Clinical trial NCT02908477
Conditions: Oropharynx Cancer
Sponsor: Mayo Clinic
Start date: 2016-10-03; Completion date: 2024-11-15
Enrollment: 228 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed for patients with a cancer of the oropharynx (tonsils or base of tongue) caused by the HPV virus. Traditional treatment involves surgery followed by six weeks of daily radiation therapy. This study investigates a less intense radiation treatment following surgery that uses half the dose of radiation given over two weeks rather than six weeks. Patients will be randomly assigned to receive the less intense treatment versus the traditional treatment by coin flip. Patients are twice as likely to receive the less intense treatment during randomization.

Detailed description:
Recent studies suggest that tumors in the oropharynx (tonsils or base of tongue) caused by the HPV virus are much more sensitive to radiation and chemotherapy. Standard treatment for HPV associated oropharynx tumor after surgery involves six weeks of radiation therapy and has many long term side effects and complications.

Mayo Clinic recently piloted a study investigating whether patients with HPV-associated oropharynx tumors can receive less radiation and chemotherapy after surgery when compared with the standard treatment. The investigators current study will compare the new, shorter treatment course (2 weeks of treatment) with the standard course of treatment (six weeks). Patients will be randomized to either the less intense or standard treatment arm. Patients will be twice as likely to receive the less intense treatment during randomization.

Arms: arm 1: Docetaxel 15 mg/m2 days 1, 8 + Radiation Therapy (RT) 30 Gy/1.5 Gy fractions twice daily (b.i.d.) days 1-12 only (intermediate risk) or 36 Gy/1.8 Gy b.i.d. fractions (high risk) arm 2: RT 60 Gy/2 Gy fractions daily (qday) days 1-40. For high risk, add weekly Cisplatin 40 mg/m2 (Around days 1, 8, 15, 22, 29, 36)
Interventions: intervention 1: Adjuvant Radiation Therapy intervention 2: Docetaxel intervention 3: Cisplatin
Intervention descriptions: intervention 1: 60 Gy / 2 Gy fractions (standard arm) 30 - 36 Gy / 1.5 - 1.8 Gy b.i.d. fractions (experimental arm) intervention 2: 15 mg/m2. Experimental arm only. intervention 3: 40 mg/m2. Standard arm only.

Protocol documents:
Prot_SAP_000.pdf: 
 
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 Mayo Clinic Radiation Oncology 
 
MC1675: DART-HPV: A Phase III Evaluation of De-escalated Adjuvant Radiation Therapy for  
 
 
 
HPV-Associated Oropharynx Cancer 
 
 
 
 
Study Chairs (MCR): 
 
 
 
 
 
 
 
 
 
 
 
 
Study Chairs (MCA): 
 
 
 
 
 
Study Co-investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
  
 
 
√Study contributor(s) not responsible for patient care. 
 
 
Document History 
(Effective Date) 
Version 1 
Modification 1 
Modification 2 
6/30/16 
9/14/16 
11/30/2016 
 
 


 
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Protocol Resources 
 
Questions: 
Contact Name: 
Patient 
eligibility*, 
test 
schedule, 
treatment delays/interruptions/adjustments, 
dose 
modifications, 
adverse 
events, 
protocol 
document, 
consent 
form, 
regulatory 
issues, 
forms completion and submission 
Xxxxxxx, Study Coordinator 
Phone: 
E-mail: 
 
 
 
 


 
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Index 
Schema 
  1.0 
Background   
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Radiotherapy Dose Modifications Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation  
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Study Finances 
20.0 
Publication Plan 
21.0 
References 
 
Appendix I    ECOG Performance Status 
Appendix II   Guidelines for the use of IMRT 
Appendix III  Radiation Therapy Quality Control Guidelines 
Appendix IV  Known inducers & inhibitors of isoenzyme CYP3A4 
Appendix V   Patient Assessment Form 
Appendix VI  QOL Forms 
Appendix VII Recommended Symptomatic Management for Patients Randomized to DART 
 
 
 
 


 
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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
 
 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
 
DART 
De-escalated Adjuvant Therapy 
IMRT  
 
 
  Intensity modulated radiation therapy 
HPV 
 
 
 
  Human papillomavirus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Registration:  
Blood and Tissue collection 
Observation  
(Starting 3 days post-XRT, then 1 month post-XRT, then Q3 
months post- XRT x2 yrs, Q6 mos for year 3, then annually 
for years 4 & 5 
Cancer Recurrence 
Intolerable Toxicity 
Refusal 
Or End of Observation 
(Whichever occurs first) 
Event Monitoring 
 (Follow-up per section 18) 
Stratification: 
 
Intermediate vs High Risk 
Smoking Status (No vs Yes) 
Randomize  
 
DART vs Standard of Care (2:1) 
Surgery + HPV testing 
DART:  Cycle 1(12 days) 
 
Docetaxel 15 mg/m2 days 1, 8 + RT 30 Gy/1.5 
Gy fractions bid days 1-12 only (int risk) or 36 
Gy/1.8 Gy fractions (high risk) 
Standard of Care:  Cycle 1 (40 days) 
 
RT 60 Gy/2 Gy fractions qday days 1-40.   
For high risk, add weekly Cisplatin 40 mg/m2 
(Around days 1, 8, 15, 22, 29, 36) 


 
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1.0 
Background   
 
1.1 
The new epidemic in oropharynx cancer 
 
Due to the success of public health initiatives in tobacco cessation, the overall rate of head and 
neck cancers (HNC) has steadily decreased in recent years (1).  However, the number of cancers 
within the oropharynx (tonsils, base of tongue, or soft palate) has seen a dramatic and unexpected 
rise within the past two decades. From 1988 to 2004, there was a 225% population-level increase 
in HPV-related oropharynx cancers (HPV+ OPC) in the United States and the Centers of Disease 
Control project that oropharynx cancer cases will likely grow to 17,000 cases/year by 2030 (2). 
This rate of growth within a specific cancer type is unprecedented and has been described as an 
oncologic epidemic by many public health authorities (3). 
 
1.2 
Role of HPV in Oropharyngeal Cancers 
 
Much of the rise in oropharynx cancer can be directly linked to the oncogenic role of the human 
papillomavirus (HPV). Oral cavity and oropharynx HPV infections are now widespread within 
the United States and upwards of 70% of the U.S. population are expected to have HPV exposure 
within their lifetime (4). While much of the population is able to clear an oral HPV infection, a 
subset of the population develops a persistent viral infection which eventually leads to 
oropharynx cancer over the course of many years.  HPV+ OPC now comprises close to 80% of 
all oropharynx cancers while smoking and alcohol-related oropharynx cancers continue to decline 
(5).  As a result, the demographics of an oropharynx patient has shifted from a more elderly 
population with significant smoking related co-morbidities to a younger, healthier population 
which is expected to live for many decades if they are cured of their cancer (6). 
 
1.3 
Long-term toxicities with standard therapies 
 
Although HPV+ OPC patients can expect high rates of cure with standard therapies, these 
treatments are also associated with high rates of permanently disabling toxicities.  The standard 
treatment for HPV+ OPC involves either seven weeks of daily radiation therapy (70 Gy) 
concurrent with cisplatin or surgery followed by six weeks of daily radiation therapy (60 Gy) 
with or without cisplatin depending upon post-surgical risk factors. Both definitive 
chemoradiation and surgery followed by adjuvant radiotherapy results in grade ≥3 toxicities rates 
of ~30% (9).  The most common of these toxicities include dysphagia requiring a permanent 
feeding tube, severe xerostomia which limits food intake and increases dental issues, 
osteoradionecrosis of the mandible requiring surgery or hyperbaric oxygen treatments, or neck 
fibrosis which severely limits range of motion. Among patients who do not have grade ≥3 
toxicities, grade 2 xerostomia, dysphagia, or neck fibrosis is nearly universal.  The mechanism 
behind these toxicities is well-established.  Post-treatment dysphagia and xerostomia are closely 
correlated with the total radiation dose received by the pharyngeal constrictors and salivary 
glands and extensive literature exists concerning the radiation dose constraints for these 
structures.  For example, a mean dose ≥26 Gy to the parotid glands is closely linked to long-term 
xerostomia while mean doses of ≥50 Gy strongly increases the risk for permanent swallowing 
difficulties (10, 11).  However, achieving these dose constraints with conventional treatment is 
problematic as standard definitive and post-operative radiation doses are 70 Gy and 60 Gy 
respectively.  Even modern treatment techniques such as intensity modulated radiation therapy 


 
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(IMRT) and proton therapy may have difficulty in reducing this normal tissue radiation exposure 
as the structures in question often lie within the volume at risk for disease recurrence, hence are 
intentionally treated.  Issues with long term toxicity are particularly germane in the HPV+ OPC 
population as these patients will likely be cured, are healthier, and are expected to live a long time 
post-treatment.  This rapidly growing patient population will therefore live for decades with the 
severe accumulated side effects incurred from therapy. 
 
1.4    
Urgent need for novel treatment paradigms 
 
Strategies for reducing treatment toxicity for HPV+ OPC patients have been identified as a 
research priority by a number of cooperative groups.  Nevertheless, these efforts are incremental 
in treatment de-escalation and may not maximize the possible improvements in quality of life for 
these patients. Furthermore, an incremental dose de-escalation strategy may ultimately be more 
dangerous than an aggressive de-escalation strategy, as salvage options for locoregional 
recurrences remain limited after 50 Gy.  An aggressive treatment de-escalation strategy is 
therefore required in order to maximize post-therapy quality of life while potentially leaving 
salvage options available. 
 
1.5 Preliminary data supporting dose de-escalation 
 
After observing the limitations with current research philosophies, the Head and Neck Disease 
Oriented Group at Mayo Clinic adopted a novel philosophy towards the issue of dose de-
escalation.  Rather than incrementally de-escalating therapy (i.e. reducing radiation from 60 to 50 
Gy or changing the dose of cisplatin), we sought to aggressively de-escalate treatment using half 
the dose of total radiation (30-36 Gy) along with one-fifth the dose of a gentler chemotherapy 
(docetaxel 15 mg/m2 x 2).   
 
The accrual goal for MC1273 was 80 patients in order to achieve 70 evaluable patients.  Accrual 
was completed in April 2016, and all patients are currently evaluable.  35 patients have reached at 
least one year of follow-up while 14 patients have at least two years of follow-up.  The current 
locoregional control rate for MC1273 is 100%.  Three patients have developed distant metastases 
for a preliminary disease free survival rate of 96%, and no patients have died.  Furthermore, no 
patients have required the placement of a PEG tube following adjuvant radiation and the grade ≥3 
toxicity rate by six months post-therapy is 0%.  Although full conclusions cannot be drawn until 
follow-up is complete, preliminary data suggest a high likelihood that MC1273 will exceed 
expectations for both disease control and quality of life preservation. 
 
1.6 Inadequacy of pathologic risk factors 
 
The need for adjuvant radiation and/or chemotherapy after surgical resection is traditionally based 
upon risk factors found during pathologic assessment.  These factors include positive margins, 
extracapsular extension, lymphovascular space invasion, perineural invasion, tumor size, and 
nodal volume. Nevertheless, these pathologic risk factors are often poor predictors for 
locoregional recurrence.  A review conducted on Mayo Clinic HPV+ OPC patients who had risk 
factors after surgery but no adjuvant care found that only 20% of patients had a locoregional 
relapse, and only 11% of patients with risk factors but without extracapsular extension had 
relapse after surgery alone (12).  While these failure rates are still above traditional thresholds for 


 
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recommending adjuvant care, these data strongly suggest that pathologic review is insufficiently 
specific for detecting residual tumor burden. 
 
1.7 Mate-pair sequencing for HPV-associated malignancies 
 
The need for improved detection of post-surgical tumor burden motivated the development of 
mate-pair sequencing for detecting HPV-associated gene rearrangements (13).  By focusing on 
gene rearrangements, mate-pair sequencing avoids the issue of variant calling errors associated 
with whole exome and whole genome techniques.  Combined with currently available techniques 
for detecting circulating tumor DNA, mate-pair sequencing performed on the primary tumor 
specimen may allow for the detection of tumor specific genetic alterations which can be 
subsequently assayed in pre- and post-surgical serum samples (14-16).   
 
2.0 
Goals  
 
2.1 
Primary 
 
 
2.11 
To compare the rates and severity of late grade 3-5 toxicities and PEG tube 
dependence between de-escalated adjuvant radiation therapy (DART) and 
standard adjuvant therapy.  (For definitions concerning toxicity timing and 
attribution, see section 7.82). 
 
2.2 
Secondary 
 
2.21 
To assess the cumulative incidence of local/regional failure at 2 years after study 
registration for patients treated with DART vs standard therapy.. 
 
2.22 
To compare overall survival, disease-free survival, and distant failure associated 
with DART vs standard treatment.   
 
2.12 
To compare the overall QOL between DART and standard adjuvant therapy at 1-
year post-treatment as measured by FACT H&N and EORTC H&N QLQ 35.   
 
 
2.3 
Correlative Research 
 
 
 
2.31 
To determine the genetic alterations of oropharynx tumor specimens and the 
detection rate of corresponding circulating DNA in the pre-surgical, post-
surgical, and post-radiation blood of oropharynx cancer patients. 
 
2.32 
To investigate the usefulness of immunologic biomarkers in predicting 
progression free survival.  
 
2.33 
To establish a patient derived xenograft panel from representative oropharynx 
patients. 
 
3.0  
Patient Eligibility    
 
3.1 
Pre-Registration (optional) 
 
 
 
 
3.11 
Provide written informed consent 
 


 
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3.12 
Submission of research blood draw and/or tumor sample.  
 
3.2 
Registration – Inclusion Criteria  
 
3.21 
Age ≥ 18 years. 
 
3.22 
Histological confirmation of HPV+ squamous cell carcinoma of the oropharynx.  
HPV positivity will be defined as positive staining for p16 on IHC. 
 
3.23 
Gross total surgical resection with curative intent of the primary tumor and at 
least unilateral neck dissection within 7 weeks of registration. 
 
3.24 
ECOG Performance Status (PS) 0 or 1 (Appendix I) 
 
3.25 
Absence of distant metastases on standard diagnostic work-up ≤ 16 weeks prior 
to registration.  (Chest CT, CXR, or PET/CT.) 
 
3.26 
Must have one of the following risk factors: 
• 
Lymph node > 3 cm 
• 
2 or more positive lymph nodes 
• 
Perineural invasion 
• 
Lymphovascular space invasion 
• 
T3 or T4 primary disease 
• 
Lymph node extracapsular extension  
 
3.27 
The following laboratory values obtained ≤ 35 days prior to registration.  
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin ≥8.0g/dL 
• 
Creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min 
• 
Total or direct bilirubin  < 2 x institutional upper limit of normal (ULN)  
• 
AST (SGOT) or ALT (SGPT) < 3 x institutional ULN 
 
3.29a 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.29b Ability to complete questionnaire(s) by themselves or with assistance. 
 
3.29c 
Provide informed written consent. 
 
3.29d Willingness to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
 
3.3 
Registration – Exclusion Criteria  
 
3.31 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 


 
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adequate contraception 
 
3.32 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.33 
Immunocompromised patients and patients known to be HIV positive.   
 
 
3.34 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.35 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.36 
Other active malignancy ≤ 5 years prior to registration.  EXCEPTIONS:  Non-
melanotic skin cancer or carcinoma-in-situ of the cervix.  NOTE:  If there is a 
history or prior malignancy, they must not be receiving other specific treatment 
for their cancer.  
 
3.37  
Prior history of radiation therapy to the affected site. 
 
3.38 
History of connective tissue disorders such as rheumatoid arthritis, lupus, or 
Sjogren’s disease. 
 
3.39 
Presence of any of the following risk factors after surgery: 
• 
Any positive surgical margin. 
• 
Adenopathy below the clavicles  
 
3.40 
Prior systemic chemotherapy.   
 
3.41  
History of allergic reaction to docetaxel 
 
3.42 
Receiving any medications or substances which in the opinion of the 
investigators would interfere with treatment.  Examples could include strong 
inhibitors of CYP3A4 at oncologist discretion (see Appendix IV). 
 
3.43 
Severe pre-existing ototoxicity or neuropathy that would, in the opinion of the 
investigator, preclude the use of cisplatin chemotherapy. 
 


 
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4.0 Test Schedule 
 
 
Assessments, 
tests and 
procedures 
 
Pre-Treatment 
Active 
Monitoring  
Observation 
Pre-reg 
(prior to 
surgery) 
≤ 10 weeks 
prior to 
registration 
≤ 2 weeks 
prior to 
registration 
 
Weekly (+/- 3 
days) 
 
At 3 days 
post-
XRT19 
At 1 mo. 
post-XRT 
(+/-  14days 
) 
Q3 months 
post- XRT x2 
yrs q6 mos for 
year 3, then 
annually for 
years 4 & 5 
(+/- 1 month) 
Evaluation by 
Radiation 
Oncologist 
and/or Medical 
Oncologist 
X8 
 
X10 
X5 
X5 
X5 
ENT/Surgeon’s 
exam 
X9 
 
 
 
X5 
X5 
CT with 
contrast, or 
CT/PET, and/or 
MRI of H & N2 
 
X 
X14 
X15 
 
 
X15 
Chest x-ray (or 
chest CT or 
CT/PET)2 
X 
 
X15 
 
 
X5,6 
Pathology 
Assessment 
(Gross total 
resection ≤ 7 
weeks 
X7 
 
 
 
 
 
Biopsy 
 
 
X4, 15 
 
 
X4, 15 
Performance 
status 
 
X 
X 
 
X 
X 
CBC w/ diff  
 
X 
X15 
 
X 
X15 
Total or Direct 
Bilirubin, AST (SGOT) 
or ALT (SGPI) 
 
X 
X15 
 
X 
X15 
Serum creatinine 
 
X 
X15 
 
 
 
Na, K, glucose, 
Ca, Mg, albumin 
 
X 
 
 
 
 
Serum 
pregnancy test 
(if applicable)1 
 
X1 
 
 
 
X15 


 
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Assessments, 
tests and 
procedures 
(cont.) 
Pre-reg 
(prior to 
surgery) 
Pre-Treatment 
Active 
Monitoring 
Observation 
≤ 10 weeks 
prior to 
registration 
≤ 2 weeks 
prior to 
registration 
 
At 3 days 
post-
XRT19 
At 1 mo. 
post-XRT 
(+/- 14 days 
) 
Q3 months post- 
XRT x2 yrs q6 
mos for year 3, 
then annually for 
years 4 & 5 
Weekly (+/- 3 
days) 
Dental 
evaluation 
X16 
 
 
 
 
 
Assessment of 
swallowing 
function 
X18 
 
 
 
X 
X11 
Adverse event 
evaluation 
 
X 
 
X 
X 
X 
Research Blood 
Specimens 
(section 14.0)12 R 
X 
 
 
X13 
 
 
 
X13 
QOL/Functional 
Assessments: 
QLQ H&N35; 
FACT-H&N;; 
EQ-5D; 
XeQOLS; 
DLQI3 
 
X17 
 
 
X17 
X17 
X17 
Patient 
Assessment 
Form (completed
by investigator) 
(see Appendix 
V) 
 
X17 
 
 
X 
X 
 
1. For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
2. Specify method (e.g., CT, MRI, or PET/CT, etc.)  Same imaging modality throughout the study is 
encouraged. 
3. Patient questionnaire booklets must be used; copies are not acceptable for this submission. 
4. If suspicion of tumor recurrence. 
5. An initial post-treatment evaluation by Radiation and/or Medical Oncology will be 
performed  3 days after completion of RT.  A general history and physical by one of the 
following: a  
Radiation Oncologist, Medical Oncologist, an ENT, or a Head and Neck 
Surgeon must be  
done at 1 and 3 months post-XRT, then q3 months for 2 years, every 6 
months for year 3,  then annually for year 4 & 5. A laryngopharyngoscopy (mirror and/or 
fiberoptic and/or  
direct procedure) is recommended at these time points but is not required. 
6. Chest imaging (at minimum a chest x-ray or chest CT or CT/PET of chest) is required once 
 
per year for a total of 5 image sets. 
7. Gross total resection/surgical pathology must be completed ≤ 7 weeks prior to registration. 


 
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8. A general history & physical by a Radiation Oncologist and/or Medical Oncologist must be 
 
done≤ 8 weeks prior to registration 
9. An examination by an ENT or Head & Neck Surgeon must be done ≤ 8 weeks prior to 
 
registration. A laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is 
 
recommended but not required 
10. A general history & physical by a Radiation Oncologist and/or Medical Oncologist must be 
 
done weekly. 
11. One year post XRT; two-year post XRT assessment is optional. 
 
12. This blood collection will only be collected for patients that are enrolled at the Mayo Clinic 
Rochester.  
13. This blood specimen only needs to be collected post-surgery but prior to radiation therapy 
treatment and then only at the 3 month post radiation therapy visit 
14. Recommended within 8 wks prior to registration 
15. As clinically indicated 
16. To be completed within 3 months of starting treatment. 
17. Questionnaires should be completed at the following time points: Baseline (prior to starting 
treatment) 3 days post treatment, and at 1, 3, 12, and 24 months post treatment.  
18. If not able to get done completed prior to starting treatment, it should be completed within 
the first week of treatment.  
19. Optional 
R. Research Funded 
 
5.0 Stratification Factors:  
 
• 
Extracapsular Extension   
o No:  Intermediate Risk 
o Yes: High Risk 
 
• 
Smoking History 
o No: < 10 pack-year equivalents of tobacco product use AND ≥5 years abstinent 
of tobacco equivalent products. 
o Yes: ≥ 10 pack-year equivalents of tobacco product use OR <5 years abstinent of 
tobacco equivalent products. 
 
 
6.0 
Randomization/Registration 
6.1 
Randomization – After stratification, patients will be randomized between DART and 
standard therapy using a 2:1 randomization favoring DART.   The treatment arms will be 
balanced based on the 2 stratification factors of interest: Risk (Intermediate vs. High 
Risk) and Smoking Status (No vs Yes).  The balancing algorithm that we will use is a 
dynamic allocation procedure that is part of Medidata Rave, known as Balance.   
6.2 
Registration Procedures 
 
Patient will be registered to the study when they have consented, met eligibility criteria, 
and have been logged into Research Participant Tracking (Ptrax). 
 
7.0 
Protocol Treatment 
 
 


 
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NOTE: FOR THIS STUDY, IMRT AND IGRT ARE MANDATORY 
 
Dose Specifications DART 
 
The prescribed radiotherapy dose will be 30-36 Gy in 1.5-1.8 Gy twice-daily fraction size 
(total of 20 fractions). Radiotherapy should strongly aim to begin on a Monday. If 
Monday therapy cannot be arranged due to Holidays or technical issues, treatment must 
start no later than Tuesday with chemotherapy arranged to begin on the same day.  
Treatments that begin on a Tuesday should be Tues – Sat b.i.d. both weeks with 
chemotherapy to start on Tuesday both weeks.  The daily dose will be prescribed such 
that 100% of the PTV volume receives at least 30 Gy.  PTV coverage has precedence 
over normal tissue constraints.  
 
 
 
Cohort 
Dose 
(Gy) 
Number of 
Fractions 
Fraction 
Size 
Rx Length 
Rx Days 
Int. 
Risk 
30 
20 
1.5 
 
Days 1-12 
M-F 
High 
Risk 
36 
20 
1.8 
Days 1-12 
 
Dose Specifications Standard of care 
 
The prescribed radiotherapy dose will be 60 Gy in 2 Gy daily fraction size (total of 30 
fractions). Radiotherapy should aim to begin on a Monday. The daily dose will be 
prescribed such that 98% of the PTV volume receives at least 60 Gy.   
 
Cohort 
Dose 
(Gy) 
Number of 
Fractions 
Fraction 
Size 
Rx Length 
Rx Days 
Int. and 
High 
Risk  
60 
30 
2 
 
Days 1-40 
M-F 
 
7.41 
Technical Factors 
Treatment Planning/Delivery: Megavoltage energy photon beam irradiation is 
required. Any treatment planning and delivery system that has been credentialed 
for head and neck IMRT is acceptable. 
 
7.42 
Image Guidance for IGRT: Daily image guidance of IMRT may be achieved 
using any one or more of the following techniques: 
• 
Orthogonal kilovoltage (KV) images, e.g. ExacTrac; 
• 
Linear-accelerator mounted kV and MV conebeam CT images; 
 
The institution’s procedure to register treatment day imaging dataset with the 
reference dataset should comply with the following recommendations: 


 
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• 
Region-of-Interest (ROI) or “clip box” for fusion should be set to encompass 
the high dose PTV and adjacent spinal cord; if the supraclavicular region is a 
part of the target volume the ROI should extend to the C6 level; 
• 
If the fusion software allows the user to create an irregular ROI (e.g., 
ExacTrac), treatment room objects seen on in-room X-rays should be 
excluded from the registration; 
• 
Both manual (e.g., based on bony anatomy) and automatic types of 
registration can be used; the result of the fusion must be visually checked for 
the alignment of the bony anatomy, such as vertebral bodies and applicable 
soft tissue structures (e.g., optic nerves and/or optic chiasm). 
 
7.43 
Localization, Simulation, and Immobilization 
 
7.431 Patients must have an immobilization device (e.g., aquaplast mask) made 
prior to treatment planning CT scan. 
 
7.432 The treatment planning CT scan can be performed with IV contrast so that 
the major vessels of the neck are easily visualized. The treatment planning 
CT scan must be performed with the immobilization device and in the 
treatment position. Slice thickness should be 0.3 cm. 
 
7.5 Target and Normal Tissue Volume Definitions 
 
7.51 Definition of Target Volumes:  
Patients randomized to DART 
 
7.510 CTV3600: This volume will receive 180 cGy per day b.i.d. and will only 
apply to patients who have +ECE (high risk cohort).  This volume will be 
restricted to the prior location of the ECE-involved lymph node, 
expanded by 1 cm, and shaving off of bone and relevant normal 
anatomy.  This volume may approach the skin but should not approach < 
2mm. In the instance where the exact ECE-involved lymph node is 
unclear, CTV3600 will be defined as the nodal station from which the 
ECE-involved node originated.  For questions, contact the Primary 
Investigator, Dr. Daniel J. Ma. 
 
7.511 CTV3000: This volume will receive 150 cGy per day b.i.d. CTV3000 
will include the primary tumor bed (based on preoperative imaging, 
preoperative physical exam/endoscopy, operative findings, pathologic 
findings) plus region(s) of grossly involved lymphadenopathy. This 
volume may approach the skin but should not approach < 2mm. It is 
recognized that after surgery, there can be considerable distortion of 
normal anatomy. If possible, map preoperative GTV(s) onto the 
postoperative radiation therapy planning CT scan, and add appropriate 
margins for microscopic spread (1.5-2 cm).  CTV3000 also will 
generally include the bilateral necks.  This usually means encompassing 
nodal levels 2, 3, and 4 for all cases. Nodal levels 1, 5a, and 5b are 
included in CTV3000 in selected circumstances. Ipsilateral neck 


 
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irradiation for the involved hemi-neck will only be allowed for a well-
lateralized tonsillar cancer without any base of tongue involvement. For 
questions, contact the Principal Investigator, Dr. Daniel J. Ma.  
 
7.512  Planning Target Volumes (PTVs): In general, the PTV should not go 
outside of the skin surface; if it does exceed the skin surface, the 
application of bolus material over this portion of the PTV may be 
considered but is generally not recommended.  
 
7.513  PTV Expansion with Daily IGRT: The minimum CTV-to-PTV 
expansion is 2.5 mm (a larger expansion may be necessary for a target 
volume subject to significant intra-fraction variability.  In general, the 
CTV-to-PTV expansion (with IGRT) should not exceed 5 mm. 
 
7.52 Definition of Target Volumes:  
 
Patients randomized to Standard therapy 
 
7.520 CTV6000: This volume will receive 200 cGy per day. CTV6000 will 
include the primary tumor bed (based on preoperative imaging, 
preoperative physical exam/endoscopy, operative findings, pathologic 
findings) plus region(s) of grossly involved lymphadenopathy. This 
volume may approach the skin but should not approach < 2mm. It is 
recognized that after surgery, there can be considerable distortion of 
normal anatomy. If possible, map preoperative GTV(s) onto the 
postoperative radiation therapy planning CT scan, and add appropriate 
margins for microscopic spread (1.5-2 cm).  CTV6000 also will include 
the involved neck and/or dissected uninvolved neck at investigator 
discretion.  This generally means encompassing nodal levels 2, 3, and 4 
for all cases. Nodal levels 1, 5a, and 5b are included in CTV in selected 
circumstances. Ipsilateral neck irradiation for the involved hemi-neck 
will be allowed for a well-lateralized tonsillar cancer without any base of 
tongue involvement only. For questions, contact the Principal 
Investigator, 
 
 
7.521 CTV5400: This optional volume will receive 180 cGy per day.  
CTV5400 will include the uninvolved at-risk neck, generally the 
contralateral neck levels 2-4.  Additional nodal levels may be included at 
investigator discretion for unusual case presentations.  For questions, 
contact the Principal Investigator, 
  
 
7.522  Planning Target Volumes (PTVs): In general, the PTV should not go 
outside of the skin surface; if it does exceed the skin surface, the 
application of bolus material over this portion of the PTV may be 
considered but is generally not recommended.  
 
7.523  PTV Expansion with Daily IGRT: The minimum CTV-to-PTV 
expansion is 2.5 mm (a larger expansion may be necessary for a target 


 
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volume subject to significant intra-fraction variability.  In general, the 
CTV-to-PTV expansion (with IGRT) should not exceed 5 mm. 
 
7.53 Definition of Normal Tissues/Organs at Risk (OARs) 
 
7.531  Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top 
of the C1 vertebral body). Superior to this is brainstem and inferior to 
this is cord. The inferior border of the spinal cord is at approximately T3-
4 (i.e., just below the lowest slice level that has PTV on it). The spinal 
cord shall be defined based on the treatment planning CT scan. In 
addition, however, a Planning Risk Volume (PRV) spinal cord shall be 
defined. The cord_prv = cord + 5 mm in each dimension. This is 
irrespective of whether or not IGRT is used. 
 
7.532  Brainstem: The inferior most portion of the brainstem is at the cranial-
cervical junction where it meets the spinal cord. For the purposes of this 
study, the superior most portion of the brainstem is approximately at the 
level of the top of the posterior clinoid. The brainstem shall be defined 
based on the treatment planning CT scan. In addition, however, a 
Planning Risk Volume (PRV) brainstem shall be defined. The 
brainstem_prv = brainstem + 3 mm in each dimension. 
 
7.533  Lips and Oral Cavity: These should be contoured as 2 separate structures 
as the goal is to keep the lip dose much lower than the oral cavity dose. 
The definition of lips is self-explanatory. For non-oral cavity cancers, the 
oral cavity will be defined as a composite structure consisting of the 
anterior ½ to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and 
palate. This should not overlap the PTVs. 
 
7.534  Parotid Glands: Parotid glands will be defined based on the treatment 
planning CT scan.  Parotid gland volume will not include any portion of 
any of the CTVs, although they can overlap the PTVs. 
 
7.535  Constrictors: This will be defined as the posterior pharyngeal wall plus 
adjacent constrictor muscles. This extends from the superior constrictor 
region (the inferior pterygoid plates level) to the cricopharyngeal inlet 
(posterior cricoid cartilage level). This should not overlap the PTVs. 
 
7.526  Esophagus: This will be defined as a tubular structure that starts at the 
bottom of constrictors and extends to the thoracic inlet. 
 
7.527  Larynx: This will be defined as a “triangular prism shaped” volume that 
begins just inferior to the hyoid bone and extends to the cricoid cartilage 
inferiorly and extends from the anterior commissure to include the 
arytenoids. This includes the infrahyoid and suprahyoid epiglottis. 
 


 
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7.528  Mandible: This includes the entire boney structure of the mandible from 
the TMJ through the symphysis. It is recognized that for oropharynx 
cancers, this may overlap with PTVs. 
 
 
7.6 Treatment Planning and Delivery 
 
7.61  
Management of the Low Neck/Supraclavicular Region (No Match) 
No Match: The entire clinical target volume (CTV) [upper and lower neck and 
primary tumor bed] is irradiated with IMRT. There is no match line between 
upper and lower portions of the regions at risk. In this technique, limiting 
radiotherapy dose to organs at risk (OARs), e.g., the cervical esophagus, is 
entirely achieved by inverse treatment planning via IMRT algorithms.  
 
7.62  
IMRT Dose Prescription to PTVs 
See Section 7.5 for definitions of CTVs and PTVs.  For inverse planning IMRT, 
the goal is for 98% of the PTVs to receive ≥ 100% of prescription dose.  It is 
recognized that portions of the PTV close to the skin may receive significantly 
less than prescription. This is acceptable as long as cold spots within PTV do not 
exist at a depth deeper than 5 mm beneath the skin.  
 
7.63  
IMRT Dose Constraints to Normal Structures 
There are two goals for the dose constraints in this protocol.  First, structures 
such as the parotid glands and the minor salivary glands within the oral cavity 
have a continuous, inverse relationship between dose and function.  Thus the 
dose constraints for these structures reflect what should be achievable using 
IMRT techniques.  Second, the dose received by critical structures such as the 
spinal cord and brainstem may limit the ability for re-irradiation if such treatment 
is required.  Thus the dose constraints on these structures have been set 
conservatively to facilitate possible future interventions. PTV coverage has 
precedence over normal tissue constraints.  
 
Dose constraints for all structures except spinal cord and brainstem are 
considered suggestions and subject to investigator clinical discretion. 
 
For patients randomized to DART: 
 
7.631  Spinal Cord: The cord_prv should not exceed 35 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord 
PRV should not exceed 30 Gy to any volume in excess of 0.01 cc.  The 
goal for treatment planning will be a mean dose < 20 Gy. 
 
7.632  Brainstem: The brainstem_prv should not exceed 35 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The goal for 
treatment planning will be a mean dose < 20 Gy. 
 
 


 
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7.634  Lips: Reduce the dose as much as possible. The mean dose should be < 
15 Gy.  
 
7.635  Oral Cavity: Reduce the dose as much as possible. The mean dose 
should be < 20 Gy. 
 
7.636  Parotid Glands: In most cases, it will be easier to spare one parotid than 
the other. The treatment planning goal will be for this individual parotid 
gland to receive a mean dose of < 10 Gy. Otherwise, the goal will be for 
the total mean parotid dose to be < 15 Gy. 
 
7.637 Submandibular Glands:  If either submandibular gland is outside of the 
target volume, the goal will be for a mean dose for that gland to be <20 
Gy.  Otherwise reduce the dose as much as possible. 
 
7.637 Constrictors: Reduce the dose as much as possible.  Target mean dose is 
<20 Gy. 
 
7.638  Esophagus: Reduce the dose as much as possible. Target mean dose is 
<20 Gy. 
 
7.639  Larynx: Reduce the dose as much as possible. Target mean dose is <15 
Gy. 
 
7.640  Mandible: Reduce the dose as much as possible. Keep 105% hotspot 
outside of mandible if possible. 
 
 
For patients randomized to Standard Therapy: 
 
7.641  Spinal Cord: The cord_prv must not exceed 45 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm).  
 
7.642  Brainstem: The brainstem_prv  must not exceed 54 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm).  
 
7.643  Lips: Reduce the dose as much as possible. The mean dose should be < 
20 Gy.  
 
7.644  Oral Cavity: Reduce the dose as much as possible. The mean dose 
should be < 50 Gy. 
 
7.645  Parotid Glands: In most cases, it will be easier to spare one parotid than 
the other. The treatment planning goal will be for this individual parotid 
gland to receive a mean dose of < 26 Gy. Otherwise, the goal will be for 
the total mean parotid dose to be < 39 Gy. 
 


 
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7.646 Submandibular Glands:  If either submandibular gland is outside of the 
target volume, the goal will be for a mean dose for that gland to be <39 
Gy.  Otherwise reduce the dose as much as possible. 
 
7.647 Constrictors: Reduce the dose as much as possible.  Target mean dose is 
<50 Gy. 
 
7.648  Esophagus: Reduce the dose as much as possible. Target mean dose is 
<34 Gy. 
 
7.649  Larynx: Reduce the dose as much as possible. Target mean dose is < 35 
Gy. 
 
 
7.650 Mandible: Reduce the dose as much as possible.  Keep 105% hotspot 
outside of mandible if possible. 
 
 
 
Chemotherapy Treatment 
 
Agent 
Dose 
Days administered 
Pre-medication* 
Docetaxel (DART) 
15 mg/m2 in 50-100 
mL 0.9% NaCL (non-
PVC container) IV 
infusion over 1 hour 
1, 8 (Mondays) 
1) Dexamethasone 10 
mg in 100 mL 0.9% 
NaCL IV infusion over 
15 minutes 
2) Benadryl 50 mg in 
100 ml 0.9% Sodium 
Chloride IV infusion 
over 15 minutes 
Cisplatin (standard of 
care) 
40 mg/m2 IV weekly 
Monday, Tuesday, or 
Wednesday 
Per institutional 
protocol 
 
*For patients who have an infusion reaction despite pre-medication with dexamethasone and 
Benadryl, stop infusion and administer Pepcid 20 mg IV and an additional dose of Benadryl 50 
mg IV.  Once symptoms resolve and additional pre-medication has been given, resume infusion.  
If the infusion reaction occurs on day 1 of treatment (1st dose of docetaxel), administer all three 
medications with the 2nd cycle (dexamethasone, Benadryl, and Pepcid).  If a patient is still 
symptomatic despite additional pre-medication, stop treatment and reschedule for the following 
day 
(day 
2 
or 
day 
9), 
and 
send 
the 
patient 
home 
with 
high-dose 
steroid 
premedication.(dexamethasone 20 mg po the evening before the planned chemotherapy, and 20 
mg po the morning of the planned chemotherapy).  When the patient presents for the infusion, 
they should receive the following premedications: dexamethasone 20 mg IV, Pepcid 20 mg IV, 
Benadryl 50 mg IV, and Ativan 1 mg IV.  If despite all of these efforts a patient still reacts, 
docetaxel should be permanently discontinued. 
 


 
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7.7 
Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the 
reason(s) for the treatment break(s). Refer to Appendix II for full details. 
 
7.81  
Adjuvant Therapy Adverse Events  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4 will be utilized for grading all adverse 
events. All appropriate treatment areas should have access to a copy of the CTCAE, v. 4. 
A copy of the CTCAE, v. 4 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
Grade 3 therapy-induced mucositis and/or dysphagia are expected to develop in about 
one third of patients receiving standard of care. Nutritional evaluation prior to the 
initiation of therapy, to determine if prophylactic gastrostomy (PEG) tube placement is 
needed, is highly recommended. Placement of a feeding tube should be recorded on the 
appropriate case report form, as should use of a feeding tube during and after treatment 
(e.g., greater than or less than 50% of nutrition by tube).  
 
Other common radiation adverse events include: fatigue, weight loss, regional alopecia, 
xerostomia, hoarseness, transient ear discomfort, dysgeusia, dysphagia, odynophagia, 
skin erythema, and desquamation within the treatment fields. 
 
Less common long-term treatment adverse events include: hypothyroidism, loss of 
hearing, chronic swallowing dysfunction requiring permanent feeding tube, and cervical 
fibrosis.  
 
Much less common radiation adverse events include: mandibular osteoradionecrosis      
(< 5% incidence with attention to dental recommendations), and cervical myelopathy     
(< 0.1% with restriction of spinal cord dose to ≤ 30 Gy). 
 
Clinical experience on MC1273 demonstrated an unexpectedly high rate of thrush in 
patients receiving DART.  Thrush prophylaxis is highly recommended for patients 
randomized to DART starting on Day 8 of therapy.  For full details of recommended 
symptomatic management for patients randomized to DART, please see Appendix 
VII 
 
7.82 Definition of Adverse Event Timing and Attribution 
 
 
 
Early onset (acute) toxicities will be defined as toxicities which begin during the start of 
adjuvant therapy upwards to 90 days post radiation therapy. 
 
 
 
Late onset (chronic) toxicities will be defined as toxicities which begin from 91 days to 
two years post radiation therapy.  Early onset toxicities can also be considered late 
toxicities if they persist for at least one day beyond the 90 days used to define late onset 
toxicities. For example, a patient who requires PEG tube placement during radiation 
therapy but has the PEG tube persist at the 6-month post-treatment evaluation will be 
considered to have both an acute and chronic toxicity. 


 
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Attribution for toxicities will follow the guidelines outlined in section 10.22.  For 
statistical purposes, only grade 3 or higher toxicities recorded as “possible”, probable” or 
“definite” in relationship to adjuvant therapy will be used for the primary endpoint.  For 
example, a patient who requires PEG placement after surgery, before the initiation of 
radiation therapy, and does not have worsening of swallowing outcomes on formal 
swallow evaluation after adjuvant therapy will be recorded as having a toxicity that is not 
probable or definite in attributable to adjuvant therapy for the purposes of the primary 
endpoint.  These toxicities will nevertheless be recorded for safety and reporting 
purposes. 
 
 
 
When ambiguity exists concerning the attribution of toxicities, an independent panel 
consisting of a radiation oncologist, ENT, and medical oncologist who were not involved 
in the patient’s care will assess attribution.  
 
 
 
 
8.0 
Dose Modifications Based on Adverse Events  
 
This study has no pre-specified radiation interruptions due to adverse events. If radiation needs to 
be interrupted, this will be approved by the Radiation chair 
 and documented.  
 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2) 
 
For patients randomized to DART 
 
Dose Level 
DOCETAXEL (Day 1 or 8) 
0* 
 
15 mg/m2 IV 
-1 
 
10 mg/m2 IV 
-2 
 
5 mg/m2 IV 
*Dose level 0 refers to the starting dose. 
- If the patient requires one docetaxel delay (Day 1 or 8), start at Dose -1 
 
 
For patients randomized to standard therapy, high risk cohort (+ECE) 
 
For patients randomized to receive standard chemoradiotherapy, cisplatin at 40 mg/m2 will be 
given intravenously (IV) over 60 minutes weekly on a Monday, Tuesday, or Wednesday of each 
week. (6 doses for a total of 240 mg/m2). Cisplatin can be given prior to or after the patient’s 
radiation on each day of chemotherapy delivery at the treating physician’s discretion. Cisplatin 
administration outside of these specified time points during radiation is only allowed in the event 
of holidays or scheduling conflicts that do not permit drug and radiation delivery on the specific 


 
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date. Cisplatin is administered concurrent with radiation therapy. In the event that radiation 
therapy is held, no cisplatin will be administered. 
 
Weekly cisplatin doses of may be reduced to 30 mg/m2 or held at the discretion of the treating 
Medical Oncologist for toxicity purposes.  Possible indications for dose modification or 
withdrawal include an absolute neutrophil count (ANC) < 1000/mm3, platelet count < 75,000, 
development of grade 2 neurotoxicity or ototoxicity, or clinically relevant elevations of serum 
creatinine.  Dose reduction will be performed at the discretion of the Medical Oncologist. 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
Investigations, 
Other, Blood/ 
Bone Marrow 
ANC < 1500/mm3 
OR 
PLT < 75,000/mm3 
docetaxel 
Hold docetaxel.  Resume treatment at one 
decreased dose level when ANC ≥ 
1500/mm3 and PLT ≥ 75,000. 
Investigations, 
Other,  Liver 
AST or ALT > 1.5 x ULN 
when AP > 2.5 x ULN 
OR 
AST or ALT > 3 x ULN 
OR 
Total or Direct Bilirubin > 
1.5 x ULN 
docetaxel 
Hold docetaxel.  Resume treatment at one 
decreased dose level when AST/ALT ≤ 3 x 
ULN, AP < 2.5 x ULN, and Total or Direct 
Bilirubin ≤ 1.5 x ULN. 
Neurology 
Grade 3+ peripheral 
neuropathy 
docetaxel 
Discontinue docetaxel. 
All other non-
hematologic 
adverse events 
Grade 2-4 
(exclude nausea/vomiting 
that has not been pre-
medicated) 
 
docetaxel 
Hold docetaxel.  Resume treatment at one 
decreased dose level when resolved to grade 
0-1 adverse event. 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  


 
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NOTE:  If the patient experiences a significant adverse event requiring a dose reduction at the start 
of the next dose, then the dose will remain lowered for that entire cycle.   
 
NOTE:  Adverse events requiring a dose-reduction step for any or all drugs beyond the two dose-
reduction steps (levels –1 and –2) will be at the discretion of the treating physician, if the decision 
is made for the patient to be kept on study.  These dose reductions must be clearly recorded in 
reported clinical data.  
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors 
should follow published guidelines of the American Society of Clinical Oncology 
(42) Update of Recommendations for the Use of Hematopoietic Colony-
Stimulating Factors: Evidence-Based, Clinical Practice Guidelines.  J Clin Oncol 
18(20): 3558-3585, 2000.  
 
9.3 
Patients should receive full supportive care while on this study.  This includes 
blood product support, antibiotic treatment, and treatment of other newly 
diagnosed or concurrent medical conditions.  All blood products and concomitant 
medications such as antidiarrheals, analgesics, and/or antiemetics received from 
the first day of study treatment administration until 30 days after the final dose 
will be recorded in the medical records. 
 
9.4 
Diarrhea:  This could be managed conservatively with loperamide.  The 
recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 
2-4 hours until diarrhea free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are 
allowed:  hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with 
fever or severe neutropenia (grade 3 or 4), broad-spectrum antibiotics may be 
prescribed.  Patients with severe diarrhea or any diarrhea associated with severe 
nausea or vomiting may be hospitalized for intravenous hydration and correction 
of electrolyte imbalances. 
 
9.5 
For mucositis, esophagitis, and nutritional support: These may include 
analgesics, antiemetics, topical mouth rinses, skin creams/ointments, etc. The use 
of amifostine as a radioprotector is not allowed.  
 
9.6 
Premedication for chemotherapy will be given per institutional protocols. 
 


 
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9.7 
Symptomatology for patients randomized to DART is unique to the regimen and 
may be unexpected for physicians without prior experience with this treatment 
schedule.  For recommended symptomatic management for patients 
randomized to DART, please refer to Appendix VII. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Definitions 
Adverse Event- An untoward or undesirable experience associated with the use of a 
medical product (i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event - Adverse events are classified as serious or non-serious.  Serious 
problems/events can be well defined and include; 
• 
death 
• 
life threatening adverse experience 
• 
hospitalization 
• 
inpatient, new, or prolonged; disability/incapacity 
• 
persistent or significant birth defect/anomaly 
 
And/or per protocol may be problems/events that in the opinion of the sponsor-
investigator may have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially compromised the research data. 
All adverse events that do not meet any of the criteria for serious, should be regarded as 
non-serious adverse events.  
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO) - Any 
unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may 
be physical, psychological, financial, social, economic, or legal) or increased 
risk for the subject or others (including individuals who are not research 
subjects). These include: (1) death; (2) life threatening adverse experience; (3) 
hospitalization - inpatient, new, or prolonged; (4) disability/incapacity - 
persistent or significant; (5) birth defect/anomaly; (6) breach of confidentiality 
and (7) other problems, events, or new information (i.e. publications, DSMB 
reports, interim findings, product labeling change) that in the opinion of the 
local investigator may adversely affect the rights, safety, or welfare of the 
subjects or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not 
already described as potential risks in the protocol, consent document, not listed 
in the Investigator’s Brochure, or not part of an underlying disease. A problem 
or event is "unanticipated" when it was unforeseeable at the time of its 
occurrence. A problem or event is "unanticipated" when it occurs at an 
increased frequency or at an increased severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 


 
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Preexisting Condition- A preexisting condition is one that is present at the start of the 
study.  A preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or the character of the condition worsens during the study period. At screening, 
any clinically significant abnormality should be recorded as a preexisting condition.  At 
the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event.  
 
10.2 
Recording Adverse Events 
 
CTCAE term (AE description) and grade: 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/protocolDevelopment/electronic_applications/ctc.htm) 
 
10.21 Adverse event monitoring and reporting is a routine part of every clinical 
trial. First, identify and grade the severity of the event using the CTCAE 
version 4.0. Next, determine whether the event is expected or unexpected 
and if the adverse event is related to the medical treatment or procedure. 
With this information, determine whether the event must be reported as 
an expedited report (see Section 10.3). 
 
 
 
 
10.22 Assessment of Attribution 
When assessing whether an adverse event is related to a medical 
treatment or procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event. 
 
 
 
10.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
a. 
Serious Adverse Events will be reported as part of regular adverse event 
reporting mechanisms via the data capture system and logged for review 
reporting. 
 


 
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10.31 
Investigator Reporting: Notifying the Mayo IRB: 
 
The IRB requirements reflect the guidance documents released by the Office of 
Human Research Protections (OHRP), and the Food and Drug Administration 
(FDA) in early 2007 and are respectively entitled “Guidance on Reviewing and 
Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events” and “Guidance for Clinical Investigators, Sponsors, and IRBs: 
Adverse Event Reporting – Improving Human Subject Protection.” 
 
10.311 
According to Mayo IRB Policy any serious adverse event (SAE) 
which the Principal Investigator has determined to be a 
UPIRTSO must be reported to the Mayo IRB as soon as possible 
but no later than 5 working days after the investigator first learns 
of the problem/event. 
10.312 
Non-UPIRTSO – the investigator reports problems or events that 
do NOT meet criteria of an UPIRTSO in summary format at the 
time of the next continuing review. The investigator monitors the 
severity and frequency of subsequent non-UPIRTSOs. 
 
Consider the following information to collect when developing any forms for 
documentation of adverse events. 
Example 
Information collected on the adverse event worksheet (and entered in the 
research database):  
• 
Subject’s name:  
• 
Medical record number:  
• 
Disease/histology (if applicable):  
• 
The date the adverse event occurred:  
• 
Description of the adverse event:  
• 
Relationship of the adverse event to the research (drug, procedure, or 
intervention):  
• 
If the adverse event was expected:  
• 
The severity of the adverse event: (use a table to define severity scale 1-
5) 
• 
If any intervention was necessary:  
• 
Resolution: (was the incident resolved spontaneously, or after 
discontinuing treatment) 
• 
Date of Resolution:  
 
The investigator will review all adverse event reports to determine if specific 
reports need to be made to the IRB and FDA.  The investigator will sign and date 
the adverse event report when it is reviewed.  For this protocol, only directly 
related SAEs/UPIRTSOs will be reported to the IRB. 
 
10.4 
Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading 
unless otherwise stated in the table below: 


 
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System Organ Class 
(SOC) 
Adverse 
Event/Symptoms 
Baseline 
Each 
evaluation 
Grading scale 
(if not CTCAE) 
Gastrointestinal disorders 
Dry mouth 
X 
X 
CTCAE 
Dysphagia 
X 
X 
CTCAE 
Mucositis oral 
X 
X 
CTCAE 
Nausea 
X 
X 
CTCAE 
Esophagitis 
X 
X 
CTCAE 
Oral Pain 
X 
X 
CTCAE 
General disorders and 
administration site 
conditions 
 
Fatigue 
 
X 
 
X 
CTCAE 
Musculoskeletal and 
connective tissue 
disorders 
Superficial soft 
tissue fibrosis 
X 
X 
CTCAE 
Vascular disorders 
Lymphedema 
X 
X 
CTCAE 
 
 
 
10.41 Submit via appropriate reporting mechanisms the following AEs 
experienced by a patient and not specified in Section 10.4: 
 
10.4.11 
Grade 2 AEs deemed possibly, probably, or definitely 
related to the study treatment or procedure. 
 
 
 
10.4.12 
Grade 3 and 4 AEs regardless of attribution to the study 
treatment or procedure. 
 
10.4.13  
Grade 5 AEs (Death) 
 
 
10.4.131 
Any death within 30 days of the patient’s last 
study treatment or procedure regardless of 
attribution to the study treatment or procedure 
 
10.4.132 
Any death more than 30 days after the patients 
last study treatment or procedure that is felt to be 
at least possibly treatment related must also be 
submitted as a Grade 5 AE, with a CTCAE type 
and attribution assigned. 
 
10.5 
Monitoring and Auditing  
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, and government regulatory agencies, of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 


 
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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices 
 
10.51 Medical Monitoring  
It is the responsibility of the Principal Investigator to oversee the safety of the 
study at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the 
construction and implementation of a site data and safety-monitoring plan (see 
section 10.5  “Monitoring and Auditing”).  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events.  “Any 
serious adverse events will be followed up by the sentinel event reporting 
procedure” 
 
 
10.52 Internal Data and Safety Monitoring Board  
 
As an interventional study, this study will be reviewed in conjunction with 
the Mayo Clinic Cancer Center DSMB processes. The study will also be 
reviewed by the Radiation Oncology Research Executive Board on a 
yearly basis to assess accrual, adverse events, and any endpoint problems. 
Any safety issues requiring protocol changes will be communicated 
through protocol amendments.   
 
The trial will be reviewed by the Cancer Center Auditing area on a bi-
annual or yearly basis dependent on random study selection to assess 
accrual, adverse events, and any endpoint problems. Any safety issues 
requiring protocol changes will be communicated through protocol 
amendments.   
 
 
11.0 
Treatment Evaluation  
 
11.1 
Patients will be evaluated at baseline, 3 days post XRT, 1 month post-XRT, then every 3 
months for 2 years post-XRT followed by every 6 months during year 3, then annually 
for years 4 & 5.  Once patients go off treatment or observation for recurrence, they will 
be followed per the Section 18.0 criteria.  
 
11.2 
At the time of reevaluation, patients will be classified in the following manner: 
 
 
 
11.21  No evidence of disease (NED). 
 
 
 
11.22  Recurrence of disease (REC). Recurrence must be confirmed by imaging and/or 
 
biopsy, with supporting materials submitted per Section 18.0.  If recurrence 
occurs, the report documenting recurrence is to be submitted per Section 18.0.   
 
 
 
11.221 The site of recurrence (or failure) will also be collected and classified as 
local vs. regional vs. distant recurrence.  The specific site of failure will also be 
collected as well. 


 
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11.222 Secondary Treatment. The date of the first retreatment and extent of 
retreatment post-recurrence (i.e. secondary resection or re-irradiation for primary 
disease), will be collected. Pathology, if available, and operative reports are 
required to be submitted per Section 18.0.  
 
 
12.0 
Descriptive Factors  
 
• 
Primary tumor site: Tonsil vs. Tongue Base vs. Soft palate vs. Pharyngeal Wall vs. Other.  
(Can choose multiple) 
• 
Neck Radiation: Bilateral vs. Unilateral. 
• 
T Stage: 1 vs. 2 vs. 3 vs. 4a vs. 4b 
• 
N Stage: 0 vs. 1 vs. 2a vs. 2b vs. 2c vs. 3. 
• 
HPV-positivity by HPV-ISH: Yes vs. No 
• 
Smoking history in pack-years. 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who have a recurrence while receiving therapy or during observation will go to 
the event-monitoring phase and be followed per Section 18.0. 
 
13.2 
Patients who go off protocol treatment or observation for reasons other than recurrence 
will go to the event-monitoring phase and be followed per Section 18.0. 
 
13.3 
Patients that complete all adjuvant treatment will then be followed during the observation 
phase at 3 days post-XRT, 1 month post-XRT, followed by every 3 months post-XRT for 
2 years, followed by every 6 months for year 3, then annually for years 4 & 5.   
 
13.4 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted.  
 
13.5 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 


 
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13.6 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary.


 
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14.0 
Body Fluid or Biospecimens   
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
 
 
NOTE: This blood collection system will only be collected for Mayo Clinic Rochester patients. 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube  
(color of 
tube top) 
Volume to 
collect per 
tube (#of tubes 
to be collected) 
Pre-
registration 
(Pre-surgery) 
Pre-
Treatmen
t 
Three 
Month 
Post 
XRT 
Proces
s at 
site? 
(Yes or 
No) 
Temperature 
Conditions for 
Storage/ 
Shipping 
cfDNA 
Optional 
Whole 
Blood 
Streck 
Two 10 mL 
whole blood 
samples in 
Streck Cell 
Free DNA BCT 
tubes 
X 
X 
X 
Yes 
Frozen 
BAP Lab 
Immunogenic 
markers 
Optional 
Serum 
Red-top, no 
anti-
coagulant 
One 10 mL 
serum in red-
top tube 
X 
X 
X 
Yes 
Frozen 
BAP Lab 
Immunogenic 
markers 
Optional 
Peripheral 
blood 
lymphocytes 
and plasma 
10 mL 
EDTA 
vacuatiner 
One 10 mL 
EDTA 
X 
X 
X 
Yes 
Frozen 
BAP Lab 
 
 
14.2  
Collection and Processing  
 
14.21 Specimens will be collected at the following time points 
• 
Prior to surgery as a pre-registration collection 
• 
Post-surgery prior to radiation therapy 
• 
3 months post radiation therapy 
 


 
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14.22 Two 10 mL blood samples will be collected in Streck Cell Free DNA BCT tubes. 
The tubes should be gently inverted 7 to 10 times to thoroughly mix the samples. 
These samples will be processed within 7 days of collection for cfDNA extraction 
using the Qiagen QIAmp Circulating Nucleic Acid kit according to manufacturer’s 
specifications. Evaluation for prespecified gene mutations will be performed using 
digital droplet PCR with the RainDrop platform (raindancetech.com). All of these 
samples must be labeled for immediate processing. The Streck Cell Free DNA BCT 
tubes will be provided for this study. 
 
14.23 Draw one 10 mL vacutainer (no anti-coagulant).  Allow to coagulate at room 
temperature for 20 minutes.  Separate by centrifugation at approximately 1200 G x 
20 minutes.  Aliquot serum into four cryovials and discard residual cells.  Samples to 
be frozen. 
 
14.24 Draw one 10 mL potassium EDTA (purple top) vacutainer, invert gently 4-5 times.  
Upon receipt at BAP, tubes will be processed to isolate plasma and buffy coat 
peripheral blood lymphocytes. Samples must be processed immediately upon receipt. 
 
14.3 
Shipping and Handling 
 
14.31 Shipping Specimens 
 
 
The Streck tubes for cfDNA should be kept at 6°C (42.8°F) to an ambient 
temperature of 37°C (98°F) during shipping. Ship cfDNA sample and CTC samples 
together to:  
 
  
  
  
  
  
 
 
Samples for the cfDNA studies should be collected and shipped Monday – 
Thursday. However, if the study participant can only be seen on Fridays, please 
contact the Biospecimen Resource Manager 
 
 
 
14.4 
Background and Methodology 
 
 
14.41 Circulating Cell Free DNA (cfDNA): Several studies indicate that circulating cell 
free DNA (cfDNA) includes representation of key genetic alterations related to 
cancer progression or resistance to systemic therapy; these alterations include 
mutations of tumor suppressor genes (e.g., TP53) and oncogenes (e.g., PIK3CA, 
KRAS and BRAF). Commercially available platforms exist with a predefined set of 
genes and point mutations of interest for use across multiple malignancies. A more 


 
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flexible system for individualized monitoring is needed. Mayo Clinic Rochester has 
developed an internal assay for this purpose.  
 
14.42 Immunogenic markers:  Given the immunogenic nature of HPV infections, we will 
investigate whether tumor antigen specific cellular immunity can serve as 
biomarkers for disease progression.  Peripheral blood lymphocytes, cytokines, and 
chemokines from post-surgery, pretreatment, and post treatment samples will be 
correlated with disease recurrence, DFS, and OS. 
 
 15.0 
Drug Information 
 
 
15.1 
Docetaxel (Taxotere®, TATER) Commercial Supply 
 
15.11 Background: Antineoplastic Agent, Antimicrotubular, Taxane derivative. Docetaxel 
promotes the assembly of microtubules from tubulin dimers, and inhibits the 
depolymerization of tubulin which stabilizes microtubules in the cell. This results in 
inhibition of DNA, RNA, and protein synthesis. Most activity occurs during the M 
phase of the cell cycle. 
 
15.12 Formulation: Note: Docetaxel is now available as a one-vial formulation in two 
concentrations: 10 mg/mL and 20 mg/mL. The older formulation included 2 vials 
which consisted of a concentrated docetaxel vial and a diluent vial, resulting in a 
reconstituted concentration of 10 mg/mL. Admixture errors could occur due to the 
concentration difference between the new formulations of 10 mg/mL and 20 mg/mL 
and the old formulation (10 mg/mL). Do not use the two-vial formulation with the 
one-vial formulation for the same admixture product. 
 
15.13 Drug procurement: 
 
Preparation, storage, and stability: Storage conditions:  Store the packaged 
docetaxel between 2 and 25°C (36 and 77°F).  Retain in the original package to 
protect from bright light. Freezing does not adversely affect the product. 
 
One-vial formulation: Note: One-vial formulation is available in two 
concentrations: 10 mg/mL and 20 mg/mL. Further reconstitution with diluent is not 
required. Further dilute for infusion in 250-500 mL of NS or D5W in a non-DEHP 
container (e.g., glass, polypropylene, polyolefin) to a final concentration of 0.3-0.74 
mg/mL. Gently rotate to mix thoroughly. Solutions prepared from the one-vial 
formulation and diluted for infusion should be used within 4 hours of preparation 
(infusion should be completed within 4 hours). 
 
Two-vial formulation: Vials should be diluted with 13% (w/w) ethanol/water 
(provided with the drug) to a final concentration of 10 mg/mL. Do not shake. Further 
dilute for infusion in 250-500 mL of NS or D5W in a non-DEHP container (e.g., 
glass, polypropylene, polyolefin) to a final concentration of 0.3-0.74 mg/mL. Gently 
rotate to mix thoroughly. Diluted solutions of the two-vial formulation are stable in 
the vial for 8 hours at room temperature or under refrigeration. Solutions prepared 
with the two-vial formulation and diluted for infusion in D5W or NS are stable for up 
to 4 weeks (Thiesen, 1999) at room temperature of 15ºC to 25ºC (59ºF to 77ºF) in 


 
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polyolefin containers; however, the manufacturer recommends use within 4 hours 
(infusion should be completed within 4 hours). 
 
15.14 Administration:  Administer IV infusion over 1-hour through non-absorbing 
polyethylene lined (non-DEHP) tubing; in-line filter is not necessary. Note: 
Premedication with dexamethasone is required (see Section 7.0) 
 
 
15.15 Pharmacokinetic information: Docetaxel exhibits linear pharmacokinetics at 
the recommended dosage range. 
Distribution: Extensive extravascular distribution and/or tissue binding; Vd: 
80-90 L/m2, Vdss: 113 L (mean steady state) 
Protein binding: ~94% to 97% 
Metabolism: Hepatic; oxidation via CYP3A4 to metabolites 
Half-life elimination: Terminal: ~11 hours 
Excretion: Feces (~75%, <8% as unchanged drug); Urine (<5%)  
 
 
15.16 Potential Drug Interactions:   
Cytochrome P450 Effect: Substrate (major) of CYP3A4; Inhibits CYP3A4 
(weak).  
Increased Effect/Toxicity: CYP3A4 inhibitors may increase the levels/effects 
of docetaxel. Concomitant use of docetaxel with a potent CYP3A4 inhibitor 
should be avoided. If systemic administration of a potent CYP3A4 inhibitor 
cannot be avoided, a 50% reduction in docetaxel dose should be considered 
along with close monitoring for docetaxel toxicity. Refer to the package insert 
or LexiComp1 for example inhibitors. When administered as sequential 
infusions, observational studies indicate a potential for increased toxicity when 
platinum derivatives (carboplatin, cisplatin) are administered before taxane 
derivatives (docetaxel, paclitaxel). Taxane derivatives may enhance the 
adverse/toxic effect of anthracyclines. 
Decreased Effect: CYP3A4 inducers may decrease the levels/effects of 
paclitaxel. Refer to the package insert or LexiComp1 for example inducers. 
Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (due to GI 
irritation). Avoid St John’s wort (may decrease docetaxel levels). 
 
15.17 Known potential adverse events: Consult the package insert for the most 
current and complete information. Percentages reported for docetaxel 
Monotherapy; frequency may vary depending on diagnosis, dose, liver 
function, prior treatment, and premedication. The incidence of adverse events 
was usually higher in patients with elevated liver function tests. 
 
Common known potential toxicities, > 10%:   
Cardiovascular: Fluid retention 
Central nervous system: Neurosensory events including neuropathy, fever, 
neuromotor events. 
Dermatologic: Alopecia, cutaneous events, nail disorder 
Gastrointestinal: Stomatitis, diarrhea, nausea, vomiting 
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, febrile 
neutropenia 
Hepatic: Transaminases increased 


 
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Neuromuscular & skeletal: Weakness, myalgia 
Respiratory: Pulmonary events 
Miscellaneous: Infection, hypersensitivity 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Left ventricular ejection fraction decreased, hypotension 
Dermatologic: Rash/erythema 
Gastrointestinal: Taste perversion 
Hepatic: Bilirubin increased, alkaline phosphatase increased 
Local: Infusion-site reactions including hyperpigmentation, inflammation, 
redness, dryness, phlebitis, extravasation, swelling of the vein 
Neuromuscular and skeletal: Arthralgia 
Ocular: Epiphora associated with canalicular stenosis 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Acute myeloid leukemia, acute respiratory distress syndrome, anaphylactic 
shock, angina, ascites, atrial fibrillation, atrial flutter, bleeding episodes, 
bronchospasm, cardiac tamponade, chest pain, chest tightness, colitis, 
conjunctivitis, constipation, cutaneous lupus erythematosus, deep vein 
thrombosis, dehydration, disseminated intravascular coagulation, drug fever, 
duodenal ulcer, Dyspnea, dysrhythmia, ECG abnormalities, erythema 
multiforme, 
esophagitis, 
gastrointestinal 
hemorrhage, 
gastrointestinal 
obstruction, gastrointestinal perforation, hand and foot syndrome, hearing loss, 
heart failure, hepatitis, hypertension, ileus, intestinal pneumonia, ischemic 
colitis, lacrimal duct obstruction, loss of consciousness (transient), MI, 
multiorgan failure, Myelodysplastic syndrome, neutropenic enterocolitis, 
ototoxicity, pleural effusion, pruritus, pulmonary edema, pulmonary embolism, 
pulmonary fibrosis, radiation pneumonitis, radiation recall, renal insufficiency, 
seizure, sepsis, sinus tachycardia, Stevens-Johnson syndrome, syncope, toxic 
epidermal necrolysis, tachycardia, thrombophlebitis, unstable angina, visual 
disturbances (transient) 
 
15.18 Nursing guidelines - 
 
 
15.181 Monitor CBC closely, as neutropenia, and thrombocytopenia are common 
and may be life threatening, and dose limiting.  Instruct patient to report any 
signs or symptoms of infection, any unusual bruising, or bleeding.  
 
15.182  Administer antiemetics as ordered. Evaluate for their effectiveness. 
 
15.183  Monitor for signs/symptoms of hypersensitivity reactions that may include 
chills, rigors, dyspnea, bronchospasms, etc.  Stop infusion immediately and 
administer proper emergency treatment. 
 
15.184  Because of the risk of anaphylaxis and development of edema, instruct 
patient that is imperative to take steroid premedications as ordered.  
 
15.185  Instruct patient on proper oral care, as mucositis may occur. 


 
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15.186 Advise patient about alopecia. 
 
15.187 Monitor liver function tests. 
 
15.188  Drug is a vesicant.  Monitor infusion site frequently for signs of irritation or 
infiltration.  Drug extravasation causes acute streaking, burning pain, and 
discoloration at the site.  Skin may be reddened for several weeks and 
occasionally blister and/or peel.  Reactions are usually reversible over time.   
Because of this central venous access may be necessary.  Discuss with MD if 
patient has poor peripheral venous access.  If docetaxel concentrate or 
diluted solution comes into contact with skin, wash with soapy water 
immediately.  If it comes into contact with mucosa, wash with warm water 
immediately. 
 
15.189a Instruct patient to report any signs of peripheral neuropathy to the health 
care team (pain, numbness, tingling). 
 
15.189b Monitor for signs and symptoms of fluid retention, weight gain, ascites and 
CHF. 
 
15.189c Instruct patient about possible facial flushing, rash, and skin and nail 
changes.  Monitor for signs and symptoms of hand/foot syndrome. However 
premedication with steroids can minimize this side effect.  Discuss with MD 
possible ways to manage itching and skin changes that may occur up to a 
week after docetaxel administration.  Advise patients that nails may crack, 
peel, or fall off all together. This may be a chronic toxicity.  Instruct patient 
to keep nails clean, short and to avoid wearing nail polish or artificial nails. 
 
15.189d In case of overdose, patient should be hospitalized and vital signs monitored.  
Patient should receive therapeutic G-CSF ASAP after discovery of the 
overdose.   
 
 15.2 
Cisplatinum (Cisplatin®) Commercial Supply. Refer to the package insert for 
detailed pharmacologic and safety information. 
 
15.2.1  Formulation: Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 
100 mg of mannitol,and hydrochloric acid for pH adjustment. One vial is 
reconstituted with 10 ml of sterile water. The pH range will be 3.5 to 4.5. 
Cisplatin injection also is available from the manufacturer in aqueous 
solution, each ml containing 1 mg cisplatin and 9 mg NaCl and HCL or 
NaOH to adjust pH. 
 
15.2.2  Mechanism of Action: The dominant mode of action of cisplatin appears to 
be inhibition of the incorporation of DNA precursors, although protein and 
RNA synthesis are also inhibited. Although this drug seems to act as an 
alkylating agent, there are data to indicate that its mode and sites of action 
are different from those of nitrogen mustard and the standard alkylating 
agents. 


 
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15.2.3 
Administration: After administering appropriate antiemetics, cisplatin will 
be infused over 1-2 hours or according to institutional guidelines along with 
vigorous hydration.  
 
15.2.4  Storage and Stability: Reconstituted solution of cisplatin is stable for 20 
hours when stored at 27°C and should be protected from light if not used 
within 6 hours. The vials and injection should not be refrigerated. Cisplatin 
has been shown to react with aluminum needles, producing a black 
precipitate within 30 minutes.  
 
15.2.5 
Adverse 
Events: 
Human 
toxicity 
includes 
nausea, 
vomiting, 
anaphylaxis,neuropathies, ocular disturbances, renal toxicity (with an 
elevation of BUN and creatinine and impairment of endogenous creatinine 
clearance, as well as renal tubular damage, which appears to be transient), 
ototoxicity (with hearing loss that initially is in the high-frequency range, as 
well as tinnitus), and hyperuricemia. Much more severe and prolonged 
toxicity has been observed in patients with abnormal or obstructed urinary 
excretory tracts. Myelosuppression, often with delayed erythrosuppression, 
is expected. 
 
15.2.6  Supply: Cisplatin is commercially available. The use of drug(s) or 
combination of drugs in this protocol meets the criteria described under 
Title 21 CFR 312.2(b) for IND exemption. 
 
 
15.3 
Neck radiation 
 
 
 
15.31 Nursing guidelines 
 
 
 
 
15.211 Assess for increased fatigue.  Instruct patient in energy saving lifestyle. 
 
 
 
 
15.213 Monitor for nutritional status.  Advise patient accordingly. 
 
 
 
 
15.214 Assess for skin reaction. 
 
15.215 Assess for possible mouth/throat soreness, dry mouth, thick secretions, 
nausea, and treat as necessary. 
 
16.0  
Statistical Considerations and Methodology  
 
This study will have two stratification factors (intermediate vs high risk and no vs yes smoking history) which 
will be used for randomization.  In addition to the primary statistical analysis, pre-planned sub-group analyses 
for each stratification factor comparing DART to standard adjuvant therapy will be independently evaluated 
for all the endpoints described below. 
 
16.1  
Overview:  This phase III study will compare DART with standard adjuvant therapy.  
Standard therapy for this disease yields a 2-year cumulative incidence of local/regional 
failure of approximately 10%, but it also has high rates of grade 3 or worse adverse events.  
Given the high rates of severe or worse adverse events (AEs), it is of high interest to find a 


 
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chemo/RT combination that can still yield low rates of local/regional failure with reduced AE 
rates.  Preliminary data from our phase II study, MC1273, suggests that local/regional control 
with dose de-escalated adjuvant radiation therapy (DART) is at least equivalent to historical 
control rates and rates of grade 3 or higher AEs are substantially better.  We seek to 
conclusively demonstrate the superiority of DART over standard therapy in terms of chronic 
AEs.  Based upon historical Mayo data, the rate of chronic grade 3 or higher AEs after 
standard treatment attributable to radiation therapy is 25%.  Based upon preliminary MC1273 
data, the rate of chronic grade 3 or higher late AEs (> 3 months) after DART attributable to 
radiation therapy is around 2%.   
 
16.2 
Late AE Primary Endpoint: 186 eligible patients (124 DART vs. 62 standard treatment) 
will be randomized in a 2:1 fashion, unless the study is stopped early.  With this sample size, 
we have 90% power to detect a reduction in the grade 3+ late AE rate (> 3 months) from 
around 25% to 7%, with a 2-sided significance level of 0.05.  The hypothesis is that the 
DART treatment will reduce the grade 3 or higher AE rate significantly as compared to 
standard treatment.  Final analysis would need p-value <= 0.05 to reject Ho hypothesis and 
conclude that active treatment had significant reduction in grade 3 or higher AE rate.  Since 
the difference in accumulated chronic toxicity rates between DART and standard therapy is 
expected to be highest at two years following adjuvant therapy, we will assess AEs out to 2 
years.   
 
 
16.3 
Total Sample Size:  This study will randomize 186 eligible patients (124 DART vs. 62 
standard).  To account for possible dropouts, cancellations, and ineligibles, we plan to 
randomize 214 total patients (148 vs. 74) and screen 256 patients.  The combined Head and 
Neck services of Mayo Clinic Rochester and Arizona saw approximately 200 patients eligible 
for this study in 2015.  Assuming even a modest accrual rate, we anticipate being able to 
finish accrual in three years.  Total follow-up for this study will be five years after completion 
of therapy.  Total study duration will therefore be for eight years. 
 
16.4 
Secondary Endpoints: 
 
• 
To assess the cumulative incidence of local/regional failure at 2 years after study registration.  
All patients meeting the eligibility criteria who have signed a consent form, and begun 
treatment will be considered evaluable for the 2-year cumulative incidence rate.   
o The 2-year cumulative incidence of local/regional failure will be estimated by the 
competing risk method (Gooley, et al.), where the competing risks are distant failures 
and deaths from other causes (i.e. deaths from distant failure or non-Oropharynx 
Cancer).   
 
o Local/Regional Failure Analysis for First 10 Smokers Randomized to DART: 
Our pilot study (MC1273) only included non-smokers for treatment with DART.  
Though published reports suggest that locol/regional control rates between smokers 
and non-smokers are equivalent following radiation therapy, the application of 
DART to a HPV-associated smoking population will nonetheless be novel.  The first 
10 smokers who are randomized to DART will be evaluated for local/regional 
control.  If three or more of these ten patients have a local or regional failure by the 
6-month post-radiation time-point, the radiation dose for this group may be modified.  
Accrual will continue while we wait for these first 10 smokers to be followed for a 


 
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minimum of six months.  As long as the radiation dose remains the same, these first 
10 smokers will be included in the final analysis as well. 
 
o Interim Analysis at around the halfway point (after first 99 patients enrolled): 
At nearly the halfway point for accrual (99 patients), we plan to conduct an interim 
analysis for the Local/Regional Failure rate in the DART patients.  At 6-months post-
treatment, we will estimate the local/regional control rate and if the confidence 
interval contains 95% for DART treatment, we will continue to full accrual.  The 
current standard of care has a local/regional control rate of around 95% at 6-months.  
With 99 patients, we’d expect 66 to be DART treated.  Of those, we hope that at least 
55 will be eligible for analysis.  With 55 DART treated patients, we’d need to 
observe an LRC rate of at least 86% (95% CI: 77-95%) to continue to full accrual.   
 
• 
To compare overall survival, disease-free survival, and distant failure associated with DART 
vs standard treatment.   All patients meeting the eligibility criteria who have signed a consent 
form, and begun treatment will be considered evaluable for these endpoints.   
 
o Overall survival:  Overall Survival (OS) is defined as the time from randomization to 
death from any cause.  OS will be estimated using the Kaplan-Meier method, where 
the log-rank test will be used to compare the 2 treatment arms. 
 
o Disease-free survival:  Disease-free survival (DFS) is defined as the time from 
randomization to the first of either disease recurrence or death from any cause.  DFS 
will be estimated using the Kaplan-Meier method, where the log-rank test will be 
used to compare the 2 treatment arms. 
 
o Distant Failure Rates:  The 2-year cumulative incidence of distant failure will be 
estimated by the competing risk method (Gooley, et al.), where the competing risks 
are local/regional failures and deaths from other causes (i.e. deaths from 
local/regional failure or non-Oropharynx Cancer).  
 
• 
Quality of Life (QOL): The patient QOL will be measured and compared between the 
treatment arms using the following tools:   1) XeQOLS form, 2) Eq-5D, 3) FACT H & N 
(Version 4), 4)  Dermatology Life Quality Index; and QLQ H&N35 (see QOL Booklet).  
These QOL measures will be assessed at baseline, 1 month post-XRT and 3, 12 and 24 
months post-XRT.  These QOL scores will be compared between arms to detect patterns and 
substantial changes over time. In addition, differences between post-baseline and baseline 
QOL scores will be compared between arms using a 2-sample t-test or the nonparametric 
equivalent to see if the QOL differs between treatment arms.     
o  NOTE: All survey responses will be reviewed by the study coordinator at the time of 
completion.  If participants self-report negative social-emotional symptoms of 
depression while completing the initial or follow-up survey, a member of the study 
staff will share the responses with a member of the participants care team who will 
determine whether the individual should be referred for additional support.  
 
• 
Swallowing Studies:  Swallowing will be scored (yes, no) for aspiration, penetration, 
velopharyngeal incompetence, epiglottic everson, tongue base retraction, and pharyngeal 
swallow response using the metric outlined by Eisbruch et al.  (Eisbruch A, Teresa L, 
Bradford CR, et al.)  Swallowing assessments will be completed at baseline, along with 1and 


 
41  
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12 months after the completion of protocol XRT.  The swallowing questions will be explored 
descriptively to detect patterns and substantial changes over time between arms.  
 
 
16.5 
Translational studies:  
• 
To determine the genetic alterations of oropharynx tumor specimens and the 
detection rate of corresponding tumor DNA in the pre-surgical, post-surgical, and 
post-radiation blood of oropharynx cancer patients.   
 
• 
To investigate the usefulness of immunologic biomarkers in predicting progression 
free survival. 
 
• 
To establish a patient derived xenograft panel from representative oropharynx 
patients. 
 
 
16.6 
Data & Safety Monitoring: 
 
16.61   The principal investigator(s) and the study statistician will review the study at least 
twice a year to identify accrual, adverse event, and any endpoint problems that might 
be developing.  The trial is monitored continually by the study team who are notified 
of every grade 4 and 5 event in real time.  The Mayo Clinic Cancer Center (MCCC) 
Data Safety Monitoring Board (DSMB) is responsible for reviewing accrual and 
safety data for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office.  Any safety issues requiring protocol changes are communicated 
through protocol amendments.   
 
16.62    Adverse Event Stopping Rules:   The stopping rules specified below are based on  
knowledge available at study development.  We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the treatment(s) 
under investigation.  The study team may choose to suspend accrual because of 
unexpected adverse event profiles that have not crossed the specified rule below. 
 
Based on data from previous studies, we expect about 20-25% of patients to 
experience Grade 3 or higher non-hematologic adverse events within 1 month post-
treatment.  Accrual will be temporarily suspended to this study if at any time we 
observe adverse events that satisfy any of the following criteria for each treatment 
arm separately: 
 
• 
If at any time 8 or more patients in the first 20 treated patients experience a 
Grade 3 or 4 non-hematologic adverse event (at least possibly related to 
treatment). 
• 
If at any time 2 or more Grade 5 events occur in the first 20 treated patients 
(at least possibly related to treatment). 
• 
If after the first 20 patients have been treated:  
o 40% or more of all patients experience a Grade 3 or 4 non-
hematologic adverse event (at least possibly related to treatment).   
 


 
42  
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o 10% or more of all patients experience a Grade 5 adverse event (at 
least possibly related to treatment). 
 
We note that we will review all Grade 5 adverse events on a case-by-case basis as 
well (regardless of attribution), and may suspend accrual after just one Grade 5 event, 
if we feel it is necessary for patient safety. 
 
16.7 
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
(i.e., “Outcome Measures”) along with other required information for this study will be 
reported on ClinicalTrials.gov.  For purposes of timing of the Results Reporting, the initial 
estimated completion date for the Primary Endpoint of this study is 60 months after the study 
opens to accrual. The definition of “Primary Endpoint Completion Date” (PECD) for this 
study is when the last patient registered has been followed for at least 2 years for the AE 
primary endpoint.   
 
16.8 
Inclusion of Women and Minorities 
 
16.81  This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.82  There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender groupings, 
the sample size is not increased in order to provide additional power for subset 
analyses. 
 
16.83   The geographical region served by the Mayo Clinic, has a population which includes 
approximately 15% minorities.  We expect about 15% of patients will be classified as 
minorities by race and about 50% of patients will be women. Expected sizes of racial 
by gender subsets are shown in the following table: 
  
 
 
 
 
 
 
Accrual Estimates by Gender/Ethnicity/Race for All Phase II and III Studies 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
5 
5 
10 
Not Hispanic or Latino 
106 
106 
212 
Ethnic Category: Total of all subjects* 
111 
111 
222 


 
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Racial Category 
American Indian or Alaskan Native 
2 
1 
3 
Asian 
7 
7 
14 
Black or African American 
7 
7 
14 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
94 
95 
189 
Racial Category: Total of all subjects 
111 
111 
222 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


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17.0  
Pathology Considerations/Tissue Biospecimens   
 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of Tissue 
to Collect 
Block, Slides, 
Core, etc. (# of 
each to 
submit) 
Prior to 
Radiation 
Treatment 
At time of 
Failure 
(if 
applicable) 
Process at 
site? 
(Yes or 
No) 
Temperature 
Conditions for 
Storage/ 
Shipping 
Tumor Genetic 
Analyses 
Optional 
FFPE\fresh 
frozen 
2 to 6 curls 
X 
X 
Yes 
Ambient 
(FFPE), -80 
(fresh frozen) 
Patient-derived 
xenograft panel 
Optional 
Fresh 
2-6 mg 
X 
X 
Yes 
Ambient 


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17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
 
 
 
Either 2-6 FFPE tissues curls, samples from fresh frozen tumor, and/or fresh tumor specimen 
will be collected from original tumor biopsy, tumor removed during surgery, or recurrent 
tumor specimens. This tissue will be used for determining tumor-specific genetic alterations 
and/or for establishing a patient-derived xenograft panel. 
 
17.3 
Correlative Tissue Collection  
 
 
17.31 Tissue Kits will not be provided for this protocol. 
 
17.32 Frozen Tissue 
 
 
17.321 
Frozen tissue will be collected at time of primary surgery and also at 
time of surgery for recurrent disease if applicable. 
 
17.322  
Samples will be directed to 
 on dry ice.  An email 
 
 
notification should be sent
 so that tissue 
 
 
sample can be picked up.  Samples will then be stored in a -150ºF at: 
 
 
 
 
 
 
 
 
 
17.33 Fresh Tissue 
 
17.331  
Fresh tissue will be collected at time of primary surgery and also at 
  
 
 
time of surgery for recurrent disease if applicable.  
 
17.332  
Samples should be directed to 
, and should be placed 
 
 
into DMEM in 50 ml tubes.  
 
 
 
 
 
 
 
17.4 
Methodology 
 
17.4.1 Mutational Analyses: Genetic alterations from tumor specimens will be 
 
sequenced using formalin-fixed paraffin-embedded or fresh frozen samples to  
determine prognostic and/or predictive biomarkers.  Techniques utilized may include 
mate-pair sequencing, whole exome sequencing, whole genome sequencing, whole 
transcriptome sequencing, or focused exome sequencing. 
 
17.4.2 Patient Derived Xenograft (PDX): PDX models for representational oropharynx 
tumors from smokers, non-smokers, and recurrent disease may be established for 
upwards to 50 samples using techniques outlined by Stein et al (PLoS One, 2014 Jun 
26;9(6):e100995.) 
 
 
18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
 
 
 


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Pre-Registration Material(s) 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
Pre-Registration Screening Failure Form 
Complete only if patient is NOT registered after he/she is pre-
registered 
Research Blood Submission  
 
≤30 days after pre-registration 
  
 
Initial Material(s) -  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Pre-Registration Eligibility checklist 
 
≤2 weeks after registration 
Baseline Adverse Events Form 
OP and Path Reports (see Section 17.0) 
Baseline Swallowing Function Assessment 
Form 
≤2  weeks after registration but prior to treatment 
Pathology Assessment Form 
≤7 weeks prior to treatment 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire Booklet 
≤2 weeks after registration but prior to treatment- Patient 
questionnaire booklet must be used; copies are not acceptable 
for this submission. 
Patient Questionnaire Booklet Compliance 
Form 
This form must be completed only if the patient Questionnaire 
Booklet contains absolutely NO patient provided assessment 
information. 
Patient Assessment Form 
≤2 weeks after registration 
Research Blood Submission 
≤2 weeks after registration 
 
Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
 
Observation 
 
Evaluation/Treatment Form 
X 
X 
 
Adverse Events Form 
X 
X 
X 
Disease Status Form4 
X 
X 
X 
End of Active Treatment/Cancel Notification 
Form 
 
X 
 
Evaluation/Observation Form 
 
 
X 
Swallowing Function Assessment Form 
 
 
X3 


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CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
 
Observation 
 
Patient Questionnaire Booklet 
 
 
X1 
Patient Questionnaire Booklet Compliance 
Form 
 
 
X2 
Patient Assessment Form 
 
 
X5 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form 
At each occurrence 
(see Section 10.0) 
 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
Research Blood Submission  
 
 
X6 
1. At 14 days post-XRT, and 1, 3, 12, and 24 months from the end of radiation treatment.  Patient 
questionnaire booklet must be used; copies are not acceptable for this submission. 
2. This form must be completed ONLY if the patient questionnaire contains absolutely NO patient provided 
assessment information. 
3.  One month post treatment, and one year post treatment (see section 4.0) 
4. As needed to report NED or disease recurrence.  
5. At 14 days post-XRT, and 1, 3, 12 and 24 months post-XRT. 
6. This will only occur 3 months post-XRT 
 
 
Follow-up Material(s)  
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the MCCC Operations Office, Attention: 
QAS for MC1273. 
 
 
18.8 
Data Handling and Record Keeping 
 
18.81 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the 
subject of the following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
CRF 
Event Monitoring Phase1 
 
 
q. 6 months 
until recurrence 
 
 
 
At 
recurrence  
 
After 
recurrence 
q. 6 mos. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring Form 
X2 
X2 
X 
X 
At each occurrence 


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• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their 
PHI.  
(This information is contained within the Mayo IRB Informed Consent Template 
Section 14) 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (long 
term survival status that the subject is alive) at the end of their scheduled study period. 
 
18.82 Source Documents 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data are contained in source documents.  Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. Source documents are kept in a secure location that is locked and 
requires approved access.  
 
18.83 Case Report Forms  
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”.  If the item is not applicable to the individual 
case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry 
error has been made, to correct such an error, draw a single straight line through the 
incorrect entry and enter the correct data above it.  All such changes must be initialed 
and dated.  Do not erase or use “white-out” for errors.  For clarification of illegible or 
uncertain entries, print the clarification above the item, then initial and date it.  If the 
reason for the correction is not clear or needs additional explanation, neatly include 
the details to justify the correction. Note what the data management system is that 
houses the CRFs. 
 
 
18.84 Data Management  
 
All data will be entered into electronic case report forms (eCRF’s) through the 
Medidata Rave system. Case report forms will be automatically rolled out based on a 
predetermined, and visit based schedule to improve study staff workflow and data 
quality. Data will be exported nightly to a secure FTP for analysis and reporting.  
 
 
 
 
18.85 Data Quality Assurance and Clarification Process 
 
Each eCRF will contain edit checks and custom functions to ensure the highest 
possible data quality. Only necessary eCRF’s will be available for data entry to reduce 
the possibility of erroneous entry.   


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The edit checks and custom functions on the eCRF’s will trigger queries requesting 
the attention  
of appropriate study staff. The fields will be marked in pink to allow 
study staff to quickly identify the data fields that require attention or actions. 
Additionally, secure email notifications will be sent for adverse event tracking and 
monitoring.  
 
 
 
18.86 Records Retention 
The investigator will maintain records and essential documents related to the conduct 
of the study. These will include subject case histories and regulatory documents. 
 
The investigator will retain the specified records and reports for; 
1. 
 
   
 
19.0  
Study Finances 
 
This study is funded through Mayo Clinic Institutional funds. 
 
 
19.1 
Costs charged to patient:  Routine clinical care 
 
 
19.2 
Tests to be research funded:  Research blood draws, Sample Collection. 
 
 
 
19.3 
Patient expenses which will be reimbursed:   
 
Adjuvant therapy with DART under our pilot study (MC1273) proved to be extremely popular among 
both patients and outside hospital physicians.  Many patients referred to the Mayo Clinic from distant 
facilities specifically for the purpose of participating in DART on study.  Furthermore, many patients 
who would have been logistically unable to stay in Rochester for 6 weeks under standard therapy have 
been willing to stay for a shortened two-week therapy course.  In our clinical experience, however, 
when patients who refer from the outside have been unable to participate in DART due to exclusion 
criteria, many have been unable to remain for the standard six weeks of therapy.  As the six-week 
treatment course is available closer to home, many returned to their home institutions for therapy.  
This situation was further compounded by the fact that radiation side effects requiring supportive care 
usually begin around the three week time point.  The additional supportive requirements for patients 
undergoing standard treatment translated into additional costs and expenses for a caretaker as well.  
Although patients generally wish to stay at Mayo for the excellence of clinical care, the additional 
time, inconvenience and expense required from a prolonged therapy course were more than many 
families could logistically endure.   
 
Since the current trial will be a randomized trial between DART (two weeks) and standard adjuvant 
treatment (six weeks), the logistical difficulties underlying a six week therapy course pose a particular 
challenge to the standard course arm.  While out-of-town patients have historically demonstrated 
willingness to logistically support a two week treatment, many out-of-town patients have also been 
historically unable to support a six-week treatment course.  If this pattern continues on the current trial, 
we would expect that our six-week treatment arm will be overly enriched with wealthy patients who 
are able to afford staying in Rochester for an extended period. Not only would this be unequitable for 
patients with lesser means, this self-selection would undermine the randomization process and disrupt 
the demographics of the study. 
 


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In order to support patients for the additional expenses and inconvenience associated with an 
additional four weeks of care, we will reimburse each subject randomized to the six-week course of 
treatment for additional meals and incidental travel expenses related to the extended period of stay at 
Rochester.  Lodging will be available through the Hope Lodge and will not require coverage.  
Reimbursement will be based upon receipts and upwards to $1000 per subject. 
 
 
20.0 
Publication Plan 
 
The principal investigators hold primary responsibility for publication of the results of this study and 
approval from the principal investigators must be obtained before any information can be used or 
passed on to a third party.   
 
 
 


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21.0 
References  
 
1. 
R. L. Siegel, K. D. Miller, A. Jemal, Cancer statistics, 2015. CA Cancer J Clin 65, 5 (Jan-Feb, 2015). 
2. 
A. K. Chaturvedi et al., Human papillomavirus and rising oropharyngeal cancer incidence in the 
United States. J Clin Oncol 29, 4294 (Nov 10, 2011). 
3. 
E. M. Sturgis, P. M. Cinciripini, Trends in head and neck cancer incidence in relation to smoking 
prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer 110, 1429 
(Oct 1, 2007). 
4. 
A. P. Stein et al., Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic 
Review. Cancer J 21, 138 (May-Jun, 2015). 
5. 
A. P. Stein, S. Saha, M. Yu, R. J. Kimple, P. F. Lambert, Prevalence of human papillomavirus in 
oropharyngeal squamous cell carcinoma in the United States across time. Chem Res Toxicol 27, 462 
(Apr 21, 2014). 
6. 
J. D. Combes, A. A. Chen, S. Franceschi, Prevalence of human papillomavirus in cancer of the 
oropharynx by gender. Cancer Epidemiol Biomarkers Prev 23, 2954 (Dec, 2014). 
7. 
K. K. Ang et al., Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J 
Med 363, 24 (Jul 1, 2010). 
8. 
A. M. Hong et al., Human papillomavirus predicts outcome in oropharyngeal cancer in patients 
treated primarily with surgery or radiation therapy. Br J Cancer 103, 1510 (Nov 9, 2010). 
9. 
J. Bernier et al., Defining risk levels in locally advanced head and neck cancers: a comparative 
analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and 
RTOG (# 9501). Head Neck 27, 843 (Oct, 2005). 
10. 
V. Moiseenko et al., Treatment planning constraints to avoid xerostomia in head-and-neck 
radiotherapy: an independent test of QUANTEC criteria using a prospectively collected dataset. Int J 
Radiat Oncol Biol Phys 82, 1108 (Mar 1, 2012). 
11. 
T. Rancati et al., Radiation dose-volume effects in the larynx and pharynx. Int J Radiat Oncol Biol 
Phys 76, S64 (Mar 1, 2010). 
12. 
R. K. Funk et al., Risk factors for locoregional relapse after transoral robotic surgery for human 
papillomavirus-related oropharyngeal squamous cell carcinoma. Head Neck,  (Dec 15, 2015). 
13. 
G. Gao et al., Mate pair sequencing of oropharyngeal squamous cell carcinomas reveals that HPV 
integration occurs much less frequently than in cervical cancer. J Clin Virol 59, 195 (Mar, 2014). 
14. 
S. J. Dawson et al., Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J 
Med 368, 1199 (Mar 28, 2013). 
15. 
A. Esposito et al., Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical 
perspectives and research opportunities. Cancer Treat Rev 40, 648 (Jun, 2014). 
16. 
W. D. Figg, 2nd, J. Reid, Monitor tumor burden with circulating tumor DNA. Cancer Biol Ther 14, 
697 (Aug, 2013). 
17. 
G. Gao, D. I. Smith, Mate-Pair Sequencing as a Powerful Clinical Tool for the Characterization of 
Cancers with a DNA Viral Etiology. Viruses 7, 4507 (Aug, 2015). 
 
 
 


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Appendices 
 
Appendix I 
 
ECOG PERFORMANCE STATUS 
 
Grade 
 
0  
Fully active, able to carry on all pre-disease 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, e.g., 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 percent of waking hours   (Karnofsky 50-60). 
 
3  
Capable of only limited self-care, confined to bed or chair 50 percent 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). 
 
5  
Dead 
 


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Appendix II 
 
 
Guidelines for the use of IMRT  
 
 
1. 
For all patients, as outlined in Section 7.0, the prescription isodose must cover 98% of the PTV 
volume for standard therapy and 100% of the PTV volume for DART.  If the minimum dose falls 
below these parameters, an unacceptable deviation will be assigned.  The maximum dose for the PTV 
should not exceed 115%.  If the maximum doses exceed these parameters, an unacceptable deviation 
will be assigned. 
 
2. 
Radiation breaks, if necessary, should not exceed one treatment day on DART or two days on 
standard therapy.  Radiation breaks should be allowed only for resolution of severe acute toxicity 
and/or for intercurrent illness and not for social or logistical reasons. Any radiation break(s) 
exceeding one treatment day for reasons other than toxicity/illness/technical issues will be considered 
a major protocol deviation.   
 
 
 
 
 
 
 


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Appendix III 
 
Radiation Therapy Quality Control Guidelines 
 
 
1. 
Tumor Volume Coverage 
a. 
No deviation -- coverage + < 1 cm of specified. 
b. 
Minor deviation -- coverage + > 1 to 2 cm of specified or failure to cover tumor volume + > 
1/2 specified margin. 
c. 
Major deviation -- > 2 cm of specified or no CT and/or MRI scans available to assess 
treatment volume appropriateness (if not initially available should be requested) or failure to 
cover the target (tumor or tumor + edema) as defined in the protocol. 
 
2. 
Isodoses - initial volume isodose plots are required on a minimum of three contours; one at central 
axis (CA), one superior to CA (2 cm below the superior field edge) and one inferior to CA (2 cm 
above the inferior field edge).  Boost volume isodose plot required at CA. 
  a. 
No deviation -- isodoses submitted as required, and inhomogeneity across the target volume 
shall be no greater than + 5%. 
*b. 
Minor deviation -- isodose information incomplete or inhomogeneity across the target volume 
> 5 but < 10%. 
*c. 
Major deviation -- no isodoses submitted or inhomogeneity across the target volume > 10%. 
 
* Deviations would occur only if isodose information is incomplete or not submitted after there has 
been a request to submit complete isodose information. 
 
3. 
Normal Tissues 
 
Normal structures are only to be included within the radiation field in as much as this is necessary to 
treat the primary tumor volume.  A minor deviation will result when normal structures are 
unnecessarily included, but this is not felt to result in unacceptable toxicity that would interfere with 
the scientific aims of the protocol.  A major deviation will result when normal structures are 
unnecessarily included in the radiation therapy field and such inclusion is felt likely to result in a 
major increase in toxicity which would potentially compromise the scientific goals of the study. 
 
4. 
Other parameters: (dose per fraction, total dose, overall treatment time and portal films). 
a. 
No deviation -- +/- < 5% of protocol specification. 
b. 
Minor deviation -- +/- > 5% to 10% of protocol specification. 
c. 
Major deviation -- +/- > 10% of protocol specification or incomplete data (i.e. no portal or 
sim films, etc.) available for review (after additional request has been made). 
 
5. 
Any individual minor deviation will result in an overall score of minor deviation; any major deviation 
will result in an overall score of a major deviation.  Multiple minor deviations will not add up to a 
major deviation. 


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Appendix IV 
 
Known inducers & inhibitors of isoenzyme CYP3A4 
 
 
Page 1 of 1 
 
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole  
 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
 
 
 


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Appendix V 
 
Patient Assessment Form 
 
 
 
INSTRUCTIONS: 
This form is completed by the investigator (rater) and submitted at each 
time point specified by the protocol, whether or not any of the patient 
assessment items (Q's 6,7,8) are answered. 
 
 
SUGGESTIONS FOR ADMINISTRATION: 
These performance scales must be rated by health professionals such as 
physicians, nurses, nutritionists, etc. Ratings are determined through use 
of  an unstructured interview format. 
 
1 
SCHEDULED DATA POINT (CHECK ONE)(1) 
1 = Pre- treatment assessment 
2 = At completion of radiotherapy 
3 = Four weeks followup 
4 =   
other followup (specify calendar date or followup 
interval, e.g., 3 months, 2 years, etc.)(2) 
5 = Other, specify  
(3) 
 
2 
IF NO PATIENT ASSESSMENT, SPECIFY REASON (CHECK ONE)(4) 
0 = Not applicable, questionnaire was completed 
1 = Patient was too ill 
2 = Patient unable to be contacted 
3 = Questionnaire not completed due to institutional error 
4 = Patient refused, including attempts by 
telephone interview, specify reason for refusal 
_________________________________________(5) 
5 = Patient refused, telephone interview not 
attempted, specify reason for refusal 
__________________________________________(6) 
6 = Other reason, specify 
__________________________________________(7) 
 
3 
WAS INFORMATION OBTAINED BY TELEPHONE INTERVIEW 
 
(CHECK ONE)(8) 
1 = No 
2 = Yes 
 
4 
  
-  
-  
DATE OF EVALUATION(9) 
 
5 
RATER'S NAME  
(10) 
 
 
 
 
 
COMMENTS(14)______________________________________
___________________________________________________  
 
6 
NORMALCY OF DIET (CHECK ONE) RATING(11) 
Begin by asking the patient what kind of foods are difficult for him/her 
to eat.  Based on patient's response, choose an item at the low end of 
the scale.  Move up the scale giving examples of foods in each 
category and ask patient if s/he can eat those food items.  The 
patient's score is the highest number to which an affirmative response 
is received. 
100 = Full diet (no restrictions) 
90 = Peanuts 
80 = All meat 
70 = Carrots, celery 
60 = Dry bread and crackers 
50 = Soft, chewable foods (e.g., macaroni, canned/soft fruits, 
cooked vegetables, fish, hamburger, small pieces of meat) 
40 = Soft foods requiring no chewing (e.g., mashed 
potatoes, apple sauce, pudding) 
30 = Pureed foods (in blender) 
20 = Warm liquids 
10 = Cold liquids 
0 = Non-oral feeding (tube fed) 
 
7 
PUBLIC EATING (CHECK ONE) RATING(12) 
Score the Public Eating scale by asking the patient where s/he eats, 
with whom s/he eats and whether s/he alters his/her diet according to 
where s/he is eating.  Choose the score beside the description that 
best fits the patient. 
100 = No restriction of place, food or companion (eats out 
at any opportunity) 
75 = No restriction of place, but restricts diet when in public (eats 
anywhere, but may limit intake to less "messy" foods, e.g., liquids) 
50 = Eats only in presence of selected persons in selected places 
25 = Eats only at home in presence of selected persons 
0 = Always eats alone 
 
8 
UNDERSTANDABILITY OF SPEECH (CHECK ONE) RATING(13) 
This scale is scored based on the interviewer's ability to understand the 
patient during conversation (in this case, based on conversation regarding 
the Normalcy of Diet and Public eating scale. Choose the score beside the 
description that best fits the patient. 
 
100 = Always understandable 
75 = Understandable most of the time; occasional 
repetition necessary 
50 = Usually understandable; face-to-face contact necessary 
25 = Difficult to understand 
0 = Never understandable; may use written communication
 
 


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Appendix VI 
 
QOL 
Patient Information Sheet 
 
You have been given a booklet to complete for this study.  The booklet contains some questions about your 
‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to better understand 
how the treatment you are receiving is affecting the way you feel. 
 
1. 
This booklet contains the EORTC-QLQ H&N 35 form, the FACT H & N (Version 4), the XeQOLS 
form, the Dermatology Life Quality Index form, and the EQ-5D form. 
 
2. 
Directions on how to complete each set of questions are written at the top of each set. 
 
3. 
You will be given the nurse’s name and telephone number.  You can call them any time with 
 
any concerns or questions. 
 
4. 
It is very important that you return the booklet with us, whether you finish the study or not. 
 
 
Please complete and return to the study staff as soon as possible. 
 
Thank you for taking the time to help us. 


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EORTC  QLQ - H&N35 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. Please answer 
by circling the number that best applies to you. 
 
During the past week: 
Not 
at all 
A 
little 
Quite 
a bit 
Very 
much 
31. 
Have you had pain in your mouth? 
1 
2 
3 
4 
32. 
Have you had pain in your jaw? 
1 
2 
3 
4 
33. 
Have you had soreness in your mouth? 
1 
2 
3 
4 
34. 
Have you had a painful throat? 
1 
2 
3 
4 
35. 
Have you had problems swallowing liquids? 
1 
2 
3 
4 
36. 
Have you had problems swallowing pureed food? 
1 
2 
3 
4 
37. 
Have you had problems swallowing solid food? 
1 
2 
3 
4 
38. 
Have you choked when swallowing? 
1 
2 
3 
4 
39. 
Have you had problems with your teeth? 
1 
2 
3 
4 
40. 
Have you had problems opening your mouth wide? 
1 
2 
3 
4 
41. 
Have you had a dry mouth? 
1 
2 
3 
4 
42. 
Have you had sticky saliva? 
1 
2 
3 
4 
43. 
Have you had problems with your sense of smell? 
1 
2 
3 
4 
44. 
Have you had problems with your sense of taste? 
1 
2 
3 
4 
45. 
Have you coughed? 
1 
2 
3 
4 
46. 
Have you been hoarse? 
1 
2 
3 
4 
47. 
Have you felt ill? 
1 
2 
3 
4 
48. 
Has your appearance bothered you? 
1 
2 
3 
4 
 
Please go on to the next page 


 
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During the past week: 
Not 
at all 
A 
little 
Quite 
a bit 
Very 
much 
49. 
Have you had trouble eating? 
1 
2 
3 
4 
50. 
Have you had trouble eating in front of your family? 
1 
2 
3 
4 
51. 
Have you had trouble eating in front of other people? 
1 
2 
3 
4 
52. 
Have you had trouble enjoying your meals? 
1 
2 
3 
4 
53. 
Have you had trouble talking to other people? 
1 
2 
3 
4 
54. 
Have you had trouble talking on the telephone? 
1 
2 
3 
4 
55. 
Have you had trouble having social contact with your family? 
1 
2 
3 
4 
56. 
Have you had trouble having social contact with friends? 
1 
2 
3 
4 
57. 
Have you had trouble going out in public? 
1 
2 
3 
4 
58. 
Have you had trouble having physical 
contact with family or friends? 
1 
2 
3 
4 
59. 
Have you felt less interest in sex? 
1 
2 
3 
4 
60. 
Have you felt less sexual enjoyment? 
1 
2 
3 
4 
 
 
During 
61. 
the past week: 
Have you used pain-killers? 
No 
1 
Yes 
2 
62. 
Have you taken any nutritional supplements (excluding vitamins)? 
1 
2 
63. 
Have you used a feeding tube? 
1 
2 
64. 
Have you lost weight? 
1 
2 
65. 
Have you gained weight? 
1 
2 
 
 
 
 
 
 
 


 
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FACT-H&N (Version 4) 
Below is a list of statements that other people with your illness have said are important.  By circling one (1) number 
per line, please indicate how true each statement has been for you during the past 7 days. 
 
PHYSICAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
I have a lack of energy ..............................................................
0 
1 
2 
3 
4 
I have nausea .............................................................................
0 
1 
2 
3 
4 
Because of my physical condition, I have trouble meeting 
the needs of my family ..............................................................
0 
1 
2 
3 
4 
I have pain .................................................................................
0 
1 
2 
3 
4 
I am bothered by side effects of treatment ................................
0 
1 
2 
3 
4 
I feel ill ......................................................................................
0 
1 
2 
3 
4 
I am forced to spend time in bed ...............................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
I feel close to my friends ...........................................................
0 
1 
2 
3 
4 
I get emotional support from my family ...................................
0 
1 
2 
3 
4 
I get support from my friends ....................................................
0 
1 
2 
3 
4 
My family has accepted my illness ...........................................
0 
1 
2 
3 
4 
I am satisfied with family communication about my illness .....
0 
1 
2 
3 
4 
I feel close to you partner (or the person who is my main 
support) .....................................................................................
0 
1 
2 
3 
4 
Regardless of your current level of sexual activity, please 
answer the following question.  If you prefer not to answer 
it, please check this box 
 and go to the next section. 
 
 
 
 
 
I am satisfied with my sex life ..................................................
0 
1 
2 
3 
4 
 


 
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Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
I feel sad ....................................................................................
0 
1 
2 
3 
4 
I am satisfied with how I am coping  with my illness ...............
0 
1 
2 
3 
4 
I am losing hope in the fight against my illness ........................
0 
1 
2 
3 
4 
I feel nervous .............................................................................
0 
1 
2 
3 
4 
I worry about dying ...................................................................
0 
1 
2 
3 
4 
I worry that my condition will get worse ..................................
0 
1 
2 
3 
4 
 
 
FUNCTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
I am able to work (including work in home) .............................
0 
1 
2 
3 
4 
My work (include work in home) is fulfilling ...........................
0 
1 
2 
3 
4 
I am able to enjoy life ................................................................
0 
1 
2 
3 
4 
I have accepted my illness .........................................................
0 
1 
2 
3 
4 
I am sleeping well .....................................................................
0 
1 
2 
3 
4 
I am enjoying the things I usually do for fun ............................
0 
1 
2 
3 
4 
I am content with the quality of my life right now ....................
0 
1 
2 
3 
4 
 


 
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Appendix VII 
 
Recommended Symptomatic Management for Patients Randomized to DART 
 
 
The DART regimen pioneered in MC1273 utilizes a novel radiation schedule for head and neck patients and has a side 
effect profile which may be unexpected to providers who have not previously utilized this regimen.  The following 
symptomatic regimen has been found to be effective for handling treatment related side effects specific to DART.  
Patients undergoing standard therapy may follow the symptomatic regimen that the treating radiation oncologist is 
most comfortable with. 
 
In our pilot study, an unexpectedly high rate of thrush developed in the immediate post-radiation period for patients 
undergoing DART without fungal prophylaxis.  Furthermore, most patients undergoing DART are essentially pain free 
during their two week therapy course, but rapidly develop a fairly brisk mucositis lasting for about one week starting 
the day after completion of therapy.   
 
 
 
□ Fungal prophylaxis starting Day 8 (beginning of second week) of DART.  Fluconazole 100 mg po qday x 15 days 
is the recommended regimen though Nystatin may be utilized if contraindications to fluconazole exist.  Nystatin should 
be utilized at least 5 times / day x 15 days. 
 
 
□ Prophylactic narcotic pain medication.  Most patients will be essentially pain free upwards to the day of 
completion of therapy.  However, a brisk mucositis generally emerges rapidly on the afternoon of the day after 
treatment completion.  For this reason, it is recommended that all patients begin a prophylactic Fentanyl patch, 12 mcg, 
on the morning following the completion of therapy (generally Saturday morning.)  Liquid oxycodone should also be 
available for breakthrough pain relief.  Stool softeners and laxatives should also be used concurrently.  
 
 
□ IV Fluids.  Even with prophylactic pain medication, most patients have approximately three days of poor oral intake 
because of the rapid onset of odynophagia / oral pain.  We recommend having IV fluid orders on hand for the first five 
days following the completion of therapy.