Building Family Caregiver Skills Using a Simulation-Based Intervention for Care of Patients With Cancer
Phase: NA
Conditions: Cancer
Sponsor: Case Comprehensive Cancer Center



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Seidman Cancer Center, University Hospitals Case Medical Center 
 
 
Kate Sandstrom, RN, MSN, APRN-BC, AOCN 
Nurse Practitioner, Radiation Oncology 
Seidman Cancer Center, University Hospitals Case Medical Center 
 
 
 
Ethan (Mendel) Singer, PhD 
Associate Professor, Department of Population and Quantitative 
Sciences, CWRU 
 
 
 
 
Research Personnel: 
To be named 
Study Site(s): 
University Hospitals and Satellites 
 
MetroHealth Cancer Center 
 
Protocol Version: 
2.1 
 
Protocol Date: 
2/13/2025 
 
Sponsor: 
Case Comprehensive Cancer Center 
 
Funding Sponsor: 
National Cancer Institute (1R37CA240707-01) 

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SUMMARY OF CHANGES 
 
Please provide a list of changes from the previous approved version of the protocol starting at IRB 
approval. This table will remain blank until initial IRB approval. The list shall be a brief overview. When 
appropriate, a brief justification for the change should be included. This is a running list for the life of the 
study. 
 
Protocol 
Date 
Section 
Change 
Initial IRB approval 
Summarize changes to first protocol amendment 
10/31/19 
5.2 
Adding the Caregiver Reaction Assessment tool 
10/31/19 
5.4 
Adding email REDCap surveys as an option to subjects 
10/31/19 
5.5 
Increasing incentives for subjects 
10/31/19 
5.6 
Updated reaction management and protection against risk section 
12/5/19 
Co-Is 
Removed Ming Li as Co-I/Statistician and added Nicholas Schiltz 
12/5/19 
5.3 
Interventionists will offer flashlights to caregivers during simulation 
1/21/20 
5.3 
Removed question about caregiver missing work/activities  
1/21/20 
5.6 
Removed study calendars and thank-you cards for participants 
3/2/20 
3.0 
Amended eligibility to include stage IVa esophageal patients 
3/26/20 
3.0 
Removed patient inclusion criterion “receiving first course of radiation therapy” 
5/28/20 
Co-Is 
Min Yao added as a Co-I 
5/28/20 
4.0 
Consent to be obtained remotely by phone or Redcap during COVID-19 
5/28/20 
5.3 
Intervention sessions 2 & 3 delivered by phone during COVID-19 
5/28/20 
5.63 
Symptom screening and masking for COVID-19 symptoms 
7/23/20 
4.0 
Opt-out period for remote consent changed to 2 days 
7/23/20 
4.0 
In-person consent will be used if remote consent is not feasible 
10/2/20 
4.0 
Removed unique identifying code from remote consent process 
12/4/20 
5.3 
Expanded time period for intervention session 2 to 3rd-4th week of XRT 
2/23/21 
5.3 
Expanded time period for intervention session 1 to first 10 days of XRT 
2/23/21 
5.53 
Added letter reminder between T3 and T4 surveys 
12/6/21 
3.0 
Amended eligibility for NSCLC to include stage II (excluding SBRT) 
1/5/22 
Co-Is 
Min Yao removed as a Co-I 
4/5/22 
5.2, 5.3 
Added COST-FACIT, MOS Social Support, and Health insurance surveys 
12/1/22 
Co-Is, 1.0, 
2.0, 3.0, 4.0, 
5.1, 5.4, 5.54, 
6.1 
Extension protocol changes: added Cheryl Killion, MetroHealth, increased sample 
size, qualitative interviews, and analysis for new sub-aims. 
6/11/24 
Co-Is 
Removed Cheryl Killion and added Christine Horvat Davey 
3/13/25 
PIs 
Removed Dr. Peter Laye and added Dr. Suzanne Russo  

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TABLE OF CONTENTS 
1.0 INTRODUCTION ...................................................................................................................6 
1.1 Overview ...........................................................................................................................6 
1.2 Background and Rationale .................................................................................................6 
2.0 OBJECTIVES .......................................................................................................................13 
3.0 RESEARCH SUBJECT SELECTION..................................................................................13 
4.0 RESEARCH SUBJECT ENTRY ..........................................................................................15 
5.0 STUDY DESIGN AND METHODS ....................................................................................17 
5.1 Design/Study Type ..........................................................................................................17 
5.2 Selection of Instruments ..................................................................................................17 
5.3 Description of Intervention ..............................................................................................20 
5.4 Data Collection ................................................................................................................22 
5.5 Description of Study Process ...........................................................................................24 
5.6 Adverse Reactions and Their Management .....................................................................25 
6.0 STATISTICAL ANALYSIS .................................................................................................27 
7.0 REFERENCES ......................................................................................................................31 
8.0 APPENDICES .......................................................................................................................38 

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INTRODUCTION 
 
1.1 
Overview 
Patients with head and neck, lung, esophageal, rectal, and anal cancers typically undergo rigorous, 
intense, combined-modality treatment (radiation, surgery, and/or chemotherapy) and experience high 
symptom burden, functional impairment, and complex psychosocial issues. Positive treatment outcomes 
and avoidance of complications are dependent to a large extent on the adequacy of care provided by 
family members. However, family caregivers (CGs) report feeling unprepared to assume the multiple, 
complex tasks of caregiving, including tangible help with tracheostomy care, tube feedings, wound and 
colostomy care, pain management, and ongoing emotional support. Despite being a critical extension of 
the oncology healthcare team, training of CGs to manage symptoms, deal with communication issues 
with the care recipients, and take care of their own physical and emotional health as CGs, is not 
integrated into clinical practice. The proposed study will measure the effect of a psychoeducational and 
skills training intervention that incorporates structured simulation or experiential learning to improve 
CG, patient, and healthcare utilization outcomes. We know that simulation is effective in training 
healthcare professionals, but little is known about its effectiveness in training family CGs. The 
intervention is designed for the period of active cancer treatment and the immediate transition to 
posttreatment survivorship, a time when the CG and patient are most vulnerable. The specific aims of 
this 2-group, prospective, randomized controlled trial are to: (1) evaluate the effect of a CG intervention, 
as compared to a control group, on CG primary (anxiety) and secondary (depression, health-related 
quality of life [HRQOL], and fatigue) outcomes; (2) measure the effect of the intervention on patient 
outcomes (HRQOL and interrupted treatment course) and healthcare utilization outcomes (unplanned 
hospital admission, unplanned emergency room visits, and unplanned use of intravenous fluids); (3) 
determine if CG self-efficacy mediates the effect of the intervention on CG anxiety; (4) determine if 
patient illness factors, care demands, and patient and CG demographic factors moderate the relationship 
between the intervention and CG outcomes; and (5) compare the costs of healthcare utilization between 
the intervention and control groups. We will recruit 244 CGs from University Hospitals Seidman Cancer 
Center at the Case Comprehensive Cancer Center and MetroHealth Cancer Center. The intervention 
involves three in-person, one-on-one sessions during radiation treatments, followed by a telephone 
contact 2 weeks posttreatment. Data will be collected at baseline, at the end of radiation treatment, and 4 
and 20 weeks postradiation treatment. 
The analysis will consist of linear mixed model repeated measures, mediation and moderation tests, and 
regression methods. The proposed project addresses NCI’s Division of Cancer Control and Population 
Sciences mission of improving the delivery of care to individuals and family members affected by 
cancer. The study findings will provide crucial information for translating the psychoeducational and 
simulation methods used in this intervention to other CG populations and clinical settings. This study is 
funded by the National Cancer Institute (1R37CA240707-01). 
 
1.2 Background and Rationale 
Many of the estimated 321,000 individuals who will be diagnosed with cancer of the head and neck 
(HNC), esophagus, rectum, anus, and lung (non-small cell lung cancer) in the United States this year17 
will undergo rigorous cancer treatment. Although symptom profiles vary with specific cancers and 
treatments, patients undergoing radiation therapy experience a high symptom burden associated with 
significant functional impairment that will persist for months after treatment. Key members of the 
investigative team (Mazanec, Sandstrom, Daly) have recently completed a longitudinal descriptive study 
of 60 patients undergoing radiation treatment for newly diagnosed HNC.18 Quality of life at the end of 
treatment was significantly lower than baseline (p < .001) and low scores persisted after treatment, with 
some recovery by 12 months. Anxiety improved with time, but fatigue did not. Other studies support our 

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finding that recovery during the first month after radiation treatment for HNC is both physically and 
emotionally challenging for patients due to persistent severe symptoms and lack of practical support and 
contact with the healthcare team.19-22 
Similarly, patients receiving radiotherapy for esophageal cancer (with or without chemotherapy) 
will typically have improvement in dysphagia, but prolonged nutritional problems (anorexia, dry mouth, 
taste changes), pain, and fatigue will persist into the posttreatment survivorship period. A prospective 
study of patients during definitive chemoradiotherapy for esophageal cancer reported that HRQOL 
steadily worsened during treatment, reaching its lowest point at 12 weeks after beginning treatment.23 
Chemoradiotherapy for patients with advanced stage non-small cell lung cancer (NSCLC) is 
associated with multiple treatment-related symptoms, including acute grade 3 to 4 esophageal toxicity, 
which can cause pain, dehydration, and dyshphagia.24 Fatigue, weakness, appetite loss, altered taste, 
nausea, and vomiting were identified as common co-occurring symptoms (symptom cluster) persisting 
from diagnosis to six months later in patients with lung cancer.25 The high symptom burden and poor 
performance status in patients with NSCLC is negatively associated with quality of life.26 
Patients treated with chemoradiotherapy for anal cancer commonly experience severe skin 
reactions during treatment (radiation dermatitis and moist desquamation), as well as pain, fatigue, bowel 
dysfunction (fecal leakage, flatulence, frequency), urinary frequency and dysuria, and sexual 
dysfunction.27 In one study, a pattern of deterioration of HRQOL and worsening symptoms by the end of 
radiation treatment was followed by some recovery 3 months posttreatment.28 However, surveys of long 
term, colostomy-free survivors reveal common, persistent issues with bowel functioning and sexual 
dysfunction that are highly distressing.29,30 
Toxicities during radiation therapy for rectal cancer, with or without chemotherapy, include bowel 
dysfunction (fecal leakage, soiling, frequency), proctitis, urinary incontinence, fatigue, skin irritation, 
and sexual dysfunction.31 Rectal problems, bowel management issues, and psychosocial distress persist 
into early survivorship, regardless of ostomy status,32 and often require lifestyle modifications, including 
use of medications, dietary changes, use of pads, and reduction of social activities.33,34 
Family CG training and support are needed to help patients manage and cope with these intense 
treatment side effects that are often more severe than other cancers commonly treated with radiation 
(e.g., breast, prostate). The impact on the CG is long-term as recovery from treatment is prolonged, with 
persistent treatment and disease effects lasting years, well into survivorship for some patients.30,32,35-37 
Patients with HNC, lung, esophageal, rectal, and anal cancer have unique care needs that are not 
addressed by general caregiver interventions. Interventions for these CGs must include specific 
technical and communication skills training, support for distress management, and education 
regarding caring for their own physical health. Demands on family CGs are substantial and often 
include quickly gaining new knowledge and technical skills to manage treatment side effects, 
medications, nutritional supplements, ostomies, and tracheostomy and gastrostomy tubes. Yet, in two 
studies of CGs of patients with mixed cancer diagnoses, up to 58 percent of CGs reported unmet training 
needs.6,38 Authors of a systematic review of randomized trials involving mostly CGs of patients with 
breast and prostate cancer found evidence that the CG interventions improved patient outcomes of pain 
and symptom management.16 The authors recommended tailored, skill-based interventions that target 
specific patient populations to increase the effectiveness of interventions on patient outcomes. Our 
intervention will address this gap in the scientific literature. 
Beyond the hands-on care, CGs must communicate with the patient, family, and healthcare 
providers about the illness. Communication skill building is essential to reduce “communication 
burden” in cancer family CGs, recently described as the CG’s perceived communication challenges, 
such as initiating discussions, sharing emotions and feelings, and providing information with others 
about the patient’s cancer.39 There is high potential for communication burden in CGs of individuals 

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with HNC, lung, rectal, anal, and esophageal cancer, as they must adapt to an often dramatically altered 
lifestyle and changing roles within the family.40-43 There is strong support in the literature for inclusion 
of communication skills training into CG interventions for colorectal and lung cancers,44-47 and although 
there are fewer studies focused on the specific communication needs of HNC, anal, and esophageal CGs, 
there is support for CG communication skills training in advanced cancer.47,48 
Although the literature describing the needs and experience of CGs of individuals with HNC, lung, 
esophageal, rectal, and anal cancer is limited, it is clear that the early phase of the cancer trajectory, 
within the first 6 to 12 months following diagnosis, is a significant time of stress for CGs.49,50 Later- 
stage disease and higher symptom burden, which is common with these cancers, are associated with 
increased CG psychological distress.51 Studies specific to HNC CGs underscore the severity of 
psychological problems: CGs have significantly higher levels of anxiety than the patients during 
treatment,52 40% can be classified as having a clinical anxiety disorder,49 and approximately 15% have a 
depressive disorder.53 It is essential to intervene with CGs early in the care trajectory, particularly during 
the treatment phase, to offer psychological support54 and to prepare them for dealing with acute 
toxicities of treatment and the unique difficulties associated with these cancers. CGs have multiple 
unmet supportive care needs, most often related to fears of the patient’s decline, concerns about 
recurrence, and feelings about death and dying.55 
There are critical gaps in attending to CG emotional and psychological needs, which may have 
a direct influence on the psychological health of the patient. There is strong evidence that the patient- 
CG dyad is a relational system and that the mood states of the patient and CG are interrelated.10,56 In a 
study of newly diagnosed dyads, greater CG anxiety symptoms were concurrently associated with both 
CG and patient depressive symptoms.11 A CG’s psychological state may also have potential for negative 
downstream effects on CG physical health.57 Proactive interventions that teach CGs skills for 
caregiving tasks, as well as for communication and management of their own psychological and 
physical health, are needed. 
Although the empirical literature underscores the need for development of interventions that 
provide not only skills training, but also strategies to reduce distress early in the treatment trajectory, 
there are very few studies of interventions that target CGs of individuals with HNC, rectal, anal, and 
esophageal cancer during the active treatment period. Studies of training interventions specific to CGs of 
patients with lung cancer are limited and have focused on coping skills,58,59 communication skills,47 and 
symptom management.60 These studies were delivered online58,59 or via telephone,47,60 and did not focus 
specifically on the active treatment phase of the illness trajectory. Our proposal fills this critical gap 
by testing a pragmatic intervention for CGs during radiation treatments that was developed by a 
multidisciplinary team of clinicians. The proposed project is a randomized controlled trial (RCT) 
of a psychoeducational, skills training intervention that will incorporate simulation experiences to 
improve CG self-efficacy for caregiving, including both technical and communication skills, as 
well as caring for oneself as a CG. 
Simulation, which is commonly and effectively used in education of health professionals, is a 
student-centered, active learning technique that uses high- or low-fidelity manikins and/or standardized 
patients to provide clinical activities that mimic real clinical practice.14 Learners can practice skills in a 
controlled setting and receive immediate feedback. Rarely used with family CGs, simulation has been 
shown to be effective in training parents of chronically ill children to manage seizures,61 home 
ventilators,62 and diabetes.63 Communication skills training for family CGs, most often noted in the 
dementia care literature, includes both didactic and role-play teaching methods and has been shown to 
be effective in improving CG communication skills, competencies, and knowledge.64 In our study, 
simulation scenarios will also be used to discuss plans to overcome barriers to practicing healthful 
behaviors during the demands of caregiving. We know from our previous study that family CGs have 

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strong intentions to engage in health-promoting behaviors during cancer treatment, but report actually 
making behavior changes to a lesser degree.65 Coping planning is a strategy used to anticipate and 
overcome barriers to enacting behavioral intentions and has been used effectively in studies of patients 
with coronary heart disease.66,67 
Only two studies were found that tested a simulation or experiential intervention with cancer CGs. 
In a study of simulation use with HNC CGs, a one-hour, group-format tracheostomy education class that 
used an anatomical trainer was effective in reducing anxiety in family CGs.68 In another study, cancer 
CG training with an experiential learning component delivered in a single session in the inpatient setting 
was effective in producing short-term improvement in self-efficacy for managing patient symptoms and 
CG stress.69 Our study differs from these studies in that the intervention is delivered in individual, 
private sessions with the CG in the practice setting; is tailored to the specific needs associated with each 
cancer type; is offered over the weeks of active treatment, allowing for real-time (point-of-care) 
attention to CG learning needs; and incorporates simulations for both technical and communication 
skills training with psychoeducational strategies. 
In summary, CGs of individuals with HNC, NSCLC, rectal, anal, and esophageal cancer experience 
unique challenges in providing care due to intense and persistent treatment side effects. The proposed 
CG intervention, which uses technical, communication, and health-promoting simulation strategies, aims 
to bolster CG skills and support during radiation therapy to improve both patient and CG outcomes. 
Theoretical Framework 
Basis for Design of Intervention. The intervention was devised based on self-efficacy, a key concept of 
Social Cognitive Theory. Perceived self-efficacy is the belief that one can successfully perform a 
specific behavior to produce an expected outcome, and according to Bandura, stronger self-efficacy 
beliefs can result in greater coping efforts to overcome challenging or threatening activities.70 CG self- 
efficacy has implications for both the patient and CG. In a study of 152 dyads of patients with lung 
cancer and their family CGs, lower levels of CG self-efficacy for pain and symptom management was 
significantly associated with higher levels of CG strain and mood disturbance, as well as higher levels of 
patient-reported pain, fatigue, anxiety, and depression, and lower levels of patient-reported quality of 
life.71 The proposed intervention components use strategies to strengthen self-efficacy for caregiving 
and self-care through vicarious experience (observing nurse modeling behavior during simulation), 
performance accomplishments (repeated simulation practice sessions), verbal persuasion (supportive 
nurse communication during intervention), and attention to the CG’s emotional state (screening and 
intervention for emotional distress). 
 
Basis for Study Model. The recently revised Self- and Family Management Framework,15 which 
acknowledges the integral role of family in managing a chronic condition, guided the conceptualization 
and design of this research. The framework identifies three broad self-management processes of 
“focusing on illness needs,” “activating resources,” and “living with the condition.” These processes are 
influenced by a complex array of facilitators and barriers at the individual, family, community, and 
healthcare system levels. The processes lead to proximal outcomes such as behaviors, cognitions, 
biomarkers, and symptom management. These proximal outcomes are mediators of more distal 
outcomes of self-management (health status, quality of life, psychosocial status, and health care). The 
proposed intervention specifically focuses on one component of this framework by targeting the 
processes for family CGs to increase self-efficacy, a cognitive proximal outcome, and to impact more 
distal CG outcomes. 
The study model is shown in Figure 1. We posit that the intervention will work directly and indirectly 
(through self-efficacy) on CG outcomes. CG self-efficacy in this study is conceptualized as having two 

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components: (1) performing the caregiving role, and (2) caring for one’s own health. We hypothesize that 
CGs in the intervention group will show significantly greater reductions in anxiety, depression, and 
fatigue, and significantly greater improvements in HRQOL than subjects in the control group. We 
also hypothesize that the intervention will improve CG skills and ability to solve problems, resulting 
in greater improvements in patient HRQOL and fewer interrupted treatment courses, unplanned 
admissions, unplanned emergency room visits, and unplanned use of IV fluids than those 
experienced by patients in the control group. 
 
 
 
For this study, all patients (regardless of diagnosis or treatment course) have documented high 
symptom burden associated with significant functional impairment.18,23,27,31 Their CGs also face similar 
challenges in coping with their loved ones’ intense physical treatment side effects (e.g., skin breakdown, 
nutritional/hydration issues), and mental health issues. However, in order to account for differences due to 
population diversity and the potential influences on outcomes, we will track and use as covariates (potential 
moderators) several patient illness factors (variables) most relevant to the population and the outcomes of 
interest. These include cancer stage, time since diagnosis, treatment type (chemoradiotherapy versus 
radiotherapy alone), HPV status (in HNC and anal cancer), palliative care use, and patient performance 
status. Care demands, defined as hours/week spent caregiving, patient and CG demographic 
characteristics (race, marital status, employment status, socioeconomic status), and use of mental health 
interventions (support group participation, social work and/or psychologist involvement) will be assessed 
as covariates. 
The outcomes were chosen because they are salient issues for CGs and may directly influence the 
CG’s ability to support and care for the patient. In a study of 436 CGs of individuals with various cancer 
diagnoses, the prevalence of borderline/clinical anxiety was 36% at 6 months and 31% at 12 months 
post-diagnosis.8 Borderline/clinical depression was reported by 15% and 16% at 6 and 12 months, 
respectively. Anxiety was chosen as the primary CG outcome, as opposed to depression, because it is 
more prevalent in CGs than depression, especially early in the care trajectory.8,11 Fatigue is a common 
and debilitating problem for CGs.72 HRQOL is a multidimensional, subjective, and dynamic construct 
reflecting an individual’s satisfaction with physical, social, emotional, functional, and spiritual 
dimensions of life as impacted by one’s health.73 
Patient outcomes will focus on HRQOL and treatment interruption, defined as the total 
number of days missed due to patient or CG reasons. Treatment interruptions in radiation therapy 

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can negatively impact patient survival and local-regional control of the tumor,74 and are particularly 
significant for patients with HNC and rectal cancer.75-77 CG interventions are effective in improving CG 
well-being,2 and more specifically, CGs who receive skill training have more confidence and experience 
less burden.38 A knowledgeable, confident, and less stressed CG will be better able to deal with the 
physical (e.g., pain due to mucositis), emotional (e.g., depression), and social factors (e.g., lack of 
transportation) that may cause a patient to miss treatment. 
Healthcare utilization outcomes include unplanned hospital admission, unplanned emergency 
room visits, and unplanned IV fluid use for treatment of dehydration. We will evaluate costs 
associated with these outcomes. Patients with HNC, NSCLC, rectal, anal, and esophageal cancer 
typically experience multiple toxicities during treatment. In a recent study of 63 elderly patients 
undergoing radiation therapy (14% with HNC, 6% with lung, 5% with rectal cancer), unplanned hospital 
admissions were most often related to treatment-induced toxicities, rather than frailty score, age, or 
functional status.78 Trained and engaged CGs will be able to adequately manage symptoms, promote 
fluid and nutritional intake, and recognize situations, such as dehydration or pain, that should be brought 
to the attention of the healthcare team, thereby preventing unplanned admissions, emergency room 
visits, or need for IV fluids. 
 
Preliminary Studies 
Building on an extensive clinical background, the PI, as an early-stage investigator, has established the 
foundation for this study through her research on the immediate postcancer treatment transition as a 
multidimensional phenomenon that includes symptom management, CG and patient activation, quality 
of life, and interventions to reduce distress and promote self-management. 
 
Pilot study of proposed research. In order to evaluate the feasibility and acceptability of the intervention 
in the current proposal, we elected to focus on one population with significant CG needs─HNC 
caregivers. Building Family CG Skills Using a Simulation-Based Intervention for Care of Patients 
with Head and Neck Cancer (Mazanec, PI), which was completed in February 2017, was conducted in 
the clinical setting where the intervention would be implemented. We approached 30 CGs of patients 
with HNC and enrolled 18, for a consent rate of 60%. Two CGs dropped out of the study. The CG who 
dropped from the intervention group cited scheduling and work issues. Participants were randomized to 
intervention (n = 8) and control (n = 8) groups and completed measures of self-efficacy, HRQOL, 
anxiety, and depression. Healthcare utilization outcomes were also measured. While underpowered for 
statistical significance, trends for the intervention group were in the hypothesized direction for self- 
efficacy, global physical health, anxiety, unplanned hospital admissions, and interrupted treatment 
course. The intervention was acceptable to both CGs and the radiation nurse who delivered the 
intervention. At exit interviews of 5 CGs, all rated their satisfaction with the intervention as “high.” All 
CGs rated the communication simulations as “very helpful” and some commented on how closely the 
simulations mirrored their reality at home. The skills simulations with manikins were also rated highly, 
as “very helpful” to “somewhat helpful.” 
Based on the feasibility and fidelity data, as well as input from the clinicians, we have made several 
refinements to the intervention. First, we retained the content of the intervention, but reduced the 
number of in-person sessions to three in response to CG feedback. Second, we eliminated the optional 
telephone format of the sessions, as CGs liked the one-on-one interaction with the nurse and being able 
to talk about how they were feeling, including their frustrations and feelings of guilt. As is common in 
pragmatic trials, we will continue to allow the nurse interventionist some flexibility in adapting technical 
simulations to the specific needs of the CG. Having conducted this small pilot to establish feasibility and 

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confirm hypothesized effects, we will now expand this intervention to other diagnoses that are similarly 
associated with significant symptom burden, CG needs, and patient adverse effects. 
 
Quality of Life and Perceived Health- 
Related Needs for Survivorship in Patients 
Receiving Radiation Treatment for Head and Neck 
Cancer (Sandstrom, PI; Mazanec, Co-I; Daly, Co-I) 
was a longitudinal, descriptive study of 60 patients 
undergoing radiation treatment for newly diagnosed 
HNC through the first year posttreatment.18 Mixed 
random intercept longitudinal models determined 
that on average, HRQOL, measured by the 
University of Washington Quality of Life (UW- 
QOL) Questionnaire,83 is 24.74 points lower (p < 
.0001) at treatment compared to baseline and 14.16 
points lower (p < .0001) at the first month after 
treatment compared to baseline. The pattern of QOL 
trajectories confirms the need for early intervention 
during treatment and for continued CG support and 
training through the month after completion of 
treatment. The results of this study informed the 
HNC educational content and timing of the 
intervention to correspond to patient’s experience. 
 
CG Studies. Several of our CG studies informed the 
current proposal. A Pilot Study of Health 
Behaviors in Family Members of Patients with 
Cancer (Mazanec, PI) used a cross-sectional design 
to survey 50 patients with mixed cancer diagnoses 
and 39 family members (enrollment rates of 75% 
and 78%, respectively) at the completion of 
definitive treatment.65 Results confirmed that this posttreatment transition is a “teachable moment” for 
family members, as CGs in the study reported low levels of physical activity, yet thought about making 
health behavior changes, expressed strong intentions for engaging in physical activity, and were 
receptive to talking with a nurse about their physical and emotional health. CGs had higher distress 
levels than patients at the completion of treatment (U = 724.5, z = -1.95, p = .05). Stress and emotional 
concerns were the most frequently reported barriers to improving CG health. The results identified the 
need for a self-care aspect to the intervention and support the need to target CG distress during 
treatment. 
 
Study of Health Management in Patients and CGs During Cancer Treatment (Mazanec, PI) was a 
descriptive, longitudinal study of activation in 42 CGs and 62 patients newly diagnosed with colorectal 
cancer.84 Using linear mixed-effects models, we found that lower CG self-efficacy for managing one’s 
own health was associated with higher levels of CG depression (p = .003) and anxiety (p = .021), as well 
as higher levels of patient symptom distress (p = .046). As a result of this study, we designed the 
intervention to include an assessment of CG emotional distress during the initial few minutes of each 

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contact with the subject. This study also gave us operational experience in enrollment procedures and 
data collection in the clinical setting. 
 
Intervention research. The proposed study builds on the team’s previous investigations targeting CGs 
and testing interventions. Recently completed, Family-Centered Intervention for the Transition to 
Living with Multiple Myeloma as a Chronic Illness (Mazanec, PI) was a randomized pilot test of a CG 
and patient intervention for distress management within the first year after diagnosis.85 This study 
demonstrates the PI’s ability to implement CG interventions during the acute treatment phase. 
Observations made during this study of the intensity of CG concerns contributed to our decision to focus 
our intervention solely on the family CG, rather than take a dyadic, patient and CG approach. 
 
2.0 OBJECTIVES 
The aims of this 2-group, prospective, randomized controlled design are: 
Aim 1: Evaluate the effect of a CG intervention, as compared to a control group, on CG primary 
(anxiety) and secondary (depression, HRQOL, and fatigue) outcomes. 
Aim 2: Measure the effect of the intervention, as compared to a control group, on patient outcomes 
(HRQOL and interrupted treatment course), and healthcare utilization outcomes (unplanned hospital 
admissions, unplanned emergency room visits, and unplanned use of intravenous [IV] fluids). 
Aim 3: Determine if CG self-efficacy mediates the effect of the intervention on CG anxiety. 
Aim 4: Determine if patient illness factors, care demands (hours per week spent caregiving), and patient 
and CG demographic factors moderate the relationship between the intervention and CG outcomes. 
 
Aim 4a: Examine which social determinants of health (aspects of vulnerability) in caregivers 
moderate the efficacy of the intervention. 
 
Aim 4b: Explore caregivers’ perspectives and experiences regarding the intervention to understand 
how the intervention should be modified to better serve vulnerable caregivers. 
Aim 5: Compare the costs of healthcare utilization (unplanned hospital admission, unplanned 
emergency room visits, and unplanned use of IV fluids) between the intervention and control groups. 
 
3.0 RESEARCH SUBJECT SELECTION AND ELIGIBILITY 
Setting 
Radiation Therapy Departments of the Seidman Cancer Center at the University Hospitals main 
campus, satellite community facilities, and MetroHealth Cancer Center. 
 
Population 
The sample will consist of family CGs of individuals with HNC, NSCLC, rectal, anal, and esophageal 
cancer. In this study, a family CG is defined as an adult who is providing daily assistance and/or 
emotional support to the individual with cancer as identified by the patient. The sample will be drawn 
from the population of patients at the Cancer Center. Data obtained from the Cancer Center tumor 
registry show that 403 adult patients with new diagnoses of HNC, rectal, anal, and esophageal cancer 
(all stages) and stage III NSCLC cancer were evaluated in 2017. Demographic characteristics were: 
62.5% male, 37.5% female, 82.4% White, 16.4% Black, and a mean age of 64 years. Fifty-seven percent 
underwent radiation therapy. 
The extension period will include family CGs and patients recruited from MetroHealth, an academic 
medical center and Cuyahoga County’s safety-net health system. It is located in the City of Cleveland, 
which is racially and ethnically diverse (49% Black, 40% White, 11.9% Hispanic). 
 
Sampling Procedure and Group Assignment 
A convenience sample of family CGs will be used. 
Inclusion criteria for patients are: (1) 18 years of age or older. (2) Diagnosis of stage I, II, III 

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cancers of the rectum and anus, stage I, II, III, IVa esophagus; stage II-III NSCLC (excluding those 
receiving SBRT due to short treatment course); and stage I – IV A/B head/neck (tongue, gum, oral 
cavity, nasopharynx, oropharynx, hypopharynx, parotid, or larynx). Stage IV A/B will be allowed for 
HNC and stage IVa for esophagus as the intent of therapy is curative. (3) Has an identified family CG 
who is willing to participate. 

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Inclusion criteria for CGs are: (1) 18 years of age or older; (2) family member or friend of an 
adult patient described above; and (3) identified by the patient as his/her primary CG, who is providing 
daily assistance and/or emotional support. 
Exclusion criteria are: Patients who do not have a caregiver will be excluded. CGs of patients who 
are receiving hospice care will be excluded because of the patient’s poor prognosis and multiple issues 
associated with end-of-life care. CGs who are themselves undergoing active cancer treatment will be 
excluded (hormonal treatment allowed). 
 
Projected Enrollment 
We estimate, based on the annual Cancer Registry data, that 131 patients with stage I, II, III rectal, anal, 
and esophageal cancers; stage III NSCLC; and stage I-IV A/B HNC will be receiving radiation therapy 
at the three study sites of the Cancer Center. Approximately 10% of these patients will not meet our 
eligibility criteria (e.g., no family CG), resulting in 118 potential participants annually. Based upon our 
current pilot study, Building Family CG Skills Using a Simulation-Based Intervention for Care of 
Patients with Head and Neck Cancer, we expect a CG refusal rate of 40%. Therefore, we project to 
enroll 71 CGs per year or 5 per month. We plan to enroll subjects for 36 months, resulting in an 
enrollment of 180 subjects over the course of the study. We will allow for a 10% dropout rate, resulting 
in 162 subjects for the final analysis. The estimated 10% attrition rate is based on a current caregiver 
intervention study in the Cancer Center, in which the rate is 9.7% (NR015464, Douglas PI). 
While 40% is a high refusal rate, it is consistent with other intervention studies that aimed to 
enroll patient-caregiver dyads.2,3,90 In addition, the use of incentives has been found to reduce the refusal 
rate in this CG population, and thus, we will offer a $100 incentive to all CGs for participation in the 
study. We will also seek IRB approval to collect additional information from CGs who refuse, including 
whether the CG is working and/or providing care to other individuals, which were common reasons for 
refusal in the pilot study. Lastly, we will monitor the refusal rate monthly. If the refusal rate is greater 
than 40% for more than 4 months, we will consider revising our strategies and seek other sites. We will 
offer a $40 incentive to all patients for participation in the study. 
For the extension period, with the increased number of study sites we project to enroll 6 
caregivers per month. We plan to enroll subjects for an additional 16 months, resulting in 96 subjects 
over the course of the extension project. We project that the parent study will enroll a total of 148 
subjects. Adding the 96 subjects in the extension project will result in a total sample size between the 
parent study and extension project of 244. With an estimated dropout rate of 12%, the sample for the 
final analysis will be 214 dyads. 
 
4.0 
RESEARCH SUBJECT ENTRY 
A convenience sample of family CGs will be used. Potential patients who meet the study inclusion 
criteria will be identified by the research assistant (RA) through review of the weekly radiation clinic 
schedules. The diagnosis will be confirmed in the medical record. Based upon pilot work, we have 
determined the optimal time to approach subjects for inclusion into the study is during the radiation 
therapy simulation visit, which is approximately 10 days prior to the start of treatment. Consent will be 
obtained in person. 
The patient will be approached by the RA in a private room in the clinic and the study will be 
explained. The patient will be asked to identify an adult family member or friend who is his/her primary 
caregiver. We will ask for the patient’s approval to talk with the caregiver about the study. If the 
caregiver is present in the clinic, the study will be explained with an opportunity for the caregiver to ask 
questions. Written consent will be sought from the patient and caregiver. If the caregiver is not present 
at that time, contact information for the caregiver will be obtained and the patient will be asked to give 
his/her caregiver an information pamphlet about the study. The RA will contact the caregiver within four 
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meeting, written consent will be sought from the patient and caregiver. 
For the duration of the COVID-19 pandemic, patient and caregiver consent will be obtained 
remotely by phone or electronically through Redcap whenever possible.  If remote consent is not 
feasible due to the timing of treatment, patient or caregiver factors, or enrollment issues, we will return 
to our previous in-person consenting protocol, following all hospital guidelines regarding masking and 
distancing. The remote consenting protocol is as follows: at the new patient visit (NPV) or CT 
Simulation visit the radiation oncology staff, such as the Nurse Partner, will give the patient our IRB-
approved study brochure and two (2) paper copies of the patient and caregiver consent forms. If the 
NPV is completed via telehealth or there are insufficient clinical notes to assess eligibility, the brochure 
and consent form will be given to the patient at the in-person CT simulation visit. The brochure contains 
opt-out information for patients who do not wish to be contacted about the study. Instructions are to call 
the study office telephone number to opt out of the study. This opt-out is a short time frame of 2 days, 
and will be pointed out to the patient by the medical staff.  If no call or email from the patient is received 
within 2 days, the study team will call the patient and discuss the research using a script (attached). If 
the patient gives verbal consent to participate and identifies a caregiver, and the caregiver lives with the 
patient and is available, we will offer to speak with them together on the phone to answer any questions 
about the consent. 
Secure REDCap links to the patient and caregiver consent forms will be sent to their preferred email 
addresses. The informed consent process will continue on the telephone and, after questions are 
answered, the patient and caregiver will electronically sign and date the REDCap consent forms. The 
consenter will also electronically sign and date the REDCap consent form. The enrollment procedure 
proceeds with contact information being completed via telephone. 
If the patient and/or caregiver do NOT have email or internet access, informed consent will proceed 
via telephone with the patient and/or caregiver signing paper copies of the consent forms, previously 
provided by the medical staff. The patient and caregiver will mail the signed forms back to the 
researcher's office via a study-provided postage-paid envelope (also given at their health care provider 
visit) and will keep the unsigned copies. The enrollment procedure proceeds with contact information 
being completed via telephone. 
Subjects’ capacity to consent will be evaluated by the RA in conjunction with the clinical team. 
Participants must be cognitively intact, as evidenced by orientation to person, place, and time. They 
must be able to speak, read, and comprehend English. 
All participants are volunteers and non-participation and withdrawal from the study are 
alternatives to study participation. Patients and caregivers will be told that they may withdraw from 
the study at any time. There are no risks to non-participation or withdrawal from the study. The RA 
will explain that participation or non-participation will have no effect on the care that the patient and 
caregiver will receive from the healthcare team. 
For the extension period, caregivers will be offered an additional qualitative interview after 
completing the intervention. The consent form will give caregivers a choice to opt in and agree to be 
contacted for an interview. Caregivers randomized to the intervention will be selected for interviews 
using purposive sampling to select participants with a low score in at least one domain of the social 
determinants of health. Interviews will be done with 15 caregivers who opted in during the consent 
process. The interviews will take place after they have completed the intervention. 
Once consent is obtained, baseline measures will be collected. All participants will be screened for 
health literacy using a 4-item Brief Health Literacy Screening Tool (BRIEF), a self-report tool that 
assesses comprehension to written and verbal health information as well as confidence in filling out 
medical forms. The research team will employ communication and teaching strategies from AHRQ’s 
Health Literacy Universal Precautions Toolkit94 for individuals identified as having limited health 
literacy. 
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two groups: control or intervention. Randomization will be done using the minimization stratified 
randomization technique (QMinim). Minimization is designed to balance pre-identified stratifying 
covariates across treatment assignments more effectively than simple randomization.87-89 Stratification 
variables will be CG gender, CG age, and patient cancer type. 
The RAs will be blinded to group assignment. 
We will not request a waiver for consent documentation from the IRB. We will request partial 
waiver of HIPAA Authorization due to the need to review the radiation oncology patient schedule to 
determine potential participants. We will use the following identifiable information in screening for 
participants in the study: patient name, diagnosis, medical record number, date and time of appointment, 
and family caregiver name and contact information. The identifiable information will be used only by 
members of the research team and will be stored on RedCap and UH Box. Identifiers of non-participants 
will be destroyed when the study is closed to enrollment. 
5.0 STUDY DESIGN AND METHODS 
5.1 Design/Study Type  
This is a 2-group, prospective, randomized controlled design to test the effect of an intervention, as 
compared to a usual care control group, on CG outcomes, patient outcomes, and healthcare utilization 
outcomes during 
treatment. As shown in 
Table 2, the intervention 
involves three in-person, 
one-on-one teaching 
sessions with the caregiver 
during radiation 
treatments, followed by a 
telephone booster contact 
2 weeks posttreatment. We will collect patient and CG data at baseline (T1), at the end of radiation 
treatment (T2), and 4 (T3), and 20 weeks (T4) postradiation treatment. We opted to measure outcomes 
at the completion of radiation treatment (and midintervention) because we want to compare groups when 
side effects, which develop gradually during radiation therapy, are intense. The timing of measures after 
treatment was based on our longitudinal descriptive study of patients with HNC and our clinical 
experience of the trajectory of patient recovery after treatment. The total number of weeks of radiation 
treatment may vary depending on the specific diagnosis. Therefore, measures taken at T3 and T4 are 
based on time since completion of radiation treatment. The independent variable is group assignment. 
The primary outcome is CG anxiety. Secondary outcomes are CG depression, HRQOL, and fatigue; 
patient HRQOL and interrupted treatment; and healthcare utilization outcomes. The mediating effect of 
self-efficacy will be assessed as well as the moderating effects of patient illness factors, care demands, 
and demographic factors.  
The study design during the extension period will not change, except for the addition of a qualitative 
interview. We will conduct qualitative interviews with a subset of 15 caregivers exploring their 
perspectives and experiences regarding the intervention.  
5.2 Selection of Instruments 
We chose measures based on our prior work with caregivers that are psychometrically sound and/or 
recommended by NIH as common data elements to facilitate cross-study analysis and increase the 
scientific impact of our study analyses. The instruments can be found in Appendix A. 
 
Caregiver Outcome Variables 

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The Patient-Reported Outcomes Measurement Information System (PROMIS) will be used to measure 
caregiver outcome variables. The PROMIS item banks and their short forms were developed and 
calibrated using item-response theory on large data samples from patients with chronic conditions 
(including cancer) and the US general population. Reliability and precision of the items in measuring 
various constructs have been reported by Cella et al.95 For each survey, the responses are summed to 
produce a total raw score, which is converted to a T-score. Higher T-scores represent greater amounts 
of the construct being measured. Each survey, in our experience, takes approximately two minutes to 
complete. 
Anxiety will be measured with the PROMIS Anxiety Short Form 7a.95 This 7-item questionnaire 
assesses self-reported fear, worry, anxiety, tension, nervousness, and restlessness in the family caregiver 
over the last 7 days. 
Depression will be measured with the PROMIS Depression Short Form 8b.95 This 8-item 
questionnaire assesses caregiver self-reported negative mood (sadness, guilt), views of self 
(worthlessness), and social cognition (loneliness), as well as decreased positive affect and engagement. 
It assesses depression over the last 7 days. 
HRQOL will be measured using the PROMIS Global Health Scale v.1.0/1.1, a 10-item 
questionnaire that evaluates global physical health and global mental health.95 Caregiver fatigue will be 
measured with the PROMIS Fatigue Short Form 7a, a 7-item questionnaire that evaluates the self- 
reported experience of fatigue (frequency, duration, intensity) and the impact of fatigue on daily 
activities.95 It assesses fatigue over the last 7 days. 
Caregiver Reaction Assessment will be used at baseline and at time 3 (4 weeks post-XRT) to 
measure caregiver's reactions to caregiving for family members with an illness. The scale uses a Likert 
response format. 
 
Patient Outcome Variables 
HRQOL in patients will be measured using the disease-specific versions of the FACT-G that include 
common HRQOL subscales (physical, social, emotional, and functional well-being) plus cancer-specific 
questions. We will analyze the effect of the intervention on HRQOL across diagnoses using the common 
FACT subscales and will describe the symptom experience within each diagnostic group using the 
cancer-specific FACT subscale. Respondent burden is minimal with the FACT surveys, with a 
completion time on average of 5 to 10 minutes.114 Participants rate their response to each item on a 5- 
point Likert-type scale. After reverse-scoring negatively worded questions, items are summed. Higher 
scores indicate better quality of life. Reliability and validity of the FACT-G scale was established in a 
sample of 854 patients with cancer.115 
The Functional Assessment of Cancer Therapy - Colorectal (FACT-C, Version 4) is a 37-item 
questionnaire that measures self-reported HRQOL in patients with colorectal cancer over the last 7 days.96 
Good internal consistency, concurrent validity, and sensitivity to change over time were supported.96 
The Functional Assessment of Cancer Therapy - Head and Neck Scale (FACT-H&N, Version 4) is 
a 39-item questionnaire that assesses self-reported HRQOL in patients with head and neck cancer over 
the last 7 days.98 Good internal consistency of the FACT-H&N was reported for the total scale (alpha = 
0.89).98 Convergent versus divergent validity was demonstrated when compared to the Performance 
Status Scale for Head and Neck Cancer Patients (PSS-HN) in a sample of patients with head and neck 
cancer receiving various cancer treatments.98 
The Functional Assessment of Cancer Therapy - Esophageal (FACT-E, Version 4) is a 44-item 
questionnaire that measures self-reported HRQOL in patients with esophageal cancer over the last 7 
days.97 Excellent internal consistency of the FACT-E subscales was reported (alphas > 0.70).98 
Convergent versus divergent validity was demonstrated when compared to the European Organization 
for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) and esophageal 
(OES 24) in a sample of patients with esophageal cancer treated with surgery with or without 

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chemoradiation.98 
The Functional Assessment of Cancer Therapy - Lung (FACT-L, Version 4) is a 33-item 
questionnaire that measures self-reported HRQOL in patients with lung cancer over the last 7 days.104,105 
Psychometric properties of the FACT-L were assessed by Cella et al.104 in a sample of 116 patients with 
various types and stages of lung cancer. Internal consistency, construct validity, and sensitivity to 
change was established. 
Interrupted Radiation Treatment Course, defined as the total number of missed treatment days due 
to patient or caregiver reasons, will be determined from the patient's radiation therapy treatment record. 
We will also record the duration (number of days) of each episode of absence from treatment. 
 
Healthcare Utilization Outcomes 
Healthcare utilization outcomes include unplanned hospital admission, unplanned emergency room 
visits, and unplanned IV fluid use for treatment of dehydration. We will evaluate the effects of the 
intervention, as compared to the control group, on these outcomes, as well as describe the costs 
associated with these outcomes. These outcomes will be measures at T2, T3, and T4. 
 
Mediating Variable 
Caregiver self-efficacy for caregiving will be measure with the Caregiver Inventory, a 21-item 
questionnaire that evaluates the domains of managing medical information, caring for the care recipient, 
caring for oneself, and managing difficult interactions and emotions.99 This scale will be administered at 
all time points. Participants rate each item on a nine-point scale, ranging from not at all confident (1) to 
totally confident (9). Scores are summed, with higher scores indicating greater confidence. Psychometric 
properties of the Caregiver Inventory were initially reported on data from 133 family caregivers of 
terminally ill patients.99 The Cronbach alpha was 0.91 and validity was supported through correlational 
analyses with other measures (Perceived Stress Scale and Caregiver Burden Inventory) as well as ratings 
by caregivers and social workers of caregiving tasks.99 
In addition, an investigator-constructed survey to measure self-efficacy for specific caregiving skills 
during radiation therapy will be used for descriptive purposes. Caregivers will rate their confidence in 
performing specific skills on a 10-point scale. 
 
Covariates 
Patient illness factors – stage of cancer, time since diagnosis, treatment type (chemoradiotherapy vs. 
radiotherapy alone), HPV status (in HNC and anal cancer), use of palliative care, and patient performance 
status – will be recorded on the enrollment form.  Updates for use of palliative care and patient performance 
status will be noted at T2, T3, and T4.  Care demands, defined as hours/week spent caregiving, will be assessed 
at all time points. Demographic characteristics of both the patient and caregiver will be collected at baseline 
(T1). Use of mental health interventions (support group participation, social work and/or psychologist 
Involvement) will be assessed at all time points.  
Three additional measures of social determinants of health are health insurance, social support, and financial 
toxicity. Health insurance will be assessed at baseline for patients and caregivers. Patient health insurance 
status will be obtained in the medical record, and caregiver insurance status will be obtained through self-
report. Financial toxicity will be assessed with the Comprehensive Score for Financial Toxicity measure 
(COST), a patient-reported outcome measure that includes an 11-item scale and a single summary item of 
financial hardship. All items are rated on a 5-point Likert scale and lower scores indicate greater financial 
toxicity. The COST measure has been found to be reliable and valid in assessing caregiver financial toxicity. 
The 19-item Medical Outcomes Study (MOS) Social Support Survey will be used to measure perceived social 
support. The survey provides an overall support index score, as well as domain scores for 
emotional/informational, tangible, positive interaction, and affectionate support. Higher scores indicate greater 
support. The Ohio Opportunity Index (OOI), which measures health and well-being based on home address, 

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will be used to describe neighborhood characteristics for caregivers. 
 
Other variables 
Intervention dose, defined as the number of intervention sessions the caregiver receives, will be recorded 
at the completion of the intervention. 
 
Other variables associated with cost analysis 
Nurse time for preparation of the simulation and delivery of the intervention (in-person and phone 
contacts) will be collected prospectively during the study period. CGs will be surveyed at each 
intervention contact (during radiation weeks 1 and 3, and at the end of radiation treatment) regarding 
any travel expenses for meetings with the intervention nurse. 
 
5.3 Description of Intervention 
The intervention was designed over a one-year period in collaboration with a small team of oncology 
clinicians. Our focus was to design an intervention that would address the specific, complex challenges 
of family CGs, while maintaining feasibility for implementation into a busy clinic schedule. The 
intervention is delivered by an experienced oncology nurse, trained in intervention components, during 
the patient’s course of radiation treatments. It consists of three in-person sessions between the CG and 
intervention nurse (interventionist) and one follow-up telephone contact after treatment is completed 
(Table 3). The intervention design was validated by: 
• Review of CG intervention literature (primary and meta-analytic research) 
• Use of an explicit conceptual framework 
• Expert opinion from oncology clinicians 
• Our prior descriptive studies 
• Qualitative interviews with participants in the pilot study regarding satisfaction and acceptability 
 
Decisions regarding timing and duration of the intervention were based on clinical experience and 
our longitudinal, descriptive study of patients with HNC, which clearly illustrated the pattern of 
increasing intensity of side effects through the weeks of radiation treatment and one-month 
posttreatment. In addition, a systematic review of cancer CG interventions found that problem-solving 
and skill-building interventions were effective in increasing CG confidence if the interventions were 
structured, of brief duration, and targeted to specific caregiving needs along the care trajectory.91 
Therefore, based on our clinical experience and these findings, we designed three CG sessions and one 
telephone follow-up to coincide with the typical patient’s experience. Each session lasts approximately 
30 minutes. The nurse interventionist will record the amount of time required for preparation and 
delivery of each session.  For the duration of the COVID-19 pandemic, sessions 2 and 3 will be 
delivered by phone rather than in-person.  The first session will remain in-person in the radiation 
oncology clinic or the CWRU School of Nursing if caregivers are not allowed in the hospital.  All 
simulation requiring the mannequins will be completed at that first in-person session. We will also offer 
an in-person option for sessions 2 and 3 if the caregiver requests additional skills training with the 
manikins. 
The themes of the intervention session are: (1) the patient’s experience, (2) the CG experience and 
the patient-CG relationship, and (3) the transition to posttreatment survivorship. Each session is 
standardized in that it begins with addressing any issues or concerns that the CG may be experiencing, 
assessing the CG’s level of distress, and providing emotional support. This is followed by provision of 
relevant information related to the theme of the session, followed by the simulation experience. 
Five simulation protocols with corresponding scenarios were developed by the PI in collaboration 
with the team of oncology clinicians. The technical simulations training with a tracheostomy tube, 
gastrostomy tube, and skin and ostomy/wound care use a low-fidelity manikin. The communication skills 

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Evaluation of each session, including CG competency during simulations, will be done by the 
intervention nurse (Figure 3). During the simulations, CG performance of expected behaviors will be 
assessed and noted by the intervention nurse on the simulation checklist. The CG level of skill 
acquisition will be determined by the percent of behaviors completed correctly and will be noted as 
little/none (less than 30% behaviors performed), some (30% - 75%), or great (more than 75%). 
Following the three in-person sessions, the intervention nurse will make a telephone contact two weeks 
after treatment to address any transition issues, to discuss any persistent side effects or issues, and to 
review self-care strategies for the CG. 
The intervention “dose” is defined as the number of sessions that the participant receives. The 
optimal intervention dose for cancer CG interventions is unknown. In a meta-analysis of CG 
interventions by Northouse et al.,2 the number of intervention sessions ranged from 2-12 and the 
duration of interventions ranged from several days to 18 months. Based on our pilot work, we tapered 
the dose of the intervention to three in-person sessions and one telephone session. We hypothesize that 
an adequate intervention 
dose is 3 of the 4 
sessions and we will 
analyze the effect of 
intervention dose on the 
outcomes. 
 
5.4 Data Collection 
For patients and 
caregivers in both the 
intervention and control 
groups, study measures 
will be obtained in- 
person, via mail, via an 
emailed RECap survey 
or by telephone by the 
RA at baseline (T1), at 
the end of treatment 
(T2), and at 4 (T3) and 
20 (T4) weeks 
posttreatment. RAs will 
ask for permission to 
use text reminders if 
participants agree to 
receive texts. 
Instruments can be 
completed in 10 minutes 
(Table 4). Surveys will 
be self-administered, but 
can also be administered 
by interview format if 
needed. We chose measures based on our prior work with caregivers that are psychometrically sound 
and/or recommended by NIH as common data elements to facilitate cross-study analysis and increase 
the scientific impact of our study analyses. 
Data will be collected primarily using Research Electronic Data Capture (REDCap). However, 
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5.5 Description of Study Process 
5.51 Instrument Administration 
Prior to data collection, both RAs and the Project Director will be trained by the PI in the administration 
of the data collection tools. For patients and caregivers in both the intervention and control groups, study 
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5.52 Intervention Administration 
Caregivers in the intervention arm will receive individual support, education, and training that 
incorporates simulation techniques focused on skill development and communication. The intervention 
will occur during three in-person sessions between the caregiver and intervention nurse (interventionist) 
during the patient’s course of radiation therapy. The intervention will be delivered in a private room in 
the Radiation Therapy Department. The themes of the intervention session are: (1) the patient’s 
experience, (2) the caregiver experience and the patient-caregiver relationship, and (3) the transition to 
posttreatment survivorship. One follow-up telephone contact will occur after treatment is completed. 
Caregivers randomized to the control group will receive per usual care, the NCI booklet, When 
Someone You Love is Being Treated for Cancer. 
Caregivers in both groups will receive usual care by nonstudy clinicians, which includes a weekly 
visit with the radiation oncologist and clinic nurse for the patient and CG. The weekly visit is brief (10- 
15 minutes) and focused on how the patient is tolerating the radiation treatments and management of any 
treatment side effects. 
 
5.53 Special Concerns 
Retention of caregivers. Various retention strategies will be employed. Retention will be maximized by: 
(a) consistent contact with the same intervention nurse, (b) minimizing amount of time needed to 
complete surveys, (c) delivering the intervention during scheduled radiation treatment visits, (d) 
conducting the intervention booster telephone call at a time convenient for the subject, and (e) mailing 
a reminder letter midway between T3 and T4 surveys to keep patients and caregivers engaged during 
the long gap in study contact. 
 
5.54 Compensation 
To compensate for time spent and to reduce attrition, caregiver participants will receive a $50 gift card 
after completing measures at 4 and 20 weeks post-treatment (T3 and T4), for a total of $100. Patient 
participants will receive a $20 gift card after completing measures at 4 and 20 weeks post-treatment (T3 
and T4) for a total of $40.  
During the extension period, caregivers who participate in the qualitative interview will receive an 
additional $30 gift card. 
 
5.6 Adverse Reactions and Their Management 
5.61 Reporting Adverse Events 
Data and Safety Monitoring Plan 
a) Monitoring Entity 
A Safety Monitoring Committee (SMC) will be formed for this grant. The SMC will consist of 
members outside the study team, including two faculty members from the Frances Payne Bolton 
School of Nursing, CWRU and a physician from the Case Comprehensive Cancer Center. Study 
team members will include: Dr Susan Mazanec, PI, and Dr. Nicholas Schiltz, Statistician. The 
chair of the committee (an outside member to be named) will be responsible for submitting 
reports to NCI within 2 weeks of the meeting. The committee members who are outside the 
study team will review data on the study as provided by Drs. Mazanec and Schiltz and will 
conduct random auditing of the research records to assess study safety and regulatory 
compliance. 
 
b) Data Safety Monitoring Committee 
Twice annually, throughout the project, this committee will review data on this study regarding: 
(1) study safety including auditing selected cases for compliance with IRB requirements, (2) 
conformance with informed consent requirements, verification of source documents, and 

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investigator compliance, (3) minimizing research-associated risk, and (4) protecting the 
confidentiality of participant data. In addition, it will review all causes of mortality and issues 
with participation. The rate of recruitment refusal (percent and reasons) and subject attrition 
(percent and reasons) will be tracked and reported at these reviews. Differential attrition from all 
study groups will be monitored. If concerns or problems are identified by the SMC, they will be 
reported to the IRB and NCI/NIH via email by the SMC within 3 business days after they are 
identified.  If there are recommendations made by the SMC, the action plan for response or 
notice of any actions taken by the IRB regarding the research and any responses to those actions 
will be provided to NCI officials within 2 weeks. 
 
c) Adverse and Unanticipated Events 
At the onset and across the duration of the study, all staff and investigators will have 
instructional review of the nature and types of unanticipated and adverse events as described by 
NCI and the University Hospitals IRB. As they occur, all unanticipated events and adverse 
events will immediately be reported to the principal investigator who will report them to the IRB 
according to the IRB protocol for both serious and non-serious adverse event and unanticipated 
problem reporting. These will be summarized in reports to the SMC twice a year. Annual 
progress reports to the IRB and NCI/NIH will include a summary of the SMC’s activities and 
findings as well as any adverse events regarding human subjects. Program officials at NCI will 
be informed within 3 business days of unanticipated problems (e.g. data breach) or unexpected 
serious adverse events that may be related to the study protocol or IRB-approved revisions to the 
study protocol that indicate a change in risk for participants. 
 
Although this study is deemed as having minimal risk, we recognize that some unanticipated or 
adverse events could occur. These situations will be noted and reported at the next SMC 
meeting. 
 
Some subjects may have personal situations that may cause them to contact our project staff for 
assistance. If a subject contacts us requiring assistance of any kind, we will note that and give 
them United Way’s “First Call for Help” telephone number and website information 
(www.211cleveland.org). They provide resources on various issues (legal, housing etc.) and can 
put the caregiver in touch with the appropriate organization in their hometown if necessary. If 
we obtain data that reveal concerns with patient care, the PI will share that information with the 
appropriate healthcare providers. If we obtain data that reveal concerns with mental health 
issues, we will put the caregiver in touch with a social worker, psychologist, or psychiatrist 
associated with the University Hospitals Seidman Cancer Center or MetroHealth Cancer Center. 
These situations will be documented and reported to the IRB and to the SMC and reviewed as 
necessary for protocol implications. For serious adverse events, the PI will report to the IRB 
within 3 business days, even if presumed to be unrelated to the study protocol. 
 
5.62 Anticipated Reactions 
Family caregivers will complete surveys about self-efficacy for caregiving, anxiety, depression, health- 
related quality of life, and fatigue. Patients will complete surveys about their HRQOL. There is a 
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There is a possible risk of a breach in confidentiality, including accidental disclosure of protected health 
information during the study or with data sharing. This research presents no more than minimal risk to 
the participants and involves no medical treatment. There are no alternative treatments or procedures. 
5.63 Reaction Management & Protections against Risk 
All research staff will receive training in human subjects research via the online Collaborative 
Institutional Training Initiative (CITI) and will undergo research credentialing procedures at University 
Cleveland Medical Center. In keeping with good clinical practice policy (NOT-OD-16-148), we will 
ensure that all key personnel and staff receive approved training in Good Clinical Practice Training. 
Documentation of successful completion of the training will be kept in our NIH Regulatory Binder. 
The consent form will specifically address the risk that the surveys may evoke emotions. Subjects 
will be told the range of topics addressed in the surveys and will be informed that they can skip a 
question if they wish and/or stop the interview at any time. If during the data collection interview a 
subject becomes distressed, we will provide a referral (with the subject’s permission) to the social 
worker for further assessment and support. The nurse interventionists will assess distress for the 
caregiver subject group and explore the nature of their distress. They will make a professional 
assessment as to whether the caregiver needs a professional referral. We are assessing caregiver 
depression and anxiety using the PROMIS measures. Since these two constructs are highly correlated, 
we will use the depression screening as a tool to determine whether the caregiver subject needs a 
referral. A score of 1.5 standard deviations above the general population will be considered the 
threshold to make a referral to the oncology social worker. The research assistant will be collecting 
these data and there is a calculated field in REDCap that will notify the research assistant if the 
caregiver subject has scored above the threshold. 
For the duration of the COVID-19 pandemic, in-person contact with research staff will be limited 
to one session with the nurse interventionist for caregivers randomized to the intervention group.  
Nurses will follow UH and CWRU policies regarding symptom screening and masking for both the 
nurse interventionist and the caregiver.  All equipment used in the intervention will be sanitized 
thoroughly before and after use.  Intervention caregivers who screen positive for COVID-19 symptoms 
will not be eligible to participate in the study. They will be informed of their ineligible status and told 
to contact their PCP regarding testing and treatment.  If a nurse interventionist screens positive, they 
will not meet with any subjects and will follow CWRU policies regarding return to work.  Another 
interventionist will meet with the caregiver instead.  If the interventionist tests positive for COVID-19, 
CWRU Employee Health and the UH IRB will be notified immediately and we will follow their 
guidance to make sure that research subjects who met with that interventionist recently are notified and 
given appropriate guidance. 
As part of protection of human subjects, data will be protected as well. Access to the database will 
be limited to the project team. Data and the study log, linking subjects' identifiers with their code 
number, will be stored on REDCap. The de-identified data from REDCap will be downloaded to a 
password-protected encrypted drive that will be kept in a locked office in the School of Nursing, as 
described above, when ready for data analysis. The separate passwords for the data files will only be 
known to the PI, project manager, research assistants, and nurse interventionists. Consent forms, the 
only paper form containing names, and any paper data forms will be kept separately in locked file 
drawers, in a locked study office in the School of Nursing. Data sharing with other investigators will 
occur once human subject identifiers have been removed from the data set and a data-sharing agreement 
has been obtained. 
 
6.0 STATISTICAL ANALYSIS 
6.1 Primary and secondary endpoints. 
The primary endpoint is difference in caregiver anxiety between the intervention and control groups at 20 

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weeks post-radiation treatment. Secondary endpoints are caregiver anxiety at the end of radiation 
treatment and 4 weeks post treatment; caregiver depression, HRQOL, and fatigue at the end of treatment 
and 4 weeks post-treatment; and patient HRQOL at the end of treatment and 4 weeks post-treatment. 
 
6.2 , 6.7, 6.8 Statistical Design, Power, Analysis plan, & Missing data.  
An intent-to-treat analysis is planned. Before carrying out inferential statistical procedures, exploratory 
data analysis will be performed: all variable distributions will be examined and descriptive summery 
statistics will be provided: including means, standard deviations, and ranges for continuous variables, as 
well as percentages and frequencies for categorical variables, will be provided to describe the study 
sample. Variable transformations will be made in cases where distributions are skewed, or otherwise fail 
to meet the assumptions for analyses; nonparametric procedures will be used where transformations 
would be inappropriate. Plots will be used to describe the data and identify outliers and influential 
observations. 
 
Aim 1 
Analysis. The primary analysis for Aim 1 will be to compare the control and CG intervention arms with 
respect to CG anxiety at T4 (20 weeks postradiation treatment). A linear mixed model repeated 
measures analysis will be used to obtain mean changes from baseline in anxiety scores at Times T2, T3, 
and T4, using baseline anxiety as a covariate, also adjusting for covariates described in Table 4. A 
contrast of means will be constructed to compare arms with respect to change in anxiety at T4 (primary 
analysis) at the 0.05 significance level. In addition, the baseline characteristics of the two treatment 
groups will be compared using appropriate 2-sample tests for continuous or binary outcomes, and in a 
secondary analysis, characteristics found to differ between groups at baseline will be adjusted for in the 
linear mixed model. A secondary analysis will test for differences between groups at the other 
postbaseline time points, using the Tukey method to control the familywise error rate on a per outcome 
basis. Other CG outcomes will be compared between groups using a similar approach. 
Power. With 180 subjects randomized and a 10% dropout rate, the sample size for the primary analysis 
will be 162 CGs (81 per arm). Assuming a correlation of 0.50 between CG anxiety scores at baseline 
and T4, when adjusting for baseline anxiety, a difference in means of 0.36 standard deviations (SDs) can 
be detected with 80% power using a 2-sided test with significance level 0.05, where SD is the within- 
group standard deviation of anxiety scores at Time T4. Here, adjustment for baseline anxiety reduces the 
detectable effect size from 0.41 to 0.36. This effect size (Cohen’s d) is intermediate between a “small” 
(0.2) and “moderate” effect size, as defined by Cohen, 106 and is close to the pooled estimate of 0.29 
from a meta-analysis of interventions (psychoeducational, skills training, and therapeutic counseling) 
with family CGs of cancer patients.2 For other outcomes, there is 80% power to detect effect sizes of 
0.41 SDs with a 2-sided test, significance level 0.05. 
 
Aim 2 
Analysis. This aim is to measure the effect of the intervention, as compared to a control group, on 
patient outcomes (HRQOL, interrupted treatment course) and healthcare utilization outcomes 
(unplanned hospital admissions, unplanned emergency room visits, and unplanned IV fluid use). Most 
outcomes will be count variables enumerating the cumulative numbers at T2, T3, and T4, which can be 
analyzed using Poisson regression methods implemented as generalized linear models, possibly allowing 
for overdispersion. Zero-inflated Poisson or negative binomial models107,108 will be considered if the 
data indicate a higher frequency of zeros than predicted by a Poisson model. HRQOL, a continuous 
measure, will be analyzed using a linear mixed model with repeated measures at T1, T2, T3, and T4. We 
will analyze the effect of the intervention on HRQOL across diagnoses using the common FACT 
subscales and will describe the symptom experience within each diagnostic group using the cancer- 
specific FACT subscale. 

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Power. From our pilot study, in the control group we expect means of 0.29 and 0.25 for the number of 
unplanned missed days and number of unplanned hospital admissions, respectively. In a Poisson 
regression model, sample sizes of 81 patients per group will provide 80% power to detect a 68% 
reduction in unplanned missed days and a 72% reduction in unplanned hospital admissions in the 
intervention group compared to the control group (2-sided test, significance level 0.05). 
 
Aim 3 
Analysis. This aim focuses on estimating and testing the mediating effects of family CG self-efficacy on 
their anxiety at Time T4 and other time points. The analysis will follow a standard (Baron-Kenny) 
approach of first testing the associations between intervention and the mediator (self-efficacy), and 
between self-efficacy and the outcome (anxiety) controlling for the intervention. If both associations are 
significant, the indirect effect of the mediator is estimated as the difference in the intervention effect on 
the anxiety before and after adjusting for the mediator.109-111 The standard error of the indirect effect, 
used to construct a confidence interval, can be estimated using a marginal regression approach with 
standard generalized estimating equations software, or using a bootstrap approach.111 
Power. If the effect size (difference in means of intervention vs. control groups divided by within-group 
standard deviation) is 0.40 for anxiety at T4, and is 0.50 for CG self-efficacy at T4 and the correlation of 
self-efficacy and anxiety at T4 is 0.40, the difference in means in anxiety after adjusting for the self- 
efficacy is reduced to an effect size of 0.20 SDs (i.e., the indirect effect of self-efficacy is 0.20, or 50% 
of the total). Simulations with n=10,000 replications showed in this scenario that the proposed approach 
had 81% power for testing that the indirect effect is zero (two-sided test, significance level 0.05). 
Increasing the indirect effect by increasing either the correlation or the effect of the intervention on self- 
efficacy results in higher power. 
 
Aim 4 
Analysis. This aim examines if patient illness factors, care demands, demographic factors, and/or use of 
mental health interventions during treatment moderate the relationship between the intervention and CG 
outcomes. Effects of potential modifiers of the treatment effect will be examined by including terms for 
the modifier by treatment interaction effect in the basic ANCOVA model used to test the primary 
hypothesis. 
Power. Analyses for Aim 4 to examine moderating effects will be primarily exploratory in nature, since 
it is well-recognized that power for testing interaction effects is not high in trials that are powered to 
detect main effects, as is the case here.112 When testing interaction of a binary factor occurring with 
frequency 0.5, power is 0.86 to detect an interactive effect size of 1.0 SDs (e.g., an intervention effect of 
1.0 in one subgroup and an effect of 0.0 in the other), using a 2-sided test, significance level 0.05. 
 
Aim 4a: Analyses for Aim 4a will examine if the SDH variables moderate the relationship 
between the intervention and caregiver outcomes. Effects of potential modifiers of the treatment effect will 
be examined by including terms for the SDH modifier by treatment interaction effect in the basic 
ANCOVA model used to test the primary hypothesis. The increase in enrollment from the extension study 
will provide additional power, as it is well-recognized that power for testing interaction effects is not high 
in trials that are powered to detect main effects, as was the case with the parent study. When testing 
interaction of a continuous SDH modifiers and the treatment, power is 0.81 to detect an interactive effect 
size of 0.40 standard deviations (SD) using a 2-sided test, significance level 0.05, for those measures that 
will be available in all subjects (e.g. Ohio Opportunity Index). For SDH measures that will only be 
available in the 96 extension study participants, we will be able to detect an interactive effect size of 0.59 at 
the same power and significance levels. 
Aim 4b: Qualitative interviews will be audio recorded and transcribed, then verified for accuracy by 
research staff. Any identifiable information will be removed from transcripts, and each will be assigned a 

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study number. Deidentified data will be analyzed with NVIVO software using thematic analysis. First, the 
research team, including the PI, will read and reread 5 transcripts to develop a codebook using an inductive 
approach. Then, all transcripts will be coded by the research team using NVIVO to organize the data. 
Additional codes, and subsequently categories of codes will be identified. Clusters of categories converged 
into themes. Each transcript will be read and coded by three members of the research team for interrater 
reliability. 
 
Aim 5 
Analysis. We will assess costs associated with healthcare utilization in both intervention and control 
groups. Medicare reimbursement rates will be used to estimate costs regardless of the age or insurance 
of the participant. Using the DRG, diagnosis and procedure codes we will determine what Medicare 
“would have paid” for those services, and will use that as a proxy for cost. Cost of IV fluids will be 
estimated using wholesale acquisition cost. We will compute a healthcare utilization cost for each 
participant. Mean differences between the two groups will be analyzed using a two sample t-test for 
independent means. If necessary, data will be transformed to satisfy normality. In addition, we will 
describe costs associated with the intervention. Data regarding nurse time for preparation of the 
simulation and delivery of the intervention (in-person and phone contacts) will be collected 
prospectively during the study period. An hourly cost will be estimated according to hourly rates 
according to the Wage and Compensation Survey of the Bureau of Labor Statistics. Equipment costs 
will be measured. We will also determine costs related to the participants. CGs will be surveyed at each 
intervention contact (during radiation weeks 1 and 3, and at the end of radiation treatment) regarding: 
(1) any travel expenses for meetings with the intervention nurse and (2) time lost from work and 
activities due to the intervention, valued at 100% and 60% of the average hourly rate. 

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Power. A sample size of 81 in each group will provide 90% power of detecting a medium effect size 
(Cohen's d=0.5) difference between the two means. A two-tailed Type I error rate of 0.05 will be 
assumed. 
 
In summary: 
(1) For the power calculation, we focused on our primary hypothesis and outcome in Aim 1 to determine 
the sample size for our study (n=162); for the rest of other 4 Aims, we assessed the powers based on the 
sample size obtained in Aim 1. We showed that the proposed sample size will provide clinical 
meaningful effect size with enough statistical power for all the aims we planned to investigate; 
(2) For model development and validation proposed in above aims, we will follow the general statistical 
model building strategy documented in detail in Harrell.113 Some major aspects we will consider are: 
(a) dealing with missing data by multiple imputing of missing predictor values to make good use of 
partial subject information, (b) allowing for nonlinear predictor effects using regression splines, (c) 
adjusting the variance-covariance matrix for multiple imputation, (d) graphically interpreting the model 
using partial effect plots and nomograms, (e) quantifying the clinical utility (discrimination ability) of 
the model, and (f) internally validating the calibration and discrimination of the model using the 
bootstrap to estimate the model's likely performance on a new observation of samples from the same 
sample stream. 
 
6.3 Stratification factors and intervention allocation plan for randomized studies. 
Randomization will be done using the minimization stratified randomization technique (QMinim). 
Minimization is designed to balance pre-identified stratifying covariates across treatment assignments 
more effectively than simple randomization.87-89 The covariates will be CG gender, CG age, and patient 
cancer type. 
 
6.5 Early stopping rules, if appropriate. N/A 
 
6.6 Definition of and allowance in design for un-evaluable/ineligible participants. N/A 
 
 
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8.0 APPENDICES 
Appendix A. Instruments (attached) 
Appendix B. Study brochure for caregivers