adequate bone marrow, hepatic and renal functions as defined below:
3.1.9.1 Hematology:

Neutrophil count > 1.5 x 109/l.

Platelet count > 100 x 109/l.

Hemoglobin > 10 g/dl (may achieve by transfusion).
3.1.9.2 Renal function: > 60 ml/min (actual or calculated by the Cockcroft-Gault 
method) as follows:
CrCl (mL/min) =      (140-age) (weight kg)
72 x serum creatinine (mg/dL)
N.B. For females, use 85% of calculated CrCl value. 
Or a Creatinine < the upper limits of normal
3.2
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for admission into 
the study.
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13
3.2.1 
Patients < age 18.
3.2.2 
Pregnant or breast feeding women.
3.2.3 
Previous or current malignancies at other sites, with the exception of adequately treated in situ 
carcinoma of the cervix, basal or squamous cell carcinoma of the skin, thyroid cancer, prostate cancer 
treated with surgery/radiotherapy, or other cancer curatively treated by surgery and with no current 
evidence of disease for at least 5 years.
3.2.4    Other serious illnesses or medical conditions including but not limited to:
3.2.4.1  Unstable cardiac disease despite treatment, myocardial infarction within 6 months
 prior to study entry.
3.2.4.2   History of significant neurologic or psychiatric disorders including dementia or  seizures
3.2.4.3 Active clinically significant uncontrolled infection 
3.2.4.4  Active peptic ulcer disease defined as unhealed or clinically active 
3.2.4.6 Active drug addiction including alcohol, cocaine or intravenous drug use defined 
as occurring within the 6 months preceding diagnosis 
3.2.4.7 Chronic Obstructive Pulmonary Disease, defined as being associated with a hospitalization for 
pneumonia or respiratory decompensation within 12 months of diagnosis. This does not include 
obstruction from tumor 
3.2.4.8 Autoimmune disease requiring therapy, prior organ transplant, or known HIV 
infection 
3.2.4.9 Interstitial lung disease 
3.2.4.10 Hepatitis C by history 
3.2.4.11 Concurrent treatment with any other anticancer therapy. 
3.2.4.12 Participation in an investigational therapeutic drug trial within 30 days of study entry. 
Participation in additional investigational radiation studies will exclude participation in SIRS. 
Participation in non-therapeutic, non-oncologic investigational studies (i.e. pain control studies, 
nutritional studies, etc.) will be allowed amongst SIRS participants, provided there is no alteration of 
treatment planning, oncologic therapy, or surveillance, and additional studies comply with SIRS safety 
criteria and stopping rules as outlined in the SIRS protocol. 
3.2.5 
Advanced Stage III,IV (N2C, N3) or surgically unresectable disease or disease that cannot be fully 
resected, obvious radiologic ECS, supraclavicular or matted metastatic disease, >3 cervical nodes. (These 
patients will be placed on the Quarterback trial due to advanced state of disease and poor prognostic features)
3.2.6
p16 or HPV negative OPSCC as determined by IHC and PCR, respectively.
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations
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14
The inclusion and exclusion criteria do not affect enrollment of women, minorities, or other under-
represented populations.
4.0
REGISTRATION PROCEDURES 
After the patient signs the informed consent the patient will be registered for screening and once the 
investigator has verified that the patient meets all inclusion/exclusion criteria, the patient will be registered for 
and started on the protocol. Patients who lack p16 and HPV PCR may proceed to surgery however they will 
not be assigned to an experimental group and registered on the protocol until p16 IHC and HPV PCR are 
completed and positive. The verification of patient’s eligibility and screening completion will be performed 
centrally after the receipt of the patient primary post-surgical registration form.  It is mandatory not to exceed 
21 days between the date of registration for screening and the start of the study treatment (surgery).  In any 
case, all events occurring after the registration for therapy must be recorded in the case report form and will 
be taken into account in the analysis, whether the patient received the study treatment or not.  Patient must 
receive surgery and be p16 IHC and HPV PCR positive to be included in the intent to treat analysis. Patients 
found to not meet entry criteria will be offered best therapy.
4.1
General Guidelines
Clinicians will register eligible participants with the Clinical Trial Office. Registration must occur prior 
to the initiation of screening, again prior to therapy, and finally at completion of therapy for assignment. 
Any participant not registered to the protocol before treatment begins will be considered ineligible and 
registration will be denied. 
A member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist for final registration.
Following registration for therapy, participants will have surgery on study and following surgery re-
registration and assignment to treatment group. Issues that would cause treatment delays should be 
discussed with the Principal Investigator. If a participant does not receive protocol therapy and assignment 
treatment following registration, the participant’s protocol status must be changed to registered not treated. 
Notify the registrar of participant status changes as soon as possible. Patients who are eligible and do not 
receive study surgery will be analyzed in a separate cohort.
4.2
Registration Process 
The registration procedures are as follows:
1.
Obtain written informed consent from the participant prior to the performance of any study related
screening procedures or assessments and register consent and register the patient for screening.
2.
Complete the protocol-specific screening and eligibility checklist using the eligibility assessment
documented in the participant’s medical/research record. To be eligible for registration to the surgery
on study, the participant must meet each inclusion and exclusion criteria listed on the eligibility
checklist, however p16 and HPV PCR results need not be necessary.
3.
Patients will be re-registered for post-surgical adjuvant treatment assignment as per the protocol
design and will require final p16 IHC and HPV PCR for this. Pathologic criteria as outlined in the
protocol will determine the post-surgical adjuvant arm assignment.
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15
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for the treatment study. 
Registration to both treatment and ancillary studies will not be completed if eligibility requirements are 
not met for all studies.
5.0
TREATMENT PLAN 
Determination of Stage
Clinical stage will be based on clinical exam, and office based endoscopic evaluation with flexible endoscopy 
of the upper aerodigestive tract as well as radiographic evaluation with CT and/or MRI  in conjunction with  
CT/PET. Formal operative endoscopy with biopsy under general anesthesia will be performed as indicated 
when diagnostic or staging dilemma occurs. A preoperative tissue biopsy will be taken and used for 
histopathological analysis and assignment of p16 status and, if possible,  HPV status. All biopsies performed 
outside the institution will be internally reviewed by pathology department according to protocol guidelines 
and repeat biopsies will be obtained if there is inadequate tissue for analysis. All patients will be presented and 
reviewed at multidisciplinary tumor board. Final staging will be performed according to standard 8th Edition 
AJCC TNM criteria.
Surgical Intervention
Patients who meet inclusion criteria and are surgical candidates will be consented for primary 
surgical therapy. Surgery will include transoral robotic resection of the tumor with negative 
intraoperative frozen section margins. Selective neck dissection of levels II-IV will be performed 
routinely ipsilateral to the primary tonsillar tumors.  Bilateral selective neck dissection of levels II-
IV will be performed for all tongue base tumors. Additional levels (i.e. I,V) will be performed at the 
discretion of the operating surgeon if indicated on the size and location of the primary tumor.  
Appropriate reconstruction will be performed at the time of tumor resection as deemed necessary by 
the operating surgeon.
Pathological Evaluation/Criteria and Post-Operative Treatment Assignments
Group I: 

Complete resection (margins: tonsil >1mm, tongue >3mm, pT1-2, pN0-2B),

No LVI, no PNI, <3 positive nodes.

No ECS, No matted or Level >III,
Group I Protocol 
–
No adjuvant therapy
–
Clinical evaluations every 3-4 months the first year
PET or CT at 4 months, 12 months, 24 months. 36 months 48 54, and 60 months unless clinically indicated 
Group II 

Complete resection (margins: tonsil <1mm, tongue <1mm, pT1-2, pN0-2B),

+LVI, +PNI, <3 positive nodes, or ≤1mm ECS.
Group II Protocol

Postoperative XRT 5000 cGy
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16

Clinical evaluations every 3-4months during the first year 

PET or CT at 4 months, , 12 months,  24 months.  36 months  48 54, 60  unless clinically indicated. 
(Newer data suggests we can substitute quarterly cfDNA  after initial clear PET through year 2 
and then q 6 months through year 4 and then yearly through year 6. Physicians have the option 
to follow with cfDNA in all groups, but with imaging, as indicated).
Group IIIA

>3+ nodes (without ECS >1mm)

+Supraclavicular nodes (without ECS >1mm)

+Contralateral nodes (without ECS >1mm)
Group IIIA Protocol
–
CCRT with cisplatin and 5000 cGy

Monthly clinical evaluation first year, 
PET or CT at 4 months, 12 months, 24 months. 36 months 48 54, and 60 months unless clinically indicated.
Group IIIB

Incomplete surgical resection with +surgical margins

>1mm ECS or matted nodes

> 6 + nodes
Group IIIB Protocol
–
CCRT with cisplatin and 5600 cGy

Monthly clinical evaluation first year, 
PET or CT at 4 months, 12 months, 24 months. 36 months 48 54, and 60 months unless clinically indicated 
PATHOLOGY REVIEW CHECKLIST
1. Primary OPSCC, location
2. Histologic differentiation (H/E)
3. HPV + PCR
4. p16+
5. Margin status in mm
6. PNI
7. LVI
8. ECS < = > 1mm
9. Number of cervical metastatic nodes
10. Location of involved nodes (i.e., supraclavicular, ipsilateral vs. contralateral)
11. pAJCC staging
DELIVERY OF RADIATION (XRT)
All patients will receive daily radiation treatment with intensity-modulated radiotherapy (IMRT).  Treatment 
will be given 5 days per week and, as per standard practice, will not be delivered on Saturday, Sunday or major 
holidays.  Radiotherapy will be administered according to the guidelines below:
Technical Factors
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17
Photon beams of >4 MV are required.  Intensity Modulated Radiotherapy (IMRT) is required for all cases. 
IMRT via dynamically moving leaves, step-and-shoot with a multileaf collimator, Rapid Arc, binary multileaf 
collimator and tomotherapy are allowed.  Three-dimensional conformal radiotherapy (3D-CRT) and proton 
therapy are not allowed.
Immobilization, Simulation, and Localization
A thermoplastic head mask (or similar immobilization device) is required for IMRT.  Bite blocks, dental rolls 
and other set-up techniques may be used at the discretion of the treating radiation oncologist.  A treatment 
planning CT scan is mandatory for defining target volumes.  IV contrast is not required for the treatment 
planning CT.  CT scan thickness should be <0.3 cm.  The treatment planning CT scan should be acquired with 
the patient in the same position and using the same immobilization device as for treatment.  Volumes for all 
structures must be contoured on each relevant CT slice. 
Treatment Planning/Target Volumes
Gross Tumor Volume (GTV)
Since radiotherapy will be given postoperatively there should not be any gross disease and therefore no GTV.  
Clinical Target Volume (CTV) –  Group II and IIIA
The clinical target volume (CTV) is generated to account for microscopic disease.  CTV50 may include the 
primary tumor bed and/or lymph node regions in the neck at risk for harboring microscopic disease.  CTV50 
should not include bone or air.  There will be only one CTV (CTV50) for patients in  Group II and IIIA.
Clinical Target Volume (CTV) – Group IIIB
CTV56 is generated to account for areas at highest risk of harboring microscopic disease (positive margin or 
positive ECS >1mm).  If there is a positive margin, CTV56 should encompass the primary tumor bed.  If there 
is extracapsular spread >1mm, CTV56 should encompass the operative bed of the lymph node that was found 
to have ECS.  Group IIIB will have a second CTV, called CTV50.4.  CTV50.4 is generated to account for 
areas at lower risk for harboring microscopic disease than CTV56.  CTV50.4 may include the primary tumor 
bed (if negative margin) and/or lymph node regions (if no ECS) in the neck.  CTV56 and CTV50.4 should not 
include bone or air.  There are 2 CTVs for the Group IIIB(CTV56 and CTV50) which will be treated with a 
simultaneous integrated boost (SIB) technique.
Planning Target Volume (PTV)
PTV incorporates a margin that accounts for daily set up variation. The PTV should be a 0.5 cm expansion of 
all CTVs. Modification of PTV is allowed at the discretion of the treating radiation oncologist for sparing of 
normal tissues, or if it is needed to facilitate the planning process, e.g. if the PTV overlaps a critical structure 
that must be spared. Each CTV will have an individual PTV designed for set-up uncertainty. 
Avoidance Structures
The following normal tissue structures will be defined.  The dose constraints are listed for each structure.
A. Spinal cord: Maximum dose <45 Gy
B. Expanded spinal cord (5 mm expansion around spinal cord): Maximum dose <50 Gy
C. Brainstem: Maximum dose <54 Gy
D. Parotid glands: Mean dose <26 Gy. If this is not possible due to adjacent disease, then the volume of
one parotid gland receiving 30 Gy or more (V30) should be <50%.
E. Larynx: Mean dose <45 Gy
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18
F.
Mandible:  Maximum dose <70 Gy
G. Oral cavity: Mean dose <45 Gy
For cases in which treatment volumes approach the base of skull, the following avoidance structures will be 
added:
A. Inner ear: Mean dose <50 Gy
B. Optic nerves: Maximum dose <50 Gy
C. Optic chiasm: Maximum dose <50 Gy
D. Expanded optic nerve and chiasm (2 mm expansion around these structures): Maximum dose <54 Gy
E. Retina: Maximum dose <45 Gy
F.
Brain: Maximum dose <60 Gy
Target Dose Prescriptions
To accommodate for tissue heterogeneity, density corrections are required, and will be applied to all plans, 
unless contraindicated, for example, by significant amounts of scatter on the planning CT scan.    
Group II and Group IIIA

PTV50 will be treated to a total dose of 50 Gy in 2.0 Gy/fraction.
Group IIIB

PTV56 will be treated to a total dose of 56 Gy in 2.0 Gy/fraction.

PTV50.4 will be treated to a total dose of 50.4 in 1.8 Gy/fraction.

PTV56 and PTV50.4 will be treated via simultaneous integrated boost (SIB) technique.
PTV Coverage 
All plans must be normalized such that 95% of the PTV is covered with the prescription dose.  No more than 
20% of the PTV may receive > 110 % of the prescription dose.  No more than 1% of the PTV may receive < 
93% of the prescription dose.  No more than 1cc of tissue outside the PTV may receive > 110% of the 
prescription dose. 
Note: in any case with a conflict/overlap between target and normal tissue, target dose considerations will take 
priority, with the exception of the spinal cord limits.
Treatment Breaks
There are no planned treatment breaks on this study; any breaks in planned radiotherapy are strongly 
discouraged. Radiotherapy interruptions will be permitted for unavoidable mechanical malfunction or serious 
illness requiring hospitalization, such as sepsis, delirium, severe respiratory compromise or hemodynamic 
instability, at the discretion of the Principal Investigator. Treatment breaks should be as short as possible. The 
reason for any interruption in treatment must be documented in the treatment chart.
Quality Assurance
Initial:  Prior to the first radiation treatment, the standard quality assurance procedures will be followed. The 
monitor units required to deliver the prescribed dose shall be calculated. The monitor units generated by the 
IMRT planning system must be independently checked prior to the patient’s first treatment.  Measurements in 
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19
a quality assurance phantom will be done for each patient that will be treated. An ion chamber measurement, 
to assess absolute dose, in addition to a film or matrix measurement will be taken during the QA period.  
On the first day of treatment each patient will have electronic portal images taken that localize the isocenter 
placement, which will be approved by a radiation oncologist prior to delivery of the first treatment, per standard 
practice.
Weekly:  Verification portal images will be taken at least once per week and approved by a radiation oncologist 
prior to continuation of treatment per standard practice.
Isodose Distribution 
All plans will have complete documentation in the patient’s chart, including representative CT slices with 
treatment isodoses. A DVH with all PTV and CTV structures and all normal tissue structures will be generated 
for each patient and documented in the patient’s radiotherapy chart.
Quality Assurance:
Each treatment plan will be reviewed by at least one non-treating radiation oncologist prior to therapy to assure 
that the appropriate fields and doses will be delivered.  
Chemoradiotherapy Treatment Plan
5.1
Chemoradiotherapy 
Chemoradiotherapy Agent Administration
Cisplatin
Dose:
   40mg/m2/week
Route:
IV over approximately 30 minutes, mixed in 250ml normal saline
Schedule:
Weekly on Monday or Tuesday any time, or Wednesday prior to radiation
Prehydration:
Prehydration IV fluids are required, KCl and Magnesium sulfate will be administered 
as well as antiemetic regimen to include a 5HT3 antagonist prior to cisplatin administration.
All patients assigned to Group IIIA and Group IIIB will receive daily radiation treatment with intensity-
modulated radiotherapy (IMRT).  Treatment will be given 5 days per week and, as per standard practice, will 
not be delivered on Saturday, Sunday or major holidays.  Radiotherapy will be administered according to the 
guidelines above.
5.2
Salvage Protocol
In the event of suspected disease recurrence in the surveillance group (Group I), appropriate imaging including 
PET/CT scan and biopsies will be performed. Biopsies will be evaluated for HPV16 and p16 expression and 
Effective Date: 2/14/2022
End Date:2/7/2023

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 0
st ore d f or f urt her a nal ysis. If t here is s olel y a l ocal re gi o nal rec urre nce,   S ur gical sal va ge will be offere d t o 
patie nts w h o ha ve resecta ble li mite d disease defi ne d as rec urre nt disease at t he pri mar y site or le vel 2 or 3 
l y m p h n o des a n d < 3 p ositi ve n o des o n sca n, f oll o we d b y p ost- o perati ve C R T as a b o ve f or gr o u p 3 patie nts. 
F or patie nts wit h li mite d rec urre nce dee me d u nresecta ble f or reas o ns of or ga n preser vati o n or a bilit y t o 
reas o na bl y e x pect a c o m plete s ur gical resecti o n, defi niti ve C R T wit h a t otal d ose of 6 6 0 0- 7 2 0 0 c g y a n d 
cis plati n as a b o ve will be perf or me d.
F or patie nts wit h e xte nsi ve l ocal re gi o nal disease defi ne d as i nfiltrati ve, > 2 p ositi ve n o des, n o dal i n v ol ve me nt 
of le vels 4, 5 or N 2c disease or t h ose wit h  metastatic disease, T P F c he m ot hera p y will be gi ve n After 
c o m pleti o n of 3 c ycles of T P F, sites of i nitial disease will be treate d wit h car b o plati n t o 5 6 0 0 c G y as defi ne d 
i n t he Q uarter bac k trial.  T P F will be gi ve n e ve n if t he metastases ha ve bee n c o m pletel y resecte d p ost T P F.  
C R T will be deli vere d t o sites a n d waters he d areas of metastatic disease t hat has bee n resecte d or is 
u nresecta ble a n d t here was n o L R rec urre nce. F or m ulti ple metastases T P F a n d C R T ma y be wit h hel d if i n t he 
o pi ni o n of t he cli nicia n t he D M are t o o n u mer o us a n d desi mi nate d t o be safel y or effecti vel y treate d. 
Patie nts i n Gr o u p II or Gr o u p III w h o fail wit h L R disease will be treate d wit h best a vaila ble t hera p y.
If a s pecific a n d hi g hl y effecti ve t hera p y is i de ntifie d d uri n g t he c o n d uct of t he st u d y t hat is a n i m pr o ve me nt 
o ver treat me nt wit h T P F a n d C R T as sal va ge, t hat t hera p y ma y be offere d t o t he patie nts as a sta n dar d 
treat me nt, a n d will be a d de d as a n a me n d me nt i n d ue c o urse.
6. 0 S T U D Y P A R TI CI P A TI O N
6. 1  
D ur ati o n of F oll o w U p 
P arti ci p a nts will b e f oll o w e d f or 5 y e ars aft er c o m pl eti o n of st u d y tr e at m e nt or u ntil d e at h, w hic he ver 
occ urs first t hr o u g h sta n dar d of care treat me nt after t hera p y as prescri be d b y t he I n vesti gat or w hic h ca n 
i ncl u de cli nic visits or ot her f oll o w- u p b y ot her mea ns.  Partici pa nts re m o ve d fr o m st u d y f or u nacce pta ble 
a d verse e ve nts will als o be f oll o we d u ntil res ol uti o n or sta bilizati o n of t he a d verse e ve nt.
6. 2  
Criteri a f or Re m o v al fr o m St u d y 
Partici pa nts will be re m o ve d fr o m st u d y w he n a n y of t he criteria liste d bel o w a p plies. T he reas o n f or st u d y 
re m o val a n d t he date t he partici pa nt was re m o ve d m ust be d oc u me nte d i n t he st u d y-s pecific case re p ort f or m 
( C R F). Alter nati ve care o pti o ns will be disc usse d wit h t he partici pa nt.
I n t h e e v e nt of u n us u al or lif e-t hr e at e ni n g c o m pli c ati o ns, p arti ci p ati n g i n v esti g at ors m ust i m m e di at el y 
n otif y t h e Pri n ci p al I n v esti g at or, R a y m o n d C a hi, M D at 2 1 2- 8 4 4- 8 5 6 0
Patie nt is re m o ve d earl y fr o m pr ot oc ol t hera p y at PI’s discreti o n
Patie nt is f o u n d i neli gi ble
Patie nt c o m pleti o n of pr ot oc ol re q uire me nts
U nacce pta ble t o xicit y
Pre g na nc y
A d verse E ve nt
Pr o gressi ve disease/ rela pse
L ost t o f oll o w- u p ( d oc u me nte d 3 atte m pts via tele p h o ne or si g nat ure c o nfir mati o n letter)
Eff e cti v e D at e: 2/ 1 4/ 2 0 2 2
E n d D at e: 2/ 7/ 2 0 2 3

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 1
N o n- C o m plia nce wit h t hera p y a n d pr ot oc ol pr oce d ures
Deat h
Ot her
7. 0 
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S 
7. 1  
A ntici p ate d T o xicities
A list of t he a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h t he a ge nts a d mi nistere d i n t his st u d y a p pear 
bel o w a n d will deter mi ne w het her d ose dela ys a n d m o dificati o ns will be ma de or w het her t he e ve nt re q uires 
e x pe dite d re p orti n g i n a d diti o n t o r o uti ne re p orti n g.
7. 1. 1  
A d verse E ve nt List(s) f or Cis plati n
T he maj or d ose li miti n g t o xicities o bser ve d wit h Cis plati n si n gle a ge nt are na usea a n d v o miti n g, 
peri p heral ne ur o pat h y, ne p hr ot o xicit y a n d ot ot o xicit y.
7. 1. 2
A d verse E ve nt List(s) f or Car b o plati n
T he maj or d ose li miti n g t o xicities o bser ve d wit h Car b o plati n si n gle a ge nt are m yel os u p pressi o n a n d re nal 
t o xicit y.
7. 2  
D ose M o dific ati o ns/ Del a ys
7. 2. 1  Cis plati n
Peri p heral Ne ur o pat h y

A ne ur ol o gical e xa mi nati o n m ust be perf or me d at least bef ore e ntr y i nt o t he st u d y a n d t he n
S h o ul d be d o ne at t he e n d or C R T f or c he m o R T gr o u ps a m n d t he n at 3 m o nt h f oll o w
u p . I n case of s y m pt o ms or si g ns e x perie nce d b y t he patie nt, m ore fre q ue nt e xa mi nati o ns
s h o ul d be perf or me d a n d d ose m o dificati o n will be as f oll o ws:

Gra de 0, 1:  N o c ha n ge

Gra de > 2: Car b o plati n at a n A U C of 2 ma y be s u bstit ute d f or Cis plati n
Ot ot o xicit y

Cis plati n is k n o w n t o ca use hi g h fre q ue nc y heari n g l oss.  If gra de 1 or 2 heari n g l oss occ urs, t he
ris k of a d diti o nal heari n g l oss vers us t he p ote ntial be nefit of c o nti n ui n g Cis plati n c he m ot hera p y
s h o ul d be ma de.  Gra de 3 a n d 4 heari n g l oss is a n i n dicati o n t o disc o nti n ue t he dr u g h o we ver t his
decisi o n ca n be ma de wit h t he patie nt a n d after f or mal heari n g tests.

A u di o meric testi n g will be perf or me d at baseli ne a n d pri or t o eac h d ose
Eff e cti v e D at e: 2/ 1 4/ 2 0 2 2
E n d D at e: 2/ 7/ 2 0 2 3

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
In case of grade 3 or 4 toxicity, Carboplatin (at dosage of AUC 2) may be used to replace Cisplatin
in the remaining chemo cycles. The dose of Carboplatin AUC 2 will be calculated based on the
Calvert formula.
Thrombocytopenia

Pre-treatment hematologic parameters prior to administration of chemotherapy will include
an ANC greater than or equal to 1.5 x 10^9/L, platelet greater than or equal to 100,000mm3
Dose Modification for Thrombocytopenia
Dose of Cisplatin
Platelets (day 1 of each cycle)
Nadir of last course
< 100,000
<100,000
>100,000
> 50,000
Hold
Cisplatin = 100%
< 50,000 (1st occurrence)
Hold
Cisplatin = 80%
<50,000 (2nd occurrence)
Hold
Cisplatin = 60%
** Please note that dose reduction percentage is calculated by taking off from the original 
dose and not the previous dose.
Dose Modification of Cisplatin in Kidney Impairment
Calculated Creatinine
Clearance (mL/min)
Percent Dose to Give
 60
100%
< 60
0% (withhold treatment for a maximum of 2 weeks and repeat serum 
creatinine weekly after additional hydration), then
If CCl was < 60 mL/min and is now: 
** The percent dose to give 
is: 
> 50 but < 60
80%
 40 but  50
50%
< 40
0%
**Please note that dose reduction percentage is calculated by taking off from the original 
dose and not the previous dose.
If creatinine clearance recovers, the dose of Cisplatin for the following cycle should be re-
escalated to the previous dose level. 
Formula to calculate Creatinine Clearance:
CrCl (mL/min) =     (140-age) (weight kg)_____
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72 x serum creatinine (mg/dL)
N.B. For females, use 85% of calculated CrCl value. 
Ototoxicity, Nausea and Vomiting
Cisplatin is the preferred therapy for TPF and chemoradiotherapy, Carboplatin may be 
substituted for Cisplatin if a patient develops grade 3 ototoxicity, or an unacceptable Cisplatin 
associated nausea and vomiting, after receiving 1 or 2 doses of Cisplatin.
Dose alteration for toxicity is to be based on single worst toxicity. Once Carboplatin dose is 
reduced, there will be no re-escalation.
Neurotoxicity

In the event of neurotoxicity (> grade 3), Carboplatin therapy is discontinued.
Nephrotoxicity
If, despite adequate rehydration, serum creatinine increases to Formula to calculate Creatinine 
Clearance:
CrCl (mL/min) =      (140-age) (weight kg)_____
72 x serum creatinine (mg/dL)
N.B. for females, use 85% of calculated CrCl value. 

Grade 0, 1:  No change

Grade > 2: Carboplatin at an AUC of 2.0 may be substituted for  Cisplatin
7.2.2   Carboplatin (AUC 2.0)
The carboplatin dose for weekly concurrent chemoradiotherapy is an AUC of 2.0.  Thereafter, the AUC will 
be changed only in case of hematological toxicity. 
See the tables below for approach to myelosuppression.
Table: Carboplatin dose modification based on ANC
ANC
(x109/L) within 24 hrs. 
of therapy
Action to be taken
 1.5
Treat at current dose
 1.0, < 1.5
Treat at AUC of 1.5
< 1.0
Hold treatment, and resume therapy at AUC of 1.5 at the next weekly 
therapy planned when ANC  1.0. If neutropenia requiring further 
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chemotherapy break occurs, carboplatin will be discontinued for the 
remainder of the therapy. 
**For febrile neutropenia, instructions for ANC <1.0 will be followed.  In addition, 
prophylactic antibiotics and growth factor support may be administered as clinically 
indicated.
Table: Carboplatin dose modification based on platelet count
Platelet count within 24 hrs. of 
therapy
Action to be taken
> 100,000
Treat at current dose
< 100,000
Hold treatment, and resume therapy at AUC of 1.0 at the 
next weekly therapy planned when platelets  100,000. 
If thrombocytopenia requiring further chemotherapy 
break occurs, carboplatin will be discontinued for the 
remainder of the therapy. 

Renal toxicity: Serum creatinine will be measured weekly within 24 hours of carboplatin
dosing.  If the serum creatinine has not changed more than 25% relative to the serum
creatinine at baseline, the creatinine clearance and carboplatin dose need not to be
recalculated.  If there is a rise or fall greater than 25% relative to baseline serum creatinine
values, then the creatinine clearance and carboplatin dose must be recalculated.
8.0 DRUG FORMULATION AND ADMINISTRATION 
Drug formulation and administration are in accordance with commercially available product guidelines 
for all agents listed in Section 5.0. 
9.0 CORRELATIVE/SPECIAL STUDIES 
9.1
Probable Laboratory Correlative Studies
This clinical trial aims to investigate a reduction in radiation intensity in patients with HPVOC. The goals of 
these exploratory translational studies are to understand the tumor biology, immunology, and epidemiology; 
and to develop predictive biomarkers to be examined in a larger prospectively randomized trial.
The following projects will be carried out with specimens from study participants: 
1.
Tumor tissue will be evaluated for the following markers (this is a preliminary list which
may change and expand as new technology and biomarkers become available: HPV copy
number, c-Met expression, BCL-x, EGFr copy number, EGFr expression and EGFr
phosphorylation.
2.
CTC assessment: The number of circulating tumor cells will be evaluated as a possible
prognostic indicator.
3.
Cytokine profiling of the patients plasma will be assessed with baseline samples obtained
prior to therapy.
4.
Circulating immune cells will be assessed including MDSC, T regulatory and T cell subsets.
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5.
The immunologic function and specificity of patient’s T lymphocyte responses to HPV
epitopes will be studied and targeted epitopes identified.
6.
Serologic responses to HPV proteins will be investigated in patients over time in response
to therapy.
7.
Tissue microarrays and IHC will be used to establish differences between primary tumors
with and without distant spread.
9.2
Specific Study Plans
The following studies are given a brief description as technology will change and samples will not be 
accessed until the study is complete. 
1)
T Cell specificity and Function in HPV Oropharynx Cancer
It is possible that preserved or improved immune responses in HPVOC patients may protect 
against distant metastases, second primaries or recurrence or may mediate some portion of 
the responsiveness. We have identified immunogenic HLA-A2-restricted peptides derived 
from HPV16E6 and E7 (Reimer, Anderson, and Reinherz, unpublished data). Here, we will 
evaluate pre and post therapy T cell function towards HPV peptides by ELISPOT in vitro 
and correlate responses with stage, clinical response and tumor control. We hypothesize 
that cured patients will have a more robust response after therapy has completed and we 
may identify preferred peptide epitopes associated with improved survival and/or response.
2)
Serologic assessments
We have developed a novel multiplex antibody assay using the Luminex system that allows 
us to establish the titers of complex and seemingly heterogeneous antibody responses to 
the full genome of HPV16. Using this system we will monitor the antibody response of the 
HPVOC prior to, and 6 months after therapy has completed  and then at 12 months and 
then at 24 Months and 36 months to determine if response can predict tumor control, and 
can establish patterns that might be useful in predicting the development of cancers.
3)
Tissue microarrays
There will be distinct differences between primary tumors and metastatic, nodal and 
persistent disease in patients. We will use TMA to evaluate biomarkers and tumor 
differences that can be used to predict metastatic behavior and response. While tumor 
control is frequently a process related to tumor volume, those cells that can metastasize 
may have a distinct signature that can point to a pathway that can be exploited for better 
anti-tumor therapy, could be identified in small numbers of tumor cells, might be present 
in CTC, etc. This is exploratory study data set.
9.3
Blood and Tissue Collection and Preparation 
Blood will be collected to measure plasma and serum factors such as antibodies, cytokines, DNA, etc. 
and cells for immune studies and germ line DNA. The target amount to be collected from each subject 
will be less than 200 mls of whole blood (46ml at baseline, 3 month (or pre-XRT) and 24 months; 16 
ml at  6, 12, and 36 months).  Blood will be collected in 1x 6ml red top tube and 4 x 10ml green top 
tubes at baseline, 3 month (or pre-XRT) and at the 24 month visit. Only 1 red top tube and one green 
top tube will be collected at the 6 month, 12 month, and 36 month visits.   Processing and labeling of 
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the blood will be done according to the “Blood Handling” section outlined below.  Lag time between 
collection and the start of processing will be within 5 hours and this time will be recorded for each 
sample.  Components will be stored from these tubes including serum, plasma and buffy coat.  If 
collected and handled properly, each of the tubes should yield approximately 3mls of serum.  Serum 
will be maintained as 1ml aliquots and frozen and stored at –80C and buffy coat will be stored from 
green tubes, at local institutional temperature guidelines.  A portion of each of these samples will be 
stored at the biospecimen repository, and a portion maintained at this facility, until exhausted.  Samples 
will be labeled a code linked to the patient case report form. All patients will have tumor testing for 
HPV and p16 in a central laboratory as part of their screening. Slides and microarrays from tumor 
tissues will be labeled similarly as blood samples above. 
Blood Handling
Blood collection will be performed before surgery (if necessary) and in the absence of any systemic 
anesthesia.
Samples (6 ml of blood/tube) will be obtained at each visit as noted, according to the table below for 
Group 1.Times refer to post-surgery collection. For Group 2 and 3 there will be a pre-radiation 
sample in place of the 3 month post-surgery collection. 
Pre-Surgery
Post-Surgery
Baseline
3 ± 1Month
Or preXRT1
6 ±1 
Month
12 ±1 
Month
24 ± 2 
Month
36 ± 2 
Month
V1
V2
V3
V4
V5
V6
Serum (red tops)
X
X
X
X
X
X
WBC (green tops)
xxxx
xxxx
X
X
xxxx
X
1 pre-XRT for Groups 2 and 3
Viable lymphocytes will be processed from green top tubes using standard ficoll-hypaque density 
gradient separation.  Buffy coat layers will be stored as viable cells in DMSO-containing media at 
-80C to -170C.
Blood for serum will be spun within 5 hours of collection.  Blood tubes will be spun at 3000 x g for 
10’ at 4C and the serum removed by pipetting.  Serum will be stored in 1ml aliquots.  All samples 
will be stored at -80C.  White blood cell fraction will be stored in a single tube at local institutional 
temperature guidelines and kept locally. 
Tissue Collection
All patients will have their tumors tested for HPV and p16 in the central laboratory at at Icahn School 
of Medicine at Mount Sinai per current standard protocol. Paraffin embedded and formalin fixed 
blocks from the original and subsequent biopsy specimens will be sent to the laboratory and will be 
cut in his laboratory for PCR testing and IHC. The primary untreated tumor will be tested for HPV 
and p16 prior to the start of radiotherapy or concurrent chemoradiotherapy. 
Additional slides, from 5-20, and tissue microarrays will be cut from the blocks and stored in the 
Mount Sinai Biorepository before they are returned to the site. Any additional biopsies from the 
primary tumor or a recurrence will be obtained and handled in the same fashion.
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Specimen Management Committee
A Specimen Management team will decide priority and allocation of samples not included in the 
original plan. The team will consist of the Overall study PI, and the Site PIs and Chairmen of the 
Pathology, Radiation Oncology, ENT, and Medical Oncology for the study and for the teams at each 
site.. Proposals will be reviewed and upon a majority agreement, samples will be allocated for each 
study. A quorum for decisions would include at least one member from each site and one of the study 
chairmen of Radiation Oncology, Otolaryngology, Pathology, and Medical Oncology. 
10.0
STUDY CALENDAR (History, Exam and Lab)
1 Ht, Wt, Performance status, neurologic examination, vital signs (heart/blood pressure/temperature). Height is only 
collected at baseline/pre-study.
Pre-Study5
Post Surgery Surveillance
Follow up
During 
Chemo/RT, groups 
2,3
Post CRT 
Follow up 
(+ 1 month)
Informed Consent
To be obtained before 
enrollment
Medical History
Within 10 days before 
registration
 Every Visit
Per SOC at all 
clinical visits
Every Visit
Smoking History
Within 10 days before 
registration
Concurrent meds4
At Screening
Every Visit
Weekly
Physical Exam1
Within 10 days before 
registration
Every Visit
Per SOC at all 
clinical visits
 CBC/BMP
Within 10 days before 
registration
Preop and post-op and then 
no requirement for Groups I 
and II and per SOC for Group 
IIIA and IIIB
Preop and post-op 
and then no 
requirement for 
Groups I and II and 
per SOC for Group 
IIIA and IIIB
Dysphagia 
Assessment 
Questionnaire
Within 10 days before 
registration
12, 24, 36 months 
(+ 1 month)
Weekly
 12, 24, 36 
months
Adverse Event 
evaluation4
Weekly
Each visit
B-HC (for WOCP)
Within 7 days before 
registration
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28
Tumor Assessment
Pre-Study
Surgery
Pathological
Evaluation
ChemoRT (if 
reassigned)
Reassessment 
(Week 8-10)
Surveillance
(+ 1 month)
Physical tumor 
Examination
Patients get 
an exam as 
part of their 
routine visits, 
same for 
TNM and will 
be done when 
the patient is 
seen and 
before they 
are consented
Intraoperative
Path Check List
X
TNM Staging 
patients get 
an exam as 
part of their 
routine visits, 
same for 
TNM and will 
be done when 
the patient is 
seen and 
before they 
are consented 
Path Check List
Nasopharyngosco
py
X
Examination 
under anesthesia 
(EUA)
Within 8 
weeks before 
registration if 
possible. 
(Does not 
need to be 
repeated if 
time period 
exceeds 8 
weeks)
May be done if 
investigator 
deems it 
necessary
PET/CT  and/or 
high resolution 
CT or MRI of the 
neck (base of 
skull clavicles)
Within 28 
days before 
registration
PET/CT or CT with 
contrast and 
examination 
At 12-16 weeks
PET/CT or CT 
with contrast 
and 
examination
Refer to Section 
5.0 “Treatment 
Plan” for the 
frequency in 
each group
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CORRELATIVE STUDIES CALENDAR (See Section 16.0 for QOL)
Pre-Study
Post-Study 
Follow-up
(+ 1 month)
Tissue Microarray
X
CTC’s  (cell Save 
tube)
X
T Cell Specificity 
and Function
X
12,and  24 
months
Serologic 
Assessments
X
6, 12, 24 and 36 
months
Effective Date: 2/14/2022
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11.0      MEASUREMENT OF EFFECT
11.1.1
Definitions
Evaluable for toxicity. All participants who go on to surgery will be evaluable for toxicity from the time 
of their first treatment. Patients who are screened will be evaluated and the reason for screen failure will 
be recorded
Evaluable for Primary Outcome: Only patients who are entered and have surgery  will be eligible for 
assessment of the  primary outcomes (LRC, PFS). All patients who have had surgery will be analyzed on 
an ITT for LRC,  PFS,  and survival.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the duration of time from start of 
treatment to time of objective disease progression or death. 
Local Regional Control (LRC) will be defined as local and regional control of disease, censored for death. 
Overall Survival (OAS) will be defined as alive at the time of analysis, this will be analyzed as for the entire 
trial, for all randomized patients  and only for those patients randomized who received one dose of 
radiotherapy. 
Post Recurrence LRC: Surveillance Patients who recur will be assessed for LRC post treatment for their initial 
recurrence
Post Recurrence PFS Surveillance Patients who recur will be assessed for PFS post treatment for their initial 
recurrence
Ultimate Disease Control will be defined as those patients who are alive and disease free at the time of analysis
12.0
ASSESSMENT OF QUALITY OF LIFE AND PATIENT REPORTED SYMPTOMS
Head and neck cancer often arises in cosmetically or functionally important areas. Thus, the ability to eat, 
speak, breathe easily, as well as the patient’s overall sense of comfort is frequently affected by therapy. In 
addition to these disease-specific symptoms, patients with head and neck cancer may also experience 
symptoms related to surgery (e.g. disfigurement) or to radiation therapy (e.g., dysphagia, xerostomia, and 
mucositis). These may lead to feeling of general overall sickness and can potentially result in social isolation. 
Patient-reported symptoms tend to be more severe than those recorded by physicians, patient reported outcome 
instruments are increasingly being used to measure symptom burden, functionality and quality of life. It can 
provide more comprehensive and improved toxicity data. Quality of life (QOL) assessment is a multi-
dimensional construct that involves an individual’s subjective assessment of the impact of an illness or 
treatment on his/her physical, psychological, social, and somatic functioning and general well-being. The 
European Organization for Research and Treatment of Cancer Core measure (EORTC QLQ-C30) is a well 
validated cancer-specific QOL scale that is used as a generic measurement for patients with cancer that in head 
and neck patients is used in conjunction with the site specific measurement tool EORTC QLQ H&N35. The 
M.D. Anderson Symptom Inventory-Head and Neck (MDASI-HN) module is a validated instrument that
provides a brief measure of the symptom distress experienced by the head and neck cancer patients as a result
of their disease and/or treatment. This symptom burden instrument was closely associated with the severity of
radiation-induced mucositis. The MDA Xerostomia and Dysphagia questionnaires are radiotherapy/head and
neck cancer directed questions which have a robust, validated assessment the specific concerns of swallowing
and salivary function in head and neck cancer treated patients.
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In this study, patients will complete the EORTC QLQ-C30, EORTC QLQ H&N35, MDASI-HN, the MDADI-
HN (dysphagia) and xerostomia questionnaires prior to therapy and then at  3, 6,  12 and every 12  months 
after therapy for 5 years for all patients. During the concomitant chemo-radiation phase of treatment, in order 
to avoid patient fatigue, the EORTC QLQ-C30, EORTC QLQ H&N35, MDASI-HN module, MDADI-HN 
(dysphagia) and xerostomia questionnaires will be completed on pre and weeks 5, 7 and post rx 3 months; and 
the . The adverse events assessments, the (see table). As shown in the statistical plan we will use these 
assessments in conjunction with adverse events assessments to compare the experiment and control arms of 
this study.
13.0   ADVERSE EVENT REPORTING REQUIREMENTS
13.1 Definitions
13.1.1 Adverse Event (AE)
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that develops or 
worsens in severity after starting the first dose of study treatment or any procedure specified in the protocol, 
even if the event is not considered to be related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests. 
13.1.2 Serious Adverse Event (SAE)
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that: 

Results in death.
Pre-Study
CRT
Post-Study 
Follow-up
Informed Consent
To be obtained 
before enrollment
EORTC QLQ-
C30, EORTC 
QLQ H&N35
Within 10 days 
before 
registration
pre and weeks 5 
7 and post rx 3 
months
3, 6, 12, and 
every 12 
months for 5 
years
MDASI-HN
Within 10 days 
before 
registration
 pre and weeks 
5 7 and post rx 
3 months
3, 6, 12, and 
every 12 
months for 5 
years
MDADI-HN 
(Dysphagia 
Assessment 
Questionnaire)
Within 10 days 
before 
registration
pre and weeks 
5 7 and post rx 
3 months
3, 6, 12, and 
every 12 
months for 5 
years
Xerostomia
 pre and weeks 
5 7 and post rx 
3 months
3, 6, 12, and 
every 12 
months for 5 
years
Effective Date: 2/14/2022
End Date:2/7/2023

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
Is life-threatening. Life-threatening means that the person was at immediate risk of death from the reaction
as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it
occurred in a more severe form.

Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour hospitalization or
prolonged a hospitalization beyond the expected length of stay). Hospitalization admissions and/or
surgical operations scheduled to occur during the study period, but planned prior to study entry are not
considered SAEs if the illness or disease existed before the person was enrolled in the trial, provided that
it did not deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than
planned).

Results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of
a person’s ability to conduct normal life functions.

Is a congenital anomaly or birth defect; or

Is an important medical event when, based upon appropriate medical judgment, it may jeopardize the
participant and require medical or surgical intervention to prevent one of the outcomes listed above.
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.
Events not considered to be serious adverse events are hospitalizations for:

Routine treatment or monitoring of the studied indication, not associated with any deterioration in
condition, or for elective procedures.

Elective or pre-planned treatment for a pre-existing condition that did not worsen.

Emergency outpatient treatment for an event not fulfilling the serious criteria outlined above and not
resulting in inpatient admission.

Respite care.
13.1.3 Expectedness
Adverse events can be 'Expected' or 'Unexpected.' 
13.1.3.1Expected adverse event
Expected adverse events are those that have been previously identified as resulting from administration of the 
agent. For the purposes of this study, an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is included in the informed consent 
document as a potential risk.  
Refer to Section 6.1 for a listing of expected adverse events associated with the study agent(s).
13.1.3.2 Unexpected adverse event
For the purposes of this study, an adverse event is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current adverse event list, the Investigator’s Brochure, the package 
insert or when it is not included in the informed consent document as a potential risk.  
13.1.4.Attribution
Attribution is the relationship between an adverse event or serious adverse event and the study treatment. 
Attribution will be assigned as follows:
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
Definite   – The AE is clearly related to the study treatment.

Probable  – The AE is likely related to the study treatment.

Possible   – The AE may be related to the study treatment.

Unlikely  – The AE is doubtfully related to the study treatment.

Unrelated –The AE is clearly NOT related to the study treatment.
13.2 Procedures for AE and SAE Recording and Reporting
Reporting: Participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation 
time points during the study. 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly observed, or 
detected by physical examination, laboratory test or other means, will be recorded in the participant’s medical 
record and on the appropriate study-specific case report forms. 
The descriptions and grading scales found in the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. The CTEP Active Version of the 
CTCAE is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
All appropriate treatment areas should have access to a copy of the CTEP Active Version of CTCAE.
13.3 Reporting Requirements
Each participating investigator is required to abide by the reporting requirements set by the MSSM. The study 
must be conducted in compliance with FDA regulations, local safety reporting requirements, and reporting 
requirements of the principal investigator. 
Each investigator will be responsible to report SAEs that occur at that institution to their respective IRB. It is 
the responsibility of each participating investigator to report serious adverse events to the study sponsor and/or 
others as described below. 
13.4 Reporting to the Study Center
13.4.1 Serious Adverse Event Reporting
All serious adverse events that occur after the initial dose of study treatment, during treatment, or within 30 
days of the last dose of treatment must be reported to the MSSM Overall Principal Investigator on the local 
institutional SAE form for the local IRB and electronically on the eRAP CRF. This includes events meeting 
the criteria outlined in Section 11.1.2, as well as the following:

Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at least possibly related/associated
with the intervention.

All Grade 4 (life-threatening or disabling) events that are unexpected or not specifically listed in the
protocol as not requiring reporting.
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
All Grade 5 (fatal) events while the participant is enrolled and actively participating in the trial OR when
the event occurs within 30 days of the last study intervention.
Note: If the participant is in long term follow up, report the death at the time of continuing review.
Participating investigators must report each serious adverse event to the MSSM Overall Principal Investigator 
within 24 hours of learning of the occurrence by Fax and email. In the event that the participating investigator 
does not become aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), 
the participating investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the adverse event. Report serious adverse events by telephone, email or facsimile 
to:
Raymond Chai at  Ph- 212-844-8560
Raymond.Chai@mountsinai.org
Within the following 24-48 hours, the participating investigator must provide follow-up information on the 
serious adverse event. Follow-up information should describe whether the event has resolved or continues, if 
and how the event was treated, and whether the participant will continue or discontinue study participation.
13.4.2 Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the MSSM Overall Principal Investigator on the toxicity Case 
Report Forms.  
13.5  Reporting to the Institutional Review Board (IRB)
Investigative sites within MSSM will report all serious adverse events directly to the MSSM Office for Human 
Research Studies 
Other investigative sites should report serious adverse events to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted institutional SAE form 
should be forwarded to:
Raymond Chai at  Ph- 212-844-8560
Raymond.Chai@mountsinai.org
The MSSM Principal Investigator will submit SAE reports from outside institutions to the MSSM Office for 
Human Research Studies according to MSSM IRB policies and procedures in reporting adverse events. 
13.6 Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any subject safety reports or 
sentinel events that require reporting according to institutional policy.
13.7 Monitoring of Adverse Events and Period of Observation
All adverse events, both serious and non-serious, and deaths that are encountered from initiation of study 
intervention, throughout the study, and within 30 days of the last study intervention should be followed to their 
resolution, or until the participating investigator assesses them as stable, or the participating investigator 
determines the event to be irreversible, or the participant is lost to follow-up. The presence and resolution of 
AEs and SAEs (with dates) should be documented on the appropriate case report form and recorded in the 
participant’s medical record to facilitate source data verification. 
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For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring visit to 
obtain additional case details deemed necessary to appropriately evaluate the SAE report (e.g., hospital 
discharge summary, consultant report, or autopsy report). 
Participants should be instructed to report any serious post-study event(s) that might reasonably be related to 
participation in this study. Participating investigators should notify the MSSM Overall Principal Investigator 
and their respective IRB of any unanticipated death or adverse event occurring after a participant has 
discontinued or terminated study participation that may reasonably be related to the study.  
14  DATA AND SAFETY MONITORING
14.1  Data Reporting
Method 
The Study team and the CCTO  will collect, manage, and monitor data for this study. 
Data Submission 
The schedule for completion and submission of case report forms (paper or electronic) to the QACT is as 
follows:
Form/eCRF
Estimated Submission Timeline
Eligibility Checklist
Complete prior to registration with MSSM
On Study Form
Within 14 days of registration
Baseline Assessment Form
Within 14 days of registration
Treatment Form
Within 10 days of the last day of the cycle
Adverse Event Report Form
Within 10 days of the last day of the cycle
Response Assessment Form
Within 10 days of the completion of the cycle 
required for response evaluation
Off Treatment/Off Study Form
Within 14 days of completing treatment or being 
taken off study for any reason
Follow up/Survival Form
Within 14 days of the protocol defined follow up 
visit date or call
14.2   Safety Meetings
Because this is a Phase II trial an internal Data Safety Monitoring  Board will be required to review and monitor 
toxicity, accrual data from this trial and interim results on this trial. The committee will be composed of Dr. 
Raymond Chai (Chair), Dr. Marshall Posner, Dr. Richard Bakst, Dr. Vishal Gupta and the statistician. The 
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Review group will meet quarterly to review survival and recurrence data from the trial.  An independent MSSM 
statistician shall be  a member. The chairman of the DSMB will prepare minutes and report to the DSMC. The 
study report will remain blinded for efficacy results unless there is sufficient reason for the DSMB to consider 
halting the trial. 
The DSMB will meet semi-annually and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include: up-to-date participant accrual; all unexpected 
adverse events that have been reported; summary of all surgical complications or deaths while being treated 
and during active follow-up; any response information; audit results, and a summary provided by the study 
team. Other information (e.g. scans, laboratory values) will be provided upon request.  
Adverse Events. safety data, including all protocol-defined and serious unanticipated adverse events, will be 
collected throughout the entire course of the study. Expedited reporting to the IRB and study sponsor will be 
required for any unexpected serious adverse event. 
Reporting of Serious Adverse Events 
All investigators NHLBI must report both expected (protocol defined) and unexpected serious adverse events. 
All serious adverse events must be reported directly to the clinical center’s IRB within 10 working days of 
knowledge of the event, or as dictated by the specific IRB policy, whichever is sooner. All deaths and 
unexpected serious adverse events must be reported to the IRB within 24 hours of  knowledge of the event, or 
as dictated by the specific IRB policy, whichever is sooner. The investigators will notify the study sponsor of 
any deaths and unexpected serious adverse events via e-mail within 24 hours of receipt of the event. These 
events will also be reported to the DSMB chair within 72 hours of notification. All serious adverse events will 
be reported to the DSMB at least semi-annually, at the discretion of the DSMB. In addition, the investigators 
are expected to comply with their institutional policies and reporting requirements.
After recruitment of half of the study subjects (100) a full dataset analysis will be performed by the 
investigators and the statistical support group to ensure that outcomes are comparable to current standards. 
This will include statistical analysis of adverse events, recurrence rates after surgical therapy, outcomes of 
adjuvant therapy arms, and disease specific survival. Deviation from the proposed recurrence rates or overall 
disease specific survival will result in halting the trial. The primary endpoints are DFS and LRC at 3 and 5 
years.  Kaplan-Meier curves will be estimated for the standard therapy and the experimental therapy groups. 
Ninety-percent one-sided confidence intervals will be calculated for DFS at 3 and 5 years in the surgical and 
surgical/adjuvant therapy groups.  The secondary endpoint of overall survival will be analyzed using Kaplan-
Meier curves and a log-rank test for the difference between the two therapy groups. Five year OAS, DFS and 
LRC will be calculated using a log-rank test will be used to test for differences between the two treatment 
groups. Toxicity is another secondary endpoint. We will compute for each arm the toxicity rate and provide 
the corresponding 90% confidence intervals based on the exact binomial distribution.
Stopping Boundaries: Based on stopping if the probability that recurrence exceeds 50% is ≥ 0.80
The following are greater-than-or-equal boundaries: 
a pair (n, m) means to stop if the number of adverse events after treating m patients is greater than or equal to n.
n  (# events)
m  (# patients)
n  (# events)
m  (# patients
7
10
35
62
8
12
36
64
9
14
37
66
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10
16
39
69
11
18
40
71
13
21
41
73
14
23
42
75
15
25
43
77
16
27
44
79
17
29
46
82
19
32
47
84
20
34
48
86
21
36
49
88
22
38
50
90
23
40
51
92
25
43
52
94
26
45
54
97
27
47
55
99
28
49
55
100
29
51
30
53
32
56
33
58
34
60
35
62
15    REGULATORY CONSIDERATIONS
15.1 Protocol Review and Amendments
This protocol, the proposed informed consent and all forms of participant information related to the study 
(e.g., advertisements used to recruit participants) and any other necessary documents must be submitted, 
reviewed and approved by a properly constituted IRB governing each study location. 
Any changes made to the protocol must be submitted as amendments and must be approved by the IRB 
prior to implementation. Any changes in study conduct must be reported to the IRB. The MSSM Overall 
Principal Investigator (or Protocol Chair) will disseminate protocol amendment information to all 
participating investigators. 
All decisions of the IRB concerning the conduct of the study must be made in writing.
15.2 Informed Consent
15.3 All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. The 
formal consent of a participant, using the IRB approved consent form, must be obtained before the 
participant is involved in any study-related procedure. The consent form must be signed and dated by 
the participant or the participant’s legally authorized representative, and by the person obtaining the 
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consent. The participant must be given a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research file15.3 Ethics 
and Good Clinical Practice (GCP)
This study is to be conducted according to the following considerations, which represent good and sound 
research practice:

E6 Good Clinical Practice: Consolidated Guidance
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf

US Code of Federal Regulations (CFR) governing clinical study conduct and ethical principles
that have their origin in the Declaration of Helsinki

Title 21 Part 11 – Electronic Records; Electronic Signatures
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html

Title 21 Part 50 – Protection of Human Subjects
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html

Title 21 Part 54 – Financial Disclosure by Clinical Investigators
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html

Title 21 Part 56 – Institutional Review Boards
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html

Title 21 Part 312 – Investigational New Drug Application
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html

State laws

MSSM research policies and procedures
It is understood that deviations from the protocol should be avoided, except when necessary to
eliminate an immediate hazard to a research participant. In such case, the deviation must be reported
to the IRB according to the local reporting policy.
15.4 Study Documentation
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information enables the 
study to be fully documented and the study data to be subsequently verified.
Original source documents supporting entries in the case report forms include but are not limited to hospital 
records, clinical charts, laboratory and pharmacy records, recorded data from automated instruments, 
microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays. 
15.5 Records Retention
All study-related documents must be retained for the maximum period required by applicable federal 
regulations and guidelines or institutional policies. 
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15.6 Multi-center Guidelines
Protocol Chair – Raymond Chai, MD
The Protocol Chair is responsible for performing the following tasks:
1. Coordinating, developing, submitting, and obtaining approval for the protocol
2. as well as its subsequent amendments
3. Assuring that all participating institutions are using the correct version of the
4. protocol.
5. Taking responsibility for the overall conduct of the study at all participating institutions and
for monitoring the progress of the study.
6. Reviewing and ensuring reporting of Serious Adverse Events (SAE)
7. Reviewing data from all sites, and performing interim analysis as indicated.
8. Initiation of stopping rules at all participating sites if necessary
Coordinating Center- Mount Sinai Health System 
The Coordinating Center is responsible for performing the following tasks:
1. Ensuring that IRB approval has been obtained at each participating site prior to the first
patient registration at that site, and maintaining copies of IRB approvals from each site.
2. Managing central patient registration
3. Collecting and compiling data from each site.
4. Establishing procedures for documentation, reporting, and submitting of AE’s and SAE’s to
the Protocol Chair, and all applicable parties.
5. Facilitating audits by securing selected source documents and research records from
participating sites for audit, or by auditing at participating sites.
6. Providing a protocol appendix for each Participating Site describing the participating site
patient population, expertise, and available resources.
7. Coordinating Center personnel and the PI will collect information from the Participating
Site and report appropriately to the IRB. Information reported may include but is not limited
to adverse events, stopping rule triggers, interim analysis results, study results, unanticipated
events related to the study, etc.
Participating Sites
1. Participating sites are responsible for performing the following tasks:
2. Following the protocol as written, and the guidelines of Good Clinical Practice (GCP).
3. Submitting data to the Coordinating Center through ERAP.
4. Registering all patients with the Coordinating Center by submitting patient registration
form, and signed informed consent promptly.
5. Providing sufficient experienced clinical and administrative staff and adequate facilities
and equipment to conduct a collaborative trial according to the protocol.
6. Maintaining regulatory binders on site and providing copies of all required documents to
the Coordinating Center.
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Meetings
Teleconferences of all investigators, research nurses and other study staff involved in the study will take place, 
starting once both sites have enrolled a subject. The following study team members involved with the conduct 
of the trial will be included as appropriate: study coordinators, data managers, research nurses, sub-
investigators, collaborators (if applicable), and the statistician. The timing of these meetings will be at minimal 
quarterly, but more frequent during initial accrual, adverse event reporting, or at any time at the discretion of 
the Participating Site or Coordinating site.
During these meetings, matters related to the following will be discussed: enrollment rate relative to 
expectation, characteristics of participants, retention of participants, adherence to protocol (potential or real 
protocol violations), validity and integrity of the data, toxicities, surgical complications, unanticipated barriers, 
acquisition of serum samples and transfer to lab, and progress of data for objectives. Any other issue related 
to the trial may be discussed with the Participating Site and the Coordinating Center. Formal minutes of these 
discussions will be provided to the appropriate personel, and if applicable, formal action plans.
16.0 STATISTICAL CONSIDERATIONS 
16.1 Study Design/Endpoints
This is a prospective clinical trial evaluating surgery alone for early stage HPV related oropharyngeal 
squamous cell carcinoma. The primary endpoints are the rate of local-regional control OAS, and PFS at 3 years 
in patients with HPV 16 and p16+ related head and neck cancer, treated with surgery alone.  The secondary 
objectives include 5 year PFS, LRC, Overall Survival, Ultimate Disease Control,  QOL, site of failure and rate 
of salvage, as well as establishing biomarkers predictive of treatment outcomes and collection of tumor tissue, 
germline DNA and a plasma bank for future studies. The main study hypotheses is that OAS and UDC at 5 
years for surgery alone for early stage HPV related oropharyngeal squamous cell carcinoma is equivalent to 
current regimens involving standardized post-operative radiotherapy (>85%) and that LRC without 
radiotherapy will be > 50%. Additional Hypotheses relate to Group 2 and 3 - OAS and PFS at 5 years for 
reduced dose XRT and CRT intermediate stage HPV related oropharyngeal squamous cell carcinoma is 
equivalent to current regimens involving standardized post-operative radiotherapy (>85%) and that LRC will 
be > 85%. 
16.2 Sample Size/Accrual Rate
Sample size justification:
The proposed sample size of 100 for Group 1 has been determined to ensure that an upper bound 
for recurrence may be estimated with adequate precision, defined as within 8-12% of the true 
recurrence rate. The upper bound is estimated by the posterior probability of recurrence given the 
observed data, assuming a non-informative beta(1,1) prior distribution. The table below provides 
the upper 95% bound (from the Bayesian credible interval) assuming the true rate of recurrence is 
.1,.2,.3,.4, or .5 and 100 patients are studied.  
True recurrence
Upper 95% bound
.1
.184
.2
.301
.3
.413
.4
.516
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.5
.614
The various specific aims outlined in Aim 1 share a common objective: determining rates of important 
measures of treatment response (progression-free survival, overall survival, local regional control and 
ultimate disease control) for patients  treated  with surgery alone and compare them to those expected in 
patients with similar diagnostic criteria.  We will assess this overall objective by using a Bayesian approach 
to estimate the posterior probability distributions for each respective sub-aim based on observed outcomes.   
This approach permits estimating probabilities with which a specified rate of interest exceeds a threshold 
value (e.g.; 50% local regional control, 85% overall survival, etc.)  
Our approach begins with the premise that surgery alone offers no improvement in expected outcomes. This 
is an exact correspondence to a “null hypothesis”. We incorporate this assumption through a prior 
distribution for each suspected rate; for example, for Group I patients we would assume that the rate of local 
regional control (LRC) at three years is 50%. After the studies are conducted, each respective rate is 
combined with the "null"  prior distribution through Bayes’ Theorem to yield the posterior distribution for 
the rate.  The table below depicts simulated results for the posterior LRC (theta) using 100 patients based on 
two differing assumptions: that LRC at three years is 50% (p=0.5 shown on the left) and 85% (p=0.85 shown 
on the right).  
Our expected sample size of 100 for Group I patients ensures that the inter-quartile range for the estimated 
probability distributions will extend from approximately 10-12 percentage points. This range is wider for 
smaller sample sizes (e.g. 30 or 50) but still less than 20 percentage points.
16.3 Stratification Factors
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Study subjects will be stratified based on final pathological data for statistical analysis and 
outcomes reporting.
16.4  
Analysis of Primary Endpoints
The primary endpoints are DFS and LRC at 3 and 5 years.  Kaplan-Meier curves will be estimated for the standard 
therapy and the experimental therapy groups.  Ninety-percent one-sided confidence intervals will be calculated 
for DFS at 3 and 5 years in the surgical and surgical/adjuvant therapy groups.  
16.5
Analysis of Secondary Endpoints
The secondary endpoint of overall survival will be analyzed using Kaplan-Meier curves and a log-rank test for 
the difference between the two therapy groups. Five year OAS, DFS and LRC will be calculated using a log-
rank test will be used to test for differences between the two treatment groups.
Toxicity is another secondary endpoint. We will compute for each arm the toxicity rate and provide the 
corresponding 90% confidence intervals based on the exact binomial distribution.
Reporting and Exclusions
Not Applicable.
17.0 PUBLICATION PLAN
The results should be made public within 24 months of the end of data collection. If a report is planned to be 
published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements 
of the International Committee of Medical Journal Editors. A full report of the outcomes should be made public 
no later than three (3) years after the end of data collection. 
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31.
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32.
Cohen MA, Weinstein GS, O'Malley BW, Jr., Feldman M, Quon H. Transoral robotic surgery
and human papillomavirus status: Oncologic results. Head Neck. Apr 2011;33(4):573-580.
33.
White HN, Moore EJ, Rosenthal EL, et al. Transoral robotic-assisted surgery for head and
neck squamous cell carcinoma: one- and 2-year survival analysis. Arch Otolaryngol Head
Neck Surg. Dec 2010;136(12):1248-1252.
34.
de Arruda FF, Puri DR, Zhung J, et al. Intensity-modulated radiation therapy for the treatment
of oropharyngeal carcinoma: the Memorial Sloan-Kettering Cancer Center experience. Int J
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19.0  APPENDICES 
Appendix 1: Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Description
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair.
10
Moribund, fatal processes 
progressing rapidly. 
5
Dead.
0
Dead.
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Appendix 2: Video Swallowing
The video swallow study report will include the following information: 
Impressions:
1. Oropharyngeal findings
a.
Penetration-Aspiration-Scale
b. Severity rating of OP function
i. Within Normal Limits
ii. Mild
iii. Mild-Moderate
iv. Moderate
v. Moderate-Severe
vi. Severe
2. Cervical Esophageal findings
a.
No stenosis
b. Partial stenosis
c.
Complete stenosis
Recommendations:
1. Diet
a.
Regular diet
b. Soft diet
c.
Puree diet
d. Liquid diet
e.
G-tube w/trials
f.
G-tube, NPO
2. Liquids
a.
Regular
b. Thickened
3. Therapeutic precautions/interventions
a.
Implement postures/strategies to decrease penetration/aspiration or residue
Consider esophageal dilation Yes or No
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Appendix 3: QOL  Questionnaires
Name_______________________  Date___________  Hospital Number________
The M. D. Anderson Dysphagia Inventory
This questionnaire asks for your views about your swallowing ability. This information will help us 
understand how you feel about swallowing.
The following statements have been made by people who have problems with their swallowing. Some 
of the statements may apply to you.
Please read each statement and circle the response which best reflects your experience in the past 
week.
My swallowing ability limits my day-to-day activities.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
E2.  I am embarrassed by my eating habits.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
F1.  People have difficulty cooking for me.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
P2.  Swallowing is more difficult at the end of the day.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
E7.  I do not feel self-conscious when I eat.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
E4.  I am upset by my swallowing problem.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
P6.  Swallowing takes great effort.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
E5.  I do not go out because of my swallowing problem.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
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F5.  My swallowing difficulty has caused me to lose income.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
P7.  It takes me longer to eat because of my swallowing problem.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
P3.  People ask me, “Why can’t you eat that?”
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
E3.  Other people are irritated by my eating problem.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
P8.  I cough when I try to drink liquids.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
F3.  My swallowing problems limit my social and personal life.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
F2.  I feel free to go out to eat with my friends, neighbors, and relatives.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
P5.  I limit my food intake because of my swallowing difficulty.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
P1.  I cannot maintain my weight because of my swallowing problem.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
E6.  I have low self-esteem because of my swallowing problem.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
P4.  I feel that I am swallowing a huge amount of food.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
F4.  I feel excluded because of my eating habits.
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree
Thank you for completing this questionnaire!
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Name_____________________  Date__________  Hospital Number__________
Xerostomia Questionnaire (XQ)
This questionnaire asks your view about your dry mouth issue. This information will help us 
understand how you feel about dry mouth.  Please rate your response which best reflects your 
experience in the past week. The higher the score, the worse your dry mouth.
1. Rate your difﬁculty in talking due to dryness
0____1____2____3____4____5____6____7____8____9____10
2. Rate your difﬁculty in chewing due to dryness
0____1____2____3____4____5____6____7____8____9____10
3. Rate your difﬁculty in swallowing solid food due to dryness
0____1____2____3____4____5____6____7____8____9____10
4. Rate the frequency of your sleeping problems due to dryness
0____1____2____3____4____5____6____7____8____9____10
5. Rate your mouth or throat dryness when eating food
0____1____2____3____4____5____6____7____8____9____10
6. Rate your mouth or throat dryness while not eating
0____1____2____3____4____5____6____7____8____9____10
7. Rate the frequency of sipping liquids to aid swallowing food
0____1____2____3____4____5____6____7____8____9____10
8. Rate the frequency of sipping liquids for oral comfort when
not eating
0____1____2____3____4____5____6____7____8____9____10
Thank you for completing this survey.
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Appendix 4 
Additional Participating Site:
Valley Health System
223 N. Van Dien Avenue
Ridgewood, NJ 07450
201-447-8000
Setting of Human Research
Valley Hospital/Valley Health System/Blumenthal Cancer Center
The Valley Health System (VHS) is comprised of three entities: The Valley Hospital (TVH), 
Valley Home Care, and Valley Physician Services. TVH is a private, not-for-profit hospital 
located in northern New Jersey.  It is a fully accredited, 450 bed, acute care institution 
serving more than 440,000 people in Bergen county and the surrounding communities and is 
affiliated with the New York - Presbyterian Healthcare System and the Mount Sinai Health 
System.  TVH earned the Gold Seal of Approval from the Joint Commission on Accreditation 
of Healthcare Organizations and is a nine-time winner of the JD Power and Associates 
Distinguished Hospital Award for Service Excellence.   
TVH has developed and established a robust research infrastructure. In 2013, research 
administration and clinical trials were centralized to form The Valley Hospital Okonite 
Research Center (TORC). This support translates into over 25 dedicated research FTEs and a 
total operating budget of over $3M annually.  TORC’s programs include, the Human 
Subjects Protection Program (HSPP), Research Administration and Sponsored Programs 
(RASP), Clinical Trials & Research Program (CTRP), and the Translational Research 
Program (TRP) which houses the institutions core facilities and robust biorespositories, 
including the Oncology Biorepository and the Cardiac Bio-registry for Translational 
Research (CBTR). 
HSPP provides the institution with regulatory policies and procedures, the IRB, regulatory 
education and training and the continual improvement processes. Valley received AAHRPP 
accreditation of its HSPP in June of 2016. RASP regulates all pre and post award activities, 
contract negotiation, coverage anaylsis, budget development and implements the cost 
accounting principles for federal awards and oversees the clinical trials management systems 
for the institution. The CTRP includes dedicated outpatient clinical research facilities and 
research coordination staff. The TRP is located in a dedicated building that houses state-of-
the-art laboratories, a freezer farm with dedicated back-up generated and fully alarmed 
systems, dark room, shared equipment and core facilities that include biostatistics and 
bioinformatics.  
Oncology Clinical Research Center
The oncology clinical research unit is comprised of dedicated research space imbedded in the 
Blumenthal Cancer Center. There is a dedicated Supervisor of Oncology Clinical Research 
and 5.0 FTEs of dedicated clinical trials research nurse and study coordinators in addition to a 
dedicated regulatory specialist. The physical location of the clinical trials staff adjacent to the 
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oncology medical practices and surgeons allows for streamlined, efficient and effective 
facilitation of investigators and patients enrolled in clinical research. On average the unit 
oversees 40 active clinical trials in the areas of lung, breast, gastrointestinal, brain, 
hematological, gyn and genitourinary cancers. In 2017, there were 16,163 oncology infusion 
visits, and 24 head and neck cancers treated at the Blumenthal Cancer Center.
Site Personel
PI: 
Thomas P. Kole, MD (Radiation Oncology)
One Valley Health Plaza
Paramus, NJ 07652
koleth@valleyhealth.com
201-634-5403
Co-I:
Kevin C. Wood, MD
One Valley Health Plaza
Paramus, NJ 07652
woodke@valleyhealth.com
201-634-5578
Research Nurse:
Alludia Francis
One Valley Health Plaza
Paramus, NJ 07652
afranci4@valleyhealth.com
201-634-5792
Regulatory Document Specialist:
Figerete Sakollari
One Valley Health Plaza
Paramus, NJ 07652
fsakoll@valleyhealth.com
201-634-5792
Clinical Trials and Research Administration Manager:
Kathleen Sayles
223 N Van Dien Avenue
Bolger Building at Linwood
Ridgewood, NJ 07652
ksayles@valleyhealth.com
201-389-0204
Study Start-up Specialist:
Nancy Bowden
223 N Van Dien Avenue
Bolger Building at Linwood
Ridgewood, NJ 07652
nbowden@valleyhealth.com
201-389-0193
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Setting of the Human Research
All patients will be evaluated and consented in the multidisciplinary head and neck cancer clinic where 
eligibility criteria, entry and disease parameters will be evaluated and documented. Subjects who enroll 
on this study must be diagnosed with HPV related squamous cell carcinoma in the oropharynx, and 
must not have received any prior chemotherapy, radiotherapy or surgery for their cancer. Potential 
participants will be screened based on their past medical history, the results of their radiological scans, 
blood work, as well as a number of other required studies that will determine their eligibility.  To be 
screened and consented on this study subjects must have had a biopsy and must display clinical features 
that are consistent with p16 positivity (i.e., no history of smoking/alcohol, age range, etc.). To be 
assigned to a group and participate in the experimental portion of the trial, surgery must be performed 
at MSSM, tumor tissue must be available, and both p16 and HPV status must be assessed and proven 
to be positive for HPV 16 or any high risk HPV subtype (i.e., 18, 33, 35, etc.) by PCR and p16 positive 
by IHC.
8.0
REGISTRATION PROCEDURES 
After the patient signs the informed consent the patient will be registered for screening and once the 
investigator has verified that the patient meets all inclusion/exclusion criteria, the patient will be 
registered for and started on the protocol. Patients who lack p16 and HPV PCR may proceed to surgery 
however they will not be assigned to an experimental group and registered on the protocol until p16 
IHC and HPV PCR are completed and positive. The verification of patient’s eligibility and screening 
completion will be performed centrally after the receipt of the patient primary post-surgical registration 
form.  It is mandatory not to exceed 21 days between the date of registration for screening and the start 
of the study treatment (surgery).  In any case, all events occurring after the registration for therapy must 
be recorded in the case report form and will be taken into account in the analysis, whether the patient 
received the study treatment or not.  Patient must receive surgery and be p16 IHC and HPV PCR positive 
to be included in the intent to treat analysis. Patients found to not meet entry criteria will be offered best 
therapy. Of note Drs Genden and Teng will be seeing patients at the Participating Site (VHS) 
to facilitate evaluation and recruitment procedures.
Procedures Involved in Human Research – Participating Site
Surgical Intervention
Transoral Robotic Resections or TORS will be peformed by the investigators listed above at 
Mount Sinai Health System (Mount Sinai Hospital and Mount Sinai West). Surgical 
guidelines will be performed as outlined in the protocol above. 
Delivery of Radiation
Radiotherapy will be delivered by VSH department of Radiation Oncology by the VSH 
investigators noted above. The delivery, dosage, and technical factors will be uniform across 
all study sites, in keeping with the primary protocol document. In addition, formal volume 
reviews will be performed by Mount Sinai prior to treatment initiation . This will ensure 
consistency in radiation treatment planning, volumes, and delivery. VSH department of 
Radiation Oncology will adhere to the protocol quality assurance measures and isodose 
distribution as noted in the protocol. Protocol deviations will be reported to the Coordinating 
Site PI, and the radiation oncology co-investigators.
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Delivery of Chemotherapy
Delivery of Chemoradiotherpy will mirror the protocol noted above for all patients accrued at 
the VHS Participating Site. Protocol deviations will be reported to the Coordinating Site PI, 
and medical oncology co-investigators.
Salvage Protocol
The salvage protocol for patients accrued at VHS will mirror the primary protocol salvage 
protocol. Referral to the Mount Sinai Health system surgeons who are investigators in the 
study will be performed in cases requiring surgical salvage. All salvage treatment plans will 
be reviewed by the Coordinating Site and Partipating Site investigators prior to initiation of 
therapy.
Number of subjects 
The total number of subjects for trial completion remains unchanged. The addition of the 
VHS study subsite is for accrual support only. We expect approximately 5-10 patients per 
year to accrue from the VHS. 
Blood Collection
Blood collection will adhere to the protocol for all patients accrued from the participating site. 
Samples (6 ml of blood/tube) will be obtained at each visit as noted in the protocol by VHS research 
personel. The exception to this will be if the intital blood sample is obtained immediately prior to 
surgery, which will be occurring at Mount Sinai Hospital and Mount Sinai West. All other blood 
samples will be stored in the VHS. Viable lymphocytes will be processed from green top tubes using 
standard ficoll-hypaque density gradient separation.  Buffy coat layers will be stored as viable cells in 
DMSO-containing media at  -80C to -170C. 
Blood for serum will be spun within 5 hours of collection.  Blood tubes will be spun at 3000 x g for 10’ 
at 4C and the serum removed by pipetting.  Serum will be stored in 1ml aliquots.  All samples will be 
stored at -80C.  White blood cell fraction will be stored in a single tube at local institutional temperature 
guidelines and kept locally. Blood samples will then be batched shipped to the Mount Sinai Health 
System Immune Core (as outlined above) at frequencies appropriate for the number of samples.
Specimen Banking 
As no surgical intervention/transoral robotic surgery will be performed at the VHS Participating Site, 
all specimens obtained from subjects accrued at VHS will be managed per the protocol, as surgical 
interventions will only occur at Mount Sinai Hospital and Mount Sinai West, and therefore from the 
standpoint of specimen management, the management is identical and will be handled the same for all 
SIRS study sujects. Any additional biopsies from the primary tumor or a recurrence obtained at VHS 
will be processed at the VHS laboratory, reviewed by VHS Department of Pathology, and then shipped 
to the main biorepository at Mount Sinai for storage for correlative studies.
Data Management 
Data Transfers
Vulnerable Populations 
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Multi-Site Human Research (Coordinating Center). Discuss how management and oversight 
of the project will occur. Describe the process by which the lead PI will collect information 
from each site and report appropriately to the IRB.
A. Recruitment materials for each site
B. Consent Template with local site PI name and address, for each site
C.
Participating Site Responsibilities:
Track Human Subjects Research education/Conflicts of Interest/administrative training
Ensure all personnel have completed the education requirements to be allowed to conduct 
research at their sites through CITIprogram.org
Ensure that all financial conflict of interest (FCOI) disclosures have been made through Sinai 
Central
Ensure that any required submission to a grants and/or contracts office to open a new study at 
a site are made
Comply with Mount Sinai Health system research committee review and recommentations: 
Peer Reviewed Monitoring Committee, Radiation Safety Committee, 
Storage and Handling of Research Data
Transfer of Specimens
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