Randomized Trial of Parotid Sparing Whole Brain Radiation
Phase: NA
Conditions: Xerostomia
Sponsor: UNC Lineberger Comprehensive Cancer Center

i 
PROTOCOL AMENDMENT #5 
LCCC 1802: Randomized Trial of Parotid Sparing Whole Brain Radiation  
AMENDMENT INCORPORATES (check all that apply): 
X       Editorial, administrative changes 
X       Scientific changes (IRB approval) 
___    Therapy changes (IRB approval) 
___    Eligibility Changes (IRB approval) 
AMENDMENT RATIONALE AND SUMMARY: 
Editorial, administrative changes 
•
Decrease accrual to 90 (section 7.2)
•
Remove any mention of Rex from the protocol (will no longer be opening at that site)
•
Updated contact info for co-investigators
THE ATTACHED VERSION DATED 01/15/21 INCORPORATES THE ABOVE REVISION 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 

ii 
 
 
PROTOCOL AMENDMENT #4 
 
 
LCCC 1802: Randomized Trial of Parotid Sparing Whole Brain Radiation   
AMENDMENT INCORPORATES (check all that apply): 
X       Editorial, administrative changes 
_      Scientific changes (IRB approval) 
___    Therapy changes (IRB approval) 
___    Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
Editorial, administrative changes 
• PI change from Kyle Wang to Colette Shen 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 08/28//2020 INCORPORATES THE ABOVE REVISION 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 

iii 
 
 
PROTOCOL AMENDMENT #3 
 
 
LCCC 1802: Randomized Trial of Parotid Sparing Whole Brain Radiation   
AMENDMENT INCORPORATES (check all that apply): 
X       Editorial, administrative changes 
X       Scientific changes (IRB approval) 
___    Therapy changes (IRB approval) 
___    Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
Editorial, administrative changes 
• Listed existing co-investigators not already identified on the protocol (cover pages) 
• Page numbers updated (table of contents) 
• Registration procedures updated (section 8.3) 
• Updated data management (section 7.4)  
 
Scientific changes 
• Accrual (section 7.2) 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 03/05//2020 INCORPORATES THE ABOVE REVISION 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 

iv 
 
 
PROTOCOL AMENDMENT #2 
 
 
LCCC 1802: Randomized Trial of Parotid Sparing Whole Brain Radiation   
AMENDMENT INCORPORATES (check all that apply): 
X       Editorial, administrative changes 
X       Scientific changes (IRB approval) 
___    Therapy changes (IRB approval) 
X       Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
Editorial, administrative changes 
• Study personnel updated (cover pages) 
 
Scientific changes 
• Wording of treatment planning and delivery description updated to provide additional 
clarification/details (section 4.3.6) 
• Additional assessments for patient treatment with steroids, narcotics, anticholinergics, 
and systemic therapy at various time points (section 4.3.10 & section 5.1) 
 
Eligibility changes 
• 
Narrowed treatment dose and fractionation range permitted for enrollment (section 3.1.1) 
• 
Allowance to use of MRI-based planning simulation (section 3.2.1) 
• 
Exclusion criterion added to explicitly state exclusion of pregnant patients (section 3.2.6) 
 
 
THE ATTACHED VERSION DATED 03/08/2019 INCORPORATES THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 

v 
 
 
PROTOCOL AMENDMENT #1 
 
 
LCCC 1802: Randomized Trial of Parotid Sparing Whole Brain Radiation   
AMENDMENT INCORPORATES (check all that apply): 
__      Editorial, administrative changes 
__      Scientific changes (IRB approval) 
___    Therapy changes (IRB approval) 
X       Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
Eligibility changes 
• 
Time frame for prior RT exclusion criterion modified from within the last year to any 
time within the patient’s life (section 3.1.2) 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 08/29/2018 INCORPORATES THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 

viii 
 
Signature Page 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
Principal Investigator (PI) Name: Colette Shen, MD, PhD 
 
PI Signature: via IRBIS certification 
Protocol Version Date: 1/15/21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ix 
 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................1 
1.1 
Study Synopsis ......................................................................................................1 
1.2 
Background ...........................................................................................................1 
1.3 
Purpose and Rationale ...........................................................................................4 
2.0 
STUDY OBJECTIVES/AIMS AND ENDPOINTS/OUTCOMES .....................5 
2.1 
Primary Objective .................................................................................................5 
2.2 
Secondary Objectives ............................................................................................5 
2.3 
Exploratory Objective ...........................................................................................6 
2.4 
Endpoints ...............................................................................................................6 
3.0 
PATIENT ELIGIBILITY ......................................................................................6 
3.1 
Inclusion Criteria ...................................................................................................6 
3.2 
Exclusion Criteria ..................................................................................................7 
4.0 
STUDY PLAN .........................................................................................................8 
4.1 
Schema ..................................................................................................................8 
4.2 
Duration of Study ..................................................................................................9 
4.3 
Study Details .........................................................................................................9 
4.4 
Expected Risks ....................................................................................................15 
4.5 
Removal of Patients from Protocol .....................................................................16 
5.0 
TIME AND EVENTS TABLE .............................................................................16 
5.1 
Time and Events Table ........................................................................................16 
6.0 
UNANTICIPATED PROBLEMS .......................................................................16 
6.1 
Definition ............................................................................................................16 
6.2 
Reporting .............................................................................................................17 

x 
 
6.3 
Monitoring and Oversight ....................................................................................17
 
STATISTICAL CONSIDERATIONS ................................................................17 
7.1 
Study Design .......................................................................................................17 
7.2 
Sample Size and Accrual .....................................................................................17 
7.3 
Data Analysis Plans .............................................................................................18 
7.4 
Data Management/Audit .....................................................................................18 
8.0 
STUDY MANAGEMENT ....................................................................................19 
8.1 
Institutional Review Board (IRB) Approval and Consent ..................................19 
8.2 
Required Documentation.....................................................................................19 
8.3 
Registration Procedures.......................................................................................19 
8.4 
Adherence to the Protocol ...................................................................................19 
8.5 
Amendments to the Protocol ...............................................................................21 
8.6 
Record Retention .................................................................................................21 
8.7 
Obligations of Investigators ................................................................................21 
9.0 
REFERENCES ......................................................................................................22 
10.0 APPENDIX ............................................................................................................23 
 
 
 
 
 
 
 
 
 
 

1 
 
1.0 BACKGROUND AND RATIONALE 
 
1.1 Study Synopsis 
 
The parotids have not been historically considered an organ at risk / avoidance structure and are 
not routinely delineated for whole brain radiation (WBRT) planning, despite receiving incidental 
dose [1] using standard fields. For this reason, we evaluated patient reported xerostomia in an 
ongoing prospective observational trial (LCCC 1540: Prospective Evaluation of Patient Reported 
Xerostomia After Whole Brain Radiation). At an interim analysis of LCCC 1540 with accrual at 
90% of the goal, we found a clinically-meaningful rate of xerostomia following routine WBRT. 
Furthermore, the incidence/severity appeared to be related to parotid dose. The goal of this 
follow-up study is to investigate whether parotid sparing WBRT can reduce or prevent patient 
reported xerostomia. The study design will principally be a prospective randomized trial where 
patients are randomized to receive parotid sparing WBRT vs. standard WBRT where the parotids 
are not avoided. We will evaluate the xerostomia scores (using the University of Michigan 
Xerostomia Questionnaire [2]) of patients treated in each arm. Patients who refuse randomization 
will be offered enrollment in an observational arm to follow their symptoms of xerostomia for 
secondary analysis. This will be a multi-site study, with patients also enrolling at High Point 
Regional Health, High Point, North Carolina, as well as possibly other sites and institutions. We 
anticipate a total accrual of approximately 90 patients (45 in each interventional arm) with a goal 
of 62 evaluable patients reaching the primary 1 month post-RT endpoint. 
 
1.2 Background 
 
1.2.1 Salivary Gland Toxicity in Head and Neck Cancer 
 
It is well known that radiotherapy for head and neck cancer is associated with significant and 
sometimes permanent dry mouth. Numerous studies have demonstrated that the degree of parotid 
gland exposure is related to the severity of xerostomia [2-5]. These studies have led to a national 
consensus guideline regarding minimization of parotid doses (e.g., mean bilateral parotid dose 
should be ≤ 25 Gy) [6]. Due to these guidelines, it is now standard to delineate the parotid glands 
and to use conformal treatment techniques such as intensity-modulated radiation therapy to 
minimize incidental irradiation to these organs in patients being treated for head and neck cancer. 
 
1.2.2 Whole Brain Radiation – Background and Quality of Life 
 
Whole brain radiation is commonly used for patients with multiple brain metastases. The 
prognosis of most patients who require whole brain radiation is poor, with many not living 
beyond six months [7]. Quality of life is thus of paramount importance in this population. 
Numerous prospective studies have reported on the well-known side effects of fatigue, alopecia, 
and neurocognitive decline following WBRT. This is balanced with the potential improvement in 
quality of life due to control of CNS disease [8-10]. While patients do occasionally complain of 
dry mouth following whole brain radiation, no prior studies have systematically assessed the 
frequency or severity of dry mouth in these patients, though one older case series did report 
several cases of parotitis following WBRT [11]. We believe that these symptoms are related to 

2 
 
incidental irradiation of the parotids, and that simple adjustments to the traditional RT fields can 
mitigate this toxicity.  
 
1.2.3 Whole Brain Radiation – Standard Approach, Organs at Risk, and Parotid Dose 
 
Due to the poor prognosis for most patients receiving whole brain radiation, and because typical 
total doses used for whole brain radiation are in the range of 20-35 Gy (vs. 60-70 Gy for patients 
with head and neck cancer), the parotids have not traditionally been considered an organ at risk 
in patients receiving whole brain radiation. Historically, whole brain radiation fields were 
designed based on the anatomy as seen on planning skull radiographs, and this ‘standard 
approach’ has not changed in several decades. While sophisticated computer-based techniques 
readily enable the consideration of 3D anatomy (e.g. from CT and/or MRI) in the treatment 
planning process, these newer approaches have not been applied in patients receiving whole 
brain radiation. The accepted standard WBRT field includes roughly 5-10mm of margin 
inferiorly around the cribiform plate and inferior skull, as well as coverage of the entire C1 and 
sometimes C2 vertebral bodies. For the purposes of WBRT, no standard normal tissues are 
delineated for avoidance, though the lenses are often delineated at the discretion of the treating 
physician. 
 
As such, the location of the parotid glands is not considered during planning for whole brain 
radiation, and there are presently no dose/volume limits for the parotids. For example, in patients 
receiving whole brain radiation on the nationwide RTOG 0933 trial using hippocampal sparing 
intensity-modulated radiation, only the hippocampus, eyes, and lenses were required to be 
delineated with set dose limits. [12] In patients receiving whole brain radiation on other 
protocols, such as N107C, [13] no organs at risk are required to be delineated. Thus, the risk of 
radiation-associated parotid injury is not appreciated.   
 
Nonetheless, the parotids do, in fact, receive substantial radiation dose during whole brain 
radiation For instance, several dosimetric studies report mean parotid doses of 10 to 20 Gy. [1, 
14, 15] However, prior to LCCC 1540 there have been no studies that have reported the clinical 
impact of this parotid exposure. Several lines of evidence suggest that incidental parotid 
irradiation may cause meaningful toxicity in patients receiving whole brain radiation: 
 
1. Gradual dose response: Though the recommended parotid “dose limit” for patients with 
head and neck cancer is  20-25 Gy, there is a gradual dose response, and it is 
recommended that parotid dose is kept as low as possible (e.g. << 20 Gy) to minimize 
xerostomia. Thus, mean parotid doses in the 10-20 Gy range (as is reported with whole 
brain radiation) may cause toxicity. 
2. Acute vs. late toxicity: Parotid dose guidelines in patients with head and neck cancer are 
based on late (e.g. ≥1 year post-RT) toxicity. Patients generally suffer greater acute 
toxicities during RT, [16] or at shorter time intervals (e.g., 1-6 months) post-RT, with 
some recovery of salivary function at later time points. These acute toxicities are what 
matter most to patients receiving whole brain radiation; given their poor prognoses, few 
will survive long enough for later (e.g. ≥1 year post-radiation) salivary recovery. 

3 
 
3. Higher doses per fraction and shorter overall radiation treatment times: Though parotid 
doses during whole brain radiation are lower than for head and neck cancer, whole brain 
radiation is delivered in larger doses per fraction (2.5-3.0 Gy per fraction as opposed to 
1.8-2.0 Gy per fraction for head and neck cancer) and in a shorter treatment time (e.g. 2-3 
weeks as opposed to 7 weeks for head and neck cancer). Higher doses per fraction and 
shorter treatment intervals are both associated with increased risks of toxicity. 
1.2.5 Preliminary Results of LCCC 1540: Prospective Evaluation of Patient Reported 
Xerostomia After Whole Brain Radiation 
 
These hypotheses culminated in the design of LCCC 1540. We used the validated University of 
Michigan Xerostomia Questionnaire [2] and a “bother score” questionnaire to assess patient-
reported xerostomia after standard whole brain radiation, in which the parotid glands were not 
prospectively delineated. The parotids were, however, retrospectively delineated to assess impact 
of parotid dose on xerostomia. Like other reports, the parotid glands received mean doses of 
roughly 17 Gy. However, LCCC 1540 provided the first data on the actual clinical significance 
of this incidental exposure. In an interim analysis with accrual at 90% of the goal, xerostomia 
was common, sometimes severe, and often persisted to the last post-RT assessment. Further, 
parotid doses were strongly correlated with xerostomia, consistent with our original hypothesis. 
These novel data have important implications for quality of life and perhaps even nutritional 
status in this vulnerable patient population, and were accepted for oral presentation this year at 
two national conferences (ACRO 2017 and ASTRO 2017). 
 
 

4 
 
Figure 1. LCCC 1540: Change in xerostomia score (y-axis) plotted against parotid dose (x-axis) 
for all 41 patients reaching the 1 month post-RT primary endpoint. Parotid doses were 
significantly correlated with xerostomia (p=0.005). (Parotid V20Gy: % of the bilateral parotid 
glands receiving at least 20 Gy). 
 
 
 
Figure 2. LCCC 1540: Mean xerostomia score change (A) and bother (B) were significantly 
worse in patients with higher parotid dose at most time points. (Parotid V20: % of the bilateral 
parotid glands receiving at least 20 Gy). 
 
These are the first data demonstrating that dry mouth is a toxicity of WBRT and have 
implications on field design during treatment planning. 
 
1.3 Purpose and Rationale 
 
Given that the results of LCCC 1540 show a relationship between parotid dose and toxicity, it is 
our new hypothesis that prospective delineation of the parotids and minimization of dose to the 
parotids can provide clinically meaningful reductions in xerostomia while still adequately 
treating the brain. This is supported by a secondary analysis of LCCC 1540, where we assessed 
whether new radiation plans designed retrospectively to avoid the parotids could meaningfully 
reduce dose to the parotids while simultaneously maintaining adequate coverage of the brain. For 
the original (and delivered plans), the median parotid mean dose was 17 Gy and median parotid 
V20Gy was 48%. With systematic re-planning to reduce parotid exposure, the median parotid 
mean dose was reduced to 8 Gy and the median parotid V20Gy was reduced to 14%. This 
reduction in parotid dose did not appear to come at significant expense to brain coverage: the 
volume of brain receiving 95% of the prescription dose was 99.86% for the parotid sparing 
plans, vs. 99.99% for the original plans (Example, Figure 3). 

5 
 
 
 
Figure 3. Panel A: Radiation fields for a patient receiving whole brain RT on LCCC 1540 with 
persistent severe post-RT xerostomia. The parotids were not prospectively delineated and 
received a mean dose of 20 Gy. Panel B: Alternative plan with fields designed to reduce parotid 
exposure resulting in a mean parotid dose of only 11 Gy. The volume of brain covered by 95% 
of prescription dose was 99.98% for the original, vs. 99.65% for the re-plan (thus parotid sparing 
does not significantly compromise target coverage). 
 
The results of LCCC 1540 have introduced an evolving standard of care in our department. 
Because coverage of the brain does not appear to be compromised with the use of parotid sparing 
(see Figure 3, above), several physicians who are familiar with data from LCCC 1540 have 
already started utilizing parotid sparing WBRT fields off trial to attempt to reduce toxicity. 
Others, on the other hand, prefer to continue to use standard WBRT without parotid avoidance 
given the preliminary nature of the available data and the hypothetical risk of marginal failure 
either in the inferior brain or upper cervical vertebrae. To investigate the hypothesis that parotid 
sparing provides a clinical benefit in a safe manner, we will randomize patients on trial to 
receive either parotid sparing WBRT vs. standard WBRT. If our hypothesis is correct, then the 
severity of xerostomia will be lower in patients randomized to parotid sparing. 
 
 
2.0 STUDY OBJECTIVES 
 
2.1 Primary Objective 
 
To assess whether the use of parotid sparing WBRT fields results in decreased xerostomia 
compared to standard WBRT fields (where the parotids are not avoided) in randomized patients. 
 
2.2 Secondary Objectives 
 

7 
 
3.1.2 No prior radiation that would have exposed the parotids to a significant (estimated >10 Gy 
mean parotid dose) level of radiation. Patients receiving prior stereotactic radiosurgery for brain 
metastasis are eligible for inclusion in this trial as this form of radiation is highly conformal and 
exposes the parotids to minimal (estimated <1 Gy) radiation. 
• Patients enrolling on the observational arm may have started their current course of 
whole brain radiation therapy within 5 days prior to completing the baseline screening 
questionnaire and consenting to study. 
 
 
3.1.3 Greater than or equal to 18 years of age (no upper age limit). 
 
3.1.4 Raw xerostomia score < 40 / 80 on the initial screening xerostomia questionnaire. This is 
calculated by adding up the values from questions 1-8. 
 
3.1.5 Initial xerostomia questionnaire and informed consent obtained within the required time 
frame (≤ 30 days before RT start for interventional arm; ≤ 5 days after RT start for observational 
arm). 
 
 
3.2 Exclusion Criteria 
 
The subject may be excluded or withdrawn from the study if any of the following apply: 
 
3.2.1 Patients receiving WBRT without the use of a CT or MRI-based planning simulation. 
 
3.2.2 Patients receiving WBRT with the use of intensity-modulated radiation therapy. 
 
3.2.3 Patient receiving WBRT as elective treatment of potentially subclinical intracranial disease 
(e.g., WBRT for prophylactic cranial irradiation of small cell lung cancer). 
 
3.2.4 Physically unable to communicate by paper or phone to complete the study survey. 
 
3.2.5 Prisoners. 
 
3.2.6 Pregnant women. 
 
 
 
 

8 
 
4.0 STUDY PLAN 
 
4.1 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Due to the expedited nature of many whole brain radiation treatment plans, we anticipate 
identifying many subjects after treatment has already begun. Because of this, we will offer these 
individuals enrollment on an observational arm of this study. Additionally, if participants do not 
wish to participate in the interventional arm of this study, they will be approached for the 
observational arm. See Section 4.3 for more details. 
 
4.2 Duration of Study 
 
Offered interventional 
randomization arm 
Consent (Form 1) 
Before treatment planning 
Post-RT Questionnaires            
2W, 1M, 3M, & 6M after RT end 
A: Standard WBRT   
Control arm 
End-RT 
Questionnaire 
B: Parotid sparing WBRT 
Intervention arm 
Offered observational arm 
(refused randomization or 
enrolled after RT start) 
Consent (Form 2) 
≤ 5 days after RT start 
C: Standard / Parotid sparing WBRT    
Physician’s choice 
RANDOMIZE  
Eligible patient identified prior 
to RT start 
Eligible patient identified after 
RT has already started 
Screening Questionnaire 
Eligible if raw XQ score < 40 
Screening Questionnaire 
Eligible if raw XQ score < 40 
Interventional Arm 
Observational Arm 

9 
 
The anticipated accrual period is around 3-5 years. 
 
4.3 Study Details 
 
This is primarily a two-arm, single-blind, randomized study of parotid sparing WBRT, with a 
third observational arm of patients who were identified after radiation had already started or who 
refused randomization but were willing to be followed for quality of life assessment. The 
primary purpose of this study is to compare the proportion of patients experiencing significant 
xerostomia in patients randomized to parotid sparing vs. standard WBRT. Patients receiving 
WBRT often receive treatment in urgent situations, making pre-treatment randomization 
logistically challenging. Therefore, the observational arm serves to increase the number of 
eligible patients and allows for comparison of xerostomia in all patients receiving parotid sparing 
vs. standard WBRT, but who were unable to be approached in time for randomization. Patients 
enrolling on the randomization arms will be consented and enrolled prior to treatment. Patients 
enrolling on the observational arm may enroll up to 5 days after initiation of treatment. Post-
treatment surveys will be collected up to 6 months post-RT. We therefore anticipate that 
patients’ active participation will last approximately 6 months. Chart abstraction will take place 
for up to 1 year post-RT for assessment of secondary endpoint #1: freedom from marginal 
relapse. 
 
4.3.1 Screening for Eligibility and Registration Details 
 
Patients identified as qualifying for the trial will be divided into those who were identified prior 
to radiation start vs. those identified after radiation start. Patients interested in participating will 
complete an anonymous screening baseline xerostomia questionnaire identical to the primary 
study assessment (see Section 4.3.9, below). Patients scoring ≥ 40 pts on the screening 
xerostomia questionnaire are ineligible. Patients scoring < 40 / 80 will be eligible and offered 
enrollment on the study. Questionnaires completed by patients who are found to be ineligible or 
who decline to enroll on the study will be destroyed. Questionnaires completed by patients who 
consent to the trial will be assigned patient information (de-anonymized) and serve as their 
baseline quality of life data. 
 
Patients identified prior to radiation start will be offered enrollment into the randomization arms 
(Consent form 1, arms A and B), with the observation arm (Consent form 2, arm C) offered to 
those who refuse randomization. Patients identified after radiation has already started, but within 
5 days of the first day of radiation, will be offered enrollment into the observational arm 
(Consent form 2, arm C). 
 
4.3.2 Randomization Details 
 
Patients who agree to be randomized will be assigned to one of the following treatment groups 
using block randomization. A randomization list will be designed by the statistician. Patients will 
be randomized after informed consent is obtained, and before treatment begins. A list of 
randomized assignments will be provided to each site prior to enrollment of participants to 
facilitate ease of trial administration. This is done because of the often urgent nature of whole 

10 
 
brain cases and the necessity of clinicians knowing the randomized assignment before treatment 
planning.  
 
Arm A: Standard WBRT (Control) 
Arm B: Parotid sparing WBRT (Intervention) 
 
4.3.3 Blinding 
 
This will be a single-blind study, where all enrolled patients are blinded to the type of WBRT 
fields used in their treatment in order to minimize reporting bias between the study arms. 
 
4.3.4 CT simulation 
 
Patients on all study arms will routinely undergo a CT scan for treatment planning. 
Immobilization is achieved with an aquaplast mask form fitted on the patient’s face and locked 
on to the table. Prior to the CT scan, a “scout X-ray” is taken to ensure the patient is in an 
acceptable position. A CT scan is then obtained through the treatment area, and including the 
entire neck. These images are used to create the radiation treatment plan. The planning CT scan 
is then transferred the treatment planning software program. 3D conformal radiation plans will 
then be created for each patient. 
 
4.3.5 Treatment Planning and Delivery – Arm A: Standard WBRT (Control Arm) 
 
Patients randomized to the control arm will receive standard WBRT without delineation or 
avoidance of the parotid glands, as per typical practice (see Figure 4, below). Patients must be 
enrolled prior to treatment. Laterally arranged beams will be designed based on digitally 
reconstructed skull radiographs. A 5-10 mm margin is used around the cribiform plate and skull 
base, with inferior extension of the field to cover the entirety of the C1 and/or C2 vertebra, with 
at least a 2mm margin anterior to the vertebral bodies. The parotids will not be delineated for 
avoidance, and delineation of other organs at risk or the brain is optional, consistent with most 
national studies utilizing WBRT (see section 1.2.3). All treatment plans are monitored for quality 
assurance at departmental meetings in which radiation fields are presented for peer review. 
Weekly X-ray films are taken to verify the accuracy of patient set up on actual treatment days. 
The initial treatment will not proceed without physician verification of accurate patient set up. 
 

11 
 
 
Figure 4. Control arm (Standard WBRT). Example of a laterally arranged treatment field for 
standard WBRT used in the control arm, where a small margin is provided around the inferior 
skull border. The C1 vertebra is covered with a small anterior margin. No organs at risk are 
standardly delineated, though providers may opt to delineate the lens and orbits for avoidance, or 
the brain to ensure coverage. 
 
4.3.6 Treatment Planning and Delivery – Arm B: Parotid sparing WBRT (Intervention 
Arm) 
 
Patients randomized to the intervention arm will receive parotid sparing WBRT (see Figure 5, 
below). Patients must be enrolled prior to treatment.  
 
- 
The left parotid will be delineated and named Parotid_Lt 
- 
The right parotid will be delineated and named Parotid_Rt 
- 
The Parotid_Lt and Parotid_Rt structures will be combined and named 
Parotids_Bilateral for use in planning and dosimetric analysis. 
- 
The brain will be delineated to the level of the foramen magnum, marked by the superior 
dens (see Figure 6, below), to ensure adequate target coverage.  
- 
Laterally arranged beams will be designed based on both digitally reconstructed skull 
radiographs and CT anatomy. Radiation fields will be altered to minimize overlap with 
the Parotids_Bilateral contour, while maintaining around a 1cm margin around the brain 
contour. All treatment plans are monitored for quality assurance at departmental meetings 
in which radiation fields are presented for peer review. Weekly X-ray films are taken to 
verify the accuracy of patient set up on actual treatment days. 
 

12 
 
Based on the results of the replanning analysis from LCCC 1540, 87% of patients were able to 
achieve a bilateral parotid V20Gy <25% while maintaining a 1cm margin around the brain, and 
the range of replanned bilateral parotid V20Gy was 1-35%. Thus, there will be a goal to limit 
the Parotids_Bilateral V20Gy to <25%, and lower if possible. The following table 
summarizes the dose constraints of the parotid-sparing arm: 
 
Parotid-sparing WBRT arm dose constraints (for Parotids Bilateral) 
Goal 
V20Gy < 25% 
Minor deviation V20Gy ≥ 25% to < 35% 
Major deviation 
V20Gy ≥ 35% 
 
 
Figure 5. Intervention arm (Parotid sparing WBRT). Example of a laterally arranged 
treatment field for parotid sparing WBRT used in the intervention arm. Cervical vertebrae are no 
longer considered in treatment planning. The parotids and brain must be delineated. Ensuring 
around a 1 cm margin around the brain contour, the treatment field is altered to minimize overlap 
with the parotid glands. 
 

13 
 
 
Figure 6. Intervention arm (Parotid sparing WBRT). Contouring of the parotids (green, blue) 
and brain (red). The brain contour extends inferiorly to the most superior point of the dens of the 
C2 vertebra (dotted circle). 
 
4.3.7 Treatment Planning and Delivery – Arm C: Observational arm (WBRT protocol not 
specified) 
 
Patients who decline randomization but consent to the observational arm will receive WBRT 
without the use of the above treatment planning guidelines. WBRT will be delivered using 
standard or parotid sparing fields, per treating physician preference. Patients may also enroll on 
this arm after initiation of WBRT, as long as the baseline questionnaire is completed within 5 
days of initiation of treatment. These patients will complete the protocol-specified study 
assessments at the same time points as randomized patients. 
 
4.3.8 Treatment Planning and Delivery – Quality Assurance 
 
Given that whole brain radiation is often delivered in situations of medical urgency, there will be 
no requirement for the PI or primary site to approve treatment plans before initiation of radiation. 
However, to ensure delivery of radiation as intended, a digitally reconstructed radiograph 
containing the treatment field and any delineated organs at risk or targets will be sent to the 
study coordinator for the first four randomized patients at each non-primary site participating in 
the protocol. If the treatment plans are not found to be adequate, the Principal Investigator will 
hold a meeting with the pertinent sites to discuss requested corrections for future patients. 
Patients who received the incorrect treatment (per randomization) will not be analyzed as part of 
the primary endpoint. 
 
4.3.9 Main Study Assessment: Xerostomia Questionnaire 
 
Patients in this study will be asked to complete the Xerostomia Questionnaire and two additional 
supplemental survey questions at baseline (prior to radiation in randomized patients and within 5 

14 
 
days of radiation initiation in patients refusing randomization but consenting for the observation 
arm), at the end of radiation (on or within 5 days after the final day of radiation), then at two 
weeks (+/- 5 days) and one, three, and six months (+/- 7 days) after radiation completion, for a 
total of six planned surveys. This survey may be administered by phone or by email, vs. in 
person if the patient has an appointment at the appropriate time point necessary for clinical 
follow-up. This survey also acts as the screening questionnaire completed by patients prior to 
enrollment, and counts as the baseline questionnaire for those consenting to enrollment. 
 
The full survey (see appendix) will consist of the validated University of Michigan Xerostomia 
Questionnaire (questions 1-8) and two additional questions related to dry mouth, (questions 9-
10). Questions 1-8 will be answered on a Likert scale ranging from 0 (least bothersome) to 10 
(most bothersome), summed, and linearly converted to a scale from 0-100. Questions 9-10 will 
be answered on a Likert scale with four responses: Not at all, a little, quite a bit, and very much. 
Questions 9-10 are designed to quantify the overall importance of dry mouth symptoms to each 
patient, and were adapted from the validated EORTC QLQ-H&N35 head and neck specific 
questionnaire [17]. 
 
4.3.10 Other Assessments 
 
At the initial / baseline assessment, patients’ Eastern Cooperative Oncology Group (ECOG) 
performance status will be recorded. Relevant demographic and clinical data will be abstracted 
from the medical record as part of this study. For patients randomized to standard WBRT, the 
parotids will be delineated retrospectively for dosimetric analysis. For patients randomized to 
parotid sparing WBRT, the parotids are prospectively delineated and dosimetric data 
prospectively collected. 
 
For the purposes of assessing factors potentially confounding the measurement of dry mouth, we 
will prospectively record at the baseline assessment whether patients are taking different classes 
of medications. At the end of RT time point. We will record whether the patients required 
steroids at any point during radiation. At the 1 month time point, we will also record whether the 
patient has received systemic therapy (including chemotherapy) after WBRT. The details of 
these assessments are found in section 5.1 (Time and Events Table). 
 
4.3.11 Follow Up 
 
Follow up for the purposes of this study is limited to the administration of surveys up to six 
months post-radiation, which is the last planned questionnaire. Participation in this study will not 
impact the actual clinical follow-up schedule of patients receiving WBRT, which is based on the 
discretion of the treating radiation oncologist. Although a secondary endpoint is the rate of 
marginal relapse around the blocked parotid glands, this will be assessed using data obtained as 
part of standard of care follow-up of these patients. No additional visits or protocol-specified 
imaging will be required, as this would unnecessarily burden these palliatively treated patients, 
given the minimal expectation that a meaningful difference in tumor control exists (see section 
below on expected risks). 
 
4.4 Expected Risks 

15 
 
 
Patients randomized to standard WBRT will not be subject to any risks specific to participation 
in this trial; these patients receive standard treatment and simply complete the study assessment 
at post-treatment time points. Several theoretic risks warrant mention for patients randomized to 
parotid sparing WBRT: 
 
1. By delineating and minimizing dose to the parotids, the target (brain) could receive a 
lower dose, which could place the patient at higher risk of inferior brain relapse. 
2. By omitting coverage of C1/C2, patients may develop bony metastases in this location 
which may be more difficult to treat with radiation in the future, given the abutment of 
the prior parotid sparing field. 
 
For the following reasons, these risks are minimal: 
 
1. The standard field arrangements of WBRT covering the upper cervical vertebrae have become 
standard practice with the advent of CT-based planning. Prior to CT-based planning, WBRT was 
delivered with an angled rectangular field splitting the cervical vertebrae. With the use of CT-
based planning, WBRT fields became horizontal, and coverage of the cervical vertebrae was 
added to provide an additional margin around the foramen magnum. However, our preliminary 
analysis of LCCC 1540 and other studies [15, 18] show that coverage of brain is minimally 
affected with alterations to the field to maximize sparing of the parotids. Some of these studies 
have done this by omitting the upper cervical vertebrae and others have simply reduced the field 
borders in areas overlapping with the parotids. Therefore, target coverage is not expected to be 
compromised. 
 
2. Regardless of any reductions in field size and the negligible impact on dose to the brain 
described above, whole brain radiation is essentially treatment of mostly subclinical disease in 
addition to areas of actual brain metastases. However, the field of radiation oncology as a whole 
has generally accepted that treatment of subclinical disease in the brain is not strictly necessary. 
This is demonstrated by the increasing use of stereotactic radiosurgery for multiple brain 
metastases with no elective brain treatment; it is generally accepted that if these patients develop 
new brain metastases they can be salvaged with additional stereotactic radiosurgery. Therefore, a 
small margin reduction with the goal of improving patient quality of life in a population with 
limited life expectancy should be acceptable and entail minimal excess risk. 
 
3. For the same reason as above, omission of the C1/C2 vertebrae should also be of minimal 
significance. Given the overall poor prognosis of patients receiving WBRT, the rate of 
significant marginal bony relapses adjacent to the inferior WBRT field is expected to be 
extremely low. Furthermore, with the advent of stereotactic radiosurgery, any such relapses 
would still be safely treatable with definitive or palliative intent. 
 
4. Finally, the willingness of many physicians and several institutions [1, 18-20] to adopt parotid 
sparing WBRT as their current standard is a testament to the generally low risk involved. 
 
4.5 Removal of Patients from Protocol 
 

16 
 
Patients will be informed that they can request to withdraw from participation in this study at any 
time. If a patient withdraws from the study, they will no longer be contacted for the purposes of 
collecting data related to this study. 
 
 
5.0 TIME AND EVENTS TABLE 
 
5.1 Time and Events Table 
 
 
Pre-study 
/ 
Baseline1 
Radiation 
End-RT2 
2 Weeks 
Post-RT3 
1 Month 
Post-RT4 
3 Months 
Post-RT4 
6 Months 
Post-RT4 
Informed Consent 
x 
 
 
 
 
 
 
Xerostomia 
Questionnaire 
x 
 
x 
x 
x 
x 
x 
ECOG Performance 
Status Assessment 
x 
 
 
 
 
 
 
Steroid 
Assessment5 
x 
 
x 
 
 
 
 
Narcotic 
Assessment6 
x 
 
 
 
 
 
 
Anticholinergic 
Assessment7 
x 
 
 
 
 
 
 
Systemic Therapy 
Assessment8 
 
 
 
 
x 
 
 
Quality Assurance 
(1st 4 pts per site) 
 
 
x 
 
 
 
 
Medical Record 
Abstraction 
 
Continuously throughout study 
1. For randomized group this should be completed before treatment start, but no more than 
30 days before treatment start. The observational arm should within 30 days of treatment 
start and up to 5 days after the first fraction of radiation is delivered. 
2. This should be completed on the last day of treatment or up to 5 days after treatment end. 
3. +/- 5 days 
4. +/- 7 days 
5. Is the patient on or has the patient been prescribed a steroid medication (eg, 
dexamethasone, methylprednisolone, or prednisone)? (Yes vs. No) 
6. Is the patient on or has the patient been prescribed a narcotic medication (eg, 
hydrocodone, oxycodone, morphine, dilaudid, or fentanyl)? (Yes vs. No) 
7. Is the patient on or has the patient been prescribed an anticholinergic medication on the 
following list? (Yes vs. No) 
a. Amitriptyline (Elavil) 

17 
 
b. Meclizine (Antivert) 
c. Prochlorperazine (Compazine) 
d. Scopolamine (Transderm Scop) 
e. Hydroxyzine (Atarax) 
f. Benztropine (Cogentin) 
g. Chlorpromazine (Thorazine) 
h. Olanzapine (Zyprexa) 
i. Quetiapine (Seroquel) 
j. Dicyclomine (Bentyl) 
k. Atropine (Donnatal) 
l. Oxybutynin (Ditropan) 
m. Solifenacin (Vesicare) 
n. Tolterodine (Detrol) 
o. Cyclobenzaprine (Flexeril) 
8. Has the patient received any systemic chemotherapy, immunotherapy, or targeted therapy 
between WBRT and the time of the 1M assessment? (Yes vs. No) 
 
6.0 UNANTICIPATED PROBLEMS 
 
6.1. Definition 
 
As defined by UNC’s IRB, unanticipated problems involving risks to study subjects or others 
(UPIRSO) refers to any incident, experience, or outcome that: 
• Is unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• Is related or possibly related to a subject’s participation in the research; and  
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the 
research than was previously known or recognized. 
6.2. Reporting 
 
Any UPIRSO that occurs during the conduct of this study and that meets all three criteria listed 
in 6.1 must be reported to the UNC IRB using the IRB’s web-based reporting system.   
 
6.3 Monitoring and Oversight 
 
The Principal Investigator will provide continuous monitoring of patient safety in this trial with 
periodic reporting to the Data and Safety Monitoring Committee (DSMC) as required. This will 
include UNC and affiliate sites.  
 
Meetings/teleconferences will be held at a frequency dependent upon study accrual and in 
consultation with the study Biostatistician. At these meetings, the research team will discuss all 

18 
 
issues relevant to study progress, including enrollment, safety, regulatory, data collection, etc. 
and the team will produce summaries or minutes of these meetings.  
 
 
7.0 STATISTICAL CONSIDERATIONS 
 
 
7.1 Study Design / Study Endpoints 
 
This is a prospective two arm randomized trial in which patients will complete the xerostomia 
questionnaire at six time points, including baseline and five post-radiation time points. The 
primary study endpoint is the change in composite xerostomia score (on a scale of 0-100, 
converted from the xerostomia questionnaire that is on a scale from 0-80; this conversion is 
made by adding up the values from questions 1-8 and dividing by 0.8, thus converting an 80 
point scale into a 100 point scale) between baseline and 1 month. The xerostomia score change 
will be assessed using two methods: 1. Proportion of patients with a minimally clinically 
important difference and 2. Mean change. In LCCC 1540 (at n=41), the mean xerostomia score 
change from baseline to 1 month was 17.8, with a standard deviation of 26.0. The minimally 
clinically important difference is commonly defined as ½ of the standard deviation. For sample 
size calculations, we will therefore define a ≥15 point xerostomia score increase as a minimally 
clinically important difference. 
 
7.2 Sample Size and Accrual 
 
In LCCC 1540 (at n=41), the proportion of patients experiencing a ≥15 point xerostomia score 
increase was 42% (95% CI 26-57%). Setting the null hypothesis proportion of patients 
experiencing ≥15 point xerostomia score increase at 42% and an alternative proportion of 14%, 
31 patients in each group are needed for 80% power to detect this difference using a two group 
chi-square test with a one-sided significance of 0.05. 
 
In order to have 62 patients with both baseline and one month post-treatment surveys, we will 
target our enrollment for this study at 90 patients, given the patterns of patient attrition observed 
in LCCC 1540 and early enrollment to this study (assuming 70% completion rate). To obtain this 
target accrual, we anticipate an accrual period of roughly 3-5 years. This number is based on 
extrapolated accrual rates from LCCC 1540, which accrued 100 patients over roughly 2 years 
and the anticipated expansion of this study to other academic centers. 
 
7.3 Data Analysis Plans 
 
The primary data analysis plan is to compare the proportion of patients in each randomization 
arm experiencing a ≥15 point xerostomia score increase between baseline and 1 month, with the 
use of a two group chi-square test. As sample size allows, linear mixed effects models will be 
explored to evaluate changes over time including all repeated measurements. It is anticipated that 
a significant number of enrolled patients will be unable to complete the 3 month (estimated 40% 
response rate) and 6 month (estimated 20% response rate) post-radiation questionnaires due to 
disease morbidity and mortality, so modeling may be limited to the earlier time points. In such a 

19 
 
scenario with significant patient dropout, separate analyses will be performed for patients with 
vs. without long term follow up. 
 
Descriptive statistics will be provided for all scores at all time-points and to summarize the 
patient population. Secondary data analyses will estimate the time to marginal relapse (defined as 
within 1 cm of the block edge overlying the blocked parotids) and the time to upper cervical 
spine relapse (defined as relapses in the C1 or C2 vertebrae) in each randomization arm using the 
Kaplan Meier method. A log rank test will be used to compare these time to event outcomes. 
Furthermore, the above analyses exploring xerostomia will also be conducted in all patients 
(including those who refused randomization but consented for the observational arm). 
 
A linear regression model will be used to further explore the dosimetric relationship between 
parotid dose and xerostomia, to supplement data from LCCC 1540. 
 
7.4 Data Management/Audit 
 
The University of North Carolina will serve as the coordinating center for this trial. All data will 
be collected, entered, and maintained in a database on secure servers at the University of North 
Carolina at Chapel Hill. Questionnaires will be collected via Qualtrics and each site will be 
responsible for ensuring all questionnaires are entered into Qualtrics. Outside sites, including the 
University of Michigan andWake Forest University(High Point Regional Health), will send any 
other data via secure email to the University of North Carolina at Chapel Hill. All data will be 
pooled at UNC where personnel there will coordinate and manage data for quality control 
assurance and integrity. Data analysis will take place at UNC as well. Accrual data will be 
collected and entered into OnCore®. As an investigator-initiated study, this trial will also be 
audited by the Lineberger Cancer Center audit committee.  
 
8.0 STUDY MANAGEMENT 
8.1 Institutional Review Board (IRB) Approval and Consent 
 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB-approved consent 
form. 
 

20 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
8.2 Required Documentation 
 
Before the study can be initiated at any site, the following documentation must be provided to 
the Clinical Protocol Office (CPO) at the University of North Carolina. 
• A copy of the official IRB approval letter for the protocol and informed 
consent 
• CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
• A copy of the IRB-approved consent form 
8.3 Registration Procedures 
 
A list of all enrolled patients will be maintained in OnCore by the study coordinators at the 
University of North Carolina at Chapel Hill. Upon enrollment, affiliate sites should send UNC a 
copy of the signed informed consent and HIPAA documents, signed eligibility checklist, and 
baseline/screening questionnaire. Additional patient information may also be requested by the 
UNC coordinator to complete registration. For the randomized group, eligibility criteria must be 
confirmed with the UNC study coordinator before the start of treatment. For the observational 
group, eligibility must be confirmed with the UNC coordinator within 5 days of treatment start. 
8.4 Adherence to the Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.   
8.4.1 Emergency Modifications 
 
UNC and Affiliate investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior UNC IRB approval.  
 
For any such emergency modification implemented, a UNC IRB modification form must be 
completed by UNC Research Personnel within five (5) business days of making the change. 
Affiliate site for this study are relying on UNC’s IRB and should follow the same procedures for 
emergency modifications. 
8.4.2 Single Patient/Subject Exceptions 
 
Any request to enroll a single subject who does not meet all the eligibility criteria of this study 
requires the approval of the UNC Principal Investigator and the UNC IRB.  
8.4.3 Other Protocol Deviations/Violations 
 

21 
 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an IRB approved 
protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets any of the 
following criteria:  
• Has harmed or increased the risk of harm to one or more research participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the investigator(s). 
• Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore® (or other appropriate 
database set up for the study), and report to any sponsor or data and safety monitoring committee 
in accordance with their policies.  Deviations should be summarized and reported to the IRB at 
the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one (1) week of 
the investigator becoming aware of the event using the same IRB online mechanism used to 
report UPIRSO.   
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO): Any events that 
meet the criteria for “Unanticipated Problems” as defined by UNC’s IRB (see section 0) must be 
reported by the Study Coordinator using the IRB’s web-based reporting system.  
8.5 Amendments to the Protocol 
 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator at UNC.  It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the patient, 
a revised consent form might be required.   
 
The written amendment, and if required the amended consent form, must be sent to UNC’s IRB 
for approval prior to implementation.   
8.6 Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 

22 
 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator.  In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
8.7 Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring 
visits will be conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. At the completion of the study, all case 
report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
 
 

23 
 
9.0 REFERENCES 
 
1. Noh O, et al. Parotid gland as a risk organ in whole brain radiotherapy. Radiother Oncol 
2011;98:223-6. 
2. Eisbruch A, et al. Xerostomia and its predictors following parotid sparing irradiation of 
head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;50:695-704. 
3. Lin A, et al. Quality of life after parotid sparing IMRT for head-and-neck cancer: A 
prospective longitudinal study. Int J Radiat Oncol Biol Phys 2003;57:61-70. 
4. Li Y, 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;67:660-69. 
5. Blanco A, et al. Dose-volume modeling of salivary function in patients with head-and-
neck cancer receiving radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:1055-69. 
6. Deasy J, et al. Radiotherapy dose-volume effects on salivary gland function. Int J Radiat 
Oncol Biol Phys 2010;76:58-63. 
7. Lin X, et al. Treatment of Brain Metastases. J Clin Oncol 2015; 33. 
8. Wong J¸et al. Symptoms and quality of life in cancer patients with brain metastases 
following palliative radiotherapy. Int J Radiat Oncol Biol Phys 2009;75:1125-31. 
9. Caissie A, et al. Quality of life in patients with brain metastases using the EORTC QLQ-
BN20+2 and QLQ-C15-PAL. Int J Radiat Oncol Biol Phys 2012;83:1238-45. 
10. Steinmann D, et al. Prospective evaluation of quality of life effects in patients undergoing 
palliative radiotherapy for brain metastases. BMC Cancer 2012;12:283. 
11. Cairncross J, et al. Acute parotitis and hyperamylasemia following whole-brain radiation 
therapy. Ann Neurol 1980;7:385-7. 
12. Radiation Therapy Oncology Group (RTOG) Foundation: RTOG 0933 Protocol 
Information: A Phase II Trial of Hippocampal Avoidance During Whole Brain 
Radiotherapy for Brain Metastases. Version date 12/5/2011. 
https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0933 
13. Alliance for Clinical Trials in Oncology: Protocol Update to N107C: Phase III Trial of 
Post-Surgical Stereotactic Radiosurgery (SRS) Compared with Whole Brain 
Radiotherapy (WBRT) for Resected Metastatic Brain Disease. 
http://www.kccop.org/pdfs/FullProtocol-2521155825.pdf 
14. Kil W, et al. Radiation exposure of parotid gland during whole-brain radiation therapy. 
ASTRO 2010 abstract. 
15. Shah M, et al. Parotid gland dose in whole-brain radiation therapy patients. ASTRO 2014 
abstract. 
16. Burlage F, et al. Parotid and submandibular/sublingual salivary flow during high dose 
radiotherapy. Radiother Oncol 2001;61:271-4. 
17. Bjordal K, et al. Quality of life in head and neck cancer patients: Validation of the 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-H&N35. J Clin Onc 1999;17:1008-19. 
18. Cho O, et al. Parotid gland sparing effect by computed tomography-based modified lower 
field margin in whole brain radiotherapy. Radiat Oncol J 2013;31:12-17. 
19. Fiorentino, et al. Letter to the editor: Whole brain radiotherapy: Are parotid glands 
organs at risk? Radiother Oncol 2012;103:130-1. 
20. Trignani, et al. Parotid glands in whole-brain radiotherapy: 2D versus 3D technique for 
no sparing or sparing. Radiol Med 2015;120:324-8. 

24 
 
10.0 APPENDIX 
 
Dry Mouth Questionnaire  
 
For questions 1 to 8, please circle a number from zero to ten, with zero representing no 
symptoms and ten representing the worst symptoms. 
 
1. Rate your difficulty in talking due to dryness. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
2. Rate your difficulty in chewing due to dryness. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
3. Rate your difficulty in swallowing solid food due to dryness. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
4. Rate the frequency of your sleeping problems due to dryness. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
5. Rate your mouth or throat dryness when eating food. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
6. Rate your mouth or throat dryness while not eating. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
7. Rate the frequency of sipping liquids to aid swallowing food. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
8. Rate the frequency of sipping liquids for oral comfort when not eating. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
For questions 9 and 10, please circle the answer that best represents how much your symptoms 
bother you. 
 
9. How much does dryness bother you when you are eating? 
Not at all 
        A little 
 
Quite a bit 
        Very much 
10. How much does dryness bother you when you are not eating? 
Not at all 
        A little 
 
Quite a bit 
        Very much