Prepare to Care, A Supported Self-Management Intervention for Head and Neck Cancer Caregivers
Phase: NA
Conditions: Caregiver, Malignant Head and Neck Neoplasm, Paranasal Sinus Squamous Cell Carcinoma, Salivary Gland Squamous Cell Carcinoma, Stage I Hypopharyngeal Squamous Cell Carcinoma, Stage I Laryngeal Squamous Cell Carcinoma, Stage I Lip and Oral Cavity Squamous Cell Carcinoma, Stage I Oropharyngeal Squamous Cell Carcinoma, Stage II Hypopharyngeal Squamous Cell Carcinoma, Stage II Laryngeal Squamous Cell Carcinoma, Stage II Lip and Oral Cavity Squamous Cell Carcinoma, Stage II Oropharyngeal Squamous Cell Carcinoma, Stage III Hypopharyngeal Squamous Cell Carcinoma, Stage III Laryngeal Squamous Cell Carcinoma, Stage III Lip and Oral Cavity Squamous Cell Carcinoma, Stage III Oropharyngeal Squamous Cell Carcinoma, Stage IV Hypopharyngeal Squamous Cell Carcinoma, Stage IV Laryngeal Squamous Cell Carcinoma, Stage IV Lip and Oral Cavity Squamous Cell Carcinoma, Stage IV Oropharyngeal Squamous Cell Carcinoma, Stage IVA Hypopharyngeal Squamous Cell Carcinoma, Stage IVA Laryngeal Squamous Cell Carcinoma, Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma, Stage IVB Hypopharyngeal Squamous Cell Carcinoma, Stage IVB Laryngeal Squamous Cell Carcinoma, Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVB Oropharyngeal Squamous Cell Carcinoma, Stage IVC Hypopharyngeal Squamous Cell Carcinoma, Stage IVC Laryngeal Squamous Cell Carcinoma, Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVC Oropharyngeal Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Lip and Oral Cavity Squamous Cell Carcinoma, Recurrent Oropharyngeal SCC, Recurrent Paranasal Sinus Squamous Cell Carcinoma
Sponsor: Wake Forest University Health Sciences

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Study Title: Prepare to Care, A Supported Self-Management Intervention for Head and Neck Cancer 
Caregivers 
 
Principal Investigator: Chandylen Nightingale, PhD 
 
Co-investigator(s): Kathryn Weaver, PhD 
                                 Janet Tooze, PhD 
                                 Kathryn Greven, MD  
                                 Bart Frizzell 
                                 Greg Kucera, PhD 
                                 Christina Hugenschmidt, PhD 
Nevine Hanna, MD 
 
Study Personnel:   Katherine Pleasant 
                                Sandra Norona 
 Alexandra Dest 
 Eliza Dewey 
 
 
                                 
 
                                  
Sponsor or funding source: National Cancer Institute; Comprehensive Cancer Center of Wake Forest 
University 
 
 
Background, Rationale and Context 
In 2016, 62,000 people are expected to be diagnosed with HNC in the United States; over 13,000 people 
are expected to die from the disease [1]. Recurrence rates are high (20%) relative to other cancer 
diagnoses [2, 3]. Treatment is complex and often includes radiotherapy (RT) for 5 days a week over 6-7 
weeks, sometimes with chemotherapy and surgery [4]. Patients experience significant side effects that 
impede core aspects of daily life, presenting challenging care tasks for informal caregivers. One of the 
most notable side effects is dysphagia, affecting as many as 75% of patients and contributing to rapid 
weight loss, malnutrition, and dehydration [5, 6]. Other life altering side effects can include pain, dry 
mouth, and difficulty hearing and speaking [7, 8]. Caregivers must often engage in special food 
preparation (e.g., pureeing food) and tube management for patients [9, 10], as well as more traditional 
informal caregiving tasks such as providing emotional support, managing medical appointments and 
insurance claims, and providing hands-on medical care with little to no training [11, 12]. Patients may be 
stigmatized due to tobacco and alcohol use, or a human papilloma virus (HPV) association (major 
contributing factors in the disease etiology) or treatment-related disfigurement [13]. Concurrently, 
patients may also experience embarrassment and isolation [10]. Not surprisingly, HNC patients have a 
high incidence of psychological distress and report higher care needs relative to other cancer patients [14, 
15].  
 
Approximately 3.5 million people provide care for patients with cancer [16]. Although caregiving can be 
personally rewarding [17], studies have overwhelmingly demonstrated a negative impact on cancer 
caregivers, including poor quality of life, risk of clinical depression, sleep disturbance, fatigue, pain, loss 
of physical strength, loss of appetite, and weight loss [18-20]. Studies focused on HNC caregivers are 
sparse. The limited literature describes a high prevalence of agoraphobia (anxiety disorder) [21], 
depression [22], and a high fear of patient cancer recurrence [23], with caregivers reporting poorer 
psychological health compared to patients and the general population [24]. Our research has shown that 

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during patient RT treatment, HNC caregivers experience increased schedule burden, decreased esteem, 
poorer self-reported health, and an abnormal cortisol response (dysregulated cortisol slope) from 
treatment initiation to five weeks into patient’s radiotherapy (RT) [25].  HNC caregivers have unmet 
informational needs and desire psychological support, self-help groups, and help with coping strategies 
[26-28]. In one study, most spouses of laryngectomized cancer patients desired to learn relaxation 
methods [29]. Such services can be addressed in a psycho-educational (education pertaining to emotional 
well-being) and stress management intervention. Our own work has highlighted high interest in wellness 
programs in HNC caregivers [30].  
 
Psychosocial interventions for informal caregivers have successfully improved burden, depression, 
subjective well-being, perceived caregiver satisfaction, and ability/knowledge, with multiple component 
interventions more effectively reducing burden versus single component interventions [31]. However, 
HNC caregivers have been neglected. One study[32] did evaluate the feasibility of a one-day 6-hour 
workshop to facilitate coping among HNC patients and family members, but the workshop was not 
restricted to those providing care. Although participants were highly satisfied with the intervention, only 
19% of families approached agreed to participate. Barriers to recruitment and participation included a 
lack of interest in seeking family support or logistical barriers. Our proposed study will overcome these 
barriers by providing caregivers with an easily accessible intervention that offers several choices designed 
to meet their specific preferences.  
 
A burgeoning area of research focuses on supported self-management (SSM) interventions. In SSM 
interventions, the recipient uses self-directed educational materials to learn information and strategies to 
manage emotions and promote healthy behaviors typically associated with chronic diseases, such as 
cancer, with the support of a health care provider [33, 34]. Accordingly, SSM interventions offer an ideal 
platform for delivery of psycho-education and stress management skills building. SSM interventions can 
be low cost, reduce health care utilization, and have greater dissemination potential [33, 35]. Further, 
SSM interventions can be used according to the participant’s preferences for place and time and combat 
logistical barriers to in-person delivered interventions. As such, they may be especially attractive to HNC 
caregivers navigating the hectic RT treatment period. To date, SSM interventions have largely been 
applied in cancer patients, particularly in more common cancer types; they successfully improve fatigue, 
depression, anxiety, and overall QOL [36]. One study did report feasibility and acceptability of a SSM 
intervention for caregivers of blood and marrow transplant cancer survivors after treatment, but caregivers 
wished they had received the intervention earlier during patient treatment [37]. Similarly, our preliminary 
data demonstrate that HNC caregivers desire wellness programs during patient treatment. 
 
Salivary cortisol response is an important indicator of stress and is helpful for evaluating efficacy of 
stress-management trials. Cortisol is a glucocorticoid and a biomarker of stress that is released from the 
hypothalamic pituitary adrenal (HPA) axis [38]. Studies within the psychoneuroendocrinology literature 
have demonstrated a relationship between psychological distress and cortisol response. For example, 
studies have demonstrated an association between cortisol and depressive symptoms[39, 40], post-
traumatic stress disorder symptoms[41], and anxiety [42]. Additionally, other similar psychosocial 
interventions have demonstrated changes in cortisol response [43, 44].  
 
Objectives 
 
Aim 1: To assess feasibility (accrual, participation, and retention) and acceptability of a supported self-
management intervention for psycho-education and stress management skills building designed for 
informal caregivers (Intervention Group, n=20; Waitlist Control Group, n=20) of HNC patients 
undergoing RT.  
 

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Aim 2a: To obtain preliminary data on caregiver intermediate (self-efficacy for (a) coping with cancer 
and (b) abbreviated progressive muscle relaxation) and outcome variables (burden, psychological distress, 
quality of life) in intervention caregivers and waitlist control caregivers at the start of radiation (T1), end 
of radiation (T2), and 6-weeks post-radiation (T3). 
 
Aim 2b: To compare intermediate (self-efficacy for (a) coping with cancer and (b) abbreviated 
progressive muscle relaxation) and outcome variables (burden, psychological distress, quality of life) 
between intervention caregivers and waitlist control caregivers at T1, T2, and T3.  
 
Hypothesis: (Aim 2a) Intermediate and outcome variables will improve in intervention caregivers 
post-intervention compared to pre-intervention and (Aim 2b) intervention caregivers will have 
better intermediate (higher self-efficacy for a) coping with cancer, and b) abbreviated 
progressive muscle relaxation) and outcome variables (less burden, less psychological distress, 
higher QOL) at T2 compared to waitlist control caregivers.  
 
Aim 3: To obtain preliminary data on caregiver cortisol response (cortisol slope, cortisol awakening 
response, area under the curve, and intra-individual cortisol variability) at T1 – T3 in intervention 
caregivers and waitlist control caregivers. 
 
Hypothesis: Intervention caregivers will demonstrate a more normal (steeper) diurnal cortisol 
rhythm (slope) at T2 compared to waitlist control caregivers.  
 
Aim 4: To refine intervention procedures and materials for future studies by examining: a) qualitative 
data from caregivers and interventionist notes and b) quantitative data regarding module utilization. 
 
Methods and Measures 
 
Design: Recruitment will include both patients and caregivers, although patients are not receiving the 
intervention. We will recruit 40 caregivers (20 intervention caregivers; 20 waitlist control caregivers) of 
patients with head and neck cancer (HNC) referred for radiotherapy (RT) and their informal caregivers, 
before or at the start of patient RT. After baseline assessment, caregivers will be randomized at the time 
of registration using a randomization scheme uploaded into the registration system, The randomization 
scheme will be developed by the statistician. Block sizes will be chosen randomly to ensure that future 
assignments cannot be inferred from previous ones.  Caregivers will be randomized to receive either a 
psycho-educational and stress management skills building intervention offered in a SSM format, 
accessible in hard copy and online, with iPads linking to study materials available during daily patient RT 
sessions, or a waitlist control group. Caregivers will complete assessments at the start of RT (T1), end of 
RT (T2), and 6-weeks post-RT (T3). Waitlist control caregivers will be offered Prepare to Care materials 
(without support from the study interventionist) after final assessment at T3. Patient participation is 
optional and restricted to providing consent for study staff to abstract information on clinical information 
from their medical record. If a patient declines to participate in the study, caregivers will be asked to 
report the patient clinical information collected at T1. See Appendix A for study schema.  
 
 
Setting: Participants will be recruited from the outpatient radiation clinics at the Comprehensive Cancer 
Center of Wake Forest University and the Lexington Medical Center or by mail. Participants will meet 
with the study interventionist at the radiation clinic or by telephone, and have the option to access 
intervention materials from the study website using i-Pads that remain at the clinic or accessing the 
website away from the clinic. The self-management intervention is designed so that caregivers can utilize 
the kit in a preferred location (e.g., at home) and time.  

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Subjects selection criteria 
Caregivers 
• 
Inclusion Criteria 
(1) providing the majority of the informal (unpaid) care during RT for a patient meeting 
inclusion criteria (see below) and participating in study, and (2) >18 years of age.  
• 
Exclusion Criteria 
(1) has a current cancer diagnosis, (2) cannot read/ communicate in English, (3) Caregivers 
who have an endocrine disorder (e.g., diabetes and thyroid disorders), or is currently 
taking a steroid-based medication will not be eligible to participate in the saliva portion 
of the study. 
 
 
Care-recipients 
• 
Inclusion Criteria 
• 
(1) has a new or recurrent AJCC stage I-IV squamous cell carcinoma of the upper 
aerodigestive tract (including lip/oral cavity, nasopharnyx, salivary gland, oropharynx, 
hypopharynx, paranasal sinus, and larynx cancers), (2) has planned external beam 
radiotherapy (+/- chemotherapy) for 6-7 weeks, (3) >18 years of age, and (4) has an informal 
(unpaid) caregiver during RT who is participating in study.  
• 
Exclusion Criteria 
(1) cannot read/ communicate in English. 
 
• 
Sample Size 
The sample size is based on feasibility (Aim 1). Our primary feasibility measures are 
participation and retention rates. About 110 patients present to our outpatient radiation clinic 
for treatment per year (9/mo). Based on previous experience, we expect approximately 75% 
of patients (n = 82) will have a caregiver and at least 75 patient-caregiver dyads will meet 
eligibility criteria (6/mo). With an estimated participation rate (consistent with PI’s 
experience) of 70%, we expect to recruit 40 patient-caregiver dyads within 8-10 months. If 
we approach 56 participants to recruit 40, we will be able to estimate the participation rate 
within +/- 12% using a two-sided 95% confidence interval; thus, we can be 95% confident 
that the true recruitment rate would be between 59% and 83%, which would support that the 
study is feasible. With 40 participants we can estimate the retention rate within +/- 12%. If 
the observed retention rate is 80%, we can be 95% confident that the true rate is between 67% 
and 92%, which would indicate a feasible study. 
 
Interventions and Interactions 
 
 
After recruitment and randomization, caregivers in the intervention group will meet with the study 
interventionist to review the intervention.  
 
Overview of Intervention (see Table 1) 
The multi-component intervention (or kit), Prepare to Care, includes:  
1) brief  introduction video on a DVD,  
2) binder including eight workbook modules offered in hard copy, and  
3) CD with audio instructions to facilitate Progressive Muscle Relaxation (PMR) Training (included in 
module 8).  
Modules 

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The first two modules provide cancer education and a list of supportive resources; modules 3-8 focus on 
stress management skills to enhance caregiver coping during RT (Table 1). Each module includes an 
introduction and rationale for the topic, strategies to overcome relevant challenges, and a weekly exercise. 
PMR training (in module 8) teaches caregivers to identify muscle tension signals and to use the signals as 
cues to trigger a relaxation response [45]. The breadth of topics and succinct modules are intended to 
provide a balance between addressing a comprehensive set of challenges and preventing participant 
burden. 
 
 
 
Table 1. Prepare to Care Kit Components 
Module: Topic 
Description 
DVD Introduction  
Brief introduction to the intervention: rationale and how to use the kit 
Educational 
1: Cancer Education 
Information about HNC, RT (+/- chemotherapy), side effects, and managing patient side 
effects 
2: Using Your Resources 
Information linking caregivers to supportive resources available within a) the CCCWFU, b) 
Forsyth County, and c) the internet 
Stress Management Skills  
3: Managing Time 
Managing a busy schedule, including recognizing competing outside demands & 
prioritizing 
4: Seeking/ Accepting Support 
Importance of social support, learning to identify supporters and ask for help when needed;  
5: Communicating with Others 
Strategies to optimize communication with provider, patient, and other friends/family 
members 
6: Healthy Behaviors 
Importance of healthy behaviors (diet, physical activity, sleep) as a cancer caregiver 
7: Positive Coping 
Learning to identify and re-frame negative thoughts[46] 
8: Muscle Relaxation 
Importance of engaging in relaxation; Also includes a CD with audio instructions for PMR 
 
Intervention Delivery and Participation: Prepare to Care kit materials are offered in a blended delivery 
format. To maximize intervention engagement, in addition to the intervention kit, modules are also 
accessible on a study website and iPads linking directly to the website will be available for use at the RT 
clinic. Modules 3-8 are designed to take 30- 45 minutes each, and each module does not have to be 
completed in one sitting; caregivers are instructed to complete at least one module per week and re-visit 
previous modules as needed. Each week, caregivers will complete a needs assessment with the 
interventionist to help direct them to relevant modules. However, if new challenges present during the 
week, caregivers are encouraged to use other pertinent modules. This preference-based approach 
empowers caregivers to build skills to address current challenges. The workbook will include a time log 
for caregivers to record the date, modules utilized, and times for starting and ending each module. 
Waitlist control caregivers will not meet with the study interventionist when provided with the 
intervention. 
 
Interactions with Interventionist: During weekly interventionist sessions (estimated to take 10-30 min), 
the interventionist will complete needs assessments, as discussed above, and inquire about modules used 
the prior week, assist in overcoming potential barriers to participation, and assist with incomplete 
activities, if desired. These sessions will occur weekly at the RT clinic when caregivers typically 
accompany the patient, capitalizing on the existing infrastructure for treatment schedules and thereby 
reducing participant burden. When necessary, sessions can also be completed via telephone. The 
interventionist will also send weekly email and/or text reminders each Wednesday to engage with 
caregivers and support adherence. The interventionist has extensive experience interacting with 
participants in psychosocial/ behavioral research studies and will be trained in intervention content. 
Waitlist control caregivers will not meet with the study interventionist when provided with the 
intervention. 
 
 
Outcome Measure(s) 

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See Table 2 for the assessment plan. For caregivers, sociodemographics and caregiving characteristics 
will be collected at recruitment. We will collect basic demographics and patient clinical information via 
medical chart review at recruitment and after RT. At T1, T2 and T3, caregivers will complete instruments 
at the RT clinic (or by phone, mail, or email using REDCAP) to assess intermediate (self-efficacy in (a) 
coping with cancer and (b) PMR and outcome variables (burden, psychological distress, quality of life). 
Caregivers may also self-collect saliva samples (see additional details below). Between T2 and T3, we 
will assess intervention caregivers’ overall acceptability of the intervention with a quantitative survey 
developed for the study and semi-structured interviews (lasting approximately 30 minutes to an hour) to 
explore factors influencing overall acceptability. Caregivers will be asked what they liked and disliked 
about content and delivery of intervention materials, weekly sessions with the interventionist, and 
email/text reminders. Interviews will be recorded and transcribed, and qualitative data will be managed 
using Microsoft Excel.  
 
Salivary Cortisol: Caregiver participants who do not have an endocrine disorder (e.g., diabetes and 
thyroid disorders), and are not currently taking a steroid-based medication are eligible for the saliva 
portion of the study. Materials for saliva collection will be mailed or distributed to eligible participants in 
person at the start of the study. Participants will collect saliva samples three times a day (at awakening, 30 
minutes post-awakening, and bedtime) for two consecutive days following T1, T2, and T3. Saliva 
samples are collected by placing a cotton roll under the tongue for approximately 1-2 minutes which is 
subsequently stored in a plastic tube and refrigerated. Participants will be instructed to refrain from 
eating, drinking, smoking, brushing their teeth, using mouthwash, or engaging in exercise or similar 
physical activity for 30 minutes prior to saliva collection. Participants will be provided with saliva 
collection diaries to record compliance to these behaviors as well as the time in which their saliva samples 
were collected. After all six samples have been collected at each time point (T1, T2, T3), participants will 
return their samples in person at the radiation clinic (T1) or by mail (T2 & T3) using pre-paid postage to 
return their samples and saliva collection diaries to the Wake Forest study site. Once received at the study 
site, all samples will be immediately centrifuged to remove the saliva from the adsorbent swabs, 
discarding the swabs and swab holder. The collection tube containing the saliva will be weighed. The 
saliva will then be transferred in approximately equal aliquots to freezer storage tubes before freezing. All 
storage tubes will be labeled using a barcode. Sample aliquots will be stored in freezer boxes at -80° C 
until assayed. The location of each group of samples in the freezer will be recorded in the sample 
database.  
 
Samples will be assayed in duplicate at Wake Forest using The Salimetrics® Cortisol Enzyme 
Immunoassay Kit (State College, PA). The saliva storage tubes will be labeled with a barcode, at no time 
in the testing process are samples identified by name of subject. On the day of analysis, samples are 
thawed at room temperature (20 to 22°C), centrifuged (1500 x g) for 15 minutes and assayed. The test 
used 25 μL of saliva per determination, has a lower limit of sensitivity of 0.003 μg/dL, standard curve 
range from 0.012 μg/dL to 3.0 μg/dL, an average intra-assay coefficient of variation of 3.5% and an 
average inter- assay coefficient of variation of 5.1%. Method accuracy determined by spike and recovery 
averaged 100.8% and linearity determined by serial dilution averaged 91.7%. Values from matched serum 
and saliva samples show the expected strong linear relationship, r (47) = 0.91, p < 0.0001. 
Samples are returned to the freezer upon completion of pipetting. Assay data are reviewed by the 
supervisor and samples needing to be retested are identified. Samples needing retesting are again thawed, 
analyzed and refrozen. After assays are complete, samples will be stored for up to three years and then 
disposed of per applicable waste handling regulations.   
 
 
Table 2. Assessment Plan 

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Assessment 
Time 
Description 
Caregiver sociodemographics 
T1 
Age, gender, race/ethnicity, education, employment, income, marital status, 
insurance status 
Patient clinical information 
T1, T3 
AJCC Stage, location of tumor, prior cancer (yes/no), time since surgery, 
new or recurrent diagnosis, chemotherapy (yes/no), # of weeks of RT, 
patient response to treatment (T3 only) 
Caregiving characteristics 
T1; T2;T3 
Living with patient (yes/no), relationship to patient (T1 only), hours of daily 
care 
Aim 1 
Feasibility 
Participation 
Study 
duration 
Proportion of eligible participants who agreed to participate 
Retention 
Study 
duration 
Number of participants who completed the T2 visit divided by the number 
who agreed to participate 
Accrual 
Study 
duration 
Number of caregivers who agreed to participate divided by the number of 
months of recruitment 
Acceptability 
Quantitative survey; Qualitative 
interview (intervention caregivers 
only)1 
Anytime  from 
T2-T3 
15-item quantitative survey developed for study to assess how much 
caregivers liked different aspects of the intervention; Qualitative interviews 
to further explore factors associated with overall acceptability. 
Aims 2a & 2b 
Intermediate Outcomes 
Self-efficacy in coping with cancer 
Caregiver Inventory (CI)[47]  
T1; T2; T3 
21-item instrument assessing caregivers’ perceived self-efficacy for coping 
with cancer (managing medical information, caring for care recipient, caring 
for oneself, managing difficult interactions/emotions); demonstrated validity 
and reliability.  
Self-efficacy in PMR  
T1; T2; T3 
3-item instrument developed for study to evaluate self-efficacy in PMR. 
 
 
Outcome Variables 
(CES-D) [48] 
T1; T2; T3 
20-item instrument how often over the past week they experienced 
symptoms associated with depression, such as restless sleep, poor 
appetite, and feeling lonely. The CESD has been widely used in caregiver 
populations. 
(PROMIS Emotional Distress 
Anxiety Short Form- 8a)[49] 
T1; T2; T3 
Brief 8-item assessment of anxiety over the past week. 
Caregiver burden  
• Caregiver Reaction Assessment 
(CRA) [50]  
T1; T2; T3 
24-item instrument assessing positive and negative aspects of caregiving 
(esteem, lack of family support, finances, schedule, and health). The CRA 
has been tested in cancer caregivers; demonstrated validity and reliability 
[50, 51].  
QOL  
• Caregiver Quality of Life Index-
Cancer (CqoL-Canc) [52] 
T1; T2; T3 
35-item instrument assessing dimensions of caregiver QOL (burden, 
disruptiveness, positive adaptation, financial concerns). The Cqol-Canc has 
demonstrated validity and reliability [51, 52].  
Aim 3 
Salivary Cortisol Collection (for 
eligible caregivers only)  
T1; T2; T3 
Collected three times a day (at awakening, 30 minutes post-awakening, 
and bedtime) for two consecutive days following T1, T2, and T3. Saliva 
samples are collected by placing a cotton roll under the tongue for 
approximately 1-2 minutes which is subsequently stored in a plastic tube 
and refrigerated. 
Aim 4 
Modules Utilized (intervention 
caregivers only) 
Study 
duration 
Frequency of intervention modules utilized; retrieved from caregiver logs 
Interventionist notes 
Study 
duration 
Process notes regarding intervention implementation 
 
 
Analytical Plan 
The analyses will provide quantitative data on participation, retention, and accrual, and estimates of the 
effect size of the intervention for intermediate and outcome variables. This information, along with 
ratings of acceptability and qualitative analyses, will allow us to refine the protocol for a larger study. 
Aim 1: To assess feasibility (accrual, participation, and retention) and acceptability of a supported self-
management intervention for psycho-education and stress management skills building designed for 
                                                 
 

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informal caregivers (Intervention Group, n=20; Waitlist Control Group, n=20) of HNC patients 
undergoing RT.  
 
Accrual rate will be defined as the number of caregivers who agreed to participate divided by the number 
of months of recruitment. Participation rate will be defined as the percent of eligible participants who 
agreed to participate. Retention rate will be defined as the number of participants who completed T3 
measures divided by the number who consented to participate. Mean accrual rate, participation rate, and 
retention rates and their associated 95% confidence intervals (CI) will be estimated. 
 
Acceptability will be summarized quantitatively and qualitatively. Descriptive statistics will summarize 
participants’ overall rating of acceptability; ANOVA and regression models will examine if acceptability 
varies by demographic, caregiving, or patient characteristics. A codebook for analyzing the qualitative 
interviews will be developed using a thematic analysis procedure, facilitating coding into discrete 
categories. Interviews will be coded by at least two raters and discrepancies will be discussed until 
consensus is reached. Frequency counts will be calculated for themes pertinent to caregivers’ 
likes/dislikes.  
 
Aim 2a: To obtain preliminary data on caregiver intermediate (self-efficacy for (a) coping with cancer 
and (b) abbreviated progressive muscle relaxation) and outcome variables (burden, psychological distress, 
quality of life) in intervention caregivers and waitlist control caregivers at the start of radiation (T1), end 
of radiation (T2), and 6-weeks post-radiation (T3).  
 
Aim 2b: To compare intermediate (self-efficacy for (a) coping with cancer and (b) abbreviated 
progressive muscle relaxation) and outcome variables (burden, psychological distress, quality of life) 
between intervention caregivers and waitlist control caregivers at T1, T2, and T3.  
 
We will use a mixed effects model with a random subject effect and time (T1,T2,T3), group, and a group 
by time interaction to model change in the intermediate variables (self-efficacy for (a) coping with cancer 
(CI) and (b) PMR) and outcome variables (burden (CRA), depression (CESD), anxiety (PROMIS Short 
Form-Anxiety 7a), and QOL (CQoL-Canc), by group from T1 to T2 to T3). We will use linear contrasts 
to compare the intervention to the control group at T1, T2, and T3. In exploratory analyses we will model 
the relationship between each outcome and the intermediate variable, by including the intermediate 
variable as a fixed effect in the model. These results are exploratory due to concurrent measurement with 
outcome variables; in future studies we would capture potential mediators at an intermediate time point.  
 
Aim 3: To obtain preliminary data on caregiver cortisol response (cortisol slope, cortisol awakening 
response, area under the curve, and intra-individual cortisol variability) at T1 – T3 in intervention 
caregivers and waitlist control caregivers. 
 
Analysis Plan: Analyses for Aim 3 will be conducted using data from caregivers who were not excluded 
from the saliva portion of the study. Several summary measures will be derived from the three daily 
cortisol values, including the mean levels at each time, the mean cortisol awakening response (CAR – 
change in cortisol from awakening to 30 minutes), the area under the curve (AUC), the diurnal slope 
(change in cortisol between awakening and bedtime), and the intraindividual cortisol variability, which 
will be estimated using the methods as described in Sannes et al.[53] to assess group differences in 
cortisol parameters. We will use a mixed model to evaluate differences between the groups in these 
parameters at times T1 and T2 and T3.  For a subset of the sample who completed measures on 
intermediate and outcome variables and cortisol, in exploratory models, we will include the cortisol 
summary measures as predictor variables in the models described for Aim 2 above. 
 

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Aim 4:To refine intervention procedures and materials for future studies by examining: a) qualitative data 
from caregivers and interventionist notes and b) quantitative data regarding module utilization.  
 
We anticipate that participants who more fully utilize the modules may derive a greater benefit than those 
who do not. We will include utilization as an interaction term in the mixed effect model to assess this 
hypothesis in an exploratory analysis. This information will help us to refine the protocol, but will not be 
fully powered to quantify effects. Quantitative and qualitative findings will be synthesized, along with 
interventionist implementation notes, and included in a final report. The report will be used to determine 
potential refinement in the recruitment process, content of intervention materials, delivery of intervention 
components, and email/text reminders. The report will be presented to advisory panel members who will 
participate in making final decisions for refinement. 
 
Human Subjects Protection 
All team investigators have completed their institution’s courses for Protection of Human Research 
Subjects and will maintain up to date certification throughout the study period. 
 
Human Subject Involvement and Characteristics.  
Caregiver involvement. This study will enroll 40 head and neck cancer (HNC) caregivers recruited from 
the outpatient radiation clinics at the Comprehensive Cancer Center of Wake Forest University 
(CCCWFU) and the Lexington Medical Center  or by mail. Caregivers will be recruited before or at the 
start of patient RT and participation will end 6 weeks after patients complete RT. Caregivers will 
participate in either an intervention group that provides psycho-education and teach stress management 
skills during the patient’s radiotherapy (RT) treatment or a waitlist control group who will receive the 
intervention at the end of the study, without interventionist support. The intervention (or kit) includes an 
introduction to the kit with a DVD, a binder including eight workbook modules offered in hard copy, and 
a CD with audio instructions to facilitate progressive muscle relaxation (PMR) training (included in 
module 8). An interventionist will meet with caregivers weekly for approximately 10-30 min. Caregivers 
will complete assessments at the start of the patient’s RT (T1), at the conclusion of RT (T2), and 6-weeks 
post-RT (T3). All quantitative data will be in the form of self-report and qualitative data (intervention 
group only) will be collected via semi-structured interviews. All assessments will take place while at the 
RT clinic, by Redcap, by mail, or by phone. 
Patient involvement. Patient participation is optional and only includes consent to abstract clinical 
information from his or her medical file or self-report this information. We will abstract clinical 
information from a patient’s medical file if the patient is receiving radiation treatment at WFBMC. 
Patients who decide to receive radiation treatment outside of WFBMC may have incomplete clinical 
information in their WFBMC medical file. In these cases, patients will be asked to self-report any 
information collected in the Patient Clinical Information Form that is not available in their WFBMC 
medical file. Patient-reported and caregiver-reported clinical data forms will be abbreviated versions of 
the medical chart review collection form and only be collected at T1 to reduce participant burden. Further, 
it is unlikely that participants will be able to report on some of the clinical items we collect from the 
medical chart review. We will not collect self-report data from WFBMC patients during the proposed 
study. No patients will participate in the intervention. 
 
 
Subject Recruitment Methods 
Participants will be recruited from the outpatient radiation clinics at the Comprehensive Cancer Center of 
Wake Forest University (CCCWFU) and the Lexington Medical Center, or by mail. Eligible patients will 
be identified through referral from the treating radiation oncologist and mailed a recruitment package for 
themselves and their primary informal caregiver (person providing the majority of unpaid care) before RT 
begins. For potential participants who have been identified before a clinic visit, the participants may be 

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contacted by a member of the study team to introduce the study and, if agreeable, the study team member 
will confirm with the patient that they will be present during their upcoming clinic visit to discuss the 
study and consent the participant(s). The study team will reach out to the patients' treatment team to 
inform them that they will approach the potential patient during their visit. 
A study team member may also make contact with patient-caregiver dyads when presenting for the 
patient’s simulation appointment, treatment consultation, or at the start of patient RT to determine 
willingness to participate. Potential participants who are identified during treatment consultation, but 
decide to receive treatment outside of WFBMC are still eligible to participate. If the primary informal 
caregiver is not present with the patient at the appointment, we will ask patients for permission to contact 
his or her caregiver by phone. A waiver of signed informed consent has been obtained in order to screen 
these participants (caregivers). At this time the study team member will confirm eligibility criteria with 
the participant. Study staff may check in caregiver medical records if accessible to confirm eligibility for 
the saliva portion of the study. Patient participation is optional, and only includes consent to abstract 
demographic and clinical information from his or her medical file. If the patient refuses to participate in 
the study, but the caregiver is still interested, he/she can still participate without patient consent. 
Caregivers will then be asked to report patient clinical information that is typically collected from the 
patient’s medical record as part of the Patient Clinical Information Form. Caregivers will receive a $20 
gift card at the completion of T1, T2and T3 assessments ($60 in gift cards total).  
Caregivers who do not plan to attend visits in person may provide consent through a mailed informed 
consent form.  The study team will contact the participant (caregiver) over the phone to review the 
Informed Consent Form.  Any questions about the study will be answered so that the potential subject is 
fully aware of what the study entails.  The study team member will mail or email the Informed Consent 
Form to the participant and the participant will be asked to print, sign, date and mail back the Informed 
Consent Form. Once the signed Informed Consent Form is received by the study team, the study member 
that consented the participant over the phone will print, sign and date the consent form. A copy of the 
completed Informed Consent Form will be mailed or emailed back to the participant. No study procedures 
will take place until both the participant and study team member sign and date the consent form.  
 
Inclusion/Exclusion Criteria. Caregivers will be eligible if they are: (1) providing the majority of the 
informal (unpaid) care during RT for a patient meeting the below criteria, and (2) >18 years of age.  
Caregivers will be excluded if they: (1) have a current cancer diagnosis, (2) cannot read/ communicate in 
English, (3) Caregivers who have an endocrine disorder (e.g., diabetes and thyroid disorders), or are 
currently taking a steroid-based medication are excluded from the saliva collection portion of this study. 
Patient criteria: (1) have new or recurrent AJCC stage I-IV squamous cell carcinoma of the upper 
aerodigestive tract (including lip/oral cavity, nasopharnyx, salivary gland, oropharynx, hypopharynx, 
paranasal sinus, and larynx cancers), (2) have planned external beam radiotherapy (+/- chemotherapy) for 
6-7 weeks, (3) >18 years of age, and (4) has an informal (unpaid) caregiver during RT. Patients will be 
excluded if they:  (1) cannot read/ communicate in English. 
Sources of Materials  
Sources of Research Material. Data for this study will be collected from self-report surveys, qualitative 
interviews, participant self-collected salivary cortisol samples (for eligible caregivers only), and patient 
and caregiver medical chart review. Study investigators will have access to identifiable private 
information on participants, but it will be restricted to necessary data only. Data will be managed in a 
password protected data system for data entry and management. Access will be limited to study 
personnel. 
Use of Data. Data will be restricted to research purposes only. 
HIPAA Guidelines. Participant data will be protected through the use of ID numbers, in accordance with 
HIPAA guidelines. No individual data or participant identifiers will be reported, and this will be 
emphasized to participants.  

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Informed Consent  
Study staff will obtain signed informed consent from each caregiver and care-recipient. Patient 
participation is optional, only includes consent to abstract treatment and disease-related information from 
his or her electronic health record or self-report this information for patients receiving treatment outside 
of WFBMC. A study investigator will explain the study and allow patients and caregivers to ask 
questions. We will carefully explain to patients that participation is restricted to collecting demographic 
and clinical information from their electronic health record and that participation will not impact their 
medical care. 
 
 
Potential Risks  
This study poses no more than minimal risks to participants. Caregivers may experience emotional 
discomfort when completing psychological instruments (coping with cancer self-efficacy, distress, 
burden, quality of life), but this is not expected to be greater than that encountered during routine 
psychological examination. Caregivers may potentially experience discomfort when completing 
workbook activities; however, the ultimate goal of these activities is to reduce negative psychological 
effects associated with providing care. The primary risk to all participants is loss of privacy and we will 
take appropriate steps (see confidentiality and privacy) to prevent this. 
Likelihood of Risks. Risks associated with this study are unlikely. 
Minimizing Risks. All study staff will be trained to interview in a sensitive manner. We will explain to 
participants that they do not have to complete any assessments that they do not wish to complete and that 
they may withdraw from participation at any time. Furthermore, caregivers’ participation in the 
intervention is preference based, so they can opt out of modules. Caregiver psychological distress (anxiety 
and depression) data will be reviewed immediately and if levels are high, we will provide caregivers with 
contact information for the psychosocial oncology professionals at the cancer center. Dr. Weaver has 
training in clinical psychology and will assist with this process when necessary. All investigators will 
maintain current institutional protection of human subjects credentials.  
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy and 
confidentiality, only a unique study identifier will appear on the data collection form.  Any collected 
patient/caregiver identifying information corresponding to the unique study identifier will be maintained 
on a linkage file, store separately from the data.  The linkage file will be kept secure, with access limited 
to designated study personnel.  Following data collection subject identifying information will be 
destroyed three years after closure of the study, consistent with data validation and study design, 
producing an anonymous analytical data set.  Data access will be limited to study staff.  Data and records 
will be kept locked and secured, with any computer data password protected.  No reference to any 
individual participant will appear in reports, presentations, or publications that may arise from the study. 
Caregivers will be offered a private room away from the patient to complete surveys and will also have 
the option to complete surveys by phone with a study researcher. All interviews and sessions with the 
study interventionist will be completed away from the patient in a private room or by phone, if necessary. 
Use of study i-Pads does not need to occur in a private room; caregivers may choose to use the devices 
when patients are receiving treatment. 
Potential Benefits of the Proposed Research. Caregivers may experience improvements in self-efficacy 
(in coping with cancer and abbreviated progressive muscle relaxation) psychological distress, burden, and 
QOL when participating in the intervention. 
Why Risks are Reasonable in Relation to Benefits. The proposed intervention is highly unlikely to 
pose risks to participants. The minimal risk is outweighed by the potential benefits of the intervention for 
the caregiver. 

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Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants.  The principal investigator will be assisted by other members of the study staff. 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
All study staff will assist in monitoring safety of study participants. Safety events related to this research 
study are very unlikely to occur; however, any unanticipated problems or serious and unexpected adverse 
events (Grade 4 or Grade 5) will be promptly reported by the principal investigator or designated member 
of the research team to the IRB and the Safety and Toxicity Reporting Committee.

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13 
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Appendices  
1.  Study Schema 
2.  Recruitment letter  
3.  Study Flyer 
4a. Patient Data Abstraction Form T1 
4b. Patient Data Abstraction Form T3 
5a. Caregiver surveys T1 
5b. Caregiver surveys T2 
5c. Caregiver surveys T3 
6.  Caregiver Saliva Collection Instructions 
7.  Semi-structured qualitative interview script for caregivers 
8.  Title Page for Workbook Binder 
9a. Intervention workbook: Cancer Education 
9b. Intervention workbook: Using your Resources 
9c. Intervention workbook: Muscle Relaxation 
9d. Intervention workbook: Social Support 
9e. Intervention workbook: Positive Coping 
9f. Intervention workbook: Healthy Behaviors 
9g. Intervention workbook: Time Management 
9h. Intervention workbook: Communicating with Others 
10. Prepare to Care Kit Time Log 
11. Weekly Needs Assessment 
12. Intervention Procedure Manual 
13. Introduction Video 
14. Patient Decline Form 
15. Caregiver Decline Form 
16. Caregiver Withdrawal Form 
17. Text Message Language