A Randomized Phase II Trial for Patients With p16 Positive, Non-Smoking Associated, Locoregionally Advanced Oropharyngeal Cancer
Phase: PHASE2
Conditions: Stage III Oropharyngeal Squamous Cell Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma, Stage IVB Oropharyngeal Squamous Cell Carcinoma, Stage IVC Oropharyngeal Squamous Cell Carcinoma, Tongue Carcinoma
Sponsor: NRG Oncology

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NRG ONCOLOGY 
 
NRG-HN002 
ClinicalTrials.gov NCT #: 02254278 
 
A RANDOMIZED PHASE II TRIAL FOR PATIENTS WITH p16 POSITIVE, 
NON-SMOKING ASSOCIATED, LOCOREGIONALLY ADVANCED  
OROPHARYNGEAL CANCER 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Cancer Research Group; and SWOG. 
 
Coordinating Center (04/29/2015) 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
Study Team (20-DEC-2017) 
Study Team continued on next page. 
 
Principal Investigator/Radiation Oncology 
Sue S. Yom, MD, PhD 
University of California, San Francisco 
1600 Divisadero St., Suite H-1031 
San Francisco, CA 94143 
415-353-7175/FAX 415-353-9883 
yoms@radonc.ucsf.edu 
Medical Oncology Co-Chair 
Maura Gillison, MD, PhD 
University of Texas MD  
Anderson Cancer Center 
1515 Holcombe, Unit 432 
Houston, Texas 77030 
713-792-6363/FAX 713-792-1220 
mgillison@mdanderson.org 
 
 
Radiation Oncology Co-Chair U.S. 
Jimmy J. Caudell, MD, PhD 
Moffitt Cancer Center/Univ. of South Florida 
12902 Magnolia Drive 
Tampa, FL 33612 
813-745-3547/FAX 813-745-7231 
Jimmy.Caudell@moffitt.org 
Medical Oncology Co-Chair 
Michael Gibson, MD, PhD  
Vanderbilt-Ingram Cancer Center 
2220 Pierce Avenue 
777 Preston Research Building 
Nashville, TN 37232 
615-936-8422 
mike.gibson.1@vanderbilt.edu 
 
 
Radiation Oncology Co-Chair Canada 
John Waldron, MD 
Princess Margaret Hospital 
610 University Avenue 
Toronto, ON M5G 2M9, Canada 
416-946-6522/FAX 416-946-2111 
John.Waldron@rmp.uhn.on.ca 
Medical Physics Co-Chair 
Ping Xia, PhD 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH 44195 
216-444-1938/FAX 216-444-8934 
xiap@ccf.org 

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NRG ONCOLOGY 
 
                                                      NRG-HN002 
 
A RANDOMIZED PHASE II TRIAL FOR PATIENTS WITH p16 POSITIVE, 
NON-SMOKING ASSOCIATED, LOCOREGIONALLY ADVANCED  
OROPHARYNGEAL CANCER 
 
Study Team Continued (20-DEC-2017) 
Translational Science Co-Chair 
Christine Chung, MD 
Moffitt Cancer Center 
12902 USF Magnolia Drive 
Tampa, FL 33612 
 813-745-4673/FAX 813-449-8210  
Christine.Chung@Moffitt.Org 
Quality of Life Co-Chair 
Minh Tam Truong, MD 
Boston Medical Center 
830 Harrison Ave., Moakley Bldg LL 238 
Boston, MA 02118 
617-638-7070/FAX 617-638-7037 
Minh-Tam.Truong@bmc.org 
 
 
Pathology Co-Chair 
Christina Kong, MD 
Stanford University 
300 Pasteur Dr., Room L235 
Stanford, CA 94305 
650-723-9016/FAX 650-725-6902 
ckong@stanford.edu 
Imaging Co-Chair 
Min Yao, MD  
University Hospitals Cleveland 
11100 Euclid Avenue 
Cleveland, OH 44106 
Phone/Fax numbers 
Min.Yao@UHhospitals.org 
 
 
Pathology Co-Chair 
Richard Jordan, DDS, PhD 
NRG Oncology Biospecimen Bank 
2340 Sutter Street, Rm S341 
San Francisco, CA 94115 
415-476-7864/FAX 415-476-5271 
richard.jordan@ucsf.edu 
Imaging Co-Chair 
Rathan Subramaniam, MD, PhD, MPH 
University of Texas Southwestern Medical 
Center 
Division of Nuclear Medicine and Molecular 
Imaging 
5323 Harry Hines Boulevard 
Dallas, TX 75039 
214-648-7770/FAX 214-648-7785 
rathan.subramaniam@UTsouthwestern.edu 
 
Swallowing Outcomes Co-Chair 
Jan S. Lewin, PhD 
University of Texas M.D. Anderson Cancer 
Center; Speech/Language Pathology 
Unit 1445, P. O. Box 301402 
Houston, TX 77030 
713-745-2309/FAX: 713-794-4662 
jlewin@mdanderson.org 
Senior Statistician 
Jonathan Harris, MS 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-3202/FAX 215-928-0153 
harrisj@nrgoncology.org 

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NRG ONCOLOGY 
 
NRG-HN002 
 
A RANDOMIZED PHASE II TRIAL FOR PATIENTS WITH p16 POSITIVE, 
NON-SMOKING ASSOCIATED, LOCOREGIONALLY ADVANCED  
OROPHARYNGEAL CANCER 
 
Study Team Continued (20-DEC-2017) 
Clincal Data Coordinators 
Vanita Patel, MS and  
Janelle Robinson  
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103  
215-574-3170 (Patel) 
215-717-0837 (Robinson) 
FAX: 215-940-8830 
patelv@nrgoncology.org  
robinsonj@nrgoncology.org 
RT Technical Details (Section 5.2)  
Nancy Linnemann, BS, RT(R)(T) and 
Marsha Radden, R.T.(R)(T) 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-717-0853 (Linnemann) 
215-717-2757 (Radden)  
nlinnemann@acr.org    
mradden@acr.org 
 
  
Protocol Administrator 
Karen McClellan, MSW 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-717-0851 
mcclellank@nrgoncology.org 
 
Head and Neck Cancer Committee Chair: Quynh-Thu Le, MD, FACR, FASTRO 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Cisplatin 
Commercial 
N/A 
Exempt 
N/A 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version Date 
Broadcast Date 
Amendment 3 
December 20, 2017 
N/A 
Closure with Amendment 2 
May 24, 2016 
February 7, 2017 
Amendment 2 
May 24, 2016 
June 20, 2016 
Amendment 1 
April 29, 2015 
June 22, 2015 

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Activation 
September 25, 2014 
October 27, 2014 
 
  
This protocol was designed and developed by NRG Oncology. It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  No 
other use or reproduction is authorized by NRG Oncology nor does NRG Oncology 
assume any responsibility for unauthorized use of this protocol. 

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NRG ONCOLOGY  
 
NRG-HN002  
 
A RANDOMIZED PHASE II TRIAL FOR PATIENTS WITH p16 POSITIVE, 
NON-SMOKING ASSOCIATED, LOCOREGIONALLY ADVANCED  
OROPHARYNGEAL CANCER 
 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION (20-
DEC-2017) 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
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 
enrolment sections of the 
protocol for instructions in 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ 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 
 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions. 
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’ web site 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 Lead Protocol Organization. 

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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.  
For detailed information on the regulatory and monitoring procedures for CTSU sites 
please review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU 
members’ web site   https://www.ctsu.org  > education and resources tab > CTSU Operations 
Information >CTSU Regulatory and Monitoring Policy 
The CTSU Website is located at https://www.ctsu.org. 
 

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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................9 
1. OBJECTIVES ............................................................................................................................10 
1.1 Primary Objective ........................................................................................................10 
1.2 Secondary Objectives...................................................................................................10 
2. BACKGROUND .......................................................................................................................10 
2.1       Rationale for Arm 1: Modestly Reduced Radiation Dose with Concurrent 
Chemotherapy (60 Gy/30 fractions/6 weeks, with weekly cisplatin at 
40/mg/m2) ..............................................................................................................12 
2.2       Rationale for Arm 1 Radiosensitizer Regimen: Weekly Cisplatin at 40 
mg/m2 .....................................................................................................................16 
2.3 
Rationale for Arm 2: Modestly Accelerated Reduced Dose Radiation 
Therapy (60 Gy/30 fractions/5 weeks) ..................................................................17 
2.4       Measuring Patient-Reported Outcomes (PROs) and Quality of Life (QOL) ........20 
2.5 
FDG-PET/CT Imaging as a Predictive Imaging Marker for  Locoregional 
Control and Progression-Free Survival ..................................................................29 
2.6 
Circulating HPV DNA as a Potential Marker for Relapse ....................................33 
2.7 
PI3K Pathway Activation and Its Associated Genomic Profile as 
Prognostic Biomarkers of HPV Related Oropharyngeal Cancer ...........................34 
3.  PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA ........................35 
3.1 
Patient Selection Guidelines ..................................................................................35 
3.2 
Eligibility Criteria ..................................................................................................36 
3.3 
Ineligibility Criteria ...............................................................................................38 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW UP ..................39 
5. TREATMENT PLAN/REGIMEN DESCRIPTION ..................................................................45 
5.1 
Chemotherapy ........................................................................................................45 
5.2 
Radiation Therapy ..................................................................................................46 
5.3 
Surgery ...................................................................................................................62 
5.4 
Imaging ..................................................................................................................63 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................63 
5.6 
Duration of Therapy ...............................................................................................64 
5.7 
Measurement of Response/Progression .................................................................64 
6. TREATMENT MODIFICATIONS/MANAGEMENT .............................................................65 
6.1 
Chemotherapy Dose Modifications .......................................................................65 
7. ADVERSE EVENTS REPORTING REQUIREMENTS .........................................................67 
7.1 
Adverse Events (AE) .............................................................................................67 
7.2 
Serious Adverse Events (SAEs).............................................................................67 
7.3 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) ............68 
7.4 
CTEP-AERS Expedited Reporting Requirements .................................................68 

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8.   REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ....................71 
8.1 Investigator Registration Requirements .......................................................................72 
8.2 
Site Registration Requirements.............................. Error! Bookmark not defined. 
8.3 
RT-Specific Pre-registration Requirements ...........................................................75 
8.4      Patient Enrollment ..................................................................................................77 
9. DRUG INFORMATION ...........................................................................................................78 
9.1 
Investigational Study Agent ...................................................................................78 
9.2 
Commercial Agent: Cisplatin ................................................................................78 
10. BIOMARKER, CORRELATIVE, AND SPECIAL studies ....................................................78 
10.1     Biomarkers .............................................................................................................78 
10.2  Quality of Life........................................................................................................83 
10.3  FDG-PET/CT Imaging ..........................................................................................87 
10.4  Determining the Extent of Dysphagia using the Modified Barium Swallow ........89 
11.      MODALITY REVIEWS ....................................................................................................90 
11.1 
Radiation Therapy Quality Assurance Reviews ....................................................90 
11.2 
Drug Quality Assurance Reviews ..........................................................................90 
12.      DATA AND RECORDS  ...................................................................................................90 
12.1    Data Management/Collection .................................................................................90 
12.2 
Summary of Data Submission ...............................................................................91 
12.3 
Digital Data Submission Requirements .................................................................94 
12.4 
Global Reporting/Monitoring ................................................................................94 
13. 
  STATISTICAL CONSIDERATIONS.............................................................................94 
13.1 
Study Design ..........................................................................................................94 
13.2 
Study Endpoints .....................................................................................................95 
13.3 
Primary Objectives Study Design ..........................................................................95 
13.4 
Study Monitoring of Primary Objectives ...............................................................96 
13.5 
Accrual Considerations ..........................................................................................97 
13.6 
Secondary/Correlative Elements ............................................................................97 
13.7 
Gender/Ethnicity/Race Distribution.....................................................................104 
REFERENCES ............................................................................................................................105 
APPENDIX I: DENTAL TOOTH COUNT AND DENTAL MANAGEMENT .......................118 
APPENDIX II: Instructions and Forms for the Modified Barium Swallow (MBS) Substudy  ...123 
 
 
 
 

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PATIENT POPULATION 
Oropharyngeal squamous cell carcinoma; p16 positive by 
immunohistochemistry;  ≤ 10 pack-year history of smoking; 
T1-T2, N1-N2b or T3, N0-N2b 
STRATIFICATION 
RT Planning: Unilateral vs. Bilateral 
RANDOMIZATION 
Arm 2 
60 Gy (2.0 Gy/fraction) in 5 weeks 
using 6 fractions per week 
REGISTRATION 
*Mandatory p16 analysis (central review) 
 
NRG ONCOLOGY  
 
NRG-HN002  
 
A RANDOMIZED PHASE II TRIAL FOR PATIENTS WITH p16 POSITIVE, NON-
SMOKING ASSOCIATED, LOCOREGIONALLY ADVANCED 
 OROPHARYNGEAL CANCER 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Patients must have positive immunohistochemical staining for p16, as confirmed by the NRG 
Oncology Biospecimen Bank, prior to randomization. 
Arm 1 
60 Gy (2.0 Gy/fraction ) in 6 
weeks+ Cisplatin, 40 mg/m2 
weekly for 6 weeks 

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1. OBJECTIVES 
1.1 Primary Objective 
To select the arm(s) achieving a 2-year progression-free survival rate of ≥ 85% without 
unacceptable swallowing toxicity at 1 year 
1.2 Secondary Objectives (5/24/16) 
 To determine patterns of failure (locoregional relapse versus distant) and survival 
(overall and progression-free) at 6 months and 2 years;  
 To determine acute toxicity profiles at the end of radiation therapy and at 1 and 6 
months;  
 To determine late toxicity profiles at 1 and 2 years; 
 To determine patient-reported swallowing outcomes at 6 months and 1 and 2 years; 
 To determine the predictive value of 12-14 week, post-treatment FDG-PET/CT for 
locoregional control and PFS at 2 years; 
 To determine the predictive value of blood and tissue biomarkers for disease 
outcomes at 2 years; 
 To determine swallowing recovery per videofluoroscopy imaging at 2 years. 
 
2. BACKGROUND 
The current standard of concurrent chemoradiation therapy produces excellent disease-free 
survival (DFS) and overall survival (OS) rates in oropharyngeal cancer. The cooperative 
groups, NRG Oncology and GORTEC, both have established the standard of care for stage 
III or IV oropharyngeal cancer to be a combination of 70 Gy of radiation therapy with 
concurrent platinum-based chemotherapy (Ang 2010, Bourhis 2012). However, these 
approaches also are associated with a high level of short- and long-term toxicities. One 
estimation is that the short-term toxicity burden, or T-score, stemming from definitive-intent 
radiation therapy can be increased by as much as 300% with the addition of the current 
standard of concurrent platinum-based chemotherapy (Trotti 2007). Long-term toxicities are 
likewise increased with intensive chemoradiation therapy (Machtay 2008). In human 
papilloma virus (HPV) positive oropharyngeal cancer patients, whose cancer-related 
outcomes often are excellent with a high probability of long-term survival, both short- and 
long-term toxicities are a growing concern among experienced head and neck oncologists. 
The philosophy of “de-escalation” or “de-intensification” has become an active topic of 
discussion in both academic and community head and neck treatment centers (Sturgis 2012).  
 
Furthermore, emerging data on dramatically improved outcomes in select populations of 
oropharyngeal cancer patients have called into question the global applicability and necessity 
of these standard chemoradiation paradigms. Oncogenic strains of HPV are associated with 
over 70% of oropharyngeal carcinomas (Chaturvedi 2011). Patients who develop HPV-
associated oropharyngeal cancer are more likely to be younger, free of competing or limiting 
medical comorbidities, and have a lesser history of smoking. While the ultimate impact of 
long-term toxicities is complex and difficult to gauge, the HPV positive population has a 
higher likelihood of a better outcome subsequent to therapy at a younger age, thus making 
the conditional relevance of late toxicities and quality-of-life outcomes a more compelling 
issue. Furthermore, the sensitivity of advanced-stage HPV positive oropharyngeal cancer to 

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both chemotherapy and radiation indicates that in some cases, the standard approach may 
result in over-treatment. For these reasons, the head and neck cancer community has voiced 
concerns about continued intensification of the chemoradiation approach, which may have 
value in other poor-risk head and neck cancer sites but which may constitute unnecessary 
additional treatment for good-prognosis HPV positive oropharyngeal cancer patients (Quon 
2013). 
 
The cyclin-dependent kinase inhibitor, p16, is overexpressed as a byproduct of HPV 
infection, via inactivation of the retinoblastoma protein (pRb) by HPV oncoprotein E7. In 
orpharyngeal cancers, p16 is an immunohistochemical biomarker that is strongly indicative 
of HPV-related etiology and has been associated with a positive clinical prognosis. p16 is 
now used as a biomarker of improved prognosis enabling selection for clinical trials and has 
become a stratification factor for all NRG Oncology head and neck cancer trials that include 
oropharyngeal cancer patients. A recent analysis of RTOG 0129 separated the prognosis for 
advanced-stage oropharyngeal cancer patients into distinct groups based on HPV status and 
smoking history. The presence of oncogenic HPV DNA and the presence of p16 in primary 
tumors showed a high level of agreement. The HPV positive group with a history of ≤10 
pack years of smoking had significantly improved outcomes on all fronts and was labeled to 
be at “low risk” for death. The 3-year rates of overall survival were 93.0% (95% CI, 88.3-
97.7) in the low-risk group; 70.8% (95% CI, 60.7-80.8) in the intermediate-risk group; and 
46.2% (95% CI, 34.7-57.7) in the high-risk group (Ang 2010). Similarly, the Princess 
Margaret Hospital published a retrospective review of their clinical experience with 
oropharyngeal cancer and identified a similar group called “low risk”; these patients were 
p16 positive, had ≤10 pack-year history of smoking, and were staged ≤ T3 and ≤ N2c. For 
these patients, the 3-year locoregional control rate was 95% (95% Cl, 91-97) and the 3-year 
distant control rate was 93% (95% Cl, 89-95). Based on very small numbers of patients, there 
was a suggestion of a lower distant control rate among minimal smokers with N2c nodal 
stage who did not receive concurrent chemotherapy. Importantly, there were no significant 
differences seen as a function of T stage in this group (O’Sullivan 2013). 
 
For p16 positive oropharyngeal cancer patients with ≤10 pack-year history of smoking, 
staged T1-2 N1-N2b M0 or T3 N0-N2b M0, NRG Oncology has recorded excellent 2-year 
PFS results. For this “low risk” population in RTOG 0129, the 2-year PFS is estimated at 
85.3% (95%CI, 76.4-94.1) and locoregional recurrence/progression as a first event is 
estimated at 8.2% (95%CI, 1.3-15.1) with competing events consisting of 3.3% experiencing 
distant metastasis or death as the first event. In RTOG 0522, the 2-year PFS is estimated at 
90.8% (95%CI, 83.7-97.8) and locoregional recurrence/progression as a first event is 
estimated at 4.6% (95%CI, 0-9.8), with competing events consisting of 4.6% experiencing 
distant metastasis or death as the first event (Zhang, personal communication, 2013). 
Therefore, this proposal seeks to define treatment paradigms for a newly emerging disease 
entity, in which high PFS rates are routinely achieved, corresponding to very low rates of 
locoregional failure. The emerging “low-risk” oropharyngeal cancer classification offers an 
opportunity to develop appropriate therapeutic paradigms for what is a recently identified and 
distinct subtype of HPV positive oropharyngeal cancer. It is worth noting that stage III/IV 
patients with stage T1N1-N3 and T2N1 disease were not eligible for RTOG 0129 or RTOG 
0522, but the proposed eligibility for this trial allows all stage III/IV patients with ≤ T3 and ≤ 

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N2b; thus, the PFS projections used in the proposed trial design are conservative, as our 
projections are estimated from previous trials that excluded the lowest-stage patients who 
will be included in this trial. 
 
2.1       Rationale for Arm 1: Modestly Reduced Radiation Dose with Concurrent 
Chemotherapy (60 Gy/30 fractions/6 weeks, with weekly cisplatin at 40/mg/m2) 
In the modern era, intensity-modulated radiation therapy (IMRT) given as a single-
modality treatment appears to produce high rates of locoregional control for the majority 
of low-volume oropharyngeal cancers. For example, RTOG 0022 was a prospective 
phase II feasibility trial designed to define standards for the use of IMRT in a multi-
institutional setting. The trial was designed for an oropharyngeal cancer population with a 
low to intermediate burden of disease; specific inclusion criteria allowed T1-2 N0-N1 M0 
oropharyngeal cancers (AJCC group stages I-III). The protocol specified a prescribed 
dose to the high-dose planning target volume of 66 Gy at 2.2 Gy/fraction in 30 fractions 
delivered over 6 weeks. Subclinical PTVs simultaneously received 54-60 Gy at 1.8-2.0 
Gy/fraction. Sixty-nine patients were accrued from 14 participating institutions. With a 
median follow up of 2.8 years, the 2-year locoregional failure rate was 9% (95% Cl, 2.1-
15.9), the DFS was 82% (95% Cl, 72.7-91.2), and the OS was 95.5% (95% CI, 90.6-
100.0). Notably, all cases of locoregional failure, metastasis, or second primary cancer 
occurred among patients identifiable as current or former smokers (54% of all enrolled), 
and no such events were seen among reported nonsmokers (defined as < 5 packs per 
lifetime, with a prevalence of 34% in this study) (Eisbruch 2010). 
 
Similarly, single-institution retrospective reviews indicate that the contemporary 
population of HPV-positive oropharyngeal cancer patients has retained excellent 
outcomes when treated with radiation therapy alone. These studies suffer from negative 
selection bias, in that many patients included in modern radiation-alone series were not 
considered appropriate candidates for the administration of concomitant chemotherapy 
and likely had other important competing risks for death. For example, a small 
retrospective series of 21 patients with HPV positive oropharyngeal cancer treated to a 
median dose of 70 Gy with a variety of techniques found 3-year overall survival, 
locoregional control, and distant metastasis-free survival rates of 82%, 88%, and 88%. 
Both instances of locoregional failure were associated with T4 primary oropharyngeal 
tumors. Among the 18 HPV-positive never-smokers, 3-year overall survival and 
locoregional control rates were 100% (Chen 2013). A larger series from Princess 
Margaret Hospital included 148 patients treated with radiation therapy alone for p16 
positive oropharyngeal cancers. A variety of conventional and altered fractionation 
radiation schemas were used, with total doses ranging from 60 to 64 to 70 Gy over 4 to 7 
weeks given in either daily or twice-daily schedules. Among all 148 HPV positive 
oropharyngeal cancer patients, the 3-year overall survival, cause-specific survival, local 
control and regional control rates were 81%, 88%, 93%, and 94%. Patients with HPV 
positive oropharyngeal cancer who had a ≤ 10 pack-year history of smoking (n = 37) had 
3-year OS, CSS, LC, and RC rates of 86%, 92%, 95% and 97%, with distant control rates 
of 92%. It was noted that there were important selection biases characterizing this series: 
20% of all 96 HPV+ oropharyngeal cancer patients who received RT alone in this series 
were elderly (over 70 years of age) and of those having an age under 70 years, 39% were 

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deemed medically unsuitable for concurrent chemoradiation therapy (O’Sullivan 2012). 
 
Given the promising results obtained with a variety of single-modality radiation therapy 
approaches, this arm tests the proposition that in combination with a systemic 
radiosensitizer, the standard doses of a highly effective, conventionally fractionated 
radiation therapy course may be modestly reduced. Radiobiological investigations 
indicate that the contribution of concurrent chemotherapy across a variety of 
chemoradiation trials may be considered equivalent to approximately 8.0-9.0 Gy10 of 
biologic effective dose (BED) (Lee 2009). One interesting study used the biologic 
effective dose equivalents from RTOG 90-03 to compare the gains achieved in that trial 
using altered fractionation against those of 14 prospective trials utilizing 
chemoradiotherapy. The mean additional BED contribution from concurrent 
chemotherapy may be at least 8.8 Gy10, or the equivalent of 3.6 fractions of 2 Gy 
translated back into total dose prescribed in standard fractionation (Kasibhatla 2007; 
Fowler 2008). Thus, if an effective concurrent radiosensitizer is given, the risks of 
reducing the radiation dose may be mitigated. Hence, Arm 1 in comparison to Arm 2 
provides the opportunity to investigate whether systemic radiosensitization provides any 
advantage over a radiation-alone altered fractionation approach. 
 
Furthermore, for these HPV positive oropharyngeal cancer patients, single institutions, 
small informal collaborations (2-3 centers), and one formal cooperative group trial have 
begun to explore “de-escalation” of radiation therapy dose in combination with a variety 
of concurrent systemic therapies. The earliest results have been reported by ECOG, 
which completed accrual to E1308, a phase II study in HPV/p16 positive, stage III-IVA 
oropharyngeal cancer patients examining the effect of a triple-agent induction regimen of 
paclitaxel, cisplatin, and cetuximab for 3 cycles followed by radiation therapy combined 
with weekly concurrent cetuximab. The radiation dose was prescribed at 69.3 Gy in 33 
fractions after a clinical assessment of partial response or stable disease, versus a de-
escalation of the dose to 54 Gy in 27 fractions for patients achieving a complete clinical 
response. For uninvolved nodes, the elective radiation dose was 51.3 Gy in 27 fractions. 
The primary endpoint was a 2-year PFS rate of ≥ 85%. Ninety patients were accrued, of 
whom 80 patients were evaluable; of these, 62 patients (78%, exceeding an expected rate 
of 69%) achieved complete clinical response and were treated on the reduced-dose 
radiation arm to 54 Gy. At a median follow up of 16.2 months, the preliminary result for 
1-year PFS (n=62) in the low-dose arm was 91% (95% CI, 80-96). One-year PFS for the 
15 patients treated to standard radiation dose was estimated at 87% (B. Burtness, personal 
communication). 
 
The ECOG trial used induction chemotherapy, which this trial does not. In addition, the 
doses used in the ECOG trial do not correspond to the proposed dose for this arm of 60 
Gy. However, the ECOG trial is important in that a detailed breakdown of the patient 
subsets in the ECOG reduced dose radiation arm lends further prospectively obtained 
data to support the retrospective evidence forming the basis of the eligibility criteria 
proposed for this trial. In E1308, for patients with T1-T3 stage, the 1-year PFS was 92% 
(95% CI, 80-97) whereas for T4, the result was 86% (95% CI, 33-98). In patients with 
N0-N2b stage, the 1-year PFS was 92% (95% CI, 78-97) whereas for N2c, it was 88% 

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(95% CI, 61-97). For patients with ≤ 10 pack-years of smoking, the 1-year PFS was 97% 
(95% CI, 83-99.6) whereas for patients with more smoking history, the result was 84% 
(95% CI, 57-94). Recently confirmatory 2-year PFS results were issued in preliminary 
form, reporting 96% PFS for patients with <10 pack-year history and T1-3 N0-N2b stage 
who were treated on the low-dose arm (Cmelak 2014). For this reason, the early results of 
E1308 support the hypothesis that our trial’s proposed selection criteria are likely to 
identify a group of patients able to achieve excellent PFS with reduced-intensity 
treatment approaches. 
 
Several small prospective trials are now accruing using various combinations of 
reductions in radiation therapy dose, substitutions of systemic therapy for radiation 
therapy, and/or novel combinations of systemic and radiation therapy in an attempt to 
maintain high locoregional control rates with reduced toxicity (Trotti and Yom, 
unpublished data summary, 2013; see table below). It should be noted that many of these 
trials were designed prior to the release of preliminary data at ASCO 2012 from 2 
important clinical trials. These 2 trials, DeCIDE and PARADIGM, were phase III trials 
testing the benefit of adding induction chemotherapy to a standard chemoradiation 
platform; neither demonstrated any additional benefits in either locoregional control or 
OS (Cohen 2012; Haddad 2012).  
 
In the PARADIGM trial, patients with stage III/IV squamous cell carcinomas of the oral 
cavity, oropharynx, larynx, or hypopharynx were eligible, but 55% of those enrolled had 
oropharyngeal cancer. By the time of the early closure of the PARADIGM trial due to 
slow accrual, 145 patients had been randomized to either induction 
docetaxel/cisplatin/5FU chemotherapy followed by radiation concurrent with either 
carboplatin or docetaxel, versus upfront cisplatin-radiation. All patients had radiation 
given to 70 Gy in 2 Gy fractions. At a median follow up of 49 months, the 3-year overall 
survival was 73% in the arm consisting of induction chemotherapy followed by 
chemoradiotherapy, versus 78% in the chemoradiotherapy group. No advantage was seen 
with the use of induction chemotherapy for patients with oropharyngeal cancer or in the 
subgroups with advanced nodal stages of N2b/N2c or N3 (Haddad 2013). 
 
No further large-scale, head-to-head trials of induction chemotherapy followed by 
concurrent chemoradiation versus concurrent chemoradiation are known to have been 
planned at this time. As both the DeCIDE and PARADIGM trials included a large 
majority of oropharyngeal cancer patients, further exploration of induction chemotherapy 
for this disease site has been deferred until the emergence of clearer indications for its 
application or until the mature results of E1308 are available. 
 

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Current Phase II Protocols for HPV Positive Oropharyngeal Cancer Patients 
Institution 
Name 
Systemic 
Agent 
Dose to Gross 
Disease 
Target 
Accrual 
Activation 
Date 
Planned 
Closure 
Primary 
Endpoint 
Univ. North 
Carolina, 
Chapel Hill 
Concurrent 
cisplatin 30 
mg/m2 weekly 
60 Gy 
40 
November 
2011 
January 
2016 
Pathologic 
response at 3 
months 
John 
Hopkins 
Univ. 
Concurrent 
Cisplatin 40 
mg/m2 weekly 
63 Gy to 
pharyngeal 
constrictors, 
larynx, parotids, 
mandible, and 
masticatory 
muscles +8 mm 
expansion, 70 
Gy to remainder 
of PTV 
60 
January 
2010 
February 
2015 
Local-
regional 
control ≥ 
80%, late 
toxicity at 2 
years 
Long Island 
Jewish 
Hosp. 
Induction TPF 
x 3, then +/- 
concurrent 
chemotherapy 
Responders: 70 
Gy; 
non-responders: 
70 Gy (with 
concurrent 
chemotherapy) 
50 
August 
2010 
January 
2013; no 
results 
reported 
Response at 3 
months 
Dana Farber 
Cancer 
Institute 
Induction TPF 
x 3, then 
concurrent 
chemotherapy 
Responders 
receive "reduced 
dose" 
50 
September 
2010 
September 
2015 
Local-
regional 
control at 2 
and 5 years 
ECOG 1308 Induction TP-
cetuximab x 3, 
then 
concurrent 
chemotherapy 
Responders: 54 
Gy; non-
responders: 70 
Gy  
90 
March 
2010 
Closed 
August 
2011; early 
results 
reported 
PFS at 2 
years in 54 
Gy group 
Memorial 
Sloan 
Kettering 
“standard 
chemotherapy
” (concurrent 
regimens) 
70 Gy to 
primary, 60 Gy 
to nodes 
followed by neck
dissection 
100 
HPV+,  
50 HPV- 
June 2004 
June 2013; 
no final 
results 
reported 
Feasibility of 
18F-MISO 
PET to detect 
hypoxia, 3-
month neck 
control ≥ 
80% 
Univ. of 
California, 
Davis 
Induction 
carboplatin-
paclitaxel x 2, 
then 
concurrent 
paclitaxel 
Complete 
response: 54 Gy;
non-responders: 
60 Gy  
50 
October 
2012 
October 
2014 
PFS at 2 
years 
 
In support of reduced total radiation doses for HPV-associated malignancy, additional 
consideration can be given to the experience of locally advanced cervical and anal 
squamous cell carcinomas, both entities etiologically related to oncogenic HPV strains 

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in a manner similar to “low risk” HPV positive oropharyngeal squamous cell carcinoma. 
Anal and cervical squamous cell carcinomas share a standard treatment of radiation or 
chemoradiation, frequently cisplatin-based. Typical goals of protocol-based radiotherapy 
treatments for these cancer types are to achieve a radiation dose equivalent to gross 
disease of approximately 54-60 Gy in conventional fractionation, in combination with 
systemic radiosensitizing chemotherapy (Ajani 2008). For cervical cancer, weekly 
cisplatin chemotherapy at 40 mg/m2 is established as a highly effective concurrent 
platform that shows activity in concert with radiation therapy (Lanciano 2005, Kim 
2008) and weekly cisplatin, due to its lesser toxicities, has for the most part replaced 5-
FU-based regimens. While dosing to cervical cancers may incorporate brachytherapy 
implant to achieve the aforementioned dose goals, anal cancers are exclusively treated 
with external beam radiation therapy. For the earliest stages of anal cancer, a minimum 
dose of 45 Gy is given, but doses of 50.4-55.8 Gy are commonly recommended for 
bulky disease. Even for the most advanced cases of anal cancer, doses of 55.8-59.4 Gy 
are generally prescribed (Poggi 2010). Therefore, there is precedent among other HPV 
associated cancers to be treated to lower radiotherapy doses than typically used in the 
head and neck cancer community. 
 
Reduced-total dose radiation therapy is expected to diminish both acute and long-term 
toxicity and if similar survival outcomes are preserved, these efforts will rapidly 
redefine the landscape of oropharyngeal cancer clinical investigations. Therefore, in 
order to remain at the forefront of clinical research initiatives in HPV-associated 
oropharyngeal cancer, the study investigators propose that these principles of “de-
escalation” be incorporated into clinical investigations. 
 
2.2       Rationale for Arm 1 Radiosensitizer Regimen: Weekly Cisplatin at 40 mg/m2 
Cisplatin is an established, effective radiosensitizing agent in head and neck cancer 
therapy. Cisplatin has been established as the concurrent systemic treatment of choice in 
multiple head and neck cancer protocols (Adelstein 2008). It also is the preferred 
systemic agent of choice in the NCCN guidelines. However, bolus cisplatin doses at 100 
mg/m2 have been of a subject of concern due to the known toxicities, particularly in terms 
of emetogenesis, renal impairment, blood counts, and ototoxicity. NRG Oncology head 
and neck cancer trials have traditionally employed 2-3 cycles of bolus cisplatin given 
every 21 days. For example, RTOG 0129 used cisplatin given for 3 cycles at 100 mg/m2, 
whereas RTOG 0522 used a similar regimen but reduced the number of cisplatin cycles 
to 2. RTOG 1016 uses 2 bolus cycles of cisplatin.  
Weekly cisplatin has been investigated as an alternative to cisplatin cycles given at 100 
mg/m2 with a lower overall toxicity profile. For nasopharyngeal cancer, where the burden 
of toxicity from systemic chemotherapy administration is particularly high, weekly 
cisplatin at 40 mg/m2 is well-established in practice as a concurrent radiosensitizing drug 
and has demonstrated a survival advantage over radiotherapy alone, while producing 
lower toxicities than the standard schedule (Chan 2002; Chen 2008; Qi 2011). In head 
and neck cancer more generally, a French randomized trial showed that patients treated 
with radiation plus weekly cisplatin at a fixed weekly dose of 50 mg (roughly equivalent 
to 30 mg/m2/week) had superior outcomes compared to those receiving radiation alone 
(Bachaud 1996). Another positive randomized trial combined cisplatin, 6 mg/m2/day 

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(equivalent to 30 mg/m2 per week) with radiation versus radiation alone (Jeremic 2004). 
However, an older ECOG trial (Quon 2011) used 20 mg/m2/week of cisplatin; the 
reduced efficacy seen in this study may be attributable to the lower cumulative dose 
achieved. 
 
A review of combined modality trials indicated that cisplatin schedules delivering a 
cumulative dose of about 200 mg/m2 concomitantly during radiation were associated with 
positive outcomes (Ang 2004); this principle may explain the radiosensitizing efficacy 
seen with cisplatin doses fractionated in a multitude of ways (daily dosing, weekly 
dosing, fractionated over a couple of days to a week for each cycle). Based on these 
various lines of evidence, weekly cisplatin at a dose of 40 mg/m2 per week is used as a 
concurrent regimen in NRG Oncology trial designs going forward in nasopharyngeal 
cancer (NRG-HN001) and high-risk postoperative head and neck cancer (RTOG 1216). 
For the purposes of this trial, we are therefore choosing weekly cisplatin administration at 
40 mg/m2, in order to maintain excellent cancer control and further reduce toxicity in this 
arm of the phase II trial and to be consistent with the emerging generation of NRG 
Oncology trials using weekly cisplatin. 
 
2.3 
Rationale for Arm 2: Modestly Accelerated Reduced Dose Radiation Therapy (60 
Gy/30 fractions/5 weeks) 
In major head and neck cancer trials over the past decade, modestly accelerated radiation 
therapy has been shown to be tolerable, even in the context of concurrent systemic 
therapy delivery. For example, RTOG 0129 tested a randomization to either a standard 
versus concomitant boost radiation therapy regimen in combination with cisplatin for 3 
versus 2 cycles, respectively; while no advantage was seen from the radiotherapy 
acceleration, a reduction in systemic radiosensitizer was shown to be possible with 
accelerated fractionation (Ang 2010). As a result, subsequent head and neck cancer trials, 
RTOG 0522 and RTOG 1016, have utilized a standard arm consisting of a modestly 
accelerated regimen of 70 Gy over 6 weeks delivered with 2 cycles of cisplatin. In both 
of these trials, patients were treated with 6 fractions of radiation therapy per week, 
utilizing a minimum 6-hour interfraction interval to assure normal tissue repair between 
fractions. Thus, a modest acceleration of the radiation regimen has been accepted as a 
feature of treatment for patients enrolled on NRG Oncology trials over the past decade. 
 
Radiation alone is already considered a standard treatment option for all patients with low 
and low-intermediate stages of oropharyngeal cancer. For T1-2, N0 oropharyngeal 
cancers, the NCCN guidelines support a treatment plan of radiation therapy alone to 
doses of 66-74 Gy, given in mildly accelerated or conventional fractionation at the 
standard evidence level of 2A. The addition of systemic radiosensitizer is only considered 
for T2N1M0 cancers and set at a lower evidence level of 2B. One should note that these 
treatment recommendations were found to be effective and installed as standard treatment 
recommendations in an era when HPV status was not known to be a critical prognostic 
factor and thus, these are considered to be standard recommendations independent of a 
patient’s HPV status. 
 
The University of Texas – M.D. Anderson Cancer Center has frequently utilized 66 Gy in 

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30 fractions over 6 weeks as a standard treatment for “small primary” (T1-T2) 
oropharyngeal cancers; patients who receive concurrent chemoradiation are typically 
prescribed approximately 70 Gy. Recently, information was shared from the MD 
Anderson institutional database with the study investigators. For 214 patients with stage 
T1-T2 oropharyngeal cancer with any degree of nodal involvement (i.e. AJCC stage III-
IVB) who had ≤ 10 pack-year history of smoking and who were treated with radiation 
therapy alone, the 2-year locoregional control rate was 95.3% and the OS rate was 90.2%. 
For 109 patients with these same characteristics treated with radiation therapy and some 
form of concurrent systemic therapy (with or without induction chemotherapy), the 2-
year locoregional control and OS rates were 92.7% and 91.8% (Garden, personal 
communication, 2012). While there were undoubtedly strong selection biases in assigning 
patients to radiation therapy alone versus concurrent chemoradiotherapy, these results 
lend additional support to the hypothesis that the use of systemic radiosensitizer may not 
be necessary to achieve excellent results in low-risk HPV positive oropharyngeal cancer 
patients. 
 
For this trial, there is interest in pursuing radiation therapy alone as a viable treatment 
option to offer to selected “low risk” oropharyngeal cancer patients. Thus, the proposed 
arm is designed to explore a further modest de-escalation using radiation therapy alone, 
without the addition of a systemic radiosensitizer. This fractionation schema would be 
given in a manner similar to those delivered in previous NRG Oncology trials, in which 6 
fractions would be delivered each week in order to produce a modest acceleration of the 
treatment course. These recent head and neck cancer trials have successfully delivered 70 
Gy in this modestly accelerated manner at 6 fractions per week, in conjunction with 
systemic cisplatin chemotherapy; and in one arm of RTOG 0522, this modest 
acceleration was accompanied by not only concurrent cisplatin but concurrent cetuximab 
administration. Therefore, it is expected that modestly accelerated radiation therapy alone 
given in this way to a total dose of 60 Gy should be very well tolerated. 
 
Substantial total dose reduction has been previously implemented in Europe using altered 
fractionation schemas without apparent losses in locoregional control. For example, from 
1966-1975, one prospectively randomized study including 734 patients with laryngeal 
and hypopharyngeal cancers demonstrated that a total dose reduction of 18-22% could be 
achieved using combinations of shortened treatment time and hypofractionation with no 
differences in laryngectomy-free survival or OS at 10-year follow up (Wiernik 1990). In 
the early 1990s, the Medical Research Council ran a multicenter trial involving 11 centers 
and 918 patients in which patients with head and neck cancer from stages II-IVB were 
randomized to either 66 Gy in 33 fractions given over 6.5 weeks or a regimen of 54 Gy in 
36 fractions given at 1.5 Gy/fraction 3 times daily over 12 consecutive days (CHART). 
At a follow-up time of over 6 years, no differences were seen between the 2 arms in 
locoregional control, disease-free interval, freedom from metastasis, or survival, and 10-
year follow up likewise showed no difference in survival endpoints (Dische 1997; 
Saunders 2010). Thus, the principle of using accelerated schedule to decrease the total 
radiation dose has been clinically validated as effective. 

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However, late toxicities have been a concern in such aggressively shortened treatment 
courses, and most investigators favor a more moderate approach to treatment 
acceleration. Most recently, NRG Oncology has adopted an acceleration schema modeled 
after that undertaken in the Danish Head and Neck Cancer Study Group (DAHANCA) 
using 6 fractions of standard radiation given per week. In the DAHANCA 6&7 
randomized trial, 1476 patients with stage I-IV squamous cell carcinomas of the oral 
cavity, pharynx, or larynx receiving the hypoxic radiosensitizer nimorazole were assigned 
to either 5 or 6 fractions per week, to a total radiotherapy dose of 66-68 Gy in 33-34 
fractions (except for T1 larynx cancer which was assigned to a lower dose). This trial 
showed improved 5-year locoregional control and DFS, with only transient acute 
morbidity related to the acceleration (Overgaard 2003). No significant differences were 
seen in late endpoints at a median follow-up time of over 4 years (Mortensen 2012). A 
report on this trial analyzing the effect of p16 expression found improvements in 
locoregional control, disease-specific survival, and OS associated with p16 positivity, as 
well improvements in locoregional control and disease-specific survival from accelerated 
radiation therapy among both p16 positive and p16 negative tumor groups. Among p16 
positive patients, the hazard ratios for the 6 fractions per week regimen as compared to 
the standard were 0.73 [0.59-0.92] and 0.43 [0.22-0.82]) for 5-year disease-specific 
survival and OS, respectively (Lassen 2011). The conclusion of the authors was that the 
use of a moderately accelerated radiotherapy regimen in this context specifically was 
advantageous for HPV/p16 positive head and neck squamous carcinoma. 
 
Clinically-based precedent exists for reduced-total dose radiation at 60 Gy delivered over 
a period of 5 weeks. In the Princess Margaret Hospital’s series of 449 oropharyngeal 
cancer patients treated with radiation therapy alone using a variety of schedules ranging 
from 60-70 Gy over 4-7 weeks, the most commonly used schedule was 60 Gy in 25 
fractions given at 2.4 Gy per fraction over 5 weeks. Of note, among 148 p16 positive 
oropharyngeal cancer patients in this series, 41% had T3-T4 tumors and 87% had stage 
grouping of III-IVB. Patients with p16 positive oropharyngeal cancer who had a ≤ 10 
pack-year history of smoking (n = 37) had 3-year overall survival, cause-specific 
survival, local control, and regional control rates of 86%, 92%, 95% and 97%, with 
distant control rates of 92% (O’Sullivan 2012). Despite these excellent overall results, 
there were negative predictive factors identified among the p16 positive patients; T4 
stage was an adverse predictor for cause-specific survival, and 13/24 patients with p16 
positive N3 disease died. These findings, similar to those consistently seen in other 
retrospective and prospective series, further confirm the decision to exclude these patients 
with a very high burden of disease from de-intensified approaches. 
 
On this basis, for patients where excellent outcomes are most likely using reduced-dose 
approaches, the study investigators have chosen a schedule of 6 fractions per week based 
on its efficacy at producing improvements in tumor control, specifically in p16 positive 
patients (based on evidence from the DAHANCA experience), without intensifying the 
late effects of treatment. It is hypothesized that shortening of the total treatment time to 5 
weeks, similar to the treatment package time used in the Canadian experience, will 

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compensate for a modest reduction of the total dose.  
 
In summary, modestly accelerated radiation therapy using an IMRT technique has been 
shown to be feasible, safe, and able to be properly delivered within single institutions and 
the national clinical trial setting as an effective single modality treatment for “low-risk” 
oropharyngeal cancer. In this highly selected, good-prognosis population, DFS and OS 
results with modestly accelerated IMRT alone appear to be comparable to those achieved 
with chemoradiation therapy. Thus, Arm 2 offers a validated,  de-escalated treatment for 
selected “low-risk” oropharyngeal cancer patients. 
 
As assistance in assessing the proposed efficacy of these regimens, we have provided a 
table of relative biologic effective dose (BED) differences between common standard 
schemas and this trial’s proposed arms, which are spread over a fairly small range of 
values (John Murnane, personal communication, 2013). 
 
Relative BED for Standard and Proposed Radiation Schedules 
 
Fractionation 
Acute BED 
Late BED 
70 Gy in 35 fx in 7 weeks + 
cisplatin 
84.0 Gy10 + additional 
cisplatin effects 
116.7 Gy3 + additional 
cisplatin effects 
66 Gy in 30 fx in 6 weeks (RTOG 
0022) 
80.5 Gy10 
114.4 Gy3 
60 Gy in 25 fx in 5 weeks (Princess 
Margaret accelerated schedule) 
74.4 Gy10 
108 Gy3 
ARM 1: 60 Gy in 30 fx in 6 weeks 
+ cisplatin 
72 Gy10 + additional 
cisplatin effects 
100 Gy3 + additional 
cisplatin effects 
ARM 2: 60 Gy in 30 fx in 5 weeks 
75.2 Gy10 
100 Gy3 
*The tumoricidal acute effect of Arm 2 is expected to be similar to that of the Canadian 
experience but with less late effect BED as compared to hypofractionated regimens. 
 
2.4       Measuring Patient-Reported Outcomes (PROs) and Quality of Life (QOL)  (20-
DEC-2017) 
The purpose of collecting PRO/QOL data in this phase II study is to evaluate the potential 
reduction in the burden of toxicity from the patient’s perspective as compared between 2 
different methods of treatment de-intensification, either using reduced-dose radiation 
with weekly cisplatin, or modestly accelerated, reduced-dose radiation alone. These 
findings will inform the selection of the least toxic arm from the patient’s perspective 
with respect to achieving a better swallowing related QOL outcome, while maintaining at 
least 85% PFS. The hypothesis is that among the 2 approaches in this trial, swallowing-
related QOL will be superior in the radiation-alone arm compared to the chemoradiation 

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arm at 1 year. The specific aim is to determine patient reported long-term swallowing 
outcomes  (≥ 6 months to 2 years) in p16 positive oropharyngeal carcinoma patients 
treated with a reduced total dose radiation therapy approach +/- concurrent chemotherapy. 
 
Participation in the PRO component of the MD Anderson Dysphagia Inventory-Head and 
Neck (MDADI-HN) instrument is mandatory in this study. To complete the MDADI, the 
patient must comprehend verbal English or one of the validated written translated 
versions of the MDADI. All protocol-eligible patients will be asked to participate in the 
additional, optional PRO component of this study which is comprised by the University 
of Washington QOL questionnaire. In order to participate in this PRO assessment, 
patients must be able to comprehend verbal English.  
 
The selection of the primary PRO instrument (MDADI) has been limited to maintain a 
primary focus on the evaluation of late dysphagia (defined as ≥ 6 months to 2 years). 
Sample size will adjust for patients at Canadian centers who are unable to complete the 
MDADI in English  (estimated at 12% based on prior enrollment to NRG Oncology head 
and neck cancer trials). Patients who are blind or illiterate may have questions and 
responses read verbatim by the investigator or research associate; non-validated 
translation of instruments is not allowed. To assess swallowing function, the MDADI (see 
Section 11.2 for details of this assessment) will be administered in each arm prior to the 
start of treatment (baseline), at completion of radiation therapy, and then at 6, 12 and 24 
months from the end of radiation. We also will compare patient-reported swallowing 
outcome to objective clinical measures using CTCAE, v. 4 clinician-reported toxicity and 
documented gastrostomy tube retention rates at each follow-up visit. Additionally, 
baseline performance status and co-morbidities will be collected by chart extraction for 
patients in each treatment arm using the Performance Status Scale for Head and Neck 
Cancer Patients (PSS-HN) and the Charlson Comorbidity Index (CCI). The MDADI 
constitutes the primary tool being used for this assessment; the PSS-HN, CTCAE, v. 4 
graded toxicities, and CCI are exploratory, secondary tools. 
 
The MDADI as Primary PRO/QOL Instrument 
The MDADI has been validated in head and neck cancer patients in a single institution 
series (Chen 2001). Reliability (internal consistency reliability) was established with the 
overall Cronbach α coefficient = 0.96, suggesting that each item of the MDADI addresses 
the same concept. Stability was tested with test and retest reliability coefficients of the 
subscales ranging from 0.69-0.88 (global, 0.69; emotional, 0.88; functional, 0.88 and 
physical, 0.86). Spearman correlation coefficients between MDADI and Short Form 36 
(SF-36) demonstrated construct validity. The MDADI also was able to detect differences 
in groups of patients with head and neck cancer who were expected to be functioning at 
different levels and also by head and neck site and pathological findings (Chen 2001). 
MDADI scores also discriminate clinically meaningful differences in swallowing 
performance among aspirators and non-aspirators, gastrostomy dependent, and 
gastrostomy-free patients, and various levels of oral intake (Hutcheson 2015). 
 
To be considered an acceptable arm in this trial, the MDADI results for the “superior” 
arm must be clinically acceptable (mean total MDADI score at 1 year ≥ 60). It is 

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expected that this baseline of clinical acceptability should be met by one or both arms, 
but the ability to meet this basic criterion has been set as a required part of the primary 
endpoint for this trial. Furthermore, to compare between arms, the primary QOL endpoint 
will measure the mean individual change in total MDADI score at 1 year from baseline in 
each arm. One of the arms will be deemed inferior to the other only if there is a mean 
change score of ≥ 5 points from baseline for that arm and there is a ≥ 5 point difference 
between the 2 arms that is statistically significant. The minimum important difference 
(MID) is defined as the smallest difference in score in the domain of interest that patients 
perceive as important, that would lead to consider a change in the patient’s management  
(King 2011). The MID for the MDADI has not been previously published; however, an 
important methodological proposal is that the MID should be within 5 to 10% of the 
instrument range (Ringash 2007). Since the MDADI score ranges from 0-100, a change 
of 5% (5 points) in the score is considered meaningful.  
 
Secondary analyses will evaluate the percentage of patients in each arm with poor 
swallowing QOL, defined as an individual patient MDADI score of ≤ 60 at 1 year. 
Secondary analyses also will evaluate poor swallowing QOL based on the subscale scores 
of the MDADI inventory, particularly the physical and functional subscales at 1 year.   
 
 
Oropharyngeal dysphagia after chemoradiation or radiation alone can have a significant 
impact on QOL. Multiple factors are thought to contribute to the severity of 
oropharyngeal dysphagia, including multimodality therapy (surgery, radiation, 
chemotherapy), total radiation dose, and dosimetry to organs at risk (OARs), including 
the larynx, oral cavity, and pharyngeal constrictors (Eisbruch 2002, Eisbruch 2011, 
Caudell 2010), as well as intrinsic patient radiosensitivity and susceptibility to late 
fibrosis. These factors will be addressed in this trial by the reduction of radiation dose, 
with improvements in dosimetric outcomes, as well as by the removal of chemotherapy 
from 1 arm. Therefore, this trial has high potential to improve post-treatment dysphagia 
and as a result, patient-reported swallowing related QOL. 
 
Correlation of MDADI to Measures of Dysphagia 
 
Bhide, et al. (2009) assessed dose volume histogram (DVH) data for superior, middle, 
and inferior constrictors in 37 head and neck cancer patients undergoing IMRT and 
correlated these to NRG Oncology-graded dysphagia at 1 year and MDADI scores in 
patients undergoing induction chemotherapy followed by high-dose cisplatin 
chemoradiation. While this study did not find a statistically a significant correlation 
between pharyngeal constrictor dose and objective measurements of dysphagia and 
MDADI parameters, only 1 time point was measured at 1 year post-treatment, and 
baseline pre-treatment QOL assessments were not obtained. Lack of correlation may have 
been due to small patient numbers and the possible confounding effects of induction 
chemotherapy and high dose cisplatin. In the patients treated with a primary 
chemoradiation approach, Bhide, et al. reported a 1-year median MDADI total score of 
74 (range, 24-100), global 4/5 or 80, PT of 27 (range, 4-40) or 67.5, ET of 23 (range, 8-
30) or 76.7, and FT of 20 (range, 5-25) or 80 (latter when scored out of 100). It also was 
noted that there was a significant correlation between observer-rated, RTOG graded 
dysphagia and all the MDADI parameters. Hence, MDADI was a valid endpoint to 

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measure swallowing toxicity from the patient’s perspective. Levendag, et al. (2007) also 
studied the relationship between pharyngeal constrictor dose, observer-reported 
dysphagia, and patient-reported swallowing QOL using the MDADI, in an oropharyngeal 
cancer population treated with chemoradiation using both IMRT and 3DCRT. A cross-
sectional survey was taken at a mean follow up of 18 months; the QOL response rate was 
88%. When these authors compared chart-reviewed dysphagia rates corresponding to 
NRG Oncology grade 3 and 4 dysphagia (in 23% of patients) to MDADI scores, a total 
MDADI score of ≤ 50 was found in 26%, and a significant correlation was found 
between observer-rated grade 3 and 4 dysphagia and MDADI total score.  
  
 
Use of MDADI to Determine Poor Swallowing QOL Outcome 
While the MDADI has been most extensively used in head and neck cancer patients 
treated with surgery, limited baseline and longitudinal data for the MDADI exist to define 
an acceptable level of swallowing QOL outcome in patients treated with either surgery or 
chemoradiation therapy. In a cross-sectional study of patients with stage III/IV head and 
neck squamous cell carcinoma (HNSCC) (Gillespie 2004), the MDADI-HN was 
administered to patients at least 12 months after treatment. Patients receiving primary 
chemoradiation for oropharyngeal primary tumors demonstrated significantly better 
scores on the emotional (p=0.03) and functional (p=0.02) subscales of the MDADI than 
patients receiving surgery and post-operative radiation. However, in this study, surgical 
techniques varied including more extensive surgery with some patients receiving wide 
excision with reconstruction involving skin graft, radial forearm free flap, or levator 
scapular flap. Mean subscale MDADI scores for the group receiving surgery with 
postoperative radiation ranged from 52.5 to 62.5, while the primary chemoradiation 
group was 64.5 to 86.4. In more recent surgical series, with emerging endoscopic 
transoral surgery approaches, improved swallowing outcomes have been observed.  Data 
from prospective single institutional series (Sinclair 2011) suggest that patients 
undergoing transoral robotic surgery (TORS) for T1 and T2 oropharyngeal squamous cell 
carcinomas have an initial decrease in mean scores on the MDADI-HN in the immediate 
postoperative period when compared to baseline pre-operative scores, although 
increasing improvement was observed over time. Additionally, global and physical 
subscales were most affected in the immediate post-operative period with recovery of 
scores observed at last follow up. Factors which predicted poorer physical MDADI 
outcomes included nodal status (p=0.049), less than 12 months follow up (p=0.01), and 
pre-operative physical scores of < 100 (p=0.01). Similar trajectories have been shown in 
nonsurgically treated cohorts (Roe 2014, Schwartz 2012, Hutcheson 2014).  
 
Expected QOL Outcomes Using the MDADI 
Since the Gillespie study (2004) describes a fairly wide range of mean subscale MDADI 
scores for patients receiving primary chemoradiation from 64.5 to 86.4 from the pre-
IMRT era, it is important to prospectively collect PRO swallowing data at baseline and 
interval follow up in this study of modestly reduced radiation therapy dose in the modern 
IMRT era.  
 

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Swallowing PROs previously have not been studied in a prospective, randomized, multi-
institutional setting to evaluate the benefit from the patient’s perspective of treatment de-
intensification using a primary radiation approach. 
 
In the proposed study, since there will be 1 radiation-alone arm, and the other concurrent 
chemoradiation arm will be using weekly cisplatin, putative dosimetric and treatment-
specific factors may be more closely examined with regards to dysphagia outcome using 
serial measurements of swallowing-related toxicity and PROs before and after treatment 
and with and without the potential confounding effects of high-dose chemotherapy. 
Based on the studies by Gillespie (2004), Chen (2001) and Bhide (2009), it is expected 
that with a primary radiation approach that expected scores would approximate mean 
total MDADI  ≥ 70 and global ≥ 80, with subscales for PT ≥ 65, ET ≥ 75, FT ≥ 80 when 
scored out of 100.  
 
Rationale for including a General QOL Instrument, the University of Washington QOL 
Questionnaire, for this Trial 
Oncologists now accept the quality of survival, in addition to the length of survival as an 
important clinical endpoint in trial design for patients with locally advanced cancers. 
While clinician-reported toxicity is able to detect adverse clinical events, PROs are 
paramount in this regard because they directly measure the patient’s perception of 
symptom burden from the treatment of the disease and its impact on QOL without bias 
from the clinician. As the treatment for HPV positive oropharyngeal carcinoma evolves, a 
high rate of acute and late normal tissue complications from definitive radiation-based 
treatment may no longer be considered acceptable, if alternatives evolve to produce 
similar rates of cure but improved QOL.  
 
In a study of 177 patients with head and neck cancer, using the University of Washington 
QOL Questionnaire (UW-QoLv.4), data suggests that QOL and long-term swallowing 
outcome in the HPV positive oropharyngeal carcinoma population are significantly better 
compared to the HPV negative population at baseline  and at 6 months to 1 year after 
treatment (Maxwell 2013). Moreover, since HPV positive oropharyngeal carcinoma 
patients are expected to have superior baseline QOL, with few co-morbidities compared 
to the HPV negative population, such patients may be less likely to accept additional 
acute or long-term toxicities, which generally have been associated with definitive head 
and neck radiotherapy even in the IMRT era. In this study we also will explore other 
exploratory QOL outcomes in this population receiving dose  de-escalated radiotherapy 
with regards to the patient’s perception of pain, their appearance, activity, recreation, 
chewing, speech, shoulder, taste, saliva function, mood and anxiety using the UW-
QoLv.4 at the same time points, in addition to the primary QOL endpoint of swallowing. 
Such items are quite applicable to this group of patients, who are relatively high-
performing and have concerns beyond (but also including) dysphagia. Other, more 
general instruments were considered in choosing UWQoLv. 4 and were judged to contain 
excessive overlap with the MDADI and, moreover, to cover too many items resulting in 
excessive burden given the exploratory nature of this instrument in the novel setting of 
reduced dose radiation therapy .    
  

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Adding the UW-QoLv.4 is justified, since this treatment paradigm essentially represents 
a new disease entity entailing a novel treatment paradigm, and there is no pre-existing 
data on the nature of outcomes in such patients receiving 60 Gy.  The targeted patient 
group is a potentially more favorable group both in terms of oncologic and long term 
QOL outcomes, and having these additional data from the UW-QoLv.4 may aid decisions 
about next research steps, particularly if no significant differences in dysphagia are found 
in either arm. As such, both the primary and exploratory QOL data from this trial will 
inform which of the 2 arms may proceed to a future phase III randomized trial comparing 
our paradigm to other treatment de-intensification approaches such as surgery or standard 
dose chemoradiation. 
 
Employment/Work Status and Return to Work after Radiotherapy  
An exploratory objective will be to determine the impact of radiotherapy de-escalation  
on the patient’s work status before and after treatment.  In a study of 85 patients in head 
and neck cancer survivors in the Netherlands (Verdonck-de Leeuw 2010), it was found 
that the median time to return to work was 6 months (range 0-24 months), while 71% 
patients returned to work within 6 months. The hypothesis is that dose de-escalation of 
radiotherapy will lead to decreased acute and late toxicities resulting in earlier return to 
the work and improved retention in the work force compared to conventional dose 
radiotherapy with or without chemotherapy.  
 
Multiple QOL factors may affect the ability of the patient to return to work including 
anxiety, oral dysfunction including xerostomia, trismus, sticky saliva, problems with 
dentition, appetite,  and social eating. Descriptive statistics will be used to assess work 
status before and after treatment. Work status will be tested for associations with 
concurrent chemotherapy use, age, gender, marital status, education level, tumor factors, 
and health-related  QOL using the UW-QoLv.4.  
 
Work status in head and neck radiotherapy is currently being evaluated in depth in  
RTOG 1016 using a detailed PRO instrument. In HN002, a very limited number of 
questions completed by the investigator and/or research associate will be integrated into 
the demographic evaluation of the patient before and after radiotherapy to assess baseline 
employment/work status and return to work status after treatment. These questions are 
not completed by patients and will not add to their burden.   
 
Optional Online Completion of QOL Assessments  
Missing data are a significant problem, particularly for QOL assessments. Unlike data for 
traditional endpoints, such as survival, QOL data can never be obtained retrospectively if 
it is not provided by the patient at the appropriate time point. This limits researchers’ 
ability to accurately perform QOL statistical analyses and negatively impacts the clinical 
relevance of this effort. Typically, QOL forms are filled out in hardcopy (paper). To 
provide a more convenient method of completing QOL assessments, NRG Oncology is 
working with VisionTree Software, Inc., San Diego, CA. VisionTree offers patients on 
this study the option of completing their QOL forms online from any location that has a 
computer with Internet access, including the patient’s home, and provides reminders to 
patients to complete the assessments. 
 

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VisionTree has developed a tool, VisionTree Optimal Care (VTOC), a HIPAA-secure, 
user friendly, web-based software system (Gorgulho 2005; Gorgulho 2007; Pedroso 
2006). The VTOC tool contains a web-based system for global patient and trial 
administration access, which allows improved compliance and accuracy of data 
collection, validation, and reporting. It is compliant with the Title 21, Code of Federal 
Regulations, Part 11 statistical process control system and provides a mobile solution for 
clinical trials. QOL data are collected with Microsoft Excel and PDF export of reports. 
VTOC also has mobile messaging and e-mail reminders. Surveys can be “pushed” to 
patients for completion at timed intervals (see http://www.visiontree.com for details). 
This technology allows consenting patients on this study to fill out their QOL forms 
online from any location and to receive e-mail reminders to complete assessments. E-
mail reminders also can be sent to research associates (RAs) at the appropriate 
institutions to remind them that a QOL time point window is about to close so that a 
patient can be contacted to fill out QOL information on time, before it becomes “missing 
data”. 
 
In a pilot RTOG study (RTOG 0828), the compliance rate of patients completing QOL 
assessments at 6 months significantly improved using electronic technology. Based on 
this pilot data, NRG Oncology is offering VisionTree as an option in other studies, 
including this one. Patients preferring to complete hardcopy QOL assessments can do so. 
 
For this trial, the baseline QOL forms must be completed in hardcopy at the time of 
enrollment. To complete subsequent QOL forms online, patients will be asked for an e-
mail address that they consent to use so that e-mail reminders may be sent to them. The 
patient’s e-mail address also will be used for password-protected access to VTOC. 
Patients who are interested in participating but do not yet have an e-mail address can 
obtain one for free from a number of sources (e.g. Yahoo!, Hotmail, or AOL). Patients 
will receive a login card (either printed or sent via e-mail) with which to log in using the 
secure, web-based VTOC portal. VTOC meets all HIPAA guidelines and is encrypted 
(via 128-bit SSL) for the security, privacy, and confidentiality of QOL information. It is 
similar to the secure login commonly used when performing online banking. The login 
card can then be kept and maintained by the patient. 
 
The patient’s e-mail address only will be used by NRG Oncology for this purpose. 
Patients will be sent e-mail reminders to complete QOL forms. A typical e-mail reminder 
would read: “Your Quality of Life forms for the study, NRG-HN001, are now due. Please 
go to http://www.optimalcare.com, use your secure login, and complete the online forms. 
If any questions make you feel uncomfortable, you may skip those questions and not give 
an answer. If you have any questions, please e-mail or call your research associate at 
[insert RA e-mail address] or [insert RA telephone number]. Thank you for participating 
in this study.” The reminders will be created by NRG Oncology and placed into a study 
template that will be sent to patients at customized intervals (at the time points when 
QOL forms are due). The first reminder will be sent at the beginning of the “window” to 
complete a QOL form, with a second reminder halfway through the window period if the 
QOL forms are not yet completed at that time point. A maximum of 3 reminders will be 
sent for each of the 4 QOL time points (following the baseline QOL forms, which are 

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completed in hardcopy). After a patient has completed all forms in the VTOC portal, a 
dialogue box will appear that says “Thank you for completing your Quality of Life 
forms,” and the patient will no longer receive any remaining notices for that time point. 
The site RA or study administrator will be informed through the VTOC “At-A-Glance” 
form management system when QOL forms have been completed. 
 
Rationale for including Modified Barium Swallow (MBS) as a Measure of Swallow 
Safety and Efficiency 
The purpose of the MBS component of this trial is to determine the long-term safety and 
efficiency profile of pharyngeal swallowing function  two years after de-escalated 
therapy in patients with low-risk oropharyngeal squamous cell carcinoma (OPSCC). 
Participating sites are given the option to participate in this NCI NCI Biomarker, Imaging 
and Quality of Life Studies Funding Program (BIQSFP)  -funded component of the 
study; MBS studies are not required for all sites to participate in the main part of the 
study. 
 
Videofluoroscopic swallowing evaluation (also known as the modified barium swallow 
[MBS] study) remains the gold-standard method to measure pathophysiology of 
swallowing dysfunction. MBS is widely utilized in clinical practice to measure safety and 
efficiency of pharyngeal bolus transport. MBS data are complementary to patient-
reported outcome (PRO) data. Patients’ perception of swallowing abilities are influenced 
by a host of factors including physical swallowing dysfunction after nonsurgical therapy 
(eg, radiation-associated dysphagia and stricture) alongside other confounding toxicities 
of therapy that make eating a less pleasant experience (eg, thick mucus, dysgeusia, 
xerostomia). As such, PROs can over or under-report the true level of physical 
impairment. MBS offers the specificity of detecting aspiration (perceived or silent) along 
with physical effects of therapy on swallowing biomechanics free of these competing 
toxicities that elevate an individual’s perception of swallow dysfunction but do not carry 
the same risk of secondary pneumonia.  
 
Much of our knowledge of aspiration and physiologic swallowing impairment comes 
from single-institution organ preservation trials that aggregate functional outcomes from 
HNSCC at multiple sites and report aspiration rates up to 40% in unselected post-radiated 
HNSCC cohorts, and in up to 80% of symptomatic patients (Eisbruch 2002, Eisbruch 
2011, Logemann 2006, Caudell 2009, Hutcheson 2012, Hutcheson 2014). These data, 
based on findings from MBS studies, confirm that when swallowing physiology is 
disrupted after head and neck radiotherapy, patients have high rates of aspiration, much 
of which is undetected by patient report because of diminished sensory awareness. Silent 
aspiration has been reported in excess of 50% of patients who aspirate (Eisbruch 2002, 
Hutcheson 2012).  
 
Data specific to patients with oropharyngeal primary tumors are limited but suggest still a 
high burden of dysphagia using traditionally prescribed doses around 70 Gy. Using 
prospective MBS (baseline through 2 years), Eisbruch and colleagues (2011) reported 
31% of OPSCC patients with elevated occurrences of aspiration relative to baseline ≥1 
year after treatment, and 22% 3-year risk of aspiration pneumonia in a trial of 

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chemotherapy and IMRT (70 Gy in 35 fractions, with weekly carboplatin AUC of 1 and 
paclitaxel 30 mg/m2) that was designed to protect dysphagia-organs-at-risk using dose 
constraints. MBS-detected aspiration significantly predicted pneumonia in this trial 
(p=0.017, Se 80%, Sp 60%), and silent aspiration was evident on MBS studies in 63% of 
patients who developed pneumonia. Pharyngeal residue on MBS studies also was 
significantly predictive of pneumonia after chemotherapy and IMRT (p<0.01 ) (Eisbruch 
2011, Hunter 2013). Using split-field IMRT (70-72 Gy/35 fractions), >6-month 
aspiration rates of 8% and 10% were detected in oropharyngeal cancer patients enrolled 
in two single-arm phase II  instititutional trials of induction chemotherapy and adaptive 
IMRT, respectively, at U.T.-MD Anderson Cancer Center, per prospective MBS analysis 
baseline through 2 years (Hutcheson 2014, Schwartz 2012). These results offer 
compelling support for the radiographic examination of swallowing outcomes to measure 
swallowing safety and efficiency as health-related endpoints cannot be fully detailed by 
PROs. Thus, we propose to evaluate swallowing using MBS studies at baseline and at 2 
years after the end of radiotherapy as a secondary measure of functional outcomes in this 
trial. This will be the first prospective MBS-driven swallowing outcomes assessment 
after de-escalated radiotherapy in low-risk OPSCC. As the radiotherapy effect on 
swallowing would be expected to be lessened as compared to the traditional treatment at 
70 Gy or more, this data will provide a clearer assessment of the impact of the addition of 
concurrent chemotherapy to a radiotherapy platform. The data will not only be important 
as a functional comparison of OPSCC patients treated with and without chemotherapy 
but will supply baseline values needed for future trial design 
 
The optimal time point for MBS is contigent on the study question. Two MBS time 
points (baseline and at 2 years after end RT) were selected for the current trial in order to 
prioritize the understanding of  baseline-adjusted, long-term swallowing recovery after 
de-escalated therapy. There is only limited data to date that delineates swallowing 
function beyond 1 year after radiotherapy. Single-institution HNSCC trials that have 
incorporated prospective MBS have examined MBS data at multiple intervals (typically 
baseline, 3-6-months, 12-months, and at 24-months after end of radiotherapy) to model 
trajectories of swallowing impairment. Trajectories suggest a nadir in MBS-detected 
swallowing function on early post-RT MBS (<6-month intervals) with partial recovery of 
function by 12-months and incremental improvement thereafter to 24 months. That is, 
most recovery of swallowing function will occur in the first year, and dysphagia events 
after that point can be taken to reflect chronic dysfunction that will likely persist lifelong. 
By 2 years, MBS analysis reflects the “new normal” swallow and the new baseline by 
which to benchmark any progressive functional deterioration in long-term survivorship. 
Progressive or late deterioriation of swallow function is possible (ie, late-radiation 
associated dysphagia or “late-RAD”), but emerging data suggest a much longer latency to 
de novo late-RAD well beyond 5 years (median  latency: 8 years) making it unrealistic to 
attempt to capture these late events in the MBS arm of the current trial (Hutcheson 
10/2015). Two-year MBS-detected swallow recovery outcomes must be obtained to set 
the foundation to evaluate late events in follow-up studies.  
 
The proposed MBS centralized scoring method for MBS studies is the Dynamic Imaging 
Grade of Swallowing Toxicity (DIGEST). With DIGEST, two MBS outcomes will be 

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rated: 1) penetration/aspiration (ie, “swallow safety”), and 2) pharyngeal residue (ie, 
“swallow efficiency”). These domains were selected as universal items reported in 
swallowing practice that have been shown to significantly predict pneumonia in patients 
with oropharyngeal cancers. Laryngeal penetration and aspiration represent impairments 
in airway protection or swallow safety, whereas pharyngeal residue represents 
impairment in bolus clearance or swallow efficiency. Factor analyses have established 
these as valid constructs of pharyngeal dysphagia in patients with head and neck cancer 
(Frowen 2008). 
 
Ratings of aspiration and penetration are highly reliable (intraclass correlation 
coefficient: 0.80- 1.0) (Stoeckli 2003, Frowen 2008). Intraclass correlation coefficients 
for inter- and intra-rater reliability on the Penetration-Aspiration Scale were 0.96 and 
0.95-0.97, respectively (Rosenbek 1996). Pharyngeal residue also is reliably measured as 
an ordinal rating (weighted kappa: 0.73 interrater, 0.85 intrarater ) (Dyer 2008). A cut-
point of 50% residue is widely used to represent a significant impairment in bolus transit 
(Eisenhuber 2002, Martin-Harris 2008, Ryu 2012). Furthermore, discriminant analyses of 
two-dimensional area measures suggested a threshold value of 55% residue correlates 
with qualitative ratings of moderate/severe residue by expert clinicians (Dyer 2008). 
Safety and efficiency profiles of the pharyngeal swallow using ordinal-scaled 
penetration/aspiration and residue scores from MBS have been mapped to the CTCAE 
taxonomy in a validation study that is currently concluding at U.T. MD Anderson – the 
Dynamic Imaging Grade of Swallowing Toxicity (DIGEST). DIGEST ratings will be 
assigned to each MBS to provide a CTCAE-compatible summary grade to the pharyngeal 
swallow: grade 1 “mild”, grade 2 “moderate”, grade 3 “severe”, and grade 4 “life 
threatening” pharyngeal dysphagia. 
 
2.5 
FDG-PET/CT Imaging as a Predictive Imaging Marker for  Locoregional Control 
and Progression-Free Survival  
The purpose of studying FDG-PET/CT in the context of  HN002 is to determine the 
predictive value of 12-14 week post therapy FDG-PET/CT for locoregional control and 
2-year PFS. Patients and investigators are given the option to participate in this 
component of the study although PET/CT scans are not required to participate in the 
parent study, HN002. 
 
The sensitivity and specificity of post-treatment FDG-PET/CT depend on the time 
interval between the completion of therapy and FDG-PET/CT. In a study of 26 patients, 
Goerres, et al. (2004) observed a sensitivity and specificity of 91% and 93%, 
respectively, for PET/CT scans performed as early as 6 weeks after chemoradiotherapy.  
However, other studies have not been able to reproduce these data (Porceddu 2005, Yao 
2005) and instead suggest that PET/CT after chemoradiotherapy should not be 
performed before 10-12 weeks after the end of radiation treatment. By that time, most 
of the post-treatment inflammatory changes will have subsided, reducing the number of 
potentially false-positive interpretations. In general, the rate of false-positive cases 
declines with the interval between the end of therapy and PET/CT imaging (Lonneux 
2000). The optimal timing of the first response assessment FDG-PET/CT after 
definitive (chemo) radiation is not precisely known, but an interval of at least 12 weeks 

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has generally been recommended to balance the drawbacks of imaging too early versus 
too late. In rare cases, early detection of residual/recurrent disease is central to 
successful surgical salvage if appropriate, while a demonstration of a clinical and 
radiographic complete response obviates the need for further unnecessary and 
potentially morbid interventions.  A recent meta-analysis involving 51 studies and 2335 
patients (Gupta 2011) estimated the sensitivity and specificity of post-treatment FDG-
PET/CT at 91.9% and 86.9% for primary tumor and 90.4% and 94.3% for neck nodes, 
respectively, when the PET/CT was performed > 12 weeks after completion of 
concurrent chemoradiation therapy. Therefore, in this study, the FDG-PET/CT should 
be obtained at 12-14 weeks post-treatment. 
 
A reliable imaging modality to predict long-term locoregional control can serve as a 
surrogate imaging biomarker to judge the effectiveness of the investigational treatment. 
Residual structural abnormalities seen on anatomic imaging such as CT or MRI after 
definitive radiotherapy may not harbor viable cancer cells (Ware 2004). FDG-PET/CT is 
a functional imaging assessment that detects glucose metabolism of the tissue, and it is 
highly sensitive in the detection of viable cancer cells due to the high metabolic rate in 
these cells. Several single-institution retrospective studies have shown that a negative 
post-radiotherapy PET/CT was highly predictive of long-term locoregional control in 
locally advanced head and neck cancer after chemoradiation. Yao, et al. (2009) from the 
University of Iowa reported 188 patients with FDG-PET/CT obtained at a median of 15 
weeks after radiotherapy. Of 151 patients with a negative FDG-PET/CT at the primary 
site, only 2 developed locally recurrent disease, with a negative predictive value of 
98.7%. Of 171 patients who had a negative PET/CT in the cervical lymphatic region, 
only 2 were falsely negative, with a negative predictive value of 99%. Ryan, et al. (2005) 
summarized the experience from Stanford University in 103 patients with 118 post-
treatment PET/CTs. PET/CT results were correlated with surgical pathology and clinical 
outcomes, and the negative predictive value of PET was 98%. In a prospective study of 
98 patients by investigators from MD Anderson Cancer Center (Moeller 2010), using a 
post-radiation maximum standardized uptake value (SUVmax) of 6.0 of the primary tumor 
as a cut-off, the investigators reported that the negative predictive value of FDG-PET/CT 
for disease-specific survival was 92%. In this study, they reported that there was no 
additional prognostic information of FDG-PET/CT in low-risk patients, i.e. HPV positive 
oropharyngeal cancer patients. However, this was assessed under conditions of standard 
regimens of chemoradiation. In addition, this study was under powered due to a low 
number of events. In this trial, 2 de-intensified regimens are being tested in p16 positive 
oropharyngeal cancer patients, and the predictive value of 12-14 week post therapy FDG- 
PET/CT for 2-year PFS is unknown when treatment intensity is reduced. Therefore, the 
assessment of PET/CT in this setting is novel and important. 
 
Currently, FDG-PET/CT is commonly used for staging and assessment of treatment 
response in head and neck cancer. The Centers for Medicare and Medicaid services and 
most third party payers in USA provide reimbursement for a pre-treatment and a post-
treatment FDG-PET/CT in head and neck cancer patients scheduled to receive definitive-
intent radiotherapy. While PET/CT has become very accepted, practice patterns among 
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Therefore, obtaining a pretreatment PET/CT and a 12-14 week post therapy PET/CT is 
highly recommended but not required, and for this study, obtaining PET/CT is left to the 
discretion of the clinician, as dictated per local clinical practice, and participation in the 
PET/CT assessment study is highly recommended but optional on the part of the patient 
and the investigator.  
 
Because of the frequent use of PET/CT in local centers, it is of interest to the study 
investigators to document the performance of PET/CT under “real-world” conditions. 
This approach may increase the future generalizability of any findings. Furthermore, 
based on the experience of RTOG 0522, a requirement for scanner accreditation would 
pose a concerning barrier to participation and produce an unacceptably low sample size. 
Therefore, a study-specific accreditation of PET/CT scanners of the participating 
institutions will not be required for participation in the PET/CT sub-study, although 
information will be requested on the facility where the PET/CT scans were performed. 
Because the PET/CT images will be centrally reviewed and scored on a qualitative basis, 
the impact of variations in the imaging technique should be substantially lessened. 
Regarding PET/CT technique, the study investigators recommend that the standard-of-
care guidelines from the National Cancer Institute and ACRIN Imaging Standards for 
PET should be followed as closely as possible (Shankar 2006).    
 
To provide a platform for standardizing interpretations of the PET/CT scans, the study 
investigators have developed a reader-based scoring system to minimize the effect of 
varying acquisition techniques. This ordinal scoring system (see below) will identify 
those patients who have complete metabolic response and those who did not have 
complete metabolic response, retrospectively. All of the post-treatment PET/CT images 
will be centrally reviewed at the end of the recruitment period and correlated with the 
clinical treatment outcomes. 
 
The proposed centralized scoring system was modified from the well-validated and 
clinically most useful five-point scoring system for mid-therapy and post-therapy 
assessment for lymphoma (Deauville criteria). This scoring system has been previously 
validated as a collapsed three-point categorization (negative for tumor, indeterminate, 
positive for tumor) for head and neck FDG-PET/CT scans performed between 4 and 24 
months after therapy completion (Paidpally 2013). The scoring system successfully 
predicted outcome in these patients and added value to the clinical assessment at the time 
of the scans. In addition, the five-point scoring system has been recently validated in head 
and neck FDG-PET/CT scans performed between five weeks and 6 months after therapy 
completion in 214 head and neck squamous cell carcinoma patients. There was 90%, 
97.2%, 94.9% and 91.3% agreement between the readers for overall, left neck, right neck 
and primary tumor site response scores, respectively. The corresponding Kappa 
coefficients for inter-reader agreement were k=0.70 (p<0.0001), k=0.81 (p<0.0001), k= 
0.69 (p<0.0001), and k=0.67 (p<0.0001), respectively. The accuracy of the scoring 
system against a 6 month clinical follow up as the reference standard is excellent with 
ROC area under the curve 0.98 (95% CI 0.97-0.99; P < 0.001). Cox regression analysis 
showed a significant difference in overall survival between the patients who had a score 
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(log-rank, P<0.0001 with a hazard ratio of 0.056 [95% CI 0.022-0.138] (Subramanian, 
personal communication, 2014; Marcus 2014). 
 
 
Proposed Harmonization of FDG-PET/CT Ordinal Scoring and Classification of Results 
The tumor response evaluation will be carried out using a 5-point ordinal scale ranging 
from Definite Complete Response (score 1) to Definite Residual Disease (score 5). 
Diffuse uptake is defined as homogeneous FDG uptake, with smooth tapering borders. 
Focal uptake is characterized by an abrupt drop-off of FDG activity at the boundaries of 
the active area. 
 
Score 1: Definite complete metabolic response: The FDG uptake in the primary tumor or 
nodal sites is less than the background blood pool FDG uptake. 
Score 2: Likely complete metabolic response: The FDG uptake in the primary tumor or 
nodal sites is greater than the background blood pool uptake but it is equal to or 
less than the liver FDG uptake. 
Score 3: Likely inflammatory: There is diffuse FDG uptake in the primary tumor or 
nodal sites. This diffuse FDG uptake is greater than the liver FDG uptake and 
likely related to post-radiation inflammation. 
Score 4: Likely residual metabolic disease: There is focal FDG uptake in the primary or 
nodal sites. The focal FDG uptake is greater than the liver FDG uptake. 
Score 5: Definite residual metabolic disease: There is intense focal FDG uptake in the 
primary tumor or nodal sites. This focal FDG uptake is greater than the liver 
FDG uptake.  
 
Definitions of ‘Positive,’ ‘Negative’ and ‘Indeterminate’ FDG Uptake and PET/CT 
Results 
A score of 1 or 2 will be interpreted as ‘Negative,’ a score of 3 as ‘Indeterminate,’ and a 
score of 4 or 5 as ‘Positive.’ A ‘Negative’ result at the primary or nodal sites is defined as 
equal or less FDG uptake than the blood pool and liver FDG uptake. Uptake for the local 
blood pool reference value will be measured from the carotid or the aortic arch. The 
‘Indeterminate’ result is defined as diffuse FDG uptake in the treatment field with 
intensity of the uptake greater than the liver FDG uptake. A ‘Positive’ result is defined as 
focal uptake visually greater than the background and at a higher level than the activity 
seen in the liver. 
 
Sites that are interested in participating are encouraged to explain this component of the 
study to patients and obtained consent from all patients. All pre and post therapy FDG-
PET/CT images for patients enrolled in this optional component will be collected. The 
first 3 studies from each site will be centrally reviewed as a ‘live read’ within 3 working 
days of submission of scans to IROC Imaging, to establish a training and quality 
assurance process that will validate the local interpretation using the 5-point scoring 
system. All positive and indeterminate post-therapy scans also will be centrally reviewed 
as ‘live reads’ within 3 working days of submission of the scans to IROC Imaging.  
 
It is important to note that local sites will decide the post-therapy management and may 
incorporate the information from FDG-PET/CT into decision making according to these 

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guidelines. However, determination of PFS events will require pathologic confirmation 
from biopsy or surgery; and an indeterminate or positive reading on FDG-PET/CT in 
itself will not be considered to affect the primary endpoint unless pathologic 
confirmation of persistent/residual cancer is obtained. 
 
Any FDG-PET/CT scan that merits an indeterminate or positive read must be followed 
by a mandated, short-term follow up (either focused clinical examination or another 
imaging study within 4 weeks). 
 
2.6 
Circulating HPV DNA as a Potential Marker for Relapse (5/24/16) 
 
Circulating HPV DNA was detected in the blood of mouse-bearing xenografts harboring 
HPV positive tumors (SCC90 & Hela cells) but not in HPV negative tumors (MiaPaCa2 
and SAS cells) using a PCR-based approach with either the L1 G5+/6+ primer or 
HPV16/18 subtype specific nested E6/E7 primers. A quantitative PCR approach using 
qPCR E6/7 primers was able to quantify plasma HPV DNA in 40 patients with HPV 
positive oropharyngeal cancer (OPC), 24 patients with HPV negative head and neck 
cancer (HNC), and 10 non-cancer volunteers. This approach detected circulating HPV 
DNA in 65% of pretreatment plasma samples from HPV positive OPC patients. None of 
the HPV negative HNC or non-cancer controls had detectable HPV DNA. In addition, 
pre-treatment plasma HPV DNA copy number correlated significantly with nodal 
metabolic tumor volume (assessed on FDG-PET/CT). Serial measurements in 14 patients  
found a rapid decline in HPV DNA, which became undetectable at completion of the 
chemoradiation treatment course. In 3 patients, HPV DNA had risen to a discernible level 
at the time of metastasis  (Cao 2012).  
 
 
One drawback about the traditional qPCR approach is its low sensitivity and the 
requirement of large amount of DNA. Recently, Newman, et al. have published on the 
use of “Cancer Personalized Profiling by Deep Sequencing” (Capp-Seq) as an 
ultrasensitive method to quantify circulating tumor (ct) DNA with broad coverage in 
patients with locally advanced non-small cell lung cancer (NSCLC) (Newman 2014). 
Capp-Seq has been shown to outperform existing methods with a mean background level 
of 0.0007% and a detection limit of 0.025% for SNV and < 0.01% for rearrangement. It 
can detect mutant or viral DNA in picograms of DNA due to its low background and high 
sensitivity. The researchers also showed that the ctDNA levels were highly correlated 
with the tumor volumes and that it could distinguish between residual disease and 
treatment related imaging changes in these patients. Moreover, measurement of ctDNA 
allowed for earlier response assessment in NSCLC than radiographic approaches. We are 
currently validating the Capp-Seq approach on HPV+ HNSCC using our samples, and the 
results are encouraging. Based on this, we would like to determine whether the levels of 
HPV ctDNA as measured by Capp-Seq reflects tumor burden in patients treated on this 
trial and whether serial measurements can be used to track response and identify patients 
at high risk of relapse after treatment de-intensification therapy. 
 
 
 
Hypothesis 1: To determine whether that HPV DNA levels as measured by the Capp-Seq 
platform correlates with the tumor volume (GTV) in HPV positive OPC.  
 

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As mentioned above, tumor ctDNA as measured by this platform significantly correlated 
with the tumor volume in NSCLC. Similarly,  we found that plasma HPV DNA copy 
number as measured by traditional qPCR approach significantly correlated with nodal 
classification and nodal metabolic tumor volume in patients with HPV+ oropharyngeal 
carcinoma. We hypothesize that Capp-Seq is more sensitive and HPV ctDNA 
measurements by Capp-Seq will be a better reflection of tumor burden than DNA copy 
from qPCR. Since all patients will undergo pre-treatment simulation with recorded GTV 
and have pre-treatment plasma collection, it should be straightforward to extract DNA 
and measure HPV DNA by Capp-Seq and qPCR and correlate with GTV. 
 
 
Hypothesis 2: To determine whether the rate of HPV DNA declines during therapy by 
Capp-Seq and whether the measured level at the completion of radiotherapy correlates 
with the rate of relapse in treated patients. 
 
 
Serial circulating HPV DNA was measured in 14 patients with qPCR during therapy and 
in all of these patients, HPV DNA declined during treatment and became undetectable 
after treatment. In this small study, the investigators were not able to distinguish the 
pattern of relapse based on these 14 patients (4 with relapse and 10 without).  However, 
with such a small sample size and the poor sensitivity of the qPCR method, it was 
difficult to distinguish those with a very low detectable versus an undetectable level. In 
contrast, Capp-Seq was able to track the NSCLC response to chemotherapy or radiation 
in a few patients evaluated. We hypothesize that the Capp-Seq approach will be superior 
to the traditional qPCR approach in detecting very low levels of HPV DNA in the blood 
after completion of radiation therapy, and those with detectable levels by Capp-Seq are 
more likely to have persistent disease or relapse after treatment. To address this 
hypothesis, this study proposes to measure HPV DNA by both qPCR and Capp-Seq pre-
therapy, mid-way into the course of treatment (after 20 Gy) and within 2 weeks of 
completion of all therapy. We will quantify the rate of HPV DNA decline measured in a 
short window after the first 20 Gy. The specific hypothesis that the rate of initial decline 
after the first 20 Gy and/or the post-treatment level reflects tumor response to therapy and 
can be used to predict for tumor persistence and relapse in these patients. 
 
 
2.7 
PI3K Pathway Activation and Its Associated Genomic Profile as Prognostic 
Biomarkers of HPV Related Oropharyngeal Cancer 
 
Recent genomic studies using next-generation sequencing (NGS) technology have shown 
that HPV related oropharynx cancer is genetically distinct compared to HPV unrelated 
oropharynx cancer (Agrawal 2011; Stransky 2011). In addition, a 182-cancer gene 
targeted analysis showed that HPV related oropharyngeal cancer has a particularly high 
prevalence of the phosphotidylinositol-3-kinase (PI3K) pathway aberration through 
activating mutation and increased gene copy number of the PI3K catalytic subunit, 
PIK3CA, and PTEN loss of function, the negative regulator of PI3K (Lechner 2013). The 
PI3K pathway is a well-known oncogenic pathway in numerous cancers and is activated 
by several receptor tyrosine kinases including epidermal growth factor receptor (EGFR), 
a key pathway in HNSCC. Activation of PI3K initiates a signal transduction cascade that 
promotes cancer cell growth, survival, and metabolism through several important 
downstream mediators, including Akt and mTOR complex 1 (mTORC1). Akt is the 

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serine–threonine kinase that is directly activated in the response to PI3K and serves as a 
major mediator within the PI3K pathway. Further downstream of Akt is the mTORC1, 
which is not only under control of PI3K–Akt signaling, but also integrates many cellular 
inputs from hypoxia to growth factor stimulation and stress response. In addition, PTEN 
loss is commonly seen in HNSCC resulting in uncontrolled activation of PI3K (Okami 
1998). However, these aberrations generally are not the only abnormal oncogenic 
pathway but co-exist with other cancer related genes within an individual oropharyngeal 
cancer. Therefore, evaluation of PI3K pathway aberrations as  prognostic biomarkers 
within the genetic contexts of other cancer gene mutations such as TP53 mutation is 
extremely important. In this proposal, the plan is to investigate mutations and copy 
number changes in genes within the PI3K pathway (PIK3CA and PTEN) and 180 
additional cancer related genes using NGS. Improved understanding of this pathway in a 
specific genetic context also may lead to development of  novel therapies and/or 
predictive biomarkers to improve the clinical outcomes of HPV related oropharyngeal 
cancer patients. 
 
Hypothesis 1: Activation of the PI3K pathway by PIK3CA activating mutation or copy 
number gain or PTEN loss of function mutation or copy number loss is associated with 
increased rates of locoregional failure in patients with HPV related oropharyngeal cancer.   
 
Hypothesis 2: Co-existence of PI3K pathway activation and TP53 mutation (or additional 
oncogene mutations such as KRAS mutation) will improve the prognostic potential of 
PI3K pathway activation. 
 
3.  PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (via the contact list on the NRG web site). For radiation therapy-related 
eligibility questions, please contact IROC Philadelphia RT (via the contact list on the NRG 
web site).  
 
3.1 
Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Women of childbearing potential and men who are sexually active should be willing and 
able to use medically acceptable forms of contraception throughout the treatment phase 
of  the trial and until at least 60 days following the last study treatment. 
3.1.3 Submission of  H&E and p16 slides to the NRG Oncology Biospecimen Bank for 
confirmation of positive immunohistochemical staining for p16 is required for all 
patients. Investigators should check with their site Pathology department regarding 
release of biospecimens before approaching patients about participation in the trial. (See 

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Sections 10 and 11.) 
 
3.2 
Eligibility Criteria (5/24/16) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
Step 1: Registration 
3.2.1 Pathologically (histologically or cytologically) proven diagnosis of squamous cell 
carcinoma (including the histological variants papillary squamous cell carcinoma and 
basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, 
or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in 
the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence 
should be documented, may consist of palpation, imaging, or endoscopic evaluation, and 
should be sufficient to estimate the size of the primary (for T stage). 
3.2.2 Patients must have clinically or radiographically evident measurable disease at the 
primary site or at nodal stations. Tonsillectomy or local excision of the primary without 
removal of nodal disease is permitted, as is excision removing gross nodal disease but 
with intact primary site. Limited neck dissections retrieving ≤ 4 nodes are permitted and 
considered as non-therapeutic nodal excisions.  
3.2.3 Immunohistochemical staining for p16 must be performed on tissue, and this tissue must 
be submitted for central review. Fine needle aspiration (FNA) biopsy specimens may be 
used as the sole diagnostic tissue if formalin-fixed paraffin-embedded cell block  material 
is available for p16 immunohistochemistry. FNA specimens prepared with adequate p16 
testing in this manner are acceptable to submit for central review. If the p16 preparation 
is not adequate, additional specimens will be required to establish p16 status. Centers are 
encouraged to contact the pathology chairs for clarification.   
3.2.4 Clinical stage T1-T2, N1-N2b or T3, N0-N2b (AJCC, 7th ed.) including no distant 
metastases based on the following diagnostic workup: 
 General history and physical examination within 56 days prior to registration; 
 Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct 
procedure) within 70 days prior to registration;  
 One of the following combinations of imaging is required within 56 days prior to 
registration: 
a) 
A CT scan of the neck (with contrast) and a chest CT scan (with or without 
contrast); 
b) or an MRI of the neck (with contrast) and a chest CT scan (with or without 
contrast); 
c) 
or a CT scan of neck (with contrast) and a PET/CT of neck and chest (with or 
without contrast); 
d) or an MRI of the neck (with contrast) and a PET/CT of neck and chest (with or 
without contrast). 
Note: A CT scan of neck and/or a PET/CT performed for the purposes of radiation 
planning  may serve as both staging and planning tools. 
3.2.5 Patients must provide their personal smoking history prior to registration. The lifetime 
cumulative history cannot exceed 10 pack-years. The following formula is used to 
calculate the pack-years during the periods of smoking in the patient’s life; the 

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cumulative total of the number of pack-years during each period of active smoking is the 
lifetime cumulative history. 
 
Number of pack-years = [Frequency of smoking (number of cigarettes per day) × 
duration of cigarette smoking (years)] / 20 
 
Note: Twenty cigarettes is considered equivalent to one pack. The effect of non-cigarette 
tobacco products on the survival of patients with p16-positive oropharyngeal cancers is 
undefined. While there are reportedly increased risks of head and neck cancer associated 
with sustained heavy cigar and pipe use (Wyss 2013), such sustained use of non-cigarette 
products is unusual  and does not appear to convey added risk with synchronous cigarette 
smoking. Cigar and pipe tobacco consumption is therefore not included in calculating the 
lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. 
There is no clear scientific evidence regarding the role of chewing tobacco-containing 
products in this disease, although this is possibly more concerning given the proximity of 
the oral cavity and oropharynx. In any case,  investigators are discouraged from enrolling 
patients with a history of very sustained use (such as several years or more) of non-
cigarette tobacco products alone. 
3.2.6 Zubrod Performance Status of 0-1 within 56 days prior to registration; 
3.2.7 Age ≥ 18;  
3.2.8 The trial is open to both genders; 
 
3.2.9 Adequate hematologic function within 14 days prior to registration, defined as follows: 
 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; 
 Platelets ≥ 100,000 cells/mm3; 
 Hemoglobin ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve 
Hgb ≥ 8.0 g/dl is acceptable. 
3.2.10 Adequate renal function within 14 days prior to registration, defined as follows: 
 Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 
24-hour collection or estimated by Cockcroft-Gault formula: 
 
 
CCr male = [(140 – age) x (wt in kg)] 
 
 
 
 [(Serum Cr mg/dl) x (72)] 
 
 
CCr female = 0.85 x (CrCl male) 
3.2.11 Adequate hepatic function within 14 days prior to registration defined as follows: 
 Bilirubin < 2 mg/dl; 
 AST or ALT < 3 x the upper limit of normal. 
3.2.12 
Negative serum pregnancy test within 14 days prior to registration for women of 
childbearing potential; 
3.2.13 
Patients who are HIV positive but have no prior AIDS-defining illness and have CD4 
cells of at least 350/mm3 are eligible. HIV-positive patients must not have multi-drug 
resistant HIV infection or other concurrent AIDS-defining conditions. Patients must 
not be sero-positive for Hepatitis B (Hepatitis B surface antigen positive or anti-
hepatitis B core antigen positive) or sero-positive for Hepatitis C (anti-Hepatitis C 
antibody positive). However, patients who are immune to hepatitis B (anti-Hepatitis 
B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B).  

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3.2.14 The patient must provide study-specific informed consent prior to study entry, including 
consent for mandatory submission of tissue for required, central p16 review. 
3.2.15 Patients who speak English (or read one of the languages for which a translation is 
available (see Section 10.2) must consent to complete the mandatory dysphagia-related 
patient reported instrument (MDADI). If the patient cannot understand spoken English 
and reads only languages not available in the MDADI translations, the patient can still 
participate in the trial, as this has been factored into the trial statistics. For all other 
patients, the MDADI is mandatory as it is included in the primary endpoint to be studied. 
 
Step 2: Randomization 
3.2.16 p16 positive by immunohistochemistry (defined as greater than 70% strong nuclear or 
nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology review; 
(see Section 10.1 for details). 
 
3.3 
Ineligibility Criteria (5/24/16) 
Patients with one or more of the following conditions are NOT eligible for this 
study. 
Step 1: Registration 
3.3.1 Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar 
ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16 positive, or 
histologies of adenosquamous, verrucous, or spindle cell carcinomas; 
3.3.2 Carcinoma of the neck of unknown primary site origin (even if p16 positive); 
3.3.3 Radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening 
fat plane;  
3.3.4 Supraclavicular nodes, defined as nodes visualized on the same axial imaging slice as the 
clavicle; 
3.3.5 Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the 
clavicles; 
3.3.6 Gross total excision of both primary and nodal disease with curative intent; this includes 
tonsillectomy, local excision of primary site, and nodal excision that removes all 
clinically and radiographically evident disease. In other words, to participate in this 
protocol, the patient must have clinically or radiographically evident gross disease for 
which disease response can be assessed. 
3.3.7 Patients with simultaneous primary cancers or separate bilateral primary tumor sites are 
excluded with the exception of patients with bilateral tonsil cancers; 
3.3.8 Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 
a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral 
cavity, or cervix are all permissible); 
3.3.9 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a 
different cancer is allowable; 
3.3.10 Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields; 
3.3.11 Severe, active co-morbidity defined as follows: 
 Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months; 
 Transmural myocardial infarction within the last 6 months; 

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 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 
 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy within 30 days of registration; 
 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, 
however, that laboratory tests for liver function and coagulation parameters are not 
required for entry into this protocol other than those requested in Section 3.2.10. 
 Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition 
with immune compromise greater than that noted in Section 3.1.13; note, however, 
that HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because the treatments involved in 
this protocol may be significantly immunosuppressive. Protocol-specific requirements 
may also exclude immuno-compromised patients. 
3.3.12 
Pregnancy; this exclusion is necessary because the treatment involved in this study 
may be significantly teratogenic.   
3.3.13 
Prior allergic reaction to cisplatin. 
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW UP 
(5/24/16) 
 
PRE-TREATMENT ASSESSMENTS 
Assessments 
Prior to Registration-Step 1 
Registration 
 (calendar days) 
Prior to Treatment 
(calendar days) 
History/physical with height 
& weight  
56 
 
Fiberoptic exam with  
laryngopharyngoscopy (see 
note below) 
70 
 
Imaging: (see note below) 
 CT with contrast of neck 
and CT of chest +/- 
contrast; 
 Or MRI with contrast of 
neck and CT of chest +/- 
contrast; 
 Or CT with contrast of 
neck and PET/CT of neck 
and chest +/- contrast; 
 Or MRI with contrast of 
neck and PET/CT of neck 
and chest +/- contrast 
56 
 

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Patient’s smoking history 
X 
 
Zubrod Performance Status 
56 
 
CBC/differential 
14 
 
Bilirubin, AST or ALT 
14 
 
Serum creatinine or creatinine 
clearance 
14 
 
Serum pregnancy test, if 
applicable 
14 
 
Na, K, Cl, glucose, Ca, Mg, 
and albumin (see note below) 
 
28 
Dental assessment (see note 
below) 
 
28 
Audiogram 
 
112 (16 weeks) 
Swallowing assessment (see 
note below) 
 
28 
MDADI 
 
Required: 28 
PSS-HN, CCI, Work Status 
 
Required 
EKG 
 
Recommended for Arm 1 
patients: 70  days (10 weeks) 
Whole body PET/CT (see 
note below) 
 
Recommended: 70 days (10 
weeks) 
Nutritional evaluation (see 
note below) 
 
Recommended: 28  
QOL:  UW-QoL, if patient 
consents 
 
Prior to start of protocol-
specific treatment 
Biospecimen Collection for 
Central Review and for 
Banking 
 
See Section 10.1 for details 
Modified Barium Swallow, if 
patient consents 
 
Prior to start of protocol-
specific treatment  
 
Notes for Pre-Treatment Assessments (table above)  
 The fiberoptic exam with  laryngopharyngoscopy can be done by the treating surgeon, 
medical oncologist, or radiation oncologist with experience in endoscopic examinations 
of cancer patients. 
 Patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may receive corrective 
magnesium supplementation but should continue to receive either prophylactic weekly 
infusion of magnesium and/or oral magnesium supplementation (e.g. magnesium oxide) 
at the investigator’s discretion. 
 The protocol-specific dental assessment is by a physician or designee (such as a 
physician's assistant, nurse or nurse practitioner, or a dentist/hygienist) to assess number 
of teeth and overall dental health with management; see guidelines at www.ctsu.org on 
the NRG-HN002 protocol page. 
 The protocol-specific swallowing assessment is a single question completed by the 
physician and/or research associate to describe the consistencies of foodstuff that the 

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patient is able to swallow.  
 The MDADI is a required PRO (if the patient can comprehend spoken English or read 
one of the validated language translations) and it is completed by the patient. 
 The EKG is recommended for Arm 1 patients (RT + cisplatin). 
 “Whole body” PET/CT may be limited to neck and chest. Note: Diagnostic quality CT 
scan of neck with contrast and/or PET/CT performed for radiation planning may serve as 
both staging and planning tools. Centers that wish to participate in the PET/CT 
correlative study component should refer to guidelines for submitting these images and 
their associated data (see Section 10.3). 
 Nutritional evaluation to include the physician’s evaluation for placement of prophylactic 
gastrostomy or other type of feeding tube; note: The decision to place a feeding tube 
should be individualized and is not mandated. Investigators may consider a number of 
factors including: prior weight loss, current nutritional status, size and location of the 
primary tumor (impacting high dose target volume), availability of feeding tube 
placement services, availability of speech and swallowing specialists, dietician 
counseling, and social support. Feeding tubes may be placed after start of treatment at the 
discretion of the clinical team. If a tube is placed, the site will document on the 
appropriate case report form (see Section 12.1) if the tube was placed prophylactically (as 
a preventative measure) or therapeutically (because of nutritional compromise or other 
clinical indications). It is highly recommended as part of the standard of care that all 
patients, but particularly those who require feeding tubes, be provided with professional 
swallowing evaluations and counseling before, during, and after treatment. 
 Quality of Life: 
 Patients are required to complete the MDADI at pre-treatment  as this assessment is 
needed for the primary objective of the trial. 
 Patients who consent to participate in the optional QOL study will complete the UW-
QoL. 
 The Performance Status Scale for Head and Neck (PSS-HN), Charlson Comorbidity 
Index (CCI), and Work Status questions are required and are completed by the 
investigator and/or research associate. 
 Patients who consent to participate in the quality of life (QOL) component of this 
study have the option of completing QOL forms online from any location, including 
home, via VisionTree Optimal Care (VTOC). Patients without e-mail or Internet 
access are still able to participate in the QOL component of the study by completing 
hardcopy (paper) forms. Indeed, at any time, any patient may choose to fill out their 
QOL form using the hardcopy form.  
 
  
If the patient wishes to complete QOL assessments online, the patient must have an e-
mail address that they consent to use for this purpose. Patients’ e-mail addresses are 
necessary so that e-mail reminders may be sent to them to remind them to fill out 
QOL forms that are due. The patient’s e-mail address also will be used for password-
protected access to VTOC. Patients who are interested in participating but do not yet 
have an e-mail address can obtain one for free from a number of sources (e.g.,Yahoo!, 
Hotmail, or AOL). Note: The site RA is responsible for setting up the patient’s 
account on VTOC. The RA may do so by logging on the VTOC portal at the 
following link https://rtog.optimalcare.com - medical team.  RA login 
information will be provided by VTOC after the patient is randomized to the 

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study. The patient’s VTOC account must be set up within 14 days after 
randomization. 
 
ASSESSMENTS DURING TREATMENT (5/24/16) 
 
Assessments 
Weekly during Treatment 
As Clinically Indicated 
Brief history  
X 
X 
Physical examination  
X 
X 
Zubrod Performance Status 
X 
 
CBC/differential 
Arm 1: Weekly 
Arm 2: At Weeks 3 and 5 
 
Serum creatinine or 
creatinine clearance 
 Arm 1: Weekly 
Arm 2: At Weeks 3 and 5 
 
Na, K, Cl, glucose, Ca, Mg, 
and albumin 
Arm 1: Weekly 
Arm 2: At Weeks 3 and 5 
 
Bilirubin, AST or ALT 
At Weeks 3 and 5 
 
 
Whole body PET/CT 
 
X 
CT or MRI or PET/CT of 
neck, with contrast 
 
X 
Biopsy 
 
If suspicion of tumor 
recurrence 
Adverse Event Evaluation 
X 
X 
QOL: MDADI 
Mandatory at completion of radiation 
QOL: UW-Qol 
For patients who consent: At completion of radiation 
QOL: PSS-HN, Work Status 
questions 
Required: Completed by the investigator and/or research 
associate at completion of radiation 
Biospecimen Collection for 
Banking  
For patients who consent: After  at least 20 Gy RT has been 
given but before 28 Gy RT has been given 
 

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ASSESSMENTS IN FOLLOW UP (5/24/16) 
 
Assessments 
At 1 Month Post-
treatment 
q3 mos. from end 
of RT for 2 yrs; q6 
mos. for 3 yrs; 
then annually 
As Clinically 
Indicated 
Brief history, physical 
examination, and 
laryngopharyngoscopy 
X 
 
X 
 
 
Zubrod Performance Status 
X 
X 
 
CBC/differential 
X 
 
 
Na, K, Cl, glucose, Ca, Mg, 
and albumin 
X 
 
 
Total bilirubin; AST or ALT 
X 
 
 
Optional imaging study, if 
patient consents: FDG-
PET/CT (see note below) 
 
12-14 weeks post-
therapy 
 
Chest CT or PET/CT 
 
At 6 mos post-RT, 
then annually for 2 
years  
After 3 years, as 
clinically indicated 
CT or MRI of the neck with 
contrast 
 
Initial post- 
treatment scan at 3 
months is required; 
recommended at 
other time points if 
disease progression 
is suspected by 
treating physician 
 
PET/CT of neck 
 
Initial post-
treatment scan at 3 
months is 
recommended; may 
be substituted for 
CT or MRI only if 
the CT component 
is performed with 
contrast as a 
diagnostic quality 
imaging study 
 

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Biopsy 
 
 
If suspicion of 
tumor recurrence 
Adverse Event Evaluation 
X 
X 
X 
Nutrition/Feeding Tube 
Evaluation 
 
 
X 
Dental Assessment 
 
At 12, 24, 60, and 
120 mos. from end 
of treatment 
 
QOL: MDADI  
Mandatory at 6, 12, and 24 months from end of radiation 
QOL: UW-Qol 
For patients who consent: At 6, 12, and 24 mos. from end of 
radiation 
QOL: PSS-HN 
Required: Completed by the investigator and/or research associate 
at 6, 12, and 24 mos. from end of radiation 
QOL: Work Status 
questions 
Required: Completed by the investigator and/or research associate 
at 6, 12, and 24 mos. from end of radiation 
Biospecimen Collection for 
Banking 
For patients who consent: No earlier than 2 weeks and up to 1 
month after the completion of  treatment  
Modified Barium Swallow, 
if patient consents 
24 months +/- 3 months from end of radiation 
 
Notes for Assessments in Follow Up (table above) 
 A brief history & physical examination by a Radiation or Medical Oncologist or an ENT 
or Head & Neck Surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic 
and/or direct procedure), must be done at 1 and 3 months from the end of radiation 
treatment, then every 3 months through year 2, every 6 months for 3 years, then annually.  
 The initial post-radiation imaging evaluation at 3 months after the completion of 
radiotherapy is required. The imaging can be contrast-enhanced CT of the neck, MRI of 
the neck with contrast,  PET/CT of the head and neck with contrast and including 
diagnostic quality imaging of the neck, or “whole body” PET/CT (minimum neck and 
chest) with contrast and including diagnostic quality imaging of the neck based on the 
preference of the treating clinician. Centers that wish to participate in the PET/CT 
correlative study component should refer to guidelines for submitting these images and 
associated data (see Section 10.3). 
 Radiographic imaging (CT, MRI, or PET/CT as appropriate) at follow-up time points is 
highly recommended if disease progression is suspected by the treating physician. If 
performed, radiographic imaging to evaluate the patient for both local-regional 
recurrence and distant metastases is highly recommended (see Section  5.7). 
 Chest imaging: A chest CT +/- contrast or a PET/CT including the chest is required once 
per year for a total of 3 image sets, then may be performed as clinically indicated. 
 Optional imaging study: A post-therapy FDG-PET/CT scan is highly recommended at 
12-14 weeks post-therapy for assessment of response to therapy. If the patient consents to 
participate, the site is required to submit the patient’s post-treatment PET/CT scan; see 
Section 10.3 for details.  
 Biopsy of any lesion(s) suspicious for tumor recurrence is recommended as clinically 
indicated. 

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5. TREATMENT PLAN/REGIMEN DESCRIPTION 
 
Intensity-modulated radiation therapy (IMRT) is required, although non-IMRT techniques  
may be used to treat the low neck, if it is the institution’s practice. For IMRT planning, 
margin expansions will be set at 0.5 cm from GTV to the high dose CTVs. Sites will have the 
option to use an additional 0.3 or 0.5 cm to the PTV, depending on the frequency of IGRT. 
 
 
If PTV margins of 0.3 cm are used, daily IGRT usage is required, and IGRT credentialing is 
required.  If using 0.5 cm PTV margins, a minimum of weekly IGRT is required and imaging 
alignment must be approved by the attending physician on the first day of treatment and 
weekly thereafter. IGRT credentialing is not required for 0.5 cm PTV margin expansion. 
 
5.1 
Chemotherapy (5/24/16)  
 
 
Protocol treatment must begin within 14 days after randomization. 
5.1.1 Arm 1 Patients: Low-dose Intravenous Cisplatin Administration Concurrent with 
Radiation  
 
Cisplatin:  40 mg/m2/day, weekly during radiation treatment, for a maximum of 6 doses.  
 
Dose should be based on actual body weight. Treatment may be administered before or 
after radiotherapy. The first cisplatin infusion should be started within 24 hours before or 
after the first scheduled radiation therapy administration. 
 
No concurrent cisplatin will be administered after the final week of radiation, but the 
final dose of cisplatin may be administered following the last dose of radiation if it is 
administered within the same calendar week. Cisplatin should be administered on 
Mondays or Tuesdays to maximize overlap of daily radiation with cisplatin 
exposure. Administration on Wednesday prior to that day’s radiation dose is acceptable 
but not preferred. Investigators should strive to administer cisplatin on the same day each 
week but variance of 1 day is acceptable for vacations, holidays, etc. If radiation 
treatments are held for toxicity, cisplatin dosing should also be held. If cisplatin is held 
for toxicity, then the dose will not be made up. 
5.1.2 Low-dose Cisplatin Concurrent with Radiation Administration Guidelines 
High dose cisplatin is highly emetogenic. While this protocol is using more frequent 
dosing of cisplatin that is considered moderately emetogenic, investigators should be 
prepared to use aggressive prophylactic antiemetics and hydration. Many institutions will 
have standard guidelines for the administration of cisplatin at the doses used in this study. 
For purposes of this protocol, individual investigators may use these local guidelines 
for cisplatin administration. One possible approach is outlined below. These 
guidelines may need to be modified based on local guidelines and patient related factors 
(e.g. the substitution of normal saline in diabetic patients). Similarly, the anti-emetic 
regimen is to be determined by the local investigator, although one possible approach is 
outlined below. 

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 Low-dose Cisplatin anti-emetic administration guidelines:  5-HT3 antagonists and 
decadron should be given (e.g. ondansetron 16 mg  PO prior to cisplatin  and 8 mg 
PO up to 3 times daily on days 2 and 3 following cisplatin weekly and 
dexamethasone x 3 days starting prior to the cisplatin dose weekly, 12 mg on day 1 
and 8 mg on days 2 and 3 each week OR palonosetron 0.25 mgs IV and decadron 12 
mgs prior to cisplatin. Use of other anti-nausea meds such as aprepitant, 
metoclopramide, or prochlorperazine is left to the discretion of the investigator. 
 Low-dose Cisplatin pre-hydration guidelines: Pre-hydration with 1 liter D5 ½ NS and 
40 meq KCL/ liter x 1 liter prior to cisplatin should be given. Mannitol 12.5 gm IV 
immediately prior to cisplatin may be given. Use of mannitol is left to the discretion 
of the investigator. 
 Low-dose Cisplatin administration: Standard administration is cisplatin, 40 mg/m2 
over 30-60 minutes IV in 250 cc NS.  Infusion rate not to exceed 2 mgs per min. See 
Section 6.0 for dose modifications. See above discussion on scheduling and number 
of doses concurrent with radiation. 
 Low-dose Cisplatin post-hydration guidelines: Following the end of the cisplatin 
administration, an additional liter of D5½ NS with 10 meq KCL/L, 8 meq MgSO4/L, 
and  25 g mannitol should be infused over 2 hours. On the second and third day 
following cisplatin, patient should be encouraged to take at least 2 liters of fluid per 
day orally.  Patients unable to orally self-hydrate should be considered for additional 
IV hydration on these days with NS. The amount of pre- and post-hydration is left to 
the discretion of the investigator.  
 
5.2 
Radiation Therapy (5/24/16) 
Protocol treatment must begin within 14 days after randomization.  
 
All patients will receive 60 Gy delivered in 30 fractions of 2 Gy. Full details of radiation 
dose prescriptions are provided in Section 5.2.7. 
 
Unilateral radiation will be permitted in selected patients; see Section 5.2.4. 
5.2.1 Treatment Technology 
All patients will be managed with IMRT delivered with megavoltage photons. A matched 
AP or AP-PA field with larynx block may be utilized to manage the low neck as 
described in Section 5.2.4. All institutions must be credentialed for IMRT if not already 
done. Treatment verification is required and required frequency of IGRT depends on the 
use of PTV margins (see Section 5 and 5.2.13). 
5.2.2 Immobilization and Simulation 
Patients will be treated supine and must have a secure head and neck immobilization (e.g. 
aquaplast mask) made prior to the treatment planning CT scan. 
 
The treatment planning CT scan should be performed with IV contrast unless 
contraindicated, obtained in the immobilization device and in the treatment position with 
a slice thickness of 3 mm or less. 
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
A diagnostic CT or MRI for structure delineation is recommended. These may be fused 
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PET/CT images may also be fused to the planning CT data set. 
5.2.4 Definition of Target Volumes and Margins 
All specified target volumes and organs-at-risk (OAR) will be contoured on the planning 
CT scan data sets and named according to the nomenclature described below. For the 
purposes of contouring, MRI and PET images, if available and clinically indicated, may 
be fused with the planning CT data set. Target volumes and OARs will be labeled 
according to published guidelines (Santanam 2012). 
 
Gross Tumor Volume (GTV)  
The GTV represents clinically or radiographically grossly involved regions of primary 
tumor or involved nodes designated GTVp_6000 and GTVn_6000 respectively. These 
volumes are defined based on physical exam and review of available imaging. FDG-PET 
may assist in GTV identification but specific GTV border delineation should not rely 
exclusively on PET signal given the known variable association between gross tumor 
extent and PET signal cutoff. For purposes of dose evaluation GTVp and GTVn will be 
labeled GTVp_6000 and GTVn_6000. 
 
Post-Biopsy GTV 
Patients undergoing gross total excision of both primary and gross nodal disease with 
curative intent are not eligible for this study (see Section 3.3.6). Patients undergoing 
diagnostic procedures at the primary site, such as simple/diagnostic tonsillectomy or 
excisional biopsy, are eligible but are not considered to have had an oncologically 
therapeutic surgical procedure even in the absence of clinically or radiologically 
appreciable gross residual disease at the primary site. As such, these patients require full 
radiation dose (60 Gy) to be delivered to a volume immediately adjacent to the tissues 
removed at the time of the biopsy. For purposes of planning, this volume will be labeled 
GTVp and it should be defined relative to the extent of disease prior to removal. This 
GTVp may be defined by fusion of pre-biopsy imaging studies (CT, MRI) with the 
planning CT data set. The gross primary tumor on the pre-biopsy imaging may be 
projected on the planning CT and defined as the intersection with the residual tissues. If 
there is not such an intersection or the residual tissues lie in a different anatomic 
orientation post-biopsy, the GTVp may be defined as a 5 mm expansion into the residual 
tissues circumferential to the area of the biopsy. In the event that pre-biopsy imaging is 
not available the GTVp must be defined relative to the clinical exam of the biopsy site 
and normal anatomic landmarks. For instance, in the specific case of tonsillectomy the 
GTVp will include, at a minimum, the tonsillar bed to include anterior and posterior 
tonsillar pillars up to the level of the soft palate and inferiorly to the pharyngoepiglottic 
fold; the GTVp should be expanded superiorly or inferiorly if the pre-biopsy tumor 
extended past these landmarks. A CTV_6000 and CTV_5400 are then defined for this 
GTVp according to methods defined below. 
 
Nodal Definitions 
 Grossly Positive Nodes (GTVn_6000) are defined as those greater than 1.5 cm in 
long axis and/or > 1 cm in short axis, a cluster of 3 or more borderline size nodes, 
radiographic evidence of extracapsular extension (ECE), or a node of any size 
with evidence of necrosis. Smaller nodes may be determined to be gross disease 

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objects depending on clinical suspicion (based on proximity to the primary site or 
other involved nodes) or demonstration of significant uptake of FDG on PET 
scanning.  
 Extracapsular extension (ECE): is defined as radiographic evidence of irregular 
borders and/or perinodal fat stranding, invasion of adjacent structures, or both. 
Any areas of potential involvement should be included within the GTV. 
Clinicians are highly encouraged to request radiologist review if the determination 
is unclear. 
 Matted Nodes: Three or more abutting nodes with loss of the intervening fat 
planes. Patients with matted nodes should not participate in this trial (see 
exclusion criteria, Section 3.3). 
 
Clinical Target Volume (CTV) 
 CTVs are defined and contoured in relation to the targets they are intended to 
encompass and the dose they are intended to receive. For gross targets (GTVs), 
the CTVs are defined by 3D isotropic expansions that should then be limited by 
potential barriers to tumor spread such as air cavities, external contours and bony 
or fascial planes through which tumor spread is not possible or apparent. 
Similarly CTVs may be expanded beyond the limits defined in this protocol in 
order to cover areas deemed at risk of tumor extension (e.g. neck musculature 
invaded by nodal disease, or pterygoid regions of infratemporal fossa in 
superiorly extending tonsilar cancers). For nodal regions of potential microscopic 
involvement CTVs are defined according to normal anatomic landmarks 
(Gregoire 2014). 
 CTV_6000: Primary Tumor and Involved Nodes 
A CTV_6000 will be defined for primary tumor and involved nodes as a 0.5 cm 
isotropic expansion of the GTVs defined for these structures. When defined for 
nodes, the CTV_6000 should be suffixed as CTVn_6000 to distinguish this from 
the primary, CTVp_6000, for the purposes of plan evaluation. CTV_6000 is the 
sum of CTVp_6000 and CTVn_6000. 
 CTV_5400: High-Risk Subclinical Sites 
High-risk subclinical sites are defined as:  i) areas of potential subclinical tumor 
infiltration beyond the primary site CTVp_6000 and ii) the first echelon node 
levels to the primary site irrespective of gross nodal involvement and all node 
levels containing gross nodes. In the event of a node excision (≤ 4 per protocol) 
that occurred at time of diagnosis, the node levels that contained grossly involved 
adenopathy should be included in CTV_5400, even if there is no residual post 
excision adenopathy. 
 
A CTV_5400 will be defined for these sites and include the following: 
i) 1.0 cm isotropic expansion of GTVp_6000 , which is an 0.5cm expansion on 
the CTVp_6000. 
ii) 1st echelon node levels based on  standard anatomic definitions. In most 
cases 1st echelon  would be ipsilateral level II, but in cases of midline 
primary site involvement this should include bilateral level II. In cases with 
soft palate or posterior pharyngeal wall involvement this should include the 

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lateral retropharyngeal lymph nodes. 
iii)  All node levels containing a CTVn_6000 that has been assigned to 
involved nodes (all grossly involved nodal levels).  
iv) Other high-risk subclinical sites may include nodes < 1cm not thought to 
harbor gross disease yet thought to be at risk of containing more than 
subclinical disease based on their location relative to the primary site. In 
such cases of clinical concern that do not meet the above criteria,  a 0.5cm 
expansion on these nodes can be added to the CTV_5400 at the discretion 
of the treating clinician.   
 CTV_4800: Node Levels at Risk of Microscopic Spread 
A CTV_4800 will be defined to treat node levels without evidence of gross 
disease yet at risk of microscopic spread and not contained in CTV_5400. These 
levels  are defined anatomically according to published Intergroup consensus 
guidelines (Gregoire 2014). The levels to be treated will depend on the site and 
extent of the primary tumor and any grossly involved lymph nodes and are 
indicated in Table 5.2.4A.  
 CTV_4400: Low Neck Nodes at Risk of Microscopic Spread 
For patients with no low neck nodal involvement,  a matched AP or AP-PA field 
with larynx block may be utilized to manage the low neck.  Under this scenario, 
CTV_4800 will not include the low neck, but rather CTV_4400 will be defined by 
contouring the prescription iso-dose line of the AP or AP-PA field.  For centers 
that use IMRT for the low neck, the low neck nodes at risk of microscopic spread 
will be included CTV_4800.   
 
Table 5.2.4A: Nodal Levels to Receive Prophylactic Microscopic Dose–(4800 cGy) 
 
CTV_4800* 
Ipsilateral Neck 
Contralateral Neck** 
N0-1 (in level II – 
IV) 
 Ib (for primary oral 
cavity extension), 
 II-IV 
 RP ( lateral 
retropharyngeal LN)  
for primary extension 
to posterior pharyngeal 
wall or soft palate 
 II-IV 
 RP (lateral 
retropharyngeal LN) 
for primary extension 
to posterior 
pharyngeal wall or 
soft palate 
N2a-b 
 Ib,II,III,IV,V,RP 
 II-IV 
 RP (lateral 
retropharyngeal LN) 
for primary extension 
to posterior 
pharyngeal wall or 
soft palate 
*Applies to neck levels not included in CTV_5400. 
** The contralateral neck may be omitted according to guidelines defined below. 
 
 Contralateral Neck 

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It is recognized that the evidence as to the efficacy and safety of a unilateral neck 
radiotherapy approach within specific patient groups is largely retrospective, yet 
increasingly compelling evidence has led some centers to consider unilateral 
radiotherapy standard practice for selected patients while others continue to treat 
in a bilateral fashion. Unfortunately, the data for patients with selected N2b or 
lateralized tongue base cancers is less well defined in the literature than that for 
N0-N2a tonsillar cancer, and additionally, substantial disparities in opinions 
remain related to the effect of extracapsular extension (Vergeer 2010; Yeung 
2012, Geropantas 2013, Lynch 2013). It also can be difficult to define the number 
of involved nodes, since it may vary depending on whether the site uses CT, MRI 
or PET/CT for initial staging. Based on these considerations, the study team has 
concluded that the use of unilateral radiation techniques should remain optional, 
in deference to the established practice and clinical judgment of the enrolling 
investigator, but have defined 3 groups of patients with respect to neck irradiation. 
 
Unilateral radiotherapy is recommended (see guidelines below) if it is the 
institution’s established practice, if the primary tumor originates in the tonsil, and 
is well-lateralized, with less than 1 cm of involvement of the soft palate or base of 
tongue, no posterior pharyngeal wall involvement, and with minimal nodal 
disease burden (N0-N2a) as assessed by clinical exam and staging radiology 
studies. For patients who share these characteristics but have N2b nodal disease 
confined to ipsilateral level 2 of the neck, unilateral radiotherapy is optional. Due 
to the imperative to maintain high PFS for this trial and the lack of prospectively 
collected data on this controversial subject, for patients with characteristics that 
fall outside these categorizations, bilateral treatment is required. 
 Groups of Patients with Regard to Unilateral or Bilateral Neck Irradiation 
Group 1: Unilateral treatment is recommended. 
T1 to T3 tonsil primaries with < 1cm clinical or radiographic extension into 
tongue base and/or palate, no posterior pharyngeal wall extension, N0-N2a (no 
ECE) 
  
Group 2: Unilateral treatment is optional.   
T1 to T3 tonsil primaries with < 1cm clinical or radiographic extension into 
tongue base and/or palate, no posterior pharyngeal wall extension, N2b (no ECE) 
with involved adenopathy confined to ipsilateral level 2 of the neck 
  
Group 3: Bilateral treatment is mandatory. 
Tongue base, palate or posterior pharyngeal wall primaries or tonsil primaries 
with >1cm soft palate and/or tongue base extension or any posterior pharyngeal 
wall extension; patients with any ECE or with involved adenopathy outside of 
ipsilateral level 2 of the neck 
 
Prior to individual patient randomization, oncologists will declare their intention 
to treat unilaterally or bilaterally, which will serve as a stratification factor 
(Unilateral vs. Bilateral) ensuring balance between the 2 study arms. Exploratory 
analyses adjusted for unilateral vs. bilateral radiotherapy will be conducted when 

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the results are available. 
 Management of the Low Neck (levels III, IV, V) 
Treatment of the uninvolved low neck may be achieved with a single IMRT plan 
encompassing the whole neck along with the primary site. Alternatively the low 
neck may be treated with AP or AP-PA fields, with a midline block to shield 
larynx and spinal cord, junctioned isocentrically with the IMRT volumes at the 
plane of the isocenter.  This may only be done in cases without gross nodes in the 
low neck and if the match is >1 cm clear of gross nodal disease and primary site 
superiorly. The dose for the low neck volumes managed with this technique will 
be 2 Gy per fraction prescribed to 3 cm depth to a total dose of 44 Gy in 22 once 
daily fractions.  
 
Table 5.2.4B: Clinical Target Volume Nomenclature and Description. 
All volumes are to be treated using IMRT in 30 fractions except CTV_4400 in 22 
fractions given to the low neck when applicable. Note: All structures marked as 
Required in the table below must be contoured, and labeled as listed under “Standard 
Name” for digital RT data submission.  All structures marked as Required if applicable 
must be contoured and labeled as listed under “Standard Name” for digital data 
submission IF they are applicable to the patient’s plan. Resubmission of data is necessary 
when labeling of structures does not conform to the DICOM Standard Name listed. 
 
 
 
Standard Name 
Description 
Detailed Specification 
GTVp_6000 
GTV to receive 60 Gy 
at the primary site 
Required 
Equivalent to GTVp as defined 
above 
GTVn_6000 
GTV to receive 60 Gy at 
involved nodes 
Required 
Equivalent to GTVn as defined 
above 
CTVp_6000 
CTV to receive 60 Gy 
at the primary site 
Required 
0.5 cm isotropic expansion of 
GTVp_6000 limited by potential 
anatomic barriers to tumor spread 
such as air cavities, external 
contours and bony or fascial planes 
through which tumor spread is not 
possible or apparent 
CTVn_6000 
CTV to receive 60 Gy at 
involved nodes 
Required 
0.5 cm isotropic expansion of 
GTVn_6000 limited by potential 
anatomic barriers to tumor spread 
such as air cavities, external 
contours and bony or fascial planes 
through which tumor spread is not 
possible or apparent 
CTV_6000 
CTV to receive 60Gy 
Required 
Sum of CTVp_6000 and 
CTVn_6000 
CTV_5400 
CTV to receive 54 Gy at 
high risk volume at the 
i) 1.0 cm expansion of 
GTVp_6000, which is an 0.5cm 

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primary site and applicable 
node levels 
Required  
expansion on the CTVp_6000  
ii) First echelon nodes (unilateral or 
bilateral) 
iii) node levels containing involved 
nodes 
iv) 0.5 cm expansion on nodes < 1 
cm thought to be at risk of 
containing more than subclinical 
disease. 
 
CTV_4800  
 
CTV to receive 48 Gy to 
right and/or left neck 
regions at risk of 
microscopic disease 
Required if applicable 
Defined anatomically according to 
consensus guidelines (Gregoire 
2014). The levels to be treated will 
depend in the site and extent of the 
primary tumor and any grossly 
involved lymph nodes.  
See table 5.2.4A for specifics 
CTV_4400 
CTV to receive 44Gy to low 
neck regions at risk of 
microscopic disease 
Required if applicable 
Option for lower neck volumes 
(levels III, IV,V) treated with non 
IMRT techniques and midline 
sparing junctioned >1cm clear of 
gross disease, defined as 
prescription isodose line of the AP 
or AP-PA field used to treat these 
volumes 
See Table 5.2.6 for corresponding PTV descriptions. 
 
5.2.5 Definition of Organs at Risk 
Note: All structures marked as Required in the table below must be labeled as listed 
under “Standard Name” for digital RT data submission.  Resubmission of data is 
necessary when labeling of structures does not conform to the DICOM Standard Name 
listed. 
Table 5.2.5: Organ at Risk Nomenclature 
For detailed descriptions see below. 
OAR Standard Name 
Description 
SpinalCord 
Spinal cord 
Required 
SpinalCord_05 
PRV = 5 mm expansion on 
spinal cord  
Required 
BrainStem 
Brain stem 
Required 
BrainStem_03 
PRV= 3 mm expansion on 
brainstem 
Required 
Lips 
Lips 

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Required 
OralCavity 
Oral cavity 
Required 
Parotid_R 
Right parotid gland  
Required 
Parotid_L 
Left parotid gland 
Required 
Submandibula_R 
Right submandibular gland 
Required, if applicable 
Submandibula_L 
Left submandibular gland 
Required, if applicable 
Pharynx 
Non-treated pharynx 
Required 
Esophagus_Up 
Cervical esophagus 
Required 
Larynx 
Larynx 
Required 
Mandible 
Mandible 
Required 
NonPTV 
Unspecified tissue, External 
minus all PTVs 
Required 
External 
External border of the 
patient  
Required 
 
 Spinal Cord: The cord begins at the cranial-cervical junction (ie, the top of the C1 
vertebral body). Superior to this is brainstem and inferior to this is cord. The spinal cord 
must be contoured at least 1 cm below the lowest extent of the neck PTVs. The spinal 
cord shall be defined based on the treatment planning CT scan. In addition, however, a 
Planning Risk Volume (PRV) spinal cord shall be defined as: SpinalCord_05 = cord + 5 
mm in each dimension.  
 Brain Stem: The inferior most portion of the brainstem is at the cranial-cervical junction 
where it meets the spinal cord. For the purposes of this study, the superior most portion of 
the brainstem is approximately at the level of the top of the posterior clinoid. The 
brainstem shall be defined based on the treatment planning CT scan. In addition, 
however, a Planning Risk Volume (PRV) brainstem shall be defined as: BrainStem_03 = 
brainstem + 3 mm in each dimension. 
 Lips: The definition of lips is self-explanatory.  
 Oral Cavity: The oral cavity will be defined as a composite structure posterior to lips 
consisting of the anterior ½ to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and 
superiorly the palate, and inferiorly to the plane containing the tip of the mandible.  
 Parotid Glands: Parotid glands will be defined in their entirety (superficial and deep 
lobes) based on the treatment planning CT scan. 
 Submandibular Glands: Submandibular glands will be defined in their entirety based on 
treatment planning CT scans. 

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 Pharynx: This will be defined as the  pharyngeal wall plus adjacent constrictor muscles 
deemed not to require treatment (external to PTVs). This extends from the superior 
constrictor region (level of the inferior pterygoid plates) to the cricopharyngeal inlet 
(level of the posterior cricoid cartilage). 
 Esophagus: This will be defined as the cervical (upper) esophagus, a tubular structure 
that starts at the bottom of pharynx (cricopharyngeal inlet) and extends to the thoracic 
inlet. 
 Larynx:  This will be defined as the glottic and supraglottic larynx, including the tip of 
the epiglottis, the aryepiglottic folds, arytenoids, false cords, and true cords, bounded by 
the thyroid cartilage laterally, anteriorly including the anterior edge of the pre-epiglottic 
fat, and posteriorly bounded by the anterior edge of the pharyngeal wall or the posterior 
edge of the arytenoid and/or cricoid cartilage.  
 Mandible: This includes the entire bony structure of the mandible from TMJ through the 
symphysis. It is recognized that for oral cavity cancers, this may overlap with CTVs and 
PTVs. 
 Unspecified Tissue Outside the Targets (NonPTV): This will be defined as tissue 
located between the skull base and thoracic inlet external to all PTVs and defined normal 
stuctures within the external contour of the patient. 
5.2.6 Planning Target Volumes 
All CTVs will have associated PTVs which represent the volumes to which radiation 
dose will be prescribed, delivered and evaluated. The PTVs are isotropic expansions of 
the CTVs to account for internal motion and residual set-up error. 
 
PTVs are defined as either a 3 mm or 5 mm expansion of the CTV in all planes, 
depending on the frequency of IGRT (see Sections 5 and 5.2.13). 
 
The simple isotropic expansion of CTVs to create PTVs will result in dosimetric 
challenges in 2 instances: 
i. 
when the CTV expansion results in a PTV that overlaps a critical OAR or 
its PRV, hence dose delivered to this PTV will exceed the acceptable dose 
limits for the OAR;  
ii. 
and when the CTV expansion results in PTVs extending beyond the 
patient external contour, making PTV dose calculation and evaluation 
unreliable. 
 
The PTVs may be modified in the following situations:  
1) When a PTV overlaps a critical OAR (spinal cord and/or brainstem) and its 
associated PRV, the PTV should be modified to exclude the PRV so as to limit the 
dose delivered to the PRV within constraints defined in table 5.2.10.  
2) The PTVs should be constrained 5 mm within the external contour. For situations 
where gross disease is external to the external contour (disease at or through the skin 
surface), the use of 5 mm tissue equivalent material (bolus) is required, and no PTV 
constraint should be used underneath the bolus. 
 

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Table 5.2.6: Planning Target Volume Nomenclature and Description 
All to be treated in 30 fractions except PTV_4400 in 22 fractions. For CTV descriptions see 
Table 5.2.4B. Note: All structures marked as Required in the table below must be contoured and 
labeled as listed under “Standard Name” for digital RT data submission. All structures marked as 
Required if applicable must be contoured and labeled as listed under “Standard Name” for 
digital data submission IF they are applicable to the patient’s plan. Resubmission of data is 
necessary when labeling of structures does not conform to the DICOM Standard Name listed. 
 
Standard Name 
Description 
Detailed Description 
PTVp_6000 
PTV to receive 60Gy at the 
primary site 
Required 
3-5mm expansion of 
CTVp_6000 
 
PTVn_6000 
PTV to receive 60 Gy at 
involved nodes 
Required 
3-5mm expansion of 
CTVn_6000 
PTV_6000  
PTV to receive 60 Gy 
Required 
Sum of PTVp_6000 and 
PTVn_6000 
PTV_5400 
PTV to receive 54 Gy at the 
primary site and applicable 
node levels 
Required  
3-5mm expansion of 
CTV_5400 
PTV_4800 
PTV to receive 48 Gy in neck 
Required if applicable 
3-5mm expansion of 
CTV_4800 
PTV_4400 
PTV to receive 44 Gy at 
lower neck (non IMRT) 
Required if applicable 
CTV_4400* 
*No expansion from CTV_4400 to PTV_4400. 
 
5.2.7 Dose Prescription 
The prescribed radiotherapy dose to gross disease for all patients will be 60 Gy delivered 
in 30 fractions of 2 Gy. For Arm 1, radiotherapy will be delivered once daily, 5 fractions 
per week Monday to Friday for 30 consecutive treatment days (6 weeks), with weekly 
concurrent cisplatin at 40 mg/m2.  
 
For Arm 2, the radiotherapy will be delivered alone (without the addition of 
chemotherapy) in an accelerated schedule over 5 weeks, which requires delivery of 6 
fractions per week.  The sixth fraction can be delivered either on a Saturday or as a 
second daily fraction, with at least a 6 hour interfraction interval if 2 fractions are given 
on one of the weekdays.   
 
Target volumes will be similar in both arms and for both, the primary tumor and involved 
nodes will receive 60 Gy (2 Gy per fraction for 30 fractions), high-risk subclinical sites 
will receive 54 Gy (1.8 Gy per fraction for 30 fractions) and nodal regions at risk of 
microscopic spread will receive 48 Gy (1.6 Gy per fraction for 30 fractions). If the low 
neck is treated with non-IMRT technique, 44 Gy (in 22 fractions) will be prescribed to a 

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point of 3 cm depth.  Unilateral radiation will be permitted in selected patients; see 
Section 5.2.4. 
 
Doses prescribed are indicated in Table 5.2.7 below. All PTVs are to be treated 
concurrently within a single IMRT plan of 30 fractions. If the low neck is treated with 
non-IMRT techniques to 44 Gy in 22 fractions once daily fractions will commence 
simultaneously and be delivered concurrently with the IMRT plan. 
 
Table 5.2.7: Doses Prescribed to PTVs 
Target 
Standard Name 
Dose (Gy) Fraction 
Size (Gy) 
# of 
fractions  
Dose 
specification 
technique 
PTV_6000  
60 
2.0 
30 
Covering ≥ 
95% of 
PTV_6000 
PTV_5400 
54 
1.8 
30 
Covering ≥ 
95% of 
PTV_5400 
PTV_4800 
48 
1.6 
30 
Covering ≥ 
95% of 
PTV_4800 
PTV_4400 
44 
2.0 
22 
100% at 3 cm 
 
5.2.8  Treatment Planning Priorities and Instructions 
 
IMRT Dose Prescription to PTVs 
Doses are prescribed to PTVs as outlined in Table 5.2.7. The treatment goal is that 95% 
of the volume of all PTVs must receive the prescribed dose with a minimum  dose 
(defined as dose to 99% of PTVs) greater than 93% of the prescription dose and a 
maximum  dose (defined as dose encompassing 0.03 cc of the PTV) less than 110-115% 
of the highest prescription dose.  
 
It is recognized that portions of PTVs close to the skin or critical PRVs (spinal cord and 
brainstem) may receive significantly less than the prescription doses. This is acceptable 
in these regions as long as cold spots within these PTVs do not exist within the GTV. In 
cases of PTVs close to skin, tissue equivalent bolus must be utilized to ensure adequate 
dose. 
 
It is also recognized that PTVs abutting or enclosing higher dose PTVs will have regions 
of maximum dose that may exceed  their prescribed dose in order to achieve acceptable 
minimal doses to the higher dose PTVs which are considered a higher priority target. 
 
Prioritization for IMRT Planning 
1. Spinal Cord 
2. Brainstem 
3. PTV_6000 
4. PTV_5400 

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5. PTV_4800 and PTV_4400 
6. a. Parotid gland contralateral to primary tumor site 
    b. Larynx 
7. a. Pharynx 
    b. Contralateral submandibular 
8. a. Oral Cavity 
    b. Lips 
    c. Esophagus 
9. a. Parotid gland ipsilateral to primary tumor site 
    b. Mandible 
10. Unspecified tissue outside the targets 
5.2.9  Doses to Normal Structure 
Dose limitations  to normal stuctures are described below. For the critical structures of 
spinal cord and brainstem these are mandatory. For other structures recommended limits 
are provided, but the doses delivered should always be as low as reasonably achievable 
without compromising doses to PTVs. 
 Spinal Cord: The PRV for spinal cord (SpinalCord_05) should not exceed 48 Gy 
to any volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In 
treatment planning, the spinal cord PRV should be given the highest priority. 
 Brainstem: The PRV for brainstem (BrainStem_03) should not exceed 50 Gy to 
any volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm).  In 
treatment planning, the BrainStem_03 should be given less priority than the 
SpinalCord_05, but more than the critical structures listed below. 
 Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy. 
 Oral Cavity: Reduce the dose as much as possible. The mean dose should be < 
32 Gy for the oral cavity. Efforts should also be made to avoid hot spots (> 60 
Gy) within the non-involved oral cavity. 
 Parotid Glands: In most cases, it will be easier to spare one parotid than the 
other. The treatment planning goal will be for this individual parotid gland to 
receive a mean dose of < 26 Gy but efforts should be made to reduce this further 
if possible without compromising dose to PTVs. 
 Contralateral submandibular gland: If contralateral level Ib is not a target, aim 
to reduce mean contralateral submandibular gland to < 39 Gy. 
 Pharynx: Reduce the dose as much as possible. Some recommended (but not 
mandatory) treatment goals include: 1) No more than 33% of the Pharynx exceeds 
50 Gy; 2) Mean dose < 40 Gy; 3) No more than 15% of the Pharynx exceeds 60 
Gy. 
 Esophagus: Reduce the dose as much as possible; recommended (but not 
mandatory) treatment goal: mean dose < 30 Gy. 
 Larynx: Reduce the dose as much as possible. The larynx mean dose is 
recommended to be ≤ 35 Gy if whole-neck IMRT is used. 
 Mandible: Reduce the dose as much as possible. Hot spots within the mandible 
should be avoided. It is recommended that maximum dose within the mandible be 
< 63 Gy. 
 Unspecified Tissue Outside the Targets (NonPTV): No more than 1cc of 
unspecified tissue outside the targets can receive ≥ 63Gy . 

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5.2.10 Dose Compliance Criteria (4/29/15) 
The compliance criteria listed in Table 5.2.10 will be used to evaluate each case. The Per 
Protocol and Variation Acceptable categories are both considered to be acceptable. The 
Per Protocol cases can be viewed as ideal plans, and the Variation Acceptable category 
can include more challenging plans that do not fall at or near the ideal results. A final 
category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable. Plans falling in this 
category are considered to be suboptimal and additional treatment planning optimization 
is recommended to avoid protocol deviation. 
 
Table 5.2.10: Planning Target Volume and Critical OAR Constraints and 
Compliance Criteria 
Name of 
Structure 
Dosimetric 
parameter* 
Per Protocol 
Dose (Gy) 
Variation 
Acceptable 
PTV_6000 
 
D95%*(Gy) 
D99%(Gy) 
Dmax**(Gy) 
 60 
 > 60 and ≤ 63 
≥ 55.8  
 ≥ 54 
≤ 66 
 ≤ 69 
CTV_6000 
  
V60 Gy (%) 
 
≥ 99 % 
   
95 to 99 % 
 
  
 
  
PTV_5400 
D95%*(Gy) 
D99%(Gy) 
  
≥ 54 
≥ 50.2 
 
≥ 51.3 
≥ 48  
  
 
 
 
 
CTV_5400 
  
V54 Gy (%) 
  
≥99 % 
  
95 to 99 % 
 
  
 
  
PTV_4800 
D95%*(Gy) 
D99%(Gy) 
≥ 48  
≥ 44.6   
≥ 44 
≥ 43.2 
 
 
 
 
CTV_4800 
  
V48 Gy (%) 
  
99 % 
  
95 to 99 % 
 
  
 
  
 
 
 
 
SpinalCord_05 
Dmax**(Gy) 
≤48 
≤50 
 
 
 
 
Spinal Cord 
Dmax**(Gy) 
≤45 
≤48 
 
 
 
 
BrainStem_03 
Dmax**(Gy) 
≤ 50 
≤52 
A Deviation Unacceptable will be scored when the Variation Acceptable limits are 
not met. 
 
*D95%(Gy) = dose to 95% of volume 
**Dmax = maximum dose to 0.03 cc of the volume  

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Recommended dose acceptance criteria for other normal tissue,  
but not to be used for plan score 
 
Structure 
Recommended dose acceptance criteria 
Parotid  
Mean dose to one parotid ≤ 26 Gy 
Larynx 
Mean dose ≤ 35 Gy 
Pharynx 
Mean dose  ≤ 40 Gy 
Submandibula_R  
Or 
Submandibula_L 
(contralateral) 
Mean Dose  ≤ 39 Gy 
OralCavity (excluding PTV’s) 
Mean dose  ≤ 32 Gy 
Esophagus_Up 
Mean dose  ≤ 30 Gy 
NonPTV 
D1cc <  63 Gy 
Mandible  
 
D0.03cc <  63 Gy 
 
5.2.11 Delivery Compliance Criteria 
Protocol treatment must begin within 14 days of randomization. Treatment breaks must 
be clearly indicated in the treatment record along with the reason(s) for the treatment 
break(s). Treatment breaks, if necessary, should not exceed 3 treatment days at a time and 
5 treatment days total. Treatment breaks should be allowed only for resolution of severe 
acute toxicity and/or for intercurrent illness and not for social or logistical reasons. Any 
treatment break(s) exceeding 2 treatment days for reasons other than toxicity/illness will 
be considered a protocol deviation. 
 
Given the importance of timeliness of treatment delivery in this study, it is strongly 
recommended that patients receive twice-daily treatments with a minimum 6-hour inter-
fraction interval to compensate for missed days including holidays and those for toxicity 
or illness once sufficiently recovered with the goal of keeping the overall treatment time 
within the limits defined in Table 5.2.11. 
 

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Table 5.2.11: Delivery Compliance Criteria 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Overall Treatment 
time 
Six week arm 
<45 days 
46-50 days 
>50 days without a 
medically 
appropriate 
indication for delay 
Overall Treatment 
time 
Five week arm 
<37 days 
38-42 days 
>42 days without a 
medically 
appropriate 
indication for delay 
Interruptions (without 
medical indication) 
0-2 days 
2-4 days 
>4 days 
 
5.2.12 Dose Calculations 
The primary data set for dose calculation is CT.  In the case in which contrast is present 
during the treatment planning CT, the density of the contrast should be overridden to a 
representative background electron density.  The dose grid size should be ≤ 3 mm in all 
directions, which means that the CT slice thickness should be ≤ 3 mm.  
 
Dose calculation algorithms have been credentialed by IROC Houston. To find whether 
your commercial treatment planning system has been credentialed by IROC Houston, 
please see the list from the following website: 
(http://rpc.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf).   
 
Any other dose calculation algorithms not listed on the web site must be 
credentialed by IROC Houston prior to the use for this study.   
5.2.13  Daily Treatment Localization/IGRT 
Daily image guidance (IGRT) of IMRT is required if  PTV margins of 0.3 cm are used,  
and IGRT credentialing is also required. (Section 8.3). Note: Sites that have been 
approved for head and neck IGRT credentialing will not have to repeat IGRT 
credentialing for this study.   
 
If using PTV margins of 0.5 cm,  a minimum of weekly IGRT will be required, and the 
imaging alignment  must be approved by the attending physician on the first day of 
treatment and weekly thereafter.  IGRT credentialing is not required for 0.5 cm PTV 
margin expansion.  
 
IGRT may be achieved using any one of more of the following techniques: 
 Orthogonal kilovoltage (KV) images, e.g. ExacTrac; 
 
Linear-accelerator mounted kV and MV conebeam CT images; 
 
Linear-accelerator mounted MV CT images (e.g., Tomotherapy); 

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 
Other mechanism, after discussion with the Radiation Oncology Co-Chair and/or 
Medical Physics Co-chair. 
 
The institution’s procedure to register the treatment day imaging dataset with the 
reference dataset should comply with the following recommendations: 
 
Region-of-interest (ROI) or “clip box” for fusion should be set to encompass the high 
dose PTV and adjacent spinal cord;  
 
If the fusion software allows the user to create an irregular ROI (e.g. ExacTrac), 
 
treatment room objects seen on in-room X-rays should be excluded from the 
registration; 
 
Both manual (e.g. based on bony anatomy) and automatic (e.g. based on mutual 
information) types of registration can be used; the result of the fusion must be 
visually checked for the alignment of the bony anatomy, such as vertebral bodies and 
applicable surgical clips and soft tissue structures (e.g. optic nerves and/or optic 
chiasm); 
 
Following the registration, the translational and (if the appropriate technology is 
available) rotational corrections should be applied to the treatment couch. If all the 
variances are less than 2.5 mm (this typically corresponds to one half of the usual 
PRV margin), the treatment can proceed without correction (however, the 
physician/team may elect to perform adjustments even for a variance < 2.5 mm). If 
one or more corrections are 2.5-5 mm, adjustment is necessary prior to treatment; 
however, reimaging is not mandatory. If one or more of the corrections are larger than 
5 mm, the imaging must be repeated in addition to performing table/positioning 
adjustments. 
 
Management of Radiation Dose to the Patient from IGRT 
NRG Oncology is concerned about the estimated doses given from IGRT, and is 
committed to limiting the imaging dose when IGRT is used in any of its protocols. This 
can be accomplished by avoiding the use of this technology to make small changes in 
patient positioning that are within the stated PTV margins. The imaging dose to the 
patient may become significant if repeated studies are done for patients with severe set up 
problems (e.g. requiring frequent corrections that are larger than the PTV margins). It is 
recommended that patients demonstrating severe set up problems during the first week of 
treatment be moved to a treatment with larger margins. 
5.2.14 Replanning 
In cases of weight loss > 10% or substantial shrinkage of lymphadenopathy during 
therapy, it is recommended that the immobilization mask be adjusted or re-made in order 
to preserve adequate immobilization, and that a repeated simulation CT be performed to 
assess the dose distributions in the current anatomy. Whether or not a new IMRT plan 
will be generated is at the discretion of the treating physician. If a new plan is made, the 
targets should be the same as those used for the initial plan and not adjusted in cases of 
disease regression, except to respect clear anatomic barriers such as skin or fascial or 
muscle planes initially uninvolved by disease. The new CT dataset should be used for 
IGRT image registration when the patient’s shape changes significantly. 
5.2.15 Radiation Therapy Adverse Events (5/24/16) 
Grade 3-4 (CTCAE, v. 4) therapy-induced mucositis and/or dysphagia, which are 

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enhanced by cisplatin, are expected to develop in about two thirds of patients. Nutritional 
evaluation prior to the initiation of therapy to decide on the use of a prophylactic 
gastrostomy (PEG) tube placement is recommended, but in the absence of significant 
pretreatment dysphagia and associated weight loss of  < 10% body weight the insertion of 
a prophylactic PEG is not recommended. If done the placement of a feeding tube should 
be recorded, as should proportion of use of a feeding tube during and after treatment (e.g. 
greater than or less than 50% of nutrition by tube). Other common radiation adverse 
events include: fatigue, weight loss, regional alopecia, xerostomia, hoarseness, transient 
ear discomfort, dysgeusia, and skin erythema and desquamation within the treatment 
fields.  
 
Less common long-term treatment adverse events include: hypothyroidism, loss of 
hearing, chronic swallowing dysfunction requiring permanent feeding tube, and cervical 
fibrosis. Much less common radiation adverse events include: mandibular 
osteoradionecrosis (< 5% incidence with attention to the dental recommendations 
provided in Appendix I, “Dental Assessment and Management Document), and cervical 
myelopathy (< 1% with restriction of spinal cord dose to ≤ 45 Gy). 
 
  
5.3 
Surgery 
Surgery is expected to play only a limited role in the favorable risk HPV-associated 
cancers included in this study. Locoregional progression is expected in <10% of patients. 
The role of neck dissection has been declining in recent years, in part due to a high rate of 
negative specimens when planned neck dissections are performed in cancers of the 
oropharynx.  
5.3.1    Post-Treatment Imaging/Timing 
While centers are allowed to follow their institutional policies in conducting earlier post-
treatment imaging evaluations, the major initial post-radiation imaging evaluation for the 
purposes of this study is required at 12-14 weeks after the completion of radiotherapy 
with diagnostic quality, contrast-enhanced CT or MRI of the neck. PET/CT may be 
conducted in this timeframe as well, based on the preference of treating clinicians, but 
does not substitute for the mandatory anatomic imaging. The required diagnostic CT may 
be performed as part of the integrated PET/CT but only if the CT is considered diagnostic 
quality and is contrast enhanced. PET/CT may facilitate pre-and post-treatment 
evaluation of metabolic response and the need for post-treatment neck dissection. Centers 
that are participating in the PET/CT correlative study component should refer to section 
10.3 for guidelines on submitting the PET/CT images. If physical examination and 
imaging suggest residual disease at the primary site, a biopsy will be performed to 
confirm residual disease; otherwise, patients will undergo serial follow up. Annual chest 
imaging is required to a maximum of 3 annual imaging sets and thereafter should be 
performed based on clinical judgment. 
5.3.2    Post-Treatment Surgical Salvage of Residual Disease 
Treatment of residual disease at the primary site will be determined by the treating 
clinicians and the clinical situation, and surgical resection, re-irradiation, chemotherapy, 
or palliative care will be done.  If the primary site is cleared of residual disease yet 
residual disease at the cervical nodal basin is strongly suggested by imaging/clinical 
evaluation, then selective neck dissection will be performed unless a cytologic sampling 

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(biopsy) of the node is negative. Post-treatment “planned” neck dissection will be defined 
as being performed for residual disease and within 20 weeks (140 days) of completion of 
radiotherapy. Positive neck specimens removed within 140 days will be considered part 
of the initial treatment plan and not considered as failures of initial management; positive 
specimens upon neck dissection beyond 140 days will be considered regional failures. 
Note that this is relaxed from the traditional definition of 105 days (15 weeks) in order to 
permit resolution of HPV-associated adenopathy, which is commonly cystic and may 
have a somewhat slower regression rate. Such post-treatment consolidation neck 
dissections will encompass only the areas (typically only levels 2 and 3) initially involved 
in the side of the neck in question. The extent of neck dissections performed for nodal 
recurrence, nodal progression, or salvage of disease at the primary ultimately will be 
determined by the treating surgeon. In the case of negative PET/CT in patients who did 
not achieve clinical or CT/MRI-based radiological nodal CR, a minimum of careful 
clinical examination is required at 3 months, and further imaging is highly recommended, 
such as follow-up imaging every 3-4 months for at least 24 months,  as well as careful 
recording of the clinical dimensions of the residual abnormality. 
 
5.4 
Imaging 
 
See Section 10.3 for details of the optional FDG-PET/CT correlative study.  
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
5.5.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. These may 
include analgesics, antiemetics, topical mouth rinses, skin creams/ointments, etc. In 
general, HIV-positive patients who are on a stable Highly Active Anti-Retroviral Therapy 
(HAART) regimen should continue HAART while receiving chemotherapy. However, 
for patients who are newly diagnosed with HIV but with laboratory parameters meeting 
the eligibility criteria, it is preferable to defer initiation of HAART until after 
chemotherapy is completed. HAART regimens containing zidovudine and stavudine 
should be avoided during chemotherapy due to concerns for overlapping toxicity with 
chemotherapy. In addition, the protease inhibitor atazanavir (RayatazTM) can cause a 
physiologically unimportant hyper-hyperbilirubinemia; however, in the setting of 
chemotherapy, some experts suggest switching that drug for another equally effective 
one. If HAART is withheld during chemotherapy, it should be resumed promptly after 
conclusion of the last cycle of chemotherapy. 
5.5.2 Prohibited Therapies 
The use of amifostine or palifermin as a radioprotectant is not allowed. The use of 
granulocyte colony stimulating factor or erythropoietin is not allowed. Transfusion is to 
be performed at the discretion of the treating physician. Any exceptions must be 
approved by the Principal Investigator, Dr. Yom, or the Medical Oncology Co-Chairs, 
Drs. Gillison and Gibson. 
5.5.3 Participation in Other Trials  
Patients may not participate in other clinical trials that are intended to treat the diagnosed 
oropharyngeal cancer or intended to reduce toxicity of therapy. 

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5.6 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.7 
Measurement of Response/Progression 
 Response versus “Tumor Clearance” versus Cancer Progression 
Response and confirmation of local (primary site) or regional (neck) “tumor 
clearance” are not endpoints in this study. Clinical or radiographic evidence of 
progressive local-regional disease beyond 20 weeks should be documented in the 
clinical record and ideally confirmed by local or regional biopsy, neck dissection, or 
salvage surgery. CT or MRI (of head and neck region, with Chest CT), or PET/CT 
(including chest anatomy) may be used as radiographic evaluation of overall cancer 
status. The primary, neck and chest portions of the scans should be evaluated and 
reported separately. The CT portion of a PET/CT may serve as sufficient radiographic 
evaluation of the chest. If CT or MRI is used for evaluation of the head and neck 
region, CT of chest will be needed to rule out distant disease or second primaries at 
the designated evaluation intervals. 
 Local or Regional Progression 
Local (primary site) or regional (neck) progression is defined as clinical or 
radiographic evidence of progressive disease at the primary site or neck. The location 
of progressive disease should be separately distinguished (local vs. neck) to document 
the precise pattern of failure if possible. Progression of local or regional disease 
should be confirmed by biopsy when possible but may be clinically assessed and 
documented in the clinical record at the judgment of the treating clinicians. Suspicion 
of disease progression exclusively on the basis of indeterminate or positive PET/CT 
scan must be pathologically confirmed. 
 Distant Metastasis 
Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended 
where possible. A solitary, spiculated lung mass/nodule is considered a second 
primary neoplasm unless proven otherwise.  
 Second Primary Neoplasm 
Tumor reappearing with the initial and immediate adjoining anatomical region of the 
primary will be considered local recurrence. Multiple lung nodules/masses are 
considered distant metastases from the index cancer unless proven otherwise. 

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6. TREATMENT MODIFICATIONS/MANAGEMENT (5/24/16) 
6.1 
Chemotherapy Dose Modifications (20-DEC-2017) 
 
Note: If adverse events prevent the administration of chemotherapy, the patient may 
continue to receive radiation therapy. 
6.1.1 Cisplatin Dose Modifications During Concurrent Radiation 
Note: Substitution of carboplatin for cisplatin during adverse events is NOT allowed. 
  
Patients will be examined and graded for subjective/objective evidence of developing 
toxicity weekly according to CTCAE, v. 4 while receiving concurrent cisplatin with 
radiotherapy.  
 
Treatment interruptions are allowed if there is symptomatic mucositis or skin reaction 
that, in the judgment of the clinician, warrants a break. For chemotherapy-attributable 
AEs requiring a break in treatment, resumption of concurrent cisplatin may begin when 
AEs have recovered to the levels specified below. Chemotherapy should be discontinued 
in the event of more than 2 events requiring dose reduction (e.g. if grade 3 or greater non-
hematologic or hematologic event occurs at the reduced dose of cisplatin, at 23 
mg/m2/week. 
 
If an AE does not resolve to the levels specified in the sections below prior to the 
calendar week of the last radiation treatment (See Section 5.1 for details concerning 
parameters for timing of last allowable concurrent cisplatin dose), then chemotherapy 
should be discontinued. 
 
There will be no dose re-escalation for concurrent cisplatin.  
 
Chemotherapy dosage modifications are based upon lab values obtained prior to cisplatin 
and interim non-hematologic toxicities during the week prior to a particular cisplatin 
dose. 
 
The dose modifications for cisplatin (below) are intended to be permanent (i.e., if the 
patient’s dose is reduced to dose level -1, it remains at the reduced dose level). 
6.1.2    Cisplatin Dose Modifications for Hematologic Adverse Events during Concurrent 
Radiation 
 
Starting Dose 
Dose Level -1 
Dose Level -2 
40 mg/m2 
30 mg/m2 
23 mg/m2 
 
Chemotherapy must not be administered until the ANC is ≥ 1,000 mm3 and platelets are 
≥ 75,000 mm3. If not, delay 7 days. Cisplatin should be held every week until the above 
ANC and platelet parameters are met. Dose reductions when cisplatin is resumed after 
delay for low ANC or platelets will be as follows, based upon counts at time cisplatin 
was held. 

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ANC 
 
Platelets 
Reduction 
< 1000 mm3 
or 
< 75,000 
One dose level 
Note: Hematologic growth factors for neutropenia or anemia are not allowed during 
concurrent cisplatin and radiation treatment. 
 
Neutropenic Fever: Grade 3 (CTCAE, v 4) neutropenic fever (ANC < 1000/mm3 with a 
single temperature of > 38.3 degrees C [101 degrees F] or a sustained temperature of ≥ 38 
degrees C [100.4 degrees F] for more than 1 hour) is an expected potential complication 
of concurrent chemotherapy and radiotherapy or chemotherapy alone. If neutropenic 
fever is noted, the chemotherapy dose reduction will be determined by the weekly blood 
counts. See above.  
6.1.3    Cisplatin Dose Modifications for Non-Hematologic Adverse Events during 
Concurrent Radiation 
Renal Adverse Events: Dose will be modified based on the serum creatinine prior to each 
cisplatin dose. If the serum creatinine is ≤ 1.5 mg/dL, creatinine clearance is not 
necessary for treatment with full dose. If the serum creatinine is > 1.5 mg/dL, a creatinine 
clearance should be obtained by urine collection or nomogram calculation (valid only if 
serum creatinine is not changing rapidly). 
 
Cisplatin must not be administered until creatinine is ≤ 1.5 or creatinine clearance ≥ 
50. Once the creatinine has met the above parameters, cisplatin may be restarted with the 
below modifications based on the creatinine at the time the cisplatin was held: In general, 
cisplatin should be held for weekly intervals (rather than restarting cisplatin later in the 
same week that a dose limiting AE is seen). 
 
Cisplatin dose modifications for creatinine during concurrent radiation 
Creatinine (mg/dL) 
 
Creatinine 
clearance, measured 
or calculated ml/min 
Cisplatin dose 
reduction 
≤ 1.5 
or 
 ≥ 50 
No change 
> 1.5 
and 
40-49 
One dose level 
 
 
< 40 
Hold drug  
 
Neurologic (neuropathy) Adverse Events: 
 
Grade (CTCAE, v. 4) 
Dose Reduction 
0-1 
None 
2 
One dose level  
3-4 
Hold drug  
 
Ototoxicity:  Should patients develop clinical evidence of ototoxicity, further audiometric 
evaluation is required. A neurologic deficit should be distinguished from a conductive 
loss from obstruction of the Eustachian tube leading to a middle ear effusion. Because no 
AE scale, including the CTCAE, v. 4, has been validated in terms of correlation with 
clinically relevant hearing loss, there are no protocol mandates requiring dose reduction 

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for audiogram-determined sensorineural hearing loss without an analogous clinical high 
grade ( > grade 2) hearing loss. However, for clinical grade 3 or higher hearing loss, 
cisplatin should be held and for grade 2 clinical hearing loss, one dose level reduction 
should be implemented. 
 
All Other Non-Hematologic Adverse Events Attributable to Cisplatin during Concurrent 
Radiation: For all other non-hematologic adverse events in which toxicity is  ≥ grade 2 
(CTCAE v. 4), investigators are advised to evaluate and manage correctable issues 
promptly to prevent worsening of toxicity. For these events in which toxicity is ≥ grade 3, 
investigators should hold cisplatin, with weekly re-evaluation until AE grade falls to 0-1,  
then restart cisplatin at one lower dose level. Note: Grade 3 mucositis is commonly 
experienced by head and neck cancer patients; the investigator generally would not hold 
the cisplatin dosing in this case, unless there is unusual concern for progression to grade 4 
mucositis. 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP 
web site at                                                                                          
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will 
be reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application 
accessed via r the CTEP web site (https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613)  
 
 In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to NRG Oncology at 1-800-227-5463, ext. 4189, for instances when Internet fails. 
Once Internet connectivity is restored, an AE report submitted by phone must be entered 
electronically into CTEP-AERS. 
7.1 
Adverse Events (AE) 
 
Definition of an 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 (investigational) product, 
whether or not considered related to the medicinal (investigational) product (attribution 
of unrelated, unlikely, possible, probable, or definite). (International Conference on 
Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements. ; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]  
7.2 
Serious Adverse Events (SAEs)  
Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table 
in section 7.2 will be reported via CTEP-AERS. SAEs that require 24 hour CTEP-AERS 
notification are defined in the expedited reporting table in section 7.2. Contact the 
CTEP-AERS Help Desk if assistance is required. 

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Definition of an SAE: Any adverse drug event (experience) occurring at any dose that 
results in any of the following outcomes: 
 Death; 
 A life-threatening adverse drug experience; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect;  
 Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner.  
7.3 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to 
treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the 
CTEP-AERS system within 30 days of AML/MDS diagnosis. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
 
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
 Myelodysplastic syndrome (MDS) 
 Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified.  
7.4 
CTEP-AERS Expedited Reporting Requirements (4/29/15) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via CTEP-AERS, the CTEP Adverse Event  Reporting 

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System, 
accessed 
via 
the 
CTEP 
web 
site, 
https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613  
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and 
satisfies NRG Oncology requirements for expedited adverse event reporting. 
 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Oncology Operations Office at 1-800-227-5463, ext. 4189, for 
instances when Internet fails. Once Internet connectivity is restored, an AE report 
submitted by phone must be entered electronically into CTEP-AERS. 
 
 CTEP-AERS-24 Hour Notification requires that an CTEP-AERS 24-hour notification 
is electronically submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS 24-hour notification must be followed by an CTEP-AERS 5 Calendar 
Day Report. Serious adverse events that require 24 hour CTEP-AERS notification are 
defined in the expedited reporting table below. 
 Supporting source document is not mandatory.  However, if the CTEP-AERS report 
indicates in the Additional Information section that source documentation will be 
provided, then it is expected.  If supporting source documentation accompanies an 
CTEP-AERS report, include the protocol number, patient ID number, and CTEP-
AERS ticket number on each page, and fax supporting documentation the NRG 
Oncology dedicated SAE FAX, 215-717-0990. 
 A serious adverse event that meets expedited reporting criteria outlined in the 
following table but is assessed by the CTEP-AERS as “expedited reporting NOT 
required” must still be reported to fulfill NRG Oncology safety reporting obligations. 
Sites must bypass the “NOT Required” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described 
in the table below. Important: All AEs reported via CTEP-AERS also must be reported 
on the AE section of the appropriate case report form (see Section 13.2).  

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Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under a Commercial Agent within 30 Days of the Last 
Administration of the Commercial Agent. 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 

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1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing a Commercial Agent: The following are 
protocol specific exceptions to expedited reporting via CTEP-AERS. Report the following AEs 
in an expedited manner only if they exceed the grade in parentheses next to the AE: nausea 
(grade 3), vomiting (grade 3), diarrhea (grade 3), dehydration (grade 3), lymphocyte count 
decreased (grade 4), and mucositis (grade 3). Routine adverse event reporting on the case report 
form fulfills safety reporting requirements for these events at the aforementioned grades. 
 
8.   REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES (20-DEC-
2017) 
Access requirements for OPEN, Medidata Rave, and TRIAD: Site staff will need to be 
registered with CTEP and have a valid and active CTEP Identity and Access Management 
(IAM) account.  
 
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 
 
 

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Documentation Required 
IVR 
NPIVR AP 
A 
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 
 
Additional information can be found on the CTEP website 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact 
the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
8.1 CTSU Registration Procedures (20-DEC-2017) 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
IRB Approval  
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 
 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. 

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Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing or amendment review. For sites using the CIRB, IRB 
approval information is received from the CIRB and applied to the RSS in an automated 
process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study 
locally.  The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution must 
inform the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
Downloading Site Registration Documents  
Site registration forms may be downloaded from the NRG-HN002 protocol page located 
on the CTSU members’ web site.  
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
 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 NRG Oncology link to expand, then select trial protocol # 
 Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.   
 
Requirements for NRG-HN002 site registration: 
 IRB Approval Letter (for sites not participating via the NCI CIRB; 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) 
 IRB/REB Approved Informed Consent (English and native language versions*) 
*Note: Institutions must provide certification/verification of IRB/REB consent 
translation to NRG Headquarters (described below). 
 IRB/REB registration number renewal information as appropriate. 
 CTSU RT Facilities Inventory Form NOTE:  Per NCI policy all institutions that 
participate on protocols with a radiation therapy component must participate in the 
Radiological Physics Center (RPC) monitoring program.  If this form has been 
previously submitted to CTSU it does not need to be resubmitted unless updates have 
occurred at the RT facility. 
 
 

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8.2 
Submitting Regulatory Documents (20-DEC-2017) 
Submit completed forms along with a copy of your IRB Approval and Informed Consent 
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 1100 
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.8.2.1 
Checking Your Site’s Registration Status 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU web site.   
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
 
Click on the Regulatory tab  
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or 
the enrolling investigator’s status with the NCI or their affiliated networks. 
 
Non-English Speaking Canadian and International Institutions: 
*Translation of documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB approved consent, must be 
provided in English and in the native language. Certification of the translation is optimal 
but due to the prohibitive costs involved NRG will accept, at a minimum, a verified 
translation. A verified translation consists of the actual REB approved consent document 
in 
English 
and 
in 
the 
native 
language, 
along 
with 
a 
cover 
letter 
on 
organizational/letterhead stationery that includes the professional title, credentials, and 
signature of the translator as well as signed documentation of the review and verification 
of the translation by a neutral third party. The professional title and credentials of the 
neutral third party translator must be specified as well. 
8.2.2 Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
In addition to the requirements above, Canadian institutions must also complete the 
following documents to the CTSU Regulatory Office via the Regulatory Submission 
Portal: 

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 Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site 
Information Form;  
 Qualified Investigator Undertaking Form;   
 Research Ethics Board Attestation Form; 
 Attestation memo for participation in FDG-PET/CT imaging.  
8.2.3 Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
 
For institutions that do not have an approved LOI for this protocol: 
International sites must submit an LOI to NRG Headquarters to receive approval to 
participate 
in 
this 
trial. 
(For 
more 
details, 
see 
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx.  
 
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to 
enrolling patients to this study. 
8.3 
RT-Specific Pre-registration Requirements 
For detailed information on the specific technology requirement required for this study, 
please refer to the table below and utilize the web link provided for detailed instructions. 
The check marks under the treatment modality columns indicate whether that specific 
credentialing requirement is required for this study. Specific credentialing components 
may require you to work with various QA centers; however, Imaging and Radiation 
Oncology Core (IROC) Houston will notify your institution when all credentialing 
requirements have been met and the institution is RT credentialed to enter patients onto 
this study.  
RT 
Credentialing 
Requirements 
 
Web Link for Procedures and Instructions: 
http://irochouston.mdanderson.org 
 
Treatment 
Modality 
 
IMRT 
Key Information  
 
Facility 
Questionnaire 
X 
The IROC Houston electronic facility questionnaire (FQ) should 
be completed or updated with the most recent information about 
your institution. To access this FQ, email 
irochouston@mdanderson.org to receive your FQ link. 
Credentialing 
Status Inquiry 
Form 
X 
To determine whether your institution needs to complete any 
further credentialing requirements, please complete the 
“Credentialing Status Inquiry Form” found under credentialing 
on the IROC Houston QA Center web site 
(http://irochouston.mdanderson.org). 
Knowledge 
Assessment 
N/A 
 
Benchmark 
Cases 
N/A 
 

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8.3.1 Digital RT Data Submission to NRG Oncology Using TRIAD 
TRIAD is the image exchange application used by the NRG. TRIAD provides 
sites participating in NRG clinical trials a secure method to transmit DICOM RT 
and other objects.  TRIAD anonymizes and validates the images as they are 
transferred. 
 
TRIAD Access Requirements: 
 Site physics staff who will submit images through TRIAD will need to be 
registered with The Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account. Please refer to 
the beginning of Section 4 for instructions on how to request a CTEP-IAM 
account. 
 To submit images, the site physics user must have been assigned the 'TRIAD site 
user' role on the relevant Group or CTSU roster. NRG users should contact your 
site Lead RA to be added to your site roster.  Users from other cooperative groups 
should follow their procedures for assignment of roster roles. 
 RAs are able to submit standard of care imaging through the same method. 
 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to 
be able to submit images. TRIAD installation documentation can be found on 
the NRG website Core Lab tab.    
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
Phantom 
Irradiation 
X 
An IMRT H&N phantom study provided by the IROC QA 
Center Houston must be successfully completed. Instructions for 
requesting and irradiating the phantom are found on the IROC 
Houston web site (http://irochouston.mdanderson.org). 
Tomotherapy and Cyberknife treatment delivery modalities 
must be credentialed individually.   
IGRT 
Verification 
Study 
X 
The institution must submit a sample of verification images 
showing their ability to reproducibly register daily IGRT 
information with a planning CT dataset (i.e. the GTV falls 
within the CT simulation defined PTV). The patient (“as if 
patient”) used for this study must have a target (or mock target) 
in the H&N region. The information submitted must include 2 
IGRT datasets (from 2 treatment fractions) for a single patient. 
This information with a spreadsheet (the spreadsheet is available 
on the IROC Houston web site: 
http://irochouston.mdanderson.org. 
Pre-Treatment 
Review 
N/A 
 
Institution 
 
IROC Houston will notify the institution and NRG Headquarters 
that all desired credentialing requirements have been met. 

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If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
8.4      Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
8.4.1 Oncology Patient Enrollment Network (OPEN) 
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. All site staff 
(NRG 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’ web site 
https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
 All eligibility criteria have been met within the protocol stated timeframes. Site 
staff should use the registration forms provided on the group or CTSU web site as 
a tool to verify eligibility. 
 All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
Access requirements for OPEN: 
 See beginning of Section 4 for information on obtaining a CTEP-IAM account.  
 To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group or CTSU roster.  
 To perform registrations on protocols for which you are a member of the NRG, 
you must have an equivalent 'Registrar' role on the NRG roster.  Role assignments 
are handled through the Groups in which you are a member.  
 To perform registrations to trials accessed via the CTSU mechanism (i.e., non-
Lead Group registrations) you must have the role of Registrar on the CTSU roster. 
Site and/or Data Administrators can manage CTSU roster roles via the new Site 
Roles maintenance feature under RSS on the CTSU members' web site. This will 
allow them to assign staff the "Registrar" role. 
 
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 located on the CTSU 
members' web site 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. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: websupport@acr.org or call the NRG 

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Registration Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. 
The registrar will ask the site to fax in the eligibility checklist and will need the 
registering individual’s e-mail address and/or return fax number. This information is 
required to assure that mechanisms usually triggered by the OPEN web registration 
system (e.g. drug shipment and confirmation of registration) will occur.  
 
9. DRUG INFORMATION  
9.1 
Investigational Study Agent 
Not applicable for this study. 
9.2 
Commercial Agent: Cisplatin 
 
 
Adverse Events: Sites must refer to the package insert for detailed pharmacologic and 
safety information.  
 
9.2.1 Availability/Supply 
 
Please see Section 5.1 for administration instructions. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage. 
 
10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
10.1     Biomarkers (5/24/16) 
Institutions must screen patients, whose tumors must be p16 positive by 
immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical 
Laboratory Improvement Amendments (CLIA)-certified laboratory. Then the institution 
must submit one H&E slide and one p16 IHC slide to the NRG Oncology Biospecimen 
Bank for central review prior to randomization  (see the table below). Note: A rigorous 
laboratory accreditation process similar to the U.S. CLIA certification, such as the 
provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) 
Program in Canada, the College of American Pathologists (CAP), or an equivalent 
accreditation in other countries, is acceptable. 
 
Central review will be conducted with rapid turnaround (1-2 business days from receipt 
of the slides) coordinated by Dr. Richard Jordan at the NRG Oncology Biospecimen 
Bank. Specifics of type and source of p16 antibody and testing method will be requested 
(although not required) at the time of specimen submission. Every effort should be made 
to obtain and submit this information at the time of specimen transmission, in order to 
ensure the fastest possible resolution should there be any questions about staining 
technique. 
 
Note: Due to potential delays in customs, Canadian sites will be permitted to submit an 
Aperio digital image of the H&E and p16 stained slide for remote central review by Dr. 
Jordan.  Prior approval for this must be obtained from the NRG Biospecimen Bank. In 
cases in which Dr. Jordan determines that the image quality or staining is inadequate, the 
site will be required to send the original slides to the Biospecimen Bank directly. 
 
H&E stained slides will be used to confirm presence of tumor in the sample and to aid in 
assay interpretation. Interpretation of each p16 immunostained slide will be performed 

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using the H-score method described by Jordan, et al. (2012) that has been validated as a 
reliable, reproducible, and accurate method to score p16 in squamous cell carcinoma of 
the head and neck. The primary reviewer will be the Pathology Co-Chair, Richard Jordan, 
DDS, PhD, with secondary analysis by the Pathology Co-Chair, Christina Kong, MD.  
p16 IHC will be scored as evaluable if strong and diffuse positivity was observed in the 
tissue mounted on each slide. The highest intensity of p16 staining present in the tumor 
will be scored on an ordinal score of 0-3, relative to the intensity of the positive (score 3) 
and negative (score 0). The percent of tumor staining at the highest intensity also will be 
estimated within 5% increments. The H score is derived from the cross product of the 
intensity score (0 to 3), and the percent of tumor staining at the highest intensity (0-
100%).  An optimal H-score cut-point of 60 on a scale of 0-300 yields an average 
sensitivity of 91.6% and specificity of 90.4% for HR-HPV oncogene expression and thus 
an H-score cut-point of 60 indicates that a tumor with diffuse low-intensity nuclear and 
cytoplasmic p16 staining in the majority of the tumor is a true positive (Jordan 2012).  
High agreement on inter-rater interpretation has been reported (Schlecht 2011, Thavaraj 
2011), indicating the familiarity of pathologists with interpretation of IHC assays.  
Similarly, comparable assay performance for p16 to that observed here has also been 
previously reported (Schlecht 2011, Thavaraj 2011). The most common p16 monoclonal 
antibody in use is E6H4 (CINtec). Other acceptable p16 antibody types include 16P04 
and JC8.  If a different p16 antibody is used, discussion with the Pathology Co-Chairs is 
strongly encouraged. 
 
In cases in which a major discrepancy arises between the primary evaluator and the 
central reviewer (Dr. Jordan), the p16 stained slide and the associated probe and testing 
specifics will be sent to a secondary central reviewer, Dr. C. Kong at Stanford University, 
to resolve the disagreement. If p16 staining cannot be established as positive through the 
central review process, the patient is not considered eligible. 
 
Ship all biospecimens for central review and banking for this trial to: 
NRG Oncology Biospecimen Bank—San Francisco 
2340 Sutter Street, Room S341 (Box 1800) 
University of California San Francisco 
San Francisco, CA 94115 
415-476-7864;  NRGBB@ucsf.edu   
 
See the tables below for mandatory and optional specimen collection. 
 
See further details of specimen collection/processing/shipping on the RTOG/NRG 
Oncology web site, 
http://www.rtog.org/LinkClick.aspx?fileticket=1SFlEVxSui4%3d&tabid=281.
 
 
 
Mandatory: Specimen Collection for Central p16 Confirmation 
The specimens are being collected for confirmation by central review (see Section 10). 
Institutions must screen patients, who must be p16 positive by immunohistochemistry in 
order to be eligible for the trial. 

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 Required Forms: ST form and pathology reports with accession number and p16 
staining result; any other personal health information (PHI) should be redacted. 
 Shipping costs: Submitting site pays cost of shipping. 
 Results: Dr. Richard Jordan, NRG Oncology Biospecimen Bank, or Dr. Christina 
Kong, Pathology Co-Chair, will report to NRG Oncology. 
 Residual Material:  p16 slides will be retained unless return is requested by the 
submitting site. 
 
For questions, contact:  
NRG Oncology Biospecimen Bank;NRGBB@ucsf.edu; 415-476-7864/FAX 415-476-
5271 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
One H&E slide 
One p16 stained 
IHC slide 
Pre-Treatment 
Enrolling institution, 
using a CLIA certified 
laboratory, screens 
patient with p16 testing 
by IHC (must be 
positive). Then 
Biospecimen Bank 
does central review 
prior to randomization. 
 
Slides shipped 
ambient 
 

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Optional Study #1: Circulating HPV DNA as a Potential Marker for Relapse 
Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as 
specified in the protocol. Sites are not permitted to delete the specimen component from 
the protocol or from the sample consent. 
 
Specimens are being collected to determine whether a novel method for detecting tumor-
derived DNA is superior to qPCR in the detection of circulating HPV DNA in the blood 
(see Section 2.6 for further details). 
 Required Form: ST form 
 Biospecimen Kits: Available from the NRG Oncology Biospecimen Bank  
 Shipping days: Monday-Wednesday (U.S. sites); Monday-Tuesday (Canada and 
Non-North American). 
 Shipping costs: Return labels are provided for frozen biospecimens only. 
 
For questions, contact:  
NRG Oncology Biospecimen Bank;NRGBB@ucsf.edu; 415-476-7864/FAX 415-476-
5271 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Plasma: 5-10 mL of 
anticoagulated 
whole blood from 
two EDTA tubes #1 
and #2 (purple/ 
lavender top) and 
centrifuge 
 
 
1) Pre-treatment; 
2) During the 
treatment, 
obtained after 
20Gy RT but 
before 28 Gy; 
3) No earlier than 2 
weeks and up to 
1 month after the 
completion of  
treatment  
Frozen plasma 
samples containing 
1 mL per aliquot in 
1 mL cryovials (5-
10) 
 
 
Need plasma from 
two tubes 
Plasma sent frozen 
on dry ice via 
overnight carrier 
 

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Optional Study #2: PI3K Pathway Activation and Its Associated Genomic Profile as 
Prognostic Biomarkers of HPV Related Oropharyngeal Cancer 
Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as 
specified in the protocol. Sites are not permitted to delete the specimen component from 
the protocol or from the sample consent. 
 
Specimens are being collected to study the PI3K pathway (see Section 2.7 for further 
details). 
 Required Forms: ST form and  pathology reports to confirm the diagnosis 
 Biospecimen Kits:  Available from the NRG Oncology Biospecimen Bank. 
 Shipping days: Frozen specimens: Monday-Wednesday (U.S. sites); Monday-
Tuesday (Canada and Non-North American). FFPE: No restriction. 
 Shipping costs: Return labels are provided for frozen biospecimens only.  
 
For questions, contact:  
NRG Oncology Biospecimen Bank 
415-476-7864/FAX 415-476-5271 
NRGBB@ucsf.edu 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Representative H&E 
stained slides of the 
primary tumor 
Pre-treatment 
H&E stained slide 
(can be the same 
one submitted for 
central review) 
 
Slide shipped 
ambient 
A corresponding 
paraffin-embedded 
tissue block or 2 
mm punch block  of 
the primary tumor 
taken before 
initiation of 
treatment 
Pre-treatment 
Paraffin-embedded 
tissue block or 
punch block (with 
punch block H&E).  
If site is unable to 
provide the block or 
punch, then 10 
unstained tumor 
slides (cut at 5 
micron) is an 
acceptable 
alternative  
 
Block or unstained 
slides shipped 
ambient (ship with a 
cold pack during hot 
weather) 
 
Whole blood for 
DNA: 5-10 mL of 
anticoagulated 
whole blood in 
EDTA tube #3 
Pre-treatment; note: 
If site missed this 
collection time point 
they may collect 
whole blood for 
Frozen whole blood 
samples containing  
1 ml per aliquot in 
1ml cryovials (3-5) 
Whole blood sent 
frozen on dry ice via 
overnight carrier 

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(purple/lavender 
top) and mix 
DNA at a later time 
point but must note 
this on the ST Form. 
 
10.2  Quality of Life (5/24/16) 
Completion of the MD Anderson Dysphagia Inventory-Head and Neck (MDADI-HN)is 
mandatory, as the MDADI is being used to assess the primary objective of the trial. 
Patients who speak English (or read one of the languages for which a translation is 
available; see below) are required to complete the MDADI assessments. If the patient 
does not understand spoken English and only reads languages not available in the 
validated MDADI translations, the patient can still participate in the trial, as this has been 
factored into the trial statistics; however, reasons for not completing this required 
component should be clearly documented. 
 
Patients must be offered the opportunity to consent to the optional quality of life 
component.  If the patient consents to participate,  the site is required to administer the 
University of Washington Quality of Life Questionnaire, version 4 (UW-QoLv.4)  at 
baseline, completion of radiation therapy, and at 6, 12 and 24 months from the end of 
radiation. Sites are not permitted to delete the quality of life component from the protocol 
or from the sample consent.  
 
Optional Online Completion of QOL Assessments  
Patients who consent to participate in the quality of life (QOL) component of this study 
have the option of completing QOL forms online from any location, including home, via 
VisionTree Optimal Care (VTOC). The baseline QOL forms must be completed in 
hardcopy at the time of enrollment, but all subsequent QOL forms can be completed by 
the patient online. Patients without e-mail or Internet access can participate in the QOL 
component of the study by completing hardcopy (paper) forms. Indeed, at any time, any 
patient may choose to fill out their QOL form using the hardcopy form. The QOL forms 
completed via VTOC are identical to the hardcopy forms; this technology does not add to 
or change the QOL assessments in this study. 
 

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Following completion of baseline QOL forms, if the patient wishes to complete any of 
the subsequent QOL assessments online, the patient must have an e-mail address that 
they consent to use for this purpose. Patients’ e-mail addresses are necessary so that e-
mail reminders may be sent to them to remind them to fill out QOL forms that are due. 
The patient’s e-mail address also will be used for password-protected access to 
VisionTree Optimal Care (VTOC), Patients who are interested in participating but do not 
yet have an e-mail address can obtain one for free from a number of sources (e.g.,Yahoo!, 
Hotmail, or AOL).  
 
VTOC will send patients e-mail reminders to complete QOL forms. The first reminder 
will be sent at the beginning of the window for completion of the form, with a second 
reminder sent halfway through the window, if the form has not yet been completed. A 
maximum of 3 reminders will be sent for each of the 4 QOL assessment time points 
(subsequent to the baseline assessments). After the patient has completed all forms, a 
dialogue box will appear thanking the patient for completing the QOL form(s), and the 
patient will no longer receive reminders for that time point.  
 
Site Research Associates (RAs) will receive training in the use of VTOC via NRG 
Oncology webinars and educational sessions. Note: The site RA is responsible for 
setting up the patient’s account on VTOC. The RA may do so by logging on the 
VTOC portal at the following link https://rtog.optimalcare.com - medical team.  RA 
login information will be provided by VTOC after the patient is randomized to the 
study. The patient’s VTOC account must be set up within 14 days after 
randomization. The RA or study administrator will be informed via the VTOC “At a 
Glance” form management system when QOL forms have been completed or when the 
window for a particular form has closed. If the site RA receives a notice that forms have 
not been completed, she or he will contact the patient to remind the patient to fill out the 
QOL form or inquire why the forms have not been completed. The RA will complete the 
cover page for each form that was not completed (either via VTOC or in hardcopy) and 
will submit the cover page (see Section 12). 
 
The Performance Status Scale for Head and Neck Cancer (PSS-HN and the Work Status 
questions will be completed by the investigator and/or research associate at the following 
time points:  at  baseline, at completion of radiation therapy, and at 6, 12 and 24 months 
from the end of radiation. The Charlson Comorbidity Index (CCI) will be completed by 
the investigator and/or research associate at baseline only. 
 
The MD Anderson Dysphagia Inventory-Head and Neck (MDADI-HN) 
The MDADI will be the primary tool to assess swallowing-related QOL. The MDADI is 
a 20-item PRO instrument, scored on a scale from 1 to 5 (lowest to highest), consisting of 
global, emotional, functional, and physical subscales. The questionnaire can be 
completed by the patient in 5-10 minutes and is available in English, Spanish, Brazilian, 
and Portugese. The MDADI is the first validated self-administered questionnaire 
designed to measure the impact of dysphagia on the health-related QOL (HRQOL) of 
patients with head and neck cancer. Scores range from 0 (extremely low functioning) to 
100 (high functioning).  The score is further divided into a global score question, six 

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emotional quotient questions (score range 6–30), five functional quotient questions (score 
range 5–25) and eight physical quotient questions (score range 8–40).   
 
The University of Washington Quality of Life Questionnaire, version 4 (UW-QoLv.4) 
The UW-Qolv.4 will be used as a secondary tool to assess general QOL. Hassan and 
Weymuller of the University of Washington, Seattle, developed the University of 
Washington Quality of Life Questionnaire and first published in 1993 (Hassan). It has 
been validated and widely used since. This questionnaire was designed specifically to 
address problems incurred by head and neck cancer patients. The first scale consists of 20 
questions on head and neck cancer symptoms that generate scores for 4 domains or 
dimensions of quality of life; communication, eating, pain, and emotional well-being. 
Global symptoms, disability attributable to head and neck cancer, and response to 
treatment also are assessed (Terrell 1998). It is a validated instrument that is available in 
English. In the original UW-QoLv.4 relevant domains were identified: Eating (6 items), 
Communication (4 items), Pain (4 items), and Emotion (6 items). Each had an internal 
consistency (Cronbach α value) of greater than 0.80. Construct validity was demonstrated 
by moderate correlations with SF-12 Physical and Mental component scores (r=0.43-
0.60). Test-retest reliability for each domain demonstrated strong reliability between the 
2 time points. Correlations were strong for each individual question, ranging from 0.53 to 
0.93 (Terrell 1997). The questionnaire was tested on 75 head and neck cancer patients 
and was compared to 2 established tools, the Karnofsky Performance Scale (KPS) and the 
Sickness Impact Profile (SIP), for validity, acceptability, reliability, and responsiveness.  
The scores of the UW-QoLv.4 correlated well with the KPS and Sickness Impact Profile, 
indicating validity. The test-retest reliability coefficient was 0.95 (Hassan 1993).   
Normative data have previously been published (Lin 2003, Terrell 1997).  
 
The UW-QoLv. 4 has undergone several improvements.  Version 3 included 10 domain-
specific questions focusing on physical symptoms, physical functioning, and social 
function. Specifically, the items address pain, appearance, activity level, recreation, 
swallowing, chewing, speech, shoulder function, taste, and saliva production. The most 
current version, Version 4, includes 2 additional questions about emotional function; the 
2 specific questions address depression and anxiety (Weymuller 2001, Roges 2002). In 
addition to domain-specific items, both versions also include 4 generic QOL questions:  
 What is your overall quality of life (‘Global QOL')?;  
 What is your health-related quality of life (“Global HR-QOL”)?  
 How has your health-related quality of life changed (“Transitional HRQOL”, 
“Incremental HR-QOL”)?  
 Free text response to describe quality of life (“Open-ended QOL”). Patients have 
used this question as an opportunity to describe their QOL in their own words or 
in drawings.  
The additional items of mood and anxiety have been tested against the Center for 
Epidemiology Studies Depression Scale (CES-D) and the Hospital Anxiety Depression 
Scale (HADS). The UW-QOLv.4 mood correlated with the scores and "case-ness" 
categories of the HADS depression and CES-D scales, whereas the UW-QOLv.4 anxiety 
correlated with the scores and "case-ness" of the HADS anxiety. Questions on mood and 

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anxiety can help identify significant psychological morbidity, taking a score of less than 
75 for UW-QOLv.4 mood and less than 70 for UW-QOLv.4 anxiety (Rogers 2006).   
 
Scoring of the UW-QoLv.4 can be found at 
http://depts.washington.edu/otoweb/research/head_neck_cancer/uw_qol_scoring_instruct
ions.pdf.  
 
Each of the domain-specific items is scored from 0 (worst QOL) to 100 (best QOL). The 
‘composite’ score is created by averaging the scores from the 10 (version 3) or 12 
(version 4) items. The 4 generic questions in the composite scoring are not included, 
because they represent different constructs. It is recommended that the questions on 
global QOL, global HR-QOL and transitional HR-QOL items be used independently as 
they provide different and useful perspectives from the composite score. Scoring of 
individual domain items range from 0 (worst QOL) to 100 (best QOL) for each item. 
Intermediate scores depend on the number of responses to each question: On 3 point 
items, scores are 0, 50, and 100. On 4 point items, scores are 0, 33, 67, and 100.  On 5 
point items, scores of 0, 25, 50, 75, and 100. For clarity, the scoring sheets list specific 
scores for each item response. The scoring sheet should not be used as the questionnaire.  
 
The Performance Status Scale for Head and Neck Cancer (PSS-HN) 
The PSS-HN will be an exploratory tool to compare clinician ratings of swallowing 
function between arms. The PSS-HN is a clinician-rated instrument consisting of 3 
subscales: normalcy of diet, public eating, and understandability of speech. The PSS-HN 
has been psychometrically validated (List 1990) and recommended by the National 
Comprehensive Cancer Network for measurement of swallowing and speech 
performance in patients with head and neck cancer. The tool is used in an unstructured 
interview format. It is not a PRO; hence, investigators or research associates can 
complete it quickly without adding to patient burden. 
 
Charlson Comorbidity Index (CCI) 
Classically, head and neck cancer patients have a high burden of comorbidity, related in 
part to risk behaviors of smoking and alcohol use. In the HPV positive population, pre-
existing comorbidities are expected to be lower compared to the HPV negative head and 
neck cancer population. The CCI (Charlson 1987) will be collected by chart extraction 
once at baseline to characterize the study cohort and assess comparability between the 
treatment arms. It is not a PRO; hence, it can be completed by investigators or research 
associates without adding to patient burden.   
 
Employment/Work Status and Return to Work after Radiotherapy  
An exploratory objective will be to determine the impact of radiotherapy de-escalation in 
HPV positive oropharyngeal cancer on the patient’s work status before and after 
treatment.  Descriptive statistics will be used to assess work status before and after 
treatment. Work status will be tested for associations with concurrent chemotherapy use, 
age, gender, marital status, education level, tumor factors and health related quality of life 
using the UW-QoLv.4.  
 

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The following questions regarding work status will be completed by the investigator 
and/or research associate on a case report form. 
 
At Baseline and Follow Up 
Q1. Which if the following best describes the patient’s current work status? 
(Select all that apply) 
1 Currently working in at least one FULL time job 
2 Currently working in at least one PART time job 
3 Not working outside of the home 
4 Student, full-time 
5 Student, part-time 
6 Not employed 
7 On disability 
8 On sick leave 
9 Retired 
10 Other, please specify_________________________________________________ 
11 Don't know 
  
Q2. How many hours a week does the patient work? ____ hours 
 
Q3. Which of the following best describes the patient’s primary income? 
1        Salaried annual 
2        Wages hourly 
3        Self employed 
4        Other specify                                                                                    _ 
  
Method of payment (for health care received) 
1.      Private insurance 
2.      Medicare 
3.      Medicare and Private Insurance 
4.      Medicaid 
5.      Medicaid and Medicare 
6.      Military or Veterans sponsored 
7.      Self-Pay (No Insurance) 
8.      No means of payment 
9.      Unknown 
 
10.3  FDG-PET/CT Imaging (5/24/16) 
Patients must be offered the opportunity to consent to the optional FDG-PET/CT 
imaging. If the patient consents to participate, the site is required to submit the patient’s 
post-treatment PET/CT scan and associated information, as specified in Section 10.3.3. 
Sites are not permitted to delete the imaging  component from the protocol; however,  it 
is acceptable for sites in Canada to remove the optional PET/CT scan from the sample 
consent  if the site does not plan to participate in this component.  
 
A post-therapy FDG-PET/CT scan is highly recommended at 12-14 weeks post-therapy 

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for assessment of response to therapy (see Section 2.5 for rationale and hypothesis). This 
scan is required for the patient to participate in this substudy. 
 
If the patient’s pre-therapy FDG-PET/CT scan is available, institutions are highly 
encouraged to submit this scan as well (see Section 10.3.3 below for details of 
submission). 
10.3.1 Recommended FDG-PET/CT Imaging Sequence and Details 
 Serum glucose must be measured (ideally within 1 hour of FDG administration).  
 If the serum glucose concentration is found to be > 200 mg/dL, the study should be 
rescheduled.  The referring physician or primary physician will be contacted to 
optimize blood glucose control.  
 It is recommended that the PET/CT scan begin 60 minutes +/- 10 minutes after FDG 
injection. 
 It is recommended that patients be imaged from the orbits through the upper thigh.  
 A dedicated head and neck imaging acquisition (orbits to upper thorax) with the 
patient’s arms down is recommended given the higher sensitivity of this exam. The 
remainder of the body is to be scanned with the patient’s arms raised over the 
patient’s head. If patients cannot tolerate these positions for the PET/CT scan, 
investigators can use different patient positioning. 
 A low-dose CT scan is required for attenuation correction and anatomical localization 
of findings in the PET scan. 
 The acquisition parameters for the dedicated head and neck CT, low-dose CT scan 
must be approximately as follows: kV = 120; effective mAs = 90-150 (patient 
dependent, auto current modification acceptable); gantry rotation time < 0.5 sec; 
maximum reconstructed slice width = 2.5 mm (overlap acceptable); standard 
reconstruction algorithm, maximum reconstruction diameter = 30 cm; and without 
iodinated contrast. 
 The acquisition parameters for the low-dose CT scan for attenuation correction must 
be approximately as follows: kV = 120; effective mAs = 30–80 (patient dependent, 
auto current modification acceptable); gantry rotation time < 0.5 sec; maximum 
reconstructed width = 3–5 mm without overlap; standard reconstruction algorithm, 
minimum reconstruction diameter = outer arm to outer arm; and without iodinated 
contrast. 
 The axial field of view of the CT scan for attenuation correction will range from the 
mid thighs to the base of the skull. Arm positioning will be the same as for the PET 
scan (see above). 
 The CT scan will be performed during the patient’s normal breathing. No respiratory 
gating is needed. 
 After the CT scan, a PET scan covering the same axial field of view will be 
performed. This scan will start at the upper thighs. The number of bed positions and 
the acquisition time per bed position will be scanner specific. Typical parameters are 
6 bed positions and an acquisition of 2 to 5 minutes per bed position. The dedicated 
head and neck PET/CT will typically follow the body exam. Two bed positions will 
often suffice for orbits to upper thorax (top of aortic arch), and acquisitions must be  
at a minimum of 6 minutes per bed position and be reconstructed into a 30 cm field of 
view (FOV) with a 256 x 256 matrix. 

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 Additional diagnostic-quality CT of the neck may be performed with contrast if 
needed to fulfill requirements for anatomic post-treatment imaging. 
10.3.2 FDG-PET/CT Image Reconstruction 
The PET/CT data will be corrected for dead time, scatter, randoms, and attenuation using 
standard algorithms provided by the scanner manufacturers. For the dedicated head and 
neck views, a post-filter with a full-width at half maximum (FWHM) in the range of 5 
mm is recommended. 
10.3.3 Submission of FDG-PET/CT Image and Site Read 
 Following the completion of PET/CT imaging at the site, the institution will submit  
images in DICOM format via TRIAD to IROC Imaging; see Section 8.3.1 for details 
regarding TRIAD. 
 Institutions must submit a case report form (CRF) for each PET/CT image in which a 
site reader characterizes the patient’s therapy response using the 5-point scale 
outlined in Section 2.5 (i.e. the local site read). 
10.3.4 FDG-PET/CT Central Image Evaluation 
 Rapid review process: For the first 3 patient cases with post-treatment PET/CT 
imaging submitted by an enrolling center, these images will be evaluated with central 
rapid review by the Imaging Co-Chairs to ensure consistency in the application of the 
scoring system and provide feedback to the local site, if advisable. Subsequently, 
central rapid review only will be conducted based on CRFs indicating an 
indeterminate or positive read by the local site. 
 For study purposes, PET/CT images will be retroactively interpreted by an NRG 
Oncology Imaging Core Panel (NRGICP) of expert PET/CT readers who will have no 
involvement or knowledge of the participant’s clinical care and who will be blinded 
to the participant’s diagnosis, local PET/CT scan results, and clinical history.  No 
NRGICP readers can be site investigators at the site producing the PET/CT scans and 
local site reads (characterization of patient response). NRGICP readers will be shown 
a group of 10 cases for training purposes. Feedback on each of these training cases 
will be provided prior to reading the HN002 patients’ PET/CT scans.  
 NRGICP readers will be provided with a case report form (CRF) that details—in a 
standardized manner—basic patient demographics that include age, gender, height, 
and weight. Readers will be instructed to characterize the therapy response using the 
5-point scale outlined in Section 2.5.  
 Each PET/CT scan will be evaluated independently by 3 NRGICP PET/CT readers.   
 
10.4  Determining the Extent of Dysphagia using the Modified Barium Swallow (5/24/16) 
10.4.1. Long-term swallowing outcomes will be measured at selected sites using modified 
barium swallow (MBS) studies according to the assessment schedule in Section 4 
(baseline and 24 months ± 3 months after the end of radiotherapy) and the instructions 
provided in the Modified Barium Swallow Study Form.  
 
Participating institutions must complete the the MBS Credentialing Checklist prior to 
enrolling patients on this substudy and must follow the instructions for the MBS and 
submission of the MBS video in Appendix II. Facilities unable to participate in the MBS 
assessments may still enroll patients on the main study, NRG-HN002, without 
participating in the swallowing evaluations.  

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11.      MODALITY REVIEWS 
11.1 
Radiation Therapy Quality Assurance Reviews  
The Principal Investigator, Sue S. Yom, MD, PhD, and the Radiation Oncology Co-
Chairs, Jimmy J. Caudell, MD, PhD, and John Waldron, MD, will perform RT Quality 
Assurance Reviews after cases enrolled have been received at IROC Philadelphia RT. 
The RTQA reviews will be ongoing, and will be facilitated by IROC Philadelphia RT. 
 
The goal of the review is to evaluate protocol compliance.  The review process is 
contingent on timely submission of radiotherapy treatment data as specified in Section 
12.2. The scoring mechanism is: Per Protocol, Variation Acceptable, and Deviation 
Unacceptable. 
11.2 
Drug Quality Assurance Reviews  
The Medical Oncology Co-Chairs, Maura Gillison, MD, PhD, and Michael Gibson, MD, 
will perform a Chemotherapy Assurance Review of all patients who receive or are to 
receive chemotherapy in this trial.  The goal of the review is to evaluate protocol 
compliance.  The review process is contingent on timely submission of chemotherapy 
treatment data as specified in Section 13. The scoring mechanism is: Per 
Protocol/Acceptable Variation, Unacceptable Deviation, and Not Evaluable.  A report is 
sent to each institution once per year to notify the institution about compliance for each 
case reviewed in that year. 
 
Drs. Gillison and Gibson will perform a Quality Assurance Review after NRG 
Headquarters has received complete data for the first 20 cases enrolled. Drs. Gillison and 
Gibson will perform the next review after NRG Headquarters has received complete data 
for the next 20 cases enrolled. The final cases will be reviewed within 3 months after this 
study has reached the target accrual or as soon as NRG Headquarters has received 
complete data for all cases enrolled, whichever occurs first. 
 
12.      DATA AND RECORDS (5/24/16) 
12.1    Data Management/Collection (20-DEC-2017) 
Data collection for this study will be done exclusively through Medidata Rave®. Access 
to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles in RSS (Regulatory Support System). 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.   
Each person responsible for data entry must be on the NRG roster in order to receive 
access to Medidata Rave®.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata 
(iMedidata-Notification@mdsol.com) to activate their account. 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 

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right-corner of the iMedidata page. Once an account is activated, eLearning modules will 
be available for Rave RDC instructions.  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 also will 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 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7.0 for information about expedited and routine 
reporting.   
 
For reporting of secondary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave, timeframes, add if loading of the pathology report is 
required. 
 
Summary of Data Submission 
 
Folder 
Form/Item 
Registration via the OPEN System 
 Subject Enrollment Form 
Enrollment 
When pushed into RAVE there 
will 
be 5 forms representing 
registration 
 
 Step Information 
 Treatment Assignment Form 
 Demography 
 Eligibility Checklist Form 
 Eligibility Checklist 2 Form 
p 16 CRF 
 p 16 CRF- to be completed prior to Step II 
registration 
Baseline 
 Work Up 
 Lab Results Baseline 
 Patient History Form (formerly known as 
the A5) 
 Protocol Specified AE Form 
 MDADI Coversheet 
 MDADI- if questionnaire completed = ‘yes’ 

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 CCI 
 PSS-HN Coversheet 
 PSS-HN- if questionnaire completed = ‘yes’ 
 Work Status 
RT Upload 
 
Digital Data-(Refer to section 12.3) 
 
End of RT  
 
 RT Administration 
 RT Treatment-if was radiation therapy 
given = ‘yes’ 
 Protocol Specific RT Form-if was 
radiation therapy given = ‘yes’ 
 Cisplatin (Arm 1 only) 
 Supportive Care 
 Hospitalization 
 Follow-up Head and Neck 
 Protocol Specified AE Form 
 
Other Adverse Event Forms– if new or 
continuing adverse events = ‘yes’ 
  MDADI Coversheet 
 
MDADI- if questionnaire completed = 
‘yes’ 
 PSS-HN Coversheet 
 PSS-HN- if questionnaire completed = 
‘yes’ 
 Work Status 
Concurrent Labs 
 Lab Units Pre-Rx, week 1-6 (During Treatment 
Labs) 
 Lab Results Follow Up (During Treatment Labs) 
MONTH 1 (Post RT) Arm 1 & 2 
MONTH 3 (Post RT) Arm 1 & 2 
MONTH 6 (Post RT) Arm 1 & 2 
MONTH 9 (Post RT) Arm 1 & 2 
MONTH 12 (Post RT) Arm 1 & 2 
MONTH 15 (Post RT) Arm 1 & 2 
MONTH 18 (Post RT) Arm 1 & 2 
MONTH 21 (Post RT) Arm 1 & 2 
MONTH 24 (Post RT) Arm 1 & 2 
MONTH 30 (Post RT) Arm 1 & 2 
MONTH 36 (Post RT) Arm 1 & 2 
 Patient Contacted 
 Follow-up- if Patient able to be Contacted =’yes’ 
 Follow-up Head and Neck -if Patient able to be 
Contacted =’yes’ 
 Disease Assessment- if Documented clinical 
assessment = ‘yes’ 
 New Primary Cancer- If New Primary 
Cancer= ‘yes’ 
 Non-Protocol Treatment- if non-protocol 
cancer therapy= ‘yes’ 
 Protocol Specified AE Form- if Patient able to 
be Contacted =’yes’ 
 
Other Adverse Events– if new or 
continuing adverse events = ‘yes’ 
 Primary Cause of Death- – if Patient’s Vital 
Status = ‘dead’ 
 Salvage surgery- if  salvage surgery= ‘yes’ 

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MONTH 42 (Post RT) Arm 1 & 2 
MONTH 48 (Post RT) Arm 1 & 2 
MONTH 54 (Post RT) Arm 1 & 2 
MONTH 60 (Post RT) Arm 1 & 2 
Year 6-15 Arm 1 & 2 
 
 
 MDADI Coversheet* 
 MDADI- if questionnaire completed = ‘yes’* 
 PSS-HN Coversheet* 
 PSS-HN- If questionnaire completed = ‘yes’* 
 Work Status* 
 
* These quality of life forms will appear in 
Month 6 (Post RT), Month 12 (Post RT) and 
Month 24 (Post RT) 
 
Source Documentation Upload 
 Source Documentation Upload- used by site in 
the event that source documentation needs to be 
uploaded to HQ 
FDG-PET/CT Imaging 
Image submission forms will appear 
in the following folders if the patient 
has consented to the Optional 
Imaging Study. (Note: Institutions 
will submit images in DICOM 
format via TRIAD to IROC 
Imaging, refer to section 8.4.1.) 
 Baseline 
 Month 3 (Post RT) Arm 1 & 
2 
 Scan submission 
 SOC imaging form 
 Site Interpretation of PET/CT * 
 
 
* This form only appears if the Scan submission form is 
submitted and 'Was the Site Interpretation form 
completed’ was answered as YES. 
Quality of Life Coversheets will 
appear in the following folders if the 
patient has consented to the Quality 
of Life Component: 
UW-QOL 
 Baseline 
 Completion of RT 
 6 months from end of RT 
 12 months from end of RT 
 24 months from end of RT 
  
 UW QOL Coversheet 
 UW-QOL* 
 
*These quality of life forms only appear if the 
corresponding cover page is submitted and 'Was 
the patient questionnaire completed’ was 
answered as YES. 
MBS CRF will appear in the 
following folders if the patient has 
consented to the modified barium 
swallowing study: 
 MBS 

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 Baseline 
 Month 24 
 
12.3 
Digital Data Submission Requirements (20-DEC-2017) 
Summary of Dosimetry Digital Data Submission  
 
Submit Digital RT Data via TRIAD; see Section 8.3.1 for TRIAD account 
access and installation instructions. Item 
Due 
Arm 1 and Arm 2 
DICOM Items 
DICOM CT Image 
Within 1 
week of start 
of RT 
DICOM Structure 
DICOM Dose 
DICOM RT Plan 
All required structures must be labeled per the tables in Section 5.2 
HN002 DVH Analysis Worksheet to be submitted via TRIAD with RT Digital 
Data listed above is located on the CTSU web site, www.ctsu.org, on the NRG-
HN002 protocol page. 
Upon submission of the digital data via TRIAD, complete an online Digital 
Data Submission Information Form (DDSI): 
  
https://www.irocqa.org/Resources/TRIAD-for-RT-QA 
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES 
WILL BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED.  
 
12.4 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
13.   STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
13.1.1 Stratification 
 
Patients will be stratified by radiotherapy planning (Unilateral vs. Bilateral), based on the 
investigator’s decision to place the patient into one of the two groups described in Section 
5.2 and the investigator’s pre-randomization declaration of the type of treatment that will 
be used (Unilateral vs. Bilateral). 
13.1.2 Randomization 
 
Patients will be randomized to each arm using a randomized permuted blocked design. 
13.1.3 Total Accrual 
 
296 patients 

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13.2 
Study Endpoints 
13.2.1 Primary Endpoint 
 
Progression-free survival (PFS) at 2 years 
13.2.2 Secondary Endpoints 
 Local-regional failure  at 6 months and 2 years; 
 Distant metastasis at 6 months and 2 years; 
 Overall survival at 6 months and 2 years; 
 Acute toxicities (≥ grade 3, CTCAE, v. 4) at the end of radiation therapy and at 1 and 
6 months; 
 Late toxicities  at  (≥ grade 3, CTCAE, v. 4) 1 and 2 years; 
 Patient-reported swallowing outcomes at 6 months and 1 and 2 years; 
 Post-treatment FDG-PET/CT; 
 Translational research. 
 
13.3 
Primary Objectives Study Design 
13.3.1 Primary Hypothesis and Endpoints 
For patients with p16 positive, locoregionally advanced oropharyngeal cancer who have a 
smoking history of ≤10 pack-years, a program of reduced-dose radiation therapy (given 
either in combination with concurrent radiosensitizing cisplatin or in modestly 
accelerated fractionation) will achieve a 2-year progression-free survival (PFS) rate of ≥ 
85%, without unacceptable swallowing toxicity. 
13.3.2 Definitions of Primary Endpoints and How These Will Be Analyzed 
Progression free survival is defined as from time of randomization to local- regional 
failure, distant metastasis, or deaths due to any causes. PFS rates will be estimated for all 
treatment arms using the Kaplan-Meier method (1958). One sample binomial test will be 
used to test the 2-year PFS for each arm. Multivariate analysis will be performed using 
the Cox proportional hazards model. 
13.3.3 Sample Size and Power Calculations:  
The estimated 2-year PFS for this population is 91% based on the eligible population of 
patients on the 2 arms of 0522 (N=65 available patients) at this time. If the 2-year PFS is 
less than 85%, we will consider it unacceptable. So, the null hypothesis for this study is: 
Neither arm achieves a 2-year progression-free survival (PFS) rate of ≥ 85%. The 
alternative hypothesis is:  One or both arms result in a 2-year progression-free survival 
(PFS) rate of > 91%. With one-sided type I error rate of 10% and 80% power, we would 
need 140 analyzable patients per arm.  
 
All head and neck cancer trials must account for post-randomization attrition. In RTOG 
1016, patients were not randomized for the following reasons: 5.3% not p16 positive; 
5.2% patient refusal; 1.2% physician preference; 0.4% disease progression; 0.4% failure 
to submit tissue assay; and 2.5% for other reasons. In addition, 3.5% of patients were 
determined ineligible after randomization and 0.5% were randomized but did not receive 
any protocol therapy.   
 
For this trial, since p16 is tested prior to registration, we anticipate lower loss due to lack 
of tissue or improper p16 determination, since that should be better controlled through 

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central review prior to randomization. p16 positive patients may be preference-sensitive 
about the arm to which they are randomized. Thus, we estimate there will be 5% loss of 
patients due to the reasons of “not p16 positive" and "patient refusal” pre-randomization 
in this study. 
  
The stated sample size for NRG-HN002 must be adequate to provide an analyzable 
cohort of 280 patients. Assuming 5% loss post-randomization, we must enroll 296 
patients to be randomized. We project a total pre-randomization loss of 10% for potential 
withdrawal of consent related to physician or patient refusal, not p16 positive, or 
progression of disease, failure to submit tissue assay, and other reasons, so we expect to 
enroll 328 patients to get the required number of patients to be randomized.   
 
The rationale for the <85% unacceptable rate for 2-year PFS is as follows: The estimated 
2-year PFS for this group of selected patients with p16 positive tumors is 91%, based on 
estimates derived from patients in RTOG 0522. If we set an unacceptable rate of 88% 
(3% difference from the expected outcome), the trial would require 500 analyzable 
patients per arm (1000 analyzable patients total) to conduct this phase II study. This was 
deemed less feasible based on the required number of patients and cost. If we set an 
unacceptable rate of 86% (5% difference from the expected outcome), then the trial 
would require 200 analyzable patients per arm (400 analyzable patients total). The 
number of patients required is more feasible but is still quite large for a 3-arm phase II 
study, in order to achieve only a 1% difference from 85%. If we set an unacceptable rate 
of 85% (6% difference from the expected outcome), then the trial would require 140 
analyzable patients per arm (280 analyzable patients total). At this time, based on the 
projected rate of accrual, this was considered the most feasible scenario to accomplish in 
a reasonable timeframe and forms the basis of the current proposal. 
 
13.4 
Study Monitoring of Primary Objectives 
Planned Interim Safety Analysis with Early Stopping Rules 
At 6 months, the estimated PFS for the eligible group of patients from RTOG 0522 is 
94%. With 95% two-sided confidence and a lower limit of 85% PFS, we plan to enroll 40 
analyzable patients for each arm to be followed for 6 months. After these patients have 
been enrolled and followed for 6 months, the interim analysis will take place. The 
stopping rule corresponds to a number of 6 or more progressions within the first 40 
patients at 6 months of follow up. 
 
The interim analysis time will be 1.56 years from the start of the study (6 months for site 
IRB approval, 0.56 years for accrual, 6-month follow up). If 1 arm has more than 
specified number of progressions, then we will suspend the arm and a panel review will 
be called to decide on next steps, including closing accrual to the arm. The trial will 
continue to accrue during that 6 month observation period, after 40 patients/arm have 
been enrolled, until adequate follow up is obtained for interim analysis. 
 
With the 2-arm design, the expected number of PFS events serving as a cut off among the 
140 analyzable patients is 15 or fewer events on each arm to reject the null hypothesis 
and the cut off number of events for the interim analysis is 6 among the 40 analyzable 

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patients. 
 
Monitoring of Study Progress for Quality of Life 
NRG Oncology will prepare reports twice a year to follow compliance with required 
quality of life data collection. Data that is missing will be requested from enrolling 
institutions at each reporting time point. Further corrective action may be taken by the 
Study Chairs if an institution is noted to have >30% non-compliance with quality of life 
data collection. 
 
Routine Interim Analysis to Monitor Study Progress 
Interim reports will be prepared twice each year until the final analysis has been accepted 
for presentation or publication. These reports will contain information about the accrual 
rate, pretreatment characteristics of patients accrued, and the frequency and severity of 
adverse events. 
 
Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 
on an “as needed” basis.  
13.5 
Accrual Considerations 
13.5.1 Accrual Rate 
 
The accrual rate is estimated to be 15 patients per month. 
13.5.2 Accrual Goal 
 
The total sample size is 296 patients. 
13.5.3 Study Duration 
Trial accrual is projected to take 1.94 years. Allowing 6 months for site IRB approval and 
2 years of follow up, the trial is estimated to take a total of 4.5 years. 
13.5.4 Estimated Duration for Completion of Primary Endpoint:  
Trial accrual is projected to take 1.94 years. Allowing 6 months for site IRB approval and 
2 years of follow up, the trial is estimated to take a total of 4.5 years. 
 
13.6 
Secondary/Correlative Elements  
13.6.1  How Secondary Endpoints Will Be Analyzed 
For the secondary endpoints listed in Section 13.2.2, OS rates will be estimated using the 
Kaplan-Meier method (1958) and the failure rates for the experimental treatment will be 
compared against the control using a log rank test. The cumulative incidence method will 
be used to estimate locoregional and distant failure rates and the failure rates for the 
experimental treatment will be compared against the control using a failure specific log 
rank test. Failure for local-regional failure and distant metastasis endpoints is as follows: 
 
First event 
Local-regional 
failure 
Distant metastasis 
None 
Censored 
Censored 
Local-regional progression or recurrence 
Failure 
Competing risk 
Distant metastasis 
Competing risk 
Failure 
Death due to study cancer or unknown 
Failure 
Competing risk 

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causes 
Death due to any other reason 
Competing risk 
Competing risk 
Salvage surgery of primary with tumor 
present/unknown 
Failure 
Competing risk 
Salvage neck dissection with tumor 
present/unknown, > 20 weeks from end of 
RT 
Failure 
Competing risk 
 
Multivariate analysis will be performed using the Cox proportional hazards model. 
 
Rates of Adverse Events (≥ grade 3, CTCAE, v. 4) for acute and late toxicities will be 
estimated using a binomial distribution along with their associated 95% confidence 
intervals and will be compared using Fisher’s exact test between the 2 treatment arms.   
13.6.2 Quality of Life (QOL) 
The primary QOL endpoint will measure the mean individual change in total MDADI 
score at 1 year from baseline with the goal of detecting a ≥ 5 point difference between the 
2 arms. 
 
In the table below, we have outlined our decision making process of interpreting the 
phase II data with regards to PFS and QOL in order to proceed to a future phase III trial. 
PFS will be the primary decision making endpoint, with QOL using the comparison of 
mean change in MDADI score in each arm from baseline to inform the subsequent choice 
of one or more arms to proceed to a phase III trial.  
 
If a PFS of ≥ 85% is not reached for any of the arms, regardless of the QOL outcome, 
none of the therapy regimens will move forward to a phase III study.  
 
If 1 or both of the arms reach ≥ 85% PFS, the swallowing-related QOL endpoint of 1 year 
mean total MDADI score must be clinically acceptable of ≥ 60, in order to move forward 
into a phase III trial. That is, if the MDADI results for an arm are not clinically 
acceptable (mean total MDADI score at 1 year < 60), then that arm will not proceed to 
phase III testing, regardless of PFS results. 
 
PFS 
Long-term Swallowing-Related 
QOL 
 (MDADI at 1 year) 
Decision Algorithm 
Only one arm achieves ≥ 
85% PFS 
Arm selected on the basis of PFS, 
and without unacceptable 
dysphagia as measured by 
MDADI. 
MDADI results for the “superior” 
arm must be clinically acceptable 
(mean total MDADI score at 1 
The arm meeting the PFS cutoff 
with acceptable swallowing 
outcome, measured by mean 
total MDADI results of  ≥ 60 at 
1 year, proceeds to phase III; 
will be compared to other 
approaches, such as primary 
surgery or 70 Gy + concomitant 

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year ≥ 60)  
cisplatin chemotherapy 
Two arms achieve ≥ 85% 
PFS; one statistically 
superior  
Arm selected on the basis of PFS, 
and without unacceptable 
dysphagia as measured by 
MDADI. 
MDADI results for the “superior” 
arm must be clinically acceptable 
(mean total MDADI score at 1 
year ≥ 60) 
The arm with statistically 
superior PFS and acceptable 
swallowing outcome, measured 
by mean total MDADI of  ≥ 60 
at 1 year, results proceeds to 
phase III; will be compared to 
other approaches, such as 
primary surgery or 70 Gy + 
concomitant cisplatin 
chemotherapy 
Two arms achieve ≥ 85% 
PFS; statistically not 
different 
One arm is deemed “inferior” only 
if (1) its MDADI mean change 
score from baseline to 1 year 
shows a statistically significantly 
difference from the other arm; (2) 
a between-arms difference of at 
least 5 points is observed; and (3) 
the “inferior” arm shows a within-
group decline of 5 points or more 
from baseline and MDADI results 
are clinically acceptable for the 
“superior” arm (mean total 
MDADI score at 1 year ≥ 60) 
The arm with “superior” QOL 
proceeds to phase III; will be 
compared to other approaches, 
such as primary surgery or 70 
Gy + concomitant cisplatin 
chemotherapy 
Two arms achieve ≥ 85% 
PFS; statistically not 
different 
Any conditions other than those 
described in the row above (e.g. 
no difference in harm is 
demonstrated between arms), and 
MDADI results are clinically 
acceptable for both arms (mean 
total MDADI score at 1 year ≥ 60) 
Both arms move to phase III* 
*If PFS and QOL are both acceptable and comparable, and neither arm has MDADI results that 
can be deemed “inferior” or “clinically unacceptable,” then both arms may move forward for 
further testing in a phase II or III trial. 
 
 
If PFS goals are met by both arms, and the MDADI results are stable or improved in one 
or both arms, then decision making will proceed as follows. If the MDADI data shows: 
 
 Stability or improvement in 1 arm at 1 year from baseline, and the other arm shows a 
within-group decline of 5 points or more from baseline, then the arm which shows 
stability or improvement will proceed to a phase III. 

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 Stability or improvement in 1 arm at 1 year from baseline, and the other arm shows a 
within-group decline of less than 5 points from baseline, and there is at least a 5 point 
difference between arms which is statistically different, the better arm will proceed to a 
phase III.  
 Stability or improvement in 1 arm at 1 year from baseline, and the other arm shows a 
within-group decline of less than 5 points from baseline, and there is less than a 5 point 
difference between arms or the difference between arms is not statistically different, both 
arms will proceed to a phase III.  
 Improvement or stability in both arms, with or without a statistical difference, then both 
will be considered for a phase III study.   
 
The table below shows statistical power for detecting potential PFS differences between 2 
arms. For example, if the 2 arms have 2-year PFS of 85% and 92.5%, based on a two-
sided log rank test (hypothesis generating) with a type I error rate of 0.1/0.2 and 140 
analyzable patients in each arm, we will have 84%/91% power. 
 
 
 
85% 
87.5% 
90% 
92.5% 
95% 
97.5% 
85% 
 
20%/32% 
51%/65% 
84%/91% 
98%/99% 
>99%/99% 
87.5% 
 
 
22%/27% 
57%/56% 
90%/84% 
>99%/99% 
90% 
 
 
 
25%/38% 
67%/79% 
96%/98% 
92.5% 
 
 
 
 
31%/44% 
82%/90% 
95% 
 
 
 
 
 
43%/58% 
 
 
With an effect size of 0.333, an expected mean change in individual MDADI score 
between the 2 arms of ≥ 5 (and SD estimated to be between 15 [Gillespie 2004]) at 1 year 
from completion of radiation, and a two-sided, two-sample independent t-test (hypothesis 
generating) with alphas of 0.2, the table below shows statistical power for various rates of 
attrition (including 12% from French-speaking Canadian sites); for example, we will 
have 80% power to detect a 5 point difference for MDADI scores between 2 arms. If PFS 
is better for one arm but not significant, then this difference between the arms in the 
mean change in MDADI scores will be used to select the best arm for phase III. 
 
 
Effect size = 0.333 
All cases (n=280) 
93% 
40% attrition (n=168) 
80% 
50% attrition (n=140) 
75% 
 
The mean summary score of the MDADI, PSS-HN, and CCI and the MDADI subscales 
including the physical, functional, and emotional domains will be determined. The mean 
change from baseline at each time point will be summarized using mean and standard 
deviations for each arm. Mean score and mean change from baseline will be compared 
between the arms using a two-sample t test. If data normality assumptions are not met, 

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the Wilcoxon rank sum test will be used to test the hypothesis. Mean change from 
baseline will be tested using an omnibus F test followed by individual comparisons of 
change scores at different time points within each treatment group. The same analysis 
will be conducted for between group comparisons at each time point. Overall trends for 
the MDADI scores and subscale scores could be modeled using the general linear mixed-
effect model. This model will be used to compare the differences of scores over time 
between the 2 arms and to compute least squares mean and SEs, including clinical 
variables and treatment by visit interaction terms. The model also allows for adjustments 
using stratification variables (unilateral vs. bilateral radiotherapy) and other covariates of 
interest. The use of general linear mixed modeling allows flexibility in analyzing data 
with missing responses. To handle poor compliance and missing data, efforts will be 
made to minimize attrition due to avoidable factors. To assess the missing data 
mechanism, we will compare possible differences between patients who dropped out of 
the study against those who remained in the study with respect to imbalance factors such 
as treatment, baseline scores, clinical, and demographic data. We will undertake 
sensitivity analyses to investigate reasons for missingness (e.g. by drop-out), considering 
various factors as mentioned earlier. A logistic regression model will be used to 
summarize number of missing data and to test if the dropout process is missing 
completely at random (MCAR). Analysis of complete cases and cases with multiple 
imputations for missing observations (before death or progression) will be done to check 
robustness of the main results. Correlation between MDADI and dysphagia as well as 
other variables will be calculated using Spearman’s correlation coefficient and the 
corresponding p values will be reported. Correlation between categorical measures will 
be summarized by odds ratios, chi square tests, and associated measures. Adjusted 
correlation may be derived from ANCOVA models or derived directly using 
nonparametric ANOVA models if normality assumption is violated. If comparison to 
historical control is needed, a one-sample t test will be utilized. Binary endpoints will be 
compared using Fisher’s exact test.   
13.6.3 FDG-PET/CT Imaging as a Predictive Imaging Marker for  Locoregional Control and 
Progression-Free Survival  
 
Primary endpoint: Determine the Negative Predictive Value (NPV) of FDG-PET/CT, 
performed at 12-14 weeks post-therapy, for locoregionally advanced oropharyngeal 
cancer treated with (chemo) radiation therapy for PFS at 2 years. 
 
Of the 280 evaluable patients, we anticipate that 140-180 (approximately one half to two 
thirds) of them will undergo 12-14 weeks post-therapy PET/CT.  We assume that 
approximately 75-80% of total available FDG-PET/CT scans will be negative, 11-12% 
positive, and 8-14% indeterminate. 
 
NPV is then the proportion of PET-negative patients that remain progression-free at 2 
years. The power is calculated to reject the null hypothesis of <90% and an alternative 
hypothesis of 95% using a one-sided binomial test at a significance level of 0.10. With a 
total of 140 available scans, which indicates 105-112 PET-negative patients, the 
statistical power is 76-77% and if the total number of scans is 180 and 135-144 PET-
negative patients, we will have 83-85% power to reject the null hypothesis regarding the 

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negative predictive value.   
13.6.4 HPV DNA As a Potential Marker for Relapse 
For Hypothesis 1, with a two-sided type error rate of 5% and based on chi-squared test 
for proportions, we have greater than 99% power to detect HPV DNA detection rate of 
65% and 95% between the 2 groups (n=140 in each arm). The rate of detection for each 
group will be summarized based on binomial distributions and a 95%CI will be provided.  
For Hypothesis 2, correlation between HPV DNA copy number and the nodal metabolic 
volume (nMTV) will be calculated using Spearman’s correlation coefficient and R2, and 
the corresponding 95%CI will be provided. 
For Hypothesis 3, first, with a two-sided type error rate of 5% and based on paired t test 
for means, we have 99% power to detect HPV DNA rate decline of 0.375 (effect size) 
within each arm (n=140). The HPV DNA rate for each group will be summarized using 
means and standard deviations.  
For Hypothesis 3, second, assuming 5%, 6%, 7%, 8% LRF for two-year PFS of 91%, 
89%, 87% and 85%, the following tables show statistical power for detecting various 
hazard ratios. For example, if the variance for HPV DNA is 15 and the two-year PFS is 
89%, then we will have 80% power to detect a hazard ratio of 1.20 with 3 arms 
combined. Univariable and multivariable cause specific analysis will be performed using 
the Cox proportional hazards model for rate of relapse. Potential covariates evaluated for 
the multivariate models would be treatment, age, Zubrod performance status, T-stage, N-
stage, smoking history, other risk behaviors.  
 
Statistical power to detect various hazard ratios, continuous variable, 2 arms combined 2-
year PFS 91%, 14 locoregional failure events, 2-sided 0.05 
 
Variance 
Hazard Ratio 
1.01 
1.05 
1.10 
1.15 
1.20 
5 
0.03 
0.06 
0.12 
0.21 
0.33 
10 
0.03 
0.08 
0.20 
0.37 
0.57 
15 
0.03 
0.10 
0.28 
0.52 
0.75 
20 
0.03 
0.12 
0.35 
0.64 
0.86 
25 
0.03 
0.14 
0.42 
0.74 
0.92 
 
Statistical power to detect various hazard ratios, continuous variable, 2 arms 
combined 2-year PFS 89%, 17 locoregional failure events, 2-sided 0.05 
 
Variance 
Hazard Ratio 
1.01 
1.05 
1.10 
1.15 
1.20 
5 
0.03 
0.06 
0.13 
0.25 
0.39 
10 
0.03 
0.09 
0.23 
0.44 
0.66 
15 
0.03 
0.11 
0.33 
0.60 
0.82 

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Variance 
Hazard Ratio 
1.01 
1.05 
1.10 
1.15 
1.20 
20 
0.03 
0.14 
0.41 
0.73 
0.91 
25 
0.03 
0.17 
0.50 
0.82 
0.96 
 
Statistical power to detect various hazard ratios, continuous variable, 2 arms 
combined 2-year PFS 87%, 20 locoregional failure events, 2-sided 0.05 
 
Variance 
Hazard Ratio 
1.01 
1.05 
1.10 
1.15 
1.20 
5 
0.03 
0.07 
0.15 
0.28 
0.44 
10 
0.03 
0.10 
0.27 
0.50 
0.73 
15 
0.03 
0.13 
0.37 
0.67 
0.88 
20 
0.03 
0.16 
0.47 
0.79 
0.95 
25 
0.04 
0.19 
0.56 
0.87 
0.98 
Statistical power to detect various hazard ratios, continuous variable, 2 arms 
combined 2-year PFS 85%, 22 locoregional failure events, 2-sided 0.05 
 
Variance 
Hazard Ratio 
1.01 
1.05 
1.10 
1.15 
1.20 
5 
0.03 
0.07 
0.16 
0.31 
0.48 
10 
0.03 
0.10 
0.29 
0.54 
0.77 
15 
0.03 
0.14 
0.40 
0.71 
0.91 
20 
0.03 
0.17 
0.51 
0.83 
0.96 
25 
0.04 
0.20 
0.60 
0.90 
0.98 
PI3K Pathway Activation and Its Associated Genomic Profile as Prognostic 
Biomarkers of HPV Related Oropharyngeal Cancer 
The predictive and prognostic potential for these proposed biomarkers may become 
scientifically obsolete or the assay technology may evolve over time, making the 
technology outlined in the current protocol obsolete when the study is finished. As such, 
no marker assays will be reviewed on the collected specimens other than those required 
for patient selection (i.e. p16 immunohistochemistry). When sufficient information is 
available from the parent study, a full correlative study protocol for the marker studies 
detailing the scientific hypothesis, research plan, assay methods for each biomarker, and 
a complete statistical section (with adequate power justification and analysis plan) will be 
submitted and subjected to CTEP review in accordance with the National Clinical Trials 
Network (NCTN) policies. 
13.6.5  Determining the Extent of Long-Term Dysphagia Using MBS (5/24/16) 
Primary endpoint: Determine the risk of grade ≥3 MBS-detected dysphagia 2-years after 
de-escalated IMRT. 

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Of the 90 evaluable patients, we anticipate that 63-72 (approximately 20-30% attrition) 
will complete the 2 year MBS. We expect <20% of patients will have DIGEST grade ≥3 
(severe) MBS-detected dysphagia at 2 years. No life threatening dysphagia (DIGEST 
grade 4) is expected.  
 
Exploratory analyses of MBS arm will include: 
 Concordance/discordance of perceived dysphagia (per PRO instrument – 
MDADI) with MBS detected dysphagia (per DIGEST) 
 Develop predictive model for DIGEST grade ≥3 MBS detected dysphagia 2 years 
after de-escalated radiotherapy per age, tumor characteristics, treatment 
parameters (including use of concurrent chemotherapy), early toxicity profiles 
(clinician and provider graded) 
 
13.7 
Gender/Ethnicity/Race Distribution 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
1 
9 
10 
Not Hispanic or Latino 
28 
258 
286 
Ethnic Category: Total of all subjects 
29 
267 
296 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
1 
0 
1 
Black or African American 
2 
12 
14 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
26 
253 
279 
Racial Category: Total of all subjects 
29 
267 
296 
 
 

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REFERENCES (5/24/16) 
 
Adelstein DJ, Rodriguez CP. Current and emerging standards of concomitant 
chemoradiotherapy. Semin Oncol. 35(3):211-20, 2008. PMID: 18544436 
 
Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous 
cell carcinoma reveals inactivating mutations in NOTCH1. Science. 333(6046): 1154-7, 2011. 
Epub 2011 Jul 28. PMID: 21798897 
 
Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs 
fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized 
controlled trial. JAMA. 23;299(16):1914-21, 2008. PMID: 18430910 
 
Ang KK. Concurrent radiation chemotherapy for locally advanced head and neck carcinoma: Are 
we addressing burning subjects? J Clin Oncol. 22(23):4657-9, 2004. Epub 2004 Nov 8. PMID: 
15534361 
 
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 
oropharyngeal cancer. NEJM. 363(1):24-35, 2010. Epub 2010 Jun 7. PMID: 20530316 
 
Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-Schveitzer N. Combined 
postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck 
carcinoma: Final report of a randomized trial. IJROBP. 36(5):999-1004, 1996. PMID: 8985019 
 
Berthiller JL, Lee YC, Boffetta, P, et al. Marijuana smoking and the risk of head and neck 
cancer: Pooled analysis in the INHANCE consortium. Cancer Epidemiol Biomarkers Prev. 
18(5):1544-51, 2009. doi: 10.1158/1055-9965.EPI-08-0845. 
 
Bhide SA, Gulliford S, Kazi R, El-Hariry I, Newbold K, Harrington KJ, Nutting CM. Correlation 
between dose to the pharyngeal constrictors and patient quality of life and late dysphagia 
following chemo-IMRT for head and neck cancer. Radiother Oncol.  93(3):539-44, 2009. Epub 
2009 Oct 31. PMID: 19883951 
 
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced 
head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between 
cetuximab-induced rash and survival. Lancet Oncol. 11(1):21-8, 2010. Epub 2009 Nov 10. 
PMID: 19897418 
 
Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of 
radiotherapy with or without concomitant chemotherapy in locally advanced head and neck 
carcinoma (GORTEC 99-02): An open-label phase 3 randomised trial. Lancet Oncol. 13(2):145-
53, 2012. Epub 2012 Jan 18. PMID: 22261362 
 

NRG-HN002 
106  
Version Date:  December 20, 2017 
 
REFERENCES (Continued) 
 
Burtness B. Personal communication. 2013. Based on data provided in 2013 ASCO oral 
presentation: Marur S, Li S, Cmelak A, et al. E 1308: A phase II trial of induction chemotherapy 
(IC) followed by cetuximab with low dose versus standard dose IMRT in patients with human 
papilloma virus (HPV)-associated resectable squamous cell carcinoma of the oropharynx 
(OPSCC). J Clin Oncol. 31, 2013 (suppl; abstr 6005). 
 
Cao H, Banh A, Kwok S, et al. Quantitation of human papillomavirus DNA in plasma of 
oropharyngeal carcinoma patients. IJROBP.82(3):e351-8, 2012. PMID: 21985946 
 
Caudell, JJ, Schaner PE, Meredith RF, et al. Factors associated with long-term dysphagia after 
definitive radiotherapy for locally advanced head-and-neck cancer. IJROBP. 73(2), 410-415, 
2009. doi: 10.1016/j.ijrobp.2008.04.048 
 
Caudell JJ, Schaner PE, Desmond RA, et al. Dosimetric factors associated with long-term 
dysphagia after definitive radiotherapy for squamous cell carcinoma of the head and neck. 
IJROBP. 76(2):403-9, 2010. Epub 2009 May 19. PMID: 19467801 
 
Cmelak A, Li  S, Marur S, et al. E1308: Reduced-dose IMRT in human papilloma virus (HPV)-
associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete 
response (cCR) to induction chemotherapy (IC).  J Clin Oncol 32:5s, 2014 (suppl; abstr 
LBA6006). 
 
Chan AT, Teo PM, Ngan RK, et al. Concurrent chemotherapy-radiotherapy compared with 
radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free 
survival analysis of a phase III randomized trial. J Clin Oncol. 20(8):2038-44, 2002. PMID: 
11956263 
 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic 
comorbidity in longitudinal studies: Development and validation. J Chron Dis. 40(5): 373–383, 
1987. PMID: 3558716 
 
Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal 
cancer incidence in the United States. J Clin Oncol.  29(32):4294-301, 2011. Epub 2011 Oct 3. 
PMID: 21969503 
 
Chen AM, Zahra T, Daly ME, Farwell DG, Luu Q, Gandour-Edwards R, Vaughan AT. 
Definitive radiation therapy without chemotherapy for human papillomavirus-positive head and 
neck cancer. Head Neck. 2013; 35(11):1652-6. doi: 10.1002/hed.23209. Epub 2013 Jan 17. 
PMID: 23335285 
 

NRG-HN002 
107  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Chen AY, Frankowski R, Bishop-Leone J, Hebert T, Leyk S, Lewin J, Goepfert H. The 
development and validation of a dysphagia-specific quality-of-life questionnaire for patients with 
head and neck cancer: The M. D. Anderson dysphagia inventory. Arch Otolaryngol Head Neck 
Surg. 127(7):870-6, 2001. PMID: 11448365 
 
Chen Y, Liu MZ, Liang SB, et al. Preliminary results of a prospective randomized trial 
comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone 
in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china. 
IJROBP.  71(5):1356-64, 2008. Epub 2008 May 9. PMID:18472356 
 
Chronowski GM, Garden AS, Morrison WH, et al. Unilateral radiotherapy for the treatment of 
tonsil cancer. IJROBP. 2012; 83(1):204-9. doi: 10.1016/j.ijrobp.2011.06.1975. Epub 2011 Oct 
20. PMID: 22019242 
 
Chung MK, Jeong HS, Park SG, et al. Metabolic tumor volume of [18F]-fluorodeoxyglucose 
positron emission tomography/computed tomography predicts short-term outcome to 
radiotherapy with or without chemotherapy in pharyngeal cancer. Clin Cancer Res.15:5861-
5868, 2009. PMID: 19737951 
 
Cohen EE, Karrison T, Kocherginsky M, et al. DeCIDE: A phase III randomized trial of 
docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients 
with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN).  2014 
Jul 21. pii: JCO.2013.54.6309. [Epub ahead of print] PMID: 25049329 
 
Dische S, Saunders M, Barrett A, Harvey A, Gibson D, Parmar M. A randomised multicentre 
trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol. 
44(2):123-36, 1997. PMID: 9288840 
 
Dyer JC, Leslie P, Drinnan MJ. Objective computer-based assessment of valleculae residue--is it 
useful? Dysphagia.23:7-15, 2008. 
 
Eisbruch A, Lyden T, Bradford CR, et al. Objective assessment of swallowing dysfunction and 
aspiration after radiation concurrent with chemotherapy for head-and-neck cancer. IJROBP. 
53(1), 23-28, 2002. 
 
Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of accelerated hypofractionated 
intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). 
IJROBP.  76(5):1333-8, 2010. Epub 2009 Jun 18. PMID: 19540060 
 
Eisbruch A, Kim HM, Feng FY, et al. Chemo-IMRT of oropharyngeal cancer aiming to reduce 
dysphagia: Swallowing organs late complication probabilities and dosimetric correlates. 
IJROBP.  81:e93-9, 2011. PMID: 21592678 
 

NRG-HN002 
108  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Eisbruch A, Lyden T, Bradford CR, et al. Objective assessment of swallowing dysfunction and 
aspiration after radiation concurrent with chemotherapy for head-and-neck cancer. IJROBP.  
53:23-8, 2002. PMID: 12007937 
 
Eisenhuber E, Schima W, Schober E, et al. Videofluoroscopic assessment of patients with 
dysphagia: Pharyngeal retention is a predictive factor for aspiration. AJR Am J Roentgenol. 
178:393-8, 2002. 
 
Fowler JF. Correction to Kasibhatla et al. How much radiation is the chemotherapy worth in 
advanced head and neck cancer? (IJROBP.  68:1491-1495, 2007). IJROBP. 71(2):326-9, 2008. 
PMID: 18474309 
 
Frowen JJ, Cotton SM, Perry AR. The stability, reliability, and validity of videofluoroscopy 
measures for patients with head and neck cancer. Dysphagia. 23:348-63, 2008. 
 
Garden AS. Personal communication. 2012. 
 
Geropantas K, Loo SW, Martin C, et al. In Regard to Chronowski et al. Re: Unilateral 
radiotherapy for the treatment of tonsil cancer. IJROBP. 85(1):7-8, 2013. PMID: 23236997 
 
Gillespie MB, Brodsky MB, Day TA, Lee FS, Martin-Harris B. Swallowing-related quality of 
life after head and neck cancer treatment. Laryngoscope. 114(8):1362-7, 2004. PMID: 15280708 
 
Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and 
progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol. 
30(17):2102-11, 2012. Epub 2012 May 7. PMID: 22565003 
 
Goerres GW, Schmid DT, Bandhauer F, et al. Positron emission tomography in the early follow-
up of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg. 130(1):105-9, 2004. 
PMID: 14732778 
 
Gorgulho A, De Salles A, Mattozo C, et al. Definition of a Treatment Modality by the Patients 
Using a Decision-Making Software. Poster presented at: Annual Meeting of the American 
Association of Neurological Surgeons;April 18-20, 2005; San Francisco, CA. 
 
Gorgulho A, De Salles A, Mattozo C, et al. VisionTree Software - Stereotactic Radiation vs. 
Conventional Surgery. Paper presented at: Annual Meeting of the International Stereotactic 
Radiosurgery Society; June 23-27, 2007; San Francisco, CA. 
 
Gregoire V, Ang K, Budach W, et al. Delineation of the neck node levels for head and neck 
tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG 
consensus guidelines. Radiother Oncol. 110(1):172-81, 2014. doi: 10.1016/j.radonc.2013.10.010. 
Epub 2013 Oct 31 

NRG-HN002 
109  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Gupta T, Master Z, Kannan S, et al. Diagnostic performance of post-treatment FDG PET or FDG 
PET/CT imaging in head and neck cancer: A systematic review and meta-analysis. Eur J Nucl 
Med Mol Imaging. 38(11):2083-95, 2011. PMID: 
21853309 
 
Haddad RI, Rabinowits G, Tishler RB, et al. The PARADIGM trial: A phase III study comparing 
sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and 
neck cancer (LANHC). J Clin Oncol.  30, 2012 (suppl; abstr 5501). 
 
Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent 
chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone 
in locally advanced head and neck cancer (PARADIGM): A randomised phase 3 trial. Lancet 
Oncol. 2013 14(3):257-64. doi: 10.1016/S1470-2045(13)70011-1. Epub 2013 Feb 13. PMID: 
23414589 
 
Hassan SJ, Weymuller EA Jr. Assessment of quality of life in head and neck cancer patients. 
Head and Neck. 15(6): 485-096, 1993. 
 
Hentschel M, Appold S, Schreiber A, et al. Early FDG PET at 10 or 20 Gy under 
chemoradiotherapy is prognostic for locoregional control and overall survival in patients with 
head and neck cancer. Eur J Nucl Med Mol Imaging. 38(7):1203-11, 2011. PMID: 
21350962 
 
Hoshikawa H, Mori T, Kishino T, et al. Changes in (18)F-fluorothymidine and (18)F-
fluorodeoxyglucose positron emission tomography imaging in patients with head and neck 
cancer treated with chemoradiotherapy. Ann Nucl Med. 27(4):363-70, 2013. PMID: 23378102 
 
Hunter KU, Lee OE, Lyden TH, et al. Aspiration pneumonia after chemo-intensity-modulated 
radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. 
Head Neck. 36(1): 120-5, 2013. doi: 10.1002/hed.23275 
 
Hutcheson KA, Lewin JS, Barringer DA, et al. Late dysphagia after radiotherapy-based 
treatment of head and neck cancer. Cancer. 118(23), 5793-5799, 2012. doi: 10.1002/cncr.27631 
 
Hutcheson KA, Lewin JS, Holsinger FC, et al. Long-term functional and survival outcomes after 
induction chemotherapy and risk-based definitive therapy for locally advanced squamous cell 
carcinoma of the head and neck. Head Neck. 36(4), 474-480, 2014. doi: 10.1002/hed.23330 
 
Hutcheson KA, Barringer DA, Gunn B, Lai SY, Barrow M, Lewin JS.  Late radiation-associated 
dysphagia (late-rad) after IMRT for oropharyngeal cancer. Dysphagia. 30 (5):597, 10/2015. 
[Abstract.  Presented at the Dysphagia Research Society 23rd Annual Meeting and Post-
Graduate Course, Chicago, IL, 3/12/2015] 
 

NRG-HN002 
110  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Hutcheson KA, Portwood M, Barringer DA, Lisec A, Gries K, Lewin JS. What is a clinically 
relevant difference in MDADI scores between groups of head and neck cancer patients? 
Laryngoscope.  2015 Nov 6. doi: 10.1002/lary.25778. [Epub ahead of print] 
 
Iseli TA, Kulbersh BD, Iseli CE, Caroll WR, Rosenthal EL, Magnuson JS. Functional outcomes 
after transoral robotic surgery for head and neck cancer. Otolaryngol Head Neck Surg. 141(2): 
166-71, 2009. PMID: 19643246 
 
Jackson SM, Hay JH, Flores AD, Weir L, Wong FL, Schwindt C, Baerg B. Cancer of the tonsil: 
the results of ipsilateral radiation treatment. Radiother Oncol. 1999;51(2):123-8. PMID: 
10435802 
 
Jeremic B, Milicic B, Dagovic A, Vaskovic Z, Tadic L. Radiation therapy with or without 
concurrent low-dose daily chemotherapy in locally advanced, nonmetastatic squamous cell 
carcinoma of the head and neck. J Clin Oncol. 22(17):3540-8, 2004. PMID:15337803 
 
Jones AS, Roland NJ, Field JK, Phillips DE. The level of cervical lymph node metastases: their 
prognostic relevance and relationship with head and neck squamous carcinoma primary sites. 
Clin Otolaryngol Allied Sci. 19(1):63-9, 1994. PMID: 8174305 
 
Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of methods for oropharyngeal 
cancer HPV status determination in US cooperative group trials. Am J Surg Pathol. 36(7): 945-
54, 2012. 
 
Kasibhatla M, Kirkpatrick JP, Brizel DM. How much radiation is the chemotherapy worth in 
advanced head and neck cancer?  IJROBP. 2007;68(5):1491-5. PMID: 17674979 
 
Kim YS, Shin SS, Nam JH, Kim YT, Kim YM, Kim JH, Choi EK. Prospective randomized 
comparison of monthly fluorouracil and cisplatin versus weekly cisplatin concurrent with pelvic 
radiotherapy and high-dose rate brachytherapy for locally advanced cervical cancer. Gynecol 
Oncol. 108(1):195-200, 2008. Epub 2007 Oct 25. PMID: 17963825 
 
King MT. A point of minimal important difference (MID): A critique of terminology and 
methods. Expert Reb Pharmacoecon Outcomes Res. 2011; 11(2): 171-184. PMID: 21476819 
La TH, Filion EJ, Turnbull BB, et al. Metabolic tumor volume predicts for recurrence and death 
in head-and-neck cancer. IJROBP.  74(5): 1335-1341, 2009. PMID:19289263 
 
Lanciano R, Calkins A, Bundy BN, et al. Randomized comparison of weekly cisplatin or 
protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced 
cervix cancer: a gynecologic oncology group study. J Clin Oncol. 23(33):8289-95, 2005. Epub 
2005 Oct 17. PMID: 16230678 
 

NRG-HN002 
111  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Lassen P, Eriksen JG, Krogdahl A, et al. The influence of HPV-associated p16-expression on 
accelerated fractionated radiotherapy in head and neck cancer: Evaluation of the randomised 
DAHANCA 6&7 trial. Danish Head and Neck Cancer Group (DAHANCA). Radiother Oncol. 
100(1):49-55, 2011.  Epub 2011 Mar 21. PMID: 21429609 
 
Lee IH, Eisbruch A. Mucositis versus tumor control: The therapeutic index of adding 
chemotherapy to irradiation of head and neck cancer. IJROBP.  75(4):1060-3, 2009. Epub 2009 
Mar 21. PMID: 19304406 
 
Lechner M, Frampton GM, Fenton A, et al. Targeted next-generation sequencing of head and 
neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors. 
Genome Med. 2013 May 29; 5(5): 49. [Epub ahead of print] PMID: 23718828 
 
Leonhardt FD, Quon H, Arahao M, O’Malley BW Jr, Weinstein GS. Transoral robotic surgery 
for orpharyngeal carcinoma and its impact on patient-reported quality of life and function. Head 
Neck. 34(2): 146-54, 2012. Epub 2011 Apr 5. PMID: 21469248 
 
Levendag PC, Teguh DN, Voet P, et al. Dysphagia disorders in patients with cancer of the 
oropharynx are significantly affected by the radiation therapy dose to the superior and middle 
constrictor muscle: a dose-effect relationship. Radiother Oncol. 85(1):64-73, 2007. Epub 2007 
Aug 21. PMID: 17714815 
 
Lin A, Kim HM, Terrel JE, Dawson LA, Ship JA, Eisbruch A. Quality of life after parotid-
sparing IMRT fo rhead-and-neck cancer: A prospective longitudinal study. IJROBP. 57(1): 61-
70, 2003. 
 
List MA, Ritter-Sterr C, Lansky SB. A performance status scale for head and neck cancer 
patients. Cancer. 66(3):564-9, 1990. PMID: 2364368 
 
Liu C, Dutu G, Peters LJ, Rischin D, Corry J. Tonsillar cancer: The Peter MacCallum experience 
with unilateral and bilateral irradiation. Head Neck. 2013 Jun 1. doi: 10.1002/hed.23297. [Epub 
ahead of print] PMID: 23729387 
 
Ljumanovic R, Langendijk JA, Hoekstra OS, Leemans CR, Castelijns JA. Distant metastases in 
head and neck carcinoma: identification of prognostic groups with MR imaging. Eur J Radiol. 
60(1):58-66, 2006. Epub 2006 Jul 10. 
 
Logemann JA, Rademaker AW, Pauloski BR, et al. Site of disease and treatment protocol as 
correlates of swallowing function in patients with head and neck cancer treated with 
chemoradiation. Head Neck, 28(1), 64-73. 2006. doi: 10.1002/hed.20299 
 

NRG-HN002 
112  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Lonneux M, Lawson G, Ide C, Bausart R, Remacle M, Pauwels S. Positron emission tomography 
with fluorodeoxyglucose for suspected head and neck tumor recurrence in the symptomatic 
patient. Laryngoscope.;110(9):1493-7, 2000. PMID: 
10983949 
 
Lynch J, Lal P , Nutting CM, Harrington KJ, Newbold KL, Bhide SA. Node stage/extracapsular 
spread predict contralateral node failure after unilateral irradiation of tonsil cancer. Radiother 
Oncol. 106(Suppl 1):S15-16, 2013. 
 
Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after 
concurrent chemoradiation for locally advanced head and neck cancer: An RTOG analysis. J 
Clin Oncol.  26(21):3582-9, 2008. Epub 2008 Jun 16. PMID: 18559875 
 
Marcus C, Ciarallo A, Tahari AK, Mena E, Koch W, Wahl RL, Kiess AP, Kang H, 
Subramaniam RM.  Head and Neck PET/CT: Therapy response interpretation criteria (Hopkins 
Criteria)-interreader reliability, accuracy, and survival outcomes.  J Nucl Med. 2014 Jun 19. pii: 
jnumed.113.136796. [Epub ahead of print] PMID:  24947059. 
 
Martin-Harris B, Brodsky MB, Michel Y, et al. MBS measurement tool for swallow impairment-
mbsimp: Establishing a standard. Dysphagia. 23:392-405, 2008. 
 
Maxwell JH, Mehta V, Wang H, et al. Quality of life in head and neck cancer patients: Impact of 
HPV and primary treatment modality. Laryngoscope. 2013 Nov 7. doi: 10.1002/lary.24508. 
[Epub ahead of print]. 
 
Moeller BJ, Rana V, Cannon BA, et al. Prospective imaging assessment of mortality risk after 
head-and-neck radiotherapy IJROBP.  78:667-674, 2010. PMID: 20171802 
 
Mortensen HR, Overgaard J, Specht L, et al. Prevalence and peak incidence of acute and late 
normal tissue morbidity in the DAHANCA 6&7 randomised trial with accelerated radiotherapy 
for head and neck cancer. Radiother Oncol. 103(1):69-75, 2012. Epub 2012 Mar 5. PMID: 
22398313 
 
Murnane J. Personal communication. 2012. 
 
Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating 
tumor DNA with broad patient coverage. M.Nat Med. 20(5):548-54, 2014. doi: 
10.1038/nm.3519. Epub 2014 Apr 6. PMID: 24705333 
 
Nijdam WM, Levendag PC, Noever I, Schmitz PI, Uyl-de Groot CA. Longitudinal changes in 
quality of life and costs in long-term survivors of tumors of the oropharynx treated with 
brachytherapy or surgery. Brachytherapy. 7(4):343-50, 2008. PMID:18786864 
 

NRG-HN002 
113  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Okami K, Wu L, Riggins G, et al. Analysis of PTEN/MMAC1 alterations in aerodigestive tract 
tumors. Cancer Res. 58(3): 509-11, 1998. 
 
O'Sullivan B, Huang SH, Perez-Ordonez B, et al. Outcomes of HPV-related oropharyngeal 
cancer patients treated by radiotherapy alone using altered fractionation. Radiother Oncol. 2012; 
103(1):49-56.. doi: 10.1016/j.radonc.2012.02.009. Epub 2012 Mar 10. PMID: 22410204 
 
O'Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human 
papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J 
Clin Oncol. 31(5):543-50, 2013. Epub 2013 Jan 7. PMID: 23295795 
 
O'Sullivan B, Warde P, Grice B, et al. The benefits and pitfalls of ipsilateral radiotherapy in 
carcinoma of the tonsillar region. IJROBP. 2001;51(2):332-43. PMID: 11567806 
 
Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of 
conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 
randomised controlled trial. Lancet. 362(9388):933-40, 2003. Erratum in: Lancet. 2003 Nov 
8;362(9395):1588. PMID: 14511925 
 
Paidpally V, Tahari AK, Lam S, et al. Addition of 18F-FDG PET/CT to clinical assessment 
predicts overall survival in HNSCC: A retrospective analysis with follow-up for 12 years. J Nucl 
Med. 2013; 54(12):2039-45. doi: 10.2967/jnumed.113.121285. Epub 2013 Oct 7. PMID: 
24101687 
 
Pedroso A, De Salles A, Mattozo C, et al. Decision Support Software Use For Patients: 
Immediate and Post Evaluation. Paper presented at: Annual Meeting of the Congress of 
Neurological Surgeons; April 28-29, 2006;Los Angeles, CA. 
 
Poggi MM, Konski AA, Suh WW, et al. American College of Radiology ACR Appropriateness 
Criteria Anal Cancer. 2010. Accessed 9-1-2013. At: 
http://www.acr.org/~/media/ACR/Documents/AppCriteria/Oncology/AnalCancer.pdf. 
 
Porceddu S, Jarmolowski E, Hicks R, et al. Utility of positron emission tomography for the 
detection of disease in residual neck nodes after (chemo)radiotherapy in head and neck cancer. 
Head & Neck. 27(3):175-81, 2005. PMID:15627258 
 
Qi M, Guangyuan H, Guoxian L, Hong Q, Qiang F, Guoqing H. A prospective study on 
therapeutic gain by concurrent chemoradiotherapy for stage II-IV a nasopharyngeal carcinoma. J 
Huazhong Univ Sci Technolog Med Sci. 31(1):58-61, 2011. Epub 2011 Feb 19. PMID:21336724 
 

NRG-HN002 
114  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Quon H, Leong T, Haselow R, Leipzig B, Cooper J, Forastiere A. Phase III study of radiation 
therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated 
carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group 
(E2382). IJROBP.   81(3):719-25, 2011. Epub 2010 Oct 1. PMID: 20888709  
 
Quon H, Forastiere AA. Controversies in treatment deintensification of human papillomavirus-
associated oropharyngeal carcinomas: Should we, how should we, and for whom? J Clin Oncol. 
2013 Jan 7. [Epub ahead of print] PMID: 23295808 
 
Ramaekers BL, Joore MA, Grutters JP, van den Ende P, Jong J, Houben R, et al. The impact of 
late treatment-toxicity on generic health-related quality of life in head and neck cancer patients 
after radiotherapy. Oral Oncol. 47(8):768-74, 2011. PMID: 21683647   
 
Ringash J, O'Sullivan B, Bezjak A, Redelmeier DA. Interpreting clinically significant changes in 
patient-reported outcomes. Cancer. 2007; 110(1): 196-202. PMID: 17546575 
 
Roe JW, Drinnan MJ, Carding  PN, Harrington KJ, Nutting CM. Patient-reported outcomes 
following parotid-sparing intensity-modulated radiotherapy for head and neck cancer. How 
important is dysphagia? Oral Oncol. 50(12), 1182-1187, 2014. doi: 
10.1016/j.oraloncology.2014.09 
  
Rogers SN, GwanneS, Lowe D, et al. The addition of mood and anxiety domains to the 
University of Washington Quality of Life scale. Head and Neck. 24(6): 521-529, 2002. 
 
Rogers SN, Miller RD, Ali K, Minhas AB, Williams HF, Lowe D. Patients' perceived health 
status following primary surgery for oral and oropharyngeal cancer. Int J Oral Maxillofac Surg. 
35(10):913-9, 2006. PMID: 17008054 
 
Rogers SN, Rajlawat B, Goru J, et al. Comparison of the domains of anxiety and mood of the 
University of Washing Head and Neck Questionnaire (UW-QoLv. 4) with the CES-D and 
HADS. Head Neck. 28(8): 696-704, 2006. 
 
Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. 
Dysphagia. 11:93-8, 1996. 
 
Rusthoven KE, Raben D, Schneider C, Witt R, Sammons S, Raben A. Freedom from local and 
regional failure of contralateral neck with ipsilateral neck radiotherapy for node-positive tonsil 
cancer: Results of a prospective management approach. IJROBP. 2009;74(5):1365-70. doi: 
10.1016/j.ijrobp.2008.10.023. Epub 2009 Jan 23. PMID: 19168295 
 
Ryan WR, Fee WE Jr, Le QT, et al. Positron-emission tomography for surveillance of head and 
neck cancer. Laryngoscope. 115:645-650, 2005. PMID: 15805874 
 

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REFERENCES (Continued) 
 
Ryu JS, Lee JH, Kang JY, Kim MY, Shin DE, Shin DA. Evaluation of dysphagia after cervical 
surgery using laryngeal electromyography. Dysphagia. 27:318-24, 2012. 
 
Saunders MI, Rojas AM, Parmar MK, Dische S. Mature results of a randomized trial of 
accelerated hyperfractionated versus conventional radiotherapy in head-and-neck cancer. 
CHART Trial Collaborators. IJROBP. 77(1):3-8, 2010. PMID: 20394851 
 
Santanam L, et al Standardizing naming conventions in radiation oncology.  IJROBP. 83(4): 
1344-1349, 2012. 
 
Schlecht NF, Brandwein-Gensler M, Nuovo GJ, et al. A comparison of clinically utilized human 
papillomavirus detection methods in head and neck cancer. Modern Pathol. 24:1295-1305, 2011. 
 
Schwartz DL, Hutcheson K, Barringer D, et al. Candidate dosimetric predictors of long-term 
swallowing dysfunction after oropharyngeal intensity-modulated radiotherapy. IJROBP.  
78(5):1356-65, 2010. Epub 2010 Jun 18. PMID: 20646872 
 
Schwartz DL, Garden AS, Thomas J, et al. Adaptive radiotherapy for head-and-neck cancer: 
Initial clinical outcomes from a prospective trial. IJROBP.  83(3), 986-993, 2012. doi: 
10.1016/j.ijrobp.2011.08.017  
 
Shankar LK, Hoffman JM, Bacharach S, et al. Consensus recommendations for the use of 18F-
FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J 
Nucl Med. 47:1059–1066, 2006. PMID: 16741317 
 
Siddiqui F, Faulhaber PF, Yao M, Le QT. The application of FDG-PET as prognostic indicators 
in head and neck squamous cell carcinoma. PET Clinics. 7:381-394, 2012. 
 
Sinclair CF, McColloch NL, Carroll WR, Rosenthal EL, Magnuson JS. Patient-perceived and 
objective functional outcomes following transoral robotic surgery for early oropharyngeal 
carcinoma. Arch Otolaryngol Head Neck Surg. 137(11): 1112-6, 2011. PMID: 22106235 
 
Sinha P, Lewis JS Jr, Piccirillo JF, Kallogjeri D, Haughey BH. Extracapsular spread and 
adjuvant therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. 
Cancer. 118(14):3519-30, 2012. Epub 2011 Nov 15. PMID: 22086669 
 
Som PM, Curtin HD, Mancuso AA. An imaging-based classification for the cervical nodes 
designed as an adjunct to recent clinically based nodal classifications. Arch Otolaryngol Head 
Neck Surg. 125(4):388-96, 1999. PMID: 10208676 
 
 

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REFERENCES (Continued) 
 
Spector ME, Gallagher KK, Light E, et al. Matted nodes: poor prognostic marker in 
oropharyngeal squamous cell carcinoma independent of HPV and EGFR status. Head Neck. 
34(12):1727-33, 2012. PMID: 22247002 
 
Steinberg DM, Fine J, Chappell R. Sample size for positive and negative predictive value in 
diagnostic research using case-control designs. Biostatistics .10(1): 94-105, 2009. 
 
Stoeckli SJ, Huisman TA, Seifert B, Martin-Harris BJ. Interrater reliability of videofluoroscopic 
swallow evaluation. Dysphagia. 18:53-7, 2003. 
 
Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous 
cell carcinoma. Science. 333(6064): 1157-60, 2011. Epub 2011 Jul 28. PMID: 21798893 
 
Sturgis EM, Ang KK. The epidemic of HPV-associated oropharyngeal cancer is here: Is it time 
to change our treatment paradigms? J Natl Compr Canc Netw.  9(6):665-73, 2011. Review. 
PMID: 21636538 
 
Subramanian, personal communication, 2014 
 
Tang C, Murphy JD, Khong B, et al. Validation that metabolic tumor volume predicts outcome 
in head-and-neck cancer. IJROBP. 83:1514-1520, 2012. PMID:22270174 
 
Terrell JE, Fisher SG, Wolf GT. Long-term quality of life after treatment of laryngeal cancer. 
Arch Otolaryngol, Head Nec Surg. 124(9): 964-71, 1998. 
 
Terrell JF, Nanavati KA, Esclamado RM, Bishop JK, et al. Head and neck cancer-specific 
quality of life. Arch Otolaryngol, Head Nec Surg. 123: 1125-1132, 1997. 
 
Thavaraj S, Stokes A, Guerra E, et al. Evaluation of human papillomavirus testing for squamous 
cell carcinoma of the tonsil in clinical practice. J Clin Pathol. 64:308-312, 2011 
 
Trotti A, Pajak TF, Gwede CK, et al. TAME: Development of a new method for summarising 
adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol. 
(7):613-24, 2007. PMID: 17543584 
 
Trotti A, Colevas AD, Setser A, Basch E. Patient-reported outcomes and the evolution of adverse 
event reporting in oncology. J Clin Oncol. 25:5121-7, 2007b. Review. PMID: 17991931  
 
Verdonk-de Leeuw IM, van Bleek W-J, Leemans CR, de Bree R. Employment and return to 
work in head and neck cancer survivors. Oral Oncology. 46: 56–60, 2010. 
 

NRG-HN002 
117  
Version Date:  December 20, 2017 
REFERENCES (Continued) 
 
Vergeer MR, Doornaert PA, Jonkman A, et al. Ipsilateral irradiation for oral and oropharyngeal 
carcinoma treated with primary surgery and postoperative radiotherapy. IJROBP. 78(3):682-8, 
2010. Epub 2010 Feb 25. PMID: 20188492  
 
Ware RE, Matthews JP, Hicks RJ, et al. Usefulness of fluorine-18 fluorodeoxyglucose positron 
emission tomography in patients with a residual structural abnormality after definitive treatment 
for squamous cell carcinoma of the head and neck. Head Neck.  26:1008-1017, 2004. PMID: 
15459925 
 
Weymuller E, Alsarraf R, Yueh B, Deleyiannis F, Colterera M. Analysis of the performance 
charactistics of the UW-QoL and modification of the instrument. Arch Otolaryngol, Head Nec 
Surg. 127(5): 489-493, 2001. 
 
Wiernik G, Bates TD, Bleehen NM, et al.  Final report of the general clinical results of the 
British Institute of Radiology fractionation study of 3F/wk versus 5F/wk in radiotherapy of 
carcinoma of the laryngo-pharynx. Br J Radiol. 63(747):169-80,1990. PMID: 2185865 
 
Wyss A, Hashibe M, Chuang SC, et al. Cigarette, cigar, and pipe smoking and the risk of head 
and neck cancers: pooled analysis in the International Head and Neck Cancer Epidemiology 
Consortium. Am J Epidemiol. 178(5):679-90, 2013. doi: 10.1093/aje/kwt029. Epub 2013 Jun 30). 
 
Yao M, Smith R, Graham M, etal. The role of FDG PET in management of neck metastasis from 
head-and-neck cancer after definitive radiation treatment. IJROBP.  63:991-9, 2005. PMID: 
16099601 
Yao M, Smith RB, Hoffman HT, et al. Clinical significance of postradiotherapy [18F]-
fluorodeoxyglucose positron emission tomography imaging in management of head-and-neck 
cancer – A long-term outcome report. IJROBP.   74:9-14, 2009. PMID: 18930358 
 
Yeung AR, Garg MK, Lawson J, et al. ACR Appropriateness Criteria® ipsilateral radiation for 
squamous cell carcinoma of the tonsil. Head Neck. 34(5):613-6. 2012. Epub 2012 Jan 17. PMID: 
22250010 
 
Zhang E. Personal communication. 2012. 
 
 

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APPENDIX I: DENTAL TOOTH COUNT AND DENTAL MANAGEMENT (5/24/16) 
 
Dental Tooth Count Diagram 
Use the diagram below as a guide to count the number of native teeth in place, not including full 
or partial dentures or bridges.  
 
The exact location of teeth does not need to be recorded, only the total number of native teeth in 
place (attached to bone in mandible or maxilla) on the day of evaluation. 
 
This exam should be completed by a physician or designee, such as a physician's assistant, nurse 
or nurse practitioner, or a dentist/hygienist. 
 
Date of evaluation:  
 
Total number of native teeth in place (0-32):  
 
 

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Dental Effects Health Scale 
 
 
0 Normal: Edentulous, with no gingival disease; native teeth in place with gingiva 
in excellent condition. 
 
1 Mild changes/good dental health: mild periodontal inflammation-routine cleaning 
indicated; < 5 restorations indicated; no extractions indicated. 
 
2 Moderate/fair dental health: moderate periodontal inflammation; deep periodontal 
cleaning indicated; 6 or more restorations indicated; less than full mouth 
extractions indicated. 
 
3 Severe changes in dental health: widespread periodontal disease with extensive 
procedure/surgery indicated; full mouth extractions indicated. 
 
4 Life-threatening dental condition: extensive abscess, extensive soft issue or bone 
infection, sepsis; urgent intervention indicated.  
  
 

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APPENDIX I (Continued) 
 
Management of Dental Problems in Irradiated Patients 
 
Goals for a dental care program include: 
1. 
To reduce incidence of bone necrosis. 
2. 
To reduce incidence of irradiation caries. 
3. 
To allow proper fitting of dentures following treatment. 
 
Pre-irradiation Care and Procedures 
The patients may be grouped into four groups in accordance with the problems they present prior 
to irradiation. 
 
 Group 1: Includes edentulous patients.  They may require surgical removal of any 
symptomatic cysts, infected retained root tips, or alveolar hyperplasia.  These patients 
require hygiene instruction and precautionary instruction about trauma with premature 
use of a prosthesis. 
 
 Group 2: Includes those with poor dental hygiene, including those patients whose teeth 
are beyond repair by ordinary dental procedure, those with generalized oral sepsis, those 
with generalized periodontal disease, and those with chronic periapical abscesses or 
granulomas. 
 
Procedures performed on this group include removal of all remaining teeth prior to 
irradiation with primary closure and surgical preparation of the alveolar ridges to laterally 
support a prosthesis.  There should be antibiotic coverage during the healing stage and 
adequate time prior to the start of radiation therapy.  These patients need complete 
hygiene instruction and precautionary instruction about premature use of a prosthesis. 
 
 Group 3: Includes those in whom dental condition is fair, including those patients whose 
teeth are restored, ordinary dental procedures, periodontal pockets are less than 3 mm 
deep, carious lesions are not in proximity to the pulp, and no more than 20 restorable 
carious lesions are present.  X-ray examinations show at least 1/2 of the bone still present 
around root surfaces.  These patients require removal of any teeth that are non-
salvageable in accordance with the above and restorations of the remaining teeth as 
required.  The patients are instructed for dental prophylaxis and the patients utilize 
custom-made fluoride carriers. 
 
 Group 4: Includes those in whom dental hygiene is good.  This includes patients who do 
not have severe malocclusion in whom few carious lesions are present.  Carious lesions 
are not in close proximity to the pulp and are correctable by conventional methods.  
These patients require periodontal evaluation and dental prophylaxis training, restorations 
as needed, no extractions prior to radiation therapy, and fitting for custom carriers. 

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Management of Dental Problems in Irradiated Patients (continued) 
 
Extraction of Teeth 
If extraction of teeth is necessary prior to radiation therapy, the bone must be contoured so that 
closure at the extraction site is possible.  All loose spicules and sharp projections must be 
removed.  The approximation of the gingival tissue must be such that the closure is neither too 
loose nor too tight.  At least 10 days are required for adequate healing prior to initiation of 
therapy. 
 
Causative Factors 
The major causative factors appear to be the reduction of the amount of saliva and secondarily, 
reduced pH in the mouth.  This occurs following high dose radiation to the major salivary glands 
using parallel opposed fields.  The decay process usually occurs in the first year following 
radiation therapy.  It tends to occur more quickly in teeth which have a large amount of root 
cementum exposed to those teeth with large amounts of plaque formation present.  Doses of 
radiation in excess of 20 Gy to salivary tissue place the teeth at risk. 
 
 Preventive Program 
The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible 
to the decay process.  This is accomplished by a combination of increasing fluoride 
concentration on the tooth surface and by the effect of fluoride on the plaque and flora that are 
present in the oral cavity.  Adequate results are obtained by:  1) cleansing the teeth thoroughly, 
followed by a good home care dental prophylaxis program, 2) construction of  
fluoride carriers, custom-made mouth guards, which provide local application of fluoride 
solution to the gingiva and tooth surfaces.  Fluoride carriers are made individually with the use 
of casts.  Material used for making a mouth guard is "Sta-Guard" plastic used in conjunction 
with vacutrole unit produced by Jelrus Technical Products, Corp., both of which are available 
through local dental supply.  This material is molded to the cast impression and allowed to 
harden.  A fluoride solution prepared at the M.D. Anderson Hospital is now available from the 
Emerson Laboratories, Inc., Dallas, Texas 75221.  It has been used to coat the plastic carrier for 
use in the mouth.  The patients are instructed to cleanse their teeth prior to placement of the 
carrier.  It is then worn in place for 5 minutes each day.  The patients are instructed to rinse their 
mouths thoroughly following the use of the carrier.  This will be continued for an indefinite 
period of time.  Close follow-up is necessary. 
 
Results 
In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 304 
patients shows that the incidence of necrosis of the jaw was reduced to approximately 21% 
compared to 37% prior to initiation of the study.  Groups 3 and 4 patients randomized with and 
without fluoride treatment showed reduction in radiation carries from 67% to 34% among Group 
3 patients, and from 65% to 22% among Group 4 patients. 
 

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APPENDIX I (Continued) 
Management of Dental Problems in Irradiated Patients (continued) 
 
Failure to Control Decay 
Management of failure to control radiation decay includes silver fillings with continued use of 
fluoride treatments.  If the decay process is sufficiently advanced that a filling will no longer stay 
in place, these teeth are merely smoothed so that there will be no sharp, irritating edges.  The 
mere existence of such a decayed tooth is not necessarily reason for extraction, for it must be 
remembered that extraction could lead to complications such as bone necrosis. 
 
Pulp exposure resulting from the decay process can usually be handled by use of antibiotics 
and/or root-canal therapy. 
 
Hypersensitivity of Teeth 
Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished 
amounts of saliva.  This has been shown to be reduced in incidence with the fluoride treatments.  
Should this problem become manifest, increasing the fluoride treatment to 10 to 15 minutes 3 
times a day is recommended. 
 
Infections 
Infections occurring in patients under or after radiation therapy are best managed conservatively 
with good oral hygiene, irrigation and flushing procedures, and systemic antibiotics. 
 
Bone Necrosis 
The patients receiving radiation therapy to a high dose to the head and neck region have 
increased susceptibility to bone necrosis for several reasons including:  impairment of normal 
metabolism, increased susceptibility to infection and severely limited repair process.  Bone 
necrosis occurs most often after dental or oral surgery in patients who have been previously 
radiated.  Conservative management should be tried first, though in more aggressive lesions a 
more radical approach may ultimately be necessary. 
 
 
 
 

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APPENDIX II: INSTRUCTIONS AND FORMS FOR THE MODIFIED BARIUM 
SWALLOW (MBS) SUBSTUDY (5/24/16) 
 
Prior to enrolling patients to this substudy, sites must complete the NRG-HN002 MBS 
Credentialing Checklist (see below). The institution will e-mail the completed form to Martha 
Portwood, MPH, mportwood@mdanderson and will receive a letter of instruction confirming 
that the site is approved to enroll patients in the substudy. Institutions should allow adequate 
processing time (10-14 days) before enrolling the first patient on this substudy.  
 
Facilities must use a standardized contrast medium (Varibar® thin liquid and pudding 
contrast, Bracco Diagnostics, Inc. Princeton, NJ, or comparable in Canadian centers) and 
digitally record MBS studies (30 frames/second, although a minimum of 15 frames/second is 
acceptable if this is made clear at the time of credentialing). DIGEST grades will be assigned 
by the site Speech-Language Pathologist conducting the MBS study and reported by research 
staff on the Modified Barium Swallow Study Form as: 0 “normal”, 1 “mild”, 2 “moderate”, 3 
“severe”, or 4 “life threatening”.  
 
Participating sites are required to perform MBS studies as specified on the Modified Barium 
Swallow Study Form (below) and then upload the MBS video to the TRIAD (Transfer of 
Images and Data) application, as specified below, for central review and scoring. The percent 
of patients with scores of 0, 1, 2, 3, and 4 dysphagia per MBS will be compared at baseline 
and 24 months (+/- 3 months) from end of radiation. 
 
Questions related to conduct of MBS studies can be directed to:  
Martha Portwood, MPH  
University of Texas MD Anderson Cancer Center  
Phone: 713-792-6364  
E-mail: mportwood@mdanderson.org  
 
Kate Hutcheson, PhD 
University of Texas MD Anderson Cancer Center 
Phone: 713-792-6513 
Email: karnold@mdanderson.org 
 
Jan S. Lewin, PhD 
University of Texas MD Anderson Cancer Center 
Phone: 713-792-5309 
Email: jlewin@mdanderson.org 
 

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APPENDIX II (Continued) 
Instructions for Submission of MBS Videos to TRIAD 
1) Download and install TRIAD 4 via https://triadinstall.acr.org/triadclient/ 
2) Launch TRIAD, click the dropdown to select Clinical Trials (NCI Oncology). Login 
using your CTEP ID and password (see Section 8 for access requirements for  OPEN, 
Medidata Rave, and TRIAD). 
 
 
3) To begin file submission: 
A. Select the HN002 Trial from the Trial dropdown. 
B. Select your Hospital from the Site dropdown. 
C. Once these options are selected, select Import Folder (to select a group of video 
files), or Import Files (to import an individual video file). 
 

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Instructions for Submission of MBS Videos to TRIAD (Continued) 
 
4) Your selected file(s) will appear in the preview screen for review. Select Move to 
Submission Queue to move your files to the submission queue. 
 
 
5) To complete, enter subject information (Subject ID, Time Point ID, Time Point 
Description, Submission Type, etc.), then select Submit. 
 
 
 

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APPENDIX II (Continued) 
Instructions and Forms for the Modified Barium Swallow (MBS) Substudy 
 
Modified Barium Swallow (MBS) Credentialing Checklist 
 
This checklist must be completed by the institution before patients can be enrolled to the MBS 
substudy of NRG-HN002.   
 
1. 
Please provide the following data specific to your site regarding conduct of modified 
barium swallow (MBS) studies to evaluate swallowing disorders. 
 
a) Number of speech/language pathologists at your institution who perform MBS 
studies:_________ 
 
b) Average number of 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:__________ 
 
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  
 
 
If no, specify frame rate used at your facility (note: 15 to 30 permitted): _____________ 
 
3. 
Do you use the Kay Pentax Digital Swallowing Workstation? (this is NOT mandatory for 
participation) 
 
YES 
NO  
 
 
If no, specify the recording system used:_____________________________________ 
 
 

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APPENDIX II (Continued) 
 
Instructions and Forms for the Modified Barium Swallow (MBS) Substudy 
 
4. 
Do you use Varibar contrast agents specified in this substudy, including Varibar Thin 
Liquid and Varibar Pudding? 
 
YES 
NO  
 
 
If no, specify the standardized contrast medium used:____________________________ 
 
 
5. 
If no, can you access Varibar contrast agents for MBS studies conducted for this 
substudy? 
  
YES 
NO 
 
 
 
Signature of Institution Speech/Language Pathologist_________________________________ 
 
 
Printed Name of Speech/Language Pathologist______________________________________ 
 
 
Institution Name______________________________________________________________ 
 
 
Site NRG number/CTEP ID Number______________________________________________ 
 

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Instructions and Forms for the Modified Barium Swallow (MBS) Substudy 
 
 
Institution Contact Person______________________________________________________ 
 
 
Institution Contact Person’s phone and fax numbers__________________________________ 
 
 
Institution Contact Person’s e-mail address_________________________________________ 
 
 
Name and e-mail address of person uploading MBS video 
 
_____________________________________________________________________________ 
 
E-mail the completed checklist to Martha Portwood, MPH, at 
mportwood@mdanderson.org.  
 
After review and approval of the form by the Swallowing Outcomes Co-Chair, Jan S. 
Lewin, PhD, the CRA will receive a letter of instruction confirming that the site is 
approved to enroll patients in this substudy.  
 
 

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Instructions and Forms for the Modified Barium Swallow (MBS) Substudy 
 
 
  
                      
 
 
 
 
 
 
  
 
   
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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