Prospective Randomized Pilot Clinical Trial of Margin-Based Vs. Robust Photon Radiotherapy Planning in Intensity-Modulated Radiation Therapy of Squamous-Cell Carcinoma of the Head and Neck
Phase: NA
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: University of Arkansas

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 1 of 21 
 
 
 
 
 
 
Study Title:  
Prospective Randomized Pilot Clinical Trial of Margin-
Based Vs. Robust Photon Radiotherapy Planning in 
Intensity-Modulated Radiation Therapy of Squamous-
Cell Carcinoma of the Head and Neck 
 
 
 
Principal Investigator:   Mausam Patel, MD 
 
University of Arkansas for Medical Sciences 
 
Department of Radiation Oncology 
 
4301 W. Markham #724 
 
Little Rock, Arkansas 72205 
 
954-205-6508 
 
MPatel2@uams.edu 
Sub-Investigators:  
Mauricio Moreno, MD 
 
 
 
 
Omar Atiq, MD 
 
 
 
 
Sanjay Maraboyina, MD 
 
 
 
 
Leslie Harrell, DO 
 
 
 
 
Jumin Sunde, MD 
 
 
Study Location: 
 
University of Arkansas for Medical Sciences 
 
 
 
 
 
 
 
 
 
 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 2 of 21 
 
BACKGROUND AND RATIONALE 
 
Xerostomia following radiotherapy cancer treatment is mainly caused by 
permanent damage to the salivary glands that are in the radiotherapy field [1]. 
Changes in salivary functionality and symptomatology show deterioration in the 
short term (< 6 months) with some subsequent improvement [2]. This decrease in 
functionality is associated with a decrease in quality of life, especially involving the 
faculties of eating, speaking and swallowing [3-4]. Radiation therapy-induced 
chronic xerostomia is a challenge for both patient and treating physician. Although, 
there are remedies available to mitigate the symptoms, the best approach would 
involve prevention or minimizing its incidence. This may be done by utilizing 
radiotherapy planning strategies that reduce normal tissue complication 
probabilities (NTCP) [5]. 
There are numerous studies that describe NTCP of different organs [6-10]. 
Regarding the parotid glands, the most commonly used model is the Lyman-
Kutcher-Burman (LKB) model using the mean dose to the parotid gland as 
predictive of xerostomia [11-12]. Although, dose-volume techniques are a 
mainstay of current treatment planning, the use of biological objectives in IMRT 
planning has shown potential for reducing radiation-induced toxicity [13-15].  
Traditionally, uncertainties in radiation therapy have been handled by the 
introduction of margins to the target(s). For example, a margin applied to the 
clinical target volume (CTV) defines the planning target volume (PTV). These 
margins ensure that there is adequate target dose coverage and at the same time 
that sufficient normal tissue is spared. A feasible approach to reducing toxicity 
while at the same time maintaining similar cure rates is to reduce the margins used 
in radiation treatment planning [5], specifically reduce the CTV to PTV margin. This 
can be achieved by the use of cone-beam CT (CBCT) imaging which has shown 
improved patient set-up to approximately 1 mm [16]. Advances in computation and 
technology in radiation therapy have allowed the possibility of integrating set-up 
uncertainties in the optimization process of the dose calculation [17-21]. This 
probabilistic approach for achieving robust radiation treatment plans take into 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 3 of 21 
 
account set-up uncertainties explicitly in the optimization process by considering 
the probability distributions of the uncertain parameters during optimization. As 
such, as an alternative to the use of biological objectives in the dose optimization 
process, robustness can be used as a tool to minimize dose to normal tissue and 
reduced toxicity leading to better quality of life [5].  
Based on the above, we hypothesize that robust radiotherapy planning can 
improve the toxicity profile of xerostomia in patients with squamous cell carcinoma 
of the head and neck (HN-SQCC) compared to margin-based radiotherapy 
planning. However, the amount of improvement to expect remains unknown.  
Therefore, we propose to perform a prospective randomized pilot clinical 
trial, stratified by primary tumor site, to evaluate the degree of xerostomia and 
quality of life (QOL) in subjects with HN-SQCC treated with radiation therapy under 
margin-based and robust radiotherapy treatment plans. Margin-based plans will 
use both biological (biological optimization) and physical objectives whereas 
robust planning will use physical objectives for sparing of the parotid glands. 
Intensity-modulated radiation therapy (IMRT) and standard chemotherapy will be 
used. QOL (quality of life) will be measured using the EORTC QLQ-C30 
questionnaire and EORTC QLQ-H&N35 (head and neck) module before 
radiotherapy (baseline) and then 3, 6, 9 and 12 months after radiotherapy. 
Xerostomia will be measured in study subjects using two patient-reported scoring 
systems completed by each subject before radiotherapy and then 3, 6, 9, and 12 
months after radiotherapy: the LENT/SOMA grading system and the University of 
Michigan’s Xerostomia Questionnaire (XQ; see Eisbruch et al. 2001). The data 
collected by this randomized pilot clinical trial will be used to inform the design of, 
and decision-making for, future larger studies that seek to compare different 
methods of radiotherapy planning in the treatment of HN-SQCC. 
 
 
 
 
 
 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 4 of 21 
 
STUDY OBJECTIVES 
 
Primary Objective   
 
To evaluate descriptively over time the prevalence and grade of xerostomia 
in subjects treated for HN-SQCC with IMRT under either biologically optimized 
margin-based or robust photon radiotherapy. 
 
Secondary Objectives 
 
1) To compare descriptively the arm treated with IMRT under the margin-
based radiotherapy plan to the arm treated with IMRT under the robust 
radiotherapy plan for possible differences in derived outcomes of interest, 
including but not limited to: (1) occurrence rate of grade≥2 xerostomia as 
determined using the LENT/SOMA scale; and (2) occurrence rate of overall 
score ≥30 on the XQ. 
2) To obtain NTCP values of the parotid glands from both margin-based and 
robust radiotherapy treatment plans using validated parameter values of the 
NTCP mean dose model. Each subject will have their parotid NTCP values 
computed under both plans, even though they will receive IMRT delivered 
under only the plan they are randomized to. 
3) To obtain dose statistics for dose delivered to the parotid glands of each 
subject via either margin-based or robust treatment plans. 
4) To determine quality of life (QoL) at baseline and at 3, 6, 9 and 12 months 
following treatment using the EORTC QLQ-C30 instrument combined with 
the EORTC QLQ-H&N35 module. The main scores of interest at each time 
point will be the global QoL scale and the individual scales for dry mouth, 
oral pain, swallowing, opening mouth, sticky saliva, and social eating. 
5) To correlate NTCP values with change in QoL results. 
 
 
 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 5 of 21 
 
STUDY POPULATION 
 
Research subjects will be recruited from the Radiation Oncology clinic on 
the UAMS campus. The potential research subject will be identified by the 
physician during their routine clinic visit. Prior to any research activities, the subject 
will be approached for participation in the study by their physician or staff member, 
who will discuss the protocol along with the risks and potential benefits of 
participating in it. Subjects currently taking saliva stimulating drugs will be asked if 
they are willing to discontinue such drugs in order to participate. A clear statement 
will be made concerning the voluntary nature of participation and that the decision 
will have no effect on their remaining care. 
We plan to consent up to 75 subjects in order to reach our maximum accrual 
of 50 subjects, randomized to the two study arms.  Eligibility waivers are not 
permitted. Subjects must meet all of the inclusion and exclusion criteria to be 
enrolled in the study. Study procedures may not begin until a subject is consented. 
 
Inclusion criteria 
 
1. Histological documentation of HN-SQCC 
2. Older than 21 years of age 
3. Subject is eligible for routine chemo-radiotherapy for treatment of HN-
SQCC 
4. Informed consent is obtained 
5. Karnofsky performance status of at least 70 points 
 
Exclusion criteria 
 
1. Women with a positive urine pregnancy test are excluded from this study; 
women of childbearing potential (defined as those who have not undergone 
a hysterectomy or who have not been postmenopausal for at least 24 
consecutive months) must agree to refrain from breast feeding and practice 
adequate contraception  
2. Unable to comply with study procedures 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 6 of 21 
 
3. Use of saliva stimulating prescription drugs such as Evoxac or Salagen 
The use of saliva stimulating drug shave the potential of confounding the 
degree of xerostomia experience by the subject due to radiotherapy. 
Because of this, these type of drugs are not allowed during the duration of 
the subject’s participation in the clinical trial. Symptomatic relief of 
xerostomia will be approached using medications that do not stimulate the 
production of saliva. Such drugs include artificial salivas and Biotene oral 
spray. Potential subjects who are currently using saliva stimulating drugs 
must discontinue the drugs to qualify for the study. A washout period of 3-5 
days is required. 
4. Unable to receive standard chemotherapy 
 
INVESTIGATIONAL PLAN 
 
Upon consenting to the study, the subject will complete a series of 
questionnaires, including the subjective LENT/SOMA xerostomia form, the 
University of Michigan’s XQ, and the EORTC QLQ-C30 and H&N35 modules.   
Then the subject will attend their scheduled routine chemotherapy as prescribed 
by the treating medical oncologist.  This will be given concurrently with radiation 
therapy as discussed with the Radiation Oncologist.   
 Following the completion of the scheduled chemo-radiotherapy, the subject 
will be seen in Radiation Oncology every 3 months for routine follow-up visits 
related to their radiation treatment.  During those visits, the subjects will once again 
complete the packet of questionnaires.  The EORTC questionnaires and the 
xerostomia assessments (the LENT/SOMA form and the XQ) will also be filled out 
at 3 months (+/- 30 days), 6 months (+/- 30 days), 9 months (+/- 30 days) and 12 
months (+/- 30 days) after chemo-radiotherapy. The packet will be completed in 
the clinic, but if necessary can be sent home with the subject with a return envelope, 
emailed to the subject, or the subject may be called to respond to the questions 
over the phone.  The subject is also to be seen at the discretion of the medical 
oncologist and surgeon as part of routine oncologic follow-up. 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 7 of 21 
 
 
 
 
 
Duration of follow-up 
 
The subject will not be followed after the completion of the questionnaires 
at the 12 month visit. 
 
Removal of subject from study 
 
Subjects will be removed from the study when any of the criteria listed below 
apply: 
 
• Subject withdraws consent from study;  
• Subject is unable to comply with protocol requirements;  
• Subject experiences toxicity that makes continuation in the protocol unsafe;  
• Treating physician judges continuation on the study would not be in the subject’s 
best interest;  
• Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event).  
 
The Principal Investigator will be notified, and treating physician will 
document the reason for study removal and the date the subject was removed in 
the subject’s medical record. The study coordinator will record the reason for 
removal and date in the Case Report Form (CRF). 
 
STUDY PROCEDURES 
 
Investigator will use one of the two strategies (i.e. Margin based or Robust) 
to plan for radio-therapy. Both of the strategies are standardly used at UAMS. 
Generally, it is just a physician’s preference that determines which is used.  

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 8 of 21 
 
Margin-based and robust radiotherapy are both standard ways of delivering 
radiotherapy; therefore, no protocol-specific procedures are required with the 
chemo-radiotherapy. 
The EORTC questionnaires and the xerostomia assessments will be filled 
out at 3, 6, 9 and 12 months after chemo-radiotherapy.  
 
 
Radiotherapy 
 
Subject will receive either routine margin-based or robust radiotherapy. The 
selection of which type of planning will be assigned to a subject will be determined 
in a 1:1 randomized fashion with stratification by primary tumor site.  
 
Follow-up visits 
 
Subjects will be seen in Radiation Oncology every 3 months for one year. 
Adverse events will be assessed during routine physical exams at each visit. In 
addition, at the time of each visit the subject will complete the EORTC quality of 
life-30 questionnaire and associated module HN-35 module, and subjective 
LENT/SOMA xerostomia scoring form. 
 
MEASURES 
 
Xerostomia:   The Late Effects of Normal Tissues Subjective-Objective 
Management Analytic (LENT-SOMA) system includes subjective (patient-rated) 
and objective (clinician-rated) indices of radiotherapy toxicities [23].  The patient-
rated xerostomia item is used in the current study.  The item is rated on a 4-point 
Likert scale with 1 being the minimum and 4 being the maximum grades shown on 
the form.  Evidence supports the convergent and construct validity of this measure 
[22, 23].  The University of Michigan’s Xerostomia Questionnaire (XQ) is a brief, 8-
item measure of patient-reported xerostomia.  Individual items are rated on a 10-
point scale with 0 being the minimum and 10 being the maximum on each item.  
The instrument has demonstrated evidence of internal consistency, test-retest 
reliability, construct validity, and sensitivity to change [24-26]. 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 9 of 21 
 
 
Quality of Life:  The European Organisation for Research and Treatment of 
Cancer (EORTC) QLQ-C30 [27] is a widely used core module, designed to capture 
multidimensional aspects of health-related quality-of-life across a wide spectrum 
of different malignancies.  It generates a global score, 5 functional scores, and 9 
symptom scores.  The H&N35 module [28] assesses concerns specific to head-
and-neck cancer patients; it yields 18 symptom scores. Scores on both modules 
are transformed to a 0-100 scale, with higher scores representing more favorable 
outcomes on the functioning scales but poorer outcomes on the symptom and 
head-and-neck-specific scales.  In the current study, scales of special interest 
include dry mouth, oral pain, swallowing, opening mouth, sticky saliva, social 
eating, and global QOL.  Evidence supports the reliability and validity of the 
EORTC scales [27-29]. 
 
Demographic and Clinical Characteristics:  Demographic information will be 
collected at the baseline assessment to record basic background information (e.g., 
age, race, gender, education, comorbidities, etc.).  Clinical variables will be 
obtained from the treatment team or medical record (e.g., stage, site, recurrence 
status, prior treatments, time since diagnosis, etc.). 
 
ADVERSE EVENTS 
 
Adverse events associated to study participants 
 
The potential risk to study participants is the potential for loss of 
confidentiality. Measures to protect the confidentiality of study participants will be 
implemented as described in the Data Handling and Recordkeeping section.  
There will be no direct benefits to the study participants; however, 
knowledge gained from the study could potentially benefits patients in the future. 
 
Adverse event monitoring 
 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 10 of 21 
 
Adverse event data collection and reporting, which is required as part of 
every clinical trial, is done to ensure the safety of subjects enrolled in the studies 
as well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of subject safety and care.  
 
All subjects experiencing an adverse event will be monitored until the 
completion of the subject’s post-radiotherapy visit:  
• the adverse event resolves or the symptoms or signs that constitute the adverse 
event’s return to baseline;  
• there is a satisfactory explanation other than the study agent for the changes 
observed; or  
• death.  
 
Definitions of adverse effects 
 
An adverse event is any untoward medical occurrence in a subject 
undergoing study assessments and which does not necessarily have a causal 
relationship with the assessments. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the study assessments, whether or not related to the 
assessments. 
 
Severity of adverse effects 
 
Adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4 is available at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
Serious adverse effects 
 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 11 of 21 
 
A “serious” adverse event is defined in regulatory terminology as any 
untoward medical occurrence that:  
• Results in death. 
o If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
• Is life-threatening.  
o The subject was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more 
severe. 
• Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 
24   hours.  
• Results in persistent or significant disability or incapacity.  
• Is a congenital anomaly/birth defect.  
• Is an important medical event.  
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the subject, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
 
Reporting requirements for adverse events 
 
Expedited reporting 
 
• The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study.  
• The UAMS IRB must be notified within 10 business days of “any unanticipated 
problems involving risk to subjects or others” (UPR/UPIRTSO; See UAMS IRB 
Policy 10.2).  
 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 12 of 21 
 
Routine reporting 
 
All other adverse events, such as those that are expected, or are unlikely or 
definitely not related to the study participation, are to be reported annually as part 
of regular IRB continuing review. 
 
 
 
STATISTICAL CONSIDERATIONS 
 
This is a randomized, two-arm, open-label pilot clinical trial conducted in 
subjects with squamous-cell carcinoma of the head and neck. Its primary objective 
is to evaluate descriptively over time the prevalence and grade of xerostomia in 
subjects treated with IMRT under either biologically optimized margin-based or 
robust photon radiotherapy of HN-SQCC. Xerostomia will be measured in study 
subject using two patient-reported scoring systems completed by each subject 
before radiotherapy and 3, 6, 9, and 12 months after radiotherapy: the 
LENT/SOMA grading system and the University of Michigan’s Xerostomia 
Questionnaire (XQ; see Eisbruch et al. 2001). 
To accomplish this study’s primary objective, the analysis will proceed as 
follows: To analyze the XQ, scores on its 8 items will be summed for each subject 
at each time point to produce an overall XQ score whose values theoretically can 
range from 0 to 80; it will be treated as a continuous variable. LENT/SOMA grades 
as written on the form will simply be recorded electronically, and non-integer 
grades will be allowed if that’s what the subject wrote on the form. Longitudinal 
LENT/SOMA grades will be summarized by treatment arm and time point as the 
number and proportion of subjects achieving each grade, and also as the mean 
and SD of grade. Longitudinal overall XQ scores will be summarized by treatment 
arm and time point as the mean, SD, median, quartiles, and range. Both the 
correlation between xerostomia measures within each time point and the 
correlation within each xerostomia measure across time points will be studied 
using Spearman correlation analysis. Estimated means, SDs, medians, and 
quartiles will be accompanied by 90% confidence intervals. In exploratory analysis, 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 13 of 21 
 
we will employ mixed-models analysis to investigate more deeply the 
interrelationships among the xerostomia measures between treatment arms and 
time points. Also in exploratory analysis to accomplish the primary objective, we 
will use means, SD, and ranges to summarize each of the 8 individual items from 
the XQ by treatment arm and timepoint, and investigate using mixed-models 
approaches to compare the XQ items descriptively for treatment-arm differences 
over time. 
This study also has the following secondary objectives: 
1) To compare descriptively the arm treated with IMRT under the margin-based 
radiotherapy plan to the arm treated with IMRT under the robust radiotherapy 
plan for possible differences in derived outcomes of interest, including but not 
limited to: (1) occurrence rate of grade≥2 xerostomia as determined using the 
LENT/SOMA scale; and (2) occurrence rate of overall score ≥30 on the XQ. 
2) To obtain NTCP values of the parotid glands from both margin-based and 
robust radiotherapy treatment plans using validated parameter values of the 
NTCP mean dose model. Each subject will have their parotid NTCP values 
computed under both plans, even though they will receive IMRT delivered 
under only the plan they are randomized to. 
3) To obtain dose statistics for dose delivered to the parotid glands from both 
margin-based and robust treatment plans. 
4) To determine quality of life (QoL) at baseline and at 3, 6, 9 and 12 months after 
treatment using the EORTC QLQ-C30 instrument combined with the EORTC 
QLQ-H&N35 module. The main scores of interest at each time point will be the 
global QoL scale and the individual scales for dry mouth, oral pain, swallowing, 
opening mouth, sticky saliva, and social eating. 
5) To correlate NTCP values with change in QoL results. 
 
To accomplish this study’s secondary objectives, the analysis will proceed as 
follows: 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 14 of 21 
 
1) Xerostomia grades from the LENT/SOMA scale will be dichotomized as 
grade≥2 versus grade<2, then summarized by treatment arm and time point as 
the number and proportion achieving grade≥2. The dichotomization is placed 
at grade </≥2 because that was the cutpoint used in the PARSPORT study [22], 
but we will also consider an alternative dichotomization at grade </≥3.  As for 
the overall XQ score (a continuous variable), we will dichotomize it at different 
cutpoints chosen for their potential clinical relevance, beginning with a cutpoint 
of </≥30, then summarize the result by treatment arm and time point as the 
number and proportion of subjects who surpass the cutpoint. For all 
dichotomized versions of both xerostomia measures, the proportions on each 
arm and proportion differences between treatment arms will be estimated at 
each time point. Estimated proportions and their differences will be 
accompanied by two-sided 90% confidence intervals. Exploratory mixed-
models analysis may be used in follow-up mode, as time permits, to explore 
more deeply the differences between treatment arms and how they change 
over time.    
2) NTCP values from both plans will be summarized by plan and treatment arm 
as the mean, SD, median, quartiles, and range. Data will be graphed using box 
plots versus treatment arm. Plans will be compared descriptively by calculating 
the paired difference between them, and summarizing the result as means, 
SDs, and ranges. Means will be accompanied by 90% confidence limits.  
3) Dose statistics on each subject (i.e., the mean, SD, median, 1st and 3rd quartiles, 
5th percentile, and 95th percentile of dose received by the subject) will be 
summarized by statistic and treatment arm as the mean, SD, median, quartiles, 
and range. Data for each statistics will be graphed using box plots versus 
treatment arm. 
4) The global EORTC QOL scale and individual scales for dry mouth, oral pain, 
swallowing, opening mouth, sticky saliva, and social eating will be summarized 
by treatment arm and time point as the mean, SD, and range, and also (for 
individual Likert-scaled items that have 5 or fewer ordered categories) as the 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 15 of 21 
 
number and proportion of subjects whose answer falls into each ordered 
category. Data will be graphed using box plots or scatter plots versus treatment 
arm and profile plots versus time point. In general, the mean differences 
between treatment arms will be estimated at each time point, and such 
estimates will be accompanied by two-sided 90% confidence intervals. 
Exploratory mixed-models analysis may be used in follow-up mode, as time 
permits, to explore more deeply the differences between treatment arms and 
how they change over time. 
5) Changes in QoL results after treatment (compared to baseline) will be 
calculated at each post-treatment time point, then assessed for correlation with 
NTCP values by Spearman correlation analysis. 
 
For analyses in support of the secondary objectives, the outcomes at all time 
points will be of interest, but outcomes at the 12-month time point will be of special 
interest because of this time point’s prominence in previous studies such as 
PARSPORT [22]. 
 
Sample-size considerations. We plan to consent up to 75 subjects in order to reach 
our maximum accrual of 50 subjects. Twenty-five subjects will be assigned 
randomly to IMRT under the margin-based radiotherapy plan, and 25 subjects will 
be assigned randomly to IMRT under the robust radiotherapy plan.  
The IMRT arm of the PARSPORT study [22] lost 17% of its enrolled subjects 
to death and dropout before they could be evaluated at 12 months for that study’s 
primary endpoint, grade≥2 xerostomia. If similar results hold in our study, and if we 
enroll 25 subjects per treatment arm, then we can expect the number of subjects 
who remain on each treatment arm for 12 months to be binomially distributed with 
expected value of 20.75 and 95% probability of being 18 or higher. 
In each analysis, the precision of the estimates can be quantified through 
their standard errors, with smaller standard errors denoting greater precision. At 3 
months, when each treatment arm should still contain 25 subjects, the standard 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 16 of 21 
 
errors on estimated means will be ±0.200 times the group SDs, while the standard 
errors on proportion estimates of 10%, 30%, and 50% will be ±6.0%, ±9.2%, and 
10.0%, respectively. At 12 months, when the number remaining on each treatment 
arm could be as few as 18 subjects, the standard errors on estimated means will 
be ±0.236 times the group SDs, while the standard errors on proportion estimates 
of 10%, 30%, and 50% will be ±7.1%, ±10.8%, and ±11.8%, respectively. These 
standard errors are considered small enough to assure that the estimates obtained 
from this pilot clinical trial will have the level of precision needed to be informative 
in the design of future larger studies that seek to compare different methods of 
radiotherapy planning in the treatment of HN-SQCC.   
 
STUDY MANAGEMENT 
 
Registration procedures 
 
All subjects must be registered with the Cancer Clinical Trials Office before 
enrollment to study. Prior to registration, eligibility criteria must be confirmed with 
the Research Staff. To register a subject, call CCTO Monday through Friday, 
8:00AM-4:30PM. 
 
Randomization 
 
Twenty-five subjects will be assigned randomly to IMRT under the margin-
based radiotherapy plan, and 25 subjects will be assigned randomly to IMRT under 
the robust radiotherapy plan. 
The study coordinator will use RPRS, a cancer Biomedical Informatics Grid 
(caBIG®, NCI) application, to randomize the subject to either the Margin-Based 
Arm or the Robust Arm. Once a subject is registered in RPRS, the computer 
system will generate a randomly assigned arm. 
 
 
 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 17 of 21 
 
Data Handling and Record Keeping 
 
Data must be submitted according to protocol requirements for ALL subjects 
registered, whether or not study procedures are performed. For screen failures, 
only the eligibility criteria case report form will be completed. Data obtained during 
the study will be collected at each subject visit and entered into the protocol 
database. Subjects will be registered in RPRS, a cancer Biomedical Informatics 
Grid (caBIG®, NCI) application. Data will be entered into OpenClinica through 
electronic web-based case report forms (CRFs). OpenClinica is a secure open 
source system for electronic data capture and clinical data management. All 
information in OpenClinica will be coded with a unique identifier and will be stored 
in the database indefinitely. In the event that a subject fails screening, only the 
eligibility criteria case report form will be completed.  
The Principal Investigator will carefully monitor study procedures to protect 
the safety of research subjects, the quality of the data and integrity of the study. 
All study subject material will be assigned a unique identifying code. Only the 
research staff will have access to the information that identifies the subject in this 
study. 
 
Ethical considerations 
 
This study will be conducted in accordance with all applicable government 
regulations and University of Arkansas for Medical Sciences research policies and 
procedures. This protocol and any amendments will be submitted and approved 
by the UAMS Institutional Review Board (IRB) to conduct the study.  
The formal consent of each subject, using the IRB-approved consent form, 
will be obtained before that subject is submitted to any study procedure. All 
subjects for this study will be provided a consent form describing this study and 
providing sufficient information in language suitable for subjects to make an 
informed decision about their participation in this study. The person obtaining 
consent will thoroughly explain each element of the document and outline the risks 
and benefits, alternate treatment(s), and requirements of the study. The consent 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 18 of 21 
 
process will take place in a quiet and private room, and subjects may take as much 
time as needed to make a decision about their participation. Participation privacy 
will be maintained and questions regarding participation will be answered. No 
coercion or undue influence will be used in the consent process. This consent form 
must be signed by the subject or legally authorized representative (only if 
applicable), and the individual obtaining the consent. A copy of the signed consent 
will be given to the participant, and the informed consent process will be 
documented in each subject’s research record. 
 
Dissemination of data 
 
Results of this study may be used for presentations, posters, or publications. 
The publications will not contain any identifiable information that could be linked to 
a participant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 19 of 21 
 
REFERENCES 
 
1) Guobis Z, Baseviciene N, Paipaliene P, Sabalys G, Kubilius R. 
Xerostomia: Clinic, etiology, diagnosis and treatment. Medicina (Kaunas) 
2006;42:171–179. 
2) Memtsa P, Tolia M, Tzitzikas I, Bizakis J, Pistevou K, Charalambidou M, 
Iliopoulou C and Kyrgias G. Assessment of xerostomia and its impact on 
quality of life in head and neck cancer patients undergoing radiation 
therapy. Mol Clin Oncol 2017; 6(5):789-793. 
3) Cooper JS, Fu K, Marks J, et al. Late effects of radiation therapy in the 
head and neck region. Int J Radiat Oncol Biol Phys 1995; 31:1141–1164. 
4) Braam PM, Roesink JM, Raaijmakers CPJ, et al. Quality of life and 
salivary output in patients with head-and-neck cancer five years after 
radiotherapy. Radiat Oncol 2007;2:3. 
5) Samuels SE, Eisbruch A, Vineberg K, Lee J, Lee C, Matuszak M, Ten 
Haken R and Brock K. Methods for reducing normal tissue complication 
probabilities in oropharyngeal cancer: dose reduction or planning target 
volume elimination. Int J Radiation Oncol Biol Phys 2016;96(3):645-652. 
6) Chao KSC, Deasy JO, Markman J, et al. A prospective study of salivary 
function sparing in patients with head-and-neck cancers receiving 
intensity-modulated or three-dimensional radiation therapy: Initial results. 
Int J Radiat Oncol Biol Phys 2001;49: 907–916. 
7) Schilstra C, Meertens H. Calculation of the uncertainty in complication 
probability for various dose-response models, applied to the parotid gland. 
Int J Radiat Oncol Biol Phys 2001;50: 147–158. 
8) Blanco A, Chao K, El Naqa I, et al. Dose-volume modeling of salivary 
function in patients with head-and-neck cancer receiving radiotherapy. Int 
J Radiat Oncol Biol Phys 2005;62: 1055–1069. 
9) Li Y, Taylor JMG, Haken RKT, et al. The impact of dose on parotid 
salivary recovery in head and neck cancer patients treated with radiation 
therapy. Int J Radiat Oncol Biol Phys 2007;67: 660–669. 
10) Dijkema T, Terhaard CHJ, Roesink JM, et al. Large cohort dose-volume 
response analysis of parotid gland function after radiotherapy: Intensity-
modulated versus conventional radiotherapy. Int J Radiat Oncol Biol Phys 
2008;72:1101–1109. 
11) Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and function 
relationships in parotid salivary glands following conformal and intensity-
modulated radiation of head and neck cancer. Int J Radiat Oncol Biol Phys 
1999;45:577–587. 
12) Roesink JM, Moerland MA, Battermann JJ, et al. Quantitative dose-
volume response analysis of changes in parotid gland function after 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 20 of 21 
 
radiotherapy in the head-and-neck region. Int J Radiat Oncol Biol Phys 
2001;51:938–946. 
13) Qi XS, Semenenko VA, Li XA. Improved critical structure sparing with 
biologically based IMRT optimization. Med Phys. 2009;36(5):1790–799. 
14) Das S. A role for biological optimization within the current treatment 
planning paradigm. Med Phys. 2009;36(10):4672–82. 
15) Doit Q, Kavanagh B, Timmerman R, Miften M. Biological-based 
optimization and volumetric modulated arc therapy delivery for stereotactic 
body radiation therapy. Med Phys. 2012;39(1):237–45. 
16) Oh YK, Baek JG, Kim OB, et al. Assessment of setup uncertainties for 
various tumor sites when using daily CBCT for more than 2200 VMAT 
treatments. J Appl Clin Med Phys 2014;15:4418. 
17) Chan T, Bortfeld T, and Tsitsiklis J. “A robust approach to IMRT 
optimization,” Phys. Med. Biol. 51(10), 2567–2583 (2006). 
18) Fredriksson A. “A characterization of robust radiation therapy treatment 
planning methods—From expected value to worst case optimization,” 
Med. Phys. 39(8), 5169–5181 (2012). 
19) Pflugfelder D, Wilkens J, and Oelfke U. “Worst case optimization: A 
method to account for uncertainties in the optimization of intensity 
modulated proton therapy,” Phys. Med. Biol. 53(6), 1689–1700 (2008). 
20) Unkelbach J, Bortfeld T, Martin B, and Soukup M. “Reducing the 
sensitivity of IMPT treatment plans to setup errors and range uncertainties 
via probabilistic treatment planning,” Med. Phys. 36(1), 149–163 (2009). 
21) Fredriksson A, Forsgren A and Hardemark B. Maximizing the probability of 
satisfying the clinical goals in radiation therapy treatment planning under 
set-up uncertainty. Med Phys 2015; 42(7):3992-3999. 
22) Nutting CM, Morden JP, Harrington KJ, et. al. Parotid-sparing intensity 
modulated versus conventional radiotherapy in head and neck cancer 
(PARSPORT): a phase 3 multicenter randomized trial. Lancet Oncol 2011; 
12(2): 127-136. 
23) Ho KF, Farnell DJ, Routledge, JA, et al. Comparison of patient-reported 
late treatment toxicity (LENT-SOME) with quality of life (EORTC QLQ-C30 
and QLQ-H&N35) assessment after head and neck radiotherapy.  
Radiother Oncol 2010; 97:270-275. 
24) Eisbruch A, Kim HM, Terrell JE, et al. Xerostomia and its predictors 
following parotid-sparing irradiation of head-and-neck cancer. Int J 
Radiation Oncol Biol Phys 2001; 50:695-704. 
25) Pacholke HD, Amdur RJ, Morris CG, et al.  Late xerostomia after intensity-
modulated radiation therapy versus conventional radiotherapy.  Am J Clin 
Oncol 2005; 28:351-358. 

IRB #217585 
Sponsor: UAMS 
Version 9 
7/20/2023 
Page 21 of 21 
 
26) Meirovitz A, Murdoch-Kinch CA, Schipper M, et al. Grading xerostomia by 
physicians or by patients after intensity-modulated radiotherapy of head-
and-neck cancer.  Int J Radiation Oncol Biol Phys 2006; 66:445-453. 
27) Aaronson NK, Ahmedzai S, Bergman B, et al.  The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-
of-life instrument for use in international clinical trials in oncology.  J Natl 
Cancer Inst. 1993; 85:365-376. 
28) Bjordal K, de Graeff A, Fayers PM, et al.  A 12 country field study of the 
EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific 
module (EORTC QLQ-H&N35) in head and neck patients.  Eur J Cancer. 
2000; 36:1796-807.  
29) Sherman AC, Simonton S, Adams DC, et al.  Assessing quality of life in 
patients with head and neck cancer: cross-validation of the European 
Organization for Research and Treatment of Cancer (EORTC) Quality of 
Life Head and Neck module (QLQ-H&N35).  Arch Otolaryngol Head Neck 
Surg. 2000; 126:459-467.