Randomized Phase II Study of Concentrated Beet Root in Participants Being Treated for Locally Advanced Unresectable, Previously Untreated Squamous Cell Cancer of the Head and Neck
Phase: PHASE2
Conditions: Mucositis
Sponsor: David Travis Thomas

13-HN-23-MCC: A Pilot study of Concentrated Beet Root in participants being
treated for locally advanced unresectable, previously untreated squamous cell
cancer of the head and neck:  
A University of Kentucky Markey Cancer Center Clinical Trial 
Principal Investigator: 
D. Travis Thomas, PhD, RD
Assistant Professor 
Phone: (859) 218-0863 
Fax: (859) 257-2454 
Email: david.t.thomas@uky.edu 
Co-Investigators: 
Mahesh Kudrimoti, MD 
Associate Professor 
Telephone:  (859) 323-6486 
FAX: (859) 257-7483 
Email: mkudr0@email.uky.edu 
Jody Clasey, PhD, FACSM 
Associate Professor 
Phone: (859) 257-8055 
Fax: (859) 323-1090 
Email: jlclas0@email.uky.edu 
Statistician 
Emily Dressler, PhD 
Assistant Professor 
Telephone: (859) 323-3076 
FAX: (859) 257-7715 
Email: emva222@uky.edu 
Version Date:  April 15, 2016 
IND: 120510 
NCT: 02058849

 
SCHEMA 
 
 
 

 
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 TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................0 
1. 
OBJECTIVES ......................................................................................................................3 
1.1 
Primary Objectives...................................................................................................3 
1.2 
Secondary Objectives...............................................................................................3 
2. 
BACKGROUND .................................................................................................................3 
2.1 
Squamous Cell Carcinoma of the Head and Neck ...................................................3 
2.2 
Reducing Toxicity to Therapy .................................................................................4 
2.3 
Concentrated Beetroot .............................................................................................4 
2.4 
Nitric Oxide Pathway and Cancer Risk ...................................................................5 
2.5 
Rationale ..................................................................................................................5 
3. 
PATIENT SELECTION ......................................................................................................6 
3.1 
Eligibility Criteria ....................................................................................................6 
3.2 
Exclusion Criteria ....................................................................................................7 
3.3 
Inclusion of Women and Minorities ........................................................................7 
4. 
REGISTRATION PROCEDURES .....................................................................................8 
4.1 
Protocol Review and Monitoring Committee and Institutional Review Board 
Review .....................................................................................................................8 
4.2 
Enrollment Guidelines .............................................................................................8 
4.3 
Informed Consent.....................................................................................................8 
4.4 
Compliance with Laws and Regulations..................................................................9 
5. 
TREATMENT PLAN ..........................................................................................................9 
5.1 
Standard of Care Treatment Administration ............................................................9 
5.1.1 Radiation Therapy ..................................................................................................10 
5.1.1.1 Dose Specifications ................................................................................................10 
5.1.1.2 Compliance Criteria ...............................................................................................10 
5.1.1.3 Radiation Therapy Adverse Events .......................................................................11 
5.1.1.4 R.T. Quality Assurance Reviews ...........................................................................11 
5.1.1.5 IMRT Dose Prescription to PTVs ..........................................................................12 
5.1.2 Drug therapy ..........................................................................................................13 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................17 
5.3 
Duration of Therapy ...............................................................................................18 
5.4 
Duration of Follow Up ...........................................................................................18 
5.5 
Criteria for Removal from Study ...........................................................................18 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................18 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................19 
7.1 
Adverse Event List(s) for Concentrated Beet Root ...............................................19 
7.2 
Adverse Event Characteristics ...............................................................................19 
7.3 
Expedited Adverse Event Reporting ......................................................................20 
7.4 
Expedited Reporting to External Agencies ............................................................21 
7.4.1 Expedited Reporting to the Food and Drug Administration (FDA) ......................22 
7.4.2 Expedited Reporting to Hospital Risk Management .............................................22 

 
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7.5 
Routine Adverse Event Reporting .........................................................................22 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................22 
8.1 
Beet Root Juice ......................................................................................................22 
8.2 
Labeling: ................................................................................................................23 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................24 
9.1 
Assessment of Body Composition and Quality of Life .........................................24 
9.2 
Blood and Saliva Collection for Plasma Nitrate, Nitrite and 25(OH)D, and 
Saliva Nitrate and Nitrite Measures .......................................................................25 
9.3 
Assessment of Muscle Strength and Endurance ....................................................25 
9.4 
Diet and nutrition status monitoring ......................................................................26 
9.5 
Other Study Measures Occurring Weekly .............................................................27 
10. 
STUDY CALENDAR .......................................................................................................27 
10.1 
Baseline Evaluations/Assessments ........................................................................27 
10.2 
Calendar for Beetroot Supplementation Cohort ....................................................27 
10.3 
Calendar for Observational Cohort ........................................................................28 
11. 
MEASUREMENT OF EFFECT........................................................................................28 
11.1 
Toxicity ..................................................................................................................28 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................34 
13. 
STATISTICAL CONSIDERATIONS...............................................................................34 
13.1 
Study Design/Endpoints.........................................................................................34 
13.2 
Sample Size/Accrual Rate ......................................................................................35 
13.3 
Data Analysis .........................................................................................................35 
13.4 
Reporting and Exclusions ......................................................................................36 
13.5 
Data Management ..................................................................................................36 
REFERENCES ..............................................................................................................................37 
APPENDIX A ................................................................................................................................40 
APPENDIX B ................................................................................................................................41 
APPENDIX C ................................................................................................................................42 
APPENDIX D ................................................................................................................................43 
APPENDIX E ................................................................................................................................44 
APPENDIX F.................................................................................................................................45 
 
 

 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
Obtain preliminary data estimates of treatment compliance of radiation alone  or 
chemoradiation (as defined by completion of initially prescribed radiotherapy and  
chemotherapy)  in patients receiving beetroot (dietary nitrate/nitrite supplementation) 
and treatment for head and neck cancer  
 
1.2 
Secondary Objectives 
• Quantify changes in strength, and body composition, before and following 
supplementation  
• Determine feasibility of beetroot supplementation in head and neck cancer patients 
defined for each patient as the proportion of days successfully consumed supplement 
during treatment schedule 
• Determine the toxicity of concentrated beetroot given in conjunction with radiation or 
chemo-radiation in SCCHN as measured by CTCAE v. 4.0 
• Evaluate the trend in grade of mucositis during radiotherapy or chemoradiotherapy as 
measured weekly by CTCAE v 4.0 
• Determine 1- and 2-year locoregional control rate and progression-free survival of 
subjects enrolled on this clinical trial. 
 
2. BACKGROUND 
 
2.1 
Squamous Cell Carcinoma of the Head and Neck 
 
Head and neck cancers are a group of geographically and biologically similar malignancies that 
originate in the upper aerodigestive tract, including the lip, oral cavity, nasal cavities, pharynx and 
larynx. The majority of these derives from the squamous mucosa, and often spread to regional 
lymph nodes of the neck, and subsequently to other distant sites. Head and neck cancer is strongly 
associated with tobacco exposure (both as smoking and chewing), alcohol consumption, and the 
human papillomavirus. Additional environmental exposures to various chemicals and dusts also 
predispose to head and neck cancer development, but are less common etiologies. These cancers 
are frequently aggressive in their biologic behavior, and some areas tend to present with more 
advanced disease, such as tumors which originate in the hypopharynx, as opposed to tonsillar or 
true vocal cord lesions, which tend to cause symptoms earlier in their course. Early-stage head and 
neck cancers have high cure rates with, though up to 50% of head and neck cancer patients present 
with advanced disease. As expected, cure rates decrease with more advanced disease cases, though 
patients with locally advanced disease, including those with regional nodal involvement, can still 
be cured with multimodality therapy. The most common regimen used in the setting of advanced 
disease is radiation 180 cGy of radiation given daily to a total dose of 6600 cGy to 7200 cGy with 
Cisplatin 100 mg/m2 every three weeks although cetuximab weekly is also given in the setting. 
Multimodality chemoradiation is toxic and approximately 50% of subjects in multiple clinical 
trials by the RTOG complete the prescribed radiation within 50 days.  In addition, only 67% of 
subjects receive all three planned doses of chemotherapy and this has been shown to impact overall 
survival and local control. Similarly patients receiving significant dose of radiotherapy to the oral 
mucosa suffers similar delays and compliance issues. Improving the tolerance of radiotherapy and 
chemoradiotherapy in head and neck cancer is an important avenue of investigation. Data from the 
American Cancer Society indicate that in 2012, an estimated 52,510 new cases of head and neck 
cancer will be diagnosed, of whom 10,500 patients will succumb to their disease (1). 

 
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2.2 
Reducing Toxicity to Therapy 
 
In head and neck cancer patients, compliance with combined modality treatment is essential to 
improve clinical outcomes. It is well known that compliance to treatment ranges from 50-70% and 
that the use of PEG tubes supports improved treatment compliance and outcomes by improving 
nutrient intake. Despite these findings, improved effectiveness has plateaued secondary to 
mucositis and side effects of multi-modal therapy including chronic fatigue, loss of muscle mass, 
and body fat. Various interventions have attempted to ameliorate the side effects of therapy in an 
effort to improve compliance. Medical therapies such as amifostine for radioprotection of normal 
tissue, and bezydamine, palifermin, and GCSF to reduce mucositis have not shown significant 
benefit.  
 
2.3 
Concentrated Beetroot   
 
Novel dietary supplementation strategies, proven helpful in other human studies, coupled with 
enteral support may serve as an inexpensive method to improve medical compliance, physical 
function/body composition, and quality of life. Looking beyond standard macronutrient 
supplementation, beet root may offer an innovative solution to improve compliance because it has 
been implicated as an effective ergogenic aid by improving endurance and strength. Moreover, due 
to the metabolism of its bioactive components, may interrupt the pathogenesis of mucositis. Beet 
root is gaining attention in the sport performance arena due to recent reports that supplementation 
improves exercise capacity, increases muscle contractile efficiency, and may elicit other 
cardiovascular benefits secondary to mediating the nitrate-nitric oxide metabolic pathway. Dietary 
nitrate from beetroot has been shown to reduce the oxygen cost of exercise and enhance muscle 
contractile efficiency by reducing the use of phosphocreatine and ATP utilization (2). Improved 
exercise capacity has been demonstrated through delayed time to exhaustion (3, 4), improved time 
trial performance (5-7), and reduced oxygen cost of exercise (3, 5, 8-11). Enhanced mitochondrial 
efficiency has been shown as well (8, 12, 13). Due to these significant muscle-related 
physiological changes observed in healthy/nitrate-sufficient subjects, it is plausible that 
improvements in physical function in a sick population that is nitrate (exogenous) deplete will be 
observed and that the active ingredients may have a significant impact on lean tissue preservation 
directly and indirectly (via increased mobility/QOL). Concentrated beet root also contains a unique 
class of strong antioxidants, known as betalains, which have been shown to inhibit lipid 
peroxidation and heme decomposition. Recently, beetroot has shown some promising results in 
head and neck cancer patients. Roszkowski, 2012 (14) recently supplemented beetroot chips to 
patients undergoing radiotherapy in an effort to learn if antioxidants from beets would influence 
parameters of oxidative stress and DNA damage. Their results indicated that beetroot did not 
worsen survival time and reduced intensification of acute radiation reactions while not influencing 
markers of oxidative stress/DNA damage. The authors suggested that beetroot supplementation 
may be a safe method for assisting medical therapy. 
 
Due to a direct correlation between compliance with medical therapy and improved clinical 
outcomes, there is a need to investigate promising interventions that may increase patient 
compliance with combined modality treatment, while concomitantly preserving muscle function 
and fat-free mass to further augment therapeutic gains. 
  
 
 

 
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2.4 
Nitric Oxide Pathway and Cancer Risk 
 
In the past, there has been concern of the effect of exposure to dietary nitrates and nitrites and an 
increased risk of cancer.  Indeed, the presence of nitrates and nitrites in food has been associated 
with an increased risk of gastrointestinal cancer in studies, predominantly the consumption of 
cured and processed meats (15). While associations of general dietary nitrite and nitrate 
consumption and cancer have guided the World Health Organization and others to recommend 
caution in ingestion, direct evidence of the negative effect on human carcinogenesis is lacking, 
despite extensive epidemiologic study (16). In addition, animal toxicological studies (17) have not 
conclusively established a relationship between nitrite exposure and the risk of cancer (18). The 
permissible concentration of nitrate in drinking water is 44 mg/L in the United States following 
World Health Organization recommendations 1970 and reaffirmed in 2004.  More recent reviews 
have suggested a difference in nitrite and nitrate exposure from fruits and vegetables which are 
generally reported as beneficial to cardiovascular health and exercise tolerance. (19-21) In one 
recent review, Bryan et al, concluded that there is no significant correlation between nitrite or 
nitrate ingestion and gastric cancer risk (20, 22). 
 
2.5 
Rationale 
 
The objective of the current proposal is to obtain pilot data to determine if concentrated beet root 
could potentially improve medical treatment compliance as defined by completion of radiotherapy 
or radiotherapy plus chemotherapy without dose reduction (primary outcome), and preserve fat-
free mass, and strength while reducing mucositis (secondary outcomes). Our central hypothesis is 
that dietary nitrate/nitrite supplementation in head and neck cancer patients receiving aggressive 
medical care will improve compliance with medical treatment by attenuating the loss of muscle 
mass and strength and reducing symptoms (mucositis) associated with treatment compared to 
patients  who do not receive dietary nitrate/nitrite supplementation. The rationale for this 
hypothesis is based on recent evidence that dietary nitrate supplementation improves measures of 
muscle strength, endurance, and performance capacity and the role nitrate may play in interrupting 
mucositis pathogenesis. Our long-term goal is to identify novel, nutrition intervention strategies to 
effectively reduce the negative side effects associated with chemotherapy and radiation that often 
impact therapeutic outcomes. Improvements in these outcomes will have a significant impact on 
augmenting the delivery of combined modal therapy and will contribute to improved quality of 
life.  
 
Our working hypothesis is that beetroot supplementation will enable head and neck cancer patients 
to improve treatment compliance as defined by completion of radiotherapy or radiotherapy plus 
concurrent chemotherapy without dose reduction as compared to historic controls. The rationale 
for improved treatment compliance is based on expected improvements in strength, endurance and 
mucositis symptoms following beetroot treatment. These improvements are hypothesized to be 
greater in a head and neck cancer patient population presumed to be nitrate deficient. 
 
 
 
 
 
 
 
 

 
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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have a histologically confirmed malignancy of the head and neck (nasopharynx, 
oral cavity, oropharynx, hypopharynx, larynx, sinuses, skin or salivary gland) without distant metastatic 
disease and be planned to receive a continuous course of conventional external beam 
irradiation to at least 55 Gy of radiation to at least 2 mucosal sites with or without 
chemotherapy.  Patients may have received induction therapy prior to definitive therapy for 
the current head and neck cancer.   
3.1.2 Patients may have a history of prior malignancy, but must be able to tolerate full dose 
radiation and chemotherapy for the current head and neck cancer, as determined by the 
treating oncologist. 
 
3.1.3 Age ≥18 years.   
 
3.1.4 ECOG performance status ≤2, see Appendix A. 
 
3.1.5 Life expectancy of greater than 3 months 
 
3.1.6 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes 
 
≥3,000/mcL 
− 
absolute neutrophil count 
 
≥1,500/mcL 
− 
platelets 
 
≥100,000/mcL 
− 
total bilirubin  
 
≤ 1.5 times ULN (upper limit of normal) 
− 
ALT and AST 
 
≤ 2.5 times the ULN  
− 
Creatinine  
 
≤ 1.5 times ULN  
 
OR 
 
− 
Measured creatinine clearance 
> 60 mL/min 
 
3.1.7 Able to swallow thin liquids or have a feeding tube for delivery of nutrition.  
 
3.1.8 No uncontrolled illness including, but not limited to, any of the following: 
— Ongoing or active serious infection  
— Symptomatic congestive heart failure  
— Unstable angina pectoris  
— Uncontrolled cardiac arrhythmia  
— Uncontrolled hypertension  
— Psychiatric illness or social situation that would preclude compliance with study 
requirements  
 

 
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3.1.9 No other concurrent anticancer therapies or agents.  
 
3.1.10 The effects of beet root on the developing human fetus are unknown.  For this reason and 
because the subjects will be undergoing radiation and chemotherapy, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 4 months after 
completion of beet root administration. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Active infection > CTCAE Grade 2, that is considered clinically serious by the treating 
physician. 
 
3.2.2 Pregnant women are excluded from this study because chemo-radiation has the potential 
for teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with chemo-
radiation, breastfeeding should be discontinued. 
 
3.2.3 While there are no well documented drug-beet root juice interactions, HIV-positive patients 
on combination antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions with these drugs and beet root juice.   
 
3.2.4 Subjects with a history of calcium oxalate nephrolithiasis are excluded. 
 
3.2.5 Subjects with a significant history of malabsorption (e.g. celiac sprue, short bowel 
syndrome, or other, as determined by the treating physician) are excluded. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. This study was 
designed to include women and minorities, but was not designed to measure differences of 
intervention effects. Men and women will be recruited with no preference to gender. No exclusion 
to this study will be based on race. Minorities will be actively recruited to participate. 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
1 
= 
1 
Not Hispanic or Latino 
8 
+ 
26 
= 
34 
Ethnic Category: Total of all subjects 
8
 
(A1) 
+ 
27 
= 
35
 
(C1) 

 
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Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
1 
= 
1 
Black or African American 
1 
+ 
2 
= 
3 
Native Hawaiian or other Pacific Islander 0 
+ 
0 
= 
0 
White 
7 
+ 
24 
= 
31 
Racial Category: Total of all subjects 
8
 
(A2) 
+ 
27
 
(B2) 
= 
35 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Protocol Review and Monitoring Committee and Institutional Review Board 
Review 
 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by the Markey Cancer Center’s Protocol Review and 
Monitoring Committee and the University of Kentucky Institutional Review Board (IRB). A 
signed and dated statement that the protocol and informed consent have been approved by the IRB 
must be maintained in the Markey Cancer Center Clinical Research Organization (MCC CRO) 
regulatory binder. Any amendments to the protocol, other than administrative ones, must be 
reviewed and approved by the PRMC, study sponsor and the UK IRB.   
 
4.2 
Enrollment Guidelines 
 
Eligible patients will be identified by the principal investigator and co-investigators of this study. 
Potentially eligible patients will be screened in the University of Kentucky Markey Cancer Center 
clinics by the investigators and study personnel. Upon obtaining proper consent, patients will be 
enrolled into the study.   
 
4.3 
Informed Consent 
 
The goal of the informed consent process is to provide people with sufficient information so they 
can make informed choices about whether to begin or continue participation in clinical research.  
The process involves a dynamic and continuing exchange of information between the research 
team and the participant throughout the research experience.  It includes discussion of the study's 
purpose, research procedures, risks and potential benefits, and the voluntary nature of 
participation. 
The informed consent document provides a summary of the clinical study and the individual's 
rights as a research participant.  The document acts as a starting point for the necessary exchange 
of information between the investigator and potential research participant.  Also, research 
participants and their families may use the consent document as an information resource and 
reference throughout participation in the trial.  The informed consent document is often considered 
the foundation of the informed consent process; it does not, however, represent the entirety of the 
process.  Nor is the informed consent document a risk-management tool for the investigator and/or 
institution. 

 
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The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time and 
that withdrawal of consent will not affect his/her subsequent medical treatment or relationship with 
the treating physician. 
 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient could 
not read or sign the documents. No patient can enter the study before his/her informed consent has 
been obtained.  The informed consent form is considered to be part of the protocol, and must be 
submitted by the investigator with the protocol at the time of IRB review. 
 
4.4 
Compliance with Laws and Regulations 
 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, any applicable local health authority, and Institutional Review Board 
(IRB) requirements.  The PI or designee will be responsible for obtaining continuing and not less 
than annual IRB re-approval throughout the duration of the study.  Copies of the Investigator’s 
annual report to the IRB and copies of the IRB continuance of approval must maintained by the 
MCC CRO.  The PI or designee is also responsible for notifying the Data and Safety Monitoring 
Committee of the MCC and the UK IRB of any significant adverse events that are serious and/or 
unexpected, as per SOP’s of those entities. The MCC DSMC will review all adverse events of this 
IIT as per its SOP.] 
 
5. TREATMENT PLAN 
 
This is a non-randomized, pilot Phase II clinical trial that will determine the safety of concentrated 
beet root given in conjunction with radiation or radiation plus chemotherapy for locally advanced 
head and neck cancer. This trial will enroll 25 subjects taking beetroot supplement with up to an 
additional 10 standard of care subjects that refuse participation in the beetroot supplementation but 
are willing to obtain strength outcomes during their cancer treatment for a maximum of 35 
patients. 
 
5.1 
Standard of Care Treatment Administration 
 
All treatment will be administered on an outpatient basis. Adult subjects with head and neck 
cancer who are planned to receive a continuous course of conventional external beam irradiation 
delivered by intensity-modulated radiotherapy 
(IMRT) as single daily fractions of 2.0 to 2.2 Gy, to a minimum cumulative radiation dose of 55 
Gy to at least 2 mucosal will be recruited through Markey Cancer Center to undergo screening and 
testing. Approximately a 3:1 ratio of males to females will be recruited based on reported cases of 
head and neck cancer, although no preference will be given to either sex. Based on Kentucky’s 
ethnicity statistics, we expect to have a Caucasian: African American ratio of 9:1, as ethnicity and 
race are not exclusion criteria. The population is readily accessible from this resource. We plan to 

 
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enroll patients who are primarily fed enterally by a percutaneous endoscopic gastrostomy (PEG) 
tube. Patients on “po” diets with thin (standard consistency) liquids are also eligible. Dr. Kudrimoti 
will initially identify patients who are eligible based on the aforementioned criteria. A research 
associate will then explain the study to eligible participants and provide a research flier. Interested 
volunteers will then complete the formal consenting process prior to participation with the research 
associate under the direction of Drs. Kudrimoti and Thomas.  
 
5.1.1 Radiation Therapy 
All radiation therapy is considered standard of care, and toxicities and dose modifications will be 
made by the treating physician based on institutional standards.  The guidelines below are 
recommended practice but may be modified at the discretion of the treating radiation oncologist. 
 
5.1.1.1 
Dose Specifications  
 
IMRT has been a standard of care in the U.S. beginning in 2005 and is now widely used in 
practice. Use of H&N IMRT in RTOG protocols (and associated QA) was begun in 2005 in RTOG 
0522, as an optional technique. At the close of the accrual phase, approximately 90% of cases 
enrolled on 0522 (>800 patients) were treated with IMRT. Oropharynx cases comprised 70% of 
the study population.  
 
IMRT will be delivered in 30-35 fractions over 6.-7 weeks, 5 fractions weekly. The primary tumor 
and involved nodes (CTV1) will typically consist of a 0.5-1.5 cm expansion of the gross tumor 
volume (GTV) to cover potential local invasion and will be prescribed 2 Gy/fraction, total 55-70 
Gy. High-risk sub-clinical disease sites, which include possible local subclinical infiltration at  the 
primary site (primary site CTV2) and first echelon nodes, which are not clinically or 
radiographically involved (nodal CTV2), should be expanded by 3-5 mm to create PTV2. PTV2 
should receive 1.6 Gy/fraction to a total dose of 52.8 Gy to 56 Gy. Lower-risk targets (PTV3) 
(such as neck nodal levels which are not first echelon nodes and are not adjacent to levels 
containing grossly involved nodes) will be prescribed 50-52.5 Gy .: If the low neck is treated, the 
preferred technique is to treat with isocentric matching AP or AP-PA fields with larynx block, 
matched to the IMRT portals just above the arytenoids. The dose will be 2 Gy per fraction 
prescribed to 3 cm depth to a total dose of 50 Gy in 25 daily fractions. Whole-neck IMRT is 
allowed.  This can be achieved by either boosting the low neck field with an additional 16 Gy in 8 
fractions, by an AP or AP-PA fields, or by planning the whole neck using IMRT. In cases of gross 
involvement of the vallecula or low neck, whole-neck IMRT should be considered.  Whole-neck 
IMRT may also be considered if level VI is considered to be at risk due to gross involvement of 
level IV nodes. All plans must be normalized such that 95% of the volume of the PTV is covered 
with prescription dose..  
 
In cases of weight loss > 10% or significant shrinkage of lymphadenopathy during therapy, it is 
recommended that the immobilization mask will be adjusted or re-made in order  to preserve 
adequate immobilization, and that a repeated simulation CT be performed to assess the dose 
distributions in the current anatomy. Whether or not a new IMRT plan will be generated is at the 
discretion of the treating physician. If a new plan is made, the targets should be the same as those 
used for the initial plan. The new CT dataset should be used for IGRT image registration when the 
patient’s shape changes significantly.  
 
5.1.1.2 
Compliance Criteria 
 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for the 

 
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treatment break(s). Treatment breaks, if necessary, ideally should not exceed 5 treatment days  at  a  
time  and  10  treatment  days  total.  Treatment breaks should be allowed only for resolution of 
severe acute toxicity and/or for intercurrent illness and not for social or logistical reasons.   Any   
treatment   break(s)   exceeding   2   treatment   days   for   reasons   other   than toxicity/illness 
will be considered a protocol deviation. The following define compliance: 
• 
Overall RT treatment time: 
 ≤ 52 days (compliant) 
 > 52 days (non-compliant)  
• 
Up to 57 days for non-medical reasons (such as holiday, machine breakdown) as 
determined by the treating radiotherapy physician.  
Missed treatments due to holidays or logistic reasons can be compensated for by delivering an 
additional BID treatment during the week, OR treating on the Saturday or Sunday of that week, 
OR adding to the end of treatment. These additions will not be considered non-compliance. 
 
5.1.1.3 
Radiation Therapy Adverse Events 
 
Grade 3-4 (CTCAE, v. 4.0) therapy-induced mucositis and/or dysphagia, which are enhanced by 
cisplatin, are expected to develop in about two thirds 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, 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, and cervical myelopathy 
(< 1% with restriction of spinal cord dose to ≤ 45 Gy). 
 
5.1.1.4 
R.T. Quality Assurance Reviews 
 
RTOG uses several approaches to ensure H&N IMRT quality assurance (QA) including H&N 
anatomic atlases, site and machine certification of H&N IMRT, and individual case reviews.  The 
department QA committee will perform RT Quality Assurance Reviews for this trial. 
Technical Factors, Localization, Simulation, and ImmobilizationPatients must have an 
immobilization device (e.g. Aquaplast mask) made prior to treatment planning CT scan. 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. 
  
Treatment Planning/Target Volume: 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 if it is judged clinically that the skin is at 
risk but is generally not recommended. In general, the CTV-to-PTV expansion (without IGRT) 
should not exceed 10 mm. In general, the CTV-to-PTV expansion (with IGRT) should not exceed 
5 mm. 
 
Definition of Normal Tissues/Organs at Risk (OARs): NOTE: Only the parts of the normal 
tissues/organs at risk outside the PTVs will be considered for dose optimization purposes. 
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 

 
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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. 
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. 
 
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 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. 
Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan. 
 
Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom of 
oropharynx and extends to the thoracic inlet. 
 
Glottic/Supraglottic Larynx (GSL): 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. 
 
Mandible: This includes the entire bony structure of the mandible from TMJ through the 
symphysis. 
 
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. 
 
5.1.1.5 
IMRT Dose Prescription to PTVs 
 
The goal is for 95% of the planned PTV to receive ≥ 2 Gy with a minimum dose (cold spot) It is 
recognized that portions of the PTV close to the skin may receive significantly less. This is 
acceptable as long as cold spots within PTV1 do not exist at a depth deeper than 8 mm beneath the 
skin  
 
For planning prioritization and priorities in dose coverage, in the final plan, PTV1 will be the 
highest priority target structure. PTV2 and PTV3, if applicable, will be ranked in the IMRT 
planning as lower priority than PTV1m although usually at a higher priority than normal structures 
other than spinal cord and brain stem. 
 
Doses to Normal Structures  
Spinal Cord: The PRVcord should not exceed ≤ 50 Gy to any volume in excess of 0.03 cc 
(approximately 3 mm x 3 mm x 3 mm).  
Brainstem: The PRV brainstem (as defined in Section 6.4.2.2) should not exceed 52 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm).  
Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy. 
Oral Cavity:  Reduce the dose as much as possible. The mean dose should be < 30 Gy for the non-

 
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involved oral cavity. Efforts should also be made to avoid hot spots (> 60 Gy) within the non-
involved oral cavity. 
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The treatment 
planning goal will be for this individual parotid gland to receive a mean dose of < 26 Gy. 
Contralateral submandibular gland: If contralateral level I is not a target, aim to reduce mean 
contralateral submandibular gland to < 39 Gy. 
Mandible: Reduce the dose as much as possible.  Hot spots within the mandible should be avoided. 
It is recommended that maximum dose within the mandible be < 66 Gy. 
Unspecified Tissue Outside the Targets: No more than 1cc of unspecified tissue outside the targets 
can receive 74 Gy or more. 
 
Prioritization for IMRT Planning 
1.   Spinal Cord 
2.   Brainstem 
3.   PTV1 
4.   PTV2 (if applicable) 
5.   PTV3 (if applicable) 
6.   a. Oropharynx b. Parotid gland contralateral to primary tumor site 
7.  a. GSL b. Esophagus  
8.  a. Lips b. Oral Cavity 
9.  a. Parotid gland ipsilateral to primary tumor site b. Mandible 
10. Unspecified tissue outside the targets 
 
5.1.2 Drug therapy 
 
All systemic therapies are considered standard of care, and toxicities and dose modifications will 
be made by the treating physician based on institutional standards.  Drugs are commercially 
available and are not considered investigational. 
 
Patients Receiving Cisplatin or Cetuximab with Concurrent Radiation Therapy (RT)  
 
Patients who receive cisplatin, will receive 100 mg/m2, administered intravenously every three 
weeks (with a three day window) as per institutional standard.  Patients who receive cetuximab 
will receive a loading dose of 400 mg/m² given at least 5 days prior to radiation initiation and 250 
mg/m² given weekly during radiation. Chemotherapy can be given either before or after the 
radiation therapy fraction that is given on the same day. If radiation is held for more than 2 days 
(for any reason), cisplatin may be held as well until radiation resumes. High dose cisplatin is a 
highly emetogenic regimen with significant incidence of delayed nausea and vomiting whereas 
cetuximab is less than that at Gen.. Institutional guidelines for anti-emetic regimens should be 
followed per physician preference and institutional guidelines. Supportive care guidelines will vary 
by drug type but are standardized at the Markey Cancer Center via standardized chemotherapy 
order sets and electronic medical record order entry for all patients. 
 
5.1.3 Beetroot Administration 
 
Study Supplements:  
Subjects will be given 10 grams of concentrated organic beetroot crystals to mix with 120ml of 
water (BEETELITE™). Beetelite study supplement readily dissolve in water and may be given via 
gastrostomy tube or orally. 
 

 
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Daily Supplement Administration: 
Subjects will begin daily supplementation following baseline measures (1-2 weeks before 7-week 
IMRT and for a minimum of 4 days) and will continue supplementation 4-6 weeks after treatment. 
Patients will be taught to self-administer their assigned study beverage by mouth and via PEG (as 
needed) by study staff during the baseline measurement period for the entirety of the trial. Patients 
requiring enteral support will be taught how to self-administer their assigned study beverage by a 
CRA or CRN. Compliance will be monitored by verbal assessment at clinic visits and by 
collection of written logs.  Written instructions (Appendices E and F) for proper mixing of study 
beverage powders with water will be provided to both study volunteers and MCC staff involved in 
supplement administration and supervision. MCC staff will supervise the initial self-administration 
to ensure uniformity of ingestion.  Subjects will be required to record the supplement intake in a 
dietary log which will be reviewed frequently at clinic visits.    
 
Beetroot will be self-administered daily (M-F) at the same time each day during the afternoon 
hours (12pm-5pm) and if possible, should be dosed after radiation to promote a consistent 
administration/habit. IDS will provide pre-measured 10g portions of the supplement powder each 
week during the IMRT period. The patient will mix and administer, and will record that they took 
the product daily in the compliance log that will be brought back and assessed at clinic.  If at any 
point during the 7-week IMRT treatment the patient is unable to self-administer, the patient’s 
family or study personnel who are recognized as clinical providers (such as a CRN) will mix the 
water and powder and will aid in supplement administration if the patient wishes to continue with 
the study. Subjects will then be discharged with beetroot for daily dosage (M-F) throughout the 
post IMRT follow-up period. Standard PEG tube care guidelines will be followed and the tube will 
be flushed with 30 to 50mL of water before and after every supplement dose. For patients 
requiring supplement administration assistance at IMRT discharge, a family member or caregiver 
of the patient will be identified and taught to provide assistance during the MP-EP follow-up 
period. An additional copy of the written mixing/administration instructions will be provided at 
this time and study staff will offer additional instructional assistance as needed.  
 
Subjects who vomit the beetroot within the first 15 minutes after administration may repeat the 
administration once that same day.  If vomiting occurs greater than 15 minutes after 
administration, the dose should not be repeated. Vomiting will be closely monitored and additional 
supplement packets will be provided at discharge in case of vomiting. 
 
Study volunteers will be asked to retain all used and unused study packaging on a weekly basis to 
turn in to study staff at the end of the week. Study packaging will be compared to the patient 
generated compliance log to document weekly compliance data.   Subjects who are deemed “non-
compliant” with the beetroot protocol (less than 3 consumed supplements during any 1 week 
period between baseline and midpoint measures) will be excluded in the per protocol analysis. 
Compliance to beet root consumption between midpoint and endpoint measure will be encouraged 
with weekly phone calls by nutrition graduate students supervised by Dr. Thomas. Dr. Thomas will 
oversee all aspects of the supplementation protocol. The Investigational Drug Service (IDS) at the 
University of Kentucky will assist with storage, supply management, quality control, and transfer 
of all beet root. 
 
Bulleted supplementation administration guidelines for each study period are provided below: 
Baseline and prior to IMRT enrollment (supplement initiation period): 
• Following randomization, participants will be taught to self-administer their supplement by 
study personnel. 

 
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• The CRA or nutrition student will then distribute the supplement needed for the 1-2 weeks 
prior to IMRT to the participant. 
• The supplement powder will be packaged in 10g portions by the IDS. Packaging will only 
be identified by the letter “A” or “B” and only IDS staff will be unmasked to supplement 
assignment. 
• Participants will begin daily, single dose supplementation (M-F during the afternoon hours) 
on the first day of receiving their supplement from study personnel. 
• Participants will be taught to mix their assigned powder with 120mL of water and self-
administer within 30 minutes of mixing. 
• Compliance during this time period will be encouraged by phone calls, a supplement 
“count,” and with a patient generated supplement log sheet. 
 
7-8 week IMRT treatment period (daily supplement observation period): 
• Participants will be asked to continue daily (M-F) self-administration of the supplement. 
The pre-measured supplement powder will be provided to the participant on a weekly basis 
and patients will be asked to consume the supplement during the afternoon hours (M-F). 
• At the beginning of treatment and throughout the IMRT period, study personnel will assess 
the need to provide additional education on proper self-administration of the study 
supplement (ex. Transitioning from PO feeding to enteral feeds).  
• CRNs serving as study personnel may offer observation or administration assistance if 
patient requests this and may document supplement compliance. 
• Patients will be instructed to make up any missed doses by taking up to 1 additional dose 
per day on the weekend days. Patients will receive 5 doses per week (for M-F) and will be 
instructed to never exceed 1 dose per day. 
 
4-6 weeks post-IMRT (discharge period): 
• After completion of IMRT the participant will be instructed to continue daily (M-F) self-
administration (PO or PEG) until completion of endpoint measures. 
• For patients requiring supplement administration assistance at discharge, a family member 
or caregiver will be identified and taught to provide assistance. 
• On the day of discharge and during scheduled follow-up visits, the CRA will distribute the 
pre-measured supplement packets needed for daily administration. 
• Participants will continue to follow the supplement mixing protocol and be reminded to 
consume their assigned supplement within 30-minutes of mixing. 
• Supplement compliance will continue to be encouraged by weekly phone calls by study 
personnel and compliance logs/supplement counts will occur at least twice per month. 
 
Supplementation on Testing Days 
 
On testing days, The BEETELITE™ solution (beet root) will be administered on-campus 20-45 
minutes before subjects undergo the baseline, midpoint (following IMRT), and endpoint (4-6 
weeks following midpoint) strength/endurance measures. Prior to testing, subjects will not have to 
refrain from standard oral care, using antibacterial mouth wash, or chewing gum 48 hours before 
testing sessions because the BEETELITE™ product does not rely on salivation/oral bacteria to 
convert dietary nitrate to nitrite (23). Previous studies have administered up to 500mL of beet root  
per day with nitrate concentrations of 5.5 mMol (24), 6.2mMol (7, 25), 5.2mMol (26), and 
5.1mMol (27). Plasma nitrite (NO2¯) levels in these aforementioned studies also increased 
following dietary nitrate supplementation.  

 
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5.1.4 Subjects will elect not to participate in beet root supplementation study 
 
Subjects to elect not to participate in the beet root supplementation study will be asked to consider 
participation in an observational study of muscle strength testing that matches the muscle strength 
testing of those receiving beet root supplementation during their cancer treatment. These subjects 
will be performing cohort of non-therapeutic interventional subjects who will provide baseline 
information in a preliminary manner as a comparator to those subjects receiving beet root 
supplementation.  This is not a randomization but rather utilization of subjects who would otherwise 
not be participating in the clinical trial. These subjects will be compensated for their time in a similar 
manner to subjects who are on the beat root supplementation study. A separate consent form will be 
used and a separate registration will be used for these patients.   
 
5.1.5 Testing procedures at Baseline, Midpoint and Endpoint of therapy 
 
All testing procedures, unless otherwise indicated, will be performed at the Markey Cancer Center 
(MCC) and the Center for Clinical and Translational Science (CCTS). Testing will occur at 
Baseline (Pre-IMRT), Midpoint (week number 7-8 following IMRT initiation), and Endpoint (4-6 
weeks following Midpoint testing). A range of testing times at midpoint and endpoint are provided 
for subject convenience and flexibility with medical follow-up appointments. Primary outcome 
measure: 1) IMRT treatment compliance- No delays in treatment of radiation and/or chemotherapy 
(Cycles: Namely 35 fraction of daily radiation therapy (Monday-Friday) with 100 mg/m2 cisplatin 
on days 1, 21, & 43. Total duration of therapy = 50 days). Treatment compliance will be defined as 
completion of all radiotherapy or completion of all radiotherapy plus  prescribed chemotherapy 
without dose reduction or delay of radiation therapy that would extend treatment beyond 50 days.; 
Secondary outcome measures: 1) muscle strength/function, 2) serum/salivary nitrate/nitrite, 3) 
preservation of fat-free mass (CT/DXA), 4) mucositis symptoms, 5) nutrition assessment, 6) 
quality of life g. Details of each test are provided in section 9.0. 
 
5.1.6 General Testing Procedures and Blinding 
 
A trained CCTS exercise physiologist will complete DXA, Biodex strength/endurance measures, 
and handgrip dynamometry under the direction of Drs. Thomas and Clasey. CT measures will be 
performed by trained MCC staff at baseline, midpoint and endpoint, and will be overseen by Dr. 
Clasey. Quality of life (FACT H/N version 4) assessment will be administered by the study 
exercise physiologist. Assessment for toxicity to radiotherapy or chemoradiotherapy and mucositis 
assessment will be completed on a weekly basis by Dr. Kudrimoti and will serve as a safety 
measure. Nutrition intake will be collected during clinical status checks by a trained clinical 
nutrition graduate student under the direction of Dr. Thomas.  
 
 
5.1.7 Testing Order 
 
As part of a scheduled medical visit, computed tomography (CT) scans at the MCC will be the first 
measurement completed on testing days unless a medical scheduling conflict requires rescheduling 
(within 7 days of other time point measures). Following CT measures, subjects will be transported 
via wheelchair by the CRA to the CCTS for QOL assessment and total body dual energy x-ray 
absorptiometry (DXA) scanning. The study supplement will then be self- administered at a discrete 
location. At 25 minutes post supplementation, plasma will be collected to measure nitrate/nitrite 
content. At 30 minutes post supplementation, saliva will be collected to measure salivary 

 
17 
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nitrate/nitrite content. At approximately 35 minutes post supplementation, Biodex strength and 
endurance assessments will be initiated (knee extensors) followed by hand-grip dynamometry 
approximately 60 minutes post supplementation in the Multidisciplinary Science Building (MDS). 
All secondary outcome measurements (with the exception of CT) will be completed at the 3 
aforementioned time points.  
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients will undergo clinical toxicity assessment on a weekly basis in the clinic. Toxicity 
assessment will be made as per the CTCAE version 4.0 as assessed by medical and radiation 
oncology physicians. All toxicities and their attribution will be recorded, regardless of attribution.  
Of particular interest will be toxicities that are possible, probable or definitely related to 
administration of beet root, as determined by the treating physician or related to acute radiation 
toxicities of: mucositis, radiation skin reaction, radiation pneumonitis, or dry mouth. Staging of 
tumors will be done as per the multidisciplinary head/neck team using AJCC staging manual 
version 7. The response to treatment will be made by repeating clinical and radiological studies as 
per standard of care (6- 12 weeks) and repeated during follow up as per NCCN guidelines. Patients 
will be followed until resolution of all grade 2 or greater toxicities.  
 
Supportive Care: 
Mucositis: 
If patients require supporting care for mucositis-related pain during concurrent chemotherapy and 
radiation treatment, the following regimen is recommended, but the local standard of care is 
permitted. 
• A compound containing viscous lidocaine and magnesium aluminum oxide (Maalox®) or 
sucralfate; 
• Liquid or solid oxycodone, 5-10 mg, every 3-4 hours as needed. 
 
Nutritional Support: 
Patients may take nutritional supplements (i.e. protein/kcal), such as Ensure®, but should refrain 
from other nutritional supplements (i.e. nutraceuticals).  Patients may take appetite stimulants as 
prescribed by treating physicians.  Feeding tubes are encouraged to prevent malnutrition.  
 
Febrile neutropenia will be managed according to accepted guidelines. Measures may include 
appropriate laboratory testing, including blood and urine cultures. If a source for the fever is not 
identified or the fever resolves when the neutrophil count recovers, antibiotics may be 
discontinued and the patient observed. 
 
Antiemetics: Antiemetics may be necessary. The use of antiemetics is encouraged to prevent 
dehydration. The specific drugs will be left to the treating physician’s discretion. 
 
Other Concomitant Medications: Therapies considered necessary for the wellbeing of the patient 
might be given at the discretion of the investigator.  Other concomitant medications should be 
avoided except for analgesics, chronic treatments for concomitant medical conditions, or agents 
required for life-threatening medical problems.  All concomitant medications, including over-the-
counter and/or alternative medications, must be recorded. 
 

 
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Other Anticancer or Experimental Therapies: No other anticancer therapy (including 
chemotherapy, radiation, hormonal treatment or immunotherapy) of any kind is permitted during 
the study period. No other drug under investigation may be used concomitantly with the study 
drug. 
 
Treatment For Diarrhea: Diarrhea should be treated promptly with appropriate supportive care, 
including loperamide.  Instruct patients to begin taking loperamide at the first signs of: 1) poorly 
formed or loose stool, 2) occurrence of more bowel movements than usual in one day, or 3) 
unusually high volume of stool.  Loperamide should be prescribed in the following manner: 4 mg 
at first onset of diarrhea, then 2 mg after each unformed stool. Daily dose should not exceed 16 
mg/day. Loperamide should not be taken prophylactically. Advise patients to drink plenty of clear 
fluids to help prevent dehydration caused by diarrhea. Avoid loperamide if there is blood or mucus 
in the stool or if diarrhea is accompanied by fever. If grade 3 or 4 diarrhea develops, discontinue 
further treatment until the diarrhea has recovered to grade 1 or less.  Although unlikely, in the event 
that fatigue is encountered, medications such as modafinil and methylphenidate may be used at the 
investigator’s discretion. 
 
5.3 
Duration of Therapy 
 
Subjects will be removed from study if one of the following occurs: 
 
• 
Subjects who do not complete at least 50% of the planned medical therapy  
• 
Intercurrent illness that prevents further administration of medical treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.4 
Duration of Follow Up 
 
The response to treatment will be made by repeating clinical and radiological studies as per standard 
of care (at 6-12 weeks) and repeated during follow up as per NCCN guidelines. Patients will be 
followed until resolution of all grade 2 or greater toxicities.  
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The following dosing delays and dose modifications refers only to adverse events which are at 
least possibly related to beetroot juice.  When grade 3 and 4 toxicities are encountered and are 
possibly, probably or definitely related to beetroot juice, please use the following  dose reduction 
table.  
 
Event 
Management/Next Dose for Beet Root  
≤ Grade 1 
No change. 
Grade 2 
No change 

 
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Event 
Management/Next Dose for Beet Root  
Grade 3 or 4 
Hold until recovery to grade 2 or less, then decrease to 
Monday-Wednesday-Friday dosing 
 
Exceptions to this procedure include: any grade alopecia and grade 3 or 4 fatigue. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via Mandatory Medwatch Forms 3500a) 
in addition to routine reporting in OnCore. 
 
7.1 
Adverse Event List(s) for Concentrated Beet Root  
 
BEET ELITE™ is an oral concentrated beet root dietary supplement and not specifically FDA 
approved. Since BEET ELITE™ is not a drug, there is no Investigator Brochure.  This supplement 
will be obtained from Neogenis® Labs, Inc., Austin, Texas. The BEET ELITE™  product is made 
from organic beet root crystals, natural flavors, malic acid, and stevia extract and is manufactured 
in a GMP certified facility. The concentration of the shot is equivalent to 6 beets in one shot. 
 
Beet Root Toxicities:  
Potential adverse effects of beet root are rare and include: stomach cramping/diarrhea, pink 
coloration of urine and stools, and allergic reactions. These side effects are consistent with events 
that may occur with normal beet consumption (as a food). There have been no reports of mucosal 
injury in the head and neck, or irritating effect on the oral mucosa.   
 
Methemoglobinemia has been reported in infants who have consumed high levels of nitrate, but 
these findings have largely been discredited due to confounding cases of gastroenteritis and co-
ingestion of sodium nitrite (from contaminated well water). Methemoglobinemia has not been 
documented in adults consuming nitrates at the level proposed in this trial. Given the oxalate 
content of beet root  (28), caution should be taken for individuals with a history of nephrolithiasis 
or gall bladder dysfunction.  
 
7.2 
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. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which is 
provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 

 
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• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 
7.3.1 For MCC Investigator-Initiated Trials (IITs), investigators must report to the Overall PI 
any serious adverse event (SAE) that occurs after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment on the local institutional SAE 
form. This applies to the following categories: 
• Grade 3 (severe) Medical Events – Only events that are Unexpected and 
Possibly, Probably or Definitely Related / Associated with the Intervention. 
• ALL Grade 4 (life threatening or disabling) Medical Events – Unless 
expected AND specifically listed in protocol as not requiring reporting. 
• ALL Grade 5 (fatal) Events regardless of study phase or attribution 
 
Note: If subject is in Long Term Follow Up, death is reported at continuing review.  
Note: Abnormal laboratory values are not considered medical events, unless determined to 
be causative of SAE by the investigator or grade 5  
 
 

 
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7.3.2 The following table outlines the required forms and reporting structure for clinical trials. 
Study type 
Expedited reporting 
to MCC 
Expedited 
reporting to 
External Agency 
Non-
expedited 
AE 
Form 
IRB 
IIT where 
MCC 
investigator 
holds the IDE 
or IND 
• 
Grade 3 – 
Unexpected AE 
PLUS Possibly, 
Probably or 
Definitely 
Related  
• 
ALL Grade 4 
Unless expected 
AND listed in 
protocol as not 
requiring 
reporting. 
• 
ALL Grade 5 
(fatal) Events 
FDA: 
Suspected AE 
that is serious 
and 
Unanticipated 
(not listed in  
consent) 
OnCore  and 
DSMC 
reporting 
only 
Mandatory 
Medwatch 
3500a for 
Serious and 
unanticipated 
 
OnCore for all 
AEs, including 
SAEs 
 
 
Yes if it meets 
the IRB 
reporting 
requirements: 
Unanticipated 
Problem and/or 
Serious AE 
(use IRB AE 
reporting form 
for all 
correspondence 
with IRB) 
 
 
 
7.3.3 MCC Expedited Reporting Guidelines for MCC IITs 
 
Investigators within MCC will report SAEs directly to the MCC DSMC per the MCC 
DSMC SOP and the University of Kentucky IRB reporting policy.  
 
 
 
 
Attribution 
MCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event. 
 
 
 
7.3.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
N/A 
 
7.4 
Expedited Reporting to External Agencies 
 
The Overall PI will comply with the policies of all external funding agencies and the UK IRB 
regarding expedited reporting, as per the UK IRB’s SOP: 
http://www.research.uky.edu/ori/SOPs_Policies/C4-0150-
Mandated_Reporting_to_External_Agencies_SOP.pdf. 
 

 
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7.4.1  Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.   
 
7.4.2 Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to the UK Office of Risk Management any participant safety 
reports or sentinel events that require reporting according to institutional policy.  
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
OnCore case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the commercial agents administered 
in this study can be found in Section 7.1. 
 
8.1 
Beet Root Juice 
 
8.1.1 List of Supplement Ingredients  
• Ingredient List: Organic Beetroot Crystals, Natural Flavors, Malic Acid and Stevia Leaf 
Extract 
• Neogenis® Labs is not able to release proprietary information that describes the specific 
formulation because of product competitors and privacy issues. 
  
 
8.1.2 Beet Root Juice (BEET ELITE™ ) Product Description 
Product description: BEET ELITE™ is an oral concentrated beet root dietary supplement. One 
10g packet contains both nitrate and nitrite. Typically, only about 5% of beet nitrates are 
metabolized to active intermediates taking at least 90 minutes. BEET ELITE™ is a revolutionary 
formula that includes a natural form of nitrite, thus bypassing the inefficient nitrate reduction 
process.  BEET ELITE™ begins working in 15 minutes and has the Nitric Oxide content of 6 beets 
in one shot. The recommended dose is typically one shot per day. Product is available through 
Neogenis® Labs, inc., and is available online as a dietary supplement.  
 
8.1.3 Solution preparation:  
BEET ELITE™ products are individually packaged in 10g packets and must be mixed with 120ml 
of water and consumed within 30 minutes of mixing. Participants will be taught to prepare and 
self-administer their assigned study supplement and IDS will provide participants with the water 
and powder packet during the IMRT treatment period. 
 
8.1.4 Route of administration:  
BEET ELITE™ products will be self-administered throughout the entire study period via enteral 

 
23 
Version Date: 4/15/2016 
tube (PEG) or by mouth as a thin liquid (PO). Participants will be asked to take this product mixed 
with water (120ml) daily (M-F) without supervision. Participants will be instructed to administer 
BEET ELITE™ in the afternoon hours by mouth or by using their PEG tube in accordance with 
standard PEG feeding tube guidelines. Participants should flush their feeding tube with 30-50mL 
of water before and after supplementation. This supplement can be served cold or at room 
temperature within 30 minutes of mixing and may be tolerated best at room temperature if given 
enterally.  
 
8.2 
Labeling:  
 
8.2.1 BEETELITE Labeling 
Below is a copy of the container label for a single dose NEoShot product. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

 
24 
Version Date: 4/15/2016 
 
8.2.2 The following label will be used for the study medication 
 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
CCTS testing procedures are described below in the planned order of occurrence on testing days: 
 
9.1 
Assessment of Body Composition and Quality of Life 
 
9.1.1 Computed Tomography (CT) 
 
Immediately following or preceding radiation simulation (Correlative Day 1) radiation treatment 
(Correlative Day 2) and follow-up period (Correlative Day 3) at the Markey Cancer Center, 
subjects will be transported to the ground level of Markey by MCC staff for CT measures. 
Computed tomography (CT) images (GE large bore 16 slice) will be used to quantify skeletal 
muscle and fat area of the right and left thighs, and the right and left forearms of each subject using 
100mA with a scanning time of 3 s and a 512 X 512 matrix. With the subject supine, one 10 mm 
thick cross-section scan of both legs will be taken corresponding to the midpoint between the 
inguinal crease and the proximal border of the patella, and one 10 mm thick cross-section scan will 
be taken corresponding to 2/3 the distance from the styloid process of the radius to the olecranon.  
Tissue area quantification will be determined using corresponding attenuation values of ≥200 HU; 
-190 to -30 HU; and 0-100 HU for bone, adipose tissue, and skeletal muscle, respectively using 
available software (NIH ImageJ; http://rsbweb.nih.gov/ij/). Total thigh fat will be further 
subdivided into two compartments including the fat above the fascia late (subcutaneous thigh fat) 
and below the fascia lata (deep thigh fat).  In addition, the skeletal muscle will be subdivided into 
areas of low attenuation (0-34 HU) representing “fat-rich” muscle, and high attenuation values 
(35-100 HU) representing muscle with normal fat content.  While the forearm scan methodology is 
unique and has been developed specifically for this study, the method of analyzing thigh 
composition has been previously described (9). All CT scans will be assessed under the direction 
of Dr. Jody Clasey. 
 

 
25 
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9.1.2 Quality of Life  
 
Following CT measures at Markey, subjects will be transported to the CCTS for Quality of Life 
and DXA measures. Quality of life (FACT H/N version 4) assessment will be administered by the 
CCTS exercise physiologist (Mr. Long) during set-up for the DXA scan. This is a 5 minute survey 
that can easily be administered by the technician while the DXA scan is calibrated. This survey 
will be completed at baseline, midpoint, and endpoint by the same DXA technician prior to the 
DXA scan. 
 
9.1.3 Dual-Energy X-ray Absorptiometry (DXA)   
 
Total body DXA scans will be performed using a GE Healthcare Lunar iDXA (Lunar Inc., 
Madison, WI) bone densitometer.  The subjects will be instructed to remove all objects such as 
jewelry or eyeglasses and will wear only a standard hospital gown or t-shirt and shorts containing 
no metal during the scanning procedure.  All scans will be analyzed by a trained investigator using 
the GE Healthcare Lunar Encore software version 14.10. Total body and regional DXA bone 
mineral content (g), DXA bone mineral density (g/cm2), DXA fat-free mass (FFM; kg), DXA fat 
mass (kg), and DXA mineral-free lean mass (kg), and DXA percent fat (DXA %Fat) will be 
assessed. 
 
9.2 
Blood and Saliva Collection for Plasma Nitrate, Nitrite and 25(OH)D, and Saliva 
Nitrate and Nitrite Measures 
 
Following the DXA scan, participants will remain in the CCTS for blood and saliva collection by 
trained CCTS phlebotomists (will occur between25-30 minutes post supplement administration on 
all testing days). Venous blood samples (~8mL) will be drawn into lithium-heparin tubes (low 
nitrate/nitrite). Within 3 minutes of collection, samples are centrifuged at 4,000rpm at 4C for 10 
minutes. Plasma will be extracted and immediately frozen at -80C for later analysis of plasma 
nitrate (NO3-) and nitrite (NO2¯) at the end of the study period.  
 
Saliva will be collected by study personnel at 30 minutes post supplement administration. Subject 
will generate saliva and place in a collection tube. Sample saliva (200μL) will be taken from the 
tube and placed in a separate tube. Sample will be vortexed and centrifuged for 10 minutes. 
Supernatant will be removed and stored at -80C for shipment and later analysis. 
 
 
9.3 
Assessment of Muscle Strength and Endurance 
 
Upper body muscle strength and endurance will be assessed by the CCTS exercise physiologist 
using a handgrip dynamometer (29) and overseen by Drs. Clasey and Thomas at all three study 
time points.  Strength and endurance measures will be collected after the blood draw and will not 
occur more than one hour following testing day beet root administration or at the time of arrival in 
the unit for the observational cohort. Strength will be determined for both the dominant and non-
dominant hands using peak force determination from 3 trials. Determining the absolute and 
relative decline in contractile force at 30, 60, and 90 sec of sustained contraction will assess 
muscular endurance. Lower body strength and endurance will be assessed by completing a one-
legged MVC using a Biodex isokinetic machine.  
 
 

 
26 
Version Date: 4/15/2016 
9.3.1 Isokinetic Strength and Endurance Testing 
 
Before the start of maximal isokinetic force (strength) testing, the participant will be instructed on 
proper lifting and breathing techniques. Isokinetic strength at 60⁰ per second will be determined in 
the subject’s dominant leg in a seated position with knee and hip angulation of 60⁰ and 120⁰ 
degrees respectively. During this time, subjects will be provided with strong verbal encouragement 
and provided with visual feedback of torque on a computer monitor to help with achievement of 
their best effort. To minimize the use of muscles other than the knee extensors, participants will be 
stabilized with two shoulder straps, and a waist strap. Strength will be recorded as the highest force 
generated during one set of 3-4 trials starting at a knee angle of 90⁰. Before recording the maximal 
effort, 3 trials will be given at a moderate intensity to provide for further muscle warm-up. A two 
minute rest period will be given between each strength trial. Following isokinetic strength testing 
of the dominant leg, endurance and fatigability will be assessed by having the participant complete 
25 reps at an angular velocity of 240⁰ per second followed by another strength trial. The fall in 
peak torque and power will be used to calculate fatigability and endurance capacity of the muscle.  
 
9.3.2 Handgrip Strength 
 
Subjects will use a handgrip dynamometer for the assessment of handgrip strength in their 
dominant and non-dominant arm. The participant will be in a standing position, arms at their side, 
not touching their body, and elbow bent slightly. The participant will squeeze the dynamometer 
with as much force as possible, being careful to squeeze only once for each measurement. Three 
trials will be made with a pause of about 10-20 seconds between each trial to avoid the effects of 
muscle fatigue. Each trial will be recorded to the nearest pound or kilogram. If the difference in 
scores is within 6.6 lbs. or 3 kgs., the test is complete. If the difference between any two measures 
is more than 6.6 lbs. or 3 kgs., then the test will be repeated once more after a rest period. 
 
9.4 
Diet and nutrition status monitoring 
 
Nutrition intake data will be collected randomly within a two week period at baseline and midpoint 
and will not be scheduled on CCTS testing days. All nutrition data collection and management 
procedures will be overseen by Dr. Thomas in collaboration with the MCC registered dietitian. 
 
Twenty four hour dietary recalls will be collected in-person twice at baseline and midpoint (4 total 
24-hr recalls per subject) by a nutrition graduate student trained in dietary assessment. During 
clinical status checks/chemo visits at the MCC, participants will be asked to report their food and 
beverage intake (enteral and/or by mouth) over the previous 24-hours. The Nutrition Data System 
for Research software (NDSR version 2012, Minneapolis, MN) will be used to organize and assess 
all dietary data collected. NDSR uses the multiple-pass method to help improve the validity of 
dietary data. This method is a standardized recall strategy that refers to the number of times a 
participant’s food intake is reviewed during the interview in - an effort to improve recall accuracy 
(10, 11). Enteral feeding regimens during the 7 week IMRT period will also be monitored closely 
with clinical progress notes and communication with the MCC registered dietitian to document 
feeding interruptions, change in formula type, volume, and tolerance. Subjects will also provide a 
daily beet root juice intake diary (Appendices C and D) and side effect profile.  A comprehensive 
summary of nutrient analysis reports will be generated for all participants.  
 
 

 
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9.5 
Other Study Measures Occurring Weekly 
 
9.5.1 Mucositis 
Severity of mucositis will also be evaluated and documented by the treating radiation oncologist, 
who will be blinded to the group assignment, according to the CTCAE v. 4.0 (Appendix B).  
 
 
10. STUDY CALENDAR 
 
10.1 
Baseline Evaluations/Assessments  
Baseline evaluations must be done ≤ two weeks prior to protocol therapy, except for radiologic 
assessments, which must be performed < 21 days prior to the initiation of therapy. The “on-study” 
tumor assessment can be from archival material. 
 
 
 
10.2 
Calendar for Beetroot Supplementation Cohort 
 
Timepoints 
Baseline 
 
Weekly 
during 
Concurrent 
Radiation 
and 
Cisplatin 
 
Midpoint 
(After 
IMRT) 
Endpoint 
(4-6 
weeks 
following 
Midpoint 
testing) 
Off-
treatment   
 
Off 
study 
Studies: 
 
 
 
 
 
 
H&P1 VS 
X 
X 
X 
X 
X 
X 
TOX 
X 
X 
X 
X 
 
 
Pregnancy Testing 
X 
 
 
 
 
 
Muscle Strength and 
Endurance Testing 
X 
 
X 
X 
 
 
Body Composition (DXA) 
X 
 
X 
X 
 
 
Plasma/Salivary 
Nitrate/Nitrite 
X 
 
X 
X 
 
 
QOL and Mucositis 
X 
 
X 
X 
 
 
Diet 
X 
 
X 
 
 
 
Ct SCAN (body comp) 
X 
 
X 
X 
 
 
Routine Cancer Imaging2 
X 
 
 
X 
 
X 
Treatments: 
 
 
 
 
 
 
Beet Root  (daily) 3 
X 
X 
X 
X 
 
 
1) Abbreviations: H&P=History and Physical examination; PS=ECOG performance status; 
VS=vital signs (blood pressure, temperature, pulse and respiratory rates, weight and 
height); TOX=toxicity assessment  
2) Routine cancer imaging will be standard of care CT or MRI scans to document disease and 
response to therapy.  These will be required pre-treatment, post-chemoradiation and at 1- 
and 2-year follow-up (+/- 6 weeks), as per standard of care.  
3)Beet root will be self-administered each day (M-F  in afternoon) 
4)Toxicity will be followed for all patients until (endpoint) testing. Any beetroot related 
toxicity > grade 2 will be followed until resolution to grade 1 or less. 
 
 

 
28 
Version Date: 4/15/2016 
10.3 
Calendar for Observational Cohort 
 
Timepoints 
Baseline 
 
Weekly 
during 
Concurrent 
Radiation 
and 
Cisplatin 
 
Midpoint 
(After 
IMRT) 
Endpoint 
(4-6 
weeks 
following 
Midpoint 
testing) 
Off-
treatment   
 
Off 
study 
Studies: 
 
 
 
 
 
 
Muscle Strength and 
Endurance Testing 
X 
 
X 
X 
 
 
Body Composition (DXA) 
X 
 
X 
X 
 
 
Plasma/Salivary 
Nitrate/Nitrite 
X 
 
X 
X 
 
 
QOL and Mucositis 
X 
 
X 
X 
 
 
Ct SCAN (body comp) 
X 
 
X 
X 
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Toxicity 
 
For the purposes of this study, patients receiving beetroot supplement will be re-evaluated for 
toxicity as listed above and weekly during radiation as per institutional standard.  All subjects 
receiving beetroot supplement will be evaluated for toxicity from the time of their first treatment 
with beet root to the end of study.  Subjects will also be required to record each dose of beet root 
juice, including date and time, and subjective side effects (i.e. nausea, diarrhea, allergic reactions) 
noted after each dose. Subjects receiving only muscle strength testing will not be followed for 
toxicity as they receive standard of care and supportive medications as per routine. These subjects 
are not considered to be part of the interventional study but certainly serve as a baseline 
observational cohort. 
 
11.2 
Antitumor Effect – Solid Tumors 
 
Response and progression are not the primary endpoints of this study, however, response and 
progression will be evaluated in this study using the new international criteria proposed by the 
revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 
45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
11.2.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with beetroot juice/. 
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 

 
29 
Version Date: 4/15/2016 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.2.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 

 
30 
Version Date: 4/15/2016 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  

 
31 
Version Date: 4/15/2016 
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 

 
32 
Version Date: 4/15/2016 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.2.4 Response Criteria 
 
11.2.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one 
or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.2.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 

 
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11.2.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
 

 
34 
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11.2.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 
11.2.6 Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to 
time of progression or death, whichever occurs first. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1.1 Method 
 
This study will be monitored by the Markey Cancer Center Data and Safety Monitoring 
Committee. Adverse event and quality assessment will be submitted to DSMC using 
electronic case report form in OnCore.  
 
12.1.2 Responsibility for Data Submission 
Study CRA’s and investigators are responsible for submitting data and/or data forms to 
OnCore. The date for submission to OnCore will be set by the CRDM SRF.  The OnCore 
Management staff is responsible for compiling and submitting study data to DSMC for all 
participants and for providing the data to the Principal Investigator for review.   
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This non-randomized, pilot study plans to enroll 35 total patients with previously untreated 
squamous cell cancer of the head and neck. As the goal of this study is to obtain preliminary data 
regarding current standard therapy compliance rates for this patient population at the University of 
Kentucky Markey Cancer Center and assess feasibility of an additional beet juice supplementation 
during therapy, the primary objective is to estimate treatment compliance defined as completion of 
radiation alone or radiation and chemotherapy with beet root supplementation during primary 
treatment. Treatment compliance is defined in more detail in section 5. Secondary objectives to 
obtain pilot estimates for cancer specific outcomes such as response rate, adverse events, mucositis 
rates, and 1 and 2 year locoregional control rates and progression-free rates Additional secondary 

 
35 
Version Date: 4/15/2016 
measures will include strength measures, CT scans, quality of life surveys, nitrate/nitrite levels,  
endurance testing, handgrip strength, and Body Composition DXA variables of interest (Bone 
Mineral Density, Bone Mineral Content, Area, % fat). Beet juice rates of completion will also be 
estimated to assess feasibility of this product. 
 
13.2 
Sample Size/Accrual Rate 
 
The primary endpoint of this study is treatment compliance, for the chemoradiation strata defined 
as completion of radiotherapy and 3 cycles of chemotherapy with no treatment delay with 
published historical rates average around 52.1% (30). For those receiving radiation alone, we 
predict higher compliance rates closer to 70% as these patients tend to experience less mucositis 
and adverse events during treatment. We anticipate 60% of patients will receive radiation alone 
versus 40% receiving chemoradiation. 25 total patients  (10 – chemoradiation, 15 – radiation 
alone) receiving beet root supplementation, will result in 90% confidence intervals around each 
estimated compliance rate with a maximum widths of +/- 27.75% and 22.85% for chemoradiation 
and radiation alone respectively. The combined estimate of compliance will still have a 90% 
confidence interval estimate with a maximum width of +/- 17.7% as previously designed. For the 
10 subjects in the observational cohort not receiving beet root supplementation, we will still be 
able to estimate compliance rates +/- 27.75% and obtain pilot data regarding strength outcomes 
during standard of care therapy. This design is not powered to compared compliance rates between 
treatment strata or beet root versus standard of care; instead it allows us to gain preliminary 
information about these rates with a certain amount of precision as pilot data for a larger, more 
definitive study. We plan to accrue patients over a 2 year period. 
 
There will be a pre-specified safety consideration after half of the planned enrollment in the beet 
root supplementation ( interim after 13) to verify acceptable treatment completion rates as 
compared to a published historical rate of 52.1%. Two prior beta distributions (non-informative 
and null-hypothesis based) will be considered with patient information collected from the first 13 
enrolled in beet root arm to calculate the posterior probability that the mean proportion of 
successful completion is less than or equal to historical rates of 52.17% with corresponding 90% 
credible intervals. The study team will reconsider continuation of the protocol due to safety and 
feasibility concerns if either arm has a high probability of experiencing a success rate lower than 
published rates.  
 
13.3 
 Data Analysis 
 
Following study completion, primary data analysis will include estimation of subjects achieving 
treatment compliance along with corresponding exact 90% binomial confidence intervals.   
 
Other secondary endpoints listed in section 13.1 will be primarily descriptive as they are 
exploratory in nature; however means and standard deviations (or N and percentages where 
appropriate) will be estimated and summarized for each time point to gain more information of 
expected effect size differences between standard therapy and BR arms. Repeated measures 
ANOVA will be utilized to test for exploratory differences in these various measures over time 
points between BR and standard therapy arms. Kaplan-Meier curves will be presented for 
locoregional control and progression-free survival along with 90% confidence interval bounds. 
Exploratory log rank tests will be performed to assess for any preliminary differences in these 
survival outcomes by treatment arm. 
 

 
36 
Version Date: 4/15/2016 
13.4 
Reporting and Exclusions 
 
13.4.1 Evaluation of Toxicity 
 
All subjects on beet root supplementation will be included in the safety analysis, with 
toxicities graded according to NCI CTCAE v4.0. Incidence tables will be generated to 
summarize incidence of patients reporting at least one episode of each specific adverse 
event, incidence of adverse events causing withdrawals and incidence of serious adverse 
events. Listing of adverse events by patients will include the time to onset, the duration of 
each event, the severity of each event, and the relationship of the event to study therapy, 
whether it was a serious event, and whether it caused withdrawal. This will also capture all 
incidence and severity of mucositis during the duration of this study. 
 
13.4.2 Evaluation of Outcomes  
 
All patients included in the study will be assessed for treatment compliance, even if there 
are major protocol treatment deviations or if they are ineligible.  All of the patients who 
met the eligibility criteria (with the possible exception of those who received no study 
medication) will be included in the intent to treat analysis for the primary completion 
endpoint as well as all secondary outcomes. 
 
Due to concerns of potential non-compliance of taking all beet supplements over the course 
of primary treatment, a per protocol analysis will also be performed for all patients that 
consume at least 3 servings of the required beet supplements per week.  Percentage of beet 
supplements taken will also be reported as part of this subgroup analysis. 
 
13.5 
Data Management 
 
All cancer treatment related data, adverse events, and compliance with BR supplementation will be 
stored in the OnCore Data Management System of the Markey Cancer Center, as well as all 
strength measurements, body composition (CT and DXA), and quality of life surveys. Case report 
forms will record all study endpoints and data will be accessed in a secure manner using this 
password protected, encrypted software.  The study statistician, along with staff from the 
Biostatistics Shared Resource Facility (BSRF), will work closely with the study PI and the MCC 
CRO staff on the development of eCRFs for the study.  Instructions for data entry will be listed in 
Study-Specific Data Management Plan created by CRO staff in conjunction with the study 
statistician.  The OnCore database is housed on secure servers maintained by the Cancer Research 
Informatics Shared Resource Facility (CRISRF) of Markey Cancer Center.  The database is backed 
up daily.   
 
Each subject will be assigned a sequence number at time of study entry through the OnCore 
system. This same sequence number will be distributed to study personnel at CCTS and utilized 
for all data. Data will be accessed by the study statistician via OnCore on a regularly scheduled 
basis to perform statistical programming to assess data quality control, study recruitment and to 
generate interim reports and analyses.  In collaboration with the study team, procedures and 
timelines will be developed for data quality control, resolution of data queries, interim reporting 
and final data analysis. 
 
 

 
37 
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1. 
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Bailey SJ, Fulford J, Vanhatalo A, Winyard PG, Blackwell JR, DiMenna FJ, Wilkerson 
DP, Benjamin N, Jones AM. Dietary nitrate supplementation enhances muscle contractile 
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3. 
Wylie LJ, Mohr M, Krustrup P, Jackman SR, Ermiotadis G, Kelly J, Black MI, Bailey 
SJ, Vanhatalo A, Jones AM. Dietary nitrate supplementation improves team sport-specific intense 
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doi: 10.1007/s00421-013-2589-8. PubMed PMID: 23370859. 
4. 
Breese BC, McNarry MA, Marwood S, Blackwell JR, Bailey SJ, Jones AM. Beetroot 
juice supplementation speeds O2 uptake kinetics and improves exercise tolerance during severe-
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Regulatory, integrative and comparative physiology. 2013;305(12):R1441-50. doi: 
10.1152/ajpregu.00295.2013. PubMed PMID: 24089377. 
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Cermak NM, Gibala MJ, van Loon LJ. Nitrate supplementation's improvement of 10-
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Muggeridge DJ, Howe CC, Spendiff O, Pedlar C, James PE, Easton C. A single dose of 
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Lansley KE, Winyard PG, Bailey SJ, Vanhatalo A, Wilkerson DP, Blackwell JR, 
Gilchrist M, Benjamin N, Jones AM. Acute dietary nitrate supplementation improves cycling time 
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8. 
Vanhatalo A, Fulford J, Bailey SJ, Blackwell JR, Winyard PG, Jones AM. Dietary 
nitrate reduces muscle metabolic perturbation and improves exercise tolerance in hypoxia. The 
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Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, Dimenna FJ, Wilkerson DP, Tarr J, 
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exercise and enhances tolerance to high-intensity exercise in humans. Journal of applied 
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Bescos R, Rodriguez FA, Iglesias X, Ferrer MD, Iborra E, Pons A. Acute 
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11. 
Lansley KE, Winyard PG, Fulford J, Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna 
FJ, Gilchrist M, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of 
walking and running: a placebo-controlled study. Journal of applied physiology. 2011;110(3):591-
600. doi: 10.1152/japplphysiol.01070.2010. PubMed PMID: 21071588. 
12. 
Kelly J, Vanhatalo A, Wilkerson DP, Wylie LJ, Jones AM. Effects of nitrate on the 
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13. 
Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, Weitzberg E. 
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14. 
Roszkowski K. Influence of Beta Vulgaris Supplementation on the Level of Oxidative 
DNA Damage/Oxidative Stress in Head and Neck Cancer Patients Undergoing Radiotherap. 
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Tjonneland A, Clavel F, Boutron-Ruault MC, Kesse E, Boeing H, Bergmann MM, Nieters A, 
Linseisen J, Trichopoulou A, Trichopoulos D, Tountas Y, Berrino F, Palli D, Panico S, Tumino R, 
Vineis P, Bueno-de-Mesquita HB, Peeters PH, Engeset D, Lund E, Skeie G, Ardanaz E, Gonzalez 
C, Navarro C, Quiros JR, Sanchez MJ, Berglund G, Mattisson I, Hallmans G, Palmqvist R, Day 
NE, Khaw KT, Key TJ, San Joaquin M, Hemon B, Saracci R, Kaaks R, Riboli E. Meat, fish, and 
colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. Journal of 
the National Cancer Institute. 2005;97(12):906-16. Epub 2005/06/16. doi: 10.1093/jnci/dji164. 
PubMed PMID: 15956652; PubMed Central PMCID: PMCPmc1913932. 
16. 
Powlson DS, Addiscott TM, Benjamin N, Cassman KG, de Kok TM, van Grinsven H, 
L'Hirondel JL, Avery AA, van Kessel C. When does nitrate become a risk for humans? Journal of 
environmental quality. 2008;37(2):291-5. Epub 2008/02/13. doi: 10.2134/jeq2007.0177. PubMed 
PMID: 18268290. 
17. 
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F344/N rats and B6C3F1 mice (drinking water studies). National Toxicology Program technical 
report series. 2001;495:7-273. Epub 2003/02/04. PubMed PMID: 12563346. 
18. 
Mensinga TT, Speijers GJ, Meulenbelt J. Health implications of exposure to 
environmental nitrogenous compounds. Toxicological reviews. 2003;22(1):41-51. Epub 
2003/10/29. PubMed PMID: 14579546. 
19. 
Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic 
context for potential health benefits. The American Journal of Clinical Nutrition. 2009;90(1):1-10. 
doi: 10.3945/ajcn.2008.27131. 
20. 
Bryan NS, Alexander DD, Coughlin JR, Milkowski AL, Boffetta P. Ingested nitrate and 
nitrite and stomach cancer risk: An updated review. Food and Chemical Toxicology. 
2012;50(10):3646-65. doi: http://dx.doi.org/10.1016/j.fct.2012.07.062. 
21. 
Milkowski A, Garg HK, Coughlin JR, Bryan NS. Nutritional epidemiology in the 
context of nitric oxide biology: A risk–benefit evaluation for dietary nitrite and nitrate. Nitric 
Oxide. 2010;22(2):110-9. doi: http://dx.doi.org/10.1016/j.niox.2009.08.004. 
22. 
Zielinska-Przyjemska M, Olejnik A, Dobrowolska-Zachwieja A, Grajek W. In vitro 
effects of beetroot juice and chips on oxidative metabolism and apoptosis in neutrophils from 
obese individuals. Phytotherapy research : PTR. 2009;23(1):49-55. Epub 2008/09/25. doi: 
10.1002/ptr.2535. PubMed PMID: 18814207. 
23. 
Petersson J, Carlstrom M, Schreiber O, Phillipson M, Christoffersson G, Jagare A, 
Roos S, Jansson EA, Persson AE, Lundberg JO, Holm L. Gastroprotective and blood pressure 
lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free radical biology 
& medicine. 2009;46(8):1068-75. doi: 10.1016/j.freeradbiomed.2009.01.011. PubMed PMID: 
19439233. 
24. 
Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, Dimenna FJ, Wilkerson DP, Tarr J, 
Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of low-intensity 
exercise and enhances tolerance to high-intensity exercise in humans. Journal of applied 
physiology. 2009;107(4):1144-55. doi: 10.1152/japplphysiol.00722.2009. PubMed PMID: 
19661447. 
25. 
Lansley KE, Winyard PG, Fulford J, Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna 
FJ, Gilchrist M, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of 
walking and running: a placebo-controlled study. Journal of applied physiology. 2011;110(3):591-
600. doi: 10.1152/japplphysiol.01070.2010. PubMed PMID: 21071588. 

 
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26. 
Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Pavey TG, Wilkerson DP, 
Benjamin N, Winyard PG, Jones AM. Acute and chronic effects of dietary nitrate supplementation 
on blood pressure and the physiological responses to moderate-intensity and incremental exercise. 
American journal of physiology Regulatory, integrative and comparative physiology. 
2010;299(4):R1121-31. doi: 10.1152/ajpregu.00206.2010. PubMed PMID: 20702806. 
27. 
Bailey SJ, Fulford J, Vanhatalo A, Winyard PG, Blackwell JR, DiMenna FJ, Wilkerson 
DP, Benjamin N, Jones AM. Dietary nitrate supplementation enhances muscle contractile 
efficiency during knee-extensor exercise in humans. Journal of applied physiology. 
2010;109(1):135-48. doi: 10.1152/japplphysiol.00046.2010. PubMed PMID: 20466802. 
28. 
Commission AS. Beetroot Juice/Nitrate AIS Website Fact Sheet- AIS Sports 
Supplement Program. 2011. 
29. 
Guo CB, Zhang W, Ma DQ, Zhang KH, Huang JQ. Hand grip strength: an indicator of 
nutritional state and the mix of postoperative complications in patients with oral and maxillofacial 
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8866070. 
30. 
Atasoy BM, Yonal O, Demirel B, Dane F, Yilmaz Y, Kalayci C, Abacioglu U, Imeryuz 
N. The impact of early percutaneous endoscopic gastrostomy placement on treatment 
completeness and nutritional status in locally advanced head and neck cancer patients receiving 
chemoradiotherapy. European archives of oto-rhino-laryngology : official journal of the European 
Federation of Oto-Rhino-Laryngological Societies. 2012;269(1):275-82. doi: 10.1007/s00405-010-
1477-7. PubMed PMID: 21472468. 
 
   
 
 

 
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APPENDIX A 
 
 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 

 
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APPENDIX B 
 
 
CTCAE version 4.0:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht 
 
  
 
 

 
42 
Version Date: 4/15/2016 
APPENDIX C 
Patient Name:_______________ 
Patient ID#:_______________ 
Date Range:___/___/_____ to ___/___/_____ 
 
Weekly Supplement Log 
 
Instructions for the participant: This is a weekly log on which you are to record each 
supplement dose you take. For each dose write down the day, time and amount consumed (only fill 
out if supplement is mixed with water). Bring the log and all supplement packaging with you to 
your next scheduled supply pick-up. 
 
Dose Number 
Day 
(Example: Monday) 
Time 
(Example: 12:00pm) 
Amount Consumed 
(percent drank: 50%, 
100%) 
How was it taken 
(mouth or tube) 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
 
Did you vomit up your supplement within 15 minutes of taking it on any day? If yes, how many 
days?  ________________ 
Did you retake the supplement each time? If yes, how many times did you retake it?  _________ 
__________ 
 
Patient Initials:_______________ 
 
 
             Date:_____________ 
 
 
 
 
Section to be completed by research personnel:  
Distribution Date:___/___/_____  
 
 
     Return Date:___/___/_____ 
Total Bags Returned:_____ 
 
 
          Number of Empty Bags:_________ 
Comments:________________________________________________________________________
_________________________________________________________________________________
_________________________________________________________________________________ 
 
__________________________  
 
 
 
__________________ 
Signature (Research Personnel)  
 
                                     Date 

 
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APPENDIX D 
Patient Name:_______________ 
Patient ID#:_______________ 
Date Range:___/___/_____ to ___/___/_____ 
Monthly Supplement Log 
 
Instructions for the participant: This is a monthly log on which you are to record each supplement dose 
you take. For each dose write down the dose number, time and amount consumed as a percent (only write 
down if supplement is mixed with water) under the day you had it. For example, write down: Dose 1, 
12pm and 50% if you drank half of the supplement. Bring the log and all supplement packaging with you 
to your next scheduled supply pick-up. 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
 
   Mouth 
   Tube 
 
Did you vomit up your supplement within 15 minutes of taking it on any day? If so, how many days?  
_______________ 
Did you retake the supplement each time? If not, how many times did you retake it?  _________ 
______________ 
 
Patient Initials:_______________ 
 
 
              
Date:_____________ 
 
 
 
 
 
Section to be completed by research personnel:  
Distribution Date:___/___/_____  
 
 
     Return Date:___/___/_____ 
Total Bags Returned:_________  
 
           Number of Empty Bags:_________ 
Comments:_________________________________________________________________________
__________________________________________________________________________________
____________________________________________________________________________ 
 
__________________________  
 
 
              __________________ 
Signature (Research Personnel)  
 
 
               Date 

 
44 
Version Date: 4/15/2016 
APPENDIX E 
 
 Beetroot Juice Supplement Instruction Sheet 
(by stomach tube) 
 
1. Mix the supplement powder with 4-8 oz of water only. 
2. Do not mix the powder with anything other than water or more than 8 oz of water. 
3. You may pour water into a glass and add in the powder or place the powder in a small bottle 
of water to pour in the tube. 
4. Flush the tube with a small amount of water before and after administration of the supplement 
according to your physician’s guidelines. 
5. Pour the entire supplement within 2-3 minutes so it is all in the stomach at the same time. 
6. On your supplement log write down the day (example: Monday), dose number (example: 1), 
approximate time you mixed the powder (example: 9:00am), and how much you administered 
(as a percent, example: 100%). 
7. Administer the supplement between afternoon hours of 12-5pm. 
8. The supplement is meant to be taken on weekdays (Monday-Friday). 
9. If a dose is forgotten, take as soon as you remember that day. Then resume the supplement 
schedule the next day. 
10. Do not consume more than 1 dose in 1 day.  However, if you vomit the dose within 15 minutes 
of putting it in your PEG tube, you may repeat the dose once that day (after recovering from 
vomiting and nausea). 
11. If 1 dose is missed during the week, you can take the missed dose on Saturday.  
12. If 2 doses are missed, you can take them on Saturday and Sunday. 
 
 
 
 

 
45 
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APPENDIX F 
 
Beetroot Juice Supplement Instruction Sheet 
(by mouth) 
 
1. Mix the supplement powder with 4-8 oz of water only. 
2. Do not mix the powder with anything other than water or more than 8 oz of water. 
3. You may pour water into a glass and add in the powder or place the powder in a small bottle 
of water to drink. 
4. Swallow as fast as possible within 2-3 minutes so it is all in the stomach at the same time. 
5. On your supplement log write down the day (example: Monday), dose number (example: 1), 
approximate time you mixed the powder (example: 9:00am), and how much you drank (as a 
percent, example: 100%). 
6. Consume the supplement between the afternoon hours of 12 and 5pm. 
7. The supplement is meant to be taken on weekdays (Monday-Friday). 
8. If a dose is forgotten, take as soon as you remember that day. Then resume the supplement 
schedule the next day. 
9. Do not consume more than 1 dose in 1 day.  However, if you vomit the dose within 15 
minutes of swallowing it, you may repeat the dose once that day (after recovering from 
vomiting and nausea). 
10. If 1 dose is missed during the week, you can take the missed dose on Saturday.  
11. If 2 doses are missed, you can take them on Saturday and Sunday. 
 
 

 
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APENDIX G 
Mucositis scoring