A Pilot Single Arm Study of Intensity Modulated Radiation Therapy Elective Nodal Dose De-Escalation for HPV-Associated Squamous Cell Carcinoma of the Oropharynx
Phase: NA
Conditions: Oropharyngeal Squamous Cell Carcinoma (OPSCCA), HPV (Human Papillomavirus)-Associated
Sponsor: Paul W. Read, MD

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Protocol Title:  A Pilot Single Arm Study of Intensity Modulated Radiation Therapy 
Elective Nodal Dose De-Escalation for HPV-Associated Squamous Cell Carcinoma of 
the Oropharynx 
 
NCT#:  NCT01891695 
 
Version date:  April 9, 2013 

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PROTOCOL TITLE  
A Pilot Single Arm Study of Intensity Modulated Radiation Therapy Elective Nodal Dose 
De-Escalation for HPV-Associated Squamous Cell Carcinoma of the Oropharynx 
 
Principal Investigator 
 
Paul W. Read, MD, PhD 
Professor 
Department of Radiation Oncology  
University of Virginia Medical Center 
Charlottesville, VA 22908-800383 
Phone: 434-924-5191 
Fax: 434-982-3262 
pwr3u@ hscmail.mcc.virginia.edu 
 
Co-Investigators  
Edwin F. Crandley, MD 
Resident in Radiation Oncology 
Department of Radiation Oncology  
ec3ru@hscmail.mcc.virginia.edu  
David D. Wilson, MD 
Resident in Radiation Oncology 
Department of Radiation Oncology  
ddw3m@hscmail.mcc.virginia.edu  
Ryan Best, PhD 
Resident in Medical Physics 
Department of Radiation Oncology 
rb2bk@hscmail.mcc.virginia.edu  
Edward B. Stelow, MD 
Associate Professor 
Department of Pathology 
es7yj@hscmail.mcc.virginia.edu 
Mark J. Jameson, MD, PhD 
Assistant Professor 
Department of Otolaryngology 
mjj4e@hscmail.mcc.virginia.edu 
Paul A. Levine, MD 
Professor and Chairman 
Department of Otolaryngology  
pal@hscmail.mcc.virginia.edu  
James F. Reibel, MD 
Associate Professor 
Department of Otolaryngology  
jfr2j@hscmail.mcc.virginia.edu 
David C. Shonka Jr, MD 
Assistant Professor 
Department of Otolaryngology 
dcs5jzhscmail.mcc.virginia.edu 
 
Biostatistician 
Gina Petroni, PhD 
Professor of Biostatistics 
Department of Public Health Sciences 
grp4c@hscmail.mcc.virginia.edu 
 
Clinical Research Coordinator 
Lisa Godwin 
Clinical Research Coordinator 
Department of Otolaryngology   
lng4n@ hscmail.mcc.virginia.edu 

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TITLE: 
A Pilot Single Arm Study of Intensity Modulated Radiation Therapy Elective Nodal Dose 
De-Escalation for HPV-Associated Squamous Cell Carcinoma of the Oropharynx 
 
 
SCHEMA  
Study Design 
This is a single arm, pilot study to estimate the toxicity, effectiveness and safety of 
intensity modulated radiation therapy in patients treated with p16+/HPV+ oropharyngeal 
squamous cell carcinoma with reduced radiation dose to the lymph nodes at risk for 
microscopic disease but clinically staged as N0. 
 
Intensity Modulated Radiation Therapy 
 Patients will be treated with intensity-modulated radiation therapy (IMRT). Planning 
Target Volume (PTV1) will include the gross disease with expansions for 
microscopic disease extension and 3 mm setup error expansion and will receive 70 
Gy/35 fractions at 2.0 Gy/fraction/day for 5 days/week of a 7 week regimen.   
 PTV2 will include the clinically uninvolved cervical lymph nodes (N0 lymph node 
volumes) with a 3 mm expansion for setup error and will be treated to 39.6 Gy/22 
fractions at 1.8 Gy/fraction/day for 5 days/week. 
 
ELIGIBILITY (see section 3) 
 Confirmed histopathologic diagnosis of p16-positive tumor by 
immunohistochemistry. 
 Must undergo pre-treatment tumor staging using the version 7 American Joint Cancer 
Committee Staging System. 
 Patients must undergo a PET CT within 8 weeks prior to cancer treatment. 
 Patients must have a contrast neck CT within 8 weeks to cancer treatment (this can be 
the CT simulation) or if they have a CT contrast allergy this can be a neck MRI scan.  
 Tumor must be measurable by physical exam and/or endoscopy, and PET CT. 
 Primary diagnosis is clinical stage I-IVb (T1-T4, N0-N3, M0). 
 18 years of age or older. 
IMRT: 
Imaging: 
Physical Exam: 
Day:                     1          8         15         22        29        36        43       50        57        64        71        78     …        90 

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 Able to lie flat on the table for IMRT and tolerate aquaplast or other immobilization 
systems that reduces intra-fraction motion to 3 mm or less.  
 Able to understand English (or a medical interpreter for their native language must be 
available for all study visits).  
 Zubrod performance status 0-2. 
 Nutritional and general medical condition must be considered compatible with the       
proposed radiotherapy treatment. 
 No prior radiotherapy to the head and neck in the volumes to be irradiated for this 
malignancy. 
 No other malignancy except non-melanomatous skin cancer or a carcinoma not of 
head and neck origin with the patient being disease free for  5 years. 
 No major medical psychiatric or neurologic illness, which in the investigators’ 
opinions would interfere with either completion of therapy or with full and complete 
understanding of the risks and potential complications of the therapy. 
 Mentally reliable to follow instructions and to keep appointments. 
 Pregnant and breastfeeding women are excluded from this study. 
o Women of childbearing potential (WOCBP) must have a negative 
pregnancy test within 14 days prior to cancer treatment. 
o WOCBP and men agree to use adequate contraception (hormonal or 
barrier method of birth control) for the duration of radiation. Should a 
woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. 
 Signed study-specific informed consent form.  
 
TREATMENT (see section Error! Reference source not found.):  
 Patients will be treated with IMRT. Planning Target Volume (PTV1) will receive 70 
Gy/35 fractions at 2.0 Gy/fraction/day for 5 days/week.   
 Clinically uninvolved cervical lymph nodes (N0 lymph nodes) will be treated to 39.6 
Gy/22 fractions at 1.8 Gy/fraction/day for 5 days/week. 
 

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TABLE OF CONTENTS 
1 
BACKGROUND AND RATIONALE 
1 
1.1 
Study Synopsis ......................................................................................................1 
1.2 
Disease Background ..............................................................................................2 
1.3 
Study Agent(s) Background and Rationale ...........................................................5 
1.4 
Rationale for Study Design ...................................................................................9 
2 
STUDY OBJECTIVES 9 
2.1 
Primary Objectives ................................................................................................9 
2.2 
Secondary Objectives ............................................................................................9 
3 
PATIENT ELIGIBILITY 
10 
3.1 
Inclusion Criteria .................................................................................................10 
3.2 
Exclusion Criteria ................................................................................................10 
4.0 
TREATMENT PLAN 11 
4.1 
Registration .........................................................................................................11 
4.2 
Intensity Modulated Radiation Therapy (IMRT) Treatment Regimen ...............11 
4.3 
Dosing Delays/Dose Modifications ....................................................................12 
4.4 
Concomitant Medications/Treatments ................................................................12 
4.5 
Other Modalities or Procedures...........................................................................13 
4.6 
Duration of Therapy ............................................................................................13 
4.7 
Duration of Follow Up ........................................................................................13 
4.8 
Pregnancy ............................................................................................................13 
4.9 
Removal of Patients from Protocol Therapy .......................................................14 
5 
EVALUATIONS AND ASSESSMENTS 15 
5.1 
Time and Events Table ........................................................................................15 
5.2 
Pre-Study Assessments .......................................................................................16 
5.3 
Treatment Assessments .......................................................................................16 
5.4 
Post-Treatment/Follow-up Assessments .............................................................17 
6 
EVALUATION CRITERIA 17 
6.1 
Parameters of Response: RECIST for Solid Tumors ..........................................17 

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6.2 
Other Measures of Effect ....................................................................................25 
6.3 
Toxicity and Safety .............................................................................................26 
7 
STATISTICAL CONSIDERATIONS 
26 
7.1 
Study Design/Endpoints ......................................................................................26 
7.2 
Sample Size and Accrual.....................................................................................27 
7.3 
Analyses ..............................................................................................................28 
7.4 
Reporting and Exclusions....................................................................................29 
8 
ADVERSE EVENTS AND REPORTING 29 
8.1 
Definitions ...........................................................................................................29 
8.2 
Expedited Adverse Event Reporting Requirements ............................................35 
9 
DATA SAFETY MONITORING PLAN 37 
9.1 
UVA Cancer Center Data Safety Monitoring Committee ..................................37 
10 
STUDY MANAGEMENT 
38 
10.1 
Institutional Review Board (IRB) Approval and Consent ..................................38 
10.2 
Registration Procedures.......................................................................................38 
10.3 
Adherence to the Protocol ...................................................................................38 
10.4 
Record Retention .................................................................................................39 
10.5 
Obligations of Investigators ................................................................................40 
11 
REFERENCES 41 
12 
APPENDICES 
47 
 

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1 BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
 
Oropharyngeal squamous cell carcinoma (OPSCC) is commonly treated 
with platinum-based chemoradiation followed by neck dissection(s) for locally 
advanced nodal disease.  Radiation schedules conventionally include 70 Gray 
(Gy) in 35 fractions to macroscopic disease and 60 Gy to the clinically 
uninvolved cervical lymphatics at high risk for microscopic metastatic disease and 
50-54 Gy to the clinically uninvolved cervical lymphatics at low risk for 
microscopic metastatic disease(1).  Despite advances in technology and the 
utilization of intensity-modulated radiotherapy (IMRT), treatment still causes 
significant acute toxicity, long term morbidity, reduced functional status, and a 
poor quality of life for many patients. Since the expected toxicities for radiation 
for this group of patients is extremely high (See Expected Toxicities Table in 
section 8.1.2) there is a great need to develop less toxic radiation regimens with 
equivalent efficacy to current standard of care regimens.  Specifically, strategies 
for personalized cancer care which reduce the toxicity of treatment for those 
patients with more sensitive disease are needed.  Oropharyngeal carcinoma is 
increasing in incidence in the United States in non-traditional populations, i.e. 
non-ethanol and non-tobacco user groups, secondary to human papilloma virus 
(HPV) infection.  HPV-associated tumors over-express p16, a protein easily 
detected by immunohistochemistry, and are more sensitive to chemotherapy and 
radiation than non-HPV-associated tumors.  We recently reported a retrospective 
analysis of 112 oropharyngeal cancer patients treated with definitive IMRT +/- 
chemotherapy with 70 Gy to PTV1 and 50.4 Gy to PTV2 showing that p16-
positive tumors are highly curable with 100% primary tumor local control, 90% 
sterilization of pathologic lymph nodes based on pathologic analysis of neck 
dissection data, and 100% control of the clinically uninvolved (N0) cervical 
nodes(2).  Given that 100% of the N0 nodes are sterilized by 50 Gy with or 
without chemotherapy we propose reducing the radiation dose to the N0 cervical 
nodal volumes in patients with HPV-associated tumors, as determined by p16 
immunohistochemical staining.  We hypothesize that we can deliver 39.6 Gy to 
the N0 nodes in OPSCC patients with p16 positive tumors and reduce toxicity 
without compromising N0 nodal control, disease-free survival, or overall survival.   
 
UVA treats approximately 20-25 oropharyngeal cancer patients annually 
with definitive radiation or chemoradiation.  We anticipate an accrual rate of 15-
20 cases per year over 3 years (n=45).  We will recruit a total of 45 patients with 
Stage I-IVb, p16-positive OPSCC who are candidates for radiotherapy.  All 
patients will receive IMRT as part of their cancer treatment and will be followed 
on this study for 3 years after treatment.  

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The purpose of this study is to test the overall hypothesis that reduced 
intensity radiation treatment (39.6 Gy) to the N0 nodes in OPSCC patients with 
p16 positive tumors can reduce toxicity without compromising treatment efficacy. 
This represents a 10% reduction from 44 Gy (the minimum dose that the current 
NCCN guidelines recommend for the elective treatment of N0 nodes of patients 
with squamous cell carcinoma of the head and neck) and a 20% reduction from 
out institutional standard of care of 50.4 Gy. Efficacy endpoints will include N0 
nodal control, disease-free survival, and overall survival. Safety will be assessed 
by grading of acute and late radiation-induced toxicity including acute radiation 
dermatitis and late subcutaneous fibrosis, neck dissection complication rate, 
xerostomia and dysphagia. 
1.2 
Disease Background 
1.2.1 Epidemiology of Head and Neck Cancer 
 
Although head and neck cancer is relatively rare, accounting for roughly 
5% of adult cancers(3), it is a devastating disease with significant treatment-
associated toxicities.  The American Cancer Society reports approximately 
40,000-50,000 cases of head and neck cancer are diagnosed annually in the 
United States(4).  Head and neck cancer represents a diverse set of tumors 
originating in the head and neck region that include squamous cell carcinomas of 
the upper aerodigestive tract above the thoracic inlet, salivary gland tumors, 
thyroid tumors, sarcomas, and rare sinus tumors(5). Squamous cell carcinomas 
make up the vast majority of head and neck cancers and can develop in the 
mucosa of various upper aerodigestive anatomic sites including the oral cavity, 
oropharynx, nasopharynx, nasal cavity, paranasal sinuses, larynx, and 
hypopharynx(5). The development of these tumors is often related to patient use 
of tobacco products and/or ethanol, but viruses (HPV and Epstein-Barr Virus) and 
immunosuppression are also etiologic factors(5). The most common head and 
neck cancer treated at UVA with radiation is squamous cell carcinoma of the 
oropharynx (OPSCC).     
1.2.2 Standard Radiotherapy for OPSCC 
 
Head and neck cancer can metastasize to cervical lymph nodes and do so 
in a predictable pattern with initial involvement of the first nodal echelon and 
sequential involvement in lower cervical and contralateral nodal regions(6-8).  
The Seventh Edition of the American Joint Committee on Cancer Staging Manual 
published in 2010 is the current staging system used by most physicians to stage 
head and neck cancer patients(9).  Patients with stage I and II disease have a small 
primary tumor without clinical evidence of lymph node metastases and are 
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are generally considered to have locally advanced disease that is manifest by large 
primary tumors and/or clinically involved cervical lymph nodes.  Therapy for 
these patients frequently involves multi-modality therapy based on the volume 
and location of both the primary tumor and lymph node disease and may include 
various combinations of surgery, radiation, cytotoxic chemotherapy (cisplatin, 
carboplatin, taxol, taxotere, 5-fluorouracil, capecitacbine), and/or biologic therapy 
(Cetuximab, an anti-epidermal growth factor receptor antibody)(10). 
 
Radiation therapy for oropharyngeal cancer can conceptually be thought 
of as treating two separate regions to be targeted by the radiation (target volumes).  
The first target volume is the planning target volume 1 (PTV1) which contains all 
known gross cancer including the primary tumor and all pathologic lymph nodes 
(See Figure 1).  Planning target volume 2 (PTV2) contains all of the clinically 
uninvolved cervical lymphatics at risk for microscopic disease spread (termed the 
N0 neck).  Standard treatment for oropharyngeal carcinoma is definitive radiation 
therapy with 70 Gy delivered to PTV1 and 44-64 Gy (commonly 50Gy) delivered 
to PTV2(11). Concurrent chemotherapy is delivered for patients with Stage III-IV 
disease, and patients with N2 and N3 cervical nodal disease may also undergo 
neck dissection(s) to resect the nodal disease at the completion of chemoradiation 
if this is still palpable or appears pathologic on post-treatment imaging.  
Irradiation of these large volumes spanning the base of skull to the clavicles 
results in significant acute toxicity (fatigue, skin redness and blistering, sore 
mouth and throat, mucosal ulceration, loss of taste, dry mouth, thick secretions, 
cough, hoarseness, dehydration, and nausea) and late toxicity (dental decay, 
permanent dry mouth, swallowing difficulties, middle ear effusions, altered taste, 
osteonecrosis of the mandible, and hypothyroidism)(5).  Given the significant 
toxicity associated with current treatment techniques for OPSCC, translational 
advancements that would reduce dose and toxicity are highly desirable. 
 
Figure 1: Diagram of PTV1 and PTV2
Red = PTV1
Yellow= PTV2

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1.2.3 HPV-associated OPSCC:  A sensitive patient sub-population 
 
OPSCC is increasing in incidence in the United States in non-traditional 
populations, i.e. non-ethanol and non-tobacco user groups, secondary to HPV-
associated malignancies(12).  Data from multiple studies reveal that 
oropharyngeal HPV-associated tumors account for 20-75% of oropharyngeal 
tumors(13, 14).  HPV16 is the most common viral subtype associated with 
malignant transformation, as it is found in 90-95% of HPV-associated 
OPSCC(13).  Over 86% of HPV-associated tumors over-express p16INK4A (p16), a 
cyclin-dependent kinase inhibitor, and only 3% of HPV-non-associated tumors 
over-express p16(15).  P16 status can be identified easily by standard 
immunohistochemical techniques.  Based on our own tissue microarray p16 
immunohistochemical analysis, approximately 60% of oropharyngeal SCCs in 
central Virginia are HPV-associated(16). 
 
Malignant transformation of HPV-associated malignancies involves the 
E6 and E7 oncoprotein pathways which functionally inactivate two human tumor-
suppressor proteins, p53 and pRb respectively, leading to cellular proliferation, 
loss of cell cycle regulation, impaired cellular differentiation, increased frequency 
of spontaneous and mutagen-induced mutations, impaired apoptosis, and 
chromosomal instability(15, 17-19).  The E6 oncoprotein binds to the cellular 
ubiquitin-protein ligase E6-AP and uses E6-AP to target the tumor suppressor 
protein p53 for ubiquitination and subsequent proteasome-mediated degradation.  
As a result of this degradation, p53 cannot initiate the apoptosis cascade or 
activate p21 to arrest the cell cycle.  The overall effect is the abrogation of both 
the p53 and p21 pathways leading to impaired apoptosis and uncontrolled cellular 
growth(15, 17-19).  The E7 oncoprotein can associate with both pRb and p21. In 
normal, non-proliferating cells, pRb blocks cell cycle progression by complexing 
with transcription factors such as E2F(18).  When pRb is phosphorylated by 
cyclin-dependent kinase (CDK) complexes, it disassociates with E2F, enabling 
the cell to advance through the cell-cycle and divide.  The p16 protein is a tumor 
suppressor that inactivates CDK4- and CDK6-cyclin D complexes and therefore 
suppresses the phosphorylation of pRb and protects against unregulated cell 
proliferation(15, 17).  The binding of pRb by E7 prevents the pRb/E2F complex 
formation and leads to uncontrolled cell division(18).  pRb acts as an inhibitor of 
p16 transcription, so pRb inactivation by E7 results in highly increased p16 
expression in HPV-positive SCC(15).  P16 is frequently inactivated epigenetically 
in HPV-non-associated tumors by means of hypermethylation(20). 
 
HPV-associated tumors in the head and neck have been reported to be 
more sensitive to chemotherapy and radiation than non-HPV-associated tumors, 
and p16 status is a highly significant independent prognostic indicator for disease-
free survival (DFS) with reported 5-year DFS of 84% for p16 positive (p16+) 

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tumors and 46% for p16 negative (p16-) tumors in one study(15).  The use of p16 
expression to predict DFS was superior to all clinicopathologic parameters 
normally used for treatment decisions and assessment of prognosis(15).  
Additional studies have confirmed that p16 immunohistochemistry is the best test 
to use for risk stratification in oropharyngeal SCC regardless of HPV status(21).   
An Affymetrix Human U133A GeneChip analysis of HPV-positive SCC and 
HPV-negative SCC reported that these tumors also had different specific gene 
expression profiles(22).  It is unknown why p16+ tumors are more radiation 
responsive, but it may be due to higher proliferation rates of these poorly 
differentiated tumors compared to p16- tumors since radiation preferentially kills 
mitotically active cells.  Cells are most sensitive to radiation-induced damage in 
the G2 and M phases of the cell cycle(23).  
1.3 
Study Agent(s) Background and Rationale  
1.3.1 Radiation-induced Xerostomia 
 
Xerostomia (dryness of the mouth) is the most prominent and common 
complication of radiotherapy for head and neck cancers (HNC), occurring in 60-
90% of patients treated(24).  During radiotherapy, the salivary glands may absorb 
enough radiation to impair or destroy their secretory function, thereby decreasing 
saliva production and causing xerostomia.  The major salivary glands (parotid, 
submandibular, and sublingual) produce about 90% of salivary secretions while 
the remainder is produced by the minor salivary glands(24, 25).  The parotid 
gland is extremely sensitive to radiation, and a median parotid dose of greater 
than 26 Gy results in permanent glandular atrophy and fibrosis(26).  If both 
parotid glands are treated above tolerance, permanent xerostomia is likely to 
result.  The resultant xerostomia in these patients contributes to a decrease in 
quality of life with adverse effects on speech, mastication, taste, swallowing, 
nutritional intake, and sense of well-being(24).  Dryness of the oral mucosa also 
creates a predisposition to mucosal fissures and ulcers, and changes in the 
composition of the oral flora lead to dental caries and infections.  The reduction in 
the salivary flow may also indirectly contribute to the risk of osteonecrosis of the 
mandible as abscessed mandibular teeth can lead to mandibular sequestration(24, 
27, 28).  
 
To relieve these symptoms, saliva substitutes are only temporarily 
effective and the usefulness of sialogogues, such as pilocarpine, is limited by 
cholinergic side effects(24).  The administration of the radiation protector WR-
2721 (amifostine) provides a benefit to a small proportion of head and neck 
cancer patients but often produces side effects including nausea and 
hypotension(29).  On the other hand, the use of intensity modulated radiotherapy 
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parotid glands and thereby reduces xerostomia and improves quality of life(26, 
30).  Due to the sensitivity of the parotid glands (tolerance dose of 26 Gy median 
dose) and the need to treat adjacent nodal volumes to 50-70 Gy, the parotid glands 
are still near tolerance even with the most advanced treatment planning and 
delivery systems such as the Helical Tomotherapy system(31, 32).  However, if 
the radiation dose to the electively treated cervical nodes could safely be reduced 
in patients with radiosensitive tumors, the dose delivered to the parotids would 
also be reduced and would therefore diminish the risk of xerostomia.  
1.3.2 Intensity Modulated Radiation Therapy (IMRT) 
 
Radiation therapy techniques for oropharyngeal SCC have undergone 
rapid technical advancements with the development of intensity modulated 
radiation therapy (IMRT) and image guidance of daily treatments.  IMRT is the 
use of radiation beam shaping through the optimization of multi-leaf collimator 
positions by opening and closing leaves to change the intensity of different 
portions of the beam.  This shaping enables the radiation dose to conform more 
precisely to the three-dimensional shape of the tumor.  In typical LINAC-based 
IMRT, combinations of several (usually 7 to 9) non-opposing intensity-modulated 
radiation fields are used to deliver highly conformal dose distributions to target 
volumes while sparing adjacent non-target tissues.  Thus, IMRT treatment 
planning requires the contouring of normal organs at risk (OARs) and target 
volumes on a kilovoltage CT (kVCT) image set, followed by daily treatment 
usually delivered with CT image guidance.   
 
The use of IMRT for HNC has achieved near-universal acceptance, with 
100% of responding US radiation oncologists reporting its use in a 2009 
survey(16).  When used in the treatment of head and neck cancer, IMRT has been 
shown to cause less biologic injury to normal adjacent structures while 
maintaining similar or improved locoregional tumor control rates(30, 33-35).  
Multiple single-institution retrospective publications have described the outcomes 
of OPSCC patients treated with IMRT.  For example, the use of IMRT in recent 
studies has yielded 2 and 3-year locoregional progression-free survival rates 
above 90%(1, 31, 36, 37), compared to rates of about 80% with non-IMRT 
techniques(36).  Studies with IMRT have reported comparable acute toxicities to 
those of conventional therapy and even reduced late toxicities, as IMRT enables 
significant sparing of the parotid glands, resulting in reduced xerostomia and 
improved quality of life(26, 30, 33, 34, 38). Recent prospective randomized 
controlled trials (RCT) have confirmed that the use of IMRT results in less 
xerostomia than conventional RT for nasopharyngeal, oropharyngeal, and 
hypopharyngeal carcinomas(39-41).  Of these RCTs, only Nutting et al mention 

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survival data, and they found no differences in overall survival or locoregional 
control rates between IMRT and conventional RT(40).  
1.3.3 Helical Tomotherapy-based IG-IMRT 
 
The Helical Tomotherapy Technology (AccuRay, Sunnyvale,CA) is an 
image-guided IMRT unit based on helical CT technology and is a fully integrated 
treatment planning and image guided delivery system.  The system has a 6 
megavoltage (MV) linear accelerator, a 6.25 mm binary pneumatic multi-leaf 
collimator (MLC) for beam modulation, and a radiation detector allowing for fan 
beam megavoltage CT (MVCT) scan acquisition built onto a standard CT gantry.  
The inverse treatment planning system calculates the MLC position every 7 
degrees of rotation or 51 times per gantry rotation.  We have previously published 
results that show that the Helical Tomotherapy system provides improved dose 
homogeneity and normal structure dose compared with LINAC-based IMRT in 
the treatment of oropharyngeal carcinomas(32).  This results in a reduced risk for 
complications from focal hotspots within the planning target volume and a 
reduced dose to the adjacent parotid glands(32).  Daily MVCT images can be 
obtained and electronically co-registered to the planning kVCT scan, allowing for 
daily image guidance for highly accurate patient positioning prior to treatment.  
We have previously published that without image guidance, the patient isocenter 
vector can shift over 3mm between treatments and result in significant errors in 
dose delivery(42).  We will deliver highly conformal IMRT to the patients in this 
study using image guided Helical TomoTherapy. 
 
1.3.4 Dose Reduction to the N0 Neck Lymph Nodes in p16+ Patients 
 
Our research group performed a retrospective analysis of 112 patients at 
UVA with OPSCC who received IMRT, of which 72 had p16 
immunohistochemical analysis of their corresponding biopsies(2).  To the best of 
our knowledge, this study was the largest reported series of OPSCC patients 
definitively treated with IMRT at the date of publication and the only IMRT study 
reporting stratification for p16 tumor status for outcome analysis.  The primary, 
pathologic nodal, and N0 nodal control rates at UVA for p16+, p16-, and p16 
unknown patients are shown in Table 1 and Table 2 (Appendix A).  This data 
confirms the findings of other investigators that patients with p16+ tumors have 
significantly better outcomes than patients with p16- tumors(15).  In our study 
with a median follow-up of 29 months, we found that patients with P16+ tumors 
treated with chemoradiation (n=28) had 100% primary tumor local control, 90% 
sterilization of pathologic nodes based on neck dissection data, and 100% control 
of the N0 volumes(2).  
 
Historically, Fletcher reported that 45-50 Gy was the necessary dose to 
treat the clinical N0 neck to achieve 90% chance of no nodal recurrence(43).  The 

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N0 status was determined by physical examination only (in the pre-CT era) and 
was reported for radiation alone without chemotherapy.  Harrison performed a 
meta-analysis to determine the dose response for local control of the N0 neck with 
radiation alone and reported that 45-50 Gy would result in a 95% chance of nodal 
control(44).  Our data revealed 2/112 (1.8%) of patients with recurrence in the N0 
cervical volumes; both had documented local recurrence of the primary, and 
neither was p16+.  Isolated N0 nodal failure is defined as failure in an N0 volume 
without associated failure in the primary tumor, failure in known pathologic 
lymph node volume, or distant metastatic disease.  Isolated N0 nodal failure in a 
CT or PET CT staged N0 nodal volume following 50 Gy with or without 
chemotherapy is rare and reported to occur in only about 2-3% of head and neck 
cancer patients(44-46). Our retrospective analysis found 0/112 (0%) of patients 
had isolated N0 lymph node failures, and p16+ patients who received 
chemoradiotherapy (n=28) had a 100% 3-year locoregional control rate.  With 
such dramatic responses in p16+ patients, it is very likely that the N0 neck in this 
cohort is receiving more radiation than necessary.  For comparison, cervical and 
anal cancers are also squamous cell carcinomas associated with HPV, but their N0 
nodes are treated with lower radiation doses than those in head and neck cancer.  
In contrast to the 50 Gy delivered to the N0 neck in HNC, N0 inguinal nodes in 
anal cancer are often only treated to 30.6 Gy(47, 48), and N0 para-aortic nodes in 
cervical cancer receive 44 Gy(49).  Thus, a reduction of the dose to the N0 neck 
in p16+ OPSCC to 39.6 Gy is consistent with doses already utilized with similar 
cancer histology in other anatomic sites. 
1.3.5 Post-treatment Surveillance with PET-CT 
 
Patients with head and neck cancer are often monitored after treatment 
with PET CT, as it has been shown to be highly sensitive in the detection of 
persistent and recurrent disease after treatment(50-52).  Multiple studies show that 
an initial negative PET CT obtained 3 months after definitive radiotherapy can 
have a negative predictive value (NPV) as high as 100% for locoregional 
recurrence with an average NPV of 95%(50-52).  However, sensitivity of PET is 
slightly lower for distant metastases(51, 52).  Most authors recommend follow-up 
PET CT from 3 to 6 months after completion of treatment because studies have 
shown higher false-negative PET scans when obtained less than 3 months after 
treatment(50, 51, 53, 54). Thus, a negative PET scan 3 to 6 months after treatment 
may have a very high probability of ruling out any locoregional recurrence in 
patients who receive a lower dose to the N0 neck.   
 
If a locoregional recurrence is going to occur, it is most likely to recur 
within 1 to 2 years, as nearly 90% of all HNC failures occur within the first 2 
years after treatment(36).  Yao et al (2005) found that 11/150 (7.3%) HNC 

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patients treated with IMRT developed locoregional recurrences in a median time 
of about 5 months (range of 2 to 16 months)(37).  Their local recurrence-free 
survivals at 2 and 3 years were equivalent at 94%, and locoregional recurrence-
free survivals at 2 and 3 years were also equivalent at 92%.  Eisbruch et al 
reported a 16% rate of locoregional recurrence at a median time of 8 months (55), 
while Huang et al (2008) reported 10% developing locoregional recurrences at a 
median time of 15 months (range of 3 to 43 months)(31).  Thus, any patient 
disease-free at 2 years has a very high likelihood of remaining disease-free.  
However, data is not available for the recurrence of the N0 volumes in the above 
studies, and they did not stratify their data according to p16 status, which provides 
vital prognostic significance.  Our p16+ patients had 100% control of the N0 
volumes at 3 years after treatment, so any isolated recurrence in the N0 volumes 
after dose reduction at any time in this current study would be suspicious for an 
inferior treatment.  
 
However, post-treatment PET CT imaging is not the national standard of 
care following definitive treatment of squamous cell carcinomas of the head and 
neck. Post-treatment PET CT imaging will therefore be optional on this study and 
can be used if post treatment contrast enhanced CT or MRI scans show equivocal 
results and/or the patient declines a recommended neck dissection.  
1.4 
Rationale for Study Design 
This is an unblinded, single arm study to demonstrate that reduced intensity 
radiation of the N0 nodes in patients (n=45) with p16+ oropharyngeal squamous 
cell carcinoma can provide improved tolerability compared with historic controls. 
The results of this study will support future studies to establish the equivalent 
efficacy and improved toxicity profile of this treatment in a larger population.  
 
2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 To estimate the N0 nodal control rate in patients with p16+ oropharyngeal 
squamous cell carcinoma (OPSCCA) treated with 39.6 Gy to the clinically 
uninvolved cervical lymphatics.   
2.2 
Secondary Objectives  
2.2.1 To evaluate safety and tolerability of treatment of p16+ OPSCCA treated with 
39.6 Gy to the clinically uninvolved neck by overall incidence of adverse events, 
incidence of acute and late radiation-induced toxicities and subject-rated quality 
of life assessments.  

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2.2.2 To estimate progression-free survival and locoregional recurrence-free survival in 
patients with OPSCCA following treatment with 39.6 Gy to the clinically 
uninvolved neck.   
2.2.3 To compare the dose volume histograms (DVH) of treatment plans for patients 
receiving 39.6 Gy to the N0 neck to the DVH of matched treatment plans with the 
standard 50 Gy to the N0 neck.   
 
3 PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
3.1.1 Patient must sign a study specific informed consent prior to study entry.  
3.1.2 Zubrod performance status 0-2. 
3.1.3 Age  ≥ 18 years. 
3.1.4 Patients must be clinically referred for radiation therapy with stage I-IVb (T1-T4, 
N0-N3, M0) squamous cell carcinoma of the oropharynx.  
3.1.4.1 Tumor must be measurable by physical exam and or endoscopy, and 
PET CT. PET CT must be performed within 8 weeks of initiating 
treatment for cancer. 
3.1.4.2 Disease must be staged using the 2010 American Joint Cancer 
Committee Staging System (version 7). 
3.1.5 HPV (p16)-positive tumor confirmed by immunohistochemistry. 
3.1.6 Patient must be able to comprehend English (or a medical interpreter for their 
native language must be available for all study visits) 
3.1.7 Patient must be capable and reliable to participate in all study related procedures. 
3.1.8 Patient must be able to lie flat on the table for IMRT and tolerate aquaplast or 
other immobilization/image tracking systems that reduces intra-fraction motion to 
3 mm or less.  
3.2 
Exclusion Criteria 
3.2.1 Patients may not be receiving any investigational agents. 
3.2.2 Prior radiotherapy to the head and neck in the volumes to be irradiated for this 
malignancy. 
3.2.3 Any other malignancy except non-melanomatous skin cancer or a carcinoma not 
of head and neck origin with the patient being disease free for  5 years. 

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3.2.4 Nutritional and general medical condition are incompatible with the proposed 
radiotherapy treatment 
3.2.5 Any major medical psychiatric or neurologic illness, which in the investigators’ 
opinions would interfere with either completion of therapy or with full and 
complete understanding of the risks and potential complications of the therapy.  
3.2.6 A serious uncontrolled medical disorder that is in the opinion of the Investigator 
would impair the ability of the patient to receive protocol therapy. 
3.2.7 Pregnant and breastfeeding women are excluded from this study.  
3.2.7.1 Women of childbearing potential must have a negative pregnancy test 
within 14 days prior to initiation of treatment. 
3.2.7.2 Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control) prior to 
study entry and for the duration of study participation.  Should a woman 
become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately. 
 
4 TREATMENT PLAN 
4.1 
Registration 
Patients who meet eligibility criteria must be registered in OnCore. The following 
minimum registration information must be entered for all patients registered: 
 demographics 
 date of signed informed consent 
 subject number 
 on-study date (date subject meets all eligibility criteria) 
 disease site 
 registering investigator 
4.2 
Intensity Modulated Radiation Therapy (IMRT) Treatment Regimen 
Patients will be treated on a Helical Tomotherapy Unit (AccuRay, Sunnyvale, 
CA) over a period of 7 weeks. Patients will receive IMRT to two regions: 
Planning Target Volume 1 (PTV1), which includes the gross disease (GTV) with 
expansions for microscopic disease extension and 3 mm setup error expansion; 
and Planning Target Volume 2 (PTV2), which includes the clinically uninvolved 
cervical lymph nodes (N0 lymph node volumes) with a 3 mm expansion for setup 
error. PTV1 will receive 70 Gy/35 fractions at 2.0 Gy/fraction/day for 5 
days/week. PTV2 will be treated to 39.6 Gy/22 fractions at 1.8 Gy/fraction/day 
for 5 days/week.  

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4.3 
Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Each patient will be assessed periodically for the development of any toxicity 
according to the Time and Events table (See Section 5).  Toxicity will be assessed 
according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0 (See Appendix A).  
 
Treatment breaks, if necessary, ideally should not exceed 5 treatment days at a 
time and 10 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. Treatment breaks must be clearly indicated in the treatment 
record along with the reason(s) for the treatment break(s). Any treatment break(s) 
exceeding 2 treatment days for reasons other than toxicity/illness will be 
considered a protocol deviation. 
4.4 
Concomitant Medications/Treatments 
4.4.1 Neck dissection 
Patients with N2 – N3 disease may undergo neck dissections at the discretion of 
the head and neck surgeon after the completion of treatment if physical 
examination or radiologic imaging reveals persistent pathologic nodal disease. 
 
4.4.2 . Chemotherapy 
Patients with T1-T2 and N0-N1 may be treated with radiation alone without 
concurrent chemotherapy. Concurrent chemotherapy is strongly recommended for 
locoregional control in the management of advanced cancer.   It is recommended 
that patients meeting any of the following criteria be treated with a concurrent 
chemoradiation regimen:  
 Definitive cases with T3-T4 primary tumors and/or N2-N3 nodal disease 
 Significant extracapsular spread (ECS >1 mm beyond capsule or 
obliteration of nodal architecture) as determined by staging imaging. 
 
The chemotherapy regimen will be selected at the discretion of the treating 
physician and will be administered according to standard institutional guidelines. 
Suggested common concurrent regimens include: 
 Cisplatin, 100mg/m2 IV infusion on days 1, 22, and 43 of the treatment 
course  
 Cisplatin, 30-40mg/m2 IV infusion q week x 6-7doses during the treatment 
course  

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o All patients must receive vigorous hydration during high dose 
cisplatin treatment 
o Treatment with cisplatin is highly emetogenic, patients must 
receive pre-treatment to prevent nausea and monitored for delayed 
nausea and vomiting 
o Cetuximab 400 mg/m2 IV loading dose 1wk before the start of 
radiation therapy, then 250 mg/m2 weekly (premedicate with 
dexamethasone, diphenhydramine, and ranitidine) 
4.5 
Other Modalities or Procedures 
Not applicable.   
4.6 
Duration of Therapy 
All patients will undergo radiation treatment regimen (IMRT) which will last a 
planned 7 weeks.  
4.7 
Duration of Follow Up 
Patients will be followed for three years after completion of the treatment or 
withdrawal from the study, or until death (whichever occurs first). All patients, 
regardless of the duration of therapy, will be asked to complete QOL 
questionnaires every 3 months for the first year (starting at 6 months post-IMRT), 
and every 6 months for the second and third years.  
4.8 
Pregnancy 
Women of childbearing potential (WOCBP) includes any female who has 
experienced menarche and who has not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not 
postmenopausal [defined as amenorrhea ≥ 12 consecutive months; or women on 
hormone replacement therapy (HRT) with documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL].  Even women who are using oral, implanted 
or injectable contraceptive hormones or mechanical products such as an 
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to 
prevent pregnancy or practicing abstinence or where partner is sterile (e.g., 
vasectomy), should be considered to be of child bearing potential. 
 
WOCBP must have a negative serum pregnancy test within 14 days prior to 
initiation of treatment. 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy.  In addition, all WOCBP should be instructed to 

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contact the Investigator immediately if they suspect they might be pregnant 
(e.g., missed or late menstrual period) at any time during study participation. 
4.9 
Removal of Patients from Protocol Therapy 
Patients enrolled in this study will receive 7 weeks of IMRT and then be followed 
for up to 3 years. Patients may discontinue from the study at any time and for any 
of the following reasons: 
 Disease progression 
 Inter-current illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator 
 Death 
The reason for study removal and the date the patient is removed will be 
documented in the Case Report Form.  Patients discontinued or withdrawn from 
protocol therapy will continue to be treated per standard of care.   
If a patient discontinues or is withdrawn from the study for the above listed 
reasons, then all data collected prior to discontinuation/ withdrawal will be 
included in the final analysis.  
 

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5 EVALUATIONS AND ASSESSMENTS 
5.1 
Time and Events Table 
 
Table 1: Treatment Assessments 
 
Pre-study1 
Treatment (weeks 1-7) 
Post IMRT 
Assessment 
once 
daily 
weekly 
once2 
Informed Consent 
X 
 
 
 
Inclusion/exclusion 
X 
 
 
 
History 
X 
 
X 
X 
Physical Exam3 
X 
 
X 
X 
p16 immunohistochemistry 
X4 
 
 
 
PET CT scan 
X5 
 
 
 
Contrast enhanced CT (or MR) 
X5 
 
 
X 
Serum pregnancy 
X6 
 
 
 
Vital Signs (BP, HR, temp)   
X 
 
X 
X 
Weight 
X 
 
 
 
Zubrod Performance Status 
X 
 
X 
X 
Toxicity Assessments 
 
X 
X7 
IMRT 
 
X 
 
 
Disease status 
 
 
 
X8 
QOL questionnaires 
X 
 
 
 
  
Table 2: Follow-Up Assessments 
 
Months9 following last IMRT 
 
3 
6 
9 
12 
15 
18 
21 
24 
30 
36 
Contrast enhanced CT (or MR) or 
PET CT  
X10 
 
 
X 
 
 
 
X 
 
X 
QOL questionnaires11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, temp)   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Zubrod Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Assessments7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease status8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                                 
1  Must be performed within 28 days of initiation of study treatment, unless a different timeframe is specified 
2 Assessments should be conducted between 4-6 weeks following the last IMRT treatment 
3  Includes height and body surface area (BSA); height is collected at pre-study visit only 
4  p16 expression for eligibility must be detected by immunohistochemistry and  in situ hybridization (HPV)  
5   Must be performed within 8 weeks of start of treatment for cancer 
6  WOCBP must have a negative serum pregnancy test at least 14 days prior to initiation of cancer treatment 
7  Acute AEs will be collected up to 90 days following the last IMRT; late radiation toxicities will be collected  from 3 
months up to 3 years following the last IMRT 
8  Disease status should be assessed at each follow-up, using RECIST criteria 
9 Assessments should be performed ± 2 weeks from date 
10The imaging assessments at 3 months post-IMRT are optional. 
11 May be completed by mail if patient is not scheduled for or misses a clinic visit 
12 Follow-up physical exams may include a flexible fiberoptic nasolaryngoscopy 

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5.2 
Pre-Study Assessments 
Patients must sign an informed consent prior to undergoing any protocol specific 
assessments. All pre-treatment evaluations must be performed within 14 days 
prior to Day 1 of IMRT, except the imaging assessments which must be 
performed within 8 weeks of start of treatment for cancer. Patients entered on 
study should be asked to complete the quality of life (QOL) questionnaires prior 
to the Day 1 visit in order to obtain an accurate baseline assessment. Instructions 
on how to complete these questionnaires are provided on the forms. 
 
The following radiologic studies must be performed to provide accurate tumor 
staging and baseline assessments (within 8 weeks of start of treatment): 
1. PET CT 
2. Contrast enhanced CT (can be planning CT) or MRI 
5.3 
Treatment Assessments 
All patients will undergo a 7 week radiation treatment regimen. The sections 
below outline the assessments to be performed at each visit. Assessments denoted 
by an asterisk (*) should be performed prior to initiation of any radiation 
treatments at that visit. 
 
Daily: The following assessments should be performed daily (5 days/week) 
during the 7 week treatment interval: 
 IMRT 
 
Weekly: The following assessments should be performed once per week during 
the 7 week treatment interval: 
 History and abbreviated physical exam (including performance status)* 
 Vital signs (HR, BP and temp)* 
 Collection of adverse events* 
 
Post IMRT: At 5 ± 1 week following the last IMRT treatment, the following 
assessments should be performed: 
 History and abbreviated physical exam (including performance status)* 
 Vital signs (HR, BP and temp)* 
 Contrast enhanced CT (or MR) to assess for disease status and nodal 
control 
 Evaluation for acute radiation toxicity (see Appendix B) 
 Evaluation by the head and neck surgeon for neck dissection of persistent 
pathologic nodal disease.  

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5.4 
Post-Treatment/Follow-up Assessments 
The below follow-up evaluations should be performed at the intervals specified in 
Table 2 following the last IMRT: 
 Contrast enhanced CT (or MR) or PET CT should be performed every 12 
months to assess for disease progression 
 The following should be performed each time a patient is seen in clinic, 
per standard care (approximately every 3 months for 2 years, every 6 
months in year 3). If a clinic visit is missed, then these assessments should 
be performed at the next visit: 
o History and Physical (including performance status) 
o Vital signs 
o Performance Status 
o Disease status 
o Acute and late toxicity assessments 
 QOL questionnaires should be performed at clinic visits. If no clinic visit 
is scheduled it can be completed by mail and reviewed with the patient at 
the next clinic visit. 
 Acute toxicity assessments should be performed to collect signs of 
radiation toxicity which occur up to 90 days following the last IMRT with 
grading per version 4 CTCAE. 
 Late radiation toxicity (effects that occur after 90 days following 
completion of IMRT) will be evaluated at the time points shown in Table 
2: Follow-up Assessments (every 3 months until 24 months after 
completion of IMRT and then every 6 months from 24-36 months after 
completion of IMRT).  Late Toxicity will be scored per version 4 CTCAE.  
 
In addition, if a patient has an unresolved adverse event at the end of study 
treatment, the event should be followed every 4-6 weeks until it has resolved, 
returned to baseline or is deemed irreversible, whichever is longer. 
 
6 EVALUATION CRITERIA 
6.1 
Parameters of Response: RECIST for Solid Tumors 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (Version 1.1) [Eur J Ca 45:228-247, 2009].  
Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in 
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6.1.1 Eligibility for response assessment 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
6.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless progression is documented or a biopsy is obtained 
to confirm persistence at least 90 days following completion of radiation therapy. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 

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Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
6.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 

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unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans), but NOT lung.   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally.  As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
PET CT At present, the low dose or attenuation correction CT portion of a 
combined PET CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET CT is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast), then the CT portion of the PET CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in 

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accurately measuring cancer lesions over time.  Note, however, that the PET 
portion of the CT introduces additional data which may bias an investigator if it is 
not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy The utilization of endoscopic techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
Cytology, Histology These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible 'new' 
disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 

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confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET 
scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought 
to represent fibrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
6.1.4 Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions). 
 

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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the 
smallest sum diameters while on study 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete 
clinical response. 
 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the 
normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
For Patients with Measurable Disease 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥4 weeks confirmation** 

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CR 
Non-
CR/Non-PD 
No 
PR 
CR 
Not 
Evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/Not 
Evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/Not 
Evaluated 
No 
SD 
documented at least once 
≥4weeks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease         
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
6.1.4.4 Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 

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smallest measurements recorded since the treatment started, including the baseline 
measurements.  
6.2 
Other Measures of Effect 
6.2.1 N0 nodal control 
The N0 nodal volumes will be defined prior to initiation of the radiation treatment 
regimen by PET scan and contrast enhanced CT and MR scans performed as part 
of the pre-study assessments. N0 control will be assessed by weekly physical 
exams performed during treatment and CT scan of the neck performed at 4- 6 
weeks and annually post-treatment. Patients with observed involvement of any of 
the N0 nodes at any post-treatment interval will be considered to have an N0 
failure. 
6.2.2 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of 
treatment to time of recurrence/progression or death from any cause, whichever 
occurs first. Progression will be measured as defined by the RECIST criteria 
(Section 6.1). Patients who do not experience an event (recurrence/progression or 
death) will be censored at date of last contact. 
6.2.3 Locoregional recurrence-free survival 
Locoregional recurrence-free survival, or locoregional control, is defined as the 
duration of time from start of treatment to time of recurrence in either the primary 
tumor or the nodal regions. Patients who do not experience an event will be 
censored at date of last contact. 
6.2.4 Dose Volume Histograms 
Dose volume histograms will be used to evaluate the difference in radiation dose 
to critical structures with the decreased dose regimen compared to what the 
organs would have received if the PTV2 received 50 Gy. DVHs will be prepared 
from the mean, max, minimum doses to structures, as well as volumes of 
particular structures receiving certain doses for comparison. 
6.2.5 Quality of Life Questionnaires  
All patients entered on study will complete the quality of life (QOL) 
questionnaires at the pre-study assessment and every 3 months for the first year 
(starting at 6 months post-IMRT), every 6 months for the second and third years. 
These can be completed in person during a routine scheduled clinic visit or by 
mail. The QOL questionnaires to be completed are: 
1. MD Anderson Symptom Inventory – Head & Neck (MDASI-HN) 

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2. MD Anderson Dysphagia Inventory (MDADI) 
3. Voice Handicap Index-10 (VH-10) 
For the MDASI-HN and VH-10, the patient provides a numerical response to 
each question. For the MDADI, the patient provides one of the following 
answers to each statement: strongly agree, agree, no opinion, disagree, strongly 
disagree.  The responses provided on each questionnaire at each interval will be 
tabulated and summarized and post-treatment responses compared to pre-
treatment values. 
6.3 
Toxicity and Safety 
Patients will be evaluated for toxicity and safety weekly during radiation 
treatments (Section 5.1).  Adverse events and other symptoms will be graded 
according to the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0. See Section 8 for more details. 
 
The following additional endpoints for toxicity will also be assessed at the 
toxicity assessments: 
1. Grade of acute radiation dermatitis and late subcutaneous fibrosis 
(stratified by neck dissection or no neck dissection) in the N0 
volumes 
2. Late radiation toxicity (events that persist or occur after 90 days of 
completion of IMRT) 
3. Neck dissection complication rate (wound breakdown) 
4. Grade of xerostomia 
5. Grade of dysphagia 
6. Acute and late grade 3 or higher adverse event 
7. Rate of PEG dependence at 6 months post-IMRT 
 
7 
STATISTICAL CONSIDERATIONS 
This is a single institution, single arm phase II trial to estimate the efficacy and 
safety of reduced intensity modulated radiation therapy (39.6 Gy to the clinically 
uninvolved cervical lymph nodes in the neck) in patients with p16+ 
oropharyngeal squamous cell carcinoma. Specifically, the study is designed to 
estimate N0 nodal control and locoregional control rates, to estimate 3-year 
progression-free survival, and to define the safety profile of the treatment regimen 
to determine if the data support further research.  
7.1 
Study Design/Endpoints 
Estimation and safety monitoring for N0 nodal control, locoregional control and 
3-year progression-free survival guided sample size determination and monitoring 

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rules. Data from sixty p16+ OP-SCCA patients treated with standard IMRT at 
UVA from 2002-2011 with adequate follow-up were used to define ‘historical’ 
outcomes. The primary endpoint is N0 nodal control rate.  In order to consider the 
treatment regimen worthy of further study the data need to support a N0 control 
rate no worse than that observed from the historical data.  Similar conditions need 
to be observed for the secondary endpoints of locoregional control rate and 3-year 
disease-free survival. 
N0 nodal control rate is defined as the percent of eligible patients who experience 
N0 recurrence within the minimum follow-up period of 3 years. Locoregional 
control rate is defined as the percent of eligible patients who experience local 
and/or regional failure within the minimum follow-up period of 3 years.  The N0 
neck represents lymph node regions of the neck that were not clinically or 
radiographically determined to be pathologically involved with metastatic disease 
to regional lymph nodes at initial presentation.  N0 recurrence = failure in the N0 
neck region. Isolated N0 recurrence = failure in the N0 neck region without 
failure elsewhere. Local (primary) recurrence = failure at the initial site of disease. 
Regional (nodal) recurrence = failure in lymph nodes in the neck (includes N0 
recurrence). Distant recurrence = metastatic failure. Progression-free survival 
(PFS) is defined in section 6.2.2.  
Safety is determined by frequency and severity of adverse events (AEs) related to 
treatment, and are classified and graded according to CTCAE version 4. AEs 
related to swallowing function during and after treatment will be assessed. Other 
endpoints of interest include locoregional recurrence-free survival, dose to 
regional organs at risk (OARs compared to if the N0 volumes received 50 Gy), 
and QOL as measured by subject-reported functional outcome questionnaires that 
will quantify patient-reported speech and swallowing function [MD Anderson 
Symptom Inventory – Head & Neck (MDASI-HN), MDADI (MD Anderson 
Dysphagia Index) and VHI-10 (Voice Handicap Index)].     
7.2 
Sample Size and Accrual 
We know of no detailed published data for the primary and secondary endpoints 
for the study specific p16+/HPV+ OP-SCCA patient population of interest.  
However, the ‘historical’ data from sixty patients (updated since publication) 
treated at UVA provides us with a reliable source to guide sample size 
determination and monitoring guidelines.  For those sixty patients, N0 recurrence 
occurred in 1/60=1.7% and locoregional failure occurred in 6/60=10% with the 
upper limit of a one-sided 95% CI being 7.7% and 19%, respectively.  Three-year 
PFS from start of radiation treatment is 80% (95% CI (67, 88%)).  For sample 
determination, these estimates will be used to define the null and alternative 3-

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year PFS rates.  Specifically, we would like to be able to differentiate between a 
null 3-year PFS rate of 80% versus the alternative of 67%.  Assuming uniform 
accrual of 15 eligible patients a year for 3 years, a minimum follow-up time of 3 
years, PFS is exponentially distributed, a one-sided 10% level test then accrual of 
45 eligible patients provides approximately 89% power at the alternative.  If the 
exponential assumption is not supported by the data then accrual of 45 eligible 
patients results in 80% power to test for a decrease of 14% in 3-year PFS with a 
one-sided 10% exact binomial level test. 
A sequential probability ratio test (SPRT) based upon a binomial test of 
proportions for N0 control rates will be used.   Only the upper boundary will be 
used for monitoring to protect against excessive failures.  The stopping boundary 
are for a SPRT contrasting a 2% versus 8% N0 control rate, with nominal type I 
and II errors of 10% and 10%, respectively.  The slope of the parallel lines for 
monitoring is 0.043 and the intercepts are 1.516 and 1.516. 
Stopping guideline for N0 Failure 
Number of participants 
Boundary 
2-9 
≥ 2 
10-33 
≥ 3 
34-45 
≥ 4 
 
For estimation of locoregional control, a sample size of 45 eligible patients 
produces a two-sided 90% confidence interval with a width equal to 0.17 when 
the sample proportion is assumed at the observed historical rate of 10%. 
7.3 
Analyses 
Point estimates and confidence interval will be calculated for all dichotomous 
endpoints (N0 control rate, locoregional control rate, AE specific rates).  The 
Kaplan-Meier product-limit method will be used to estimate PFS and locoregional 
recurrence-freesurvival.  Confidence intervals will be estimated for all efficacy 
endpoints.  Under the assumption of exponential PFS we will estimate the 
exponential parameter () and test whether the data support the alternative 
hypothesis that that =0.1335 versus the null hypothesis that =0.0744. Repeated 
measure models will be used to describe the change over time in QOL as 
measured by questionnaire. Data from the treatment planning software which 
produces graphs on mean, max, minimum doses to structures, as well as volumes 
of particular structures receiving certain doses will be used to compare the dose 
volume histograms (DVH) of treatment plans for patients receiving 39.6 Gy to the 
N0 neck to the DVH of matched treatment plans with the standard 50 Gy to the 

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N0 neck (i.e., to quantify the difference in radiation dose to critical structures in 
the neck with the decreased dose regimen compared to standard practice).       
7.4 
Reporting and Exclusions 
All patients will be evaluable for toxicity and adverse events from the time of 
protocol intervention (start of treatment). 
Evaluation of efficacy – All patients included in the study should be assessed for 
efficacy endpoints, even if there are major protocol treatment deviations or if they 
are ineligible.  All of the patients who met the eligibility criteria will be included 
in the main analysis of the efficacy.  
 
8 ADVERSE EVENTS AND REPORTING 
Adverse events will be collected from the initiation of the radiation treatment until 
at least 30 days following completion of study treatment (i.e. end of seven week 
regimen or date of discontinuation). All adverse events should be reviewed by the 
treating physician to determine if expedited reporting is required. The following 
sections provide definitions for adverse event characteristics and reporting 
requirements.   
8.1 
Definitions 
8.1.1 Adverse Event 
An adverse event is any undesirable medical experience occurring to a subject who 
has been given an investigational product, whether or not related to the study 
drug(s). Medical conditions present before starting the investigational 
drug/intervention will be considered adverse events only if they worsen after 
starting study treatment. The following are adverse events: 
 All unfavorable, harmful or pathological changes in the general condition 
of a patient. 
 Subjective or objective symptoms (spontaneously offered by the patient 
and/or observed by the Investigator or the study nurse). 
 All intercurrent events or exacerbation of pre-existing diseases which 
occurred after the administration of the study drug. 
 All clinically significant changes in laboratory abnormalities. 
 Any undesirable and unintended effect of research occurring in human 
subjects as a result of the collection of identifiable private information 
under the research. 
 

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AEs should be followed to resolution or stabilization, and reported as SAEs if 
they become serious (see below, definition of SAE).  This also applies to patients 
experiencing AEs that cause interruption or discontinuation of investigational 
product, or those experiencing AEs that are present at the end of their 
participation in the study.  Such patients should receive post-treatment follow-up 
as appropriate.  AEs will be collected at least for 30 days post last day of radiation 
treatment in all cases including early study termination.  If an ongoing AE 
changes in its severity or in its perceived relationship to study drug, a new AE 
entry for the event should be completed. 
8.1.2 Expectedness 
The expectedness of the adverse event will be determined by the Investigator 
based on current literature and the Investigator’s experience. Below is a listing of 
the adverse events, and maximum grade of event, expected in this study: 
Adverse Events with Possible Relationship to Study Treatment 
 
Maximum Grade 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
 
1 
 
Anemia 
 
 
2 
Lymphopenia 
 
 
 
2 
Lymph Node Pain 
 
 
 
1 
 
Lymph Node Pain 
 
 
2 
CARDIAC DISORDERS 
 
 
 
Tachycardia (any type) 
 
 
2 
EAR AND LABYRINTH DISORDERS 
 
 
Ear Pain 
 
 
 
1 
 
Ear Pain 
 
 
2 
 
 
Ear Pain 
 
3 
Hearing Impaired  
 
 
 
1 
 
Hearing Impaired 
 
 
2 
 
 
Hearing Impaired 
 
3 
Middle Ear Inflammation 
 
 
 
2 
Tinnitus 
 
 
 
1 
 
Tinnitus 
 
 
2 
 
 
Tinnitus 
 
3 
 
Vertigo 
 
 
1 
 
 
Vertigo 
 
2 
ENDOCRINE DISORDERS 
 
 
 
 
Hypothyriodism 
 
 
 
1 
 
Hypothyriodism 
 
 
2 
EYE DISORDERS 
 
 
 
 
 
Cataract 
 
 
1 
 
Conjunctivitis 
 
 
1 
 
 
Retinopathy 
 
2 
 
Watering Eyes 
 
 
1 
GASTROINTESTINAL DISORDERS 
 
 
Dental Caries 
 
 
 
2 

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Dental Caries 
 
 
3 
Dry Mouth 
 
 
 
2 
 
Dry Mouth 
 
 
3 
Dysphagia 
 
 
 
3 
 
 
Dysphagia 
 
4 
Esophageal Stenosis 
 
 
 
1 
 
Esophageal Stenosis 
 
 
3 
 
 
Esophageal Stenosis 
 
4 
Gingival Pain 
 
 
 
2 
Lip Pain 
 
 
 
1 
 
Lip Pain 
 
 
2 
Mucositis Oral 
 
 
 
3 
Nausea 
 
 
 
2 
 
Nausea 
 
 
3 
Oral Pain 
 
 
 
3 
 
Peridontal Disease 
 
 
3 
Salivary  Duct Inflammation 
 
 
 
2 
 
Salivary Duct Inflammation 
 
 
3 
 
Toothache 
 
 
2 
Vomiting 
 
 
 
1 
 
Vomiting 
 
 
3 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Edema Face 
 
 
 
1 
 
Edema Face 
 
 
2 
 
 
Edema Face 
 
3 
Fatigue 
 
 
 
3 
Irritability 
 
 
 
2 
 
Irritabiity 
 
 
3 
Neck Edema 
 
 
 
1 
 
Neck Edema 
 
 
2 
 
 
Neck Edema 
 
3 
Pain Generalized 
 
 
 
2 
INFECTIIONS AND INFESTATIONS 
 
 
Mucosal Infection 
 
 
 
2 
 
Mucosal Infection 
 
 
3 
 
Otitis Media 
 
 
2 
 
Sinusitis 
 
 
2 
 
Soft Tissue Infection 
 
 
2 
 
Tooth Infection 
 
 
2 
 
Tracheitis 
 
 
2 
 
Upper Respiratory Infection 
 
 
2 
 
 
Upper Respiratory Infection 
 
3 
INJURY, POISING AND 
PROCEDURAL 
 
 
 
 
Dermatitis Radiation 
 
 
 
2 
 
Dermatitis Radiation 
 
 
3 
 
Injury to Carotid Artery 
 
 
3 
 
 
Injury to Carotid Artery 
 
4 
INVESTIGATIONS 
 
 
Creatinine Increased 
 
 
1
1 
 
Creatinine Increased 
 
2
2 
Lymphocyte Count Decreased 
 
 
 
2 
 
Lymphocyte Count Decrease d 
 
3 
 
Platelet Count Decreased 
 
 
1 

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Platelet Count Decreased 
 
2 
Weight loss 
 
 
 
1 
 
Weight Loss 
 
 
2 
 
 
Weight Loss 
 
3 
White Blood Cell Decreased 
 
 
 
1 
 
White Blood Cell Decreased  
 
2 
 
 
White Blood Cell Decreased 
 
3 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
3 
 
 
Anorexia 
 
4 
Dehydration 
 
 
 
1 
 
Dehydration 
 
 
2 
 
 
Dehydration 
 
3 
 
Hyperkalemia 
 
 
1 
 
 
Hyperkalemia 
 
2 
 
Hypercalcemia 
 
 
1 
 
 
Hypercalcemia 
 
2 
 
Hypomagnesemia 
 
 
1 
 
 
Hypomagnesemia 
 
2 
 
Hyponatremia 
 
 
1 
 
 
Hyponatremia 
 
2 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Generalized muscle weakness 
 
 
 
1 
 
 
Head Soft Tissue Necrosis 
 
3 
Neck Pain 
 
 
 
2 
 
Neck Pain 
 
 
3 
 
Osteonecrosis of Jaw 
 
 
2 
 
 
Osteoradionecrosis ofJaw 
 
3 
Trismus 
 
 
 
1 
 
Trismus 
 
 
2 
 
 
Trismus 
 
3 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED  
 
 
 
Treatment-related Second 
Malignancy 
 
 
3 
 
 
Treatment-related Second 
Malignancy 
 
4 
Tumor Pain 
 
 
 
2 
 
Tumor Pain 
 
 
3 
NERVOUS SYSTEM DISORDERS 
 
 
 
Brachial Plexopathy 
 
 
1 
 
 
Brachial Plexopathy 
 
2 
 
 
Central Nervous System 
Necrosis 
 
3 
Dysguesia 
 
 
 
2 
Lethargy 
 
 
 
1 
 
Lethargy 
 
 
2 
 
Myelitis 
 
 
1 
 
 
Myelitis 
 
2 
 
 
Stroke 
 
3 
 
 
Syncope 
 
3 
PSYCHIATRIC DISORDERS  
 
 
 
Agitation 
 
 
 
1 
 
Agitation 
 
 
2 
Anxiety 
 
 
 
2 

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Anxiety 
 
 
3 
Depression 
 
 
 
1 
 
Depression 
 
 
2 
 
 
Depression 
 
3 
Insomnia 
 
 
 
2 
 
Insomnia 
 
 
3 
Libido decreased 
 
 
 
1 
 
Libido decreased 
 
 
2 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Aspiration 
 
 
 
2 
 
Aspiration 
 
 
3 
 
 
Aspiration 
 
4 
Cough 
 
 
 
2 
 
Cough 
 
 
3 
 
Dyspnea 
 
 
2 
Hoarseness 
 
 
 
1 
 
Hoarseness 
 
 
2 
Laryngeal Edema 
 
 
 
1 
 
Laryngeal Edema 
 
 
2 
 
 
Laryngeal Edema 
 
4 
Laryngeal Mucositis 
 
 
 
3 
Nasal Congestion 
 
 
 
1 
 
Nasal Congestion 
 
 
2 
 
 
Nasal Congestion 
 
3 
Pharyngeal Mucositis 
 
 
 
3 
 
 
Pharyngeal Necrosis 
 
4 
Pharyngolaryngeal Pain 
 
 
 
2 
 
Pharyngolaryngeal Pain 
 
 
3 
 
 
Stridor 
 
3 
Tracheal Mucositis 
 
 
 
1 
 
Tracheal Mucositis 
 
 
2 
 
 
Tracheal Mucositis 
 
3 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
 
1 
Pain of Skin 
 
 
 
2 
 
Pain of Skin 
 
 
3 
Skin Atrophy 
 
 
 
1 
 
Skin Hyperpigmentation 
 
 
2 
Skin Induration 
 
 
 
1 
 
Skin Induration 
 
 
2 
 
 
Skin Induration 
 
3 
Telangiectasia 
 
 
 
1 
VASCULAR DISORDERS 
 
 
Hypotension 
 
 
 
1 
 
Hypotension 
 
 
2 
 
 
Hypotension 
 
3 
Lymphedema 
 
 
 
1 
 
Lymphedema 
 
 
2 
 
 
Lymphedema 
 
3 
 
8.1.3 Severity 

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The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for AE reporting. All appropriate treatment areas should have access to a copy of 
the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site (http://ctep.cancer.gov). 
To assess severity of adverse events not included in the CTCAE version 4.0, use 
Table 3 below.  
Table 3. Adverse Event Severity Grading Scale for Adverse Events Not Specifically 
Listed in the NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL1 
3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self care ADL2 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE 
1Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
2Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
8.1.4 Attribution Assessment 
The Principal Investigator will evaluate all AEs and assess their toxicity and 
attribution, if any, to study drug.  The following criteria will define the attribution: 
 
Definite:  The AE is clearly relation to the investigational agent. 
Probable: The AE is likely related to the investigational agent. 
Possible: The AE may be related to the investigational agent. 
Unlikely: The AE is doubtfully related to the investigational agent. 
Unrelated: The AE is NOT related to the investigational agent. 
8.1.5 Serious Adverse Event  
A serious adverse event or experience (SAE) or serious adverse drug reaction 
(ADR) is any adverse event temporally associated with the subject’s participation 
in research that meets any of the following criteria: 
 Death; 
 Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 

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 Requires inpatient hospitalization or prolongation of existing 
hospitalization;* 
 Results in congenital anomaly/birth defect; 
 Results in a persistent or significant disability/incapacity; 
 Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
8.2 
Expedited Adverse Event Reporting Requirements 
8.2.1 UVA Cancer Center DSMC Reporting Requirements 
All adverse events will be recorded on appropriate case report forms. In addition, 
all adverse events must be recorded into the University of Virginia Cancer Center 
OnCore database within the time frame specified below:  
 
8.2.2 UVA IRB Reporting Requirements 
The Principal Investigator (PI) or designee is responsible for reporting AEs and 
unanticipated problems to the UVA HSR-IRB according to the following guidelines.  
 
Table 5 
Type of Event 
To whom will 
Time Frame for 
How reported? 
Table 4:  Medium Risk Studies 
Reporting requirements for AEs that occur within 30 days of the last day of radiation treatment 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 & 5 
Expected 
and 
unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Without 
hospitalizatio
n 
With 
hospitalization 
Without 
hospitalization 
With 
hospitalization 
Unrelated 
Unlikely 
Not required Not required Not required 
ONCORE 
30 days 
ONCORE 
15 days 
ONCORE 
30 days 
ONCORE 
15 days 
ONCORE 
15 days 
ONCORE 
15 days 
Possible 
Probable 
Definite 
ONCORE 
30 days 
ONCORE 
30 days 
ONCORE 
15 days 
ONCORE 
30 days 
ONCORE 
15 days 
ONCORE 
15 days 
ONCORE 
15 days 
ONCORE 
15 days 
ONCORE 
(24-hrs)* 
7 days 
 
*Enter into Oncore within 24 hours if unexpected and definitely related to protocol specified treatment 
Hospitalization defined as an inpatient hospital stay or prolongation of a hospital stay equal to or greater than 24 hours 

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it be reported: 
Reporting 
Any internal event resulting in 
death that is deemed 
DEFINITELY related to 
(caused by) study participation
An internal event is one that 
occurs in a subject enrolled in 
a UVa protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected 
adverse event  
 
See Oncore reporting 
requirement  
 
IRB-HSR 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event. 
 
Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that 
are not adverse events or 
protocol violations  
This would include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
Unanticipated Problem report 
form.  
 
http://www.virginia.edu/vprgs/ir
b/HSR_docs/Forms/Reporting_R
equirements-
Unanticipated_Problems.doc ) 
 
  
Protocol Violations 
 (The IRB-HSR only requires 
that MAJOR violation be 
reported, unless otherwise 
required by your sponsor, if 
applicable.) 
 
Or  
 
Enrollment Exceptions 
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
 
Protocol Violation and 
Enrollment Exception Reporting 
Form 
 
 
http://www.virginia.edu/vprgs/ir
b/hsr_forms.html 
 
Go to 3rd bullet from the bottom. 
  
Data Breach  
The UVa 
Corporate 
Compliance 
and Privacy 
Office, a 
 
 
ITC:  if breach 
involves  
electronic data-  
 
 
 
UVa Police if 
breach includes 
such things as 
stolen 
computers.  
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
 
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
IMMEDIATELY.  
 
 
UVa Corporate Compliance and 
Privacy Office- Phone 924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
http://www.itc.virginia.edu/secur
ity/reporting.html 
 
 
Phone- (434) 924-7166 

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Table 6 
INDEPENDENT DSMB/DSMC 
DSMB/DSMC Reports 
IRB 
  
15 calendar days of 
the study team 
receiving the report 
Copy of DSMB/ DSMC report 
 
9 DATA SAFETY MONITORING PLAN 
The Principle Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the UVA Cancer Center Data Safety 
Monitoring Committee (DSMC). 
9.1 
UVA Cancer Center Data Safety Monitoring Committee 
 The University of Virginia Cancer Center Data and Safety Monitoring Committee 
(DSMC) will provide oversight of the conduct of this study.  The CC DSMC will 
report to the UVA Protocol Review Committee (PRC). 
 
 
The DSMC will review the following: 
 All adverse events 
 Audit results 
 Application of study designed stopping/decision rules 
 Whether the study accrual pattern warrants continuation/action 
 Protocol violations 
 
The CC DSMC will meet every month for aggregate review of AE data.  Tracking 
reports of the meetings are available to the PI for review.  Issues of immediate 
concern by the DSMC are brought to the attention of the PI (and if appropriate to 
the PRC and IRB) and a formal response from the PI is requested.   Per the 
Cancer Center NIH approved institutional plan this study will be audited 
approximately every 12 months. 
  

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10 STUDY MANAGEMENT 
10.1 Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
10.2 Registration Procedures 
All patients must be registered with the OnCore database at the University of 
Virginia Cancer Center before enrollment to study.   
10.3 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
10.3.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB-HSR 
approval/favorable opinion.   
 

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For any such emergency modification implemented, a UVA IRB modification 
form must be completed by study Personnel within five (5) business days of 
making the change.   
10.3.2 Single Patient Exceptions 
Any request to enroll a single patient who does not meet all the eligibility criteria 
of this study requires the approval of the Principal Investigator and the IRB.  
10.3.3 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB.   
 
Protocol Deviations: A protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
 Is generally noted or recognized after it occurs 
 Has no substantive effect on the risks to research participants 
 Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
 Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
Study personnel will record the deviation, and report to the IRB and DSMC as 
described in Sections 8.2.2 and 9.1, respectively. 
 
Protocol Violations: An unplanned protocol variance is considered a violation if 
the variance: 
 Has harmed or increased the risk of harm to one or more research 
participants. 
 Has damaged the scientific integrity of the data collected for the study. 
 Results from willful or knowing misconduct on the part of the 
investigator(s). 
 Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
Violations should be reported by study personnel to the IRB within one (1) week 
of the investigator becoming aware of the event.  
10.4 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 

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logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
10.5 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification 
of proper entry of data. At the completion of the study, all case report forms will 
be reviewed by the Principal Investigator and will require his/her final signature 
to verify the accuracy of the data. 

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55. 
Eisbruch, A., Marsh, L. H., Dawson, L. A., Bradford, C. R., Teknos, T. N., 
Chepeha, D. B., Worden, F. P., Urba, S., Lin, A., Schipper, M. J., and Wolf, G. T. 
(2004) Recurrences near Base of Skull after Imrt for Head-and-Neck Cancer: 
Implications for Target Delineation in High Neck and for Parotid Gland Sparing. 
International journal of radiation oncology, biology, physics. 59, 28-42. 
 

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12 APPENDICES 
APPENDIX A: Performance Scale 
 
ZUBROD PERFORMANCE SCALE 
0
  
Fully active, able to carry on all predisease activities 
without restriction (Karnofsky 90-100). 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature. For example, light housework, office 
work (Karnofsky 70-80). 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities. Up and about more than 
50% of waking hours (Karnofsky 50-60). 
3 
Capable of only limited self-care, confined to bed or 
chair 50% or more of waking hours (Karnofsky 30-40). 
4 
Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair (Karnofsky 10-20). 
 
 
 
 

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APPENDIX B: Toxicity Criteria 
Acute and Toxicity 
Version 4.0 will be used to define acute toxicity in this trial. An electronic copy of the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 can be 
obtained from the World Wide Web CTEP site.  The web address is:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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