Phase II Randomized Trial of Transoral Surgical Resection Followed by Low-Dose or Standard-Dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer
Phase: PHASE2
Conditions: Human Papilloma Virus Infection, Stage III Squamous Cell Carcinoma of the Oropharynx, Stage IVA Squamous Cell Carcinoma of the Oropharynx, Stage IVB Squamous Cell Carcinoma of the Oropharynx
Sponsor: ECOG-ACRIN Cancer Research Group

E3311 
 
1 
Phase II Randomized Trial of Transoral Surgical 
Resection followed by Low-dose or Standard-dose IMRT 
in Resectable p16+ Locally Advanced Oropharynx Cancer 
STUDY CHAIR: 
Robert L. Ferris, M.D. Ph.D 
STUDY CO-CHAIR: 
Harry Quon, M.D., M.S. 
STUDY STATISTICIAN: 
Shuli Li, Ph.D. 
MEDICAL ONCOLOGY CO-CHAIR: 
Ranee Mehra, M.D. 
RADIATION THERAPY CO-CHAIR: 
Harry Quon, M.D. 
SURGICAL QUALITY ASSURANCE CO-CHAIR: 
Gregory Weinstein, M.D., FACS 
PATHOLOGY CO-CHAIR: 
Joaquín García, M.D. 
LABORATORY CO-CHAIRS: 
Christine H. Chung, M.D. 
 
Robert L. Ferris, M.D., Ph.D. 
PATIENT OUTCOMES AND QUALITY OF LIFE 
 
CO-CHAIRS: 
Maura L. Gillison, M.D., Ph.D. 
 
Lynne Wagner, PhD. 
 
Jolie Ringash, M.D., M.Sc. 
 
Jan Lewin, Ph.D 
HEAD AND NECK COMMITTEE CHAIR: 
Barbara Burtness, M.D. 
Version Date: October 9, 2020 
NCI Update Date: January 15, 2014 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology  
July 9, 2013 
NRG / NRG Oncology Foundation, Inc 
 
Addendum #1 Incorporated prior to activation 
SWOG / SWOG 
 
Update #1 Incorporated prior to activation 
 
 
Update #2 – 7/13 
 
 
Addendum #2 – 2/14 
 
 
Update #3 – 1/14 
 
 
Addendum #3 – 6/14 
 
 
Addendum #4 – 2/15 
 
 
Addendum #5 – 6/15 
 
 
Addendum #6 – 1/16 
 
 
Addendum #7 – 9/16 
 
 
Addendum #8 
 
 
Addendum #9 
 
Agents 
NSC# 
Supply 
Cisplatin 
NSC# 119875 
Commercial 
Carboplatin 
NSC# 241240 
Commercial 
Rev. Add8 
Rev. 2/15

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Table of Contents 
Schema .................................................................................................................... 6 
1. Introduction ...................................................................................................... 7 
1.1 Study Disease .......................................................................................... 7 
1.2 HPV Positive Oropharynx Tumors............................................................ 7 
1.3 Role of Surgery in Head and Neck Cancer ............................................... 8 
1.4 Postoperative radiotherapy (PORT) with or without cisplatin 
chemotherapy ....................................................................................... 15 
1.5 Role of IMRT and Lower Dose RT in Oropharynx Squamous Cell 
Carcinoma ............................................................................................. 17 
1.6 Correlative Studies Background............................................................. 19 
1.7 Clinical Functional Outcomes ................................................................ 21 
1.8 Functional Swallowing Outcomes .......................................................... 21 
1.9 Patient-Reported Outcomes .................................................................. 22 
2. Objectives ....................................................................................................... 23 
2.1 Primary Objective .................................................................................. 23 
2.2 Secondary Objectives ............................................................................ 23 
2.3 Laboratory Research Objectives: ........................................................... 23 
3. Selection of Patients ....................................................................................... 24 
3.1 Registration to Surgery (Arm S) ............................................................. 24 
3.2 Registration/Randomization to Step 2 - Arms A, B, C, and D ................. 27 
4. Registration and Randomization Procedures .................................................. 28 
4.1 Registration To Surgery (Arm S) ............................................................ 31 
4.2 Registration/Randomization To Step 2 (Arms A, B, C, and D) ................ 35 
5. Treatment Plan ............................................................................................... 37 
5.1 Primary Surgical Therapy (Arm S) .......................................................... 37 
5.2 Adverse Event Reporting Requirements ................................................ 59 
5.3 Dose Modifications ................................................................................ 64 
5.4 Supportive care ..................................................................................... 67 
5.5 Duration of Therapy .............................................................................. 69 
5.6 Duration of Follow-up ........................................................................... 69 
6. Measurement of Effect ................................................................................... 70 
6.1 Time to Progression ............................................................................... 70 
6.2 Methods of Measurement .................................................................... 70 
7. Study Parameters ............................................................................................ 71 
7.1 Therapeutic Parameters ........................................................................ 71 
7.2 Biological Sample Submissions .............................................................. 73 
8. Drug Formulation and Procurement ............................................................... 74 
8.1 Cisplatin ................................................................................................. 74 
8.2 Carboplatin ............................................................................................ 76 
9. Statistical Considerations ................................................................................ 79 

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9.1 Objectives .............................................................................................. 79 
9.2 Sample Size and Accrual Rate ................................................................ 80 
9.3 Primary Objective: Efficacy .................................................................... 80 
9.4 Primary Objective: Feasibility ................................................................ 82 
9.5 Secondary Objectives ............................................................................ 83 
9.6 Handling Missing Data ........................................................................... 85 
9.7 Laboratory Endpoints ............................................................................ 85 
9.8 Randomization Scheme ......................................................................... 85 
9.9 Monitoring Plan ..................................................................................... 85 
9.10 Gender and Ethnicity ............................................................................. 86 
10. Functional Outcomes, Patient Reported Outcomes and Quality of Life .......... 87 
10.1 Observer-Assessed Outcomes ............................................................... 87 
10.2 Patient Reported Outcomes (PROs) ...................................................... 88 
11. Specimen Submissions .................................................................................... 90 
11.1 Collection and Submission Schedule ..................................................... 90 
11.2 Specimen Collection Guidelines ............................................................ 91 
11.3 Shipping Procedures .............................................................................. 92 
11.4 ECOG-ACRIN Sample Tracking System ................................................... 93 
11.5 Use of Specimens in Research ............................................................... 94 
11.6 Sample Inventory Submission Guidelines .............................................. 94 
12. Specimen Analyses: Diagnostic Review and Research Studies ........................ 95 
12.1 Diagnostic Review and Classification (MANDATORY) ............................ 95 
12.2 Research Studies ................................................................................... 95 
12.3 Lab Data Transfer Guidelines ................................................................. 97 
13. Electronic Data Capture .................................................................................. 98 
13.1 ECOG-ACRIN Radiation Oncology Quality Assurance Materials............. 98 
14. Patient Consent and Peer Judgment ............................................................... 98 
15. References ...................................................................................................... 98 
Appendix I  Pathology Submission Guidelines ..................................................... 105 
 Appendix II  Patient Thank You Letter ................................................................ 109 
Appendix III  AJCC Head/Neck Staging Criteria .................................................... 110 
Appendix IV  ECOG-ACRIN Checklist for Submission of Radiation Oncology Quality 
Assurance Materials ...................................................................................... 114 
Appendix V  Patient Reported and Functional Outcomes (PRO) Administration . 116 
Appendix VI  Modified Barium Swallow (MBS) Credentialing Checklist ............... 118 
Appendix VII  Surgeon Credentialing Questionnaire ............................................ 120 
Appendix VIII  Modified Barium Swallow Study Form ......................................... 121 
Appendix IX  Letter Explaining Modified Barium Swallow Video Upload Instructions123 
Appendix X  E3311LGS1 Identification of novel biomarkers and therapeutic targets 
of higher-risk disease in ECOG 3311.............................................................. 125 
 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
4 
 
STUDY CHAIR 
Robert L. Ferris, M.D., Ph.D. 
5115 Centre Avenue 
Hillman Cancer Center, Room 2.26b 
Pittsburgh, PA 15213 
Tel: 412-623-0327 
Fax: 412-623-4840 
Email: ferrisrl@upmc.edu  
 
STUDY CO-CHAIR 
Harry Quon, M.D., M.S. 
Sidney Kimmel Comprehensive Cancer Center 
401 North Broadway 
Weinberg Building, Suite 1440 
Baltimore, MD  2123 - 2410 
Tel: 410-502-3877 
Fax: 410-502-1419 
Email: hquon2@jhmi.edu 
 
 
Rev. 1/16, 
9/16 

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Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  
Please see the data 
submission section of the 
protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev. Add8 

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Schema 
Arm A: (7 weeks)
Observation8
Arm D: (5-7 weeks)
Radiotherapy 
IMRT 66 Gy/33 Fx + 3
CDDP 40 mg/m2 weekly
High Risk6
Low Risk5
R
E
G
I
S
T
E
R
R
A
N
D
O
M
I
Z
 E4
Intermediate Risk7
Stratify:
=  10 pk-yr vs.
> 10 pk-yr
Arm B: (5-7 weeks)
Radiotherapy
IMRT 50 Gy/25 Fx3
Arm C: (5-7 weeks) 
Radiotherapy
IMRT 60 Gy/30 Fx3
Transoral
Resection
with neck
dissections
Step 11,2
R
E
G
I
S
T
E
R
1. Resectable oropharynx carcinoma, p16+ by IHC, PS 0-1
2. Credentialing of surgeon required as part of site participation, neck levels dissected and nodal yield (> nodes/neck)
3. Radiotherapy will be given with an intensity modulated radiotherapy (IMRT) technique. Standard ECOG credentialing through QARC will be required.
4. Stratify by current/former smoking history(< 10pk-yr vs. > 10pk-yr)
5. Low Risk: T1-T2, N0-N1 AND clear (> 3mm) margins, AND no ECE or PNI/LVI.
6. High Risk: Any of the following features: one or more positive margin(s) with any T stage, OR “Extensive” (> 1mm) ECE, OR > 5 metastatic lymph nodes 
(regardless of primary tumor margin status).
7. Intermediate Risk: Any of the following features: one or more "close" (< 3mm) margin(s), OR "Minimal" (< 1mm) ECE, OR N2a (1 or more lymph node >3cm in 
diameter), OR N2b (2-4 lymph nodes positive, any diameter < 6cm), OR with perineural invastion or lymphovascular invasion.
8. If = 2 events are observed among the first ten patients registered on Arm A within one year, currently enrolled and subsequently enrolled low risk patients who 
have not progressed will be treated with IMRT 50 Gy
9. Patients found to have N2c (bilateral nodes), OR N3 (>6cm node) disease on final pathologic analysis.
Accrual: 515
Arm S
Step 2
Unknown  Risk9
L
O
N
G
T
E
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M
F
O
L
L
O
W
-
U
P
 
Rev. 6/14, 2/15,  
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Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
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1. 
Introduction 
1.1 
Study Disease 
Head and neck cancer remains a significant cause of morbidity worldwide, with 
approximately 400,000 new cases per year. Squamous cell carcinoma is the 
most common histological type, accounting for >90% of head and neck tumors. 
At presentation, more than half of patients present with advanced locoregional 
disease1.  
Ongoing advances in multidisciplinary management of this complex and multi-
varied disease process are resulting in improved function, organ preservation, 
quality of life and survival.  
Major developments include primary chemoradiotherapy (CRT) for unresectable 
disease with the goal of organ preservation, the addition of chemotherapy (CT) to 
adjuvant radiotherapy (RT) and improvement in surgical and radiation 
techniques2. A consistent result of these aggressive multi-modality approaches is 
improvement in local-regional control but the impact on the development of 
metastases is variable. Despite these advances, 50% of all patients recur either 
locally or at distant sites (30%) 2. A minority of patients will undergo successful 
surgical salvage of recurrent disease. While single institution series evaluating 
intensified CRT regimens suggest a shift in failure pattern to distant metastases, 
better control of local disease remains paramount to improve survival of patients 
with HNSCC 2. 
1.2 
HPV Positive Oropharynx Tumors 
Approximately 95% of head and neck cancers are of squamous cell histologic 
origin, and arise from the lip/oral cavity, nasopharynx, oropharynx, hypopharynx, 
and/or the larynx. Among these sub-sites, the incidence of base of tongue and 
tonsillar carcinomas has been increasing over the past decade, especially in 
individuals under the age of 45 3 .This change has been attributed to the 
increasing prevalence of human papillomavirus (HPV) infection in developed 
countries, the practice of oral sex and increasing number of sexual partners3. 
Interestingly, patients with HPV-positive SCC have shown better overall survival 
and higher cure rates as compared to those with HPV-negative SCC4. HPV is 
now recognized to play a role in the pathogenesis of head and neck squamous 
cell carcinoma (HNSCC) 5. Both molecular and epidemiologic studies 
demonstrate that approximately 60% of oropharynx cancers, specifically of the 
lingual and palatine tonsils, are HPV associated5.  
High-risk HPV genotypes (i.e. 16, 18, and 31) are known to be tumorigenic in 
human epithelial tissues. The E6 and E7 viral oncoproteins of high-risk HPV 
promote tumor progression by inactivating the TP53 and Rb tumor suppressor 
gene products, respectively6. These tumors appear to be clinically and 
molecularly distinct from HPV-negative tumors. HPV-positive tumors are more 
likely to arise from the oropharynx, exhibit poor differentiation and basaloid 
morphologic features, and present at a lower T stage than HPV-negative 
primaries5-9.  
Recently, HPV-associated head and neck carcinoma, largely presenting in the 
oropharynx, has been identified and appears to be rapidly increasing in 

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incidence8, 10. In the US, some two-thirds of patients with OPSCC have HPV-
associated tumors. Hence, in 2010 approximately 4200 squamous cancers of the 
oropharynx caused by tobacco and alcohol and 8400 new HPV-associated 
oropharynx cancer presented for treatment. HPV-associated OPSCC typically 
present as smaller primary tumors than those caused by substance abuse. 
Because HPV-associated OPSCC more frequently present in a younger 
population and seem particularly responsive to treatment with a better overall 
survival11, attention has begun to focus reduction of treatment toxicity.  In 
particular, attention has focused on the development of late effects from CRT 
(CRT) as the number of survivors have increased. While the organ-preservation 
CRT approach has become a standard of care12, 13, there remain serious 
concerns about both short and long-term toxicity. Furthermore, the changing 
epidemiology of HPV-associated OPSCC has caused many to re-think this 
approach.  Given the potential long-term sequelae of radiation therapy for a 
younger population, 14 an alternative treatment paradigm is needed.  The clearly 
better prognosis of this group of patients supports re-evaluation of adjuvant 
treatment intensity, and in particular the prognostic and predictive role of 
traditional pathologic biomarkers obtained at surgery. 
Results from ECOG 2399 using induction chemotherapy with carboplatin and 
paclitaxel followed by CRT with taxol/70Gy showed that HPV-positivity in 
oropharyngeal cancer patients was associated with a significantly improved 
overall response to 2 cycles of paclitaxel/carboplatin induction chemotherapy 
(82% vs. 55%, p=0.01), as well as 2-yr PFS (85% vs. 50%, p=0.05) and overall 
survival (94% vs. 58%p=0.004) following weekly paclitaxel/RT 16 . Although acute 
toxicity was acceptable with this regimen, a substantial number of OP patients 
have long-term consequences following CRT. In E2399, 49% of OP patients had 
moderate to severe swallowing impairment 3 months following treatment, and 3% 
were still PEG dependent after 12 months. These results have generated interest 
in less toxic regimens for HPV-positive patients who experience substantial 
treatment side effects with contemporary CRT regimens 
1.3 
Role of Surgery in Head and Neck Cancer 
Background/Rationale: 
Our central hypothesis is that transoral surgery (TOS) is feasible and effective in 
low- to intermediate-risk, HPV+ oropharyngeal squamous cell carcinoma 
(OPSCC) patients. We hypothesize that this permits pathologic-risk adjusted 
reduction in adjuvant therapy and radiotherapy treatment planning benefits, and 
may be associated with favorable functional and quality of life benefits without 
negatively impacting oncologic results. We will test this hypothesis in a 
randomized phase II design, to gather prospective data that will be essential to 
guide the design of a future, randomized phase III trial comparing the 
surgery/adjuvant therapy with standard non-surgical therapy. 
The current standard of care for primary nonsurgical treatment of locally 
advanced HNSCC is concurrent platinum-based chemoradiotherapy (CRT), 
which has been shown to significantly improve overall survival (OS), progression-
free survival (PFS), and/or locoreginal control compared with radiotherapy (RT) 
alone or the sequential administration of chemotherapy and RT2.  In a meta-
analysis of 63 trials with nearly 11,000 patients with HNSCC, the addition of 
chemotherapy to RT resulted in an absolute survival improvement of 6% at 5 

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years15. The results of this meta-analysis were confirmed in subsequent updated 
meta-analyses, the most recent of which included 93 randomized trials and 
17,346 patients 16. Cisplatin CRT (CRT) regimen is efficacious but also 
associated with significant toxicities and is suitable for patients with good 
performance status and without severe comorbidities 17. In addition to the 3-
weekly schedule, a variety of other cisplatin schedules of administration have 
been employed (e.g. weekly as proposed here)18. More recently, the combination 
of RT plus cetuximab, a monoclonal antibody against the epidermal growth factor 
receptor, was proved superior to RT alone in patients with oropharyngeal, 
laryngeal, and hypopharyngeal HNSCC 19, 20, 21. The addition of cetuximab to RT 
was most effective in younger, good performance status, nonsmoking individuals, 
as tend to be present in p16+ patients22.          
The last twenty years have seen many advances in the management of HNSCC. 
The recognition that, through combined modality therapy, many advanced 
cancers could be controlled without a highly morbid operation (and without 
compromising the chance for cure) led to the development of new treatment 
schedules and the incorporation of new agents in the therapeutic 
armamentarium. These approaches were largely predicated on the assumption 
that normal tissue preservation would equate to functional preservation most 
notably for swallow function.  Unfortunately, organ preservation does not always 
equate to functional preservation.  These apparent therapeutic gains have been 
accompanied by significant early and late toxicity due to CRT23.  Chronic 
aspiration and dysphagia have been identified as important, but often 
underreported late toxicities of organ preservation regimens for HNSCC.  Severe 
(grade 3-4) late laryngopharyngeal toxicity was reported in 43% of HNSCC 
survivors evaluated in a pooled analysis of 3 RTOG trials of concomitant CRT.   
It is now clear that late swallowing injury is at least related to the dose of the 
radiotherapy and the use of concurrent chemotherapy.  Both have been 
established as independent risk factors in several multivariate analyses24-26.  
Dose correlation studies suggest that the threshold upon which late injury to the 
swallowing muscles such as the constrictor muscles occur in the range of 55-60 
Gy when a large volume of the muscles are exposed to these doses of radiation.  
In addition, recent data show that most patients who develop severe refractory 
dysphagia years after radiotherapy for HNSCC have been treated with doses of 
70 Gy or more 27. Hence, one strategy to reduce the risk of late swallowing injury 
would be to de-intensify the dose of radiation, particularly in patient populations 
with a favorable prognosis. 
Initial hypotheses that these young patients, with fewer morbidities, would 
tolerate treatment better and have less quality of life (QOL) impairment have 
been refuted; in fact, evidence suggests a greater acute QOL disadvantage in 
this cohort28, 29.  Thus, attention has focused on the development of late effects 
from CRT as the number of survivors have increased.  
While the organ-preservation CRT approach has become a standard of care 12, 
13, there remain serious concerns about toxicity, both short and long-term. 
Furthermore, the changing epidemiology of head and neck cancer has caused 
many to re-think this approach.  Given the potential long-term sequelae of 
radiation therapy for a younger population14, an alternative treatment paradigm 
must be found, particularly for patients with oropharyngeal SCC. A common 
transoral route of exposure, incorporating minimally invasive techniques with 

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transoral laser CO2 microsurgery (TLM) 30 and transoral robotic surgery (TORS) 
31, 32 has emerged33 
Role of transoral surgery (TOS) for OPSCC 
As HPV-associated OPSCC more frequently present in a younger population and 
seem particularly responsive to treatment with a better overall survival11, 
attention has begun to focus on the reduction of treatment toxicity.  In particular, 
attention has focused on the development of late effects from CRT (CRT) as the 
number of survivors have increased. While the organ-preservation CRT 
approach has become a standard of care 12, 13, there remain serious concerns 
about toxicity, both short and long-term. Furthermore, the changing epidemiology 
of head and neck cancer has caused many to re-think this approach.  Given the 
potential long-term sequelae of radiation therapy for a younger population,14 an 
alternative treatment paradigm must be developed, especially for patients with 
OPSCC. A common transoral route of exposure, incorporating minimally invasive 
techniques with transoral CO2 laser microsurgery 30 (TLM) and transoral robotic 
surgery (TORS) 31, 32 has emerged.33  
TOS dramatically limits the morbidity of surgical exposure and substantially 
reduces the acute and late effects of resection.  It is important to recognize that 
the morbidity of past surgeries was a function of the injury that occurred with the 
required transcervical neck exposure.  What is not clear is to what extent 
resection of important swallowing structures impact on this.  The experience to 
date with TLM and TORS would suggest that resection can be safely performed 
for T1-2 oropharyngeal tumors without contributing to increased late swallowing 
complications as measured by dependence on percutaneous gastrostomy (PEG) 
tube. This is a particular attractive approach as HPV-associated OPSCC typically 
present as smaller primary tumors than those caused by substance abuse 34, 35. 
TOS for OPSCC using traditional headlight visualization, C02 laser-based TLM 
and more recently, robotic-assisted surgery, has been practiced at an increasing 
number of North American institutions. Case series suggest that excellent long-
term function may be anticipated after resection. Indications, contraindications, 
standards of practice and outcome reporting are being defined. Surgical 
resection of OPSCC can be a curative single modality for appropriately selected 
Stage I-III tumors and for many Stage IV tumors when combined with standard 
adjuvant therapy. The adjuvant therapy that has been applied has been based on 
clinical studies evaluating adjuvant therapy for squamous cell carcinomas in 
multiple tumor sites 36, 39. Clearly, patients who receive single modality transoral 
surgery have the functional advantage of swallowing preservation as a result of 
the ability to spare adjacent musculature critical to swallowing function.  Whether 
this advantage is maintained with the addition of adjuvant radiation or 
chemoradiation remains unknown. Thus, the role of modern low-morbidity 
resection in the multidisciplinary management of Stage III-IV oropharynx cancer 
remains undefined.   
The Head and Neck Committees of the Radiation Therapy Oncology Group and 
the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) have performed 
surgical trials in the recent past. Surgical interest in cooperative group activity 
remains high. For example, ECOG 4393 represented a large study evaluating 
surgical margins, demonstrating the ability to perform surgical/adjuvant trials. 
While only a handful of institutions initially pursued transoral resection, it is now 

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undertaken at an increasing number of academic medical centers increasing 
clinical investigation by qualified academically-oriented head and neck surgeons 
increasing the successful collection and storage of fresh, untreated tumor for 
scientific investigation. 
Numerous retrospective single-institution reports and a few important multicenter 
trials have generated significant enthusiasm for these transoral approaches in 
the multidisciplinary approach. Indeed, many surgeons advocate its use as part 
of a de-intensification approach that warrants a comparative trial.  In addition, 
while adjuvant therapy trials for oral cavity carcinoma have been published 37, 
little prospectively gathered data on postoperative therapy for p16+  OPSCC are 
available. 
Transoral resection of many pharyngeal and laryngeal tumors is now technically 
feasible and increasingly utilized. This dramatically limits the morbidity of surgical 
exposure and reduces substantially the acute and late effects of resection.  It is 
important to recognize that the morbidity of past surgeries was a function of the 
injury that occurred with the required transcervical neck exposure.  What is not 
clear is to what extent resection of important swallowing structures impact on 
this.  The experience to date with TLM and TORS would suggest that resection 
can be safely performed in some oropharyngeal tumors, such as T1-2 tumors, 
without contributing to increased late swallowing complications as measured by 
dependence on percutaneous gastrostomy (PEG) tube. 37 
 HPV-positive SCC, which often presents with a small primary tumor, is 
particularly amenable to such an approach because the functional deficit 
resulting from their removal is low. Thus, more than 7,500 of the 12,600 
oropharynx cancers anticipated in 2010 are expected to be amenable to this type 
of transoral surgical approach, either as a single treatment modality or as part of 
a combined modality regimen.  
Transoral resection of oropharyngeal cancers using the C02 laser or, more 
recently, robotic surgery, has been practiced at an increasing number of North 
American institutions. Furthermore, case series suggest that excellent long-term 
function may be anticipated after resection of early T1-T2 tumors.(ADD 
CITATIONS) The da Vinci surgical robot (Intuitive corp., Sunnyvale, CA) is now 
FDA-cleared for the resection of T1-T2 cancers of the oropharynx, and the 
machine is widely available. Robotic and laser transoral resection, while 
promising and increasingly utilized, should be investigated prospectively in order 
to design the most appropriate randomized phase II trial comparing this approach 
with CRT.  
Surgical resection of oropharynx cancer is a curative therapy and can be a single 
modality for patients with Stage I-III tumors.  For many Stage IV patients, 
adjuvant radiation therapy has the advantage that the radiotherapy dose is 
reduced (60 Gy) and may not require the addition of concurrent CT. Hence, 
surgical therapy has the potential to substantially diminish the application of high-
dose radiation treatment as well as CRT for patients who are expected to do well. 
In those patients with more advanced disease, surgical resection in combination 
with post-operative CRT also has the potential to increase locoregional control. 
Clearly, patients who receive single modality transoral surgery have the 
functional advantage of swallowing preservation as a result of the ability to spare 
adjacent musculature critical to swallowing function.  Whether this advantage is 

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maintained with the addition of adjuvant radiation or CRT remains unknown. 
Thus, the role of modern low-morbidity resection in the multidisciplinary 
management of Stage III-IV oropharynx cancer remains undefined.  
The Head and Neck Committees of the Radiation Therapy Oncology Group and 
the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) have performed 
surgical trials in the recent past and surgical interest in cooperative group activity 
remains high. ECOG, for example, completed a large study of surgical margins, 
demonstrating the ability to perform surgical/adjuvant trials. While only a handful 
of institutions initially pursued transoral resection, it is now undertaken at an 
increasing number of academic medical centers. A significant additional benefit 
will result from increasing the numbers of qualified academically oriented 
surgeons in head and neck cancer clinical investigation. The last decade’s 
emphasis on non-surgical management of head and neck cancer has resulted in 
impediments to the collection and storage of fresh, untreated tumor for scientific 
investigation. Biopsy material has been collected, but is frequently limited in 
volume. Even dedicated institutions continue to struggle with surgery and 
pathology algorithms and protocols that encourage adequate and reproducible 
specimen accrual. Involvement of head and neck surgical investigators in the 
primary treatment of this disease is critical to the development of protocols for 
tissue collection, processing and storage, and to the creation of large, shared 
tissue repositories. 
Human papillomavirus-associated head and neck cancer:  analysis of E2399, 
RTOG 0129 and ECOG 1308 
Human papillomavirus has been linked to the pathogenesis of HNSCC. 
Approximately 50-60% of OPSCC cases are positive for HPV. HPV-positivity is 
associated with a better prognosis. The effect of tumor HPV status on therapeutic 
response and survival has been evaluated in a phase II clinical trial conducted by 
the ECOG (E2399) 11 as well as in the context of two phase III trials, RTOG 0129 
and TROG 02.02 40, 41.  
In E2399, patients with stage III or IV oropharyngeal or laryngeal SCC were 
treated with induction CT followed by CRT. The impact of tumor HPV status—as 
determined by in situ hybridization—on survival was evaluated using proportional 
hazards models. Genomic DNA of HPV genotypes 16, 33, or 35 was located 
within tumor cell nuclei of 38 of 96 cases (40%, 95%CI 29.7- 50.1). In a total of 
96 patients (out of 105 eligible) who had HPV testing performed, 58 (60%) were 
HPV-negative and 38 (40%) HPV-positive. In oropharyngeal primaries (n=60), 
the incidence of HPV positivity was 60%; in laryngeal primaries (n=36) it was only 
6%. HPV-positive tumors were significantly associated with Caucasian race, fully 
active performance status, oropharyngeal cancers, early tumor stage, and 
basaloid histomorphology. Response rates after induction CT (81.6% vs. 55.2%, 
p=0.01) and CRT (84.2% vs. 56.9%, p=0.07) were higher in patients with HPV-
positive tumors when compared to patients with HPV-negative tumors. After a 
median follow-up of 39.1 months, patients with HPV-positive tumors had a risk of 
progression that was 72% lower (HR=0.28, 95% CI: 0.07-1.0) and a risk of death 
that was 79% lower (HR=0.21, 95% CI: 0.06-0.74) than patients with HPV-
negative tumors. The 2-year overall survival rate was 62% (±0.06) for HPV-
negative patients and 95% (±0.05) for HPV-positive patients (log rank test, p-
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for HPV-negative patients and 86% (±0.07) for HPV-positive patients (log rank 
test, p-value=0.02). 
RTOG 0129 was a phase III trial that compared standard and accelerated boost 
RT regimens, both with concurrent cisplatin. There were no differences in 
efficacy between the two arms. A retrospective analysis of the patients enrolled 
in RTOG 0129 has been published 40. This analysis combined cases of OPSCC 
in both arms of the trial (n=317) and demonstrated that tumor positivity for HPV-
16 was associated with HR for death of 0.36 (p =0.0001). Patients with HPV-
negative OPSCC cancer had essentially identical progression-free survival as 
those with hypopharynx and larynx primaries, with an approximate 60% 1-year 
rate. Smoking history modified the risk of relapse in the RTOG 0129 analysis. 
OPSCC patients who were HPV-positive but smoked 20 pack-years or more had 
a HR for OS of 1.91 (95% CI, 1.20-3.05) over patients who were HPV positive 
but smoked less than 20 pack-years; patients who were HPV-negative and 
smoked less than 20 pack-years had a HR of 2.25 (1.44-3.50) and patients who 
were HPV-negative but smoked 20 pack-years or more had a HR 4.30 (2.40-
7.71); and the 2-year PFS was 95%, 80%, 71% and 63%, respectively. Within 
the HPV-positive group, patients could be further divided by tobacco use history 
(in pack-years, = 10 vs. >10) and N stage (N0-2a vs. N2b-3). Patients with > 10 
pack-years and N2b-3 disease make up the intermediate risk group; all others 
comprise the low-risk group. Looking into smoking history further, patients who 
were p16+ and smoked >5 pack-years can be categorized as “unfavorable” or 
“intermediate risk”: with a 2-year PFS of 65% and a 3-year PFS of 61% using 
CRT in RTOG 0129. Therefore, a smoking history of 5 pack-years has been 
proposed as the cut-off to define favorable vs. unfavorable HPV-positive OPSCC 
(essentially using p16 immunoreactivity as a surrogate marker for HPV infection).    
A common transoral route of exposure, incorporating minimally invasive 
techniques with transoral laser CO2 microsurgery 30 (TLM) and transoral robotic 
surgery (TORS) 31, 32 has emerged.33 Transoral resection of many pharyngeal 
and laryngeal tumors is now technically feasible and increasingly utilized. This 
approach dramatically limits the morbidity of past transcervical surgical exposure 
techniques reducing the acute and late effects of resection including the impact 
on swallowing function. What is not clear is to what extent resection of important 
swallowing structures can impact functional and QOL outcome, thus 
necessitating prospective level I evidence to be generated.  The experience to 
date with TLM and TORS would suggest that resection can be safely performed 
in some oropharyngeal tumors such as T1-2 tumors without contributing to 
increased late swallowing complications as measured by dependence on 
percutaneous gastrostomy (PEG) tube 42.  
In order to gather essential oncologic and functional data for the design of a 
future, randomized phase III trial, this protocol aims to determine the feasibility 
and oncologic efficacy of prospective, multi-institutional trial of TOS for HPV-
associated OPSCC, followed by risk-adjusted adjuvant therapy. In addition, we 
will assess the functional and quality of life outcomes following transoral 
resection and adjuvant therapy in patients determined to be at an “intermediate 
risk” for recurrence based on pathologic evaluation. 
We base our study design on the successfully completed, ECOG 1308 trial of 
p16+ OPSCC patients treated with induction chemotherapy, followed by risk-
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therapy versus 69.3Gy for all others]. In the current E3311 study, a surgical “CR” 
would be obtained by R0 resection using transoral surgery and neck dissection, 
including “intermediate” risk factors such as N2 status, close margins and 
microscopic ECE in good prognosis, p16+ disease, to permit de-intensification 
with lower RT dose (50GY or 60GY) without chemotherapy. 
We will test our hypothesis that upfront surgery permits treatment de-
intensification through selection of risk-adjusted adjuvant therapy based on 
pathologic biomarkers used to define an “intermediate risk” cohort (defined 
below).  This proposal will seek to differentiate a cohort of patients following post-
transoral resection defined by the absence of high risk features, including a 
positive margin (defined as carcinoma at the cut-specimen edge), 5 or more 
positive lymph nodes or ECE.  Patients with no pathologic risk factors 
constituting a low risk cohort will be observed.  For the remaining intermediate 
risk patients, we propose that the primary tumor bed with indications for 
irradiation such as perineural invasion or lymphovascular invasion but negative 
margin can be effectively treated to either 50 Gy or 60 Gy.  This represents an 
experimental reduction of approximately 13% from the lowest dose range that 
has been administered for the postoperative cohort of patients (57.6 Gy).  The 
necessity for postoperative radiotherapy (PORT) following surgery to a tumor bed 
that fails to demonstrate any adverse pathologic features is a controversial 
practice, rooted historically in the use of transcervical neck exposures and the 
early and seminal observations of Fletcher 43 that was intended to also address 
the risk of tumor surgical seeding.  The risk of local-regional relapse without 
adjuvant PORT for transcervical surgery would appear to be on the order of 10% 
36.  In the setting of a transoral approach where no cervical fascial planes are 
disrupted, the evidence to date suggests that the risk of local relapse with either 
TLM or TORS is approximately 5% 44, 42 
In summary, the suggestion is that cases of HPV-associated OPSCC have a 
more favorable prognosis in part due the natural biology of the cancer and 
possibly more radiosensitivity.  In vitro analyses have demonstrated evidence to 
support that HPV infection can associated with increased intrinsic chemo-
radiosensitivity 45, 46; though it is recognized that there is no consensus on this 
issue.  Nevertheless, there is compelling evidence both from the perspective of 
cancer cytotoxicity and normal tissue functional preservation (see above) to 
reduce the dose of postoperative radiotherapy in HPV-positive OPSCC to doses 
on the order of 55 Gy or less. 
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This proposal will seek to differentiate low-risk and intermediate-risk post-TOS 
patients defined by the absence of high-risk features that include a positive 
margin (defined as carcinoma at the cut-specimen edge), extensive/gross ECE 
(defined as greater than the 1mm cutoff) or the presence of ≥5 LN 47. We 
propose that the primary tumor bed/neck that has intermediate-risk indications for 
irradiation (perineural invasion or lymphovascular invasion but negative margin) 
can be effectively treated to either 50 Gy or 60 Gy. In the neck, N2a-N2b disease 
consisting of 5 or fewer positive nodes 47), or with microscopic (<1mm) ECE 48, 49 
also demonstrate outstanding prognosis and data do not current support the use 
of chemotherapy in prospective trials, given that the survival of HPV+ OPSCC 
approximates 85-90%. Recent, large retrospective analyses of the prognostic 
role of ECE has indicated that in a subset of HPV+ patients with microscopic 
ECE survival is excellent (85-90% 2 year PFS, see Figure 1), and may be spared 
treatment intensification using high dose cisplatin, However, this emerging data 
must be validated prospectively, including establishment of consistency in 
pathologic measurement.   
1.4 
Postoperative radiotherapy (PORT) with or without cisplatin chemotherapy 
Current postoperative radiotherapy (PORT) doses derive from a series of 
seminal investigations conducted at MD Anderson Cancer Center 39, 50.  The 
cumulative experiences from these randomized trials demonstrated that for SCC 
of all anatomic sites in the head and neck (32% of subjects with SCC of the oral 
cavity), the recommended PORT dose can be pathologically guided with high 

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rates of local-regional disease control.  While various risk stratification schema 
have been evaluated, the presence of a positive margin (not defined) and nodal 
ECE warrant at least 63 Gy 51.  In the presence of any pathologic risk factors 
identified in the tumor specimen, an increased risk of local relapse was 
statistically identified if < 54 Gy was administered compared to 57.6 Gy 39 (63% 
vs. 92%, p=.02). While the optimal postoperative dose for ECE and positive 
margins has not been established, several institutional reports have used doses 
typically in the range of 65-66 Gy or greater 37, 38. 
There is also indirect supportive evidence that a lower PORT dose may be 
sufficient when irradiating the pathologically involved neck.  Investigators from 
the Netherlands (University Medical Center Groningen) demonstrated in a large 
retrospective review of over 800 patients (52% of subjects with SCC of the oral 
cavity) that postoperative irradiation of the pathologically involved cervical neck 
to only 56 Gy was associated with 85-93% 5-year regional control rates 
depending on whether only a single or multiple nodes were involved (Vergeer et 
al, personal communication).   
Neither of these clinical experiences distinguished the local or regional control 
rates by HPV status and potentially may have represented a predominantly HPV-
negative study population based on the predominantly oral cavity SCC patients 
treated.  Nevertheless, it demonstrates that high rates of cancer control may be 
seen in the pathologically involved site.  For these reasons, the optimal 
postoperative radiotherapy dose for the HPV-positive OPSCC patient remains 
undefined. 
As such, this proposal will seek to differentiate a cohort of patients following post-
transoral resection defined by the absence of high risk features, including a 
positive margin (defined as carcinoma at the cut-specimen edge), 4 or more 
positive lymph nodes or ECE.  Patients with no pathologic risk factors 
constituting a low risk cohort will be observed.  For the remaining intermediate 
risk patients, we propose that the primary tumor bed with indications for 
irradiation such as perineural invasion or lymphovascular invasion but negative 
margin can be effectively treated to 50 Gy.  This represents an experimental 
reduction of approximately 13% from the lowest dose range that has been 
administered for the low risk postoperative cohort of patients (57.6 Gy).   
The necessity for PORT following surgery to a tumor bed that fails to 
demonstrate any adverse pathologic features is a controversial practice, rooted 
historically in the use of transcervical neck exposures and the early and seminal 
observations of Fletcher 43 that was intended to also address the risk of tumor 
surgical seeding.  The risk of local-regional relapse without adjuvant PORT for 
transcervical surgery would need to be on the order of 10%.  In the setting of a 
transoral approach where no cervical fascial planes are disrupted, the evidence 
to date suggests that the risk of local relapse with either TLM or TORS for T1/T2 
primary OPSCC is approximately 5% 44.  
While concurrent CT, typically cisplatin, has been administered for the high-risk 
patient cohort following surgery, it is clear that the use of chemotherapy can also 
unnecessarily increase the risk of late swallowing complications 23-26. 
Retrospective cohorts of TORS followed by RT have reported on the risk of 
swallowing complications, but whether reduced dosage (50 Gy vs 60 Gy) should 
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CRT is now yet known.  This proposal hypothesizes that reduced dose RT may 
provide comparable 2-year PFS rates with the potential for reduced, late normal 
tissue injury.   
1.5 
Role of IMRT and Lower Dose RT in Oropharynx Squamous Cell Carcinoma 
A significant long-term toxicity in the irradiated oropharynx cancer patient is 
xerostomia caused by radiation delivered to the major salivary glands. 
Technologic advancements that now permit conformal fields using intensity 
modulated radiotherapy [IMRT] initially applied dose-constraints to reduce the 
volume of parotid gland parenchyma exposed to high radiation doses. However, 
the salivary glands continue to receive lower radiation doses that can still result 
in long-term xerostomia, albeit of lower severity, despite the use of IMRT.  This 
can still result in significant impairment based on patient reported quality of life 
measures. 
Dysphagia is the primary functional complication encountered after radiotherapy 
for oropharyngeal cancer.  Impaired laryngopharyngeal physiology that results 
from neuromuscular fibrosis, independent of xerostomia, contributes to 
radiation-induced dysphagia. Even in the era of IMRT for oropharynx cancer, 
authors report rates of aspiration ≥1-year of 6% to 31% and g-tube dependence 
of 6% to 8%.25, 52, 53…Recent studies have demonstrated significant associations 
between swallowing outcomes and dose-volume coverage to key structures 
after IMRT including the anterior oral cavity, superior pharyngeal musculature, 
and inferior larynx/CP inlet. Dose-volume correlations have been observed for 
late objective endpoints of swallowing dysfunction such as nutritional 
dependence on a gastrostomy tube, measures of swallowing efficiency, 
aspiration, and swallowing-related QOL. 52, 54, 55  Pharyngeal dose to superior as 
well as inferior constrictor musculature is consistently found to relate to a variety 
of swallowing measures in numerous studies. Threshold pharyngeal doses as 
low as 50 Gy to the inferior constrictors (V50) 54 and as high as 65 Gy to the 52, 55 
superior constrictors have been significantly associated with aspiration, stricture, 
and swallowing efficiency.  In addition, mean pharyngeal dose is associated with 
55 QOL scores.  As such, there exists supportive evidence that reductions in the 
prescribed RT dose to the pharynx and neck offer the potential to reduce the 
risk of both objective and patient-reported evidence of late RT-induced 
swallowing dysfunction.  Based on these data, a dose threshold of at least 55 
Gy to the superior pharyngeal musculature is felt to portend dysphagia.  
Moreover, IMRT has not historically used dose-limiting constraints with the 
primary goal of preserving swallowing function.  These data also suggest early 
guidelines for dose-constraints to dysphagia-specific organs-at-risk using IMRT 
that may further improve long-term functioning after treatment for HNSCC.   
Given the favorable prognosis that has been well described for the HPV-
associated OPSCC patient, we hypothesize that the prescribed RT dose may be 
safely reduced following transoral surgical resection and pathologic risk 
stratification for the risk of relapse.  On the other hand, patients with traditional 
high-risk pathologic features would be treated with current CRT to 66 Gy.  
Similarly, low-risk patients could be observed.  For the intermediate-risk patient, 
we hypothesize that the prescribed dose may be safely reduced from a standard 
intermediate-risk prescription of 60 Gy to 50 Gy without compromise in local-

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regional control rates.  Moreover, we expect a reduction in the development of 
both objective and patient-reported measures of late RT toxicities.   
Radiotherapy dose reduction has been studied in the recently completed E1308.  
This study prospectively examined the oncologic efficacy of reducing the RT 
dose to 55 Gy following a complete clinical response to induction CT.  No 
pathologic evaluation of the primary site was required.  The long-term results of 
this remain pending.  Thus, the current hypothesis is predicated on transoral 
resection leaving a comparable, if not favorable, microscopic burden of residual 
cancer cells.   
Theoretical mathematical modeling of radiation response and cancer control in 
human solid tumors has been extensively reported and is based on the modeling 
of reported local-regional control rates.  Withers et al has evaluated the published 
literature and concluded that a dose of 50 Gy is associated with a 90% control 
rate for subclinical microscopic cancer.  Evaluation of the clinical data has 
permitted mathematical modeling of the biologic effect of fractionated RT 
demonstrating that it may be modeled with linear quadratic equation, with most 
solid human tumors requiring an average of 3 Gy (D0) to reduce the surviving 
cells to 37% which reflects the intrinsic biology of the cell to the radiation and its 
repair response.  Modeling suggests that a cytoreduction of 10-10 is required to 
achieve a 90% probability tumor control rate summarized by the D10 parameter 
that represents the relative dose that would be required to sterilize a tumor with 
90% probability of tumor control.  The D10 can be represented by: 
D10 = 2.3 x D0, where 2.3 is the natural logarithm of 10.  
Thus, the dose required would be: 
D10 = 2.3 x D0 = 2.3 x 3 = 6.9 Gy. 
The probability of achieving tumor control is influenced by the number of tumor 
cells present.  While this is largely unknown and likely varies from patient to 
patient, it has been estimated that 109 cells may be present in a typical 4 cm 
tumor mass.  Thus, the estimated modeled dose required would be: 
10 x 6.9 Gy = 69 Gy. 
For a tumor cytoreduced to microscopic burden, it is estimated that there may be 
107 or less residual cancer cells.  Thus, it has been estimated that the radiation 
dose required to obtain a 90% likelihood of cure is:  
D8 = 8 x 6.9 Gy = 55.2 Gy 
This dose is consistent with the minimum dose (57.6 Gy) that has been found to 
be required in patients with pathologic evidence of risk for recurrence 
(intermediate-risk group).   
This proposal will randomize patients to an experimental arm of 50 Gy based on 
the hypothesis that HPV-associated cells will be more radiosensitive modeled by 
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1.6 
Correlative Studies Background 
1.6.1 
TP53 Mutation and Prognosis 
TP53 mutation is frequent in HPV-negative HNSCC while it is rare in 
HPV-positive HNSCC. However, it is suggested that HPV-positive 
patients with mutated TP53 have a poorer prognosis when compared 
to HPV-positive patients with wild type TP53 (Licitra, C, JCO, 2006). 
In addition, the location of mutations within TP53 can manifest as an 
abnormally truncated protein (nonsense mutation), disruption of DNA 
binding capacities (missense mutation), or without functional 
consequence (silent mutation). Poeta ML, et al. found that 53.3% of 
SCCHN patients had TP53 mutations; functionally non-disruptive 
33%, disruptive 20%, and wild type 47% (41). The patients with any 
p53 mutations associated with the worse overall survival compared to 
wild-type TP53 (HR to death, 1.4; 95% confidence interval 1.1-1.8, 
p=0.009) while the association was stronger with functionally 
disruptive TP53 mutation (HR 1.7; 1.3-2.4, p<0.001). Therefore, we 
hypothesize that the patients with HPV-positive and functionally 
disruptive TP53 mutations will have shorter time to disease 
progression and overall survival compared to patients with wild type 
TP53. In addition to TP53, a panel of 200 common cancer-related 
genes will be sequenced in one assay which may yield novel 
prognostic and/or predictive biomarkers. 
1.6.2 
Quantification of EGFR Expression by Automated Image Analysis 
Technique AQUA 
Epidermal growth factor receptor (EGFR) is known to be 
overexpressed and prognostic in HNSCC (29,30). Also, there is 
evidence that higher expression of EGFR is associated with poor 
outcome in HPV-positive patients (Kumar, B. JCO, 2008)(18). 
However, quantification of EGFR receptors using conventional 
immunochemical staining is unreliable due to poor inter- and 
intraobserver reproducibility, limited quantification range of peroxidase 
staining and difficulty delineating signals within cellular compartments. 
These limitations can be partly alleviated by automated quantitative 
analysis (AQUA) technology (33). Using AQUA, protein expression 
has been shown to provide reproducible analysis of target signal 
expression in fixed tissues on a continuous and more quantitative 
scale while preserving spatial information such as subcellular 
localization. The use of this technology has been successfully applied 
to several protein targets for biomarker identification in other solid 
tumors, including measurement of EGFR in head and neck cancers 
(33). We hypothesize that higher expression of EGFR will associate 
with poor prognosis in HPV-positive patients when compared to the 
HPV-positive patients with lower expression of EGFR because of the 
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1.6.3 
Excision Repair Cross-complementation Group 1 (ERCC1) Single 
Nucleotide Polymorphism (SNP) and XPF Protein Expression in 
HNSCC 
Excision repair cross-complementation group 1 (ERCC1) is a rate-
limiting enzyme in the nucleotide excision repair pathway that 
removes cisplatin-induced DNA adducts (24,25). Recent studies have 
shown that ERCC1 SNP (Thr259Thr) and high ERCC1 protein 
expression in tumors are associated with poor survival in HNSCC (26-
28). When patients with stage I or II were treated with radiation 
therapy alone, the patients with ERCC1 SNP resulting in Thr259Thr 
(4.1%) compared to Thr259Lys (25.5%) or Lys259Lys (70.4%) had 
shorter time to progression (11.6 vs. 87.6 or 85.2 months) and median 
survival (27.9 vs. 89.9 or 88.3 months) (28). Furthermore, low ERCC1 
protein expression in the tumors was seen in 27-29% of the patients 
and associated with higher response rate and lower risk of death 
when the patients were treated with cisplatin-based induction 
chemotherapy or cisplatin-based concurrent CRT (26,27). Therefore, 
we hypothesize that the patients with ERCC1 SNP Thr259Thr will 
have shorter time to progression and survival compared to the 
patients with Thr259Lys or Lys259Lys because of radiation resistance 
associated with Thr259Thr. We also hypothesize that the patients with 
lower expression of ERCC1 protein in their tumors will have higher 
response to cisplatin-based chemoradiotherapy, and longer time to 
progression and survival. 
1.6.4 
Correlation of radiologic markers with pathologic nodal status 
Preoperative CT/MRI scans will be analyzed for nodal stage and 
prediction of ECE, and correlated with final pathologic nodal stage, 
presence and extent of ECE (< or >1mm). 
1.6.5 
HPV DNA measurement and alteration in serum and saliva  
HPV DNA and seropositivity to HPV antigens will also be measured 
quatitatively and qualitatively, before and after surgical and adjuvant 
treatment to measure stability and predictive ability over time in a 
prospective treated population. Baseline and posttreatment cytokines 
are potentially predictive of outcome. Furthermore, the association 
between serologic markers (detected in blood at baseline and two 
other timepoints, including cytokines, chemokines, growth factors, and 
angiogenic factors in blood and treatment efficacy will also be 
examined.  
DNA from buffy coat or PBMCs will be analyzed for quantitative and 
qualitative alterations in HPV DNA. These analyses will be performed 
under the direction of Robert L. Ferris, MD, PhD.  
1.6.6 
Oral or serum HPV DNA level may correlate with PFS 
Given the ability to detect HPV DNA in salivary and serum specimens, 
we will perform an exploratory correlation between pre-treatment and 
post-treatment (1- and 2- year) HPV DNA, using QRT-PCR for HPV 
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value of incorporating this potential biomarker into the future 
randomized phase III trial. 
1.6.7 
Tumor antigen specific cellular immunity 
We and others have characterized the antigen specific cellular 
immune response to OPSCC, including HPV-, EGFR- and other 
antigens. PBL from pretreatment and post treatment patients will be 
correlated with disease recurrence, DFS, and OS. 
1.6.8 
Quantification of HPV DNA and serology in serum and saliva 
Presence of HPV DNA and seropositivity has been reported in healthy 
individuals HPV/p16+ OPSCC patients, in approximately 60-70% of 
patients’ serum and saliva. We collect blood and saliva from all 
patients for prediction of clinical response based on quantitative or 
qualitative alterations in these biomarkers in each specimen type after 
therapy and correlated with clinical outcome/response and Arm of 
adjuvant therapy. 
1.7 
Clinical Functional Outcomes 
Clinical outcomes are those readily tracked by the clinical assessment team and 
trialist, most of which reflect assessment utilized in routine clinical practice.  
These include patient weight (and weight loss), ECOG performance status, 
tracheostomy tube status (present/absent), and enteral feeding tube status 
(present/absent).  In addition, the [49, 64]Performance Status Scale – Head and 
Neck (PSS-HN) will be measured.  This instrument consists of 3 items rated by 
the research associate, requiring less than 5 minutes and no patient effort, and 
measuring speech, swallowing and diet.  Classically, H&N cancer patients have a 
high burden of comorbidity, related in part to risk behaviours of smoking and 
alcohol use.  While comorbidity is expected to be lower in HPV-related cancers, 
Charlson comorbidity index will be collected by chart extraction once at baseline 
to characterize the study cohort and assess comparability of the 4 treatment 
arms.  
1.8 
Functional Swallowing Outcomes 
Swallowing is a complex biomechanical process involving 5 cranial nerves and 
over 25 muscles in the upper aerodigestive tract.  Swallowing impairments can 
occur as the result of surgery alone, radiotherapy or CRT.  Although there are 
many ways to report swallowing outcomes, the MBS study remains the only 
measure that defines physiology and is predictive of adverse health effects (i.e., 
pneumonia).  Although patient-reported outcomes provide an important, 
complementary perspective of swallowing abilities, they do not accurately reflect 
swallowing competency.  Much of our knowledge of aspiration and physiologic 
impairment comes from data of laryngeal preservation trials that aggregate 
functional outcomes from multiple sites of HNSCC and show aspiration rates up 
to 40% in unselected cohorts, and in up to 80% of symptomatic patients when 
laryngopharyngeal function is impaired. These data based on findings from MBS 
studies confirm that when physiology is impaired, patients have high rates of 
aspiration, much of which is undetected by patient report because of a lack of 
sensory awareness.  Hence, silent aspiration has been reported in excess of 
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with oropharyngeal primary tumors continue to demonstrate a high burden of 
dysphagia.  In a population-based analysis of over [52, 67] 8,000 HNSCC, 
patients with cancers of the oropharynx had the second-highest prevalence of 
dysphagia.  In addition, 31% of patients demonstrated elevated occurrences of 
aspiration relative to baseline >1 year after treatment, and 22% developed 
pneumonia in a trial of chemoIMRT that was designed to protect dysphagia-
organs-at-risk using  dose-constraints for oropharyngeal cancer[46, 61].  
Furthermore, aspiration based on MBS findings was significantly predictive of 
pneumonia in this trial of chemoIMRT for oropharyngeal cancer (p=0.017, Se 
80%, Sp 60%), and silent aspiration was evident on MBS studies in 63% of 
patients who developed pneumonia.  In addition, pharyngeal residue on MBS 
studies was significantly associated with the development of pneumonia after 
[53] chemoIMRT (p<0.01) [68].  These results offer compelling support for the 
examination of swallowing physiology (i.e., “airway protection” and “pharyngeal 
transit”) as these health-related endpoints cannot be obtained by PROs. Thus, 
we propose to evaluate swallowing using MBS studies as the primary objective 
functional measure of this trial. 
1.9 
Patient-Reported Outcomes 
Patient-reported outcomes will include head-and-neck specific symptoms 
(MDASI-HN), cancer and head and neck-specific quality of life (FACT-H&N), 
swallowing perception and performance (MDADI), voice outcomes (VHI-10), 
overall health status (EQ-5D) and a cost questionnaire. Additionally, ability to 
return to employment will be assessed using a return to work instrument in use 
by the Radiation Therapy and Oncology Group (RTOG).  Head and neck-specific 
symptoms include issues of dry mouth, mucositis and mucosal sensitivity, 
shoulder and neck discomfort, and skin changes as well as swallowing and 
voice-related problems.  It is well documented that head and neck cancer 
patients experience a profound, acute decrement in the level of general physical 
functioning and general cancer-specific QOL as a result of both surgery and 
adjuvant RT/CRT. Data regarding the late effects of treatment on disease-
specific function is more limited; however, available studies indicate that a 
significant percentage of patients fail to return to baseline functioning. Patient-
perception of swallowing performance has been shown to be associated with 
long-term swallowing related quality of life, and to remain depressed from 
baseline levels after treatment for [54, 69]oropharyngeal cancers.  Voice-related 
changes that include alterations in resonance, pitch variation, loudness, and 
quality (i.e., hoarseness, raspiness, etc) more commonly result from treatments 
that affect the oropharynx, compared with articulatory changes that result from 
management of oral cavity cancers. 
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2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
Accrual, risk distribution, and surgical quality will be used to determine 
the feasibility of a prospective multi-institutional study of transoral 
surgery for HPV+ oropharynx cancer followed by risk-adjusted 
adjuvant therapy.  
2.1.2 
To assess the oncologic efficacy following transoral resection and 
adjuvant therapy in patients determined to be at “intermediate risk” 
after surgical excision, the 2-year PFS rate will be examined. 
2.2 
Secondary Objectives 
2.2.1 
To estimate the patient distribution with various histologic risk 
features. 
2.2.2 
To assess and compare early and late toxicities associated with TOS 
and the different doses of adjuvant PORT. 
2.2.3 
To evaluate swallowing function before and after TOS and risk-
adjusted adjuvant therapy. 
2.2.4 
To evaluate QOL, swallowing perception and performance, voice 
outcomes, and head and neck symptoms. 
2.3 
Laboratory Research Objectives:  
2.3.1 
To correlate tumor TP53 mutation and other associated mutation 
profile with pathologic findings, with PFS and other outcome 
parameters in patients with resectable HPV-associated OPSCC after 
the above treatments. 
2.3.2 
To evaluate radiation resistance markers, including ERCC1 single 
nucleotide polymorphism and protein expression, and correlate them 
with treatment efficacy.  
2.3.3 
To investigate the usefulness of biomarkers in predicting progression-
free survival and biomarkers, including tumor ERCC1, EGFR, plasma 
cytokine/chemokines, cellular immunity to HPV, and oral HPV DNA  
 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. 
 
 
Patient’s Initials (L, F, M) 
 
 
Physician Signature and 
Date 
 
NOTE: All questions regarding eligibility should be directed to the study chair. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Registration to Surgery (Arm S) 
3.1.1 
Age >/= 18 years. 
3.1.2 
ECOG performance status of 0 or 1. 
3.1.3 
Patients must register to Step 1 prior to surgery. 
3.1.4 
Patients must have newly diagnosed, histologically or cytologically 
confirmed squamous cell carcinoma or undifferentiated carcinoma of 
the oropharynx. Patients must have been determined to have 
resectable oropharyngeal disease. Patients with primary tumor or 
nodal metastasis fixed to the carotid artery, skull base or cervical 
spine are not eligible 
3.1.5 
Patients must have AJCC TNM tumor stage III, IV a, or IV b (with no 
evidence of distant metastases) as determined by imaging studies 
(performed < 30 days prior to registration) and complete neck exam, 
from the skull base to the clavicles. The following imaging is required: 
CT scan with IV contrast or MRI. 
AJCC TNM tumor stage III, IV a, or IV b?  
Stage _________ Date scans performed___________  
CT scan with IV contrast or MRI?  
The primary tumor should be cT1 or T2 and cervical nodes cN1, N2a, 
or N2b based on clinical or radiographic criteria. 
3.1.6 
Patients must have biopsy-proven p16+ oropharynx cancer; the 
histologic evidence of invasive squamous cell carcinoma may have 
been obtained from the primary tumor or metastatic lymph node.  It is 
required that patients have a positive p16 IHC (as surrogate for HPV) 
status from either the primary tumor or metastatic lymph node. 
_____
_____
_____
_____
_____
Rev. 6/14 
Rev. 2/15
Rev. 2/15
_____
Rev. 2/15 
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3.1.7 
Carcinoma of the oropharynx associated with HPV as determined by 
p16 protein expression using immunohistochemistry (IHC) performed 
by a CLIA approved laboratory. Using p16 antibody obtained from 
Roche mtm laboratories AG (CINtec, clone E6H4) is recommended. 
Confirmed p16+ disease? Yes ______ No ____ 
3.1.8 
No prior radiation above the clavicles. 
3.1.9 
Patients with a history of a curatively treated malignancy must be 
disease-free for at least two years except for carcinoma in situ of 
cervix, melanoma in-situ (if fully resected), and/or non-melanomatous 
skin cancer.  
History of curatively treated malignancy?  
Yes________ No________ 
If yes, disease-free for at least two years?  
Yes________ No________ 
3.1.10 
Patients with the following within the last 6 months prior to registration 
must be evaluated by a cardiologist and/or neurologist prior to entry 
into the study.  
Congestive heart failure > NYHA Class II? 
Yes _____ No _____ Date ______ 
CVA/TIA?  Yes _____ No _____ Date ______ 
Unstable angina?  Yes _____ No _____ Date ______ 
Myocardial infarction? (with or without ST elevation) 
Yes _____ No _____ Date ______ 
3.1.11 
Patients must not have evidence of extensive or “matted/fixed” 
pathologic adenopathy on preoperative imaging. 
3.1.12 
Patients must have acceptable renal and hepatic function within 4 
weeks prior to registration as defined below: 
• 
Absolute neutrophil count ≥1,500/mm3 
Yes______ No______ 
ANC______ Date of Test_______ 
• 
Platelets ≥ 100,000/mm3 
Yes______ No______ 
Platelets______ Date of Test_______ 
• 
Total bilirubin ≤ the upper limit of normal (ULN) 
Yes______ No______  
Total bilirubin______ Institutional ULN ______  
Date of Test _______ 
_____
_____
_____
_____
_____
_____
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• 
Calculated creatinine clearance must be > 60 ml/min using the 
Cockcroft-Gault formula : 
(140-age)*wt(kg)/([Cr]*72). 
For women the calculation may be multiplied by 0.85 
Creatinine clearance ______ Date of Test_______ 
3.1.13 
Women must not be pregnant or breast-feeding due to the 
teratogenicity of chemotherapy. All females of childbearing potential 
must have a blood test or urine study within 2 weeks prior to 
registration to rule out pregnancy. A female of childbearing potential is 
any woman, regardless of sexual orientation or whether they have 
undergone tubal ligation, who meets the following criteria: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not 
been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive 
months). 
Female of child bearing potential? ______ (Yes or No)  
Date of blood test or urine study: ___________________ 
3.1.14 
Patient must not have an intercurrent illness likely to interfere with 
protocol therapy or prevent surgical resection.  
Intercurrent illness? Yes______ No______ 
3.1.15 
Patients must not have uncontrolled diabetes, uncontrolled infection 
despite antibiotics or uncontrolled hypertension within 30 days prior to 
registration.  
• 
Uncontrolled diabetes? 
Yes_____ No_____ Date _________  
• 
Uncontrolled infection? 
Yes _____ No _____ Date _________  
• 
Uncontrolled hypertension? 
Yes _____ No _____ Date _________  
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to use 
the eligibility checklist as source documentation. 
_____
_____
_____
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3.2 
Registration/Randomization to Step 2 - Arms A, B, C, and D 
3.2.1 
Histopathologic assessment of surgical pathology must include 
examination for perineural invasion (PNI) and lymphovascular 
invasion (LVI) and reported as absent or present. The absence or 
presence of extracapsular extension (ECE) requires gross and 
microscopic assessment and is defined to be: 
• 
absent (negative or nodal metastasis with smooth/rounded leading 
edge confined to thickened capsule/pseudocapsule), 
• 
present - minimal (tumor extends ≤ 1 mm beyond the lymph node 
capsule), or 
• 
present - extensive (Gross, tumor extends >1 mm beyond the 
lymph node capsule (includes soft tissue metastasis) 
3.2.2 
Patient must be stratified/classified into one of the following risk 
categories: 
The highest risk feature assessed pathologically will determine the 
patient's category/treatment arm assignment. 
• 
Low Risk: T1-T2, N0-N1 AND clear (≥ 3mm) margins, AND no 
ECE or PNI/LVI. 
• 
High Risk: Any of the following features: one or more positive 
margin(s) with any T stage, OR “Extensive” (> 1mm) ECE, OR ≥ 5 
metastatic lymph nodes (regardless of primary tumor margin 
status). 
• 
Intermediate Risk: Any of the following features: one or more 
“close” (< 3mm) margin(s), OR “Minimal” (≤ 1mm) ECE, OR N2a 
(1 or more lymph node > 3cm in diameter), OR N2b (2-4 lymph 
nodes positive, any diameter ≤ 6cm), OR with perineural invasion 
or lymphovascular invasion. 
• 
Unknown Risk: Patients found to have N2C or N3 disease on final 
pathologic analysis are at unknown risk for recurrence, but are not 
candidates for deintensified adjuvant therapy in this trial. These 
patients will be treated on Arm C. 
• 
Patients not categorized into the appropriate risk category 
will be considered ineligible for the study. 
3.2.3 
Patient must be registered/randomized to Step 2 within a maximum of 
7 weeks following surgery. 
3.2.4 
Women of childbearing potential and sexually active males are 
strongly advised to use an accepted and effective method of 
contraception 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to use 
the eligibility checklist as source documentation. 
_____
_____
Rev. 6/14 
Rev. 2/15
_____
_____
Rev. 2/15
Rev. 1/16 
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4. 
Registration and Randomization Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, please 
contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
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• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Requirements for E3311 site registration: 
• 
IRB approval (local IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form, or combination is accepted) 
Downloading Site Registration Documents 
Site registration forms may be downloaded from the E3311 protocol page located on the 
CTSU members’ website. 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol #E3311 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org/ (members’ area)  Regulatory Tab 
Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
Required Protocol Specific Regulatory Documents 
1.  
CTSU Regulatory Transmittal Form. 
2.  
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
3.  
A.  
CTSU IRB Certification Form. 
Or 

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B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
Or 
C.  
IRB Approval Letter 
4.  
Surgeon Certification Form (See Section 4.1.5.6). 
NOTE: The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Patients must not start protocol treatment, including surgery, prior to registration. 
Surgery should take place within 3 weeks, and not more than 4 weeks after 
registration to Arm S. 
If more than one surgery is performed as part of the Arm S resection, all surgeries 
must be completed within 4 weeks of registration to Arm S. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam>) and a 'Registrar' role on either the LPO or 
participating organization roster. Registrars must hold a minimum of an AP registration 
type. 
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study. 
It is integrated with the CTSU Enterprise System for regulatory and roster data and, 
upon enrollment, initializes the patient position in the Rave database. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of 
the website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in 
OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number 
used on the site’s IRB approval. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
Rev. 2/14 
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4.1 
Registration To Surgery (Arm S) 
The following information will be requested  
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.1.2.2 
Investigator’s name (NCI number) 
4.1.2.3 
Cooperative Group Credit 
4.1.2.4 
Credit Investigator 
4.1.2.5 
Protocol specific contact information 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials (first and last) 
4.1.3.2 
Patient’s Hospital ID and/or Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Gender 
4.1.3.3.2 
Birth date 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.1.3.3.7 
Country of residence 
4.1.4 
Eligibility Verification  
Patients must meet all the eligibility requirements listed in Section 3.1. 
4.1.5 
Additional Requirements  
4.1.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office - Boston. 
4.1.5.2 
Patients unable to read/write in English fluently will 
complete patient-reported/QOL instruments in their own 
language if/when validated translations are available. They 
will be coded as ineligible for analysis of patient-reported 
instruments unavailable in their language. 
4.1.5.3 
Submission of pathology materials for diagnostic review 
and classification is mandatory.  Submission guidelines 
outlined in Section 11. 
4.1.5.4 
Biological materials are to be submitted as indicated in 
Section 11. 
4.1.5.5 
Data collection for this study will be done exclusively 
through the Medidata Rave clinical data management 
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system.  Access to the trial in Rave is granted through the 
iMedidata application to all persons with the appropriate 
roles assigned in Regulatory Support System (RSS).  To 
access Rave via iMedidata, the site user must have an 
active CTEP-IAM account (check at < 
https://ctepcore.nci.nih.gov/iam ) and the appropriate Rave 
role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site 
Investigator) on either the LPO or participating organization 
roster at the enrolling site. To the hold Rave CRA role or 
CRA Lab Admin role, the user must hold a minimum of an 
AP registration type.  To hold the Rave Site Investigator 
role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be listed in the 
upper right pane of the iMedidata screen. 
Users that have not previously activated their 
iMedidata/Rave accounts will also receive a separate 
invitation from iMedidata to activate their account. Account 
activation instructions are located on the CTSU website, 
Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on 
the CTSU website under the Rave tab at 
http://www.ctsu.org/RAVE/ or by contacting the CTSU Help 
Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.1.5.6 
Surgeon Credentialing 
Surgeon credentialing in transoral oncologic surgery 
will be required for participation in this study. Only 
transoral oropharynx cancer resections are applicable; oral 
cavity and larynx surgeries are not applicable, even if 
transoral in approach. Surgeons must be proficient at the 
proper open technique for OPSCC resection. 
Surgeons performing robotic or laser procedures must be 
credentialed for those procedures at their respective 
institution, providing evidence of sufficient training and 
active credentialing by their Hospital medical staff 
privileging board(s). 
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Surgeons must have performed at least 20 transoral 
OPSCC resections using any oncologic technique (at least 
5 transoral cancer resection cases) in the immediately 
preceding year.  
The most recent 10 consecutive cases must be submitted 
(de-identified) with accompanying operative notes and 
pathology reports. The submitted 10 cases (above) will 
undergo review by the E3311 PI and the surgical quality 
assurance members. Ultimately the PI has responsibility 
for final approval of all surgical investigators. 
Surgeons interested in participating in the trial must have 
an active CTEP ID number. Surgeons who do not have a 
CTEP ID number must first register with the 
Pharmaceutical Management Branch, Cancer Therapy 
Evaluation Program (PMB, CTEP) at https://eapps-
ctep.nci.nih.gov/iam/. For additional information on 
obtaining a CTEP ID number and joining ECOG-ACRIN, 
go to www.ecog.org/general/newmember_indiv.html. If you 
have any questions, please contact 
ecog.membership@jimmy.harvard.edu. 
Access to the Medidata Rave “E3311/RTOG1221 Surgical 
Credentialing Database” will be granted when IRB 
approval is obtained. A Head and Neck Surgeon 
Credentialing Questionnaire must be completed as part of 
the initial credentialing process. The questionnaire will be 
completed directly in Rave. Please see Appendix VII to 
reference a copy of the Surgeon Credentialing 
Questionnaire. 
To register a surgeon and to complete the credentialing 
questionnaire, the responsible CRA must send an email to 
HNsurgicalcredentialing@jimmy.harvard.edu with the 
following information: 
Surgeon First and Last Name 
Surgeon CTEP ID number 
Institution Site name 
CTEP Site ID number 
Surgeon’s fax number 
Surgeon’s telephone number  
Surgeon’s email address 
A confirmation email will be sent to the CRA when the 
Head and Neck Surgeon Credentialing Questionniare is 
ready for their completion. 
CREDENTIALING DURING THE CONDUCT OF THE 
TRIAL: Active surgeon credentialing will be in force until 
the first 5 cases per surgeon are accrued. If no grossly 
positive margins are encountered, an additional 5 case 
may be accrued by that surgical investigator. Positive 
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margins are not permitted to exceed 10% of accrued 
patients per surgeon – thus a single case with grossly 
positive margins is acceptable per 10 cases per surgeon. 
In the event that a single surgeon accrued two cases out of 
10 consecutive cases with grossly positive margins 
(yielding a rate > 10% for positive margins), that surgeon 
will be placed on hold, and may become reactivated as an 
accruing surgeon through the submission of an additional 
5 consecutive cases with clear margins. This process will 
be in effect for each accruing surgeon for the duration of 
the trial. If a surgeon is not reactivated due to recurrent 
positive margins, the previously accrued cases will be 
included in the study but no further cases are allowed to be 
enrolled. If an active surgeon accrues zero patients for 18 
months, they will be required to repeat the credentialing 
process. 
4.1.5.7 
Site Participation in Modified Barium Swallow (MBS) 
Studies 
The Modified Barium Swallow (MBS) Credentialing 
Checklist must be completed by the institution before 
patients can be registered to E3311.  Once the form is 
completed please fax this to the ECOG-ACRIN Operations 
Office - Boston at (617) 632-2990, Attention: E3311 Data 
Manager. You will receive an email from the ECOG-ACRIN 
Data Manager confirming the receipt of the checklist. A 
contact from MD Anderson will then email you with 
instructions and reminders for video uploads. 
If a site agrees to participate in the study, MBS videos 
completed by the site will be uploaded to the Box® Cloud-
based storage account maintained by MD Anderson 
Cancer Center. It will be the responsibility of the site to 
upload the videos to this cloud account. For sites that 
agree to participate in the study a designated contact will 
need to be identified on the MBS Credentialing Checklist. 
This contact will be given access to the MD Anderson 
Box® Cloud-based storage account to upload MBS videos 
to the cloud. Please contact 
E3311_MBS@jimmy.harvard.edu for questions regarding 
access and questions for Box® Cloud-based storage. 
The MBS studies are optional, however, they will be 
required at baseline and after treatment for patients from 
sites that have declared participation in the MBS studies, 
and strongly encouraged from other institutions that use 
the MBS study as standard-of-care for patients with 
swallowing dysfunction. 
Please refer to Appendix VI for details of study 
participation. Please refer to Section 10.1.6 and Appendix 
IX for details regarding MBS video upload. 
Rev. 7/13, 2/15, 
6/15 
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4.1.6 
Instructions for Patients who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
through Medidata Rave according to the schedule in the E3311 Forms 
Completion Guidelines. 
4.2 
Registration/Randomization To Step 2 (Arms A, B, C, and D) 
Treatment should start within ten working days after registration to Step 2. 
The following information will be requested  
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2.2 
Investigator’s name (NCI number) 
4.2.2.3 
Cooperative Group Credit 
4.2.2.4 
Credit Investigator 
4.2.2.5 
Protocol specific contact information 
4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials (first and last) 
4.2.3.2 
Patient’s Hospital ID and/or Social Security number 
4.2.3.3 
Patient demographics 
4.2.3.3.1 
Gender 
4.2.3.3.2 
Birth date 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit ZIP code 
4.2.3.3.6 
Method of payment 
4.2.3.3.7 
Country of residence 
4.2.4 
Stratification and Classification Factors 
4.2.4.1 
Classification Factors 
• 
The highest risk feature assessed pathologically will 
determine the patient's category/treatment arm 
assignment. 
o Low Risk: T1-T2, N0-N1, with clear (≥ 3mm) 
margins, and without any ECE or PNI/LVI. 
o  High Risk: Any T stage with positive margin(s), 
meaning tumor at the specimen edge, not 
superceded by an additional, tumor free margin, 
OR “Extensive” (> 1mm) ECE, OR ≥ 5 metastatic 
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lymph nodes, regardless of primary tumor margin 
status. 
o Intermediate Risk: Any T stage with one or more 
“close” (<3mm) margin(s) OR “Minimal” (≤ 1mm) 
ECE, OR 1 or more lymph node >3cm in diameter 
(N2a neck disease), OR 2-4 lymph nodes positive, 
any diameter ≤ 6cm (N2b neck disease (regardless 
of primary tumor margin status)], OR with 
perineural invasion or lymphovascular invasion. 
o Unknown Risk: Pathologic N2c (bilateral nodes), 
OR Pathologic N3 (> 6cm node) 
4.2.4.2 
Stratification Factors - Intermediate Risk 
• 
Smoking Status: ≤ 10pk-yr  vs. >10pk-yr 
4.2.5 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.2. 
4.2.6 
Additional Requirements  
4.2.6.1 
Participation in the Quality of Life Studies  
4.2.6.2 
Biological materials are to be submitted as indicated in 
Section 11 
4.2.6.3 
Patients with oropharynx squamous cell cancer are at a 
nutritional risk at baseline, and this risk will increase during 
chemo-radiotherapy. Patients who are at nutritional risk at 
baseline will be considered for prophylactic feeding tube 
placement prior to the initiation of radiation therapy.  Given 
the importance of preservation of physiology, patients who 
maintain adequate adequate oral nutrition at baseline will 
be closely monitored by the clinical team throughout the 
treatment regimen to ensure optimal nutrition.  
4.2.6.4 
Data collection for this study will be done exclusively in 
Medidata Rave. Prior to beginning data entry in Rave, 
study staff must be registered in Medidata and complete 
the required training modules. Study staff will receive an 
invitation to join the study in Rave after evidence of IRB 
approval is submitted to RSS. 
4.2.7 
Instructions for Patients who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
through Medidata Rave according to the schedule in the E3311 Forms 
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5. 
Treatment Plan 
5.1 
Primary Surgical Therapy (Arm S) 
Patients will be assessed clinically with a complete head and neck exam and 
radiographically with imaging studies. The tumor should be >1cm from the 
midline. The attending surgeon will determine the ultimate preoperative disease 
stage for trial accrual/eligibility. 
Swallowing evaluation including MBS will be performed prior to starting therapy 
in all patients from sites that declared participation in the MBS studies. In 
addition, patient-reported outcome measures will be administered before starting 
therapy. 
Any transoral approach intended to obtain negative margins of p16+ Stage III/IV 
(T1-T2N0-N2) oropharynx SCC  
Neck dissection (Levels II-IV) to be performed during resection of the primary 
tumor or within 4 weeks of the study entry. If more than one surgery is performed 
as part of the Arm S resection, all surgeries must be completed within 4 weeks of 
registration to Arm S. 
5.1.1 
Surgical Credentialing/Quality Control  
Surgeons must be credentialed prior to enrolling patients on the trial. 
Adequate experience in at least one of the three categories of 
transoral surgery (TLM, TORS and non-laser/non-robotic transoral 
resections) must be demonstrated to ensure quality control. Only 
transoral oropharynx cancer resections are applicable; oral cavity and 
larynx surgeries are not applicable, even if transoral in approach. For 
each category of transoral surgery this experience will be confirmed, 
as follows: 
• 
Each participating surgeon must document that he/she has 
performed a minimum number of 20 cases of transoral excision for 
OPSCC  as the primary surgeon; 
• 
Each participating surgeon must document that he/she has 
performed at least 10 transoral resections of OPC in the past 12 
months; 
• 
The Principal Investigator will review each surgeon’s submitted 
pathology report and operative notes for 10 OPSCC cases 
excised using a modality specific technique for which credentialing 
is being sought; 
• 
Responses to a surgeon questionnaire; 
Surgical technique (for both TLM and TORS) will be standardized. 
Transoral resection of the oropharyngeal tumor will be performed at 
the discretion of the attending head and neck surgeon. The type of 
resection chosen should provide complete removal of the primary 
lesion with negative gross margins; this is not subject to quality 
assurance review; documentation of margins by frozen section at 
surgery is required.  For en bloc resections, the gross margins will be 
assessed by palpation.  If it is clear that a margin is close or positive - 
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the specimen will be inked and frozen section margins will be taken 
from the surgical specimen.  3- 5 mm of mobile soft tissue, then the 
surgeon will do a wide re-resection of that margin. The specimens will 
then be inked by the surgeon, avoiding ink on the main specimen in 
areas of a close or positive margin (which has undergone re-
resection) will be done by the surgeon.  Standard terminology will rely 
on a deep margin and four quadrants: anterior, posterior, medial, 
lateral.  However, specific issues and approaches should vary by 
subsite, as detailed below. 
 Surgery should be performed within 3 weeks after registration onto 
the study and not more than 4 weeks after study registration. If more 
than one surgery is performed as part of the Arm S resection, all 
surgeries must be completed within 4 weeks of registration to Arm S. 
Reconstruction of surgical defects should be performed using 
conventional techniques at the discretion of the surgeon, most often 
with primary closure or healing by secondary intention. In general, 
patients with T1 and T2 OPC do not require microvascular 
reconstruction flaps, therefore patients requiring free flaps will be 
replaced with another patient and listed as a minor protocol deviation. 
Secondary intention healing is recommended when appropriate but 
should not be pursued at the expense of obtaining wide, tumor-free 
margins.  Reconstructive closure with local flaps is at the discretion of 
the surgeon. 
For tonsillar carcinoma, the extent of en bloc-resection must include a 
tongue base margin, soft palate margin, complete constrictor margin, 
a complete anterior tonsillar pillar margin and a complete posterior 
tonsillar pillar margin. ). Simple “tonsillectomy” should not be 
performed.. The surgeon should aim to achieve resection of tumor 
and surrounding structures, with an attempt made to achieve a 1 cm 
gross visual mucosal margin, with a minimum of 3 mm microscopic 
margins. For tonsillar fossa cancers,the exception to this will be  the 
superior constrictor, which represents the deep margin which will 
necessarily obviate a stipulated microscopic margin but must be 
histologically negative . However, the constrictor margin must have a 
gross margin of 5 mm of mobile tissue. Therefore, given the three-
dimensional complexity of the superior constrictor, margin status will 
be assessed as a binary endpoint: as clear or positive.   These 
stipulations are subject to quality assurance review.  
For tongue-base carcinoma, a standard en bloc resection is preferred 
to include, wide mucosal margins,  resection of the underlying muscle, 
as well as the inferior portions of the  tonsillar pillars (anterior and 
posterior). The surgeon should aim to achieve an en-bloc resection of 
tumor and surrounding structures, with an attempt made to achieve a 
minimum of 1 cm gross visual margins with ≥ 3mm microscopic 
margins. These are recommendations subject to quality assurance 
review.  
For lesions with glossotonsillar sulcus involvement, the same 
principles of four-quadrant margin assessment will apply, with 
appropriate deep margin constituting the base of tongue (BOT) and/or 
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constrictor muscle and/or parapharyngeal fat as the deep margin. Of 
note, cancers which involve extrisinic muscles of the tongue (e.g. 
hyoglossus muscle),as evident by preoperative imaging, are excluded 
since they are T4a cancers. 
Surgeon credentialing and standardization of technique will be 
consistent between the two proposed transoral surgical trials, the 
current one coordinated by ECOG-ACRIN and the other by RTOG. 
5.1.2 
Surgical technique  
5.1.2.1 
Evaluation for Surgery 
5.1.2.2 
Access for Transoral Endoscopic Head and Neck Surgery.  
The attending surgeon will perform such preoperative 
assessments as necessary to determine the likelihood of 
transoral exposure for tumor resection, including ASA 
classification, Mallepatti classification, dentition, difficulty 
with c-spine extension, etc. In the judgement of the 
operating surgeon, the oropharynx should be sufficiently 
exposed intraoperatively to proceed with enrollment on this 
trial. 
5.1.2.3 
Surgical Staging will be performed by the attending 
surgeon, based on clinical and radiographic criteria as well 
as endoscopic examination and measurements (see AJCC 
T-stage criteria in Appendix III).  
5.1.3 
Primary tumor resection. Transoral resection of the oropharyngeal 
tumor will be performed at the discretion of the attending head and 
neck surgeon. The type of resection chosen should provide complete 
removal of the primary lesion with negative gross margins. The type of 
instruments utilized and surgical technique are not subject to quality 
assurance review. Documentation of margins by frozen section at 
surgery is required. Standard terminology will rely on at least a deep 
margin and four quadrants:  anterior, posterior, medial and lateral.  
However, specific issues and approaches should vary by subsite, as 
detailed below. 
5.1.3.1 
Surgery should be performed within 3 weeks after 
randomization, and no more than 4 weeks after 
randomization. Reconstruction of surgical defects should 
be performed using conventional techniques at the 
discretion of the surgeon. Primary closure is recommended 
when appropriate but should not be pursued at the 
expense of obtaining wide, tumor free margins.  
Reconstructive closure is at the discretion of the surgeon. 
Need for microvascular (free flap) reconstruction is an 
exclusion criterion 
5.1.3.2 
For tonsillar carcinoma, a transoral lateral pharyngectomy 
should be performed to include resection of the underlying 
superior constrictor muscle, as well as the tonsillar pillars 
(anterior and posterior) and cranial and caudal margins. 
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The surgeon should aim to achieve resection of tumor and 
surrounding structures, with an attempt made to achieve a 
1cm gross visual margin, with a minimum of 3 mm 
microscopic margins. For tonsil and tonsillar fossa cancers, 
the superior constrictor represents the deep margin. These 
stipulations are subject to quality assurance review. 
5.1.3.3 
For tongue-base carcinoma, a standard en bloc resection 
is preferred to include resection of the underlying superior 
constrictor muscle, as well as the tonsillar pillars (anterior 
and posterior) and cranial and caudal margins. The 
surgeon should aim to achieve an en-bloc resection of 
tumor and surrounding structures, with an attempt made to 
achieve a minimum of 1 cm gross visual margins with 3 
mm microscopic margins. These are recommendations 
subject to quality assurance review. The tongue base 
musculature represents the deep margin, to be sent 
separately for margin analysis. 
5.1.3.4 
For hybrid lesions, the same principles of four-quadrant 
margin assessment will apply, with appropriate deep 
margin constituting the base of tongue and/or constrictor 
parapharyngeal fat as the deep margin.  
5.1.3.5 
A positive margin is defined as carcinoma in situ or 
invasive carcinoma at the margin of resection, which is not 
superceded by additional tissue (a new separate margin) 
found to be histopathologically free of disease. If a new 
separate margin is obtained adjacent to a specimen or 
margin containing CIS or invasive SCC is deemed 
pathologically negative, the patient will be considered to 
have “close” margins. 
5.1.4 
Margin excision and histopathologic assessment.  
Intraoperatively, the surgeon must send 4 quadrant margins plus deep 
margin (recommend 3 mm diameter at minimum), submitting the 
oriented specimen to the pathologist. A positive margin found on final 
pathologic analysis after negative frozen sections will be classified as 
a “close” negative margin resection (R0) and entered in the RT 
randomization (Arms B-C) if additional histopathologically benign 
tissue surrounding and deep to the region of concern is removed and 
analyzed pathologically. 
Recommendation for standard practice (permanent section 
histopathology). It is recommended to perform photodocumentation of 
the specimen by the pathologist after these procedures, using high 
resolution digital photography with annotation. If the surgeon obtains 
additional margins from the patient, the “new margins” should refer 
back to the geometric orientation of the resected tumor specimen.  A 
statement by the pathologist in the final surgical pathology report 
should point out that this “new” margin represents the final margin of 
resection in addition to its histologic status. 
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5.1.4.1 
An adequate resection is defined as clear resection 
margins with at least enough clearance from gross tumor 
to obtain clear frozen section and permanent margins 
(defined as at least 3 mm grossly) 
5.1.4.2 
The details of resection margins should be included in the 
operative dictation.  The margins may be assessed on the 
resected specimen or alternatively from the surgical bed 
with proper orientation.   
5.1.4.3 
A “clear margin” is defined as a distance from the invasive 
tumor front that is ≥ 3 mm from the resected margin.  If the 
surgeon obtains additional margins from the patient, the 
“new” margins should refer back to the geometric 
orientation of the resected tumor specimen.  A statement 
by the pathologist in the final surgical pathology report 
should point out that this “new” margin represents the final 
margin of resection in addition to its histologic status. 
5.1.4.4 
A “close margin” is defined as a distance from the invasive 
tumor front that is < 3 mm from the resected margin 
5.1.5 
Neck Dissection 
5.1.5.1 
A formal selective or modified radical neck dissection, level 
II-IV, will be performed in all cases. Numbering and/or 
nomenclature outlined in the “Neck Dissection Guide” will 
be used. Resection of levels II-IV are required, with levels I 
and/or V electively dissected at the discretion of the 
attending surgeon. The neck dissection should be oriented 
or separately partitioned in order to identify levels of lymph 
nodes encompassed in the dissection.  
5.1.5.2 
Extent of neck dissection 
Patients will undergo ipsilateral selective or modified 
radical neck dissection of levels II-IV for lateralized lesions 
of the tongue-base, tonsillar region and/or 
glossopharyngeal sulcus.  Midline lesions are discouraged 
from accrual to this trial. For patients with SCC of the base 
of tongue that approaches within 1 cm of the midline, a 
contralateral neck dissection should be performed, also of 
levels II-IV. For ipsilateral and contralateral 
lymphadenectomy, level I-b and V may be electively 
dissected at the discretion of the attending surgeon, but is 
not required. 
5.1.5.3 
A minimum of 20 lymph nodes per dissected side of the 
neck is required and is subject to quality assurance review. 
Removal of < 20 but > 15 lymph nodes will be considered 
a minor protocol deviation and recorded. 
5.1.5.4 
For patients with SCC of the base of tongue where the 
tumor is within 1 cm of the midline, a contralateral neck 
dissection should be performed, also of levels II-IV. For 
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ipsilateral and contralateral lymphadenectomy, level I 
and/or V may be electively dissected at the discretion of 
the attending surgeon, but is not required.  For lateralized 
base of tongue cancers not within 1 cm of midline, the 
contralateral neck treatment is at the discretion of the 
treating surgeon. The neck dissection should be oriented 
or separately partitioned in order to identify levels of lymph 
nodes encompassed in the neck dissection specimen. 
5.1.5.5 
Adequacy of Nodal Harvest: Histopathologic assessment 
of 20 nodes is required for all neck dissection specimens. 
Realizing that there is some anatomic variation from 
patient to patient, an absolute minimum of 15 nodes is 
required. More specifically, specimens of < 20 but > 15 
lymph nodes would be an acceptable protocol violation.   
5.1.5.6 
Pathologic assessment of extracapsular extension (ECE): 
Lymph nodes ≤ 2 cm in greatest dimension are considered 
adequately assessed with one section.  Multiple lymph 
nodes ≤ 2 cm in greatest dimension may be submitted in a 
single cassette.   Lymph nodes > 2 cm in greatest 
dimension require multiple sections (and possibly multiple 
cassettes); specifically, one section per 1 cm should be 
submitted. Sections should include the edge of the lymph 
node that interfaces with surrounding fibroadipose tissue.   
5.1.5.7 
Ligation of arterial blood supply of the primary 
oropharyngeal tumor is required to avoid major 
postoperative pharyngeal hemorrhage.78, 79 
• 
At a minimum, it is recommended that the surgeon 
ligate the ipsilateral lingual and facial arteries. At the 
surgeon’s discretion and judgment, ligation of other 
arteries, such as the ascending pharyngeal and 
superior thyroid, may be considered. 
• 
If the external carotid arterial trunk itself is ligated, the 
surgeon must ligate the vessel at an adequate distance 
from the carotid bulb to avoid injury to the internal 
carotid artery. Care should be taken to avoid injuring 
the internal carotid artery if ligating the ascending 
pharyngeal artery, since its takeoff may occur 
posteriorly putting the ICA at risk. 
• 
The attending surgeon is directed to perform this 
portion of the procedure him/herself. 
• 
The arteries should be ligated but not divided. 
• 
The case report form will now require the 
documentation, taken from the operative report, 
confirming that arterial ligation was performed and 
delineating which vessels were ligated. 
• 
Please contact the study chair, Dr. Ferris, with any 
questions or to clarify. 
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Failure to perform arterial ligation, and provide written 
documentation of this critical aspect of the surgery, will 
constitute a reportable deviation which will be forwarded to 
the Credentialing Committee and subject to peer-review 
and appropriate action. Such action may include 
suspension of the surgeon’s credentials for involvement in 
the trial, thus preventing further accrual to the trial. 
5.1.6 
Surgical Quality Assurance Reviews 
5.1.6.1 
The study chair, Robert L. Ferris, MD, PhD, and 
designated Surgical Quality Assurance co-Chairs will 
review surgical preoperative eligibility criteria and operative 
reports for both the transoral endoscopic resection as well 
as the neck dissection(s) (i.e., the Operative and Surgical 
Pathology reports for the initial evaluation of lymph nodes 
and the surgical resection). 
5.1.6.2 
Dr. Ferris will perform a Quality Assurance Review after 
complete data for the first 15 cases enrolled has been 
received at ECOG-ACRIN Headquarters. Dr. Ferris will 
perform the next review after complete data for the next 15 
cases enrolled has been received at ECOG-ACRIN 
Headquarters. The final cases will be reviewed within 3 
months after this study has reached the target accrual or 
as soon as complete data for all cases enrolled has been 
received at ECOG-ACRIN Headquarters, whichever occurs 
first. 
5.1.6.3 
Goals of Surgical Quality Assurance 
• 
To assure eligibility and correct surgical staging of 
patients; 
• 
To assure safety of patients undergoing resection  
• 
To assure adequate resection of primary tumor and 
neck dissection 
5.1.6.4 
Surgical Protocol Compliance Criteria 
Deviations Minor:  
• 
“Close” margin, (< 3mm) 
• 
suboptimal neck dissection (< 20 nodes removed) 
Deviations Unacceptable: Those deviations that affect 
patient safety/outcome, which will result in an institution 
being suspended from further participation in the study, 
such as: 
• 
Positive Margin rate exceeding 20% (assessed every 5 
cases accrued) 
• 
Inadequate nodal dissection (< 15 nodes removed) 
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• 
Postoperative bleeding requiring return to the operating 
room for control, exceeding 20% of submitted patients 
(assessed every 5 patients accrued) 
5.1.7 
Pathologic Analysis of Surgical Specimens  
Within RTOG / ECOG-ACRIN centers, a designated surgical 
pathologist will be responsible for quality control of surgical pathology 
material processing, evaluation and reporting at their respective 
institution.   
Histopathologic Assessment:  Histopathologic assessment of surgical 
pathology frozen and permanent sections must include examination 
and reporting of the following parameters: 
• 
Perineural invasion (PNI) and lymphovascular invasion (LVI) 
Absent, or Present 
• 
Extracapsular extension (ECE) requires gross and microscopic 
assessment 
o absent (negative or nodal metastasis with smooth/rounded 
leading edge confined to thickened capsule/pseudocapsule), 
o present - minimal (tumor extends ≤1 mm beyond the lymph 
node capsule), or 
o present - extensive (tumor extends >1 mm beyond the lymph 
node capsule (includes soft tissue metastasis) 
p16 Immunohistochemistry (must be performed in a CLIA-certified 
laboratory); p16 antibody obtained from Roche mtm laboratories AG 
(CINtec® clone E6H4™) is recommended.  
o negative (cytoplasmic immunoreactivity noted in < 70% of tumor 
cells), and 
o positive (cytoplasmic immunoreactivity noted in ≥ 70% of tumor 
cells). 
Pathology materials are required to be submitted for central review as 
outlined in Section 11. 
5.1.8 
Post-operative Management 
Treatment should start within ten working days after registration 
to Step 2.  
The highest risk feature assessed pathologically will determine 
the patient's category/treatment arm assignment. 
5.1.8.1 
Definition of Low-Risk Patient Cohort and Management: 
Arm A (7 weeks) 
Low-risk stratification will require the presence of both 
primary site and neck dissection low-risk pathologic 
features, and pathologic stages T1N0, T1N1, T2N0, and 
T2N1, with no ECS and clear margins (≥ 3mm). This 
category will include the absence of close margins  
(< 3mm), perineural invasion and lymphovascular invasion 
in the primary site surgical specimen. Low-risk neck 
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dissection pathologic features include no more than N1 
nodal disease without extracapsular extension. 
The adjuvant management plan for low-risk HPV-
associated OPSCC patients treated with transoral surgery 
and neck dissection will be prospective observation. 
Summary of acceptable pathologic stage for “low risk” 
Arm A: 
T1-2N0-1, with clear (≥ 3mm) margins, and without any 
ECE or PNI/LVI. 
5.1.8.2 
Definition of High-Risk Patient Cohort and Management: 
Arm D (5-7 weeks) 
High-risk stratification will be applied when the presence of 
primary site or neck dissection high-risk pathologic 
features are identified.  High-risk primary site pathologic 
features will include a positive surgical margin or the 
presence of “extensive” (> 1mm) ECE (i.e. present – 
beyond minimal). Within the context of this protocol, only 
patients with tumor that extends > 1 mm beyond the lymph 
node capsule (including soft tissue metastasis) will be 
considered for concurrent cisplatin.   
Patients with extensive N2b neck disease (≥ 5 metastatic 
lymph nodes) regardless of primary tumor margin status 
will also be considered high-risk.  
Summary of acceptable pathologic stage for “high 
risk” Arm D: 
• 
Any one of the following features constitutes “high 
risk” status and will assign the patient to Arm D. 
• 
Any T stage with positive margin(s), meaning 
tumor at the specimen edge that is not superceded 
by an additional, tumor free margin 
• 
“Extensive” (> 1mm) ECE 
• 
≥ 5 metastatic lymph nodes) regardless of primary 
tumor margin status. 
• 
Please contact the PI, Dr. Ferris with any questions 
or to clarify. 
The adjuvant management plan for high risk HPV-
associated oropharyngeal carcinoma patients treated with 
transoral surgery and neck dissection will be concurrent 
postoperative CRT to 66 Gy in 33 daily fractions.   
Concurrent cisplatin will be administered at a dose of 40 
mg/m2 on days 1, 8, 15, 22, 29, 36, 43. 
5.1.8.3 
Definition of Intermediate-Risk Patient Cohort and 
Management: Arms B-C (5-7 weeks) 
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Intermediate-risk stratification will be applied when the 
presence of primary site or neck dissection intermediate-
risk pathologic features are identified.  Any one of the 
pathologic features below will constitute “intermediate 
risk” and assign the patient to the randomized RT 
dose arms B or C.  
Summary of acceptable pathologic stage for 
“intermediate risk” Arms B or C – randomized RT 
dose: 
• 
Any one of these features constitutes 
“intermediate risk” status and will assign the 
patient to Arm B or C. 
• 
Any T stage with one or more “close” (<3mm) 
margin(s) 
• 
“Minimal” (≤ 1mm) ECE 
• 
1 or more lymph node >3cm in diameter (N2a neck 
disease). 
• 
2-4 lymph nodes positive, any diameter ≤ 6cm (N2b 
neck disease), regardless of primary tumor margin 
status. 
• 
perineural invasion 
• 
lymphovascular invasion 
• 
Please contact the PI, Dr. Ferris with any questions 
or to clarify. 
The adjuvant management plan for intermediate risk HPV-
associated OPSCC patients treated with transoral surgery 
and neck dissection will be postoperative RT alone.  
Patients will be randomized to either 60 Gy or 50 Gy 
fractionated daily over 30 or 25 fractions, respectively.  For 
all patients, bilateral cervical nodal chains and the primary 
site will be irradiated. For selected patients randomized to 
60 Gy, the ipsilateral nodal regions involved with 
carcinoma and the primary surgical site will receive a 10 
Gy boost to a total of 60 Gy 
5.1.8.4 
Definition of Unknown-Risk Patient Cohort and 
Management: Arm C (5-7 weeks) 
Patients found to have N2C or N3 disease on final 
pathologic analysis are at unknown risk for recurrence, but 
are not candidates for deintensified adjuvant therapy in this 
trial. These patients will be treated on Arm C. 
5.1.9 
Postoperative Radiation Therapy 
5.1.9.1 
Credentialing 
Institutions not previously credentialed for use of IMRT in 
NCTN trials must irradiate IROC Houston’s head and neck 
phantom. Contact IROC Houston 
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(http://irochouston.mdanderson.org) for information about 
their phantoms. 
Patients will be considered unevaluable if required 
credentialing has not been completed. 
5.1.9.2 
Equipment 
5.1.9.2.1 
Modality: Accelerator x-ray beams with 
nominal energy of at least 4 MV shall be 
used. Linear accelerators must be capable 
of delivering treatment using multi-leaf 
collimation.  
5.1.9.2.2 
Intensity Modulated Radiation Therapy 
(IMRT) is mandatory for this study. 
Guidelines developed by the NCI for the use 
of IMRT in clinical trials should be followed. 
(See IROC website, 
http://www.irocri.qarc.org).  
5.1.9.2.3 
Calibration: All therapy units used for this 
protocol shall have their calibrations verified 
by the IROC Houston QA Center (RPC). 
5.1.9.2.4 
CT Simulation:  CT simulation will be 
required in all patients.  A thermoplast mask 
shall be used for patient immobilization 
(shoulders along with head strongly 
encouraged, although an alternative method 
of ensuring reproducible shoulder position is 
acceptable) for both CT-simulation and for 
each daily treatment. IV contrast is required 
in all patients (unless renal function 
prohibits contrast). Slice thickness of ≤ 3mm 
is required.  The patient should be 
simulated and immobilized with the neck in 
a hyper-neck extended position as best 
tolerated by the patient that will be 
reproducible on a daily basis.  Surface 
delineation of surgical scars with radio-
opaque markers will also be required at the 
time of CT simulation. 
5.1.9.2.5 
Image Fusion:  Additional images of the 
patient in the treatment position such as 
with MRI and 18-fluorodeoxyglucose PET 
will be permitted to facilitate the treatment 
planning process.  However, the primary 
image set for the treatment planning will be 
the CT image set. 
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5.1.10 
Organs at Risk (OAR) Delineation 
In general, the OARs that require delineation are dictated by the 
superior and inferior extent of the planning target volumes.  For 
example, if the superior extent of the target volume extends to the 
level of the C1 vertebral body, the brainstem at this level will need to 
be delineated.  
5.1.10.1 
OARs that are required for delineation include the following 
if they lie within the superior and inferior extent of the 
planning target volumes: 
• 
spinal cord 
• 
brainstem 
• 
right and left middle and inner ears 
• 
right and left globe of the eye 
• 
right and left lacrimal gland 
• 
right and left optic nerves 
• 
optic chiasm 
• 
right and left lens 
• 
superior constrictor muscle 
• 
middle constrictor muscle 
• 
inferior constrictor muscle 
• 
cricopharyngeus muscle 
• 
esophagus 
• 
endolarynx:  This volume will consist of the tissues 
medial and contained within the laryngeal cartilage and 
will include the endolaryngeal structures from the level 
of the tip of the suprahyoid epiglottis to the inferior 
extent of the cricoid cartilage that does not overlap with 
any adjacent PTV.  This OAR will be gapped from the 
adjacent PTV by 5-15 mm.  Where the adjacent PTV is 
to be prescribed 50 Gy, the endolarynx will be gaped 
from the PTV by 5 mm.  Where the adjacent PTV is to 
be prescribed 60 Gy, the endolarynx will be gapped 
from the PTV by 10 mm.  Where the adjacent PTV is to 
be prescribed 66 Gy, the endolarynx will be gapped 
from the PTV by 15 mm.  
• 
right and left parotid glands 
• 
right and left submandibular glands 
• 
skin 
• 
midline oral avoidance (MOA): This midline avoidance 
structure will include the portion of the oral cavity and 
oropharynx that is not included in the planning target 
volume.  The avoidance structure will be delineated 
such that there is a gap between the avoidance 
structure and the adjacent PTV that may range from 5-

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15 mm.  Where the adjacent PTV is to be prescribed 
50 Gy, the MOA will be gaped from the PTV by 5 mm.  
Where the adjacent PTV is to be prescribed 60 Gy, the 
MOA will be gapped from the PTV by 10 mm.  Where 
the adjacent PTV is to be prescribed 66 Gy, the MOA 
will be gapped from the PTV by 15 mm 
• 
mandible 
5.1.10.2 
Additional OARs that may be contoured but not required 
include  
• 
right and left temporal-mandibular joint 
• 
right and left thyroid gland 
• 
right and left brachial plexus 
• 
laryngeal cartilage 
• 
hyoid bone 
• 
thyroid gland 
5.1.10.3 
Planning OARs 
For critical neurologic OARs such as the brainstem, spinal 
cord, chiasm and optic nerves a systematic margin of 2 
mm may be added to generate additional planning OAR 
volumes (PRVs). 
To avoid the potential under-dosing of the CTV-N50 or 
CTV-N60 volumes where they overlap with the deep 
parotid lobes, a planning parotid volume may be 
delineated that represents the non-overlap portion of the 
parotid glands. This planning OAR will be referred to as 
“parotid-PTV”. 
5.1.11 
Target Volume Delineation 
5.1.11.1 
Target Volumes Definitions: The definition of volumes will 
be in accordance with ICRU Reports #50 and #62. Target 
volume nomenclature shall include the following:  
• 
Clinical Target Volume (CTV) is defined as all areas 
that may have subclinical carcinoma based on 
assessment of the preoperative imaging, intraoperative 
findings by the surgeon and the final pathologic 
evaluation.  Where there is potential discordant 
findings especially between the final pathology and the 
intraoperative findings typically with regards to the 
extent of the primary tumor, communication between 
the radiation oncologist and the surgeon is required for 
a consensus to be reached regarding the original 
extent of the primary carcinoma.  
Planning Target Volume (PTV) will provide a margin 
around the CTVs to compensate for variabilities in daily 
treatment set up, patient positioning, and internal organ 
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around the CTVs is required in all directions to define 
each respective PTV (i.e. PTV-P60, PTV-N60, PTV-
N50).  The extent of the PTV margin is influenced by 
the set-up reproducibility at each institution.  
Where there is a concern of gross tumor identified 
postoperatively and where further surgery is not 
possible, the radiotherapy treatment plan may be 
modified to include delineation of a gross tumor volume 
(GTV). 
• 
Gross Tumor Volume (GTV) is defined as all known 
areas of gross disease determined from CT, MRI, 
clinical information, and endoscopic findings. Grossly 
involved lymph nodes are defined as any lymph node 
≥1cm or nodes with a necrotic center or that have 
abnormal FDG uptake on PET. It is strongly 
encouraged that the radiation oncologist outlines the 
radiographic extent of the primary tumor and neck 
nodes along with neuro-radiologist. Whenever 
possible, it is recommended that diagnostic images be 
fused to the planning CT scan image dataset to more 
accurately determine the GTV. The gross tumor at the 
primary site will designated as GTV-P, and clinically 
involved gross lymph nodes are designated GTV-N.    
5.1.11.2 
Guidelines for Target Volume Delineation 
• 
CTV-P60:  CTV-P60 will represent the primary 
invasive tumor base. As the surgery will be transoral, 
the need to comprehensively treat the surrounding 
normal tissues that would otherwise be at risk for tumor 
seeding is not a major consideration.  The primary 
factor influencing the delineation of the CTV-P60 
volume should be influenced by the intra-operative 
assessment of the invasive base of the tumor.  These 
findings should be compared to the preoperative 
imaging to reconcile any discrepancy.  CTV-P60 
should not include the preoperative intra-luminal extent 
of the primary tumor that did not invade the 
oropharyngeal mucosa.  This volume shall include a 3-
5 mm margin of uncertainty around the estimated 
extent of the invasive tumor base that is deemed at 
risk. 
• 
CTV-N60:  CTV-N60 will represent the dissected 
cervical nodal volume found to have nodal metastases.  
This nodal volume will include the peripheral extent of 
the sternocleidomastoid muscle laterally and medially, 
will include a portion of the levator scapulae and the 
scalene muscles. 
• 
CTV-N50:  CTV-N50 will represent the either dissected 
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metastases or the undissected contralateral cervical 
neck when it is treated.  This nodal volume will include 
the peripheral extent of the sternocleidomastoid muscle 
laterally and medially, will include a portion of the 
levator scapulae and the scalene muscles.  Anteriorly, 
the posterior aspect of the submandibular gland and 
the medial pterygoid muscle will be the anterior 
boundary of level II nodal region. 
a. For the ipsilateral dissected neck, CTV-N50 should 
be extended to nodal volumes adjacent to 
pathologically involved nodal volumes.  For 
example, if the neck dissection reveals nodal 
metastases in level II, the adjacent level I and level 
V should be included in CTV-N50.  This nodal 
volume will include the peripheral extent of the 
sternocleidomastoid muscle laterally and medially, 
will include a portion of the levator scapulae and 
the scalene muscles. 
b. Indications for inclusion of the lateral 
retropharyngeal lymph nodes include the presence 
of ipsilateral level II nodal metastases or primary 
tumor extension to involve the posterior pharyngeal 
mucosa or suspected to be at risk due to 
involvement of the posterior tonsil pillar mucosa.  
The ipsilateral lateral retropharyngeal lymph nodes 
lie medial to the internal carotid artery and are 
predominantly located at the level of C1 vertebral 
body and occasionally at the C2 vertebral body 
level.  The medial retropharyngeal lymph nodes are 
not to be delineated.   
c. The contralateral retropharyngeal lymph nodes will 
be delineated as part of CTV-N50 when there is 
clinical/pathologic findings of ipsilateral 
retropharyngeal lymph node metastases. 
d. For the contralateral undissected neck, CTV-N50, 
the nodal volume should include the contralateral 
level II, III and IV nodal regions beginning at the 
level of the posterior digastric muscle.  This nodal 
volume will include the peripheral extent of the 
sternocleidomastoid muscle laterally and medially, 
will include a portion of the levator scapulae and 
the scalene muscles. 
e. Ipsilateral neck will be permitted, ie. omitting the 
contralateral CTV-N50 when the mucosal invasive 
base of the tumor is > 1 cm from the midline 
mucosa as judged at the time of the surgery.  For 
base of tongue cancers, the primary tumor adverse 
pathologic features including the positive surgical 
margins should not be present on the medial tumor 
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specimen.  For base of tongue cancers, the primary 
tumor should also not demonstrate a deep invading 
tumor front at the time of the surgery.  The distance 
from the midline mucosa will require documentation 
including the mucosal surface that is involved when 
the contralateral CTV-N50 is omitted.  Omitting the 
contralateral neck CTV-N50 is not permitted for 
N2c tumors and where clinical/pathologic findings 
of ipsilateral retropharyngeal lymph node 
metastases. 
• 
CTV-P66:  CTV-P66 will represent the region in the 
primary tumor bed deemed to be at risk due to the 
presence of a positive involved surgical margin.  
Typically, this will be at the deep surgical resection 
margin and thus will not be significantly extending into 
the pharyngeal lumen. 
• 
CTV-N66:  CTV-N66 will represent the region in the 
dissected neck found to have grade 4 ECE.  This 
volume should include sternocleidomastoid muscle in 
the nodal levels found with ECE present - beyond 
minimal (tumor extends > 1 mm beyond the lymph 
node capsule (includes soft tissue metastasis).   
• 
CTV-P70 or CTV-N70:  CTV-P70 or CTV-N70 will 
represent postoperative gross tumor that requires 
treatment to 70 Gy. 
5.1.12 
IMRT Prescription and Treatment Planning 
5.1.12.1 
The prescription dose will be administered with a cone-
down prescription with daily doses of 2 Gy.  No 
simultaneous in-field boost / dose-painting will be 
permitted.  Treatment will be delivered once daily, 5 
fractions per week. Treatment breaks, if necessary, should 
not exceed 5 treatment days and the reason(s) for the 
break must be clearly recorded in the treatment record. 
Any treatment break(s) exceeding two (2) treatment days 
for reasons other than toxicity/illness will be considered a 
protocol deviation. The reason for the missed treatment or 
treatments must be clearly indicated in the copy of the 
patients treatment record submitted to IROC Rhode Island.  
• 
PTV-N50: will be prescribed 50 Gy in 25 daily fractions 
• 
PTV-P60 or PTV-N60: will be prescribed 60 Gy in 30 
daily fractions 
• 
PTV-P66 or PTV-N66: will be prescribed 66 Gy in 33 
daily fractions 
• 
PTV-P70 or PTV-N70: will be prescribed 70 Gy in 35 
daily fractions 
As a cone-down IMRT technique will be used, a dose-
summary that represents all the phases of IMRT treatment 
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planning shall be generated. For example, if the maximum 
PTV prescription for a patient is to PTV-P66, then the first 
phase will deliver 50 Gy to both the primary and unilateral 
(see section 5.1.11.2.e) or bilateral cervical nodal volumes 
followed by a second phase to the primary surgical bed for 
an additional 10 Gy and a third phase to the just the boost 
volume at the site of the positive surgical margin for an 
additional 6 Gy. 
5.1.12.2 
Tissue Heterogeneity: The dose calculation shall take into 
account the effect of tissue heterogeneities. The method 
used for tissue heterogeneity calculations shall be 
reported. The dose prescription is to be based on a dose 
distribution corrected for heterogeneities.  
5.1.12.3 
No specific beam arrangements will be specified.  
Commonly, a co-planar beam arrangement is used.   
5.1.12.4 
Treatment Planning Objectives:  The treatment plan(s) 
used for each patient will be based on an analysis of the 
volumetric dose, including dose-volume histogram (DVH) 
analyses of the PTVs and critical normal structures.  
Inverse optimization algorithms will be used to achieve at 
least 95% of the volume of the specified PTVs is covered 
by the prescribed isodose surface while meeting the dose 
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Priority 
Structure Name 
Treatment Planning Objective 
Coverage Volume 
OAR Maximum 
Dose 
Constraint(Gy) 
OAR Partial Volume 
Dose Constraint 
Volume Dose (Gy) 
1 
PTVs 
D95= 
prescription 
dose 
 
 
 
 
1 
spinal cord 
 
1 cc 
45 Gy 
 
 
1 
brainstem 
 
1 cc 
54 Gy 
 
 
1 
R and L optic nerve 
 
0.1 cc 
45 Gy 
 
 
1 
optic chiasm 
 
0.1 cc 
45 Gy 
 
 
 
 
 
 
 
 
 
2 
R and L optic nerve PRV 
 
0.1 cc 
50 Gy 
 
 
2 
R or L parotids 
 
 
 
50% 
< 20 Gy 
2 
R and L parotids combined 
 
 
 
mean 
< 26 Gy 
2 
midline oral avoidance 
 
5 cc 
45 Gy 
50% 
< 35 Gy 
2 
endolarynx 
 
1 cc 
50 Gy 
50% 
< 30 Gy 
2 
cricopharyngeus 
 
1 cc 
50 Gy 
50% 
< 30 Gy 
2 
esophagus 
 
1 cc 
45 Gy 
 
 
2 
R and L middle and inner ear 
 
0.1 cc 
45 Gy 
 
 
2 
R and L optic globe 
 
1 cc 
50 Gy 
 
 
2 
R and L lacrimal gland 
 
1 cc 
40 Gy 
 
 
2 
R and L lens 
 
1 cc 
30 Gy 
 
 
2 
mandible 
 
1 cc 
70 Gy 
 
 
2 
skin 
 
5 cc 
60 Gy 
 
 
3 
submandibular gland 
contralateral to the side of the 
neck dissection 1 
 
 
 
50% 
< 35 Gy 
1 when the contralateral level I nodal group is not part of CTV-N50 
5.1.12.5 
For treatment planning purposes, the dosimetric 
constraints that will be used for each phase of the IMRT 
treatment planning will be modified by a proportion that 
reflects the maximum dose for that phase to the total 
prescription dose.  For example, if the maximum 
prescription is 60 Gy, the first phase that will deliver 50 Gy 
will utilize the dose constraints modified by 5/6. 
5.1.13 
Definitions of Dosimetric Variation - Minor Variation/Major Variation 
To avoid a minor variation: no more than 3% volume of the PTV will 
receive greater than 108% of the prescribed dose, and no tissue 
(target or non-target) shall receive more than 110% of the prescribed 
dose. In addition, no more than 5% volume of any PTV shall receive 
less than 95% of the prescribed PTV dose, and no more than 1% of 
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Reported doses for PTVs shall include the prescription dose, 
maximum point dose for each PTV, % PTV receiving 110%, 108% 
and 95% and 93% dose. Also, the mean dose must be reported.  
5.1.14 
Repeat Simulation and Planning  
There are circumstances where it may be appropriate to repeat a 
patient’s simulation. Examples may be when there is excessive weight 
loss and either the thermoplast mask is no longer tight or the patient’s 
external contour no longer matches the original contour typically due 
to weight loss. The original PTVs should continue to be treated to the 
original volume. 
5.1.15 
Dose Calculation and Reporting  
• 
Digital Submission:  
Submission of radiation therapy treatment plans in digital format 
as DICOM RT is required for this study. Instructions on digital data 
submission are available online from the IROC Rhode Island 
website at http://www.irocri.qarc.org/ (See Digital Data section). 
• 
Dose Volume Histograms:  
Dose volume histograms must include GTV’s, CTV’s, PTV’s, and 
organs at risk as noted above. A DVH shall also be submitted for 
a category of tissue called “unspecified tissue,” which is defined 
as tissue contained within the skin, but which is not otherwise 
identified by containment within any other structure.  
• 
Re-planning:  
If the patient is re-simulated and re-planned on a new CT dataset, 
the individual plans shall be submitted. For such cases, the fused 
data-set with the target volumes and critical normal structures 
should also be submitted. If your planning system has the 
capability of exporting a DICOM spatial registration file, the spatial 
registration file shall be submitted along with the two CT scan 
sets.  Otherwise screen captures of the fused datasets with the 
target volumes and critical normal structures shall be submitted. 
• 
IMRT Plan Verification:  
The monitor units generated by the IMRT planning system must 
be independently checked prior to the patient’s first treatment. 
Measurements in a QA phantom can suffice for a check as long 
as the plan’s fluence distributions can be recomputed for a 
phantom geometry.  
5.1.16 
QA Documentation 
Digital Submission: 
Submission of treatment plans in digital format as DICOM RT is 
required. Digital data must include CT scans, structures, plan, and 
dose files. Submission may be by either sFTP or CD. Instructions for 
data submission are on the IROC Rhode Island web site at 
http://www.irocri.qarc.org/ under "Digital Data."  Any items on the list 
below that are not part of the digital submission may be included with 
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the transmission of the digital RT data via sFTP or submitted 
separately. Screen captures are preferred to hard copy for items that 
are not part of the digital plan. 
Please submit the following data within 3 days of the start of 
radiation therapy: 
External Beam Treatment Planning System  
• 
RT treatment plans including CT, structures, dose, and plan files.  
These items are included in the digital plan.  
• 
Dose volume histograms (DVH) for the composite treatment plan 
for all target volumes and required organs at risk. When using 
IMRT, a DVH shall be submitted for a category of tissue called 
“unspecified tissue.” This is defined as tissue contained within the 
skin, but which is not otherwise identified by containment within 
any other structure. DVHs are included in the digital plan. 
• 
Treatment planning system summary report that includes the 
monitor unit calculations, beam parameters, calculation algorithm, 
and volume of interest dose statistics. 
• 
If replanning is done on a new CT dataset and your planning 
system has the capability of exporting a DICOM spatial 
registration file, submit the spatial registration file along with the 
two CT scan sets.  Otherwise screen captures of the fused 
datasets with the target volumes and critical normal structures 
delineated shall be submitted. 
Supportive Data 
• 
Copies of the pre-study diagnostic imaging used to define the 
GTV’s and CTV’s. Copies of the corresponding radiology reports, 
exam notes, clinical information, and copies of the endoscopic 
findings must also be submitted. Imaging studies shall be 
submitted as DICOM files and either copied to a CD or submitted 
via SFTP. Multiple studies for a patient may be included on a CD, 
but please include only one patient per CD.  
• 
Documentation of an independent check of the calculated dose 
when IMRT is used. 
• 
Prescription sheet for the entire treatment. 
Forms 
• 
RT-1 Dosimetry Summary Form. 
• 
A copy Appendix III (AJCC Head/Neck Staging Criteria).  
• 
Copy of Appendix V “ECOG-ACRIN Checklist for Submission of 
Radiation Oncology Quality Assurance Materials”  
Within 1 week of the completion of radiotherapy submit the 
following items: 
• 
Radiotherapy record (treatment chart) including prescription and 
daily and cumulative doses to all required areas and organs at 
risk. 
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• 
RT-2 Radiotherapy Total Dose Record Form. 
• 
If emergency RT is administered, documentation should be 
provided in the form of the RT-2 Total Dose Record Form and the 
radiotherapy record (treatment chart). 
• 
Copy of Appendix V “ECOG-ACRIN Checklist for Submission of 
Radiation Oncology Quality Assurance Materials”  
These data should be forwarded to: 
IROC Rhode Island QA Center 
640 George Washington Highway, Building B, Suite 201 
Lincoln, Rhode Island 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753 7601 
E-mailed data can be sent to: DataSubmission@QARC.org  
Questions related to the radiotherapy treatment planning can be 
directed to: 
Harry Quon, MD 
Johns Hopkins University 
Phone: 410-502-3877  
E-mail: hquon2@jhmi.edu 
Questions regarding the dose calculations or documentation should 
be directed to: 
IROC Rhode Island QA Center 
Quality Assurance Review Center 
640 George Washington Highway, Building B, Suite 201 
Lincoln, Rhode Island 02865-4207 
Phone: (401) 753-7600 
If there are any changes in the patient’s status (i.e., early 
discontinuation of protocol treatment, delay in starting radiotherapy, or 
break in radiotherapy) these should be communicated in writing to 
IROC Rhode Island by fax (401) 753-7601 or email to 
ECOG@qarc.org.  
5.1.17 
Definitions of Deviations in Protocol Performance  
Dose: 
Minor deviation: The delivered dose to the prescription volume differs 
from protocol specification by more than 5% but less than 10%.  
Major deviation: The delivered dose to the prescription volume differs 
from protocol specification by more than 10%.  
Dose Uniformity:  
Minor deviation: More than 3% of the PTV receives more than 108% 
of the prescription dose or more than 1% of the PTV receives less 
than 93% of the prescription dose.  
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Major deviation: More than 5% of the PTV receives more than 115% 
of the prescription dose.  
Volume:  
Minor deviation: Margins for PTV less than specified, or field(s) 
excessively large.  
Major deviation: GTV (or corrected GTV if not appropriately drawn) 
not included within the 95% dose volume  
Treatment Breaks:  
More than two missed treatment days for any reason other than a 
toxicity is considered a deviation.  
Minor deviation: 3-5 days.  
Major deviation: > 5 days  
Evaluation After Completion of Concurrent Therapy  
Patients will be re-evaluated after the completion of treatment to 
assess clinical and radiographic response by complete head and neck 
exam and imaging studies. 
Patients with persistent disease will be evaluated and where indicated 
undergo appropriate surgical resection.  
5.1.18 
Administration of cisplatin 
Patients on Arm D will receive cisplatin 40 mg/m2 as an IV infusion in 
normal saline over 60 minutes weekly (Days 1, 8, 15, 22, 29, 36, 43) 
during 7 weeks of radiation therapy. Cisplatin administration outside of 
these specified days during radiation is only allowed in the event of 
holidays that do not permit drug and radiation delivery on the specified 
date. Subsequent chemotherapy doses should follow the protocol 
specified days of treatment. No cisplatin will be prior to day 1 of 
radiation therapy. In the event that radiation therapy is held, no 
cisplatin will be administered during the week of the radiation break. 
The use of colony stimulating factors (G-CSF, GM-CSF) and 
amifostine in this trial is explicitly discouraged. Erythropoietin 
stimulating agents, such as erythropoietin and darbepoietin, are 
prohibited. 
• 
Cisplatin administration should be accompanied by vigorous 
forced hydration (1000ml delivered over 1-2 hours just prior to 
treatment, and immediately after treatment) and Mannitol diuresis. 
Hydration/diuresis may be adjusted where clinically indicated at 
the discretion of the investigator, or according to standard 
institutional or regional practice. Potassium chloride and/or 
magnesium sulfate may be added to the hydration solutions per 
institutional practice. Magnesium wasting is a well-known 
complication of cisplatin therapy.  
• 
Routine premedication should include a 5 – HT3 receptor 
antagonist and dexamethasone. Aprepitant is encouraged for 
prevention of severe nausea, and should be administered on the 
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following schedule: aprepitant 125mg orally day 1, aprepitant 80 
mg orally day 2, day 3 
• 
Careful attention should be paid to urine output with supplemental 
fluids or diuretics given as appropriate. Serum potassium and 
magnesium levels should also be monitored regularly. 
• 
Regular administration of aminoglycoside antibiotics, iodinated CT 
contrast, or other nephrotoxic agents within 48 hours of cisplatin 
should be avoided in view of their potentiating effect on cisplatin 
nephrotoxicity. 
• 
Aluminum-containing needles should not be used for cisplatin 
administration. 
5.1.19 
Patient Reported Outcomes (PROs) 
Quality of Life (QOL) assessments will be performed at baseline, end 
of treatment, and at 3, 6, 12, and 24 months after completion of 
treatment. If an additional tumor assessment is done prior to 3 years 
from study entry, one final QOL assessment is requested.  Please 
refer to Appendix V for the complete schedule. 
QOL will continue to be collected for all patients post recurrence. 
Paper questionnaires will be completed by the patient, and then data 
from the questionnaire should be entered into Medidata Rave within 7 
days of completion. The original copy needs to be kept in the study 
subject’s research binder. Refer to the ECOG website for a copy of 
the questionnaire. 
5.2 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting:  Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.   
• 
Expedited reporting:  In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
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• 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
• 
Expectedness:  Any adverse event, the type or severity of which 
is consistent with the current investigator’s brochure, product 
label, and/or the protocol document 
5.2.3 
Reporting procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) 
• 
the FDA (1-800-FDA-1088)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
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5.2.4 
Determination of reporting requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
the relationship to the study treatment (attribution) 
• 
the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E3311 and outline 
the specific expedited adverse event reporting requirements for 
study E3311.   

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5.2.5 
Steps to determine if an event is to be reported in an expedited 
manner 
 
Identify the type and grade of the 
event using CTCAE v5.0 
Determine if the event is related to 
the protocol treatment (attribution) 
With this information, review the 
chart in Section 5.2.6 to determine if 
event is reportable via CTEP-AERS 
Refer to footnote b in Section 
5.2.6 to determine if the event 
meets the protocol specific 
reporting requirements for this 
study. If so, report the event via 
CTEP-AERS 
Is the event 
reportable? 
No 
Yes 
Report the event via CTEP-AERS. 
Determine the expectedness of the 
event.  An unexpected event is 
defined as one where the type of 
severity of the event is not listed in 
the investigator’s brochure, package 
insert or protocol. 
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5.2.6 
Expedited Reporting Requirements for Arms S, A, B, C and D on 
protocol E3311 
Commercial Agents: Cisplatin, Carboplatin   
Expedited reporting requirements for adverse events experienced by patients on arm(s) with 
commercial agents only 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of 
learning of the event. 
a This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  
Any death that occurs > 30 days after the last dose of treatment and is attributed possibly, 
probably, or definitely to the treatment must be reported within 7 calendar days of learning 
of the event.   
b Protocol-specific expedited reporting requirements: The adverse events listed below also require 
expedited reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported 
via CTEP-AERS within 7 calendar days of learning of the event.  For instructions 
on how to specifically report these events via CTEP-AERS, please contact the 
AEMD Help Desk at aemd@tech-res.com or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
Bleeding: Any grade 3-4 bleeding (requiring hemostasis in the operating room), regardless of 
attribution or expectedness, must be reported via CTEP-AERS within 7 calendar days 
of learning of the event. 
5.2.7 
Other recipients of adverse event reports and supplemental data 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.8 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine 
reporting as follows: 

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1. Complete a Second Primary Form in Medidata Rave in 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave in 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
• 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata  Rave and submit a copy to NCI/CTEP confirming 
the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form 
5.3 
Dose Modifications 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.3.1 
The use of colony stimulating factors (G-CSF, GM-CSF), and 
amifostine are explicitly discouraged. Erythropoietin stimulating 
agents, such as erythropoietin,and darbepoietin, are prohibited. 

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5.3.2 
Cisplatin 
5.3.2.1 
Hematologic 
Cisplatin will not be given until the ANC ≥ 1000/mm3 and 
the platelet count ≥ 75, 000/mm3. Complete blood count, 
differential and platelets will be checked weekly during 
therapy.  Dose modifications are as per table below: 
Toxicity 
Cisplatin Modification 
ANC < 1000/mm3  
or 
Platelets 
 < 75,000/mm3 
Hold therapy 1 week, and treat at full dose if ANC ≥ 1000 and platelets ≥ 75,000 
If ANC and/or platelets have not recovered after 7 days, lower cisplatin to 30 
mg/m2 weekly and re-initiate therapy once ANC ≥ 1000 and platelets ≥ 75,000 
If after dose reduction, ANC < 1000 and/or platelets < 75,000 on the next day of 
treatment, hold cisplatin until ANC ≥ 1000 and platelets > 75,000 
and restart at 20mg/m2. 
If on the subsequent treatment day, ANC < 1000 and/or platelets < 75,000, 
discontinue further chemotherapy 
Neutropenic fever 
Hold cisplatin until ANC ≥ 1000, and re-start at 30mg/m2. If cisplatin is already at 
30mg/m2, restart cisplatin at 20mg/m2. If cisplatin was given at 20mg/m2, 
discontinue further chemotherapy. 
NOTE: 
No dose re-escalations will be allowed.  
5.3.2.2 
Renal 
Cisplatin will not be given if the serum creatinine is > 1.6 
mg/dl.  Serum creatinine is required before each dose of 
cisplatin. Modify the cisplatin dose using the following 
parameters for calculated creatinine clearance determined 
in the well-hydrated patient using the modified Cockcroft-
Gault formula: 
{ (140 - age) (Wt in kg)* } /72 (serum creat mg/dL) 
* Wt is actual body weight. With provision to multiply by 0.85 in 
women. 
Calculated Cr clearance 
Chemotherapy dose 
> 60 ml/min 
100% (40 mg/m2) 
40-60 ml/min 
30mg/m2 
< 40 ml/min 
Hold cisplatin 
5.3.2.3 
Neurotoxicity 
Significant (grade 3) myopathy, weakness, or neuropathy; 
seizure or paralysis should prompt discontinuation of 
cisplatin. Carboplatin at an AUC of  2 weekly may be 
substituted under these circumstances. 
For grade 2 neurotoxicity hold cisplatin until toxicity 
improves to ≤ grade 1, then reduce all subsequent doses 
of cisplatin to 30mg/m2. 
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5.3.2.4 
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, consider obtaining an audiogram and reduction of 
cisplatin to 30 mg/m2 if there is evidence of significant 
hearing loss. If tinnitus persists on the day of treatment, or 
if it recurs despite this dose reduction, or for if there is new 
hearing loss requiring a hearing aid, discontinue cisplatin 
and switch to carboplatin.   
Grade 3 hearing loss in the speech frequency range is an 
indication to discontinue cisplatin and switch to carboplatin.  
5.3.2.5 
Other non-hematologic toxicities: For any grade 3 or 4 
toxicities not mentioned above and excluding alopecia, 
nausea, dehydration and mucositis, treatment with cisplatin 
should be delayed until < grade 2. For grade 1 or 2 
toxicities no delays will occur. If cisplatin is held > 2 weeks, 
it will be permanently discontinued. For grade 4 toxicity 
requiring hospitalization, cisplatin may be interrupted at the 
discretion of the treating physician.  
5.3.3 
Carboplatin Administration Schedule  
Subjects unable to tolerate cisplatin as indicated in above, may be 
given carboplatin instead, administered to target AUC 2.  Carboplatin 
will be dosed using the Calvert formula:  
Total dose(mg)= (target AUC) x (glomerular filtration rate [GFR] 
+25)  
Calculated creatinine clearance will be used to estimate the GFR. The 
modified Cockcroft-Gault formula below should be used to calculate 
the creatinine clearance:  
140 -age (yrs) x actual weight (kg) / 72 x Serum creatinine(mg/dl) 
• 
Multiply by a factor of 0.85 if female  
• 
Intended for ages 18-100, serum creatinine 0.6-7 mg/dl 
• 
Carboplatin will be administered over 30 minutes. 
5.3.3.1 
Dose Modifications for Carboplatin 
Carboplatin Dose Modification Guidelines  
Hematological toxicity  
Carboplatin Dose  
ANC < 1000 mm3  
Hold dose  
Platelet count < 75,000 mm3  
Hold dose  
NOTE: 
Dose modifications for carboplatin will be based 
on the labs on the day of treatment.  If labs are 
above thresholds in the subsequent week, 
treatment can resume at the original doses.  
5.3.3.1.1 
Renal dysfunction: If serum creatinine 
increases or decreases by > 20% from 
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baseline, the carboplatin dose must be 
recalculated.  
5.3.3.1.2 
Other non-hematologic toxicities: For any 
grade 3 or 4 toxicities not mentioned above 
and excluding alopecia, nausea, 
dehydration and mucositis, treatment with 
carboplatin should be delayed until < grade 
2. For grade 1 or 2 toxicities no delays will 
occur. If carboplatin is held > 2 weeks, it will 
be permanently discontinued. For grade 4 
toxicity requiring hospitalization, carboplatin 
may be interrupted at the discretion of the 
treating physician.  
5.3.4 
Radiation Dose Modifications  
There will be no radiation dose modifications. Radiotherapy will be 
interrupted for > grade 3 radiotherapy-related toxicity except for grade 
3 mucositis and skin reaction that may be managed with supportive 
care. Treatment may resume when toxicity resolves to grade 2.  
For grade 4 toxicity requiring hospitalization (even if unrelated to 
radiotherapy), the treatment may be interrupted at the discretion of the 
treating physician.  
If radiation therapy is held for toxicities (whether related to protocol 
treatment or not) for > 4 weeks, all protocol therapy will be 
discontinued.  
5.4 
Supportive care 
5.4.1 
Oral Care  
Dental status must be evaluated and documented by the surgeon 
prior to the day of surgery. A referral and consultation with a dental 
hygienist may be needed prior to surgery if abnormalities are noted. 
Dental evaluation should include: examination with radiographs, 
removal of diseased teeth, restorative work, periodontal therapy, 
smoothing of rough or irregular dental surfaces, and assessment of 
dental appliances for fit. In addition, patients should be assessed for 
trismus and if present, patients should be provided with range of 
motion exercise. Patients should be provided with adequate dental 
education including: the risk for radiation induced dental decay, 
methods for maintaining good oral hygiene, the appropriate use of 
prescription fluoride treatment, and dietary influences on oral and 
dental health. 
Appropriate oral hygiene includes the following: brushing teeth after 
each meal, flossing daily, the frequent use of oral rinses with salt 
and/or baking soda (every two to four hours), and the daily use of 
prescription fluoride therapy. Additional therapy, such as the routine 
use of high calcium/phosphate (Caphosol) suspensions for the 
prevention of mucositis and dental decay should be considered.  
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During therapy, patients oral should be assessed on a routine basis to 
determine the following: compliance with oral hygiene regimens, the 
development of oral infections such as candidiasis, the development 
of oral mucositis, and the impact oral health on dietary intake. 
Ongoing education regarding the importance of oral care may be 
needed. Oral care regimens may need to be adjusted in patients who 
develop severe oral mucositis. Patients who develop mucosal 
sensitivity may require dietary counseling to help guide food choice. 
Patients should be told not to wear dental appliances in the presence 
of inflamed or ulcerated mucosa.  
After therapy is completed, patients need to resume an aggressive 
routine dental follow-up. In addition, patients must be encouraged to 
continue oral hygiene regimens, the use of prescription fluoride and 
maintain good dietary habits.  
5.4.2 
Nutritional Support  
At the time of diagnosis, it is strongly encouraged that all patients with 
head and neck cancer undergo an initial dietary assessment by a 
trained dietician. Nutritional status (weight loss) must be evaluated 
and documented by the surgeon prior to the day of surgery. A referral 
and consultation with a dietician may be needed prior to surgery if 
abnormalities are noted. Patients with weight loss and inadequate oral 
intake should receive a feeding tube prior to initiation of therapy. For 
patients with adequate oral intake, the prophylactic placement of a 
feeding tube is at the discretion of the treating physician. Patient 
should be followed by dieticians routinely throughout the course of 
treatment. Dietary recommendations should include: recommended 
total caloric intake, recommended intake of protein, daily requirement 
for free water, feeding tube should be placed. Close monitoring by 
dieticians is important for patients with feeding tubes, particularly 
immediately after tube placement as patients often experience 
problems with enteral feeding or formulations. All patients who have a 
feeding tube placed should be evaluated and monitored by the 
Dietitian and Speech Pathologist to ensure adequate nutrition and 
return to oral intake. 
5.4.3 
Rehabilitation  
It is strongly encouraged that all patients be referred for an 
assessment by a certified physical therapist after the completion of 
concurrent therapy. Components of the evaluation should include: 
neck shoulder and jaw range of motion, general conditioning level, the 
degree of treatment related fatigue, and postural issues. Patients with 
significant levels of deconditioning, postural abnormalities, or 
decrease in range of motion may require physical therapy. 
Occupational therapy may be needed in patients with extreme 
degrees of dysfunction. Patients with lymphedema should be referred 
for lymphedema therapy which should include: education, manual 
lymph drainage and the use of compression garments.  
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5.4.4 
Speech and Language Pathology  
Swallowing assessment and therapy is considered a critical 
component of care for all head and neck cancer patients. An MBS 
study will be required at baseline and after treatment for patients from 
sites that have declared participation in the MBS studies, and strongly 
encouraged from other institutions that use the MBS study as 
standard-of-care for patients with swallowing dysfunction.  
Assessments should be done by a trained Speech-Language 
Pathologists (CCC-SLP). The SLP should be consulted during 
treatment planning and should provide routine follow-up throughout 
the trajectory of the patient’s treatment and recovery. The treating 
physician should communicate with the SLP in order to coordinate 
care in those patients found to have significant swallowing 
abnormalities. Critical component of the swallowing evaluation should 
include: 1) identification of any swallowing abnormalities, 2) 
recommendations for further testing, 3) formation of a treatment plan, 
4) dietary recommendations, and 5) clear identifications of patients at 
risk for aspiration. Patients should be referred immediately for 
evaluation if any of the following “trigger symptoms” are identified: 
coughing or clearing the throat before, during or after eating, inability 
to control food, liquids or saliva in the oral cavity, complaint of difficulty 
swallowing or food “sticking” in the throat, nasal regurgitation of food, 
or pocketing of food in the cheek. 
5.4.5 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Treatment is interrupted for 4 consecutive weeks; patient’s protocol treatment 
will be discontinued  
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued  
• 
Patient develops unacceptable toxicity; then the patient will discontinue 
protocol therapy  
• 
Patients may withdraw consent and withdraw from the study at any time for 
any reason 
5.6 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 5 years from the date of registration. 
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6. 
Measurement of Effect 
6.1 
Time to Progression  
This interval will be measured from the date of entry on the study to the 
appearance of new metastatic lesions or objective tumor progression. 
6.2 
Methods of Measurement  
Imaging based evaluation is preferred to evaluation by clinical examination. The 
same imaging modality must be used throughout the disease evaluation. 
6.2.1 
CT and MRI  
CT and magnetic resonance imaging (MRI) are the best currently 
available and most reproducible methods for measuring target 
lesions.  
6.2.2 
Chest X-Ray  
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by an aerated lung. However, 
CT is preferable. 
6.2.3 
Tumor Markers  
Tumor markers alone cannot be used to assess response.  
6.2.4 
Clinical Examination  
Clinically detected lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes). 
For skin lesions, documentation by color photography, including a 
ruler to estimate size of the lesion, is recommended. Photographs 
should be retained at the institution. 
6.2.5 
Cytology and Histology  
Cytologic confirmation of the neoplastic nature of any effusion that 
appears or worsens during treatment is required when the 
measurable tumor has met response or stable disease criteria. 
6.2.6 
Ultrasound  
Ultrasound may be used only as an alternative to clinical 
measurements for superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules. 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
1. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done 
within 30 days prior to randomization/registration. 
2. Prestudy CBC (with differential and platelet count) should be done ≤ 4 weeks before randomization/ registration.  
3. All required prestudy chemistries, as outlined in Section 3, should be done ≤ 4 weeks before 
randomization/registration – unless specifically required on Day 1 as per protocol. 
Table 3. 
 
Prior to 
Registration/ 
Randomization 
Day of 
Surgery 
First Post-
operative 
week 
4-6 Weeks 
After 
TORS 
At completion of treatment 
(Arms B, C, D), observation 
(Arm A) , or Arm S patients 
who do not register to Step 2 
LTFU Arms B, C, D 
Observation  
(Arm A), or Arm S patients who 
do not register to Step 2 
Medical history, PE, Vital signs  
X 
X 
X 
 
X 
X2 
Height  
X 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
X2 
ECOG Performance status  
X 
X 
X 
X 
X 
X2 
CBC w/diff, plts 
X 
X5 
X 
 
X 
X2 
Serum chemistry 
X 
X5 
X 
 
X 
X2 
Adverse event evaluation  
X 
 
X 
 
X 
X2 
Disease Evaluation by clinical methods3 
X 
 
 
 
 
X 
Tumor tissue 
X 
 
 
 
 
 
CT SCAN with contrast/MRI of neck3 
X 
 
 
 
 
X 
B-HCG 
X 
 
 
 
 
 
Dental evaluation6 
X 
 
 
 
 
 
Nutrition consult6 
X 
 
 
 
 
 
SLP consult with MBS4 
X 
 
 
X 
 
X1 
Feeding tube placement 
 
 
optional 
 
 
 
Patient Reported Outcomes  
See Appendix V 
Biological specimen submissions 
See Section 7.2 
1. 6 months and 24 months after treatment. These are required for sites participating in the MBS sub-study (See Appendix V). Results of these 
tests are also requested from sites that perform these as standard of care. Videos should be uploaded to the cloud at MD Anderson Cancer 
Center. 
2. Arms B, C, D assessments will be done at 10-12 weeks after completion of treatment, Arm A will be done 17-19 weeks from registration to 
step 2, and Arm S will be done 23-25 weeks following surgery; then every 3 months for the first 2 years, every 6 months for the third year, 
and every 12 months for the fourth and fifth year or until progression. 
Rev. 2/14, 
Rev. 2/15 
Rev. 6/14 
Rev. 2/15
Rev. 2/14, 
6/15 
Rev. 2/14.  
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3. Disease evaluation by clinical methods and a CT and/or MRI will be obtained at baseline (≤ 30 days before registration), 10 - 12 weeks after 
completion of treatment [Arms B, C, D] or 17-19 weeks from registration to step 2 [Arm A] or 23 -25 weeks following surgery [Arm S]; then 
every 6 months for the first 3 years, and every 12 months for the fourth and fifth year, or until progression. 
4. For sites participating in the MBS substudy, MBS videos completed by the site will be stripped of patient identifiers, renames with and EA-
designated ID number, and uploaded to the Box® Cloud-based storage account maintained by MD Anderson Cancer Center. EA-designated 
ID number is obtained via the ECOG-ACRIN Sample Tracking System. Follow the instructions for the submission of these outlined in Section 
10.1.6. 
5. All labs may be completed within 7 days of surgery. 
6. Dental status and nutritional status (weight loss) must be evaluated and documented by the surgeon prior to the day of surgery. A referral 
and consultation with a specialist may be needed prior to surgery if abnormalities are noted. 
 
 
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7.2 
Biological Sample Submissions  
Samples are to be submitted as outlined in Section 11. Submission requirements are indicated by Treatment Arm in 
the table below. 
NOTE: All samples submitted must be logged and tracked in the ECOG-ACRIN Sample Tracking System (STS). 
 
Baseline 
Within 4 wks 
post-surgery 
Step 2, 
Week 42 
Step 2, 
End of trt 
Step 2,  
1st RTC appointment 
after EOT (~12 weeks) 
q 3mon2 
x 2 yrs 
q 6mon2 
x 2 yrs 
MANDATORY:  Submission of these materials are REQUIRED to determine patient evaluability and for surgical quality assurance review.   
Diagnostic p16 Tumor Slide 
S1 
 
 
 
 
 
 
Pathology and Surgical Reports 
S1 
S1 
 
 
 
 
 
Per patient consent: Submit from patients who have answered “Yes” to “I agree to provide additional specimens for research. 
Serum, from 1 x 10 mL Red-top no anti-coagulant4 
S 
S 
B,C,D 
B,C,D  
B,C,D 
 
A,B,C,D, S 
Peripheral Blood lymphocytes and plasma, 4 x 
10mL EDTA vacuatiner3 
S 
S 
B,C,D 
B,C,D 
B,C,D 
 
A,B,C,D, S 
Oral rinse5,6 
S 
S 
 
B,C,D 
 
A,B,C,D,S 
 
Tumor Tissue, Fixed and Frozen4 
 
S 
 
 
 
 
 
1. 
The requested pathology materials and reports are to be submitted as outlined in Section 11 upon finalization of the 
surgical pathology report but no later than 4 weeks following the performance of the surgery.  
2.  For Arms A, B, C, and D the collection time points are from the start of Step 2 treatment. Arm S patients not registered/randomized to Step 
2, collection time points are from time of surgery. 
3. Collect Monday – Thursday only. Do not collect the day before a weekend or holiday.  Samples are shipped the day of collection and must 
be processed immediately upon receipt. 
4. Frozen Samples are to be shipped on dry ice. Original diagnostic or surgical specimens may be submitted. 
5. Samples may be batched and submitted on a quarterly basis. 
6. Samples should be collected 30 minutes prior to or 2 hours after eating to reduce potential contamination from food. 
 
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2/15 
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8. 
Drug Formulation and Procurement 
8.1 
Cisplatin 
8.1.1 
Other Names  
Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II), 
diaminedichloroplatinum, cis-platinum, platinum, Platinol , Platinol-AQ 
, DDP, CDDP, DACP, NSC 119875 R R 
8.1.2 
Classification  
Alkylating agent  
8.1.3 
Mode of Action  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. 
Other possible mechanisms include chelation of DNA and binding to 
cell membranes thereby stimulating immune mechanisms. 
8.1.4 
Storage and Stability  
Intact vials of cisplatin are stored at room temperature. Solutions 
diluted with saline solution are stable for up to 72 hours at room 
temperature. Due to the risk of precipitation, cisplatin solutions should 
not be refrigerated.  
8.1.5 
Dose Specifics  
40 mg/m2 IV day 1, each week of radiation therapy, on Arm D only. 
8.1.6 
Preparation  
The desired dose of cisplatin is diluted with 250-1000 ml of saline 
solution. 
Varying concentrations of 0.225-5% sodium chloride may be used. To 
maintain stability of cisplatin, a final sodium chloride concentration of 
at least 0.2% is recommended. 
8.1.7 
Route of Administration  
Cisplatin is administered as an intravenous infusion over 60 minutes. 
8.1.8 
Incompatibilities  
Amsacrine, cefepime, gallium nitrate, mesna, piperacillin, sodium 
bicarbonate, thiotepa. Cisplatin may react with aluminum which is 
found in some syringe needles or IV sets, forming a black precipitate. 
8.1.9 
Compatibilities  
Admixture: Amphotericin-B, aztreonam, carmustine, cefazolin, 
cephalothin, droperidol, etoposide, floxuridine, hydroxyzine, 
ifosphamide, leucovorin, magnesium sulfate, mannitol, potassium 
chloride.  
Y-site: Allopurinol, bleomycin chlorpromazine, cimetidine, 
cyclophosphamide, dexamethasone, diphenhydramine, doxapram, 
doxorubicin, famotidine, filgrastim, fludarabine, fluorouracil, 

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furosemide, ganciclovir, heparin, hydromorphone, lorazepam, 
melphalan, methotrexate, methylprednisolone, metoclopramide, 
mitomycin, morphine, ondansetron, paclitaxel, prochlorperazine, 
ranitidine, sargramostim, vinblastine, vincristine, vinorelbine. 
Consult your pharmacist regarding specific concentrations 
8.1.10 
Availability  
Commercially available as a 1 mg/ml solution in 50 and 100mg vials. 
Vials of lyophilized powder are no longer commercially available, but 
may be obtained directly from the manufacturer for 
chemoembolization use.  
8.1.11 
Side Effects 
1. Renal: A dose-related, cumulative renal tubular injury can occur; 
adequate hydration and diuresis usually minimize the risk. Salt-
wasting nephropathy and/or orthostatic hypotension with 
hyporeninemic hypoaldosteronism can occur in up to 10% of 
patients. 
2.  Neurologic: A dose-related ototoxicity, manifested by high-
frequency hearing loss and tinnitus, occurs in about 30% of 
patients. Paresthesias, decreased vibratory, position, and touch 
sensations are less common; particularly at cumulative doses 
<400 mg/m2.  
3.  Hematologic: Mild leukopenia and thrombocytopenia occur in 25-
30% of patients, but are rarely dose-limiting; anemia is less 
common. A potentially fatal hemolytic uremic syndrome has been 
reported. 
4.  Gastrointestinal: Severe, dose-limiting nausea and vomiting occur 
in almost 100% of patients unless adequate antiemetic 
prophylaxis is given. Even with successful prophylaxis of acute 
nausea a delayed (72-96 hour) reaction, requiring additional 
therapy may occur. Anorexia and taste changes may also occur. 
5.  Hypersensitivity: Allergic reactions are reported in up to 20% of 
patients Symptoms include: rash, facial edema, wheezing, 
hypotension, and tachycardia. Severe anaphylaxis is rare. 
6. Other: Electrolyte wasting (magnesium, potassium and sodium), 
papilledema, optic neuritis, retrobulbar neuritis are reported. 
8.1.12 
Nursing/Patient Implications  
1. Prior to administration, assess: 
A. Labs: CBC, platelet count, BUN, creatinine. 
B. Urine output: 100-150 ml/hr for at least 4-6 hours. 
C. Signs of ototoxicity or neurotoxicity. 
2. Administer supportive medications: 
A. Premedicate with antiemetics – prophylaxis with a 5 – HT3 
receptor antagonist and dexamethasone (+/- aprepitant) is 
standard. 

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B. Hydration 
C. Diuretics - may be ordered. 
3. Observe for signs of allergic reaction. 
8.1.13 
References 
Alberts DS. Carboplatin versus cisplatin in ovarian cancer. Semin 
Oncol 1995;22(5 Suppl 12):88-90. 
Bonomi P. Platinum/etoposide therapy in non-small cell lung cancer. 
Oncology 1992;49(Suppl 1):43-50. 
Dabholkar M, Reed E. Cisplatin. Cancer Chemother Biol Response 
Modifiers 1993;14:86-97. 
Fram RJ. Cisplatin and platinum analogues: recent advances. Curr 
Opin Oncol 1992;4:1073-9. 
Garrow GC, Johnson, DH. Treatment of "good risk" metastatic 
testicular cancer. Semin Oncol 1992;19:159-65. 
Markman M. Current status of intraperitoneal therapy for ovarian 
cancer. Curr Opinion Obstet Gynecol 1993;5:99-104. 
Ozols RF, et al. Advanced ovarian cancer. Dose intensity. Ann Oncol 
1993;(4 Suppl 4):49-56. 
Saxman S. Salvage therapy in recurrent testicular cancer. Semin 
Oncol 1992;19:143-7. 
Wheeler RH, Spencer S. Cisplatin plus radiation therapy. J Infusional 
Chemother 1995;5:61-6.  
ECOG 6/96 
8.2 
Carboplatin  
8.2.1 
Other Names 
CBDCA, Paraplatin, JM-8, NSC-241240 
8.2.2 
Classification 
Second-generation tetravalent organic platinum compound 
8.2.3 
Mode of Action 
Like cisplatin, carboplatin binds to DNA, thereby inhibiting DNA 
synthesis, in a cell cycle nonspecific manner.  Carboplatin must first 
undergo activation to produce antineoplastic activity.  Bidentate 
carboxylate ligands of carboplatin are displaced by water forming 
(aquation) positively charged platinum complexes which bind to 
nucleophilic sites in DNA, such as the O-6 position on guanine.  
Carboplatin produces predominantly interstrand DNA crosslinks rather 
than DNA-protein crosslinks. Intrastrand crosslinks result from the 
formation of adducts between the activated platinum complexes of the 
drug and the N-7 atom (not exclusively) atom on guanine to produce 
1,2 intrastrand links between adjacent guanine molecules, between 
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neighboring guanine molecules.  Interstrand cross-linking within the 
DNA helix also occurs.  Platinum adducts may inhibit DNA replication, 
transcription and ultimately cell division. 
8.2.4 
Storage and Stability 
Intact vials are stored at room temperature protected from light. The 
reconstituted solution is stable for at least 24 hours. When further 
diluted in glass or polyvinyl plastic to a concentration of 10mg/mL with 
normal saline or 5% dextrose carboplatin is stable for 8 hours at 25 
degrees C.  Stability with further dilution to 0.5mg/mL has been 
reported for up to 8 hours.  Other stability data indicate that 
carboplatin is stable for up to 24 hours and may be refrigerated, 
however, the manufacturer recommends that reconstituted solutions 
be discarded after 8 hours due to the lack of preservative in drug 
formulation. 
8.2.5 
Dose Specifics 
Carboplatin will be given by IV at an area under the curve (AUC) dose 
of 2. Routine premedication should include at least a 5 – HT3 
antagonist and dexamethasone. The dose of carboplatin based on 
target AUC is calculated using the Calvert equation: 
Dose (total mg) = Target AUC X (GFR + 25). The patient’s creatinine 
clearance (GFR) in mL/minute is calculated by the Cockgraft Gault 
equation. 
NOTE: 
When using the Calvert equation, GFR should not exceed 
125 mL/min. Thus, the maximum carboplatin dose is 2 x 
(125 + 25), or 300 mg. 
8.2.6 
Preparation 
Add 5, 15, or 45 mL sterile water, normal saline, or 5% dextrose to the 
50, 150, or 450 mg vial, respectively. The resulting solution contains 
10 mg/mL. The desired dose is further diluted, usually in 5% dextrose. 
8.2.7 
Administration 
Infuse over 30 minutes.  
8.2.8 
Incompatibilities 
Aluminum displaces platinum from the carboplatin molecule, resulting 
in the formation of a black precipitate and loss of potency.  
Carboplatin solutions should not be prepared or administered with 
needles, syringes, catheters, or IV administration sets containing 
aluminum parts that might be in contact with the drug. 
8.2.9 
Drug Interactions 
Concomitant myelosuppressive drugs or radiation therapy may 
potentiate the hematologic toxicity of carboplatin. 
Concomitant nephrotoxic drugs may potentiate the nephrotoxicity of 
carboplatin, particularly when carboplatin is given in high-dose 
chemotherapy regimens. 

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8.2.10 
Compatibilities 
Carboplatin (0.3 mg/mL) and etoposide (0.4 mg/mL) are chemically 
compatible in normal saline or 5% dextrose for 24 hours at room 
temperature. 
8.2.11 
Availability 
Commercially available as a lyophilized powder in 50, 150, or 450 mg 
vials. 
8.2.12 
Side Effects 
1. Hematologic: Thrombocytopenia (dose limiting), neutropenia, 
leukopenia, anemia. 
2. GI:  
Nausea and vomiting (frequent but less severe than with 
cisplatin), treatable with appropriate antiemetic prophylaxis. 
Anorexia, diarrhea and constipation have also been reported. 
3. Dermatologic: Rash, urticaria. Rarer reactions include alopecia, 
mucositis, and hypersensitivity reactions. 
4. Hepatic: Abnormal liver function tests, usually reversible with 
standard doses. 
5. Neurologic: Rarely peripheral neuropathy is seen. May be more 
common in patients greater than 65 years of age. May also be 
cumulative, especially in patients with prior cisplatin treatment. 
Ototoxicity (rare). 
6. Renal: Elevations in serum creatinine, BUN; electrolyte loss (Mg, 
K, Na, Ca). 
7. Miscellaneous: Pain, asthenia, flu-like syndrome. 
8.2.13 
Nursing Implications 
1. Monitor CBC and platelet count routinely. 
2. Premedicate with antiemetics – prophylaxis with a 5HT3 receptor 
antagonist and dexamethasone (+/- aprepitant) is standard. 
3. Monitor fluid status – maintain adequate hydration. 
4. Assess skin/mucous membranes. 
5. Assess for signs of peripheral neuropathy – coordination, sensory 
and hearing loss. 
8.2.14 
References 
1. American Hospital Formulary Service 2003-Drug Information. 
2. Calvert AH, et al. Carboplatin dosage: Prospective evaluation of a 
simple formula based on renal function. J Clin Oncol 7: 1748-56, 
1989. 
3. Carboplatin package insert, Princeton, NJ; Bristol Laboratories 
Oncology Products 1998; June 
4. Christian MC. Carboplatin. In: Principles and Practice of 
Oncology, PPO Updates 3(11): 1-16, 1989. 
5. Woloschuk DMM, Pruemer JM, Cluxton RJ. Carboplatin: A new 
cisplatin analog. Drug Intell Clin Pharm 22;843-9, 1988. 

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9. 
Statistical Considerations 
This is a phase II trial of p16+ (using immunohistochemistry (IHC)) OPSCC patients that 
will undergo transoral surgery (TOS, Step 1) followed by risk-adjusted radiotherapy 
(Step 2). Patient risk status is determined after surgical excision and is defined in 
Section 5.1. Patients with low-risk will be assigned to the observation group (Arm A). 
Patients with intermediate-risk (the primary study group) will be equally randomized to 
receive radiotherapy IMRT 50 Gy (Arm B) or 60 Gy (Arm C), stratified by current/former 
smoking history (≤ 10 vs. > 10 pack-years). Patients with pathological N2C/N3 disease 
without extensive ECS (and do not meet the high risk feature) will be directly assigned to 
Arm C receiving IMRT 60 Gy. Patients with high-risk will receive concurrent cisplatin and 
IMRT 66 Gy (Arm D). Among the first 10 patients enrolled on Arm A, if 2 or more 
progress or die within 1 year, currently enrolled and subsequently enrolled patients with 
low risk who have not progressed will be directly assigned to radiotherapy 50 Gy (details 
are given below). 
The study requires 180 evaluable patients with intermediate risk (to be randomized 
between Arms B/C). Based on results from the interim analysis prepared for the Fall 
2015 DSMC meeting, the overall proportion of evaluable patients with intermediate risk 
is estimated to be 35% (~73% patients are evaluable, among whom ~48% are 
intermediate risk), which is lower than the originally estimated 48% (80% evaluable, 
among whom 60% would be intermediate risk). Here, patients who are eligible and 
started treatment on step 2 are considered as evaluable. As stated in the original design, 
if the observed proportion of patients with intermediate risk is off over 5% from the 
anticipated 60%, accrual goal would be adjusted. Therefore, the current section 
incorporates a sample size increase from the originally proposed 377 to 515 
(180/0.35=515), to ensure 180 evaluable patients with intermediate risk to be 
randomized. Based on the observed accrual rate of 18.5 patients per month, this new 
accrual goal can be achieved in February, 2017. 
9.1 
Objectives 
The primary objectives of this phase II study are: 1) to examine the feasibility of 
a prospective multi-institutional study of TOS followed by risk-adjusted adjuvant 
therapy in this patient population; and 2) to assess the oncologic efficacy of the 
proposed treatment strategy (TOS + reduce dose radiotherapy) for the 
intermediate risk group. The accrual rate, patient risk distribution (especially the 
proportion of the intermediate risk group), and surgical quality are used to 
evaluate feasibility of the study. The 2-year progression-free survival (PFS) rate 
will be used to evaluate the efficacy in the intermediate risk group. The table 
below gives a summary of the stopping rules / decision rules to be implemented 
with regard to these two primary objectives. Details are given in following 
sections. 
Rev. 2/15 
Rev. 1/16 
Rev. 2/15 

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Objective 
Endpoint 
Assessment Time point 
Suspension rules / Decision Rules 
Efficacy 
1-year PFS rate 
First 10 patients in arm A followed 
for 1 year 
Currently enrolled and subsequent 
patients who have not progressed will 
receive radiotherapy 50 Gy if 2 or more 
patients progress or die within 1 year 
 
1-year PFS rate 
First 10 patients with p N2C/N3 
disease followed for 1 year 
Currently enrolled and subsequent 
patients with p N2C/N3 disease who 
have not progressed will receive IMRT 
66 Gy + cisplatin (Arm D treatment) if 2 
or more patients progress or die within 
1 year 
 
1-year PFS rate 
First 40 patients in each of arms 
B and C followed for 1 year 
Suspend trial and review if ≥ 6 patients 
(per arm) progress or die within 1 year 
 
2-year PFS rate 
End of study 
Treatment worthy of further study if 
higher limit of the 90% CI > 85% 
Feasibility Accrual 
13-18 months post-activation 
Accrual will be monitored by DSMC and 
NCI (see section below) 
 
Risk distribution 
First 59 patients evaluated for risk Suspend trial and review if ≤ 21 
patients with intermediate risk 
 
Surgical quality 
First 59 patients completed 
transoral resection and have 
CTCAE forms submitted 
Suspend trial and review if ≥ 13 
patients reported with grade 3-4 
bleeding or positive margins 
Secondary objectives include assessing quality of life (QOL) and swallowing 
function before and after treatment, evaluating toxicity, and investigating the 
prognostic effects of various biomarkers (details follow).  
9.2 
Sample Size and Accrual Rate  
We plan to accrue 515 patients, expecting ~376 (73%) total patients would be 
evaluable (eligible and treated on step 2), among whom 180 would be 
intermediate risk. Observed accrual rate (18.5 patients per month) is higher than 
the original assumption of 8 patients per month, so accrual of 515 patients is 
expected to complete in February, 2017. 
9.3 
Primary Objective: Efficacy 
Primary Endpoint─2-year PFS rate 
The sample size calculations are based on the efficacy endpoint of 2-year PFS 
rate, which is defined as the proportion of patients alive and progression-free at 
24 months measured from date of registration onto Step 1. Patients who die 
without disease progression within 24 months and patients who begin non-
protocol therapy without evidence of progression within 24 months will not be 
considered to be progression-free at 24 months. The 2-year failure proportions 
that include second primary cancers from the head and neck region as event will 
also be reported. 
The regimen of TOS + low-dose radiation (Arm B and Arm C, separately) may be 
considered worthy of further study if the true 2-year PFS rate is close to 85% (the 
observed rate among high-dose radiation patients in E2399). 
Assuming 90 analyzable patients per arm for the intermediate group, the 
following table displays the exact 90% binomial confidence intervals (CIs) for the 
2-year PFS rate for each of Arm B and C, assuming various observed 2-year 
Rev. 6/14 
Rev. 2/15 

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PFS rate. For example, if 79 out of 90 analyzable patients per arm are alive and 
progression free at 2 years, the 90% confidence interval will be 81% to 93% with 
a width of 12%. This study will need 180 analyzable patients in total for the two 
randomized arms (Arms B + Arm C).  
 
Number of Alive and Progression Free at 2 Years 
 
71 
75 
79 
83 
90% CI 
(0.71, 0.86) 
(0.76, 0.89) 
(0.81, 0.93) 
(0.86, 0.96) 
With regard to p16 status, while central evaluation of pathology reports will be 
conducted retrospectively, actual assays will not be run or reviewed centrally. 
Patients who drop-out prior to radiation therapy due to any reason will also be 
excluded from the primary analysis . 
In the original design, the risk distribution was assumed to be 10% low risk, 60% 
intermediate risk, and 30% high risk, and an interim analysis for the first 59 
patients who complete transoral resection was scheduled. Based on the analysis 
results, among the 104 evaluable patients (not ineligible based on current 
evaluation, and started treatment on step 2), the estimated risk distribution is: 8% 
low risk, 48% intermediate risk and 32% high risk (13 (12%) patients had 
potentially misclassified risk category/ arm based on their surgical data and the 
study team is taking various actions trying to improve this). As was stated in the 
original design, in case the proportion of the intermediate risk patients is off over 
5% from the anticipated 60%, the accrual goal would be adjusted, With this new 
accrual goal, we expect at the end of the study ~180 evaluable patients would be 
intermediate risk, ~120 high risk, and ~30 low risk. 
In analyzing the 2-year PFS rate, 90% exact binomial confidence intervals will be 
computed for each arm.  Only eligible patients with confirmed P16+ status who 
started radiotherapy will be analyzed (by arm). The regimen will be considered 
worthy of further study if the higher limit of the computed 90% CI exceeds 85%.  
Comparisons of 2-year PFS rates between Arms B and C, Arms B and D, and 
Arms C and D are exploratory endpoints. Since one of the randomized arms 
proposed in this study is likely to be selected for a follow-up phase III study, the 
exploratory comparison of 2-year PFS rate between the two randomized arms is 
more important and a p-value ≤ 0.05 will be considered statistically significant. 
For the other two comparisons (Arms B and D; Arms C and D), the Type I error 
rate of 5% will be divided by the two tests (i.e., 0.05/2 considered statistically 
significant). Therefore, the family-wise error rate of 0.10 will be protected for the 
multiple comparisons in the 2-year PFS rate among arms. Power for various 
differences in the 2-year PFS rate is shown below, assuming a two-sided 
Fisher’s exact test and 90 analyzable patients in Arms B or C, and 120 
analyzable patients in arm D. 

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Difference in 2-year PFS rate 
between arms 
Arm C vs. Arm B 
Arm B (or C) vs. Arm D 
10% (85% vs. 75%) 
0.32 
0.27 
15% (85% vs. 70%) 
0.62 
0.58 
20% (85% vs. 65%) 
0.85 
0.83 
25% (85% vs. 60%) 
0.96 
0.96 
Interim Analysis─1-year PFS rate  
To safeguard against an unacceptably high failure rate for Arm B and Arm C, in 
which both the radiation dose is reduced and chemotherapy is removed, an 
interim look at 1-year PFS rate will be performed for the first 40 eligible and 
treated patients in Arm B and Arm C, separately. It is expected, for either arm, 
90% of patients will be alive and progression free at 1 year (Fakhry, C, JNCI, 
2008). The event rate will be deemed too high if 6 or more such events are 
observed within 1 year, which corresponds to an empirical progression rate of 
15%. In this case, the trial will be suspended and a panel review will be called. 
The following table summarizes the probability of suspending the trial under 
various true 1-year progression rates in Arm B (and Arm C). For instance, the 
probability of suspending the trial is at least 84% if the true 1-year progression 
rate is 20% or higher. The study will continue accrual while we are waiting for the 
decision from this interim analysis. 
True 1-yr progression rate for 
patients with intermediate risk 
0.10 
0.15 
0.20 
025 
0.30 
Probability of suspending the trial 
0.21 
0.57 
0.84 
0.96 
0.99 
Similarly, to safeguard against an unacceptably high failure rate for the 
observational Arm A, an interim look at 1-year PFS rate will also be performed for 
the first 10 eligible and treated patients (a total of 38 patients is expected to be 
accrued to this arm). Among these 10 patients, if 2 or more patients progressed 
or died within 1 year, currently enrolled and subsequently enrolled low risk 
patients who have not progressed will be directly assigned to radiotherapy IMRT 
50 Gy. The same interim monitoring rule will be applied to the patients with 
pathological N2C/N3 disease who are directly assigned to Arm C (expected to be 
5% of the total population). That is, if 2 or more patients among the first 10 such 
patients progress or die within the first year, currently and subsequently enrolled 
patients with p N2C/N3 disease will be treated with IMRT 66 Gy + cisplatin (Arm 
D treatment).  The following table summarizes the probability of observing 2 or 
more events, under various true 1-year PFS rate for this group of patients.  
True 1-yr PFS rate 
0.10 
0.15 
0.20 
025 
0.30 
Probability of observing 2 or more 
events 
0.26 
0.46 
0.62 
0.76 
0.85 
9.4 
Primary Objective: Feasibility 
Three endpoints will be used to evaluate the feasibility of the proposed trial. 
Rev. 2/15 

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Accrual Rate of the Entire Study  
The following monitoring plan for accrual was specified in the original design. If 
the accrual during quarters 5 and 6 (that is, during months 13-18 after activation) 
is ≤ 20% of the projected rate during that period, then the study will be 
terminated. If the quarter 5-6 accrual rate is > 20% but < 50% of the planned 
rate, then the study team will be given 6 months to improve accrual. If the 
average accrual rate in quarter 8 is still < 50% of the planned rate, then the study 
design will be amended to reflect the actual accrual rate. The currently observed 
accrual rate is 18.5 patients per month. 
Risk Distribution 
Given the distribution of the histologic risk is unknown, this trial provides an 
opportunity to find out patient distribution in each risk cohort. A 90% binomial 
confidence interval will be estimated for the percentage of patients in each risk 
group. All eligible patients on Step 2 will be analyzed. It was expected 60% 
patients would be intermediate risk in the original design. 
An interim analysis was planned in the original design: among the first 59 
patients who have completed transoral resection and have risk status evaluated, 
if 21 (36%) or fewer are intermediate risk, the percentage will be deemed too low. 
Based on results from the interim analysis, the estimated proportion for the 
intermediate risk category is 48%, among the 104 evaluable patients. 
Surgical Quality 
Frequency and percentage will be used to report grade 3-4 bleeding events 
during surgery and positive margins after surgery, separately.  A 90% binomial 
confidence interval will be estimated for these events as well. All eligible and 
surgery treated patients will be analyzed. For any targeted event (bleeding or 
positive margins), if the lower limit of the 90% CI is above the expected rate, 
transoral resection surgery is deemed infeasible for future study.  
An interim analysis was planned in the original design for grade 3-4 bleeding and 
Positive Margins. It was expected 3% of patients will experience grade 3-4 
bleeding during surgery (requiring hemostasis in the operating room). It was 
anticipated 5% of patients with transoral surgery would have positive margins. 
Among the first 59 eligible patients who have completed transoral resection, had 
data submitted, and the surgical results are known, the percentage would be 
deemed too high if 13 (22%) or more patients are reported with grade 3-4 
bleeding in the operating room or with positive margins.An interim analysis was 
performed for the Fall 2015 DSMC meeting. Among the first 59 patients with 
surgical data submitted in iMedidata Rave (59th patients registered on January 
15, 2015), 5 grade 3 bleeding events and 2 positive margins were reported (total 
7 events), and among the 10 patient who entered prior to January 15, 2015 with 
no surgical data, no bleeding event was reported.  Based on results from the 
interim analysis, the specified stopping rule was not met. 
9.5 
Secondary Objectives 
Secondary endpoints include toxicity, overall survival, swallowing function, and 
patient-reported outcomes. 

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Toxicity. For each arm, all treated patients (regardless of eligibility) will be 
evaluated by CTCAE version 4.0. Descriptive statistics will be provided (by arm). 
Difference between the low-dose RT arm (Arm B and Arm C separately) and Arm 
D and between Arm B and Arm C will be evaluated using Fisher’s exact test.  
Overall Survival. Overall survival will be determined as the time from registration 
onto the study until death from any cause. Patients who were alive at the time of 
analysis will be censored at the date last known alive.  Kaplan-Meier estimates 
will be calculated, along with their corresponding 95% confidence intervals. The 
median, 1-year, and 2-year survival rates will be estimated. Only eligible and 
treated patients will be analyzed for overall survival (by arm). 
Swallowing Function and Voice. Descriptive statistics will be provided (by arm) 
for swallowing function, evaluated using the MBS ratings, PSS-HN normalcy of 
diet scale, and the validated survey MDADI instrument. Longitudinal analysis will 
be performed, by arm, on each of these measures. All eligible and treated 
patients (on both steps) will be analyzed for PSS-HN diet scale, MDADI, and 
VHI-10.  The MBS analysis will be performed on eligible and treated patients only 
if accrued at vetted participating centers.    
Quality of Life. The primary variable of interest in the QOL analysis is the 
individual change in the FACT-H&N total score from baseline (prior to TOS) to 6 
months post-RT. Patient QOL will be grouped as “improved” (change ≥ 7 points, 
6 mo post-RT vs. baseline), “worsened”  (change ≤ -7 points) and “stable”  
(-6 ≤ change ≤ 6). QOL data is very limited in this setting (P16+ OPSCC patients 
treated with TOS + RT), and estimates from this phase II trial may serve as the 
basis of choosing an effect size in a possible future phase III trial comparing TOS 
+ RT vs. primary CRT treatment.  
In the primary QOL analysis, we plan to combine the post-operative RT arms (B 
& C) and compare to patients selected for post-operative chemoRT (arm D), 
which would be expected to have toxicity similar to, but less severe than, a 
primary CRT approach. This comparison is most similar to the setting of a 
possible future phase III trial. From a prior trial of CRT approach, about 25% of 
the patients had improved FACT-H&N from baseline to 6 months, 25% were 
stable, and 50% worsened, which is expected to be similar to, or slightly worse 
than the experience of arm D in this phase II trial. Given the more severe overall 
toxicity and probable greater late toxicity associated with the use of both radiation 
and chemotherapy, we hypothesize that a higher proportion of patients in arm 
B/C will have recovered their FACT-H&N scores to baseline level or higher at 6 
months, and we consider a difference, or Delta, of 10% (Arms B/C vs. Arm D) to 
be important outcome. Comparison between Arm B and Arm C (in mean score 
change and/or proportion of patients with improved/stable score at 6 months) is 
also important endpoint but this will be only exploratory. Any comparison results 
will be interpreted with caution. Descriptive statistics will be provided for FACT-
H&N and MDASI-HN at various measurement points.  
The table below shows the power of detecting various Delta value (Arms B/C vs. 
D) under various compliance rate (the proportion of patients who complete PRO 
surveys at both baseline and 6 months post-RT visits), using a one-sided 
Fisher’s exact test with type I error rate of 0.10, assuming 48% intermediate risk 
patients and 32% high risk patients among evaluable patients. 

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Compliance 
Rate 
No. of analyzable pts 
(Arms B/C vs. Arm D) 
Delta (Arms B/C vs. D) 
10% (65% 
vs. 55%) 
15% (70% 
vs. 55%) 
20% (75% 
vs. 55%) 
40% 
120 (72 vs. 48) 
0.35 
0.58 
0.79 
60% 
180 (108 vs. 72) 
0.46 
0.73 
0.91 
80% 
240 (144 vs. 96) 
0.56 
0.83 
0.96 
One of the randomized arms is likely to be selected for a future phase III study. 
Although the QOL endpoint is not built into the primary selection criteria, in case 
that the efficacy outcomes for the two randomized arms are similar, the 50Gy 
schedule will be considered in the phase III study with the expectation that QOL 
will also be better in this arm, unless there is evidence otherwise. 
9.6 
Handling Missing Data 
The primary analysis will treat missing data as missing at random then analyze 
cases with complete data. The method of multiple imputation will be used to 
handle missing data if more than 20% of the cases have missing data in the 
variables of interest. If so, sensitivity analysis will be performed to compare 
results from the complete case analysis and imputation analysis. In case of 
discrepancies, possible explanations will be discussed. For longitudinal data, 
given the expected high level of missingness in these data, data will be analyzed 
according to the methods described in Schluchter (1992) and in Schluchter, 
Greene, and Beck (2001). These methods take into account the possibility of 
informative missingness by jointly modeling the longitudinal response and the 
time to dropout. 
9.7 
Laboratory Endpoints  
When sufficient information is available from the parent study, a separate 
correlative science proposal (or a protocol amendment) detailing the scientific 
hypothesis, research plan, assay methods for use of the biospecimens, and a 
complete statistical section (with adequate power justification and analysis plan) 
would be submitted and reviewed by CTEP in accordance with the NCI National 
Clinical Trials Network (NCTN) review policies. 
9.8 
Randomization Scheme 
Patients enrolled into this study will be assigned to one of the four treatment 
arms after transoral surgery based on their histologic risk status. Patients with 
low-risk will be assigned to the observation group (Arm A). Patients with 
intermediate-risk will be randomized (with a 1:1 allocation ratio) into either Arm B 
(IMRT 50 Gy) or Arm C (IMRT 60 Gy). Patients with high-risk will receive post 
surgery concurrent cisplatin and IMRT 66 Gy (Arm D). The method of permuted 
blocks will be used for randomization with current/former smoking history  
(≤ 10 vs. > 10 pack-years) as stratification factor. 
9.9 
Monitoring Plan 
This study will be monitored by the Data Safety and Monitoring Committee 
(DSMC). The DSMC meets twice each year, and all monitored studies are 

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reviewed for safety and progress toward completion. The toxicity reports 
prepared for the DSMC meetings are included in the study reports prepared for 
the ECOG-ACRIN group meetings. Reports of these analyses are sent to the 
ECOG-ACRIN Principal Investigator or Senior Investigator at the participating 
institutions. Expedited reporting of certain adverse events is required as specified 
in the protocol.  
9.10 
Gender and Ethnicity 
The total accrual goal will be 515 patients. Based on previous data from E1308, 
the anticipated accrual in subgroups by gender and race is/as follows:  
Racial Categories 
Ethnic Categories 
Total 
 
Hispanic or 
Latino 
Not Hispanic or 
Latino 
 
 
Females Males Females Males  
American Indian or Alaskan Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
12 
12 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
24 
24 
White 
6 
36 
24 
413 
479 
Total 
6 
36 
24 
449 
515 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. 
Therefore, overall accrual to the study will not be extended to meet individual 
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10. 
Functional Outcomes, Patient Reported Outcomes and Quality of Life 
10.1 
Observer-Assessed Outcomes 
10.1.1 
Performance Status (PS):  Performance status will be assessed using 
the ECOG performance status scale and must be 0-1 at baseline for 
study eligibility.  Changes in ECOG PS will be tracked at all PRO 
endpoints. 
10.1.2 
Weight Loss: The degree of weight loss may contribute to fatigue, 
weakness and deconditioning. Weight loss during therapy will be 
documented as well as post-treatment weight changes.  
10.1.3 
Tracheostomy and Enteral Feeding Tube Status: The presence of 
either assistive device will be tracked prospectively at all PRO time 
points. 
10.1.4 
Charlson Comorbidity Index: Comorbidity will be documented by chart 
abstraction at baseline. 
10.1.5 
Head and Neck Cancer Specific Performance Status: The 
Performance Status Scale (PSS-HN)49 is a clinician-rated instrument 
consisting of 3 questions: normalcy of diet, public eating, and 
understandability of speech.  The PSS-HN has been psychometrically 
validated and recommended by the National Comprehensive Cancer 
Network for measurement of swallowing and speech performance in 
patients with head and neck cancer.  It is not a PRO; it can be 
completed quickly by the trialist without adding to patient burden.   
10.1.6 
Swallowing Endpoint: Swallowing outcomes will be measured as a 
secondary endpoint of this trial using modified barium swallow (MBS) 
studies according the assessment schedule in Appendix V (baseline, 
within 4 weeks of TORS, 6 months pos-treatment, and at 2-years). 
Participating institutions will be vetted prior to study activation to 
ensure adherence to a standard protocol. Institutions must be 
assessed and declare their participation in this aspect of the study 
prior to site opening to accrual; facilities unable to participate in the 
MBS assessments may still enter patients on the study. Facilities 
must use a standardized contrast medium (Varibar® thin liquid and 
pudding contrast, Bracco Diagnostics, Inc. Princeton, NJ) and digitally 
record MBS studies (30 frames/second). Three swallowing outcomes 
will be rated by the SLP conducting the MBS study and reported by 
research staff: 1) laryngeal penetration (yes, no); 2) aspiration (no, 
sensate, silent), and 3) pharyngeal residue (no, < 50%, > 50%). 
These have been selected as universal items generally reported by 
swallowing clinicians that have been shown to significantly predict 
pneumonia in patients with oropharyngeal cancers. Prevalence of 
these dysphagia endpoints will be estimated at each time point, and 
compared between arms. 
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Sites are to complete the required MBS credentialing checklist 
(Appendix VI) and fax to the ECOG-ACRIN Operations Office - 
Boston at 617-632-2990, Attention DA E3311. 
Questions related to MBS studies can be directed to: 
University of Texas MD Anderson Cancer Center 
Phone: 713-792-6364 
Email: E3311_MBS@jimmy.harvard.edu 
Submission of MBS Videos to MD Anderson:  
Upon completion of the credentialing checklist, the designated site 
contact will be given access to the MD Anderson Box® Cloud-based 
storage account to upload MBS videos to the cloud. Please contact 
E3311_MBS@jimmy.harvard.edu for questions regarding access and 
questions for Box® Cloud-based storage. 
Videos must be uploaded in .mpeg or .avi format.   
To ensure the security of the uploaded video all patient identifiers are 
to be removed and the video files are to be re-labeled with a unique 
identification code. 
To obtain the code:  
1. Log the videos into ECOG-ACRIN’s Sample Tracking System 
(STS), indicating the “Ship Date” as the date the video is to be 
uploaded to the MD Anderson Box Cloud Account.  Be sure to 
select the correct protocol-specified time point for the video.  (e.g., 
Baseline, after surgery…). Remember to save the shipment data 
before exiting the application. Generation of a shipment manifest 
is not necessary. 
https://webapps.ecog.org/Tst/ 
2. Exit STS and enter the Patient Video Identifier Lookup application.  
Select the protocol and enter the ECOG-ACRIN E3311 patient 
identifier to pull up the patient specific information. The code is the 
“Sample ID” and is a unique code linked to the patient and the 
time point of the video as entered into STS.  
https://webapps.ecog.org/PatientVideoIdentifyLookup/ 
Rename the electronic video file using only the STS-generated 
sample ID prior to uploading to the MD Anderson Cloud. For more 
complete guidelines pertaining to allowed upload formats and 
guidelines on removing patient identifiers, see Appendix IX.   
10.2 
Patient Reported Outcomes (PROs) 
10.2.1 
Quality of Life: Quality of life will be assessed using the Functional 
Assessment of Cancer Therapy – Head and Neck Cancer (FACT-
H&N). The FACT-H&N (version 4)51 consists of a cancer-specific 
questionnaire, FACT-G, in addition to 12 H&N cancer-specific items 
(the HN subscale). FACT-G is a 27-item measure that assesses 
general cancer quality of life [Cella, 1993; Cella, 1997]. The FACT-G 
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functional well-being. Individuals are asked to indicate how true 27 
statements are for them, using the past 7 days as the timeframe. 
Responses range from not at all (0), to very much (4) on a 5-point 
scale. Psychometric properties of the FACT-G have been examined in 
a variety of oncology populations with alpha coefficients ranging from 
.65 to .89 [Cella, 1997]. After reverse coding selected items in the 
physical and emotional subscales, items are summed to provide total 
subscale scores, which will be used in our analyses. Using this 
scoring, higher values reflect better quality of life. 52. The full FACT-
H&N provides a summary score for overall head and neck cancer 
related QOL and has been used frequently in clinical trials. 
10.2.2 
Head and Neck Symptom Burden: The MD Anderson Symptom 
Inventory-Head & Neck (MDASI-HN53) measures treatment related 
symptom burden in head and neck cancer patients. The MDASI 
measures both severity and burden of symptoms and their effect on 
patients’ daily activities, using a numeric rating scale of 0-10.  This 
instrument includes 13 core symptoms and 9 head and neck specific 
items. The instrument was validated in a cohort of more than 200 
patients. The coefficient alpha was highly reliable. The MDASI takes 
less than 5 minutes for patients to complete.  
10.2.3 
Swallowing and Voice: Data regarding swallowing perception and 
performance and voice outcomes will be obtained from the MD 
Anderson Dysphagia Inventory (MDADI) 50 and Voice Handicap 
Index-10 (VHI-10).   
The MDADI measures swallowing-related quality of life (QOL) in 
patients with swallowing dysfunction in a 20 – item written 
questionnaire.  It evaluates the patient’s physical (P), emotional (E) 
and functional (F) perceptions of swallowing dysfunction. This 
instrument has been psychometrically validated in head and neck 
cancer patients.   
The VHI-10 55is a patient self-assessment instrument that quantifies 
patients’ perception of their voice handicap.  It evaluates patient’s 
physical (P), emotional (E), and functional (F) perceptions of voice 
and has shown to be highly reliable for internal consistency and test-
retest stability.  The VHI-10 utilizes a 10-item questionnaire in which 
the patient circles the response that most accurately reflects his or her 
own experience on a linear scale (from “never” to “always”). 
10.2.4 
Return to work: Return to work will be tracked prospectively following 
treatment using an instrument currently in use on the RTOG 1016 
trial.  While this data is patient reported, it does not generate a score 
requiring psychometric validation.  It has been judged to have face 
validity and is brief and practical for use in a clinical trial. 

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11. 
Specimen Submissions 
Representative original diagnostic and surgical pathology materials are required to be 
submitted for diagnostic review and classification for purposes of determining patient 
evaluability AND quality review of the surgery.  Blood specimens and additional tissue 
specimens are requested for the research studies from consenting patients.  
All specimens must be labeled with the ECOG-ACRIN protocol number, the patient’s 
initials and ECOG-ACRIN sequence number, the collection date, and the type of sample. 
For pathology materials, it is strongly recommended that full patient names be provided. 
All specimens must be logged and tracked via the ECOG-ACRIN Sample Tracking 
System (STS) Web Application (Section 11.5) and submitted with an STS generated 
shipping manifest. 
Direct questions regarding submission of specimens to the ECOG-ACRIN CBPF by 
email at eacbpf@mdanderson.org or phone (1-844-744-2420). 
11.1 
Collection and Submission Schedule 
See Section 7.2 for a table summarizing the submission requirements. 
11.1.1 
Pathology Materials from ALL PATIENTS 
11.1.1.1 
MANDATORY 
Mandatory submissions are to be submitted upon 
completion of the surgical pathology report by the site, but 
no later than 4 weeks following completion of the surgery.   
11.1.1.2 
Consenting patients: 
Fixed and frozen (if available) tissue are to be submitted. 
11.1.2 
Specimens from consenting patients 
Collect from patients who answer “Yes” to “I agree to provide 
additional specimens for research” at the following timepoints: 
A. Plasma, Serum and Peripheral Blood are to be collected: 
o Prior to surgery (Arm S)  
o Within 4 weeks after surgery (Arm S)  
o Step 2, Week 4 (Arms B,C, D)  
o Step 2, End of Treatment (Arms B, C, D)  
o Step 2, at first end of treatment follow-up visit ( Arms B,C,D) 
o Months 6, 12, 18 and 24 from start of Step 2 treatment (Arms 
A,B,C,D) 
o Months 6,12, 18 and 24 from time of surgery (Arm S patients 
who did not register to Step 2) 
B. Oral Rinse is to be collected: 
o Prior to surgery (Arm S)  
o 4 weeks after surgery (Arm S)  
o Step 2 End of Treatment (Arms B,C,D) 
o Months 3, 6, 9, 12, 15, 18, 21 and 24 from start of Step 2 
treatment (Arms A,B,C,D) 
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Rev. 6/14
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o Months 3, 6, 9, 12, 15, 18, 21 and 24 from time of surgery 
(Arm S patients who did not register to Step 2) 
Peripheral blood samples are to be shipped day of collection, and are 
to be collected Monday – Thursday only.  Plasma, serum and saliva 
specimens are to be batched at <-70oC and shipped on a quarterly 
basis. If a <-70oC freezer is unavailable, store at -20 oC and ship on 
dry ice within 24 hours (or next business day if drawn on Friday).   
11.2 
Specimen Collection Guidelines 
11.2.1 
Tissue Submission 
Guidelines for pathologists are provided in Appendix I. Representative 
tumor specimens of the following are to be submitted: 
• 
MANDATORY: 
o Original p16 tumor slide. Stained slides from cytology blocks 
are acceptable. 
• 
From consenting patients who answer “Yes” to “I agree to 
provide additional specimens for research”  
o Fixed, paraffin-embedded primary tumor tissue block. Either 
pre-trial diagnostic or surgical specimen may be submitted. 
NOTE: 
If blocks are not available for submission, the 
following alternative is to be submitted: 1 H&E 
(from the source block), 1-2 core punches (4 mm 
minimum) and 20 unstained slides. Slides, 
including the H&E, are to be numbered 
consecutively in the order cut. 
o Frozen surgical specimen, if available 
The following forms MUST be submitted via Medidata Rave. 
Additionally, the relevant pathology and surgical reports must 
accompany all tissue submissions: 
• 
Copy of the original diagnostic Pathology Report 
• 
The p16 IHC report from the original diagnostic specimen must be 
submitted 
• 
Surgical pathology and surgical procedure reports.   
Histopathologic assessment of surgical pathology must include 
examination for perineural invasion (PNI) [absent or present], 
lymphovascular invasion (LVI) [absent or present], and 
extracapsular extension (ECE) [absent, present-minimal, present-
beyond minimal] 
Surgical margin status must be reported as i) Negative (tumor ≥ 
3mm from designated margin); ii) Close (tumor < 3mm of the 
designated margin); or iii) Positive (tumor at the cut specimen 
edge not superseded by another margin) 
• 
Other Immunologic and cytologic reports 
• 
STS generated shipping manifest for all submitted tissue. 
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11.2.2 
Additional Submissions 
From patients who consent “Yes” to “I agree to provide additional 
specimens for research.” 
Draw the blood tubes in the following order: no anti-coagulant (red top 
or SST), EDTA (purple top). Note that vacutainer top color are for BD 
vacutainers.  Verify tube contents prior to the collection of any 
samples. 
1. Serum   
• 
At each time point specified, draw one (1) 10mL vacutainer (no 
anti-coagulant)   
• 
Allow to coagulate at room temperature for 20 minutes 
• 
Separate by centrifugation at approximately 1200g x 20 
minutes 
• 
Aliquot serum into four cryovials. Discard residual cells  
• 
Samples will be batched and shipped on dry ice. 
2. Peripheral Blood, EDTA  
As these samples are to be shipped the day of collection, they are 
to be drawn Monday – Thursday. Do not draw on a Friday or day 
before a holiday as the receiving laboratory is not open on 
weekends or holidays.  This is essential so the time between 
collection and processing by the central laboratory is minimized. 
• 
At each time point specified, draw four (4) 10mL potassium 
EDTA (purple top) vacutainer, invert gently 4-5 times. 
• 
Ship the day of collection at ambient temperature overnight. 
Upon receipt at the central laboratory, tubes will be processed to 
isolate plasma and buffy coat peripheral blood lymphocytes (PBL). 
The second tube will be used for the isolation of DNA. 
3. Oral Rinse. For oral rinse, the patient should pour approximately 
15cc of mouthwash or saline into his/her mouth and vigorously 
swish it against the cheeks for 10 seconds  and deliver the 
solution with a sterile beverage straw into a labeled 15cc 
polypropylene test tube. Among mouthwashes, the Scope brand 
fares best in collecting oral DNA/cells for the preparation of high-
quality DNA in high yield. Ship the day of collection at ambient 
temperature overnight. 
11.3 
Shipping Procedures 
The mandatory pathology materials are to be submitted upon completion of the 
surgical pathology report, but no later the 4 weeks from time of surgery. Tissue 
samples are to be shipped at ambient (use a cool pack in warm weather). 
It is requested that the frozen tissue and blood samples be batched and shipped 
frozen on dry ice (at least 5 pounds) on a quarterly basis. If -70oC freezer is not 
available, blood samples are to be stored at -20oC and shipped on dry ice within 
24 hours of collection. Frozen samples are to be shipped SUNDAY THROUGH 
Ship Frozen   
Ship Ambient   
Ship Ambient  
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THURSDAY only via overnight courier.  Do not ship samples the day before a 
Holiday. 
Shipping manifest generated from the ECOG-ACRIN STS system must 
accompany the samples. 
Access to the shipping account for specimen shipments to the ECOG-ACRIN 
CBPF at MD Anderson can now only be obtained by logging into fedex.com with 
an account issued by the ECOG-ACRIN CBPF. For security reasons, the 
account number will no longer be given out in protocols, over the phone, or via 
email. If your site needs to have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International 
Sites) 
Fax: 713-563-6506 
11.4 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst 
Important:  Any case reimbursements associated with specimen submissions 
will not be credited if specimens are not logged into STS. Additionally, please 
note that the STS software creates pop-up windows, so you will need to enable 
pop-ups within your web browser while using the software.  A user manual and 
interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
If the STS is unavailable, the Generic Specimen Submission Form (#2981) is to 
be used as a substitute for the STS shipping manifest. The completed form is to 
be faxed to the receiving laboratory the day the samples are shipped. Indicate 
the appropriate Lab ID# on the submission form: 
• 
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Retroactively enter all specimen collection and shipping information when STS is 
available. 
11.5 
Use of Specimens in Research 
Specimens submitted will be processed to maximize their utility for current and 
future research projects and may include, but not limited to, extraction of plasma, 
serum, DNA and RNA.  
The appropriate materials will be distributed to investigators for the diagnostic 
reviews and research studies. 
Specimens from patients who consented to allow their specimens to be used for 
future approved research studies, including residuals from the currently defined 
reviews and research studies, will be retained in an ECOG-ACRIN-designated 
central repository. For this trial, specimens will be retained at the ECOG-ACRIN 
Central Biorepository and Pathology Facility. Specimens will be de – identified 
prior to distribution for any approved research products. 
If future use is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. Pathology materials may be 
retained for documentation purposes or returned to the site. All other specimens 
will be destroyed per guidelines of the respective repository. 
11.6 
Sample Inventory Submission Guidelines  
Inventories of all samples submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized for the will be submitted by the laboratory to 
the ECOG-ACRIN Operations Office - Boston on a monthly basis in an electronic 
format defined by the ECOG-ACRIN Operations Office - Boston. 
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12. 
Specimen Analyses: Diagnostic Review and Research Studies 
12.1 
Diagnostic Review and Classification (MANDATORY) 
Original diagnostic and surgical pathology materials (tissue and reports) will be 
retrospectively reviewed by Dr. Joaquín García at Mayo Clinic Rochester.  The 
results of the evaluations will not be reported to the sites and will not impact 
patient participation in the trial, but will be used to determine the evaluability of 
patient data in the analysis of the clinical data. 
Surgical materials will be evaluated for:   
A. Perineural Invasion, surgical: Reported as absent or present 
B. Lymphovascular Invasion, surgical: Reported as absent or present  
C. Extracapsular Extension, surgical:  The absence or presence of ECE should 
be documented in the final surgical pathology report in the following manner: 
• 
absent (nodal metastasis with smooth/rounded leading edge confined to 
thickened capsule/pseudocapsule), 
• 
present - minimal (tumor extends ≤1 mm beyond the lymph node 
capsule), or 
• 
present - beyond minimal (gross, tumor extends >1 mm beyond the lymph 
node capsule (includes soft tissue metastasis) 
The p16 status and reporting from the original diagnostic assessments will be 
also be reviewed to confirm patient evaluability. p16 immunohistochemistry must 
have been performed in a CLIA laboratory. Positivity is defined by strong 
cytoplasmic immunoreactivity noted in ≥ 70% of tumor cells. 
Data from the preoperative CT/MRI scans analyzed for nodal stage and 
prediction of ECE will be correlated with final pathologic nodal stage, presence 
and extent of ECE (≤ or > 1mm). 
12.2 
Research Studies 
The following correlative studies are proposed as outlined below. Final analysis 
of the proposed studies require the results of the parent study. Specifically, the 
percentage of patients distributed into each Arm of the trial is necessary to carry 
out a realistic statistical power calculations, but cannot be ascertained until the 
parent study is well underway. When sufficient information is available from the 
parent study, a planned early interim analysis to assess futility and 
accrual/distribution proportions of patients into each Arm, a full correlative 
science proposal or amended protocol document with formal statistical analysis 
plan for the marker studies will be submitted to and reviewed by CTEP. 
12.2.1 
Mutational Analyses: Tumor TP53 and common cancer-related genes 
Tumor TP53 and a panel of 200 common cancer-related genes will be 
sequenced in one assay using formalin-fixed and paraffin-embedded 
tumors to determine prognostic and/or predictive biomarkers    
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12.2.2 
Excision Repair Cross-complementation Group 1 (ERCC1) Single 
Nucleotide Polymorphism (SNP) and Protein Expression 
ERCC1 SNP (Thr259Thr) and ERCC1 protein expression in paraffin-
embedded tumor tissue will be analyzed. 
12.2.3 
Quantification of EGFR Expression 
EGFR protein levels will be analyzed by automated quantitative 
analysis (AQUA) technology 
12.2.4 
Serum cytokines/chemokines. 
Baseline and posttreatment cytokines are potentially predictive of 
outcome. Furthermore, the association between serologic markers 
(detected in blood at baseline and two other timepoints, including 
cytokines, chemokines, growth factors, and angiogenic factors in 
blood and treatment efficacy will also be examined.  
Multiplex analysis of circulating soluble 
inflammatory/immunosuppressive mediators will be measured 
12.2.5 
Markers of p16+ OPSCC Susceptibility 
Future correlatives are proposed to determine gender differences in 
carcinogen metabolism, as well as further evaluation of the 
importance of various hormone pathways in lung cancer. Analysis will 
be done on both tissue and blood samples submitted. 
12.2.6 
HPV DNA measurement and alteration in blood and saliva  
Given the ability to detect HPV DNA in salivary and blood specimens, 
we will perform an exploratory correlation between pre-treatment and 
post-treatment (1- and 2- year) HPV DNA, using QRT-PCR for HPV 
E6/E7.  HPV DNA and seropositivity to HPV antigens will also be 
measured quatitatively and qualitatively measure stability and 
predictive ability over time in a prospective treated population.  
DNA from buffy coat or PBMCs will be analyzed for quantitative and 
qualitative alterations in HPV DNA. These analyses will be performed 
under the direction of Robert L. Ferris, MD, PhD.  
The data will be used to determine the feasibility and potential value 
of incorporating this potential biomarker into the future randomized 
phase III trial. 
12.2.7 
Tumor antigen specific cellular immunity 
We and others have characterized the antigen specific cellular 
immune response to OPSCC, including HPV-, EGFR- and other 
antigens. PBL from pretreatment and post treatment patients will be 
correlated with disease recurrence, DFS, and OS. in tumor-bearing 
individuals, an hypothesis to be tested in the correlative phase of this 
proposal. 
Lymphocyte Markers 
• 
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97 
• 
T cell activation status: CD3, CD4, CD8, HLA-DR, ICOS1 and 
CD45RO (memory marker),Tregs and MDSCs (TAMs) 
• 
Profiling of tumor infiltrating lymphocytes using pretreatment 
tissue and PNMC will also be considered as markers for TIL, CD8, 
CD4, FoxP3, CD33 (MDSC marker), etc.  
• 
Monitoring adaptive and humoral immune responses toward 
specific tumor antigen [such as p53 and EGFR(76-78) and HPV 
E6 and E7 antigens (65, 79, 80)   
• 
Expression of checkpoint/inhibitory receptor expression on 
PBMC/TIL, i.e. CTLA-4, PD-1, TIM-3, BTLA-4, LAG3, etc. 
12.2.8 
Quality of Life Associated Biological Correlatives:  
Rapid telomere shortening has been documented in head and neck 
cancer patients undergoing radiation based treatment. In addition, 
telomere shortening has been associated with fatigue. We plan to 
measure telomere length at baseline and 1 and 6 months post 
treatment.  
In the general population, ACE polymorphisms have been correlated 
with the ability to build muscle mass. In the cancer lung patient 
population, there is data to indicate that ACE levels correlate with 
weight loss. We propose to measure ACE polymorphisms and 
correlate them with weight loss, fatigue and the level of general 
physical functioning.  
Finally, we plan to measure inflammation using c-reactive protein 
level.  
12.3 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office - Boston 1 week after these cut-off 
dates. 
 

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13. 
Electronic Data Capture 
Please refer to the E3311 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
13.1 
ECOG-ACRIN Radiation Oncology Quality Assurance Materials 
All radiotherapy quality assurance materials should be submitted to the IROC 
Rhode QA Center (QARC). See Section 5.1.16. 
Electronic submission via sFTP for all radiation data is preferred. Alternatively the 
supportive data and forms may be sent to: 
IROC Rhode Island QA Center 
ATTN: ECOG-ACRIN Materials 
640 George Washington Highway, Building B, Suite 201 
Lincoln, RI 02865-4207 
Tel:(401) 753-7600 
Fax: (401) 753-7601 
14. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
15. 
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differences associated with human papillomavirus status in head and neck 
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79. Gleysteen J, Troob S, Light T, Brickman D, Clayburgh D, Andersen P, Gross N. The 
impact of prophylactic external carotid artery ligation on postoperative bleeding after 
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Oncol. 2017 Jul;70:1-6. 

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Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Appendix I 
 
Pathology Submission Guidelines 
 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
 
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Guidelines for Submission of Pathology Materials 
E3311: 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Pathologic Analysis of Surgical Specimens  
Within RTOG / ECOG-ACRIN centers, a surgical pathologist should be designated as the 
primary pathologist responsible for quality control of surgical pathology material processing, 
evaluation and reporting at their respective institution.   
Histopathologic Assessment:  Histopathologic assessment of surgical pathology frozen and 
permanent sections must include examination for perineural invasion (PNI) and lymphovascular 
invasion (LVI) and reported as absent or present.  The absence or presence of extracapsular 
extension (ECE) requires gross and microscopic assessment and should be reported in the 
following manner:  
− 
absent (negative or nodal metastasis with smooth/rounded leading edge confined to 
thickened capsule/pseudocapsule), 
− 
present - minimal (tumor extends ≤ 1 mm beyond the lymph node capsule), or 
− 
present - extensive (tumor extends > 1 mm beyond the lymph node capsule (includes soft 
tissue metastasis) 
p16 Immunohistochemistry assessment of the original diagnostic biopsy, 
Immunophenotyping of tumor cells using p16 immunohistochemistry must be performed in the 
following manner: 
− 
Validated immunostaining performed using p16 antibody obtained from Roche mtm 
laboratories AG (CINtec®, clone E6H4™) within a CLIA certified laboratory 
− 
Strong cytoplasmic immunoreactivity noted in ≥70% of tumor cells qualifies as a positive 
result while less immunoreactivity qualifies as negative 
The following materials are to be submitted upon completion of the surgical pathology report by 
the site, but no later than 4 weeks following completion of the surgery 
Pathology materials required for pathology review and, per patient consent, research 
Adequate patient identifying information must be included with every submission.   It is strongly 
recommended that full patient names be provided. The information will be used only to identify 
patient materials, will expedite any required communications with the institution (including site 
pathologists).   
1. Representative tumor specimens of the following are to be submitted: 
• 
MANDATORY: 
o Original p16 tumor slide 
NOTE: 
If blocks are not available for submission, the following materials are to be 
submitted: 1-2 core punches (4 mm minimum) and 20 unstained slides. 
• From consenting patients  
o Fixed Paraffin-embedded tumor tissue block.  Original diagnostic or surgical 
specimen may be submitted. 
NOTE: If blocks are not available for submission, the following materials are to be 
submitted: H&E from the relevant source blocks, 1-2 core punches (4 mm 
Rev. 6/14
Rev. 6/14
Rev. 6/14 
Rev. 1/16 

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minimum) and 20 unstained slides. Slides, including the H&E are to be 
numbered consecutively in the order they are cut. 
o Frozen tumor tissue specimen, if available 
2. Forms and reports: 
− 
Copy of the original diagnostic pathology report 
− 
Surgical pathology and surgical procedure reports.  Reports, documentation must be 
included. 
o Histopathologic assessment of surgical pathology must include examination for 
perineural invasion (PNI) [absent or present], lymphovascular invasion (LVI) [absent 
or present], and extracapsular extension (ECE) [absent, present-minimal, present-
beyond minimal] 
o Surgical margin status must be reported as i) Negative (tumor ≥ 3mm from 
designated margin); ii) Close (tumor < 3mm of the designated margin); or iii) Positive 
(tumor at the cut specimen edge not superseded by another margin) 
− 
Other Immunologic and cytologic reports 
3. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any problems in 
meeting the pathology material submission deadline of one month, contact the Pathology 
Coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by telephone or 
email. 
 
 
Rev. 6/14
Rev. 2/15 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
108 
 
MEMORANDUM 
TO: ___________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
________________________________________ 
SUBJECT: 
Submission of Pathology Materials for E3311: Phase II Randomized Trial of 
Transoral Surgical Resection followed by Low-dose or Standard-dose IMRT in 
Resectable p16+ Locally Advanced Oropharynx Cancer 
 
Materials are requested from a patient who has been entered onto the above ECOG-ACRIN 
protocol by ______________________________ (ECOG-ACRIN Investigator).  This protocol 
requires the submission of pathology materials for central pathology review and laboratory 
research studies.  
The CRA will forward all required pathology material to the ECOG-ACRIN Central Biorepository 
and Pathology Facility. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies. Paraffin blocks will be returned upon written request for purposes 
of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the Central Biorepository and 
Pathology Facility 1-844-744-2420 (713-745-4440 Local or International Sites) or email: 
eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: _______________________________________________ 
Address: ______________________________________________ 
 
Phone: _______________________________________________ 
 
 
Thank you. 
 
Rev. 6/14
Rev. 6/14
Rev. 2/15

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
109 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN and the 
NCI to increase awareness of the importance of clinical trials and improve accrual and follow-
through. We appreciate your help in this effort. 
____________________________________________________________________________ 
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions remain 
unanswered in cancer. With the participation of people like you in clinical trials, we will improve 
treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will maintain 
very close contact with you.  This will allow me to provide you with the best care while learning 
as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank you 
again and look forward to helping you. 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
Rev. 6/14

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
110 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Appendix III 
 
AJCC Head/Neck Staging Criteria 
 
 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
111 
 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
112 
 
 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
113 
 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
114 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Appendix IV 
 
ECOG-ACRIN Checklist for Submission of Radiation Oncology Quality Assurance 
Materials 
Attention: ECOG-ACRIN Materials Address  
Building B, Suite 201 
640 George Washington Highway 
Lincoln, RI  02865-4207 
Checklist for Submission of Radiation Oncology Quality Assurance Materials 
Patient Initials:  ________ 
Registration #:  _______________________ 
RT Start Date:  _______________________ 
Sender’s Name:  ______________________________________________ 
Phone #:  ____________________________ 
Email:_______________________________ 
Radiation Oncologist: 
Email:_______________________________ 
Please enclose a copy of this Checklist together with the RT materials you submit. All 
materials must be labeled with the protocol and assigned registration number.   
Digital treatment plan, screenshots of other RT data and diagnostic imaging may be submitted 
via sFTP or on CD.  For data sent via sFTP, a notification email should be sent to 
sFTP@qarc.org with the protocol # and registration # in the subject line.  Please refer to 
IROC Rhode Island website for instructions on sending digital data (www.QARC.org).   
Data not sent via sFTP may be sent via email to datasubmission@qarc.org with the protocol # 
and registration # in the subject line.  Data may also be sent via courier to the address 
below. 
The following materials must be submitted within 3 days of the start of radiotherapy for 
review:  
DATE  
SUBMITTED 
 
Copy of pre-study diagnostic imaging AND radiology report (s), exam notes and 
endoscopy reports used to define the GTVs 
 
Digital RT Treatment Plan (DicomRT or RTOG format) 
 
Prescription sheet for entire treatment 
 
Treatment planning system summary report that includes the MU calcs, beam 
parameters, calculation algorithm, and volume of interest dose statistics 
 
DVH for “unspecified tissue (this is included in the digital RT Plan) 
Rev. 1/16 
Rev. 7/13 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
115 
 
If replanning is done on a new CT dataset and your planning system has the 
capability of exporting a DICOM spatial registration file, submit the spatial 
registration file along with the two CT scan sets. Otherwise screen captures of the 
fused datasets with the target volumes and critical normal structures delineated 
shall be submitted.  
 
Copy of Appendix III (AJCC Head/Neck Staging Criteria) 
 
RT-1 Dosimetry Form www.qarc.org/forms/IROC_RT-
1DosimetrySummaryForm.pdf 
Final Review materials must be submitted within 1 week of the completion of radiation: 
___________ Completed RT Daily Treatment Chart, including prescription, daily and 
cumulative doses 
___________ RT-2 Total Dose Record 
www.qarc.org/forms/IROC_RT2RadiotherapyTotalDoseRecord.pdf  
Please contact study CRA by email (ECOG@qarc.org) or phone: (401) 753-7600 for clarification 
as necessary. Thank you for your ongoing co-operation. 
 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
116 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Appendix V 
 
Patient Reported and Functional Outcomes (PRO) Administration 
Questionnaires will be available on-line for centers to print as need. They will be administered 
by trained personnel. It is recommended that PROs be administered to patients at the time of 
a clinic visit, before the patient is assessed by the doctor.  In the event that a patient needs 
extra time, it is permissible for the instruments to be taken home for completion and mailed 
back; trialists should follow-up by telephone within 1 week to insure the instrument has been 
completed and if necessary, complete it over the phone by reading items and responses 
verbatim. 
At each time point, the completed questionnaires must be entered into Medidata Rave by the 
site. Please note that in the chart below, the top two rows specify when each assessment 
should be done in relation to the completion of step 1 or step 2 treatment. Within Rave, it is 
ECOG-ACRIN's convention that the reporting periods for all Long-term Follow-up (LTFU) 
folders are based off of the patient's registration to step 1, and this applies to all arms of 
E3311. Therefore, the reporting periods within the LTFU forms and protocol-specified 
assessments should be looked at separately. In order to determine which LTFU folder an 
assessment should be reported in, you should look at the third row, entitled "Time (from 
registration to step 1)" to determine when this assessment will occur in relation to step 1 
registration. As an example, if you had a patient that was registered on 01/01/2016 and 
completed RT on 06/15/2016, the follow-up assessments that are supposed to be completed 
6 months post RT would occur around 12/15/2017. Row 3 of the chart notes that the 6 
months post RT assessments should be done 42-28 weeks after registration to step 1 
registration, which is between 10.5 and 12 months post step 1 registration. Therefore, this 
assessment would not fall within the 6 months post-registration LTFU folder, and would 
instead fall within the 12 months post-registration LTFU folder. 
Assessment 
Baseline 
4-6 wk 
post 
TORS-TOS 
End of 
RT 
3 mo 
post RT 
6 mo post 
RT 
1 year 
post RT 
2 year 
post RT 
Time (post 
TORS/TOS) 
Baseline 
 
12-16 wk 
24-28 
36-40 
60-64 
112-116 
Time (from 
registration to 
Step 1)* 
 
 
18-24 
30-36 
42-48 
70-76 
122-128 
Clinical 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
Trach y/n 
X 
X 
X 
X 
X 
X 
X 
Feed tube y/n 
X 
X 
X 
X 
X 
X 
X 
PSS-HN 
X 
X 
X 
X 
X 
X 
X 
Charlson 
X 
 
 
 
 
 
 
Swallowing 
 
 
 
 
 
 
 
MBS 
X 
X 
 
 
X 
 
X 
Rev. 7/13 
Rev.7/13, 
Rev.2/15,  
6/15, 9/16 
Rev. Add8
Rev. 6/14

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
117 
Assessment 
Baseline 
4-6 wk 
post 
TORS-TOS 
End of 
RT 
3 mo 
post RT 
6 mo post 
RT 
1 year 
post RT 
2 year 
post RT 
Pros 
 
 
 
 
 
 
 
FACT-H&N 
X 
X 
X 
X 
X 
X 
X 
MDADI 
X 
X 
 
 
 
X 
X 
MDASI-HN 
X 
X 
X 
X 
X 
 
X 
VHI-10 
X 
X 
 
 
 
X 
X 
EQ-5D 
 
 
X 
 
 
 
 
Cost 
Questionnaire 
 
 
X 
 
 
 
 
Ret to work 
X 
 
 
X 
X 
X 
X 
* Arm A patients and Arm S patients who do not register to Step 2: QOL submission will 
be based on “Time (From registration to Step 1)” schedule/row.   
 
PLEASE NOTE: QOL will continue to be collected for all patients post recurrence. 
Rev. 7/13,  
Rev. 2/15 
Rev. 7/13, 
2/14 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
118 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
 
Appendix VI 
 
Modified Barium Swallow (MBS) Credentialing Checklist 
This form needs to be completed by the institution before patients can be 
registered to E3311.  Once the form is complete, please fax this to the ECOG-
ACRIN Operations Office - Boston at (617) 632-2990, Attention: E3311 Data 
Manager.  You will receive an email from the ECOG-ACRIN Data Manager 
confirming the receipt of the checklist. 
1. Do you conduct modified barium swallow (MBS) studies to evaluate swallowing 
disorders in your institution? 
YES_______ NO_______ 
If “NO”, skip to number 8; if “YES”, please answer questions 2-8. 
2. Are your MBS videos recorded digitally at a minimum frame rate of 30 frames/second 
(i.e., accurate to 0.01 time code imprints)? 
YES_______ NO_______ 
3. Do you use the Kay Pentax Digital Swallowing Workstation (this is NOT mandatory for 
participation)? 
YES_______ NO_______ 
4. Do you use Varibar contrast agents specified in this protocol, including Varibar Thin 
Liquid and Varibar Pudding? 
YES_______ NO_______ 
a. If no, can you access Varibar contrast agents for MBS studies conducted per  E3311 
YES_______ NO_______ 
5. Are you (speech pathologists) willing to follow the MBS protocol as written in E3311 
(including the sequence of bolus administration, use of Varibar products, and 
volumes/viscosities specified)? 
YES_______ NO_______ 
6. Please provide the following data specific to your site: 
a. Number of speech pathologists at your institution who perform MBS studies? 
_______ 
b. Average number of total MBS studies conducted at your institution each week? 
_______ 
c. Average number of MBS studies conducted on patients who have head and neck 
cancer each week? _______ 
Rev. 7/13 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
119 
7. 
8. 
_______________________________ 
__________________________________ 
Signature of Speech Pathologist 
Institution Name 
completing this form 
 
__________________________________ 
 
Contact Person 
 
__________________________________ 
__________________________________ 
Printed Name of Speech Pathologist 
Telephone Number 
 
 
 
_________________________________ 
Name and email of person registering to 
Email Address 
cloud account and uploading video 
__________________________________ 
_________________/________________ 
Fax Number 
Site ECOG-ACRIN Institution Number/ 
CTEP ID Number 
Rev. 2/15 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
120 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Appendix VII 
 
Surgeon Credentialing Questionnaire 
1. This study requires careful documentation of stage of disease prior to registration.  CT 
MR and PET scan findings are not accepted as sole criteria of the extent of the primary 
tumor. Pre-treatment endoscopy, even in the operating room, if deemed appropriate, is 
sometimes necessary for patients. Is this a procedure that you perform routinely and 
would you agree to do for this protocol, if needed? 
YES ________ 
NO                   Comments: 
2. Please check the item that best describes the scope of your practice: 
             
General Otolaryngology 
             
Head and Neck Surgery with some endoscopic surgery (TLM or TORS) 
             
Head and Neck Surgery with a focus on endoscopic surgery (TLM or 
TORS) 
3. Please estimate the number of neck dissections you perform per year. _______ 
4. Please estimate the number of transoral endoscopic surgical procedures you perform 
each year     (TLM or TORS).  _______ 
5. As attending surgeon, have you performed a minimum number of 20 cases of transoral 
excision for oropharyngeal carcinoma as the primary surgeon? 
YES_______ NO_______ 
6. As attending surgeon, have you performed at least 5-10 transoral resections of 
oropharyngeal carcinoma in the past 12 months? 
YES_______ NO_______ 
7 Please upload paired pathology report and operative notes for ten transoral eHNS 
cases, including at least one tonsil and one tongue-base primary tumor. 
8. If there are other surgeons at your institution who will be participating in this program, 
have they also completed one of these forms? 
YES_______ NO_______ 
 
NOTE: 
This form is for reference only. The information will be entered directly into 
Medidata Rave in the “E3311/RTOG-1221 H&N Surgeon’s Questionaire – 
Credentialing” database. 
NOTE: 
Only transoral oropharynx cancer resections are applicable; oral cavity and 
larynx surgeries are not applicable, even if transoral in approach. 
Rev. 2/14 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
121 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Appendix VIII 
 
Modified Barium Swallow Study Form 
 
                      Modified Barium Swallow Study Form 
E3311: Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
INSTRUCTIONS: To be filled out by the speech pathologist after the modified barium swallow study. 
Dates are recorded as mm-dd-yyyy unless otherwise specified. 
MBS PROTOCOL: 
All MBS studies must follow a standard protocol as outlined below.  
Additional bolus presentations or swallowing strategies may be tested after completing bolus trials in the 
study protocol, at the discretion of the clinician conducting the MBS study.   
Studies will be done in lateral and AP views with focus fixed on the soft palate superiorly, 
cricopharyngeus inferiorly, lips anteriorly, and cervical spine posteriorly. 
Video-recordings will require time code imprints accurate to 0.01 seconds (30 frames/second).  Video-
recordings between 15-30 frames/second will be accepted as long as the recording rate is clearly 
documented in advance.  Video-recordings below 15 frames/second will not be accepted. 
Studies must be recorded in AVI or MPEG format.  All centers must use the Kay Digital Swallowing 
Workstation for the studies; or alternatively, have the ability to convert files to AVI of MPEG format. 
Centers must use Varibar products. Consistencies and quantities are listed below.  Liquids must be 
administered first to avoid confounding the results from remaining residue in the pharynx after solid 
consistencies. 
A dime must be taped to the subject’s chin during the swallowing study.  The circular shape of the dime 
minimizes the impact of head rotation and the known diameter of the dime allows for calibration of pixels 
per cm and thus calculation of distances and areas on the lateral view of the x-ray. 
Lateral view: 
• 5mL thin (2 trials, tsp). Instruction to the patient: please hold this in your mouth until asked to swallow. 
• 20mL thin (1 trial). Instruction to the patient: please try to take the whole amount and hold it in your 
mouth until I ask you to swallow. Self administration is optimal, but clinician administration is 
acceptable. 
• 5mL pudding (1 trial tsp). Instruction: swallow when you are ready. 
• 1/2 cookie or cracker, barium coated - coated with 3 ml (1/2 tsp) of Varibar pudding (1 trial). Instruction 
to the patient: chew this up and swallow when you feel comfortable and ready to swallow. 
A-P view: 
10mL thin (1 trial). Instruction: slightly raise your chin (neutral position, not tucked or extended), hold this 
in your mouth until asked to 
RATING RULES: 
Rate MBS outcomes below on the basis of bolus trials in the ECOG-ACRIN protocol.  Do not rate based 
on additional bolus trials that are administered outside of the protocol or based on bolus trials in which a 
swallow strategy/posture was tested.  Please select a SUMMARY RATING based on the highest level of 
impairment you observe on any bolus trial in the protocol. 
Rev. 2/15 
MBS 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
122 
 
                      Modified Barium Swallow Study Form 
E3311: Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
1 DATE OF MBS  _____-_____-_____ 
2 □TIME OF MBS 
1. Baseline  
2. After surgery (before adjuvant therapy)  
3. Six months after treatment 
4. Twenty-four months after treatment 
Outcome Variables 
Definition 
Scoring Rules 
(Rate the worst of 
impairment across all bolus 
trials in the MBS protocol) 
Rating 
3 LARYNGEAL 
PENETRATION 
PENETRATION: Bolus 
enters the larynx but does 
not pass below the TVFs 
Select “1” if LARYNGEAL 
PENETRATION occurred on 
any bolus in the protocol. 
□  No penetration (0) 
□  Penetration (1) 
4 ASPIRATION 
ASPIRATION: Bolus enters 
the larynx and passes  
below the TVFs. 
SENSATE: attempts to 
eject aspirate from airway 
(e.g., cough, throat clear) 
SILENT: no effort to eject 
aspirate from airway (no 
cough, throat clear)  
Select the highest level of 
aspiration that occurred during 
the protocol. 
Select “1” if SENSATE 
ASPIRATION ocurred on any 
bolus in the protocol, but silent 
aspiration NEVER occurred. 
Select “2” if SILENT 
ASPIRATION occurred on any 
bolus in the protocol.  
□  No aspiration (0) 
□  Yes, sensate (1) 
□  Yes, silent (2) 
5 PHARYNGEAL 
RESIDUE 
RESIDUE: bolus remaining 
on or within the pharynx at 
the conclusion of the initial 
swallow.  The conclusion of 
the initial swallow is when 
the hyoid bone returns to 
rest.  If the patient 
spontaneously swallows 
several times to clear the 
bolus, residue is rated after 
the 1st swallow attempt. 
Rate the highest level of 
residue that occurred during 
the protocol.   
Select “0” is no residue or only 
pharyngeal coating occurred 
during the protocol. 
Select “1” if pharyngeal 
residue of <50% of the original 
bolus remained in the pharynx 
on any bolus in the protocol. 
Select “2” if pharyngeal 
residue of half or more of the 
original bolus remained in the 
pharynx on any bolus in the 
protocol. 
□  No residue (0) 
□  <50% pharyngeal 
residue (1) 
□  ≥ 50% pharyngeal 
residue (2) 
PERSON COMPLETING FORM:  
NOTE: This form is for reference only. The MBS information for each registered patient will be 
entered directly into the Medidata Rave database. MBS Videos will be uploaded to a 
cloud account held by MD Anderson Cancer Center. Instructions on how to upload the 
videos can be found in Section 4.1.5.7. 
MBS 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
123 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Appendix IX 
 
Letter Explaining Modified Barium Swallow Video Upload Instructions 
Dear [CRA SALUTATION], 
Thank you for participating in the MBS data collection efforts for ECOG-ACRIN protocol 
E3311, “Phase II Randomized Trial of Transoral Surgical Resection followed by Low-
dose or Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx 
Cancer.” 
E3311 will archive MBS video files on MD Anderson Cancer Center’s Box® Cloud-based 
storage account.  You are receiving this e-mail because you were designated as the 
individual who will be responsible for uploading and archiving MBS video files to Box.   
Details regarding the HIPAA compliance and MD Anderson’s Business Association 
Agreement associated with the Box Cloud account can be found at:  
http://www.mdanderson.org/about-us/for-employees/employee-resources/box-cloud-
storage/faqs.html#security 
Additional information regarding the security of Box is located at: 
 https://support.box.com/hc/en-us/articles/200526618-Box-HIPAA-and-HITECH-
Overview-and-FAQs  
Shortly, you will receive e-mail notification that you have been added as a collaborator to 
the E3311 MBS Video Files folder on Box.  Upon receipt of the e-mail, click on the icon 
that reads “View Folder.”  You will then be taken to a webpage that asks you to create 
an account with Box.  When you are ready to upload video files in the future, you will 
need to return to this site (www.box.com) and log in.  Once logged into your account, 
click on the shared folder.  To upload videos, click on the grey button entitled “Upload” in 
the top left-hand corner of your screen and select Upload Files from the drop-down 
menu (please make sure that you are uploading your files inside of this folder). If you 
forget your password, please click the link labeled “Reset Password” (below the space 
where you would log into Box) for instructions on obtaining a new password.  
To ensure the security of the uploaded video all patient identifiers are to be removed and 
the video files are to be re-labeled with a unique identification code. To obtain the code:  
3. Log the videos into ECOG-ACRIN’s Sample Tracking System (STS), indicating the 
“Ship Date” as the date the video is to be uploaded to the MD Anderson Box Cloud 
Account.  Be sure to select the correct protocol-specified time point for the video.  
(e.g., Baseline, after surgery…) 
https://webapps.ecog.org/Tst/ 
4. Exit STS and enter the Patient Video Identifier Lookup application.  Select the 
protocol and enter the ECOG-ACRIN E3311 patient identifier to pull up the patient 
specific information. The code is the “Sample ID” and is a unique code linked to the 
patient and the time point of the video as entered into STS.  
https://webapps.ecog.org/PatientVideoIdentifyLookup/ 
Rev. 6/15 
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ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
124 
Videos must be uploaded in .mpeg or .avi format.  Rename the electronic video file using 
only the STS-generated sample ID prior to uploading to the MD Anderson Cloud. For 
example, if the sample ID obtained from STS is “123456” and the video is in .avi format, 
the file to be uploaded should be named “123456.avi”.  Any and all PHI contained within 
the video or as part of its name must be removed prior to upload on Box.   
We have attached instructions for saving video files in the desired format as well as 
editing tips that may be helpful for removing PHI from the MBS videos prior to upload to 
the Box account. 
Should your site have a change in staff responsible for upload of video files to Box, 
please notify E3311_MBS@jimmy.harvard.edu with the name and e-mail address of the 
individual requesting access to Box. 
Please do not hesitate to contact us should you need further assistance or encounter 
problems uploading videos. 
Regards, 
MD Anderson Cancer Center 
Department of Head and Neck Surgery 
Section of Speech Pathology and Audiology 
T: 713-792-6364 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
125 
Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or 
Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer 
Appendix X 
 
E3311LGS1 
Identification of novel biomarkers and therapeutic targets of higher-risk disease in ECOG 
3311 
Principal Investigator: Robert L. Ferris, MD PhD 
Statistician: Yael Flamand, PhD 
 
 
Co-Investigators: Xiaosong Wang, PhD 
Danielle Normolle, PhD 
Daniel Faden, PhD 
Barbara Burtness, MD
Rev, Add9 

ECOG-ACRIN 
E3311 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: January 15, 2014 
126 
The majority of Human papillomavirus- (HPV) mediated head and neck squamous cell 
carcinoma (HNSCC) have favorable outcomes compared to non-HPV mediated HNSCC. 
Thus, much interest is focused on treatment de-intensification in HPV-mediated disease 
in an attempt to maintain this survival advantage while decreasing treatment morbidity. 
Currently, no biomarkers exist in HPV-mediated HNSCC to predict patients who can 
safely undergo treatment de-intensification. 
 
1) Objectives 
The primary objective is to identify genomic biomarkers in HPV-mediated HNSCC that predict 
an aggressive tumor phenotype and, thus, patients who should not undergo treatment de-
intensification with trans-oral robotic surgery (TORS). 
a. Objectives: 1) Develop a predictive model that, using Whole Exome Sequencing and 
RNA-Seq, predicts risk stratification and clinical outcome after observation, radiation 
alone, or chemoradiation. Generate a rich genomic and transcriptomic dataset for a novel, 
rapidly increasing subset of H&N cancers to provide collaborative opportunities for 
translational research to understand this newly emerging cancer. 2) In an independent set 
of samples from ECOG 3311, test the one-side null hypothesis that the AUC of the ROC 
curve of the predictive model is less than 0.6 at α=0.05. This test is to be performed by the 
ECOG Statistical Center to ensure independence of the validation from the training. 
b. Hypotheses: 1) A predictive model that can be used to predict patients with HPV-
mediated who are candidates for de-intensification can be developed using Whole Exome 
Sequencing and RNA-Seq. 2) In an independent validation set, it can be demonstrated 
that the AUC of the ROC curve of this predictive model is greater than 0.6.  
2) Background and Rationale 
Traditionally, the major risk factors for Head and Neck Squamous cell carcinoma (HNSCC) 
were tobacco and alcohol exposure [1-3]. However, HPV is now recognized as the major risk 
factor for HNSCC of the lingual and palatine tonsils. Molecular and epidemiologic studies 
have confirmed that nearly 70% of HNSCC of the oropharynx (OPSCC) are HPV-mediated 
[4, 5]. Risk of death from HPV-mediated OPSCC patients is 50 percent lower than for non-
HPV mediated OPSCC. This improvement is portended both by the favorable biology of 
HPV-mediated OPSCC, but is also related to the younger age and decreased medical 
comorbidities seen in this patient population. While <15% of HNSCC in the TCGA are HPV-
mediated, it has become clear that these tumors have distinct genomic underpinnings 
compared to non-HPV mediated HNSCC. 
Favorable tumor biology, in combination with the younger age of HPV-mediated HNSCC 
patients, leads to not only improved overall survival, but more potential life years after cure. 
Thus, interest is now focused on reducing treatment-associated morbidity. In particular, 
attention has been brought to the development of late effects from chemoradiotherapy, as an 
organ-preservation approach has become a standard of care. In E2399, 49% of OPSCC 
patients had moderate-to-severe swallowing impairment at 3 months following treatment, and 
some patients were still PEG dependent after 12 months. Severe swallowing dysfunction 
following radiation therapy to the oropharynx is a major source of decreased QOL in HPV 
mediated OPSCC patients.  
Traditionally, surgical resection of OPSCC carried significant morbidity due to the difficulty of 
accessing the oropharynx, necessitating aggressive surgical maneuvers. More recently, 
trans-oral surgery (TOS) has gained favor as a method for achieving surgical extirpation with 
limited morbidity. TOS has been shown to be able to achieve complete surgical extirpation of 

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T1/T2 OPSCC with oncologic outcomes similar to chemoradiotherapy in single institution 
studies [6]. Further, TOS has improved QOL measures and swallowing outcomes, compared 
to chemoradiotherapy [6-8]. As expected, patients who receive single-modality TOS have 
improved swallowing outcomes, compared to patients who receive adjuvant radiation [9]. 
ECOG 3311 was designed to explore the role of TOS in treatment de-intensification for HPV-
mediated OPSCC. 
Preliminary evaluation of ECOG 3311 arm stratification has shown that ~30% of patients 
enrolled were stratified into arm D (tri-modality therapy), based on adverse pathologic risk 
factors. Tri-modality therapy is well established to have a more severe side effect profile, 
compared to surgery alone and surgery with adjuvant radiation, particularly, in regards to 
swallowing. Thus, identification of patients with biologically more aggressive cancers prior to 
treatment decision-making is vital for avoiding tri-modality therapy, if not absolutely 
necessary. All patients enrolled in ECOG 3311 have cT1 or T2 and cN1, N2a, or N2b 
disease, based on clinical or radiographic criteria, and are thus indistinguishable pre-
operatively. At this time, no biomarkers exist that predict a more aggressive tumor phenotype 
or clinical pathologic features that would necessitate stratification into arm D of ECOG 3311 
and, thus, tri-modality therapy. ECOG 3311 presents a unique opportunity to investigate such 
biomarkers in a cohort of HPV+ OPSCC patients with tightly annotated clinical and pathologic 
data. Of note, Dr. Ferris is the PI, the highest accruing surgeon nationally to E3311, and 
personally funded the preliminary genomic/transcriptomic analysis and characterization, 
using UPMC specimens, to provide feasibility for the proposed studies using additional 
specimens from this trial. 
Our primary preliminary objective was to determine the feasibility of identifying genomic 
biomarkers that would predict patients who stratify into arm D, pre-operatively. Identifying 
these patients prior to surgery would allow practitioners to choose alternative therapies, 
avoiding tri-modality therapy. We first sought to better define the genomic profile of HPV-
mediated HNSCC in general. Existing data support HPV-mediated HNSCC having a distinct 
genomic profile from non-HPV mediated HNSCC [10]. However, a limited number of HPV-
mediated HNSCCs had been comprehensively profiled and available to the scientific 
community. For example, TCGA contains <75 HPV-mediated HNSCCs. From that cohort, 
and others, we knew that HPV-mediated HNSCC typically lack TP53 mutations, the most 
common driver mutation in non-HPV mediated HNSCC and CDK2NA alterations, and instead 
possess high rates of PIK3CA mutations and E2F1 amplifications. However, how specific 
genomic and transcriptomic alterations relate to tumor behavior within HPV mediated 
HNSCC is not known. While many potentially promising biologic pathways and hypotheses 
have been reported to be of importance in HPV mediated HNSCC, for example, the presence 
of TRAF3/CYLD mutations has been shown to correlate with tumor behaviors [11], to date, 
no established biomarkers exist. 

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To determine if the approach was feasible, we generated and analyzed WES and RNA-Seq 
datasets for 40 patients from the University of Pittsburgh. Briefly, after pathologic review, 
DNA and RNA was extracted from 43 HNSCC tumors (FFPE), as well as germline DNA from 
peripheral blood. One patient had low quality nucleic acid on QC and was removed. Tumor 
and germline DNA underwent WES at 85% of targeted bases at 50X or greater coverage 
(~150X MTC) paired end reads for the tumor DNA and 85% of targeted bases at 20X or 
greater coverage (~60X MTC) for germline DNA. Tumor RNA underwent RNA-Seq at 50M 
paired end reads at the Broad Institute using standard library prep and sequencing 
approaches (76-bp paired end on Illumina HiSeq 2500). Two patients had low coverage or 
failed fingerprint SNP analysis and were removed. Our workflow for the remaining 40 patients 
is represented in Figure 1. More detailed methods are presented in Laboratory Methods. 
Predictive Gene Expression Signature 
In order to investigate gene expression signatures that could predict arm stratification, we 
divided our patients into two cohorts and performed principal component analysis (PCA) for 
dimensionality reduction (see workflow in Figure 2a). We used Limma for supervised feature 
selection between cohorts, which identified 231 differentially expressed genes (DEGs). We 
then applied a neural network to the 231 DEG expression matrix to compute a classification 
score. The ROC curve of the resulting classifiers is presented in Figure 2b. The resulting 
area under the receiver operating characteristic (AUC) is 0.92. This estimate of the AUC, 
being based on the training set, is optimistically biased and we do not anticipate a validated 
AUC this close to 1, but it demonstrates the feasibility of the approach. Developing a clinically 
actionable predictive model requires a larger training set and an independent validation set 
from the ECOG 3311 cohort. 

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Ongoing work 
The predictive signature discussed above employs only gene expression data. However, 
numerous genomic features may be important in predicting arm stratification. Thus, we are 
currently employing more advanced and comprehensive modeling to generating predictive 
signatures which include more varied data input including from both DNA and RNA (Figure 
3). These more comprehensive approaches will help refine and improve the accuracy of our 
predictive signature. 
 
Funding for the project will come from Hillman Cancer Center funds, and R01 submission in 
progress (depends on a support letter from ECOG providing and ensuring access to the 
national specimens, beyond the UPMC -enrolled patients which comprise the preliminary 
data). 
3) Biospecimen Requirements 
Tissue (slides, cores, etc.): 10 tumor blanks (or 1 3-4mm core) or if pre-processed 300ng 
DNA (>20ul and >10ng/ul) and 1ug total RNA (>20ul and >10ng/ul) 
Blood (tube type, volume, etc.): 5ml of blood or if pre-processed 300ng DNA (>20ul and 
>10ng/ul). Blood can come from any time collection point 

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1 of each sample type is to be requested per case.  
266 cases in the trial currently have these sample types available and all 266 will have these 
samples requested. This analysis will not exhaust any cases of material. 
4) Sample Processing/Laboratory Methods 
Tissue  
Microdissection of FFPE primary tumor from 10 FFPE slides at 5 microns will be performed 
manually using an inverted microscope (Nikon Eclipse TE200) to obtain a minimum of 95% 
tumor cells avoiding domains with infiltrating inflammatory cells, necrotic tissue or normal 
cells. Dissection involves scraping tumor cells from unstained sections of 5 micron thickness 
on slides aligned in register with serially cut hematoxylin and eosin stained specimens 
including tumor domains demarcated by consensus analysis of two surgical pathologists or 
as provided by ECOG 
Whole Exome Sequencing (WES) 
DNA extraction and QC: Genomic DNA will be purified from tumors using the Qiagen 
QIAamp FFPE DNA protocol (Qiagen, Valencia, CA). DNA concentration and quality will be 
determined by fluorometry and spectrophotometry respectively (Qubit 2.0 fluorometer, 
Thermo Fisher, Waltham, MA; Nanodrop ND-1000 spectrophotometer, NanoDrop, 
Wilmington, DE) and molecular size distribution (20Kb to 150Kb) is evaluated on the 
Bioanalyzer 2100 (12000 DNA Chip, Agilent Technologies, Santa Clara, CA). Samples that 
do not meet the minimum picogreen quantified input requirements (≥300ng DNA, preferred 
concentration 10ng/ul, or a minimum Kapa quality score of > 0.3) will be held for further 
evaluation. 
Library construction: Library construction will be performed at the Broad Institute according to 
established protocols with the ligation-based KAPA HyperPrep Library Preparation Kit 
followed by hybrid capture with the Rapid Capture Exome enrichment kit (Illumina) with 38Mb 
target territory. All samples will be validated against the Fluidigm Fingerprint Check to confirm 
sample identity and fidelity. One positive control, NA12878 is included in each library 
preparation.  
Sequence generation: All libraries will be sequenced to 85% of targets covered at greater 
than 50x coverage (+/- 5%) (~150X MTC) for tumor samples, and 80% of targets covered at 
greater than 20x coverage (+/- 5%) for matched-normal samples utilizing the Laboratory 
Picard bioinformatics pipeline. All sequencing will be performed on the Illumina HiSeq 
instruments with 76 base pair, paired‐end sequencing. The Picard pipeline will aggregate all 
data from a particular sample into a single BAM file which will include all reads, all bases 
from all reads, and original/vendor-assigned quality scores. 
Somatic variant calls and copy number variants (CNV): GATK best practices core variant 
calling workflow including pre-processing and Variant Discovery will be used. Pre-processing 
includes mapping (BWA mem) and duplicate marking for individual sequencing output. Local 
indel realignment is subsequently performed jointly on the tumor normal pair, prior base 
quality score recalibration (BQSR), and contrastive evaluation between the tumor and normal 
using Mutect and Indelocator in order to provide somatic SNV and Indel calls. These variants 
are further annotated and visualized using maftools. 
Whole Transcriptome Sequencing (WTS) 
RNA extraction and QC: Specimens with projected yield >1 µg RNA will be extracted with the 
Qiagen FFPE RNeasy kit (#73504, Qiagen, Inc., Venlo, Netherlands) while specimens with 

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projected yields less than that utilize the Zymo RNA FFPE extraction kit (#R1008, Zymo 
Research, Irvine, CA). Total RNA purity will be measured by the absorbance ratio 
(260nm/280nm) in Tris buffer (10mM TRIS-Cl, pH 7.5) using the Nanodrop 1000 
spectrophotometer (ThermoFisher, Wilmington, DE) with a pure RNA A260/280 of 2.0 and 
low cutoff of 1.8. Samples ≥1.8 undergo further processing. The concentration of RNA (> 20 
nucleotides) is determined on the Qubit fluorometer (ThermoFisher) High Sensitivity assay on 
RNA diluted to 50ng/µl using the Nanodrop concentration. The micro-RNA Qubit assay will 
then be used to quantitate RNA that is present <20 nucleotides length. Agilent Bioanalyzer 
2100 (Agilent Technologies, Santa Clara, CA) will be used to determine the RNA size profile 
(RNA Integrity Index: RIN) and the DV200% of the eluted RNA using the RNA Nano chip 
assay (>50 ng) or the Pico chip for RNA samples with less than 50 ng. Samples that do not 
meet the minimum quantified input requirements (≥550ng RNA, preferred concentration 
10ng/ul, DV200 score >0.3) will be held for further evaluation. 
Library construction: Library construction will be performed at the Broad Institute according to 
established protocols with the True-Seq RNA Exome Kit (Illumina). All samples will be 
validated against the Fluidigm Fingerprint Check to confirm sample identity and fidelity. 
Sequence generation: All libraries will be sequenced to 50M reads aligned in pairs (+/- 5%) at 
76bp read length using the Illumina HiSeq platform as measured using the Picard 
bioinformatics pipeline. The Picard pipeline aggregates all data from a particular sample into 
a single de-multiplexed, aligned BAM file which includes all reads, all bases from all reads 
and original/vendor assigned quality scores.  
Read counts: Quality checked and adapter trimmed fastq reads will be mapped to the 
reference genome using HISAT2 aligner and gene level quantitation performed using HT-Seq 
counts. Count data are used to perform differential gene expression between two conditions 
using edgeR, a bioconductor R package. 
Informatics for Objective 1.  
The predictive model will be developed as follows based on the sequencing from 200 
samples (100 samples from UPMC and 100 samples from Arms A+B+C of ECOG 3311). For 
RNA-seq data, the gene level, transcript level, and exon level expression profiles will be 
extracted and submitted to unsupervised PCA analysis, to observe the PCA clusters that can 
facilitate stratification. In addition, we will use TopHat2 and MapSplice2, together with the 
fusion zoom pipeline we developed, to detect splice junctions and gene fusions from RNAseq 
data, and use MuTect2 and GATK4 to detect somatic mutations, such as SNVs and indels, 
and CNVs from WXS data, which can be used as additional levels of genomic features for 
stratification. The individual discriminative features for arm stratification will be selected and 
Autoencoder will be applied to transform these discriminative features into synthetic features 
for dimensionality reduction. We will then classify tumor samples based on these synthetic 
features using Neural Network, Ridge, Lasso, and Elastic Net, selecting the method with the 
best cross-validated predictive performance. In addition to these machine learning methods, 
we will also apply a Universal Genomic Signature Analysis (uniGenSig), developed in our 
laboratory, to explore the universal genomic correlates that can be deployed for stratification. 
This method does not require dimensionality reduction, but instead extracts the universal 
genomic correlates via feature selection and then eliminates their redundancy by assessing 
their co-occurrence in large cohorts of human tumors. Together, these comprehensive 
genomic analyses will characterize the individual, synthetic, and universal genomic correlates 
for stratification. 

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Informatics for Secondary Objectives in 1. 
1. Generate genomic and transcriptomic profile of all tumors from ECOG 3311. From DNA, 
SNVs, indels and CNVs for each sample will be annotated and collated. From RNA, as 
well as gene expression and gene fusions will be generated. Profiles will be compared 
against existing HPV+ samples from TCGA. This data will be available to the scientific 
community as a reference for investigation.  
2. Test if TRAF3/CYLD mutation presence predicts arm stratification: Somatic alterations, 
including CNVs in TRAF3 and CYLD will be annotated for each tumor and grouped by 
arm to examine differences between arm D and others.  
3. Neoantigen prediction requires three components: somatic variant calls, expression 
levels of mutant genes and HLA genotyping. Somatic variant calls and gene expression 
will be generated as part of the primary objective, HLA genotyping will be performed 
using the BWAkit and Polysolver algorithms from the WES data. Neoantigen prediction 
will then be performed according to the methods described by Rooney[12]. Number of 
neoantigens will then be pooled and averaged across study arms and compared between 
arms.   
4. Test if APOBEC mutational burden predicts arm stratification: APOBEC mutational 
burden will be calculated for each sample using established functions[13], pooled and 
averaged by study arm, and compared between arms. 
5. Test if an inflamed expression profile predicts arm stratification: Keck and Seiwert have 
defined an inflamed expression profile for a subset of HPV+ HNSCCs[14]. We will apply 
this inflamed vs classical expression profile to all samples and test if expression subtype 
predicts arm stratification according.  
6. Test if CYT score and T-cell infiltrate predicts with arm stratification. Rooney et defined 
an immune cytolytic activity score (CYT) based on transcript levels of granzyme A and 
perforin[12]. Using RNA-Seq data will we calculate CYT scores for each sample and 
correlate this with arm stratification. Senbabaoglu et al defined methods for establishing 
T-cell infiltration scores using RNA-Seq data via ssGSEA[15]. Mandal et al later applied 
these methods to HNSCC[16]. We will calculate T-cell infiltration scores using ssGSEA 
methodology as defined by Senbabaoglu for each sample. Scores will then be correlated 
with arm stratification. 
7. Clinical outcome and progression-free survival will also be modeled in a fashion similar to 
that of the primary informatics objective, but this is considered exploratory and will not be 
submitted to validation. 
Nucleic acid extraction will be performed at the UPMC Hillman Genomics Core. Over the last 
2 years, this group has extracted DNA and RNA from >200 FFPE samples that have gone on 
to NGS with success, including the 40 FFPE patient samples from patients at University of 
Pittsburgh. Robert Ferris will oversee this process. 
QC, library preparation and sequencing will be performed at the Broad Institute of MIT and 
Harvard in collaboration with Daniel Faden (MEEI/MGH/HMS). Robert Ferris will oversee this 
process. Broad Genomics has a 25-year track record of leading the field of genomics 
(Human Genome Project, 1000 Genomes Project, The Cancer Genome Atlas, etc.) and is 
the largest producer of human genomic information in the world, producing genomic data at a 
rate of one 30X human whole genome every 12 minutes. The group has processed more 
than 1.5 million samples from more than 1400 groups in over 50 countries. Their success is 
well published. 

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5) Statistical Considerations 
Shu Li, PhD and Xiaosong Wang, MD, PhD will be responsible for the Bioinformatics 
analysis, while Daniel Normolle, PhD will be responsible for statistical analysis of the 
predictive model during the training stage (Objective 1). The ECOG Statistical Center will be 
responsible for the independent validation in Objective 2. 
Endpoints (outcomes): The primary objective of this project is to develop and then 
independently validate a predictive model to distinguish between HPV-mediated HNSCC 
patients who may receive de-intensified treatment versus patients who should undergo more 
intensive treatment, including trans-oral robotic surgery. All participants in ECOG 3311 
underwent such surgery, and then were classified into three strata; patients from the 
intermediate-risk strata were then randomized to two levels on de-intensification. These 
populations are represented by Arm D of ECOG 3311, versus Arms A-C. While the 
development of the model will be primarily the responsibility of the bioinformatics component 
at the University of Pittsburgh, the statistical validation of the model, including the estimation 
of the area under the receiver operating curve (AUC) using an independent validation set, will 
be responsibility of the ECOG Statistical Center.  
Case selection: For training, 100 cases from ECOG 3311 Arms A+B+C are requested; the 
University of Pittsburgh will supply 100 cases similar to those from ECOG 3311 Arm D. For 
validation, 70 cases from ECOG 3311 Arms A+B+C and 70 cases from Arm D are requested. 
We will request up to 90 cases of each category to obtain at least 70 with sufficient material 
for DNA/RNA extraction and sequencing. 
Statistical analysis plan for addressing the primary objectives: Please see Section 
9.f.d, Informatics for Objective 1, for the plan for the development of the predictive model. 
The statistical analysis plan applies to Objective 2, independent validation of the predictive 
model, which is to be carried out by the ECOG Statistical Center. The 140 ECOG 3311 
samples with sufficient material for sequencing will be assayed for somatic alterations and 
gene expression profiles in a similar fashion to the training set, and then submitted to the 
ECOG Statistical Center so that they can perform an independent validation of the trained 
model. They will generate an ROC curve and calculate the area under that curve with a 90% 
confidence interval to test the null hypothesis that AUC<0.60. 
Statistical justification for sample size 
Sample size estimate: Objective 1: 100 samples from Arms A+B+C; the University of 
Pittsburgh will provide 100 samples similar to those of Arm D. Objective 2: 140 samples; 70 
from Arm D and 70 from Arms A+B+C. 
Rationale for the sample size estimate: Objective 1: Systematic determination of required 
sample sizes for training of predictive models has proven intractable, but, based on our 
previous experience and the preliminary work described in Section 8.e, 200 samples should 
be adequate for an effective classifier. Objective 2: The method presented in Pepe [17] (pp. 
224-227) for determining the sample size for a test on AUC using binormal ROC curves was 
used, based on a one-sided null hypothesis test AUC<0.6 at α=0.05 and 80% power. We 
used the binormal parameters a0=0.36 and b0=1 for the reference AUC (0.6) and a1=0.81 
and b1=1 for the expected AUC (0.72). It was determined that we will achieve the stated 
power if the true AUC≥0.75 on independent samples, which we believe is achievable based 
on our preliminary analysis, where we observed AUC>0.9 on the training set. 

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