Adjuvant De-escalation, Extracapsular Spread, P16+, Transoral (ADEPT) Trial for Oropharynx Malignancy
Phase: PHASE3
Conditions: Oropharyngeal Neoplasms
Sponsor: Washington University School of Medicine

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Adjuvant De-escalation, Extracapsular spread, P16+, Transoral (A.D.E.P.T) 
Trial for Oropharynx Malignancy 
 
Washington University School of Medicine 
Department of Otolaryngology – Head & Neck Surgical Oncology 
660 South Euclid Avenue, Campus Box 8115 
St. Louis, MO  63110 
 
Protocol#:  201207059 
  Version Date: 10/22/19 
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator:     
Jason Rich, MD 
Washington University School of Medicine  
Phone: (314) 747-3742 
Fax: (314) 747-1531 
E-mail: richj@ent.wustl.edu  
 
 
 
 
 
 
ClinicalTrials.gov #:  
NCT01687413 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 

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Sub-Investigators 
Institution 
Modality 
Hiram Gay, M.D. 
Washington University 
Radiation Oncology 
Wade L. Thorstad, M.D. 
Lanis Hall, M.D., M.P.H 
Anupama Chundury, M.D. 
Washington University 
Washington University 
Washington University 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Douglas R. Adkins, M.D. 
Washington University 
Medical Oncology 
Tanya Wildes, M.D. 
 
Washington University 
 
Medical Oncology 
 
Samir El-Mofty, Ph.D. 
Rebecca Chernock, M.D. 
Washington University 
Washington University 
Pathology and Immunology 
Pathology and Immunology 
Brian Nussenbaum, M.D. 
Washington University 
Head & Neck Surgical Oncology 
Randal Paniello, M.D. 
Washington University 
Head & Neck Surgical Oncology 
Ravindra Uppaluri, M.D., Ph.D. 
Jay Piccirillo, M.D. 
Parul Sinha, M.D. 
Ryan Jackson, M.D. 
Washington University 
Washington University 
Washington University 
Washington University 
Head & Neck Surgical Oncology 
Head & Neck Surgical Oncology 
Head & Neck Surgical Oncology 
Head & Neck Surgical Oncology 
 
 
 
Fei Wan, Ph.D. 
Washington University 
Biostatistics 
James S. Lewis, Jr., M.D. 
Vanderbilt University 
Pathology and Immunology 
Michael L. Hinni, M.D. 
Mayo Clinic – Arizona 
Otorhinolaryngology 
Kelly K. Curtis, M.D. 
Mayo Clinic – Arizona 
Hematology/Oncology 
Samir H. Patel, M.D. 
Jonathan Ashman, M.D. 
John Camoriano, M.D. 
Richard Hayden, M.D. 
William Rule, M.D. 
Michele Haylard, M.D. 
William Wong, M.D. 
Nina Karlin, M.D. 
Donald Northfelt, M.D. 
Harshita Paripati, M.D. 
Carlos Vargas, M.D. 
Andrew Gaines, M.D. 
Darlene Bugoci, M.D. 
Todd Capizzi, M.D. 
Thomas Kenney, M.D. 
Seth Reiner, M.D. 
John Campana, M.D. 
Andrew Nemecheck, M.D. 
Christopher Oliver, M.D. 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Mayo Clinic – Arizona 
Centura Health Research Center 
Centura Health Research Center 
Centura Health Research Center 
Centura Health Research Center 
Centura Health Research Center 
Centura Health Research Center 
Centura Health Research Center 
Centura Health Research Center 
Radiation Oncology 
Radiation Oncology 
Medical Oncology 
Otolaryngology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Medical Oncology 
Medical Oncology 
Medical Oncology 
Radiation Oncology 
Head & Neck Surgical Oncology 
Radiation Oncology 
Hematology/Oncology 
Hematology/Oncology 
Radiation Oncology 
Head & Neck Surgical Oncology 
Head & Neck Surgical Oncology 
Head & Neck Surgical Oncology 
 
 
 
 
 
 
 
 
 
         
 
 
 

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Adjuvant De-escalation, Extracapsular spread, P16+, Transoral (A.D.E.P.T) Trial for 
Oropharynx Malignancy 
 
Protocol Revision History 
 
Version Date 
Revision Summary 
06/15/12 
Initial Approval 
02/27/13 
Amendment #1 
09/19/13 
Amendment #2 
10/29/14 
Amendment #3 
11/26/14 
Amendment #4 
10/29/15 
Amendment #5 
02/11/16 
Amendment #6 
07/12/17 
Amendment #7 
10/22/19 
Amendment #8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Adjuvant De-escalation, Extracapsular spread, P16+, Transoral (A.D.E.P.T) Trial for 
Oropharynx Malignancy 
 
Principal Investigator Signature Page 
 
 
Study Chair: 
 
Jason Rich, MD 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/HRPO procedures, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical 
studies. 
 
 
 
 

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TABLE OF CONTENTS 
 
STUDY SCHEMA........................................................................................................................ 77 
1.0 
INTRODUCTION AND BACKGROUND ...................................................................... 88 
1.1 
Oropharynx Squamous Cell Carcinoma: Trends ........................................................... 88 
1.2 
Transoral Approach to Oropharynx Cancers ................................................................. 88 
1.3 
p16 as a Surrogate Biomarker in HPV-related OPSCC ................................................. 99 
1.4 
Extracapsular Spread in Head and Neck Squamous Cell Carcinoma: Dilemma #1 .. 1010 
1.5 
Adjuvant Therapy for HNSCC with ECS: Dilemma #2 ............................................ 1010 
1.6 
ECS in p16+ OPSCC ................................................................................................. 1111 
1.7 
Quality of Life and Functional Outcomes .................................................................. 1414 
1.8 
Study Rationale and Summary Statement .................................................................. 1515 
1.9 
ADEPT Study Planning, 2-10-2012 ........................................................................... 1515 
2.0 
OBJECTIVES ................................................................................................................ 1616 
3.0 
ELIGIBILITY CRITERIA ............................................................................................. 1616 
3.1 
Inclusion Criteria ........................................................................................................ 1616 
3.2 
Exclusion Criteria ....................................................................................................... 1717 
3.3 
Inclusion of Women and Minorities ........................................................................... 1818 
4.0 
REGISTRATION PROCEDURES ............................................................................... 1818 
4.1 
Confirmation of Patient Eligibility ............................................................................. 1818 
4.2 
Patient Registration in the Siteman Cancer Center Database .................................... 1919 
4.3 
Assignment of UPN ................................................................................................... 1919 
4.4 
Registration for Study Therapy .................................................................................. 1919 
4.5 
Companion Protocol for All p16+ Patients ................................................................ 2020 
4.6 
Study Track Log ......................................................................................................... 2020 
5.0 
STUDY PROCEDURES ............................................................................................... 2121 
5.1 
Surgery Guidelines ..................................................................................................... 2121 
5.2 
Pathological Evaluation of Surgical Specimen .......................................................... 2222 
5.3 
Treatment Randomization .......................................................................................... 2424 
5.4 
Radiotherapy Treatment Planning and Administration .............................................. 2424 
5.5 
Chemotherapy Administration ................................................................................... 2727 
5.6 
General Concomitant Medication and Supportive Care Guidelines .......................... 3030 
5.7 
Women of Childbearing Potential .............................................................................. 3030 
5.8 
Quality of Life and Functional Outcome Evaluation ................................................. 3131 
5.9 
Duration of Therapy ................................................................................................... 3333 
5.10 Duration of Follow-up ................................................................................................ 3333 
6.0 
PHARMACEUTICAL INFORMATION ...................................................................... 3434 
6.1 
Cisplatin (CDDP, Platinol-AQ®) .............................................................................. 3434 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ........................................... 3636 
7.1 
Adverse Events (AEs) ................................................................................................ 3636 
7.2 
Unanticipated Problems ............................................................................................. 3636 
7.3 
Noncompliance........................................................................................................... 3636 
7.4 
Serious Noncompliance .............................................................................................. 3737 
7.5 
Protocol Exceptions .................................................................................................... 3737 

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7.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality Assurance 
and Safety Monitoring Committee (QASMC) at Washington University ............................ 3737 
7.7 
Reporting Requirements for Secondary Sites ............................................................ 3737 
7.8 
Reporting to Secondary Sites ..................................................................................... 3838 
7.9 
Timeframe for Reporting Required Events ................................................................ 3838 
8.0 
STUDY CALENDAR ................................................................................................... 3939 
9.0 
DATA SUBMISSION SCHEDULE ............................................................................. 4141 
10.0 DATA AND SAFETY MONITORING ........................................................................ 4141 
10.1 Early Stopping Rules .................................................................................................. 4242 
11.0 AUDITING .................................................................................................................... 4343 
12.0 STATISTICAL CONSIDERATIONS........................................................................... 4343 
12.1 Study Endpoints ......................................................................................................... 4343 
12.2 Study Design .............................................................................................................. 4444 
12.3 Sample Size and Power Estimation ............................................................................ 4444 
12.4 Analysis ...................................................................................................................... 4646 
13.0 MULTICENTER REGULATORY REQUIREMENTS ............................................... 4848 
14.0 REFERENCES .............................................................................................................. 4949 
 
 

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STUDY SCHEMA 
 
 
 
 
 

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1.0 
INTRODUCTION AND BACKGROUND 
 
1.1 
Oropharynx Squamous Cell Carcinoma: Trends 
 
Current head and neck cancer trends demonstrate emergence of a steadily progressive 
epidemic of human papillomavirus (HPV)-related oropharynx squamous cell carcinoma 
(OPSCC). This disease, with primary malignancies in the tonsil and tongue base runs 
counter to a declining incidence of classic, tobacco-associated cancers. HPV-related 
OPSCC incidence increased from 1973 to 2004 in the United States, particularly among 
younger (< 60 years) individuals, men, and whites (Figure 1) (1,2,3). A concomitant 
improvement in the population-based survival for OPSCC has been noted (3-6), despite 
almost universal neck node metastasis. The increasing incidence and improved survival are 
clearly shown to result from the increased proportion of OPSCCs caused by the HPV. 
Prevalence of HPV in oropharyngeal tumors increased substantially from 16.3% during the 
1980s to 72.7% during the 2000s (3).  Institutional incidence here at Washington University 
is approximately 90% (7). In comparison to non-HPV head and neck cancers, HPV-
associated oropharyngeal tumors exhibit a distinct molecular biology, characterized by p16 
over-expression, plus other favorable clinico-pathological attributes. Together, these 
translate into markedly improved disease control and survival rates (4-11).  
 
 
 
Figure 1. Trends in annual incidence of OPSCC in US. Jemal A, Cancer Statistics (SEER) 2004 – 
2010 (2) 
 
1.2 
Transoral Approach to Oropharynx Cancers 
 
Independently, but co-incident with this rise in OPSCC, there has been a marked 
improvement in surgical methods for oropharynx resection, most procedures now using a 
minimally invasive approach. 
 

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Surgical resection with adjuvant radiotherapy was the main modality of management for 
OPSCC in the past. Classic surgical management of cancer in the oropharynx included 
open en bloc “commando” resections. These entailed external incisions through the face 
and neck, transection of the musculoskeletal framework, displacement and disruption of 
cranial nerves and sophisticated reconstruction for wound closure and functional 
restoration.  Such procedures were time- and resource-consuming, had an appreciable 
complication rate and were often associated with a certain degree of functional and 
aesthetic morbidity.  
 
Advances in technology have driven a transition in the treatment paradigm of 
oropharyngeal cancers from the open surgical resection and non-surgical treatment towards 
minimally invasive transoral (through the mouth) approaches, which in 2012 is represented 
by transoral laser microsurgery (TLM) and transoral robotic surgery (TORS). First 
performed by Panje in 1984, TLM for OPSCC was then popularized further in Europe by 
Iro, Eckel and Steiner et al (12). Use of a robot to aid in transoral tumor resection is the 
alternative technology, with feasibility first reported in 2006 (13, 14).The end result from 
the patient’s perspective, however, is identical, i.e., resection of all known primary tumor 
to a negative margin. Hundreds of such transoral procedures have been performed at 
Washington University (11).  
 
In addition to locoregional control and survival being comparable to open surgery, transoral 
approaches have minimized morbidity, functional deficits, and cost. TLM allows primary 
tumor-targeted treatment with optimum disease control for all resectable OPSCC tumors 
(T1-T4a). It is also allows reduced blood loss, rapid wound healing, shorter hospital stay, 
and faster rehabilitation. Tracheotomy is avoided except for extensive oropharyngeal 
resections where occasional swelling occurs, or flap reconstruction required.  
 
Swallowing, oral function and speech is usually maintained by endoscopic procedures 
because there is less disruption of the neuromuscular structure of the pharynx. Laser 
wounds also heal with less scarring than conventional surgical wounds: improved quality 
of life is likely to follow. The surgical approach also facilitates decision-making for 
adjuvant therapy, allowing many cases to be adjuvant therapy de-escalated, based on 
precise pathological staging and prognostication. 
 
1.3 
p16 as a Surrogate Biomarker in HPV-related OPSCC 
 
The distinct molecular characteristics between HPV-related and non-HPV associated 
OPSCC suggest different pathways of carcinogenesis. p16 gene functions as a cell-cycle 
checkpoint regulator and a tumor suppressor gene. Inactivation of p16 has been found to 
be the earliest change occurring in the molecular progression model of head and neck 
carcinogenesis due to effects of mutagens like tobacco. In HPV-related HNSCC, the 
oncoprotein E6 binds and degrades tumor suppressor gene products of p53 whereas the 
HPV oncoprotein E7 binds and degrades tumor suppressor gene products of pRB. pRB 
negatively regulates p16 promoter. Therefore, there is over-expression of p16 in case of 
HPV-mediated carcinogenesis since HPV causes absence of functional pRB (15-18). 
 

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As p16 over-expression is very rarely seen in non-HPV related OPSCC, it is considered a 
surrogate marker for HPV-positive OPSCC. p16 immunohistochemistry (IHC) also 
represents a less expensive and simpler alternative and can be applied to routinely fixed 
and processed tissues. It is also the frequently recommended/reported strategy for assessing 
HPV positivity in comparison to HPV polymerase chain reaction (PCR) (19). 
 
OPSCC tumors characterized by p16 over-expression have been recognized to possess a 
favorable clinical and molecular biology in several published studies (4-11). p16 staining 
is now routinely performed for OPSCC primary tumors and/or their neck metastases, 
diagnosed at Washington University. 
 
1.4 
Extracapsular Spread in Head and Neck Squamous Cell Carcinoma: 
Dilemma #1 
 
Extracapsular spread (ECS) in nodal metastases is traditionally one of the most important 
negative prognosticators in p53 mutant head and neck cancer, the presence of which is 
believed to endow a higher degree of aggressiveness and reduced survival outcomes (20-
24). However, there is a significant degree of uncertainty regarding criteria that define the 
phenomenon of ECS and/or its extent. This also obfuscates the determination of differences 
in prognostic impact, relative to variations in the extent of nodal metastasis. Literature 
review of ECS and its detected extent in head and neck squamous cell carcinoma (HNSCC) 
metastases reveals that there is little consistency in the pathological definition of either the 
presence of ECS or the pathological sub-categories of microscopic vs. macroscopic ECS. 
Most of the studies that categorize extent of ECS show a trend towards visibly macroscopic 
spread into soft tissues and/or desmoplastic response, vs. microscopic ECS, as the 
significant negative prognosticator. Routine reporting/measurement of extracapsular 
spread varies markedly both in quantity and character, between institutions and even 
between one institution’s pathologists. Nonetheless, this prognosticator, however reported, 
has been a common trigger for escalated adjuvant therapy in “traditional,” p53 mutant head 
and neck cancer. 
 
1.5 
Adjuvant Therapy for HNSCC with ECS: Dilemma #2 
 
Extracapsular spread is considered an indication for chemoradiotherapy (CRT) based on 
two prospective trials (RTOG 9501 and EORTC 22931) of patients with “high-risk” 
HNSCC published in 2004 (25, 26). Unfortunately, no subset analyses by tumor primary 
site or risk factors (ECS vs. positive margins) were reported in either of the trials. 
Oropharynx was the primary site in only 30% of cases in the EORTC (26), and 42% in the 
RTOG trial (25). ECS as a “high-risk” criterion was present in only 57% of patients in 
EORTC (26). What is worse, its prevalence in the RTOG trial (25) could not even be 
estimated, because patients with ECS and or ≥ 2 positive lymph nodes were clustered 
together. These studies were not powered to stratify for these variables, nor was HPV status 
taken into account. Thus, the findings and conclusions from the trials are too general, and 
obscure the relevance of ECS as a risk factor or adjuvant therapy determinant in an 
individual patient, especially with HPV-related OPSCC.  
 

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To compound the problem, addition of chemotherapy resulted in a 2-fold or more increase 
in treatment-related severe acute toxicity compared to radiotherapy (RT) alone, from 34% 
in the RT group to 77% in the CRT group in RTOG (25), and from 21% to 41% in the 
EORTC trial (26). Neither the RTOG trial nor the EORTC trial found significant reduction 
in distant metastasis in “high-risk” patients receiving CRT (20%, CRT versus 23%, RT) 
and (21%, CRT vs. 25%, RT), respectively. Finally, in the ten-year report from RTOG 
9501, a subset analysis of the OPSCC patients with ECS showed no significant 
chemotherapy treatment effect. (27). 
 
1.6 
ECS in p16+ OPSCC 
 
Our TLM database research on oncologic outcomes of OPSCC patients treated by primary 
surgery (in the form of TLM ± neck dissection) and adjuvant therapy, revealed p16 
positivity as the strongest (favorable) prognosticator in multivariate analyses, with 
reduction in risk of death by 90-96% (HR=0.04-0.10) (7,11). Despite their high prevalence 
there was a lack of prognostic significance for both nodal metastasis, and ECS in those 
metastases (7, 11, 28, 29). Level of functional preservation in terms of swallowing was 
high, in general, for the study cohort but progressive, statistically significant reduction in 
swallowing function was observed as adjuvant treatment intensified (7, 11), in line with 
the prospective RTOG trials.  
 
In a focused, 152 patient cohort study, all with p16+ oropharyngeal cancer, we further 
confirmed that ECS was not a predictor of poor prognosis (28). Excellent locoregional 
control (97%) and survival outcomes (3-year disease-free survival: 90%, disease-specific 
survival: 93%) were observed for this cohort. Presence of ECS, both as measured from the 
routine pathology reports and by using a stringent histological grading, failed to show any 
significant reduction in disease-free survival (DFS) (3-year DFS; ECS (routine report)-
positive vs. negative: 89% vs. 94%, p=0.21 (Figure 2); ECS(stringent grading)-positive vs. 
negative: 92% vs. 97%, p=0.08). Notably, addition of chemotherapy in the adjuvant 
treatment regimen was not associated with any benefit to survival both for the overall 
cohort and for patients with ECS. The 3-year DFS was 91.8% for ECS-positive patients 
who received CRT, and 94.5% in patients who received RT (p=0.74) (Figure 3). The 
probability of disease control by type of adjuvant treatment was also similar in patients 
with extracapsular spread who received CRT compared to those receiving RT alone 
(p=0.96) (Figure 4). These findings were also intuitively reasonable if our first premise 
(that ECS is not prognostic) was correct, since the commonest indication for chemotherapy 
was extracapsular spread. 
 
In our Cancer publication (29), the above findings were confirmed in a case-matched 
study, where again there was complete overlap of the curves for all ECS patients (measured 
by stringent histological grading) in the CRT vs. RT alone groups, matched for T stage and 
surgical margins and with no significant differences in other potentially relevant variables 
such has age, smoking history and N stage. Subsequent studies from several centers in 
United States and worldwide (University of Pittsburgh, Memorial Sloan Kettering Cancer 
Center, Mayo Clinic Cancer Center, University of Prague), have since duplicated our 

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finding, to also find no adverse risk associated with ECS in the HPV+ OPSCC patient (30-
34). 
 
 
Figure 2. Kaplan-Meier disease-free survival (DFS) estimates are shown for the study 
cohort stratified according to the presence (N=124) or absence (N =28) of extracapsular 
spread (ECS) measured from routine reporting (ECSreport) (p= .21). 
 

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Figure 3. Kaplan-Meier DFS estimates are shown for patients who had positive ECSreport results 
stratified according to the receipt of adjuvant chemoradiotherapy (ChemoRT) (N=65) versus 
radiotherapy alone (RT) (N=48) (p= .74). 

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Figure 4. Kaplan Meier estimates for probability of disease control by type of adjuvant treatment 
in patients with extracapsular spread who received CRT compared to those receiving RT alone 
(p=0.96) 
 
1.7 
Quality of Life and Functional Outcomes 
 
With the improved prognosis and younger age of onset associated with HPV-positive 
squamous cell carcinoma of the oropharynx, awareness of the impact of acute and long-
term toxicity (viz swallowing disability) of therapy and its influence on quality of life are 
increasing (35). Given the markedly increased severe acute toxicity measured in 
prospective studies (25, 26) when chemotherapy is added to postoperative adjuvant 
radiotherapy, assessment of symptoms and their impact on patient-reported quality of life 
is important to this trial. In a long term study comparing toxicities in trials of nonsurgical 
management of head and neck cancers, chemoradiotherapy regimens showed up to 500% 
more acute toxicity burden versus standard postoperative radiotherapy (36). Late sequelae, 
with an increase in swallowing dysfunction in the concurrent chemotherapy versus 
radiation alone have also been reported (37). 
 

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1.8 
Study Rationale and Summary Statement 
             
Advanced nodal stage and extracapsular spread are considered to be markers of poor 
prognosis and survival outcomes in HNSCC, which are triggers for up scaling treatment 
intensity in adjuvant settings. Being a category 1 recommendation by the National 
Comprehensive Cancer Network (NCCN), presence of ECS in postoperative OPSCC 
patients is frequently treated with chemoradiotherapy (38, 39).  This recommendation is 
based on the two prospective trials discussed above (25, 26). Most importantly, however 
neither of these trials takes into account HPV status. Furthermore, the updated long-term 
i.e. 5-year results for one of these trials, the RTOG 9501, demonstrated that both 
locoregional control (p=0.086) and DFS rates (p=0.098) were not statistically significant 
and only trends toward improvement with the addition of adjuvant chemotherapy to the 
postoperative regime were observed (40). This renders these data somewhat obsolete, and 
of dubious practical contemporary relevance. 
 
Recent literature on surgically treated HPV-positive malignancy of the tonsil and tongue 
base has identified pathological attributes which exhibit prognostic relevance, but distinct 
from traditional tobacco-related head and neck cancer. The degree of aggressiveness added 
to the disease by presence of extracapsular spread is reduced or eliminated in exclusively 
p16+ surgically treated OPSCC cohorts, matched for other prognostic variables. As a 
consequence, chemotherapy is not associated with better survival, locoregional control or 
distant metastatic rate. This finding is especially pertinent with the expanding use of 
transoral procedures which, by minimally invasive means, eradicate all known primary 
disease simultaneous with selective neck dissection and preserve swallowing. 
 
In view of this change in prognosticators and the questions it creates regarding the 
indications for adjuvant chemotherapy, it is now critical to perform prospective research 
that will inform future management options. 
 
1.9 
ADEPT Study Planning, 2-10-2012 
 
Following many months of comprehensive institutional meetings involving all relevant 
specialties (head and neck surgery, medical and radiation oncology, pathology) plus 
Siteman Cancer Center/Biostatistics Core staff, a one day Multidisciplinary Multicenter 
Planning Meeting was hosted at Washington University on 2-10-2012. Fifty five people 
attended from all relevant specialties from the six noted Academic Medical Centers invited 
to participate in ADEPT.  
 
At that event, a comprehensive plan for the ADEPT trial was discussed in detail (see 
attached Agenda) and consensus built on inclusion/exclusion criteria, data collection, 
treatment protocols and end-points of interest. The protocol herewith submitted is the 
product of that convocation of experts. 
 
 
 

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2.0 
OBJECTIVES 
 
The broad objective of this study is to demonstrate that de-intensified adjuvant therapy (i.e., 
radiotherapy alone) following minimally invasive surgical resection of p16+, ECS-positive 
oropharyngeal cancer is not inferior to chemotherapy-containing adjuvant protocols, using disease 
free survival and locoregional control as primary outcome measures. 
 
The secondary hypothesis is that toxicity will be lower and function/quality of life better in the de-
intensified, radiation alone group. 
 
The specific aims are to compare in a prospective trial, the two postoperative regimens of i) 
cisplatinum-based chemoradiotherapy to ii) radiotherapy alone, whilst maintaining excellent 
oncologic outcomes and minimizing toxicity. 
 
 
3.0 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
1. 
Patient must have histologically confirmed p16 positive squamous cell carcinoma 
of the oropharynx (OPSCC).  (See Section 4.0.) 
 
2. 
Patient must have undergone transoral resection of their T1-4a oropharynx primary 
to a negative margin, and a neck dissection(s). 
 
3. 
Patient’s disease must be pathological N-stage positive. 
 
4. 
Patient’s disease must show extracapsular spread (ECS) in their nodal metastasis.  
(See Section 4.0.) 
 
5. 
Patients with synchronous primaries are included. 
 
6. 
Patients with unknown primaries are included if the diagnosis and resection of a 
primary site in the oropharynx is made from an endoscopic or robotic surgical 
procedure(s). 
7. 
Patients with recent excisional node biopsies/neck dissections are included if 
material is evaluable for extracapsular spread. 
 
8. 
Patient must be ≥ 21 years of age. 
 
9. 
ECOG performance status ≤ 2 (Karnofsky ≤ 60%; see Appendix A). 
 
10. 
Patients must have normal organ and marrow function as defined below: 
 
- leukocytes  
 
 
 
 
≥3,000/mcL 
- absolute neutrophil count  
≥1,500/mcL 

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- platelets 
 
 
 
 
 
≥100,000/mcL 
- total bilirubin  
 
 
 
<1.5 X upper normal institutional limit 
- AST(SGOT)/ALT(SGPT) 
≤2.5 X institutional upper limit of normal 
- creatinine  
 
 
 
 
within normal institutional limits 
OR 
- creatinine clearance  
 
≥60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
11. 
Patient (or legally authorized representative) must be able to understand and willing 
to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
1. 
Patient must not have pathologically N stage negative disease. 
  
2. 
Patient must not have outside nodal tissue from previous neck biopsy/neck 
dissections in which ECS cannot be confirmed or denied. 
 
3. 
Patient must not have a true unknown primary in which permanent section results 
are negative for malignancy in completely excised ipsilateral oropharyngeal tissue 
(palatine and lingual tonsil). 
 
4. 
Patient must not have known distant metastatic disease at presentation.  
 
5. 
Patient must not have gross residual and/or microscopic disease present after 
surgery including re-resection(s), per the operative and pathology report. 
 
6. 
Patient must not have transoral robotic surgery (TORS) for a T3 or T4 primary 
tumor. 
 
7. 
Patient must not have a history of prior invasive malignancy (except non-
melanomatous skin cancer) unless disease free for a minimum of 3 years; 
noninvasive cancers (for example, carcinoma in situ of the oral cavity, larynx, 
breast or cervix are all permissible) are permitted even if diagnosed and treated < 3 
years ago.  
 
8. 
Patient must not have had previous systemic chemotherapy for the study cancer. 
(Note: prior chemotherapy for a different cancer is allowable). 
 
9. 
Patient must not be receiving any other investigational agents. 
 
10. 
Patient must not have had any prior radiotherapy to the region of the study cancer 
that would result in overlap of radiation therapy fields 
 
11. 
Patient must not have any life-threatening comorbid illnesses e.g. stroke with major 
sequelae or myocardial infarction/ unstable angina within the preceding 3 months 

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or psychiatric illness/social situations that would limit compliance with study 
requirements.  
 
12. 
Patient must not be pregnant or breastfeeding.  If a woman of childbearing potential, 
patient must agree to use medically acceptable forms of contraception. 
 
3.3 
Inclusion of Women and Minorities  
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
 
4.0 
REGISTRATION PROCEDURES 
 
After the patients have signed the consent form, they become eligible for entry into the study when 
they meet each of the criteria listed above. In particular, patients with p16 positive oropharyngeal 
tumors meet eligibility only after their surgery and pathology specimen analysis, in which presence 
of ECS in nodal metastasis must be centrally verified. The consent process allows for patients to 
participate in either the randomized or non-randomized pathways, according to their choice. 
Following this, registration will be performed. Patients must not start any protocol-specific 
intervention, the first of which is central pathological review of their neck dissection specimen, 
prior to consent. Patients who do not consent to participate either on the randomized or on the 
nonrandomized pathways will be excluded from ADEPT and advised to receive adjuvant therapy 
regimens of their and their physicians’ choice, but will be eligible for close follow-up on the 
minimally invasive, endoscopic head and neck cancer surgery database (HRPO# 201105387). 
 
The following steps must be taken: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN)  
 
Once the patient has been entered in the Siteman Cancer Center database, the WUSM coordinator 
will forward verification of enrollment and the UPN via e-mail. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by e-mailing/faxing (email preferable) the information listed 
below to the research coordinator listed in the Siteman Cancer Center Clinical Trials Core 
Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 
1. Your name and contact information (telephone number, fax number, and e-mail 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 

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5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Dispatch date of sample shipment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database  
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by e-mail or fax within one business day. 
Verification of eligibility and pre-registration should be kept in the patient chart. 
 
Patients at all sites must be registered through the Siteman Cancer Center OnCore database 
at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.    All 
data will be recorded with this identification number on the appropriate case report forms 
(CRFs). 
 
4.4 
Registration for Study Therapy 
 
4.4.1 Patients Who Consent for Participation on the Randomized Pathway 
 
Patients with p16+ OPSCC and extracapsular spread will be registered for ADEPT 
after they consent for participation and randomization. If found to meet all other 
eligibility criteria, they will be randomized to either of the two study treatment 
arms.  Patients will undergo radiation oncology and medical oncology consults 
prior to randomization.  The same UPN will be used for randomization (for details 
of randomization, see Section 5.3). 
 
4.4.2 Patients Who Consent for Participation on the Non-Randomized 
Pathway 
 
Patients with p16+ OPSCC and extracapsular spread will also be registered for 
ADEPT if they give consent to participate, but refuse randomization and select the 
ADEPT treatment arm of their choice, adjuvant radiation or chemoradiation. The 
treatment regimens will be exactly the same as specified in the protocol for 
randomized patients. These patients will comprise the observational cohort for 
ADEPT.  
 
Each of these patients will be identified with a unique patient number (UPN) ending 
in the letters NR (non-randomized). All data will be recorded with this 

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identification number on the appropriate CRFs. The reason(s) for refusal of 
randomization will be documented and recorded in the CRF. 
 
4.4.3 Patients Who Refuse to Undergo the Assigned Treatment Arm after 
Randomization  
 
In addition to patients who consent for ADEPT’s non-randomized pathway, there 
may be patients who initially choose to be randomized but change their decision 
after randomization. Such patients who refuse to be treated in the arm to which they 
are randomized but who still want to receive treatment as specified in the study 
protocol for the other arm will be allowed to participate in the study. These patients 
will be considered as the study’s prospective observational cohort.   
 
4.5 
Companion Protocol for All p16+ Patients 
 
A separate companion protocol is anticipated for use in those institutions where 
identification of all presenting p16+ OPSCC cases can be accomplished. The lead 
investigators of this study will support this protocol, which will track treatment pathways 
for those patients who are not eligible for, or who do not randomize on the ADEPT 
protocol. 
 
This will be implemented to determine an answer to a separate question, i.e. what fraction 
of patients with p16+ OPSCC proceed forward with the transoral surgery/neck dissection 
treatment paradigm, and what  proportion , for whatever reason, do not. 
 
4.6 
Study Track Log 
 
All p16+ OPSCC patients detected to have ECS after the surgical resection and who meet 
all other eligibility criteria will be offered the opportunity to participate in the trial.  If the 
patient refuses to consent and participate, the reason and refusal will be recorded in a 
separate log.  Reason for non-participation will also be recorded if there is failure to 
randomization and/ or treatment initiation after the patient consents. A Study Track Log 
will be created in the form of an Excel spreadsheet without any identifying information.  
The log will have the columns as shown in the table below.  The first column labeled as 
“Serial Number” will be entered as sequentially increasing numbers such as Non-
participant 1, Non-participant 2, etc…Other participating centers will be asked and 
encouraged to maintain a similar Study Track Log and the template for the spreadsheet will 
be sent to them for uniformity. 
 
Serial Number 
Primary surgeon’s  
initials 
Time of trial proposal 
(Month-Year e.g. Jan-
13) 
Reason for 
refusal to 
participate 
Non-participant 1 
 
 
 
Non-participant 2 
 
 
 
 
 

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5.0 
STUDY PROCEDURES  
 
5.1 
Surgery Guidelines 
 
5.1.1 Surgery Guidelines for Primary  
 
Transoral resection of the primary will be performed to a negative margin with 
resectional tools of the surgeon’s choice, although robotic techniques will not be 
used for larger, T3 or T4 primaries. The surgeon will attempt to achieve a clear 
margin around the primary (which will vary in dimension, and does not need to be 
recorded). A negative surgical margin in the oropharynx will be verified by 
intraoperative frozen section taken from the margins of the patient’s wound or the 
specimen.  
 
Reconstruction is at the surgeon’s discretion but may include primary closure, local, 
regional pedicled or free flap repair. 
 
5.1.2 Surgery Guidelines for Unknown Primary 
 
In cases going forward to surgery with an unknown primary, preliminary 
microscopic or telescopic endoscopy under anesthesia frequently reveals areas of 
suspicion. The laser can be used to make precise exploratory incisions into deeper 
layers of lingual or palatine tonsillar tissue to expose an occult submucosal 
carcinoma. Once exposed, these small lesions may be confirmed by frozen section 
and excised to a negative margin, completeness confirmed by frozen-section 
margin re-evaluation, taken from the defect. If the primary is not identified by 
frozen section, the ipsilateral palatine and lingual tonsil(s) and/or remnants are 
excised and submitted for pathological section. 
 
If the primary is discovered on permanent section, the case may remain in the study, 
as long as a negative margin is achieved. Patient with unknown primaries where 
the submitted tissue is negative on the permanent section pathological report must 
be considered ineligible for randomization and excluded from the study. 
 
5.1.3 Surgery Guidelines for the Neck 
 
At the same surgical session as the TLM, patients with clinically positive necks or 
with a high risk of occult metastasis will undergo neck dissection. A selective neck 
dissection including levels II through IV lymph nodes is the standard minimum 
procedure. Neck dissections may be extended to other levels e.g. IB or V depending 
upon the clinical and/ or image-based evidence of nodal disease. The selective neck 
dissection may be converted to a modified or radical, if necessary. Especially with 
tumors of the tongue base and/ or other oropharyngeal site approaching or 
extending across the midline, patients may undergo a contralateral elective neck 
dissection, either simultaneous or staged. Retropharyngeal lymph nodes, if detected 

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pre- or intra-operatively (usually for tonsil or oropharyngeal wall primaries), may 
be removed transorally through the posterior aspect of the pharyngeal defect. 
 
5.2 
Pathological Evaluation of Surgical Specimen 
     
5.2.1 p16 Immunohistochemistry 
 
Immunohistochemistry for p16 will be performed on the oropharyngeal squamous 
cell carcinoma surgical specimens on representative 4mm sections cut from 
formalin-fixed, paraffin-embedded tissue blocks using a monoclonal antibody to 
p16 (MTM Laboratories; monoclonal) on autostainers according to standard 
protocols, with appropriate positive controls. Positive p16 expression will be 
defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of 
the tumor cells. 
 
5.2.2 Neck Dissection Specimen 
 
The neck dissection will be grossed in according to the standard institutional 
procedure. All lymph nodes will be inspected grossly for evidence of ECS and 
nodal sectioning designed accordingly. Participating center pathologists will 
perform the initial histopathological screening for ECS, and if positive, the case 
will be registered and informed consent presented to the patient at the participating 
center. If consent is obtained, all sections showing metastatic carcinoma in neck 
dissection material will be submitted for central review and presence of ECS 
confirmed and graded. Randomization will be based on the results of this central 
review/confirmation, not on the results of institutional review.  
 
Extracapsular spread, the primary determinant of eligibility, will be defined                 
in a range from absence of the nodal capsule up to soft tissue metastasis which 
obliterates the entire lymph node. It should be noted that some of the study 
pathologists do not consider a thickened, fibrous capsule or pseudocapsule with no 
intervening normal lymphoid tissue to represent “true” ECS, so it is anticipated that 
those institutions will submit fewer patients for central review. However, from 
institutions where this finding is considered to be ECS, those patients will be 
allowed in the trial.  To account for this differential in classification, all ECS data 
will be stratified for extent of ECS based on central review and strict definitions, 
which will enable an ultimate discriminating analysis of all grades of ECS 
represented in the trial. It should be noted that our preliminary published data 
demonstrate that neither the presence of, nor varying degrees of ECS make any 
difference to oncologic outcome in the presence of adjuvant therapy, which will be 
delivered to all patients in this trial. 
 
All hematoxylin and eosin slides that show metastatic carcinoma in neck dissection 
material shall be sent for central review (along with the corresponding outside 
pathology report) shall be sent to the lab of Dr. James Lewis, Jr. at the address 
below: 

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Vanderbilt University Hospital 
1211 Medical Center Drive 
Room 3020D – Surgical Pathology 
Nashville, TN 37232-7415 
(615) 322-2302 
james.lewis@vanderbilt.edu  
 
Prior to shipment, confirm with the Washington University research coordinator 
that specimens should be shipped to Dr. Lewis.  The back-up central reviewer will 
be Dr. Rebecca Chernock at Washington University.  The WU research coordinator 
will provide shipping instructions to Dr. Chernock if required. 
 
The outside institution slides will be retained at the central site until all data is 
accumulated. 
 
5.2.3 Margin Reporting 
 
The margins of the primary resection will be determined and recorded as positive, 
negative or “close” (<5mm) in the final resection or re-resection specimen, 
according to institutional practices. Patients with final positive margins are 
ineligible. 
 
5.2.4 Tumor Banking 
 
Tumor banking is allowed for patients in this protocol and data reflecting tissue 
entered into a participating institution’s tumor bank will be collected as part of the 
database. Every patient who consents to participate in this protocol will be offered 
the opportunity to participate in the site specific tumor bank protocol (at 
Washington University, the tumor bank protocol for head and neck cancer [Tissue 
Acquisition Protocol, TAP] is IRB protocol #201102323). Linked translational 
studies in future, covered under separate protocols will thus be facilitated. 
 
 
 

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5.3 
Treatment Randomization 
 
Patients will be randomized 1:1 to concurrent chemoradiation or radiotherapy using a 
formal probability model implemented by SAS proc plan.  Assignments will be balanced 
within blocks of random size.  
 
Furthermore, the treatment arms will be stratified by T-stage (T1-T2 vs. T3-T4) and 
smoking history (≤ 10 pack years vs.>10 pack years). 
 
After eligibility and registration is completed, each patient will be added to the 
randomization table, created by the study statistician at Washington University, 
incorporating all patients from the primary and secondary sites. This process will assign 
the treatment arm, centralize and balance assignment of patients to the two treatment arms, 
and allow for patient-initiated withdrawals following randomization. The secondary sites 
will be able to access their patient enrollee’s randomization result via a website which will 
create access to information for a particular patient via their UPN. All this information will 
be communicated to each secondary site via the secondary site packet.   
  
5.4 
Radiotherapy Treatment Planning and Administration 
 
All patients regardless of arm assignment will receive radiotherapy as detailed below. 
 
5.4.1 Dose Specifications 
 
The prescribed radiotherapy dose will be 60 Gy in 2 Gy once-daily fraction size 
(total of 30 fractions). The daily dose of 2 Gy will be prescribed such that 95% of 
the Planning Target Volume 60 (PTV60) volume receives at least 60 Gy. PTV52 
also may be defined. The spinal cord dose may not exceed 48 Gy to any volume 
larger than 0.03 cc. 
 
5.4.2 Technical Factors 
 
1. 
Linear accelerator: Megavoltage energy photon beam irradiation is 
required. 
2. 
CT simulator 
3. 
Image Guidance for IGRT: Daily image guidance of IMRT may be used. 
4. 
Proton beam: Proton beam is not allowed due to insufficient published data 
on its use in an adjuvant setting for head and neck cancer patients. If data 
become available during the study supporting proton beam treatment for 
head and neck cancer patients, a protocol amendment to allow this 
technology will be considered. 
 
 
 

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5.4.3 Localization, Simulation, and Immobilization 
 
Patients must have an immobilization device (e.g., Aquaplast mask) made prior to 
treatment planning CT scan. 
 
The treatment planning CT scan should be performed with IV contrast if possible 
so that the major vessels of the neck are easily visualized. The treatment planning 
CT scan must be performed with the immobilization device and in the treatment 
position. 
 
5.4.4 Target and Normal Tissue Volume Definitions 
 
Clinical Target Volume 60(CTV60): This volume will receive 2 Gy per day. 
CTV60 will include the primary tumor bed (for T3 or T4 disease only; T1 and T2 
patients will receive neck only irradiation) (based on preoperative imaging, 
preoperative physical exam/endoscopy, operative findings, and pathologic 
findings). This volume may approach the skin but should not approach < 3mm. It 
is recognized that after surgery, there can be considerable distortion of normal 
anatomy. If possible, map preoperative Gross Target Volumes (GTV) onto the 
postoperative radiation therapy planning CT scan to help guide target delineation. 
 
CTV60 will include the ipsilateral pathologically positive neck node basins with 
ECS. If both sides of the neck are proven pathologically positive, CTV60 will 
include both sides). This generally means encompassing nodal levels 2a, 3, and 4 
for all cases. Nodal levels 1, 2b, 5a, and 5b are included in CTV60 in selected 
circumstances. If neck dissection clearly demarcates nodal level, the nodal level(s) 
outside of the involved level may receive a subclinical dose.   
 
CTV52: This will include all other regions felt to be at risk for harboring 
microscopic cancer that do not meet the criteria for CTV60. For example, this 
would apply to the contralateral hemineck being irradiated electively, or ipsilateral 
level(s) of the neck outside of the level with pathologically involved lymph nodes. 
This volume should not approach the skin < 3 mm. This volume will receive 1.7 
Gy per day. 
 
PTV: In general, the PTV should not go outside of the skin surface; if it does exceed 
the skin surface, the application of bolus material over this portion of the PTV may 
be considered but is generally not recommended. It is also allowable to define two 
PTVs for a given CTV: 
1) PTV Planning, which extends beyond the skin surface and is used for 
planning treatment segments 
2) PTV Evaluation, which does not reach the skin surface within 2 mm 
and is used for evaluation of the dose volume histogram to determine if 
treatment goals have been met. 
 
The minimum CTV-to- PTV expansion with daily IGRT is 3-5 mm. 

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5.4.5 Definition of Normal Tissues/Organs at Risk (OARs) 
 
1. 
Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of 
the C1 vertebral body). Superior to this is brainstem and inferior to this is 
cord. The inferior border of the spinal cord is at approximately T3-4 (i.e., 
just below the lowest slice level that has PTV on it). The spinal cord shall 
be defined based on the treatment planning CT scan. In addition, however, 
a Planning Risk Volume (PRV) spinal cord shall be defined. The PRVcord 
= cord + 5 mm in each dimension. This is irrespective of whether or not 
IGRT is used. 
2. 
Brainstem: The inferior most portion of the brainstem is at the cranial-
cervical junction where it meets the spinal cord. For the purposes of this 
study, the superior most portion of the brainstem is approximately at the 
level of the top of the posterior clinoid. The brainstem shall be defined based 
on the treatment planning CT scan. In addition, however, a Planning Risk 
Volume (PRV) brainstem shall be defined. The PRVbrainstem = brainstem 
+ 3 mm in each dimension. 
3. 
Lips and Oral Cavity: These should be contoured as 2 separate structures as 
the goal is to keep the lip dose much lower than the oral cavity dose. The 
oral cavity will be defined as a composite structure consisting of the anterior 
1∕2 to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and palate.  
4. 
Parotid Glands: Parotid glands will be defined based on the treatment 
planning CT scan. Parotid gland volume will not include any portion of any 
of the CTVs, although they can overlap the PTVs.  
5. 
Glottic/Supraglottic Larynx (GSL): This will be defined as a “triangular 
prism shaped” volume that begins just inferior to the hyoid bone and 
extends to the cricoid cartilage inferiorly and extends from the anterior 
commissure to include the arytenoids. This includes the infrahyoid but not 
suprahyoid epiglottis. 
6. 
Mandible: This includes the entire bony structure of the mandible from TMJ 
through the symphysis.  
7. 
Unspecified Tissue outside the Targets: This will be defined as tissue 
located between the skull base and thoracic inlet that is not included in either 
the target volumes or the normal tissues described above. 
 
5.4.6 Treatment Planning and Delivery 
 
IMRT dose constraints to normal structures: 
 
1. 
Spinal Cord: The PRVcord should not exceed 48 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord 
PRV should not exceed 50 Gy to any volume in excess of 0.01 cc. In 
treatment planning, the spinal cord PRV should be given the highest 
priority. 

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2. 
Brainstem: The PRVbrainstem should not exceed 52 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment 
planning, the PRVbrainstem should be given less priority than the PRVcord 
but more priority than the other critical structures listed below. 
3. 
Lips: Reduce the dose as much as possible. The mean dose should be < 20 
Gy. For non- oral cavity cancers, the maximum dose will be < 30 Gy. For 
non-oral cavity cancers, the mean dose should be < 30 Gy. For oral cavity 
cancers, the mean dose should be < 50 Gy. Efforts should be made to avoid 
hot spots (> 60 Gy) within the oral cavity. 
4. 
Parotid Glands: In most cases, it will be easier to spare one parotid than the 
other. The treatment planning goal will be for this individual parotid gland 
to receive a mean dose of < 20 Gy. 
5. 
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as 
possible. In patients with resected oral or oropharyngeal carcinoma, it is 
recommended that the dose to the larynx should be kept < 45 Gy whenever 
feasible. 
6. 
Mandible: Reduce the dose as much as possible. It is recognized that 
particularly for some oropharynx tumors especially those extending 
forwards beyond the anterior tonsil pillar, laterally to the medial pterygoid 
muscle or forwards into the deep floor of mouth, significant portions of the 
mandible will overlap the CTVs and/or PTVs; however, hot spots within 
the mandible should be avoided. It is recommended that maximum dose 
within the mandible be < 60Gy, recognizing that this is the maximum dose 
and only a small volume of the mandible in some patients will get 60 Gy 
 
5.5 
Chemotherapy Administration 
 
For patients randomized to receive chemoradiotherapy, cisplatin at 40 mg/m2 will be given 
intravenously (IV) over 60 minutes on Days 1, 8, 15, 22, 29, and 36 of radiation therapy (6 
doses for a total of 240 mg/m2).  Cisplatin can be given prior to or after the patient’s 
radiation on each day of chemotherapy delivery at the treating physician’s discretion. 
Cisplatin administration outside of these specified time points during radiation is only 
allowed in the event of holidays or scheduling conflicts that do not permit drug and 
radiation delivery on the specific date. Subsequent chemotherapy doses should follow the 
protocol specified days of treatment. Cisplatin is administered concurrent with radiation 
therapy. In the event that radiation therapy is held, no cisplatin will be administered. 
 
Note: Carboplatin and other agents (cetuximab or taxanes) cannot be substituted for 
cisplatin. 
 
Laboratory studies required <7 days of the start of each cycle: complete blood count and 
differential (to calculate absolute neutrophil count) and chemistry (to include creatinine).  
 
Dose reduction will be considered for patients developing severe toxic adverse effects (see 
Section 5.5.3). 
 

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Criteria to receive the first dose of cisplatin include: 
 creatinine clearance > 60 mL/min (by Cockcroft-Gault) or serum creatinine within 
normal limits 
 ECOG performance status < 2 
 no active serious infections 
 absolute neutrophil ≥ 1500/mcL 
 platelets ≥ 100,000/mcL 
 
Patients who do not meet these criteria may not receive cisplatin. 
 
5.5.1 Premedication Administration 
 
Premedication with palonosetron (0.25 mg IVPB) and dexamethasone (20 mg 
IVPB) is recommended prior to each dose of cisplatin. 
 
Hydration consisting of 1L IVF NS + 10 meq KCL/L + 8 meq MgSO4/L over 60 
minutes before and after cisplatin is recommended.  Additionally, 1L IVF NS over 
60 minutes on the two days following cisplatin is recommended. 
 
5.5.2 Cisplatin Administration 
 
Cisplatin shall be given at a dose of 40 mg/m2 IV over 60 minutes. 
 
5.5.3 Cisplatin Dose Modifications  
 
Neutropenia: If on the day of scheduled weekly cisplatin the absolute neutrophil 
count (ANC) is < 1000/mm3, then the cisplatin will not be given that week. The 
next dose cisplatin will be given at full dose only if ANC has recovered to ≥ 
1000/mm3. 
 
If ANC remains < 1000/mm3 for more than 7 days, all subsequent cisplatin doses 
will be reduced to 30 mg/m2, and the next weekly dose only given when the ANC 
is > 1000/mm3. In the event of neutropenic fever, reduce all subsequent doses of 
cisplatin to 30 mg/m2 and administer only when the ANC is > 1000/mm3. 
 
If, on the day of scheduled treatment, the patient again experiences an ANC < 
1000/mm3 despite the first cisplatin dose reduction, the cisplatin dose for that week 
will again not be given. 
 
If recovery has not occurred by the following week, or if neutropenic fever 
develops, there will be a second dose reduction to 20 mg/m2 for all remaining 
cisplatin doses, which can be given only after recovery of the ANC to >1000/mm3. 
 
Any subsequent ANC < 1000/mm3 on the day of scheduled treatment or any 
recurrent neutropenic fever after two dose reductions will mandate discontinuation 
of all remaining doses of cisplatin chemotherapy. 

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If hematologic recovery requires more than 3 weeks, irrespective of cisplatin dose, 
all subsequent cisplatin will be discontinued. 
 
Thrombocytopenia: If on the day of cisplatin chemotherapy the platelet count is < 
75,000, the dose will be held for the week. Cisplatin will be given full dose the 
following week if the platelets recover to ≥ 75,000/mm3. 
 
If the platelets remain < 75,000/mm3 for more than 7 days, then all subsequent 
cisplatin doses will be reduced to 30 mg/m2, and the next weekly dose only given 
when the platelet count ≥ 75,000/mm3.  
 
If the platelet count is again < 75,000/mm3 on the day of scheduled treatment 
despite the first dose reduction, that dose of cisplatin will be held. 
 
If recovery has not occurred by the following week, there will be a second dose 
reduction to 20 mg/m2 for all remaining cisplatin doses, which can be given only 
after recovery of a platelet count to ≥ 75,000/mm3. 
 
Any subsequent platelet count < 75,000/mm3 on the day of scheduled treatment, 
after two dose reductions will mandate discontinuation of all remaining cisplatin 
doses. 
 
If hematologic recovery requires more than 3 weeks, irrespective of cisplatin dose, 
all subsequent cisplatin will be discontinued. 
 
Neurotoxicity: If grade 2 neurotoxicity develops, hold cisplatin until toxicity 
improves to ≤ grade 1, then reduce all subsequent doses of cisplatin to 30mg/m2. If 
the patient experiences grade 3 or greater neurotoxicity or if grade 2 neurotoxicity 
recurs, all remaining doses of cisplatin will be discontinued. 
 
Renal: Cisplatin will only be administered if serum creatinine is < than 2 mg/dl. If 
a patient develops a rise in serum creatinine ≥ 2 mg/dL on the day of treatment, 
cisplatin will be discontinued for that week and held until recovery to < 2 mg/dL. 
All subsequent cisplatin doses will then be reduced to 30 mg/m2. If, despite this 
first dose reduction, the serum creatinine is again ≥ 2 mg/dl on the day of treatment, 
that week’s cisplatin dose will not be given, treatment will be held until renal 
recovery, and all subsequent cisplatin doses reduced to 20 mg/m2. If the creatinine 
is again ≥ 2 mg/dl on the day of treatment despite two dose reductions, or if the 
serum creatinine does not improve to < 2 mg/dL in 14 days, all remaining cisplatin 
doses will be discontinued. 
 
Nausea and Vomiting: Maximum supportive therapy will be given, and cisplatin 
will be continued at full dose for ≤ grade 2 nausea and vomiting. For grade 3 nausea 
and vomiting refractory to supportive therapy, cisplatin will be held until recovery 
to < grade 2. No dose reductions will be made. 

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Mucositis: Significant mucositis from both the radiation and the cisplatin is 
expected. However, grade 4 mucositis will prompt decision to not administer 
cisplatin on that day. 
 
Ototoxicity: For clinical hearing loss not requiring a hearing aid or for tinnitus that 
interferes with activities of daily living but that resolves prior to the next scheduled 
dose of cisplatin, reduce cisplatin to 30 mg/m2. If intolerable tinnitus persists on the 
day of treatment or if there is new hearing loss requiring a hearing aid, discontinue 
cisplatin. 
 
All other grade 3-4 non-hematological, fatigue, and alopecia adverse events: 
Discontinue cisplatin until toxicities have recovered to grade 1.  
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
Adequate hydration is strongly encouraged for patients receiving cisplatin; at least 1 liter 
of normal saline is recommended prior to the administration of the cisplatin dose and 1 liter 
of normal saline is recommended after the administration of cisplatin.  Additional IV fluids 
(1-2 liters of normal saline per day) for two consecutive days after each dose of cisplatin 
are recommended. 
 
Prophylactic antiemetics prior to cisplatin administration are also strongly encouraged. At 
a minimum, a combination of a 5-HT3 antagonist, neurokinin inhibitor and corticosteroids 
is recommended. 
 
Use of Growth Factors: Use of myeloid growth factors such as G-CSF is permitted if 
clinically indicated. Use of erythropoietin is not permitted. 
 
5.7 
Women of Childbearing Potential 
 
Women of childbearing potential (women with regular menses, women with amenorrhea, 
women with irregular cycles, women using a contraceptive method that precludes 
withdrawal bleeding, and women who have had a tubal ligation) are required to have a 
negative urine pregnancy test within 7 days prior to surgery.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 6 months following the last dose of either radiotherapy or cisplatin.  
 
If a patient is suspected to be pregnant, radiotherapy (and cisplatin, if applicable) should 
be immediately discontinued.  In addition a positive urine test must be confirmed by a 
serum pregnancy test.  If it is confirmed that the patient is not pregnant, the patient may 
resume dosing. 
 

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If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 6 months after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.8 
Quality of Life and Functional Outcome Evaluation 
 
5.8.1 Patient-reported Assessments to Be Performed 
 
1. 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire (EORTC QLQ-C30) The EORTC Quality of Life Group 
has developed a strategy for measuring QOL in clinical trials which consists 
of a questionnaire with 30 questions (41). 
2. 
MD Anderson Dysphagia Inventory (MDADI) The MDADI is a 20 item 
questionnaire designed to evaluate the impact of dysphagia on quality of 
life in head and neck cancer patients and covers physical, functional, 
emotional and global domains. The Cronbach coefficient was 0.96 for the 
questionnaire; the test-retest correlations on subscales ranged from 0.58 to 
0.93 (42). 
3. 
Speech Handicap Index The Speech Handicap Index is a 30 item speech-
specific questionnaire, validated in head and neck cancer patients and 
covering speech and psychosocial domains. Internal consistency reliability 
using Cronbach’s  for the total index and subscales were 0.95-0.98. Test-
retest reliability correlation coefficients were 0.78-0.92 in the different 
domains (43). 
4. 
Scale of Subjective Total Taste Acuity (SSTA) The SSTA is a 1-item scale 
evaluating change in taste perception and its impact on daily life (44). 
5. 
Hearing Handicap Inventory – Adult (HHIA-S) The HHIA-S is an 11 item 
screener which has been validated against pure tone audiometry, with test-
retest correlation coefficient of 0.84 (45).  
6. 
Cognitive Failures Questionnaire Cancer therapy is associated with patient-
reported changes in cognition, particularly multi-tasking, and has been 
dubbed “chemobrain.”  The CFQ is a 25 item questionnaire assessing self-
reported failures in perception, memory, and motor function (46). 
7. 
Neck Dissection Impairment Index (NDII) The NDII is a 10 item 
questionnaire designed to assess quality of life with respect to shoulder 
impairment.  Domains include physical, functional, and social. The 
questionnaire is reliable (test-retest correlation 0.91 and Cronbach  
coefficient 0.95 (47). 
8. 
University of Michigan Xerostomia Index 
 
5.8.2 Time Points at Which Assessments Will Be Performed 
 
The battery of questionnaires will be completed at the following time points: 
 prior to initiation of adjuvant therapy 
 1 month after completion of adjuvant therapy 
 6 months after completion of adjuvant therapy 

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 12 months after completion of adjuvant therapy 
 24 months after completion of adjuvant therapy 
 
Following is a calendar for administration of QOL and function questionnaires:  Goal time 
points are specified; actual time points may vary due to patient compliance with f/u 
schedule, logistics, transportation issues, cost of gasoline, treatment for co-morbid illness, 
etc. 
 
 
5.8.3 Post-Operative Therapy Patient Experience Questionnaire 
 
Patients will be encouraged to answer four open-ended questions at 6 months (+4 - 
8 weeks) from completion of the adjuvant therapy. This is not a validated 
questionnaire but has been created due to the significance of patient-reported 
outcomes in the study design of ADEPT. This questionnaire will enable patients to 
report from their perspective the information which the validated QOL and function 
questionnaires (see section 5.8.2) do not completely capture. In addition to 
checking a response, they will be encouraged to add any comments that they want 
to make in addition to the questions asked. 
 
5.8.4 Objective Measures of Functional Outcomes 
 
Modified barium swallow studies are allowed to be performed by speech pathology 
as per standard clinical practice within 1 year of completion of therapy, but these 
are optional. 
 
Baseline  (prior 
to initiation of 
adjuvant Rx) 
1month after 
completion of 
adjuvant Rx 
6 months after 
completion of 
adjuvant Rx 
12 months  
after 
completion of 
adjuvant Rx 
24 months  
after 
completion of 
adjuvant Rx 
EORTC Quality of Life 
Questionnaire-C30 
X  
X  
X  
X  
X  
MD Anderson 
Dysphagia Inventory 
X  
X  
X  
X  
X  
Speech Handicap Index 
X  
 
 
X  
 
Subjective Total Taste 
Acuity 
X  
X  
X  
X  
 
Hearing Handicap 
Inventory - Adult 
X  
X  
 
X 
 
Cognitive Failures 
Questionnaire 
X  
X  
 
X  
X  
Neck Dissection 
Impairment Index 
X  
 
 
X  
X  
University of Michigan 
Xerostomia Index 
X  
X  
X  
X  
X  

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5.9 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
 Death 
 Documented and confirmed disease recurrence/progression during adjuvant 
therapy 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of radiation or chemotherapy 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious non-compliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.10 
Duration of Follow-up 
 
Patients will be followed for a minimum of 2 years, but will also be followed beyond this 
if available, and reported on at 5 years, to document rare late recurrences or second 
primaries. Patients removed from study for unacceptable adverse events will be followed 
clinically until resolution or stabilization of the adverse event.  
 
As of Amendment 8 – 10/22/2019, patients will no longer be followed beyond 2 years.  
 
Follow up examination will include: 
 Appointments will be scheduled at 1 and 3 months post-completion of adjuvant 
therapy, then every 3-4 months for year 1 and, every 4-6 months for year 2. After 
year 2, we will collect survival data through internal sources.  
 General H&P, full head and neck examination, laryngo-pharyngoscopy (mirror 
and/or fiberoptic and/or direct procedure), imaging and laboratory evaluations as 
indicated by clinical findings.  
 Whole body PET at 6 months (± 6 weeks) after completion of adjuvant therapy, 
contingent on patient compliance with follow-up schedule. PET is recommended 
but head and neck CT/MRI and chest imaging can also be performed if whole body 
PET cannot be performed due to logistic reasons such as insurance, compliance, 
etc. 

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 Neck and Chest imaging at 12 months (± 6 weeks) after completion of treatment 
and then semi-annually (± 6 weeks) for year 2, contingent on patient compliance 
with follow-up schedule.  Chest-CT or CT/PET will be strongly preferred for the 
first 2 years, although a chest X-ray will be acceptable depending on patient 
compliance and insurance.  
 
5.10.1 Determination of recurrent disease 
 
Any possible signs of disease recurrence will be carefully evaluated.   All lesions 
suspected for recurrent disease at the primary site, the neck or distant sites will 
undergo histological evaluation with biopsy or cytology. Histological confirmation 
of recurrence does not require central review. 
                        
  
6.0 
PHARMACEUTICAL INFORMATION 
 
6.1 
Cisplatin (CDDP, Platinol-AQ®) 
 
6.1.1 Cisplatin Description 
 
Molecular formula: PtCl2H6N2 
Molecular weight: 300.1. 
 
6.1.2 Formulation 
 
Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, 
and hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of 
sterile water. The pH range will be 3.5 to 4.5. Cisplatin injection also is available 
from the manufacturer in aqueous solution, each ml containing 1 mg cisplatin and 
9 mg NaCl and HCL or NaOH to adjust pH. 
 
 
 

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6.1.3 Mechanism of Action 
 
The dominant mode of action of cisplatin appears to be the inhibition of the 
incorporation of DNA precursors, although protein and RNA synthesis are also 
inhibited. Although this drug seems to act as an alkylating agent, there are data to 
indicate that its mode and sites of action are different from those of nitrogen 
mustard and the standard alkylating agents. Additional information can be found in 
the package insert. 
 
6.1.4 Supplier 
 
Cisplatin is commercially available as 1 mg/mL in both 50 mL multiple dose vial 
and 100 mL multiple dose vial. 
 
6.1.5 Dosage Form and Preparation 
 
The stability of cisplatin in solution is dependent upon the chloride ion 
concentration present in the diluent. Cisplatin should be diluted into an IV solution 
containing NaCl at a minimum chloride ion concentration of 0.040 mol/L (0.2% 
NaCl). Needles, syringes, catheters and IV administrations sets containing 
aluminum must be avoided during preparation and administration due to cisplatin-
aluminum reaction causing precipitation and loss of potency. Mannitol 12.5 to 25 
gm may be added per institutional guidelines.  
 
6.1.6 Storage and Stability 
 
The dry, unopened vials should be stored at room temperature (15° -25° C). The 
unopened container should be protected from light and stored in the carton until 
contents are used. The vials and injection should not be refrigerated. Reconstituted 
solution of cisplatin is stable for 20 hours when stored at 27°C and should be 
protected from light if not used within 6 hours. Cisplatin has been shown to react 
with aluminum needles, producing a black precipitate within 30 minutes. 
 
6.1.7 Administration 
 
Patients will receive cisplatin via IV infusion over 60 minutes.  Adequate hydration 
must be maintained during and after administration as described in the treatment 
section. All patients should be premedicated with antiemetics. 
 
 
 
 

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7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
7.1 
Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.03: June 14, 2010) will 
be utilized for all toxicity reporting.  A copy of the CTCAE version 4.0 (v4.03: June 14, 
2010) can be downloaded from the website below. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can 
be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.2 
Unanticipated Problems 
 
Definition: 
 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the 
research); and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
7.3 
Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human 
subjects 
research 
or 
failure 
to 
follow 
the 
determinations 
of 
the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
 
 
 

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7.4 
Serious Noncompliance 
 
Definition: Noncompliance that materially increases risks that result in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 
 
7.5 
Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the event.  For 
secondary sites, the Washington University PI will issue approval of the exception, but it 
must also be submitted to the local IRB with documentation of approval forwarded to 
Washington University.  HRPO approval is not required for protocol exceptions occurring 
at secondary sites. 
 
7.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality 
Assurance and Safety Monitoring Committee (QASMC) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.7 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and research coordinator of all reportable events (as described in Section 7.6) 
within 1 working day of the occurrence of the event or notification of the secondary site’s 
PI of the event.  This notification may take place via e-mail if there is not yet enough 
information for a formal written report (using either an FDA MedWatch form if required 
or an institutional SAE reporting form if not).  A formal written report must be sent to the 
Washington University PI and research coordinator within 10 working days of the 
occurrence of the event or notification of the secondary site’s PI of the event.  The death 
of a research participant that qualifies as a reportable event should be reported within 1 

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working day of the occurrence of the event or notification of the secondary site’s PI of the 
event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines. 
 
7.8 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary 
site of all reportable events that have occurred at other sites (as described in Section 7.6) 
within 10 working days of the occurrence of the event or notification of the PI of the event.  
This includes events that take place both at Washington University and at other secondary 
sites, if applicable. 
 
7.9 
Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study 
treatment. 
Deaths 
Any reportable death while on study or within 30 
days of study 
Immediately, within 24 hours, to PI and 
the IRB 
Any reportable death while off study  
Immediately, within 24 hours, to PI and 
the IRB 
Adverse Events/Unanticipated Problems 
Any reportable adverse events as described in 
Sections 7.1 and 7.2 (other than death) 
Immediately, within 24 hours to PI and 
within 10 working days to the IRB 
All adverse events regardless of grade and 
attribution should be submitted cumulatively  
Include in DSM report 
Noncompliance and Serious Noncompliance 
All noncompliance and serious noncompliance as 
described in Sections 7.3 and 7.4 
Immediately, within 24 hours, to PI and 
within 10 working days to the IRB 
 

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8.0 
STUDY CALENDAR 
 
For all time points from completion of therapy:  goal time points are specified; actual time points may vary due to patient compliance with f/u schedule, logistics, 
transportation issue, cost of gasoline, treatment for co-morbid illness, etc. 
 
   
Prior to 
registration 
Within 6-
8 wks of 
surgery** 
Weekly 
during 
RT/CRT 
At 1 mo. 
post-
RT/CRT 
At 3 mos.  
post- 
RT/CRT 
Every 3-4 months up 
to 12 mos. and every 
4-6 mos. between 12 
and 24 mos. post-
adjuvant completion 
At 6 & 12 mos.  
post- RT/CRT 
At 24 mos. post-
RT/CRT 
Pre-treatment biopsy* 
 
 
 
 
 
 
 
 
Surgeon’s exam to confirm site and clinical stage* 
 
 
 
 
 
 
 
 
USG Neck or CT, or CT/PET or MRI of H&N* 
 
 
 
 
 
 
X [At 12 mos. (± 6 weeks) and then 
semi-annually (± 6 weeks) for the 
year 2 or if suspicion of recurrence] 
Chest imaging (X-ray or CT or CT/PET) (also see 
Section 5.10)* 
 
 
 
 
 
 
X  [At 12 mos. (± 6 weeks) and then 
semi-annually (± 6 weeks) for the 
year 2  
Whole body PET* 
 
 
 
 
 
 
X (6 mos)§ 
 
Radiation oncology consult (also see Section 4.4)* 
 
 
 
 
 
 
 
 
Medical oncology consult (also see Section 4.4)* 
 
 
 
 
 
 
 
 
Surgery [TLM/TORS + neck dissection(s)] 
X 
 
 
 
 
 
 
 
Pathology assessment at participating center & 
tissue banking (separate institutional consent)* 
 
 
 
 
 
 
 
 
Central pathology assessment 
 
X 
 
 
 
 
 
 
Informed consent after surgery & path assessment 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
Comorbidity 
 
X 
 
 
 
 
 
 
Height and weight (height only w/in 6 wks of 
surgery) 
 
X 
X 
X 
X 
X 
X 
X 
Performance status 
 
X 
X 
X 
X 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
Adjuvant therapy (RT/CRT) 
 
X 
 
 
 
 
 
 
QOL/Function Assessments ( per QOL metrics in 
Section 5.8.1) 
 
X 
 
X 
 
 
X 
X 
Focused H & P by surgeon 
 
 
 
X (6-12 weeks) 
X 
X 
X 
 
Focused H&P by radiation oncologist  or medical 
oncologist 
 
 
X (± 2 
days) 
X (± 2 
weeks) 
X (± 4 
weeks) 
 
 
 
Image-guided or direct biopsy 
 
If suspicion of recurrence 
Pregnancy test (if applicable) 
X* 
X 
 
 
 
 
 
 
CBC w/diff & Absolute Granulocyte count 
X* 
X 
X*** 
X (± 2 
weeks)*** 
 
 
 
 

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Basic metabolic panel 
X* 
X 
X*** 
X (± 2 
weeks)*** 
 
 
 
 
Bilirubin, AST or ALT  
X* 
X 
X*** 
 
 
 
 
 
Serum creatinine or Creatinine Clearance 
 
X 
X*** 
 
 
 
 
 
Adverse event evaluation 
 
 
X 
X 
X 
 
 
 
Dental evaluation if necessary 
 
X 
 
 
 
 
 
 
Modified barium swallow if done≠ 
 
X 
 
 
 
 
X (6 mo) 
X 
Baseline Audiometry if done 
 
X 
 
 
 
 
 
 
 
*Interventions that are generally performed as part of the initial work-up prior to primary surgical resection and are not interventions related to the trial. Each of these interventions 
individually or collectively is not required for enrolment, e.g., imaging may include any, but not all of the following modalities; CT or MRI or PET-CT. 
 
**The goal will be 6 weeks from surgery; however complications/logistical delays for a minority of patients are inevitable.  An outer range for the interventions including initiation 
of adjuvant treatment will be 8 weeks after surgery. 
 
***These lab investigations will be done only if the patient gets randomized to chemoradiation arm. 
 
§ Timing is contingent on patient compliance with follow-up schedule. Head and neck CT/MRI and chest imaging can be done instead of PET due to logistic reasons (see section 
5.10). 
 
≠ Modified Barium Swallow in patients with T3-T4 tumors which receive radiation to the pharynx (optional, for trial purpose)

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9.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration, after surgery & pathologic analysis 
Registration Form 
After consent, Prior to randomization 
On Study 
Pathology 
Registration & Eligibility Checklist 
Randomization and Treatment Assignment 
 
After central pathology confirmation 
 
Surgery Form 
After Registration and Eligibility confirmation  
Adjuvant Treatment Record 
Due within 4 weeks after completion of adjuvant treatment 
Follow-up Form* 
Per study calendar (see section 8.0) 
EORTC QLQ-C30 
MDADI 
Speech Handicap Index 
Subjective Total Taste Acuity 
Hearing Handicap Inventory – Adult 
Cognitive Failures Questionnaire 
Neck Dissection Impairment Index 
U Mich Xerostomia Questionnaire 
 
 
Prior to adjuvant therapy initiation and 1 month, 6 months, 12 
months, and 24 months after completion of adjuvant therapy 
according to the QOL metrics (Section 5.8.2)* 
Adverse Events Form 
At the time of any toxicity 
SAE Reporting Form 
At the time of any SAE 
*Goal time points are specified; actual time points may vary due to patient compliance with f/u schedule, 
logistics, transportation issues, cost of gasoline, treatment for co-morbid illness, etc. 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 
10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Data and Safety Monitoring Committee (DSMC) will meet to review toxicity data at least every 6 
months following the activation of the first secondary site.  The report will be prepared by the 
statistician with assistance from the study team and will be submitted to the Quality Assurance and 
Safety Monitoring Committee (QASMC).  This report will include: 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 

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error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
 Protocol activation date at each participating site 
 Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
 Expected accrual end date, accrual by site, and accrual by arm 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
 Summary of toxicities at all participating sites and separated by arm 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study 
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to 
be prepared by the study team will be submitted to the QASM Committee beginning 6 months 
after study activation at Washington University. 
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
A DSMC will consist of no fewer than 3 members including 2 clinical investigators (none of whom 
is involved in this trial) and a biostatistician.  Like investigators, DSMC members are subject to 
the Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMC will disclose any potential conflicts of interest to the 
trial principal investigator and/or appropriate university officials, in accordance with institution 
policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMC must also 
be disclosed.  
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources/
Protocol_Review_and_Monitoring_Committee/QASMCQualityAssurcance.pdf 
 
10.1 
Early Stopping Rules 
 
A. Greater than 15% rate of loco-regional recurrence events in the POART only arm.  
B. Greater than 10% rate of local recurrence in the T1 or T2 patients (who do not receive 
RT   targeted to the primary site). 
C. For POACRT, >50%, and for POART, > 30% severe acute toxicity rates in the form 
of ≥ Grade III [(CTCAE) version 4.0 (v4.03: June 14, 2010)] dysphagia or xerostomia, 

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up to 100 days post completion of adjuvant therapy. We will perform the first check 
when 40 patients are 6 months post-completion of therapy. 
D. A 3% treatment-related mortality (TRM) in either arm, POART or POACRT. 
 
The study statistician has developed check points that regularly assess frequency of events 
(recurrences, severe acute toxicity) in the above categories (A,B,C) and the probability that 
such rates would, or would not be due to chance. The stopping rules were based on the trial 
size, recurrence rate and median time to recurrence, and toxicity rates, allowing the study 
to be suspended if the recurrence rate or the severe toxicity rate is unacceptable.  
 
 
11.0 
AUDITING 
 
Since Washington University is the coordinating center, each site will be audited annually by 
Siteman Cancer Center personnel (QASMC) unless the outside institution has an auditing 
mechanism in place and can provide a report. The outside sites will be asked to send copies of all 
audit materials, including source documentation.  The audit notification will be sent to the 
Washington University Research Patient Coordinator, who will obtain the audit materials from the 
participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Additional details regarding the Auditing Policies and procedures can be found at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources/
Protocol_Review_and_Monitoring_Committee/QASMCQualityAssurcance.pdf  
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Endpoints  
 
The study’s primary endpoints will be (1) disease-free survival and (2), locoregional 
control. Disease-free survival (DFS) is defined as the time from surgery to the date of death 
or recurrence of disease. Locoregional failure will include local recurrence at the primary 
oropharyngeal site and regional recurrence in the neck nodal basins. Local recurrence will 
be defined as biopsy proven tumor in the immediate vicinity (i.e. within 2 cm) of the 
original primary. Regional recurrence will be defined as development of histologically 
proved metastases in cervical lymph nodes.  
 
The secondary oncological endpoints will be distant metastasis rates and disease specific 
survival. After completion of treatment, biopsy or imaging-detected recurrent disease at 
sites away from the original primary and cervical zone will constitute a distant metastasis. 

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Disease-specific survival (DSS) is defined as the time from surgery to death from recurrent 
oropharyngeal cancer or treatment-related death.  
 
The secondary toxicity endpoints are the incidence of adverse events as defined by CTCAE 
4.0 (see above under Section 7.0 "Regulatory and reporting requirements"). 
 
The secondary quality of life endpoints will include the EORTC-QLQ-C30, which has a 
total score, one general QOL and one “within the last week” subscale, as well as a single 
general health item and a single overall QOL item. The MDADI has 1 global dysphagia 
item, physical, function and emotional subscales and one summary scale, which is the sum 
of the 3 subscales rescaled to 0-100. The SHI has one global speech handicap item and a 
summary score, which is a sum of the remaining 29 items on a 0-120 scale. The SSTA has 
a single 5-point item. The HHI-A has 12 sensory and 13 emotional items, which are 
summed separately for form 2 summary subscores. The CFQ has 3 subscales describing 
perception, memory and motor function. The NDII has 3 subscales describing physical, 
functional and social components of neck dissection and a total score, which is the sum of 
the three subscale scores rescaled to 1-100. The UMXI has a single, total score, which is 
the sum of the 8 items rescaled to 0-100. 
 
12.2 
Study Design 
 
A multicenter, randomized, two-armed prospective trial has been planned with equal 
allocation of patients to each arm stratified by T stage and smoking history (see above 
under Section 5.3 "Treatment randomization"). Power calculations are based on non-
inferiority analyses of the two primary endpoints. The definitive analysis will be performed 
when each of the study patients has been followed for a minimum of two years.  One 
interim analysis will be performed midway through the recruitment period and at the end 
of it. An interim report will be issued once all data is collected on the last accrued patient 
two years from closure of enrolment and a further report at 3 years from closure. Patients 
who do not consent to randomization or who refuse participation in the arm to which they 
are randomized prior to receiving any treatment on study will be followed in a separate, 
observational cohort.  
 
12.3 
Sample Size and Power Estimation 
 
12.3.1 Primary Endpoints 
 
Sample size calculation for the planning of a prospective non-inferiority trial with 
a time-to-event endpoint was performed by the Siteman Cancer Center Biostatistics 
Core, assuming power=0.8 and a family-wise type I error rate =0.05 (48). Based on 
our preliminary data from 112 patients with p16+ oropharynx cancer and ECS, for 
a margin of 5% clinically allowable difference in the disease-free survival of 
patients receiving CRT versus adjuvant RT alone, a total of approximately 496 
patients would be required, with equal numbers in both arms. The 2 year DFS 
estimate in adjuvant RT alone group was 92.7% versus 94.7% in the group 
receiving adjuvant CRT. 

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The same data indicate an expected locoregional failure rate of 0/65 with chemoRT 
(0% with 95% confidence interval (0.37%, 4.5%)) and 2/66 with RT alone (3% 
with 95% confidence interval (0.37%, 10.5%)). The proposed sample size will 
provide power=.80 at a 0.025 significance level to reject the null hypothesis of 
inferiority of locoregional failure rate with RT alone. The assumptions of the power 
calculation are that a Z-test will be used with a noninferiority margin of 5%, a 
baseline failure rate of 1% with chemoRT and a maximum failure rate of 3.2% with 
RT alone. The power calculation for DFS was carried out using Jung et al (48) 
methodology. The power calculation for locoregional control rate was carried out 
using  SAS 9.3 proc power. The sample size and power calculations above apply to 
patients randomized to treatment, but would also have formed the basis for a purely 
non-randomized observational cohort design, driven by the same hypothesis. 
 
12.3.2  Secondary Oncologic and Toxicity Endpoints 
 
Disease specific survival will be described by estimation of median DSS and DSS 
rates at 2 years with 95% confidence intervals. This endpoint is primarily 
descriptive, and no power calculation has been performed. 
 
Approximately 50 tests for difference of proportion are anticipated when 
comparing rates of complications and adverse events. Expected frequencies in the 
two study arms are not well documented, and many of these events are rare. At a 
minimum, the proposed sample will provide power ≥ .80 to detect a difference of 
19% using a Hochberg step-up method to limit the familywise type I error rate to 
.05. 
 
12.3.3 Secondary Quality of Life Endpoints 
 
Mean or median quality of life will be compared in the two study arms to determine 
whether the observed difference is larger than noise (total variance, including 
within-patient and between-patient variance). Patient-specific and clinical 
significance of observed differences will be a matter for discussion at the end of the 
study; that is, the study does not intend to determine a minimal important difference 
(MID) (49). The study does use current empirical guidelines for the EORTC-QLQ-
30 global score (50)with the understanding that both the magnitude and variance of 
scores vary considerably from patient to patient, from one time point to another and 
by such factors as disease condition, age and comorbidity. MIDs are undefined for 
patients similar to those to be included in this study, although SHI scores > 7 are 
considered to indicate significant worsening function. For the remaining scales, a 
change of 1 standard deviation can be considered a perceptible difference; that is, 
a change of 20.0 for the subscales of the MDADI, 15.0-20.0 for the subscales of 
the HHI-A, 2.8-4.1 for the items of the NDII and ~24.4 in the UMXI. The proposed 
sample will have ≥ .80 power at a multiplicity corrected α=.001 to detect a 
difference of 3 points in the EORTC-QLQ-30 global score. It will have > .95 power 

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at the same significance level to detect the "small" 7 point difference documented 
by Cocks et al (50). 
 
12.3.4 Patient Accrual 
 
Six centers are currently participating in the study. Each center is anticipated to 
enroll about 20 - 25 patients per year. This enrollment rate would complete accrual 
in approximately three to four years, with a further two year minimum follow up 
from completion of last patient enrolment. Any loss of anticipated accrual due to 
smaller than expected numbers of patients with extracapsular spread will be 
compensated for by recruitment of additional study sites, once we have a fully 
approved protocol. These new sites will be unanimously agreed upon by the 
foundational member institutions of the study. 
 
12.3.5 Drop Offs 
 
Patients who do not start adjuvant therapy for whatever reason will be followed, 
but not entered into the analysis of adjuvant therapy- randomized groups. 
 
12.4 
Analysis 
 
12.4.1 Analysis Population 
 
All patients who receive a randomized assignment will be included in the intent-to-
treat analysis, regardless of the treatment received. Randomized and observational 
cohorts will be analyzed jointly with stratification by cohort to adjust for systematic 
differences between patients choosing and those refusing randomization. 
Additional exploratory analyses also may be carried out within each cohort. 
 
12.4.2 Analysis Plan  
 
The statistical analysis will commence after the final enrolled patient has reached 
the minimum two-year follow-up. 
 
12.4.3 Analysis Plan for Primary Endpoints  
 
The primary analysis of disease free survival, including patients from both cohorts, 
will be carried out using Kaplan-Meier models and p-values calculated by log-rank 
test. Additional Cox proportional hazards models may be created to estimate hazard 
ratios by study arm and to allow for covariate adjustment.  
 
Locoregional control failure rates will be compared using a chi-square test with 
normal approximation. Fisher's exact test may be used if failure frequencies are too 
low to allow a valid chi-square test.  
 

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To correct for testing two primary endpoints, non-inferiority of DFS and 
locoregional control failure rate, a Hochberg step-up method will be used (51). Both 
endpoints will be tested without multiplicity correction. Following this step, the 
decision criteria are: if the larger p-value is < .05, then the study would conclude 
that non-inferiority has been shown. If the larger p-value is ≥ .05 and the smaller 
one is < .025 (that is, α/2), then the study would conclude that non-inferiority has 
been shown. If the larger p-value ≥ .05 and the smaller one is ≥ .025, then the study 
would fail to show non-inferiority. 
12.4.4 Analysis Plan for Interim Analysis 
 
A Lan–DeMets alpha spending function with the O’Brien–Fleming stopping 
boundary will be applied to the interim analysis of primary and secondary endpoints 
(52). If the stopping boundary is not crossed, patients will continue to receive the 
group assignments until the final analysis. Analyses of primary and secondary 
endpoints are performed in the intention-to-treat population.  
 
12.4.5 Analysis Plan for Secondary Endpoints  
 
Chi-square tests will be used to compare distant metastasis rates and Kaplan-Meier 
models to compare disease specific survival by study arm. Additional Cox 
proportional hazards models may be created to estimate hazard ratios by study arm 
and to allow for covariate adjustment.  
 
Chi-square or Fisher's Exact tests will be used with Hochberg step-up multiplicity 
correction to test for differences in rates of complications and adverse events.  
 
Tables and histograms will be used to explore change in the subscales and summary 
scales at each time point and over time. Multiplicity corrected tests for trend (such 
as the non-parametric Jonckheere-Terpstra test) will be used to compare patients 
with and without chemotherapy at single time points. Spearman’s rank correlation 
or, where there are a large number of tied scores, Kendall’s tau-b will be used to 
explore correlation (redundancy) between QOL (sub)scales prior to modeling. 
Generalized estimating equations (GEE) will be used to model the probability of 
each (sub)scale score by study arm at each of 6 time points (study entry 1, 3, 6, 12 
and 24 months).  
 
 
 
 

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13.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Each participating institution must have the following documents on file at Washington University 
prior to first subject enrollment: 
 Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 
 Documentation of IRB approval of an informed consent form. The consent must 
include a statement that data will be shared with Washington University, including the 
Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if 
applicable), and the Washington University study team. 
 Documentation of Federal Wide Assurance, signed FDA Form 1572, and signed and 
dated CVs of all participating investigators. 
 Documentation of training in protection of human subjects by all participating 
investigators. 
 Protocol signature page signed and dated by the investigator at each participating site. 
 
The Principal Investigator is responsible for disseminating to the participating sites all study 
updates, amendments, reportable adverse events, etc.  There will be one current version of the 
protocol document at any given time and each participating institution will utilize that document.  
Protocol/consent modifications and IB updates will be forwarded electronically to the secondary 
sites within 2 weeks of obtaining Washington University IRB approval with acknowledgement of 
receipt requested.  Secondary sites are to submit protocol/consent/IB modifications to their local 
IRBs within 4 weeks of receipt, and confirmation of submission must be forwarded to the 
appropriate contact person on the Washington University study team at the time of submission.  
Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to the 
Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 
 
 

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14.0 
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