Conditions: Human Papillomavirus Infection Stage I Oropharyngeal Squamous Cell Carcinoma Stage II Oropharyngeal Squamous Cell Carcinoma Stage III Oropharyngeal Squamous Cell Carcinoma Stage IVA Oropharyngeal Squamous Cell Carcinoma Stage IVB Oropharyngeal Squamous Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 81
Healthy volunteers: no

Brief summary:
This phase II trial studies how well radiation therapy and docetaxel work in treating patients with human papillomavirus (HPV)-related oropharyngeal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving radiation therapy with docetaxel my kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the cumulative incidence of local/regional failure at 2 years after study registration.

SECONDARY OBJECTIVES:

I. To characterize the rate of acute grade 3 or higher functional mucosal adverse events (up to 1 month post-radiation therapy \[XRT\]) associated with adjuvant docetaxel + hyperfractionated radiotherapy (key secondary endpoint).

II. To assess changes in overall survival, disease-free survival, distant failure rates, and quality of life (QOL) associated with adjuvant docetaxel and hyperfractionated radiation.

III. To characterize other acute adverse events (up to 1 month post-XRT) and late grade 3 or higher non-hematologic adverse events (up to 2 years post-XRT) associated with adjuvant docetaxel + hyperfractionated radiotherapy.

TERTIARY OBJECTIVES:

I. To determine the genetic alterations of oropharynx tumor specimens and the detection rate of corresponding cell-free deoxyribonucleic acid (cfDNA) in the pre-surgical, post-surgical, and post-radiation blood of oropharynx cancer patients.

OUTLINE:

Patients receive docetaxel intravenously (IV) over 1 hour on days 1 and 8 and undergo hyperfractionated intensity-modulated radiation therapy (IMRT) twice daily (BID) 5 days a week on days 1-12 for a total of 20 fractions.

After completion of study treatment, patients are followed up at 14 days, 1 month, every 3 months for 2 years, every 6 months for 1 year and then annually for 2 years.

Arms:
arm 1: Patients receive docetaxel IV over 1 hour on days 1 and 8 and undergo hyperfractionated IMRT BID 5 days a week on days 1-12 for a total of 20 fractions.

Interventions: intervention 1: Docetaxel intervention 2: Hyperfractionation intervention 3: Intensity-Modulated Radiation Therapy intervention 4: Laboratory Biomarker Analysis intervention 5: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo hyperfractionated IMRT intervention 3: Undergo hyperfractionated IMRT intervention 4: Correlative studies intervention 5: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
1 
 MC1273 
Protocol Version Date:  October 03, 2017 
 
 
 
Mayo Clinic Cancer Center 
 
MC1273, Phase II Evaluation of Adjuvant Hyperfractionated Radiation and Docetaxel for HPV 
Associated Oropharynx Cancer 
 
 
 
 
Study Chairs: 
Daniel J. Ma, M.D.  
Mayo Clinic 
200 First Street, SW 
Rochester, MN 55905 
507/284-2511 
507/284-5280 (FAX) 
 
 
 
 
 
Study Co-chairs: 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
.D. 
 
 
  
 
 
 
Statistician: 
  
 
  
 
 
Drug Availability 
 
 
Commercial Agents:  Docetaxel (Taxotere) 
 
Study contributor(s) not responsible for patient care. 
 
 
Document History 
(Effective Date) 
Activation 
September 4, 2013 
Addendum 1 
Addendum 2 
Addendum 3 
October 14, 2013 
November 27, 2013  
April 16, 2014 
Addendum 4 
Addendum 5 
Addendum 6 
November 12, 2014 
December 16, 2015 
June 12, 2016 
Addendum 7 
April 11, 2017 
Addendum 8 
November 8, 2017 
 
 
 
 


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MCCC Addendum 8 
 
Protocol Version Date:  October 03, 2017 
 
 
 
 
Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Quality Assurance Specialist 
(Phone: 
 
E-mail:
  
Drug administration, infusion pumps,  
nursing guidelines 
 
Phone:
 
E-mail: 
  
 
Forms completion and submission 
 Clinical Research Associate 
Phone:
 
E-mail:
  
 
Protocol document, consent form, 
regulatory issues 
, Research Protocol Specialist  
Phone: 
 
Email:
   
 
Adverse Events (AdEERS, MedWatch, 
Non-AER, AML/MDS) 
, SAE Coordinator 
Phone:  
 
E-mail:  
 
  


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Protocol Version Date:  October 03, 2017 
 
Index 
Schema 
  1.0 
Background  
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping Factor  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification 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 
Budget 
20.0 
References 
Consent Form  
 
Appendix I: ECOG Performance Status 
Appendix II: Guidelines for the use of IMRT (including Intra-Thoracic Treatments) 
Appendix III: Radiation Therapy Quality Control Guidelines 
Appendix IV: Known inducers & inhibitors of isoenzyme CYP3A4 
Appendix V: Patient Assessment Form 
Appendix VI – QOL Forms 
 
 
 
 
 


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Protocol Version Date:  October 03, 2017 
Schema 
 
 
 
    
 Surgery (HPV Testing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
 
Generic name:   Docetaxel 
Mayo abbreviation: Taxotere 
Availability: Commercially available 
Registration 
Observation  
(Starting 14 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 
(whatever occurs first) 
Event Monitoring 
 (follow-up per section 18) 
Grouping Factor 
 
(+/- ECE) 
No-Cohort A 
 
Cycle 1(28 days) 
 
Docetaxel 15mg/m2 days 1, 8 + RT 30 
Gy/1.5 Gy fractions bid days 1-12 only 
Yes- Cohort B 
 
Cycle 1(28 days) 
 
Docetaxel 15mg/m2 days 1, 8 + RT 36 
Gy/1.8 Gy fractions bid days 1-12 only 
Pre-Registration 
Blood Draw 


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Protocol Version Date:  October 03, 2017 
1.0 
Background   
 
1.1 
Oropharynx Cancer: Current State of Practice and Purpose of this Trial 
 
Several treatment modalities are available for patients with oropharyngeal cancer, 
including definitive surgery, definitive radiotherapy, and chemoradiation.  After 
definitive surgery, certain factors place patients at increased risk for disease recurrence.  
These patients receive either adjuvant radiotherapy or adjuvant chemoradiotherapy.  
Advances in both systemic and radiation therapy in the adjuvant setting have been 
associated with improved survival and local control.   
 
Adjuvant treatment comes at the cost of increased acute and late toxicity.  Furthermore, it 
is unclear if recent improvements in outcome can be completely attributed to the 
aggressiveness of adjuvant care.  The recent rise in the incidence of oropharyngeal 
cancers associated with human papilloma virus (HPV) have prompted a re-evaluation of 
past trial outcomes.  HPV associated oropharyngeal cancers have been demonstrated to 
be more chemo and radiation sensitive compared to non-HPV related tumors.  Large 
phase II/III studies which evaluate less morbid treatment approaches for definitive 
chemoradiation in HPV-associated patients are currently ongoing.  However, clinical 
trials designed for patients in the post-surgical setting are lacking.   
 
The overall goal of this trial is to identify a less toxic approach to HPV-associated 
cancers of the oropharynx while preserving the high survival currently associated with 
aggressive adjuvant radiation courses.  We first aim to demonstrate the feasibility of a 
novel adjuvant therapy course using low-dose, hyperfractionated radiation with 
concurrent docetaxel.  We also aim to show that low-dose, hyperfractionated 
chemoradiation will substantially reduce the burden of acute toxicity, result in faster 
recovery, carry lower rates of late effects, with similar rates of long-term survivorship 
compared with historical results from standard adjuvant care. 
 
1.2 
Role of HPV in Oropharyngeal Cancers 
 
HPV-associated cancers have been shown to be distinct from HPV-negative cancers in 
regards to risk factor profiles, molecular characteristics, treatment response, and 
prognosis.  In a meta-analysis of retrospective studies, HPV-associated oropharynx 
cancer had an estimated 50% reduction in risk of death when compared to patients with 
HPV-negative tumors.  (Dayyani F, Etzel CJ, Liu M, et al.)  This may be due to the fact that 
HPV-associated tumors are more responsive to chemotherapy and radiation.  In an ECOG 
trial prospectively evaluating the effect of tumor HPV status, HPV-associated tumors 
were found to have a higher response rate to induction paclitaxel and carboplatin when 
compared to HPV-negative tumors. (Fakhry C, Westra WH, Li S, et al.)  Similarly, an 
analysis on survival outcomes in RTOG 0129, a randomized trial where patients received 
accelerated versus standard fraction radiotherapy, patients who were HPV-associated had 
a 51% reduction in risk of progression or death compared to HPV-negative patients.  
Among HPV-associated patients, there is a further stratification of outcome based upon 
smoking status.  In a further sub-group analysis of RTOG 0129, HPV-associated patients 
who had <10 pack-year smoking history were found to have a 3 year OS of 93% 
compared with a 70.8% OS among HPV-associated patients with a >10 pack-year 
smoking history.  (Ang KK, Harris J, Wheeler R, et al.) 


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Protocol Version Date:  October 03, 2017 
 
Given these excellent results, two large clinical trials are currently investigating whether 
HPV-associated patients can be spared the long-term complications of intensive, 
multimodal therapy without compromising their survival.  RTOG 1016 is a Phase III trial 
that randomizes HPV-related oropharyngeal patients to receive definitive chemoradiation 
consisting of 70 Gy in 2 Gy fractions delivered over 6 weeks with cisplatin vs cetuximab.  
ECOG 1308 is a phase II trial that uses induction chemo followed 54 Gy in 2 Gy 
fractions with cetuximab if patients have a complete response to induction.  Patients with 
partial response receive the standard dose of 70 Gy with cetuximab.   
 
Though RTOG 1016 and ECOG 1308 both address the issue of treatment de-escalation 
for HPV-associated oropharynx patients, both trials are testing de-escalation in the setting 
of definitive chemoradiation.  There currently are no large trials testing equivalent 
strategies for de-escalating radiation for post-operative patients.   Whether HPV-
associated patients could benefit from milder treatment in the post-operative setting is 
now a highly relevant clinical question.   
 
1.3 
Adjuvant Radiation Therapy: Risk factors and Dose  
 
 
Previous retrospective trials have highlighted risk factors that place patients at increased 
risk for local recurrence and death after definitive surgery.  (Lundahl RE, Foote RL, Bonner 
JA, et al.)  These risk factors include positive margins, extracapsular extension of tumor 
from a lymph node (ECE), number of involved lymph nodes, lymph nodes larger than 3 
cm, lymphvascular space invasion (LVSI), close margins, and perineural invasion (PNI).   
 
For patients with positive margins or extracapsular extension, adjuvant radiation therapy 
plus concurrent cisplatin has historically been the standard of care.  These risk factors 
were identified as high risk on a meta-analysis of the two largest randomized trials 
addressing adjuvant radiotherapy (RTOG 9501 and EORTC 22931.)  (Bernier J, Cooper JS, 
Pajak TF, et al.)  In this analysis, patients with ECE or positive margins had a benefit to 
local control and overall survival from high dose chemoradiation.  In this joint analysis, 
however, the addition of chemotherapy to adjuvant radiotherapy did not improve overall 
survival in patients with intermediate risk factors such as 2+ lymph nodes, PNI, LVSI, or 
Stage III-IV disease.   
 
The optimal implementation of adjuvant radiotherapy in patients with only intermediate 
risk factors is less clear.  Only one prospective randomized trial opened in 1983 has 
investigated the post-operative radiation dose for these patients. (Kokal WA, Neifeld JP, 
Eisert D, et al.)  This study was limited by using outdated treatment techniques (60Co 
machines) in a patient era that was pre-HPV.  Despite these limitations, the control rate 
for the neck in patients with intermediate risk factors was 89% with doses between 52.2-
54.0 Gy.  The current standard of care for adjuvant radiation alone is a dose of 60-66 Gy.  
This is based upon the control arm of the EORTC/RTOG trials, not prospective data.   
 
The use of ECE as a high risk factor for adjuvant therapy is also unclear in the HPV era.  
Both RTOG 9501 and EORTC 22931 were conducted in an era where oropharynx cancer 
was mostly secondary to smoking and alcohol, rather than HPV.  A recent large, multi-
institutional retrospective analysis on HPV-associated patients, for example, 
demonstrated that ECE was a poor predictor of disease recurrence after surgery in the 


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Protocol Version Date:  October 03, 2017 
modern era (Lewis JS, Carpenter DH, Thorstad WL, et al.)  These data have been the 
foundation for the ADEPT trial, an ongoing treatment de-escalation trial for post-
surgical, HPV-associated patients with positive ECE.  However, the treatment de-
escalation in ADEPT is restricted to chemotherapy (radiotherapy plus/minus cisplatin) 
and does not the address the question of radiation de-escalation. 
 
1.4    
Toxicity of Standard Adjuvant Treatment 
 
Adjuvant radiotherapy is associated with acute and late toxicities that significantly impact 
a patient’s quality of life.  When looking at acute reactions on EORTC 22931, adjuvant 
radiation alone was associated with a 21% rate of severe, grade 3+ mucositis, a 20% risk 
of severe xerostomia, and a 5% risk of grade 3+ muscular fibrosis.  These acute reactions 
also translated into late complications.  The rate of late, severe xerostomia was 22% 
while the rate of severe muscular fibrosis was 5%.  Similar numbers were also seen in 
RTOG 9501.  In this trial, 34% of patients receiving adjuvant radiotherapy alone had an 
acute adverse effect of grade 3 or higher while 17% of the radiotherapy alone group had 
severe late adverse effects.   
 
The etiology of these acute and late complications is well known. Radiation 
complications are related both to the total dose received by normal structures, and the 
size of each individual radiation fraction.  The radiation dose limits for a variety of 
normal tissues within the head and neck have been previously documented.  For example, 
a mean radiation dose of 26 Gy to a parotid gland has a 20% risk of rendering the organ 
non-functional, while a mean dose of 50 Gy to the pharyngeal constrictors carries a 20% 
risk of long-term dysphagia and aspiration.  (Eisbruch A, Ten Haken RK, Kim HM, et al.)  
(Blanco AI, Chao KS, El Naqa I, et al.)  (Kuhnt T, Jirsak N, Muller AC, et al.)  (Levendag PC, 
Teguh DN, Voet P, et al.)  (Debelleix C, Pointreau Y, Lafond C, et al.)  Since these normal 
structures directly abut against areas standardly treated to 60 Gy, it is often impossible to 
keep these normal structures below their radiation dose constraints.  Furthermore, using 
twice-daily fractionation with smaller radiation doses has been previously demonstrated 
to decrease toxicity in head and neck patients.  Thus an adjuvant therapy strategy that 
utilizes both decreased total radiation dose, and twice daily fractionation is expected to 
have a large impact on patient quality of life.  
 
1.5 
Preliminary Data: Increased treatment sensitivity of HPV+ tumors 
 
Cell and animal studies have detailed the increased sensitivity of HPV-associated tumors 
to both radiation and chemotherapy.  Cell lines containing E6 isoforms associated with 
HPV have an eightfold reduction in surviving cells fraction after receiving 10 Gy of 
radiation when compared to cell lines containing non-HPV related isoforms.  (Pang E, 
Delic NC, Hong A, et al.)  In vitro studies of HPV-associated tumors implanted within 
immunocompetent mice have demonstrated complete clearance of tumor with 20 Gy of 
treatment while the HPV-negative counterparts demonstrated persistent growth after 20 
Gy.  The sensitivity of HPV-associated tumors was also seen with cisplatin in this study.   
Cisplatin in vivo cleared HPV-associated tumors but not HPV-negative tumors.  (Pradier 
O, Rave-Frank M, Lehmann J, et al.)  Collectively, these data support the hypothesis that 
patients with HPV-associated  tumors do not require as much chemotherapy nor 
radiotherapy for complete disease clearance. 
 


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Protocol Version Date:  October 03, 2017 
1.6 
Selection of Chemoradiation Dose 
 
 The doses and schedule for chemoradiation were chosen based upon the results of prior 
and current multi-institutional studies.  Docetaxel at 15 mg/m2 was used as part of a 
radiosensitizing regimen in RTOG 0234 with a milder toxicity profile compared to 
cisplatin.  Preliminary results also suggest that docetaxel may have a greater 
radiosensitizing effect when compared with cisplatin.  (Le QT, Raben D. et al.) 
 
The radiation dose of 30-36 Gy in 1.5-1.8 Gy fractions b.i.d. was selected to be 
proportionally equivalent to the degree of dose reduction seen for HPV-status and 
treatment acceleration seen on past and current multi-institutional clinical trials.  Using 
the linear quadratic model for determining a biologically equivalent dose (where n = # 
fractions, d = fractional dose, and α/β = 10):   
 








/
1
d
nd
BED
 
 
yields that 30 Gy in 1.5 Gy fractions is equivalent to 34.5 Gy10. (Hall EJ, Giaccia AJ., et 
al.)  
 
Concerning HPV-status, ECOG 1308 is an ongoing multi-institutional trial for definitive 
treatment of HPV-associated oropharyngeal cancers.  The standard of care for treating 
definitive oropharyngeal cancers is 70 Gy in 2 Gy fractions (84 Gy10) with concurrent 
cisplatin.  On ECOG 1308, patients receive induction chemotherapy followed by 54 Gy 
in 2 Gy fractions (64.8 Gy10) with concurrent cetuximab.  (Peres J.)  This translates into a 
23% dose reduction in chemoradiation compared with standard of care due to HPV-
positivity. 
 
Concerning accelerated radiation, a multi-institutional trial run by the University of 
Chicago (9502b) used 39 Gy in 1.5 Gy b.i.d. fractions (44.85 Gy10) for microscopic 
disease while the standard dose for microscopic disease is 54 Gy in 1.8 Gy fractions 
(63.72 Gy10.)  (Haraf DJ, Rosen FR, Stenson K, et al.)  This translates into a 29% dose 
reduction compared with standard of care due to treatment acceleration. 
 
Combining the dose reduction due to HPV-positivity and treatment acceleration yields a 
dose reduction of 52% compared to standard of care.  A dose reduction of 52% on the 
standard of care dose of 60 Gy in 2 Gy fractions (72 Gy10) is equal to 34.56 Gy10, a figure 
essentially equivalent to 30 Gy in 1.5 Gy fractions bid.   
 
In terms of normal tissue toxicity (using an α/β = 3), 30 Gy in 1.5 Gy fractions is equal to 
45 Gy3.  This compares favorably to the equivalent normal tissue dose of the standard 
post-operative dose (60 Gy in 2 Gy fractions), which is 100 Gy3. 
 
1.7 
QOL Evaluation 
 
Quality of life will be measured using previously validated metrics and compared to a 
prospective cohort of similar patients under standard treatment.  Acute effects will be 
assessed weekly during treatment using the CTCAE version 4.  After the completion of 
radiation and chemotherapy, the patient will receive clinical follow-up including physical 


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Protocol Version Date:  October 03, 2017 
examination, flexible nasopharyngoscopy, and late effect assessment (xerostomia with 
the University of Michigan Inventory, dysphagia with the MD Anderson Dysphagia 
Inventory, quality of life with the Performance Status Scale for Head and Neck) every 3 
months for the first two years.   
 
A baseline swallowing assessment consisting of a videofluroscopic examination, 
including a modified barium swallow study, and an esophagogram will be performed by 
Speech Therapy after surgery, before the initiation of radiation.   Swallowing will be 
scored (yes, no) for aspiration, penetration, velopharyngeal incompetence, epiglottic 
everson, tongue base retraction, and pharyngeal swallow response using metric outlined 
by Eisbruch et al. (Eisbruch A, Teresa L, Bradford CR, et al.)  A swallowing assessment 
will be performed by Speech Therapy after surgery, before the initiation of radiation, and 
will be repeated at one month and 12 months after the completion of protocol treatment  
 
2.0 
Goals   (same for each cohort) 
 
 
2.1 
Primary 
 
2.11 
To assess the cumulative incidence of local/regional failure at 2 years after study 
registration. 
 
2.2 
Secondary 
 
2.21 
To characterize the rate of acute grade 3 or higher functional mucosal adverse 
events (up to 1 month post-XRT) associated with adjuvant docetaxel + 
hyperfractionated radiotherapy (key secondary endpoint). 
 
2.22 
To assess changes in overall survival, disease-free survival, distant failure rates, 
and quality of life (QOL) associated with adjuvant docetaxel and 
hyperfractionated radiation.  The QOL measures will include an evaluation of 
swallowing, xerostomia, and mucositis.  
 
2.23 
To characterize other  acute adverse events (up to 1 month post-XRT) and late 
grade 3 or higher non-hematologic adverse events (up to 2 years post-XRT) 
associated with adjuvant docetaxel + hyperfractionated radiotherapy. 
 
2.3 
Correlative Research – 
 
2.31 
To determine the genetic alterations of oropharynx tumor specimens and the 
detection rate of corresponding cfDNA in the pre-surgical, post-surgical, and post-
radiation blood of oropharynx cancer patients. 
 
 
 
 


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Protocol Version Date:  October 03, 2017 
  
 
3.0 
Patient Eligibility   
 
3.1 
Pre-Registration 
 
 
 
3.11 
Provide written informed consent 
 
3.12 
Submission of research blood draw to be stored until after surgical resection of 
the primary tumor and confirmation of HPV positivity (Mayo Clinic Rochester 
patients only)  
 
3.13 
Patients with oropharynx carcinoma with a smoking history of ˂ 10 pack-year or 
equivalent 10 year history of tobacco product use and no recent history (within 
last 5 years) of tobacco use.  
 
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 
Smoking history < 10 pack years or equivalent 10 year history of tobacco product 
use. 
 
3.26 
Absence of distant metastases on standard diagnostic work-up ≤ 10 weeks prior 
to registration.  (Chest CT, CXR, PET/CT, etc…) 
 
3.27 
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 microscopic T4a primary disease 
 
Lymph node extracapsular extension  
 
3.28 
The following laboratory values obtained 14 days prior to registration.  
 
Absolute neutrophil count (ANC) ≥1500/mm3 
 
Platelet count 100,000/mm3 
 
Hemoglobin ≥9.0 g/dL 
 
Direct bilirubin within upper limit of normal (ULN)  
 
Creatinine  ULN x 1.5  
 
 
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. 


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Protocol Version Date:  October 03, 2017 
 
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 significant tobacco history within the past five years. 
 
3.32 
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 
adequate contraception 
 
3.33 
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. 
 
3.34 
Immunocompromised patients and patients known to be HIV positive.   
 
 
3.35 
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. 
 
3.36 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.37 
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.  
 
3.38 
History of myocardial infarction ≤ 180 days prior to registration, or congestive 
heart failure requiring use of ongoing maintenance therapy for life-threatening 
ventricular arrhythmias. 
 
3.39  
Prior history of radiation therapy to the affected site. 
 
3.39a 
History of connective tissue disorders such as rheumatoid arthritis, lupus, or 
Sjogren’s disease. 
 
3.39b Presence of any of the following risk factors after surgery: 
 
 
Any positive surgical margin. 
 
Adenopathy below the clavicles  
 


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Protocol Version Date:  October 03, 2017 
3.39c 
Prior systemic chemotherapy for the study cancer.  NOTE:  Prior chemotherapy  
for a different cancer is allowable. 
 
3.39d History of allergic reaction to docetaxel.   
 
3.39e 
Receiving any medications or substances that are strong or moderate inhibitors 
of CYP3A4 (for a listing of medications or substances see Appendix IV). 
 
Use of strong or moderate inhibitors is prohibited < 7 days prior to registration. 
 
3.39f 
Receiving any medications or substances that are inducers of CYP3A4 (for a 
listing of medications or substances see Appendix IV). 
 
Use of inducers is prohibited < 12 days prior to registration. 


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4.0 
Test Schedule 
 
 
Assessments, 
tests and 
procedures 
Pre-Treatment 
Active 
Monitoring 
Active Monitoring Observation 
 
Pre-reg 
(prior to
surgery)
≤ 10 weeks 
prior to 
registration 
≤ 2 weeks 
prior to 
registration 
 
Weekly 
(+/- 3 
days) 
 
 
As clinically 
indicated 
At 14 days 
post-XRT 
At 1 mo. 
post-XRT 
Q3 months 
post- XRT x2 
yrs q6 mos for 
year 3, then 
annually for 
years 4 & 5 
 
As clinically 
indicated 
Evaluation by 
Radiation 
Oncologist and/or 
Medical Oncologist 
 
X8 
 
X10 
 
X5 
X5 
X5 
 
ENT/Surgeon’s 
exam 
 
X9 
 
 
 
X5 
X5 
X5 
 
CT with contrast, 
or CT/PET, 
and/or MRI of H &
N2 
 
 
X 
Recommended
within 8 wks 
prior to 
registration 
 
X 
 
 
As clinically 
indicated 
 
Chest x-ray (or 
chest CT or 
CT/PET)2 
 
X 
 
 
X 
 
 
X5,6 
 
Pathology 
Assessment (Gross
total resection ≤ 7 
weeks 
prior to 
registration) 
 
X7 
 
 
 
 
 
 
 
 
Biopsy 
 
 
 
 
X4 
 
 
 
 
X4 
Performance status
 
 
X 
X 
 
 
X 
X 
 
CBC w/ diff & 
AGC 
 
 
X 
X 
X 
X 
X 
 
X 


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Protocol Version Date:  October 03, 2017 
Bilirubin, AST or 
ALT 
 
 
X 
X 
X 
 
X 
 
X 
 
Serum creatinine 
 
 
 
X 
X 
 
 
 
 
 
Na, K, glucose, 
Ca, Mg, 
albumin 
 
 
X 
 
 
 
 
 
 
Serum pregnancy 
test (if 
applicable)1 
 
 
X 
 
 
 
 
 
X 
 
Dental evaluation 
 
 
≤ 3 mos. prior to 
start of treatment 
 
 
 
 
 
 
Assessment of 
swallowing 
function 
 
 
≤ 2 weeks prior to 
treatment 
 
 
 
X 
 
X11 
Adverse event 
evaluation 
 
 
X 
X 
 
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 
 
 
Prior to Treatment
(Baseline) 
 
 
X 
X 
 
 
At 3, 12, and 24 months from 
the end of radiation treatment 
Patient Assessment
Form (completed 
by investigator) 
(see Appendix V) 
 
 
Prior to Treatment
(Baseline) 
 
 
X 
X 
 
At 3, 12, and 24 months from 
the end of radiation treatment 
 
 


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Protocol Version Date:  October 03, 2017 
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.)  Use same imaging throughout the study. 
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 Medical Oncology will be performed 14 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. 
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. 
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 
R. Research Funded 
 


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Protocol Version Date:  October 03, 2017 
 
5.0 
 Grouping Factor:  
 
Extracapsular Extension   
o No  Cohort A 
o Yes Cohort B 
 
 
6.0  
Pre-Registration/Registration Procedures 
 
NOTE: Once accrual for a cohort is complete, that cohort will be closed and the other 
cohort will remain open. 
6.1 
To pre-register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and 
enter the registration/randomization application.  The registration/randomization 
application is available 24 hours a day, 7 days a week.  Back up and/or system support 
contact information is available on the Web site.  If unable to access the Web site, call the 
MCCC Registration Office at
 between the hours of 8 a.m. and 4:30 p.m. 
Central Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available on the 
MCCC web page 
and detail the process for 
completing and confirming patient registration.  Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent.  Patient pre-registration via the registration/randomization application can be 
confirmed in any of the following ways: 
 
Contact the MCCC Registration Office 
.  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
Prior to accepting the pre-registration, registration application will verify the following: 
 
IRB approval at the registering institution 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.2 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at
 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
 


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Protocol Version Date:  October 03, 2017 
The instructions for the registration/randomization application are available on the 
MCCC web page
and detail the process for 
completing and confirming patient registration.  Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent.  Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
 
Contact the MCCC Registration Office 
  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.3 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
).  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
6.4 
Prior to accepting the registration, registration application will verify the following: 
 
IRB approval at the registering institution 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.5 
Treatment cannot begin prior to registration and must begin  14 days after registration. 
 
6.6 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.7 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
 
6.8 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
radiation oncologist. 
 
6.9a 
Patient questionnaire booklet is available on site; copies are not acceptable for this 
submission.  
 
6.9b 
Patient has/has not given permission to give his/her blood sample for research testing. 
 
7.0 
Protocol Treatment 


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Protocol Version Date:  October 03, 2017 
 
 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention. 
 
7.11 
Pretreatment medication  (Same for Cohort A and B) 
 
Agent 
Dose 
Route 
Day 
 
DXM 
 
8 mg 
 
 
PO BID 
Day before, day of, and day after 
docetaxel (may substitute IV if 
patient did not receive PO 
dexamethasone).  
 
 
Agent 
Dose Level 
Route 
Day 
Docetaxel 
15mg/m2 
IV 
Day 1 
Docetaxel 
15mg/m2 
IV 
Day 8 
 
 
7.3 
For this protocol, the patient must return to the Mayo Clinic for evaluation every 7 days 
during treatment and then at 14 days post-XRT, 1 month post-XRT, followed by every 3 
months post-treatment for 2 years, followed by every 6 months for year 3, then annually 
for years 4 & 5. 
 
 
7.4 RADIATION THERAPY  
NOTE: FOR THIS STUDY, IMRT AND IGRT ARE MANDATORY 
Dose Specifications for both Arms 
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 aim to begin on a Monday. 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.  
 
Field 
Dose 
(Gy) 
Number of 
Fractions 
Fraction 
Size 
Rx Length 
Rx Days 
Cohort 
A 
30 
20 
1.5 
 
Days 1-12 
M-F 
Cohort 
B 
36 
20 
       1.8 
Days 1-12 
 
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 (e.g., based on 
mutual information) types of registration can be used; the result of the fusion 
must be visually checked for the alignment of the bony anatomy, such as 
vertebral bodies and applicable soft tissue structures (e.g., optic nerves and/or 
optic chiasm). 
 
Following the registration, the translational and (if the appropriate technology is 
available) rotational corrections should be applied to the treatment couch. If all the 
variances are less than 2.5 mm (this typically corresponds to one half of the usual PRV 
margin), the treatment can proceed without correction (however, the physician/team may 
elect to perform adjustments even for a variance < 2.5 mm). If one or more corrections 
are 2.5-5 mm, adjustment is necessary prior to treatment; however, re-imaging is not 
mandatory. If one or more of the corrections are larger than 5 mm, the imaging must be 
repeated in addition to performing table/positioning adjustments. 
 
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 should 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 
 
7.510 CTV_HIGH: This volume will receive 1.8 Gy per day bid and will 
only apply to patients who have ECE.  This volume will be restricted 
to the prior location of the ECE-involved lymph node, expanded by 1.5 
cm, and shaving off of bone and relevant normal anatomy.  In the 
instance where the exact ECE-involved lymph node is unclear, 
CTV_HIGH 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 CTV_LOW: This volume will receive 1.5 Gy per day bid. CTV 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 


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Protocol Version Date:  October 03, 2017 
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).  CTV also will include the 
bilateral necks.  This generally means encompassing nodal levels 2a, 3, 
and 4 for all cases. Nodal levels 1, 2b, 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. 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 Normal Tissues/Organs at Risk (OARs) 
 
7.521  Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top 
of the C1 vertebral body). Superior to this is brainstem and inferior to 
this is cord. The inferior border of the spinal cord is at approximately T3-
4 (i.e., just below the lowest slice level that has PTV on it). The spinal 
cord shall be defined based on the treatment planning CT scan. In 
addition, however, a Planning Risk Volume (PRV) spinal cord shall be 
defined. The PRVcord = cord + 5 mm in each dimension. This is 
irrespective of whether or not IGRT is used. 
 
7.522  Brainstem: The inferior most portion of the brainstem is at the cranial-
cervical junction where it meets the spinal cord. For the purposes of this 
study, the superior most portion of the brainstem is approximately at the 
level of the top of the posterior clinoid. The brainstem shall be defined 
based on the treatment planning CT scan. In addition, however, a 
Planning Risk Volume (PRV) brainstem shall be defined. The 
PRVbrainstem = brainstem + 3 mm in each dimension. 
 
7.523  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. For oral cavity cancers, the oral cavity will be defined as the 
subset of this composite structure that does not overlap with PTV. 
 


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7.524  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. 
 
7.526  OARpharynx: This will be defined as the “uninvolved” 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. 
 
7.527  Cervical Esophagus: This will be defined as a tubular structure that starts 
at the bottom of OARpharynx and extends to the thoracic inlet. 
 
7.528  Glottic/Supraglottic Larynx (GSL): Obviously, for patients who have had 
a total laryngectomy, this structure is not applicable. This will be defined 
as a “triangular prism shaped” volume that begins just inferior to the 
hyoid bone and extends to the cricoid cartilage inferiorly and extends 
from the anterior commissure to include the arytenoids. This includes the 
infrahyoid but not suprahyoid epiglottis. 
 
7.529a Mandible: This includes the entire boney structure of the mandible from 
TMJ through the symphysis. It is recognized that for oral cavity cancers, 
this may overlap with CTVs and PTVs. 
 
7.529b Unspecified Tissue Outside the Targets: This will be defined as tissue 
located between the skull base and thoracic inlet that is not included in 
either the target volumes or the normal tissues described above. 
 
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 6.4.1 for definitions of CTVs and PTVs. As described in Section 6.1, 
prescribed radiotherapy dose will be 30-36 Gy in 1.5-1.8 Gy twice-daily fraction 
size. For inverse planning IMRT, the goal is for 100% of the PTV_LOW to 
receive ≥ 1.5 Gy / fraction.  It is recognized that portions of the PTV_LOW close 
to the skin may receive significantly less than 30 Gy. This is acceptable as long 
as cold spots within PTV do not exist at a depth deeper than 8 mm beneath the 
skin (see Section 6.7, compliance criteria).  At least 98% of PTV_HIGH should 
receive at least 1.8 Gy / fraction.  For prioritization, PTVs will be the highest 
priority target structure.  
 
7.63  
IMRT Dose Constraints to Normal Structures 


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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.  
 
7.631  Spinal Cord: The PRVcord (as defined in Section 6.4.2.1) 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.  
 
7.632  Brainstem: The PRVbrainstem (as defined in Section 6.4.2.2) should not 
exceed 35 Gy to any volume in excess of 0.03 cc (approximately 3 mm x 
3 mm x 3 mm).  
 
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  OARpharynx: Reduce the dose as much as possible.  
 
7.638  Cervical Esophagus: Reduce the dose as much as possible.  
 
7.639a  Glottic and Supraglottic larynx (GSL): Reduce the dose as much as 
possible.  
 
7.639b  Mandible: Reduce the dose as much as possible.  
 
7.7 
Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the 
reason(s) for the treatment break(s). Radiation breaks, if necessary, should not exceed 
one treatment day. 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 will 
be considered a major protocol deviation. 


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7.8  
Radiation 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. Nutritional evaluation prior to the initiation of therapy for a 
prophylactic gastrostomy (PEG) tube placement 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, and skin erythema and 
desquamation within the treatment fields. 
 
Less common long-term treatment adverse events include: hypothyroidism, loss of 
hearing, chronic swallowing dysfunction requiring permanent feeding tube, and cervical 
fibrosis.  
 
Much less common radiation adverse events include: mandibular osteoradionecrosis (< 
5% incidence with attention to dental recommendations), and cervical myelopathy (< 
0.1% with restriction of spinal cord dose to ≤ 30 Gy). 
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table.  If multiple adverse events are seen, administer 
dose based on greatest reduction required for any single adverse event observed.  Reductions 
are based on adverse events observed since the prior dose. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2) 
 
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 
- If patient requires more than one docetaxel delay (Day 1 or 8), start at Dose -2   
 


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Protocol Version Date:  October 03, 2017 
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.  If no 
recovery after 3 weeks despite institution 
of all clinically appropriate symptomatic 
treatment, discontinue docetaxel.   
Investigations, Other,  
Liver 
AST or ALT > 1.5 x 
ULN when AP > 2.5 x 
ULN 
OR 
AST or ALT > 3 x 
ULN 
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 Direct 
Bilirubin ≤ 1.5 x ULN.  If no recovery 
after 3 weeks despite institution of all 
clinically appropriate symptomatic 
treatment, discontinue docetaxel.   
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.  If no recovery 
after 3 weeks despite institution of all 
clinically appropriate symptomatic 
treatment, discontinue docetaxel.   
 
* 
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  
 
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. 
 


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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.  Journal of Clinical Oncology, Vol 24, No 19 (July 
1), 2006: pp. 3187-3205.  
 
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 must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should 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.  
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
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)     
 
10.11 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 (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4).  Important: Expedited adverse 
event reporting requires submission of a MedWatch report(s). Expedited reports 
are to be completed within the timeframes and via the mechanisms specified in 


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Protocol Version Date:  October 03, 2017 
Sections 10.4. All AEs reported via expedited mechanisms must also be reported 
via the routine data reporting mechanisms defined by the protocol (see Sections 
10.52 and 18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected 
 
 
The determination of whether an AE is expected is based on the agent-
specific information provided in Section 15.0 of this protocol. 
 
 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of this protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is 
neither identified in nature, severity, or frequency of risk in the information 
provided for IRB review nor mentioned in the consent form.  
 
10.3 
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.  
 
10.4  
Expedited Reporting Requirements for CIP Studies using Commercial Agent(s) 
ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND/IDE trial within 30 Days of the Last Administration of a Commercial Agent 1, 2  
 


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MCCC Addendum 5 
 
 
 
Protocol Version Date:  October 03, 2017 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via MedWatch within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-
hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
 All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
 Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Instructions: 
1. An increased incidence of an expected adverse event (AE) is based on the patients treated 
for this study at their site.  A list of known/expected AEs is reported in the package insert 
or the literature, including AEs resulting from a drug overdose. 
2. Complete and submit all appropriate sections of the three page of the FDA MedWatch 
3500A, (Mandatory reporting form) available at: 
 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.p
df 
 
Instructions on how to complete the form may be found at the following website:  


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MCCC Addendum 5 
 
 
 
Protocol Version Date:  October 03, 2017 
 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/UCM
387002.pdf 
Mayo Clinic Cancer Center (MCCC) Institutions:   
 
Submit copies, along with the Event Reporting coversheet, to the following email 
address: CANCERCROSAFETYIN@mayo.edu. This email will be managed by the 
SAE, IND and Safety Reporting Coordinators. 
 
EVENT TYPE 
REPORTING PROCEDURE 
Other Grade 4 or 5 Events 
and/or Any Hospitalizations 
During Treatment Not 
Otherwise Warranting an 
Expedited Report 
 
Complete a Notification Form: Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form electronically via the 
MCCC Remote Data Entry System or paper form within 5 
working days of the date the clinical research associate (CRA) is 
aware of the event(s) necessitating the form. 
If an expedited written report has been submitted, this form does 
not need to be submitted. 
 
 
10.5 
Other Required Reporting 
 
10.51 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions (formerly referred to as disabilities), congenital abnormities or birth 
defects, must be reported immediately if they occur at any time following treatment with an 
agent under an IND/IDE since they are considered to be a serious AE and must be reported to the 
sponsor as specified in 21 CFR 312.64(b). 
 
10.52  Death 
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 24-
hours. 
 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Reportable categories of Death  
 
 
Death attributable to a CTCAE term. 
 
 
Death Neonatal:  A disorder characterized by cessation of 
life during the first 28 days of life. 
 
 
Death NOS:  A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
 


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MCCC Addendum 5 
 
 
 
Protocol Version Date:  October 03, 2017 
 
Sudden death NOS:  A sudden (defined as instant or within 
one hour of the onset of symptoms) or an unobserved 
cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
 
 
Death due to progressive disease should be reported as Grade 
5 “Neoplasms benign, malignant and unspecified (incl 
cysts and polyps) – Other (Progressive Disease)” under the 
system organ class (SOC) of the same name.  Evidence that 
the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: 
clinical deterioration associated with a disease process) 
should be submitted. 
 
10.53 Secondary Malignancy 
 
 A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not 
considered a metastasis of the initial neoplasm. 
 
 All secondary malignancies that occur following treatment with an agent 
under an IND/IDE be reported. Three options are available to describe 
the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.54 Second Malignancy 
 
 A second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy).  Second 
malignancies require ONLY routine reporting. 
 
10.6 
Required Routine Reporting 
 
 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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MCCC Addendum 5 
 
 
 
Protocol Version Date:  October 03, 2017 
 
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 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in Section 10.6 
 
10.611 
Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.612 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.613    
Grade 5 AEs (Deaths) 
 
10.6131 
Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
 
10.6132 
Any death more than 30 days after the patient’s 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. 
 
11.0 
Treatment Evaluation  
 
11.1 
Patients will be evaluated at baseline, 14 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 


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MCCC Addendum 5 
 
 
 
Protocol Version Date:  October 03, 2017 
 
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. 
 
 
 
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 
 
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 14 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 


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Protocol Version Date:  October 03, 2017 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
 
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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MCCC Addendum 5 
 
Protocol Version Date:  October 03, 2017 
 
14.0 
Body Fluid 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-
Treatment  
Three 
Month 
Post 
XRT 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
 
 
 
CfDNA for Mayo 
Clinic Rochester 
patient only 
Optional  
Whole 
Blood 
Streck 
Two 10 mL 
whole 
blood 
samples in 
Streck Cell 
Free DNA 
BCT tubes 
 
 
 
X 
X 
X 
Yes 
Ambient 
BAP Lab 


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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
 
14.2  
Collection and Processing  
 
14.21 Circulating Cell Free DNA (cfDNA)  
14.21.1 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 
 
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. 
 
14.3 
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:  
 
BAP Freezer  
Mayo Clinic  
 
 
  
 
 
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 
 for 
additional instructions Tel: 
Email: 
 
 
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 flexible system for individualized monitoring is needed. 
Mayo Clinic Rochester has developed an internal assay for this purpose.  
 
 
 


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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
 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 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 nonsorbing 
polyethylene lined (non-DEHP) tubing; in-line filter is not necessary. Note: 
Premedication with dexamethasone 8 – 10 mg orally twice daily for 3-5 days, 
beginning the day before docetaxel administration is recommended to decrease 
the incidence and severity of fluid retention and prevent hypersensitivity 
reactions and pulmonary/peripheral edema.  When administered as sequential 


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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
infusions, taxane derivatives should be administered before platinum derivatives 
(cisplatin, carboplatin) to limit myelosuppression and to enhance efficacy.  
 
 
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 
Neuromuscular & skeletal: Weakness, myalgia 
Respiratory: Pulmonary events 
Miscellaneous: Infection, hypersensitivity 
 
Less common known potential toxicities, 1% - 10%:  


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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
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. 
 
15.186 Advise patient about alopecia. 
 
15.187 Monitor liver function tests. 
 


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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
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 
Neck radiation 
 
 
 
15.21 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 
 
 Note:   The first patient enrolled will be excluded from all analyses because they received Docetaxel (15 
mg/m2) on days 1, 8 and Docetaxel 75 mg/m2 on day 15 as well.  All other patients will only 
receive Day 1 and 8 of Docetaxel (15 mg/m2 each day).  This first patient was still eligible per 
protocol.  Per Addendum 1, day 15 was removed for all subsequent patients. 
 
In addition, this study will be stratified into two patient cohorts: patients who do not have ECE (“cohort 
A”) and patients who have ECE (“cohort B”).  Cohort B patients will be treated with a slightly higher 


MC1273 
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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
radiation dose (36 rather than 30 Gy), but will be followed and evaluated in the same fashion as patients 
in Cohort A.  Each cohort will be independently evaluated for all the endpoints described below 
 
16.1   
Overview:  This phase II study, with a feasability analysis in the first 5 pts, will 
evaluate adjuvant hyperfractionated radiation and docetaxel for HPV-associated 
Oropharynx Cancer using a 1-stage design.  Standard therapy for this disease 
yields a 2-year cumulative incidence of local/regional failure of approximately 
10% (Ang KK, Harris J, Wheeler R, et al.), but it also has high rates of grade 3 or 
worse adverse events (Bernier J, Domenge C, Ozsahin M, et al).  Given the high 
rates of severe or worse functional mucosal adverse events (AEs), especially, it is 
of high interest to find a chemo/RT combination that can still yield low rates of 
local/regional failure with reduced AE rates.  If this new treatment combination 
can achieve a 2-year cumulative incidence of local/regional failure of no more 
than 20% (primary endpoint), while significantly reducing the acute grade 3+ 
functional mucosal AE rate as compared to historical controls (key secondary 
endpoint), further study would be warranted.  In addition to the 2-year 
cumulative incidence rate and the acute functional mucosal adverse event rate, 
this study will assess many additional secondary endpoints, including, overall 
survival, disease-free survival, distant failure rates, quality of life (QOL) 
measures, swallowing studies, other acute adverse events, and late adverse events 
and translational studies.     
 
16.2 
Primary Endpoint: The 2-year cumulative incidence of local/regional failure associated 
with adjuvant hyperfractionated radiation and docetaxel in patients with intermediate risk 
HPV+ Associated Oropharynx Cancer.  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.   
 
16.21  Analysis plans: Given that the current standard therapy yields a 2-year 
cumulative incidence of local/regional failure of around 10% (Ang KK, Harris J, 
Wheeler R, et al.), this study treatment will be of interest for further study if the   
2-year cumulative incidence of local/regional failure does not exceed 20%, while 
also significantly reducing AE rates (see 16.3, key secondary endpoint).  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).  If the 2-year cumulative incidence of local/regional failure 
does not exceed 20%, this will give evidence that a 2-year local/regional failure 
rate of around 10% can not be ruled out, since the 2-sided 85% confidence 
interval would contain 10% (85% CI: 10 – 30%) with 35 evaluable patients  
using nQuery Advisor version 6.01 for confidence intervals for a single 
proportion.   
 
 
16.3  
Key Secondary Endpoint:  To characterize the acute grade 3 or higher functional mucosal 
adverse events (up to 1 month post-XRT) associated with adjuvant hyperfractionated 
radiation and docetaxel in patients with intermediate risk HPV+ Associated Oropharynx 
Cancer.  All patients meeting the eligibility criteria who have signed a consent form, and 
begun treatment will be considered evaluable for this key secondary endpoint.  
 
16.31 Definition of success:  A success will be defined as a patient who does   


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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
not experience a grade 3+ functional mucosal adverse event in the first 
month post- XRT.  
 
16.32 Power, Sample Size:  The current standard of care yields acute grade 3+ 
functional mucosal AE rates of approximately 40% (Bernier J, Domenge 
C, Ozsahin M, et al.).  This regimen will be of high interest based on 
safety if the acute grade 3+ functional mucosal AE rate could be reduced 
to around 20% or lower.   
 
With 35 evaluable patients per cohort, this study would have 85% power 
to detect an acute grade 3+ functional mucosal AE-free rate of 80%, with 
a 0.06 level of significance if the true grade 3+ AE-free rate is 60%.  The 
decision rule for this trial is as follows:  If 25 or fewer patients are grade 
3+ AE-free after 1 month post-XRT, we will conclude that the AE rate is 
not significantly reduced in this patient population.  If 26 or more 
patients are grade 3+ AE-free, this will be considered adequate evidence 
of safety for this treatment and it may be recommended for further 
testing in subsequent studies, especially if the primary endpoint 
discussed above meets criteria as well (see 16.21).  
 
16.4  
Sample Size:   We will enroll 35 evaluable patients per cohort  to the combination of 
adjuvant hyperfractionated radiation and docetaxel (total patients = 70 evaluable 
patients.)  We anticipate accruing an additional 5 patients per cohort to account for 
ineligibilities, cancellations, major violations, or other reasons.  Therefore, maximum 
accrual will be 80 patients. Following the approval of addendum 6, overall accrual will 
increase to 81 patients so that additional patient data can be used for analysis.  
 
16.5  
Accrual Time and Study Duration:  The anticipated accrual rate is approximately 1 
patient per month or 12 patients per year per cohort. Therefore, the accrual period for this 
Phase II study is expected to be around 3 years.  The final analysis can begin 
approximately 5 years after the trial begins, i.e., as soon as the last patient registered has 
been observed for 24 months. 
 
16.6 
Safety Analysis in First 5 patients:  In the first 5 patients, acute adverse events (up to 1 
month post-XRT) will be closely monitored to make sure that nothing unusual occurs.  
Based on the current standard of care, we expect that no more than 50% of patients will 
have a grade 3+ non-hematologic AE (regardless of attribution).  If 3 or more patients in 
the first 5 have a grade 3+ non-hematologic AE, we will consider lowering the dose even 
further for further evaluation.  In addition, if 1 or more of the first 5 patients has a local or 
distant failure or expires from this cancer during the first 6 months, the dose for the study 
may be modified going forward.  Accrual will continue while we wait for the first 5 
patients to be followed for a minimum of 6 months.  As long as the dose remains the 
same, the first 5 patients will be included in the final analysis as well.     
 
16.7 
Definitions and Analyses of Secondary Endpoints: 
 
16.71   Overall Survival (OS) is defined as the time from registration to death due to any 
cause. The distribution of OS will be estimated using the method of Kaplan-
Meier (Kaplan E, Meier P).   
 


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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
16.72  Disease-free survival (DFS) is defined as the time from registration to the first of 
either disease recurrence or death. The distribution of DFS will be estimated 
using the method of Kaplan-Meier (Kaplan E, Meier P).    
 
16.73 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).   
 
16.74    Quality of Life (QOL): The patient QOL will be measured 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, 14 days post-XRT and 3, 12 and 24 
months post-XRT.  These QOL scores will be explored descriptively to detect 
patterns and substantial changes over time. In addition, differences between post-
baseline and baseline QOL scores will be analyzed using a paired-sample t-test or 
the nonparametric equivalent to see if the QOL tends to improve over time with 
treatment.   
 
16.75 Patient Assessment Form (Appendix V): The data from this form will be 
analyzed descriptively, using frequencies and percentages for each timepoint 
(baseline, 14 days post-XRT, and 3, 12 and 24 months post-XRT). 
 
16.76 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 12 months after the 
completion of protocol XRT.  The swallowing questions will be explored 
descriptively to detect patterns and substantial changes over time. In addition, 
McNemar’s test for paired samples will be used to see if the swallowing 
questions significantly change over time for each post-baseline timepoint.   
 
16.77  Acute Adverse Events (up to 1 month post-XRT):  All eligible patients that have 
initiated treatment will be considered evaluable for assessing acute adverse 
events, defined as any adverse event that occurs in the 1st month post-XRT.  The 
maximum grade for each type of acute adverse event will be recorded for each 
patient, and frequency tables will be reviewed to determine patterns, especially 
focusing on grade 3+ adverse events, regardless of attribution to the study 
treatment. 
 
16.78 Late Adverse Events (up to 2 years post-XRT):    All eligible patients that have 
initiated treatment will be considered evaluable for assessing adverse event 
rate(s).  The maximum grade for each type of adverse event will be recorded for 
each patient for up to 2 years post-treatment, and frequency tables will be 
reviewed to determine patterns, especially focusing on grade 3+ non-hematologic 
adverse events, regardless of attribution to the study treatment.  Hematologic 
adverse events will not be followed closely long-term given that adjuvant 
treatment is only given for 1 month.   
 


MC1273 
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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
16.79 Translational studies: Due to the limited sample size in this study, the proposed 
translational studies are considered exploratory and hypothesis generating.   
Tumor specimens (at baseline) will be assessed for E6/E7 mRNA of HPV16 and 
other high-risk serotypes on a chromogenic RNA ISH assay called RNAscope 
(see 17.4).  In addition, serum collected before and one week post-radiation will 
be assessed for changes in TGF-beta1 levels (see 14.3).  We will also assess the 
pre-surgery blood samples as well for patients that are pre-registered to the trial.  
We plan to correlate these markers with clinical endpoints like acute adverse 
events, cumulative incidence rates of local/regional failure, overall survival, and 
disease-free survival.  Statistical and graphical techniques will be used to explore 
the relationships between tumor markers and clinical data. For time-to-event 
endpoints, we will use Cox proportional hazards models, and for binary 
endpoints we will use Logistic regression models. In addition, we will use the 
Chi-square or Fisher’s exact tests to test the association between categorical 
marker data and binary endpoints. All these statistical techniques will allow us to 
explore whether these tumor markers are potentially related to the clinical 
endpoints of acute adverse events, cumulative incidence rates of local/regional 
failure, overall survival, and disease-free survival. 
 
16.8 
    
Data & Safety Monitoring: 
 
16.81   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.   
 
16.82    Adverse Event Stopping Rules:   The stopping rules specified below are based on  
the 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 50% of patients to 
experience Grade 3+ 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: 
 
 
If at any time 12 or more patients in the first 20 treated patients 
experience a Grade 3 or 4 non-hematologic adverse event (regardless of 
attribution). 
 
If at any time 2 or more Grade 5 events occur in the first 20 treated 
patients (regardless of attribution). 
 
If after the first 20 patients have been treated:  


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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
o 60% or more of all patients experience a Grade 3 or 4 non-
hematologic adverse event (regardless of attribution). 
o 10% or more of all patients experience a Grade 5 adverse event 
(regardless of attribution). 
 
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. 
 
16.9 
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 2-year cumulative incidence rate.   
 
16.10 
Inclusion of Women and Minorities 
 
16.11  This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.12  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. 
 
16.13   The geographical region served by the Mayo Clinic, has a population which 
includes approximately 5% minorities.  We expect about 5% of patients will be 
classified as minorities by race and about 40% of patients will be women. 
Expected sizes of racial by gender subsets are shown in the following table: 


MC1273 
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MCCC Addendum 5 
 
 
Protocol Version Date:  October 03, 2017 
 
Accrual Estimates by Gender/Ethnicity/Race for All Phase II and III Studies 
(Updated March 22, 2002, for January 1, 2002, Requirements) 
 
Ethnic/Racial Categories 
Sex/Gender 
 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
0 
0 
0 
Not Hispanic or Latino 
32 
48 
0 
80 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all subjects* 
32 
48 
0 
80* 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
2 
0 
2 
Black or African American 
2 
0 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
30 
46 
0 
76 
More than one race 
0 
0 
0 
0 
Unknown 
0 
0 
0 
0 
Racial Category: Total of all subjects* 
32 
48 
0 
80* 
 
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.” 
Article I. 
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. 
 


MC1273 
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MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
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.  
Prior to 
Radiation 
Treatment  
Temperature 
 Conditions 
for Storage 
/Shipping  
 
Tumor Genetic 
Analyses 
Optional 
FFPE\fresh 
frozen 
2 to 6 curls 
Yes 
Ambient 
 
17.2 
Diagnostic Slides from Original Tissue 
 
Either 2-6 FFPE tissues curls or samples from fresh frozen tumor will be collected from original 
tumor biopsy, tumor removed during surgery, or recurrent tumor specimens. This tissue is already 
being collected and shared through 
 protocol 50-97.  This tissue will be 
used for determining tumor-specific genetic alterations. Detected alterations may be compared to 
upwards of 50 samples of normal tissue from IRB 13-000883. 
 
Additionally, we may examine tumor specimens from Tissue Registry through our collaborators 
either within Mayo Clinic or at Memorial Sloan Kettering Cancer Center (MSKCC).  This may 
include whole genome sequencing, whole exome sequencing, focused exome sequencing, mate-
pair analysis, HPV-subtyping, immunologic profiling, RNA sequencing, in situ hybridization, 
cytogenetics, molecular testing, protein expression, or immunohistochemistry.  Towards this end, 
up to 30 slides (5 microns thick) will be retrieved from tissue blocks from the primary tumor, 
nodal disease, and/or sites of metastatic/ recurrent disease.  If slides need to be obtained from 
FNA or core biopsy specimens, particular care will be taken to minimize the slides taken so that 
the block is not exhausted.  Slides sent to MSKCC will be de-identified of patient data and 
labelled with the patient study number from MC1273.   
 
Samples may be sent to: 
 
 
 
 
 
 
 
 
 
 


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MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
18.0 
Records and Data Collection Procedures  
  
18.1 
Submission Timetable 
 
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) 
On-Study Form 
 
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 
 
X 
 


MC1273 
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MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
 
Observation 
 
Form 
Evaluation/Observation Form 
 
 
X 
Swallowing Function Assessment Form 
 
 
X3 
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)  
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 
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. 
 


MC1273 
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MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
19.0  
Budget 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
 
19.2 
Tests to be research funded by Mayo Clinic Institutional funding. 
 
 
19.3 
Other budget concerns: 
 
 
20.0 
References 
 
1. Ang KK, Harris J, Wheeler R, et al.  Human papillomavirus and survival of patients with 
oropharyngeal cancer. N Engl J Med 2010;363:24-35.) 
2. Bernier J, Domenge C, Ozsahin M, et al.  Postoperative Irradiation with or without Concomitant 
Chemotherapy for Locally Advanced Head and Neck Cancer.  N Engl J Med 2004;350:1945-52.). 
3. Gooley, et al. Estimation of failure probabilities in the presence of competing risks. Statist. Med. 
18, 695-706(1999)), 
4. Bernier J, Domenge C, Ozsahin M, et al.  Postoperative Irradiation with or without Concomitant 
Chemotherapy for Locally Advanced Head and Neck Cancer.  N Engl J Med 2004;350:1945-52). 
5. Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 
53:457-481, 1958.).   
6. Dayyani F, Etzel CJ, Liu M, et al. Meta-analysis of the impact of human papillomavirus (HPV) 
on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC). Head 
Neck Oncol 2010;2:15. 
7. REF:  Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat 
Assoc 53:457-481, 1958.) 
8. Gooley, et al. Estimation of failure probabilities in the presence of competing risks. Statist. Med. 
18, 695-706(1999). 
9. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-
positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 
2008;100:261-269. 
10. Lundahl RE, Foote RL, Bonner JA, et al. Combined neck dissection and postoperative radiation 
therapy in the management of the high-risk neck: a matched-pair analysis. Int J Radiat Oncol Biol 
Phys 1998;40:529-534. 
11. Bernier J, Cooper JS, Pajak TF, 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 2005;27:843-850. 
12. Kokal WA, Neifeld JP, Eisert D, et al.  Postoperative radiation as adjuvant treatment for 
carcinoma of the oral cavity, larynx, and pharynx: preliminary report of a prospective randomized 
trial. J Surg Oncol. 1988 Jun;38(2):71-6. 
13. Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and function relationships in parotid 
salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. 
Int J Radiat Oncol Biol Phys 1999;45:577-587.  
14. Blanco AI, Chao KS, El Naqa I, et al. Dose-volume modeling of salivary function in patients with 
head-and-neck cancer receiving radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:1055-1069. 
15. Kuhnt T, Jirsak N, Muller AC, et al. [Quantitative and qualitative investigations of salivary gland 
function in dependence on irradiation dose and volume for reduction of xerostomia in patients 
with head-and-neck cancer]. Strahlenther Onkol 2005;181:520-528.   
16. Levendag PC, Teguh DN, Voet P, et al. Dysphagia disorders in patients with cancer of the 
oropharynx are significantly affected by the radiation therapy dose to the superior and middle 
constrictor muscle: a dose-effect relationship. Radiother Oncol 2007;85:64-73. 


MC1273 
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MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
17. Debelleix C, Pointreau Y, Lafond C, et al. [Normal tissue tolerance to external beam radiation 
therapy: larynx and pharynx]. Cancer Radiother 2010;14:301-306. 
18. Pang E, Delic NC, Hong A, et al. Radiosensitization of oropharyngeal squamous cell carcinoma 
cells by human papillomavirus 16 oncoprotein E6 *I. Int J Radiat Oncol Biol Phys 2011;79:860-
865. 
19. Pradier O, Rave-Frank M, Lehmann J, et al. Effects of docetaxel in combination with radiation on 
human head and neck cancer cells (ZMK-1) and cervical squamous cell carcinoma cells (CaSki ). 
Int J Cancer 2001;91:840-845. 
20. Gallet P, Berengere P, Merlin J, et al.  PLoS 6:12, Dec 2011. 
21. Martin M, Lefraix J, Delanian S.  IJROBP 47:2, 2000. 
22. Eisbruch A, Teresa L, Bradford CR, et al.  Objective Assessment of Swallowing Dysfunction and 
Aspiration After Radiation Concurrent with Chemotherapy for Head and Neck Cancer.  IJROBP, 
2002.  Vol 53, No 1. 
23. Ukpo OC, Flanagan JJ, Ma X, et al.  Am J Surg Pathol. 35:9, September 2011 
24. Le QT, Raben D.  Integrating Biologically Targeted Therapy in Head and Neck Squamous Cell 
Carcinomas.  Semin Radiat Oncol.  2009 January; 19(1): 53–62. 
25. Hall EJ, Giaccia AJ.  Radiobiology for the Radiologist.  6th ed.  2006 by Lippincott Williams and 
Wilkins.  pp. 391-393. 
26. Peres J.  HPV-Positive Oropharyngeal Cancer: Data May Justify New Approach.  JNCI 2010, 
Vol. 102, Issue 19. 
27. Haraf DJ, Rosen FR, Stenson K, et al.  Induction Chemotherapy followed by Concomitant TFHX 
Chemoradiotherapy with Reduced Dose Radiation in Advanced Head and Neck Cancer.  Clin 
Cancer Res 2003;9:5936-3943. 
28. Eisbruch A, Teresa L, Bradford CR, et al.  Objective Assessment of Swallowing Dysfunction and 
Aspiration After Radiation Concurrent with Chemotherapy for Head and Neck Cancer.  IJROBP, 
2002.  Vol 53, No 1. 
29. Lewis JS, Carpenter DH, Thorstad WL, et al.  Extracapsular extension is a poor predictor of 
disease recurrence in surgically treated oropharyngeal squamous cell carcinoma.  Mod Path, 
2011.  Vol 24, No 11. 
 


MC1273 
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MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
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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MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
 
 
Appendix II 
 
 
Guidelines for the use of IMRT (including Intra-Thoracic Treatments) 
 
3/2009 
 
 
1. 
For all patients, as outlined in Section 7.0, the prescription isodose must cover 100% of the PTV 
volume; therefore, the total dose in the PTV_LOW volume will be 3000 cGy.  The minimum 
acceptable dose within PTV_LOW will be 3000 cGy.  If the minimum dose falls below these 
parameters, an unacceptable deviation will be assigned.  At least 98% of PTV_HIGH should be 
covered by 36 Gy.  The maximum dose for the PTV should not exceed 115%.  If the maximum 
doses exceed these parameters, an unacceptable deviation will be assigned. 
 
2. 
Up to 1 day of radiation treatment interruption is permitted for any reason. For interruptions of 2 
days or greater, an unacceptable deviation will be assigned.  In the case of toxicity there should 
be no deviation for breaks greater than one day. 
 
 
 
 
 
 
 
 


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MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
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. 


MC1273 
53  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
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 
 
 
 


MC1273 
54  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
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


MC1273 
55  
MCCC Addendum 6
 
 
 
Protocol Version Date:  October 03, 2017 
 
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. 


MC1273 
56  
MCCC Addendum 6
 
 
 
Protocol Version Date:  October 03, 2017 
 
 
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 


MC1273 
57  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
 
 
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 
 
 
Dur 
 
61. 
ing 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 
 
 
 
 
 
 
 
 
 
 


MC1273 
58  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
 
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 
 


MC1273 
59  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
 
 
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 
 


MC1273 
60  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
I am able to eat the foods that I like ..................................
0 
1 
2 
3 
4 
My mouth is dry ................................................................
0 
1 
2 
3 
4 
I have trouble breathing ....................................................
0 
1 
2 
3 
4 
My voice has its usual quality and strength ......................
0 
1 
2 
3 
4 
I am able to eat as much food as I want ............................
0 
1 
2 
3 
4 
I am unhappy with how my face and neck look ................
0 
1 
2 
3 
4 
I can swallow naturally and easily ....................................
0 
1 
2 
3 
4 
I smoke cigarettes or other tobacco products ....................
0 
1 
2 
3 
4 
I drink alcohol (e.g. beer, wine, etc.) ................................
0 
1 
2 
3 
4 
I am able to communicate with others ..............................
0 
1 
2 
3 
4 
I can eat solid foods ...........................................................
0 
1 
2 
3 
4 
I have pain in my mouth, throat or neck ...........................
0 
1 
2 
3 
4 
 
 
 
© Copyright 1994 EORTC Quality of Life Study Group, version 1.0 All rights reserved 
 
 


MC1273 
61  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
University of Michigan Xerostomia – Related Quality of Life Scale 
(XeQOLS) 
 
These questions are concerned with your oral health and how it affects your life.  Please answer the 
questions by checking the box that describes best how true each statement has been for you 
during the past 7 days. 
 
1. My mouth/throat dryness limits the kinds or amounts of food I eat. 
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
2. My mouth/throat dryness causes discomfort. 
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
3. My mouth/throat dryness causes a lot of worry or concern. 
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
4. My mouth/throat dryness keeps me from socializing (going out).  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
5. My mouth/throat dryness makes me uncomfortable eating in front of other people.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
6. My mouth/throat dryness makes me uncomfortable speaking in front of other people.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
7. My mouth/throat dryness make me nervous.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
8. My mouth/throat dryness makes me concerned about the looks of my teeth and mouth.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
9. My mouth/throat dryness keeps me from enjoying life.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
10. My mouth/throat dryness interferes with my daily activities.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
11. My mouth/throat dryness interferes with my intimate relationships.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
12. My mouth/throat dryness has a bad effect on tasting food. 
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
13. My mouth/throat dryness reduces my general happiness with life.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
14. My mouth/throat dryness affects all aspects of life.  
 
 
Not at all 
A little 
Somewhat 
Quite a bit 
Very much 
 
15. If you were to spend the rest of your life with your mouth/throat dryness just the way it is now, how 
would you feel about this?  
  
Delighted 
Mostly  
Mixed: equally 
Mostly  
Terrible 
 
 
    satisfied 
      satisfied/dissatisfied     dissatisfied 


MC1273 
62  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
DERMATOLOGY LIFE QUALITY INDEX 
 
Hospital No: 
Date: 
Name: 
 
Score: Address: 
 
Diagnosis: 
 
The aim of this questionnaire is to measure how much your skin problem has affected your 
life 
OVER THE LAST WEEK.  Please tick ; one box for each question. 
 
1. 
Over the last week, how itchy, sore, 
painful or stinging has your skin 
been? 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
 
2. 
 
Over the last week, how embarrassed 
or self conscious have you been because 
of your skin? 
 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
3. 
 
Over the last week, how much has your 
skin interfered with you going 
shopping or looking after your home or 
garden? 
 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
 
 
 
Not relevant 
Ɖ
 
 
4. 
 
Over the last week, how much has your 
skin influenced the clothes 
you wear? 
 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
 
 
 
Not relevant 
Ɖ
 
 
5. 
 
Over the last week, how much has your 
skin affected any social or 
leisure activities? 
 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
 
 
 
Not relevant 
Ɖ
 
 
6. 
 
Over the last week, how much has your 
skin made it difficult for 
you to do any sport? 
 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
 
 
 
Not relevant 
Ɖ
 
 
7. 
 
Over the last week, has your skin prevented 
you from working or studying? 
 
Yes 
No 
Ɖ
Ɖ
 
Not relevant 
Ɖ
 
 
 
If "No", over the last week how much has 
your skin been a problem at 
work or studying? 
 
A lot 
A little 
Not at all 
Ɖ
ƉƉ
 
 
8. 
 
Over the last week, how much has your 
skin created problems with your partner 
or any of your close friends 
or relatives? 
 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
 
 
 
Not relevant 
Ɖ
 
 
9. 
 
Over the last week, how much has your 
skin caused any sexual 
difficulties? 
 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
 
 
 
Not relevant 
Ɖ
 


MC1273 
63  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
 
10. 
 
Over the last week, how much of a 
problem has the treatment for your 
skin been, for example by making 
your home messy, or by taking up time? 
 
Very much 
A lot 
A little 
Not at all 
Ɖ
ƉƉƉ
 
 
 
 
Not relevant 
Ɖ
 
 
 
 
Please check you have answered EVERY question. Thank you. 
 
 


MC1273 
64  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
EQ 5-D 
By placing a checkmark in one box in each group below, please indicate which statement best 
describe your own health state today. 
 
Mobility 
 I have no problems in walking about 
 I have some problems in walking about 
 I am confined to bed 
 
Self-Care 
 I have no problems with self-care 
 I have some problems washing or dressing myself 
 I am unable to wash or dress myself 
 
Usual Activities (e.g. work, study, housework, family or leisure activities) 
 I have no problems with performing my usual activities 
 I have some problems with performing my usual activities 
 I am unable to perform my usual activities 
 
 
Pain/Discomfort 
 I have no pain or discomfort 
 I have moderate pain or discomfort 
 I have extreme pain or discomfort 
 
Anxiety/Depression 
 I am not anxious or depressed 
 I am moderately anxious or depressed 
 I am extremely anxious or depressed 
 
 
 
 


MC1273 
65  
MCCC Addendum 6 
 
 
Protocol Version Date:  October 03, 2017 
 
Best imaginable 
health state 
 


 
 
 
 
To help people say how good or bad a health state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can imagine is marked 100 and the worst state you can 
imagine is marked 0. 
  
We would like you to indicate on this scale how good or bad your  own  health  is  today,  in  
your  opinion. Please do this by drawing a line from the box below to whichever point on the scale 
indicates how good or bad your health state is today. 
 
 
 
 
 
 
 
 
Your own health state today 


 
 
100 
 
 
 
 
 
9 0 
 
 
 
 
8 
0 
 
 
 
 
7 
0 
 
 
 
 
6 
0 
 
 
 
 
5 
0 
 
 
 
 
4 
0 
 
 
 
 
3 
0 
 
 
 
 
2 0 
 
 
 
 
1 
0 
 
 
 
     0     
Worst imaginable health state