Using SMART Design to Improve Symptom Management Strategies Among Cancer Patients
Phase: NA
Conditions: Cancer
Sponsor: Michigan State University

 
 
 
 
Using SMART Design to Improve Symptom 
Management Strategies Among Cancer Patients 
 
National Cancer Institute Grant # 1 R01 CA193706 
Study Protocol and Statistical Plan 
 
May 28, 2020 
 
 
 
 

 
 
 
Research Strategy 
B. Significance 
1. Symptoms during Treatment: Solid Tumor Cancer Patients. By 2030, cancer will surpass 
heart disease as the leading cause of death in the United States, with new cases expected to 
increase nearly 45% from 1.6 million to 2.3 million annually.1 Of highest significance to clinical 
practice, these patients are likely to experience the burden of symptoms resulting from cancer 
and its treatment,2-4 leading to diminished health related quality of life (HRQOL).5-9 The  adapted 
Barsevick symptom management model10 (Figure 2) guides this study.  Based on the model, 
improved symptom management, especially fatigue, is the proposed mechanism for improving 
HRQOL. 
Symptoms are defined as patient’s perceptions of abnormal emotional and physical states.11  
Primary Outcome: Fatigue is the most prevalent and often distressing symptom related to 
cancer and its treatment.12 The prevalence of cancer-related fatigue during active treatment 
ranges from 25% to 
99% based on the 
sample and methods 
of assessment.13 
Cancer-related fatigue 
is the perception of 
unusual tiredness that 
varies in pattern and 
severity and has a 
negative impact on 
ability to function in 
people who have or 
have had cancer.10 
Due to the high 
prevalence of fatigue 
and this team’s completed work showing efficacy of two interventions for this symptom,5,14 
fatigue is the primary outcome of the proposed study. Fatigue is known to affect HRQOL 
outcomes.10,15-20 The biological changes due to chemotherapy and the resulting inflammatory 
processes may be responsible for the persistence of fatigue, as well as related symptoms.21-23 
Physical, emotional and cognitive components of fatigue will be captured in this study.  
Secondary Symptom Outcomes:  In a survey of a 1000 cancer patients, the mean number of 
symptoms reported was eleven.24 Therefore we will evaluate three secondary outcomes: 1) 
summed severity score across an array of symptoms other than fatigue (to avoid duplication 
with primary outcome) from the expanded M.D. Anderson Symptom Inventory (MDASI)25,26 pain, 
nausea, disturbed sleep, distress, shortness of breath (dyspnea), difficulty remembering, 
decreased appetite, drowsiness, dry mouth, sadness, vomiting, numbness/tingling, cough, 
constipation, diarrhea, sore mouth, rash, and hair loss; 2) depressive symptoms; and 3) anxiety. 
A key symptom example from the MDASI is dyspnea, a multidimensional subjective experience 
of breathing distress that impairs functional status, and is associated with thoughts about 
Cancer/ 
Treatment 
Primary Outcome 
Fatigue 
! physical
Secondary Outcomes 
1. Single Summed symptom Score 
8 weeks of: 
 
!  Reflexology 
            or 
!  Meditation 
 
Health Related 
Figure 2: Adapted Symptom Management Model 

 
 
disability, lowered hopefulness, and existential problems in individuals with cancer.27,28 In our 
completed studies with reflexology and meditative practices, there was a significant 
improvement in self-reported dyspnea.5,29 We will also assess  two symptoms not specifically 
included in MDASI: depression and anxiety that are common in cancer patients and are a 
source of high distress and decrease in HRQOL.30,31  Our preliminary data,32,33 published 
work,5,14 and work of others13,26-30 indicate the interventions we propose in this study may impact 
primarily fatigue, but also dyspnea, depression and anxiety.14,26,34-37 One primary and three 
secondary outcomes evaluated in this study will reflect the burden of multiple symptoms that 
cancer patients experience.  
2. Home-Based Symptom Management with Caregivers. This project is also significant 
because it meaningfully engages a friend or family member in their patients’ supportive care 
over time. Many randomized controlled trials (RCT) of symptom management interventions, 
including complementary therapies, consist of an intervention period of several weeks, which 
does not cover the full duration of cancer treatment. Since symptom management is needed not 
just for a few weeks, but for the entire cancer treatment and beyond, the engagement of a friend 
or family caregiver may represent a significant solution to the sustainability of home-based 
symptom management interventions. In our nearly completed R01 with reflexology for cancer 
symptom management, we engage friend or family caregivers.33 A friend or family caregiver is 
identified as such by the patient and provides unpaid assistance to a person with a chronic or 
disabling condition such as cancer.38,39 Currently, the estimated number of cancer patient 
caregivers is 5.7 million people. The value of this unpaid labor force of caregivers in the U.S.40,41 
is appraised to be at least $306 billion annually.42,43 It is recognized that the support provided by 
caregivers may influence the outcomes of their patient’s cancer treatment.38,44-46 Caregivers may 
also be an important influence on patient care options since they are key stakeholders in 
patients’ symptom management. In this sense, interventions that support the patient may also 
indirectly support the caregiver.47,48 For these reasons, our project targets the caregiver along 
with the patient to engage in the home-based symptom management intervention/s.  
Home-based Interventions. Despite the high needs for symptom care, patients undergoing 
cancer treatment have limited choices, given their unique vulnerabilities.49 Reduced functional 
status can lead to difficulties with the use of supportive therapies that require travel or a group 
format.14 Further, patients with symptoms such as dyspnea are at a higher risk due to weather 
changes, another factor which reduces function and accessibility to interventions that are 
provided outside the home.27,37 While home-based interventions during cancer treatment are 
potentially significant, many do not produce clinically or practically meaningful improvements. 
For example, while the effects of supervised exercise interventions on the improvement in 
fatigue are moderate to large (e.g., d=0.75-0.8750 and d=0.95-1.00), 50-52 the effects of home-
based unsupervised exercise interventions are generally small,53 with standardized mean 
difference for high-quality studies in meta-analysis being as small as 0.13.52 Further, limited 
evidence from quality randomized trials exists to support the use of dietary supplements for 
fatigue during chemotherapy, with dietary counseling being more promising compared to 
supplementation. When bundled with exercise interventions, the added benefit of dietary advice 
does not appear to increase the effect sizes, compared to those reported from exercise 
interventions alone.54 Supervised exercise interventions bundled with dietary advice produce 
moderate to large effect sizes,55 and self-directed home-based bundled interventions produce 
small effect sizes.56-58 

 
 
Home-based symptom management interventions in this study, reflexology and 
meditative practices, have been tested against controls and attention controls in 
randomized controlled trials, and have been shown to produce moderate to large effect 
sizes (see preliminary work).5,32 Each home-based intervention provides a significant strategy 
to manage fatigue during chemotherapy. However in practice, individual patients vary in their 
responses to interventions and may try various combinations of symptom management 
strategies.59 So the next innovative step after establishing efficacy against controls is 
individualization and sequencing of interventions using the SMART design.60,61 The two 
interventions considered in the proposed research use different approaches; one is physical 
(reflexology) and one psychological (meditative practices). Therefore the success of these 
interventions may be different for different patients, and there is a need to either lengthen the 
time with one therapy or test the effects of adding a different therapy when one does not 
produce the desired outcomes in a given period of time. The SMART design provides a rigorous 
framework for such testing because of the strength of conclusions that will be derived from 
randomized comparisons.  
3. Interventions: Two Complementary and Alternative Medicine (CAM) Therapies. An 
increasing number of cancer patients turn to CAM therapies for symptom management.62 Our 
team’s program of research focuses on building the evidence base for CAM that may enhance 
symptom management among cancer patients, in order to determine which therapies warrant 
translation to practice, and which elicit comfort or placebo effects but do not add to the pool of 
effective symptom management interventions.63 The widespread use of complementary 
therapies in patients is exemplified by a significant increase (p≤.001) over a 7-year time span for 
common chronic conditions.64 The National Health Interview Survey reported that 38% of 
Americans use some type of complementary therapy.65 The highest users of CAM therapies are 
younger adult females.66 Additional factors associated with CAM use vary across studies and 
include higher education, private insurance, regular exercise, or attending support groups.66-70 
Surveys have found that over time more minority patients are using CAM, with some variation 
on the types of therapies selected by racial and ethnic underrepresented.67,68,71  Recent 
literature also indicates high prevalence of CAM use among men and in low-income urban 
minority populations.66 When complementary therapies are used by the public to this extent and 
without adequate knowledge of safety and efficacy, they run the risk of interfering with 
conventional health care. Therefore, before complementary therapies can become part of 
evidence-based symptom management practice, they need to be rigorously tested in RCTs 
against controls and other therapies, and evidence-based decision rules for best selections and 
sequences of therapies need to be determined.   
The National Center for Complementary and Alternative Medicine (NCCAM)72 identified five 
categories of complementary therapies:  mind-body; body-based; biologically based; energy 
therapies; and alternative medical systems. We have selected a body-based therapy and a 
mind-body therapy because these two therapy groups are the most widely used by 
cancer patients,73 provide different approaches, and  both have a demonstrated evidence 
base against controls.5,14,74,75 This evidence is summarized below. 
Reflexology. Reflexology is similar to massage in that it manipulates soft tissue for therapeutic 
purposes, but differs due to the focus on the special areas of the feet called reflexes and the 
use of a firm thumb-walking motion.76 It is based on the premise that foot reflexes correspond to 
organs, glands, and body systems. Stimulating these reflexes may positively affect function of 

 
 
the target tissue to facilitate health and healing.76 Current research regarding the impact of 
reflexology on symptom management is burgeoning.5 Our team’s completed R01 
(5R01CA104883-5) demonstrated a significant decrease in fatigue when foot therapy was 
provided by a lay caregiver.5 A systematic review of RCTs77 found that in two cancer studies, 
reflexology resulted in a significant decrease in anxiety,78 and a significant improvement in 
QOL.79  A second review80 demonstrated an immediate post-intervention reduction in pain. 
Since these systematic reviews, five RCTs focused on a cancer patient population. One study 
reported significantly lower anxiety among multiple types of cancer patients,81 another found 
lower pain with a mixed cancer group,82 a third reported decreased pain among digestive cancer 
patients,83 a fourth, using a bundled intervention, found that eight weekly sessions of reflexology 
plus self-initiated support significantly promoted relaxation among post-surgical early-stage 
breast cancer patients (n=60),84 and a fifth study involved a mixed sample of hospitalized cancer 
patients (n=42) where a partner provided one session, resulting in an immediate decrease in 
pain intensity and anxiety.74 Our team completed the first large scale RCT with reflexology 
(n=385 breast cancer patients), and demonstrated a significant improvement in physical 
functioning and dyspnea following 4 weekly sessions by a reflexologist.5 The results from the 
completed RCT of reflexology and the preliminary results from our nearly completed trial 
(1R01CA157459-01), where reflexology is delivered by a friend or family caregiver, are 
presented under justification and feasibility.  
 Reflexology is a significant body-based intervention selection because it: 1) is non-invasive; 
2) extremely low risk; 3) does not interfere with cancer treatment the patient is receiving;5  4) 
can easily be taught in the home to a friend or family caregiver;33 and 5) based on a national 
survey, patients are highly likely to use it.85  
Meditative Practices. Meditative practices are purposeful strategies aimed towards building 
capacities to attend to the present moment, including one's thoughts, emotions, bodily 
sensations, and the environment with nonjudgmental openness and acceptance.86 This therapy 
selection is grounded in evidence that meditation training with gentle yoga and breathing 
exercises enhance patients’ ability to adapt to serious medical concerns.87-91   
In our completed work presented under justification and feasibility, teaching meditative 
practices demonstrated feasibility, acceptability and efficacy for symptom management among 
lung cancer patients.14,32 Studies that incorporate meditation-based therapies in cancer are 
increasing and are showing promise in modifying psychological distress and improving 
HRQOL.92-94 Such research in cancer groups include studies incorporating observational,35,95-97 
non-randomized prospective experimental,98,99 and  RCT designs.100-104 Studies in cancer report 
that training in meditative practices resulted in significant improvements in mood,105,106 anxiety 
31,75,97,101,105,107, depression,31,75,101,108  fatigue,36,102,105 HRQOL,75,98,101 stress,97,101,108,109 
coping,97,109,110 and sleep quality.96,99,104 In two RCTs, engagement in meditative practices 
reduced perceived stress,103 and psychological distress,75,105 demonstrating efficacy in 
modulating emotional symptoms.  
Meditative practices are a significant mind-body intervention selection because they: 1) have 
been tested with solid tumor cancer patients;97-99,101,104,110 2) are a highly-utilized supportive 
therapy with vulnerable cancer patients;75,93 3) have been shown to promote adjustment, reduce 
psychological distress, and improve HRQOL in cancer patients;94,109 4) are economically 
delivered and feasible for patients to use on their own at home;94 and 5) are a non-toxic option 
for symptom management during active treatment.  

 
 
Rationale for sequencing of therapies (reflexology and meditative practices). While there are 
likely several physiological mechanisms involved that contribute to the positive outcomes from 
reflexology and meditative practices, the benefits derived from reflexology, a direct body 
manipulation are primarily physically mediated; whereas, the effects derived from training in 
meditative practices are cognitively-mediated.91 Reflexology has been implicated in the 
activation of oxytocin, and to optimize circulatory capacity to eliminate toxins and support 
immune, nervous, and glandular systems.84,111 In Magnetic Resonance Image brain scans, 
meditative practices have demonstrated growth in brain regions that are involved in emotion 
regulation, attention, learning, and memory function.112 Both reflexology and meditative 
practices result in activation of a relaxation response84,111 characterized by calmness, 
sensations of wellbeing, and acceptance which may contribute to heightened HRQOL. We will 
test one therapy, and if it is inadequate, we will either: 1) add the alternative therapy -- 
recognizing that an alternate therapy may evoke benefits by targeting another pathway to yield 
the sought benefits, or 2) provide a longer duration of the first therapy. Because of these 
potential systemic effects, the benefits of reflexology and meditative practices are not limited to 
immediate results and may be cumulative over time. Therefore extending duration of a single 
therapy is one possibility to achieve desired symptom reduction. On the other hand, the use of 
two therapies, that evoke the relaxation response via different pathways to gain similar symptom 
management, may optimize the potential for therapeutic benefits. Some people may prefer or 
respond better to a cognitive therapy over direct physical contact, while others may favor body-
based reflexology, and the optimal intervention choice and sequencing may depend on such 
individual differences. The SMART design allows for rigorously testing and tailoring intervention 
sequences to patients. 
4. SMART Design. Existing static symptom management interventions deliver a predetermined 
dose at specific intervals. These interventions are tested in standard RCTs against controls, and 
this has already been done for reflexology and meditative practices. Dynamic tailoring of 
interventions to patient responses is needed to enhance the science of symptom 
management.113,114 This gap in science is filled by the SMART design in which we will test 
interventions that target symptom severity and adjust intensity based on patient response to the 
management of fatigue. Our approach builds sequences which start with one therapy, and then 
at a decision point, symptom response is evaluated and one intervention may continue so as to 
give it more time, or the intervention is intensified by adding a second therapy. If one therapy of 
4 or 8 weeks is successful, this information is important for both patient and caregiver who can 
then target the one best therapy. Other dyads may need the intensity of two therapies. In this 
case, an important question is whether it is best to start with reflexology or with meditative 
practices and then add the second therapy, and the proposed research will assess which 
patient and caregiver characteristics are important in making this decision for future work. While 
SMART designs do not typically include a control group (since first and second stage 
interventions have been pre-tested in standard RCTs), we included one to help gauge the 
clinical significance of improvements in symptoms from sequences of interventions that 
originate from the first randomization. The evidence obtained in the analysis of the intervention 
sequences will guide refined algorithms for allocating intervention resources in a way that leads 
to the best possible patient outcomes. 
 
 

 
 
C. Innovation 
The key innovations that maximize the potential of the intervention sequences to improve 
symptom outcomes are: 
1. Involvement of a friend or family caregiver in delivery of a multistage home-based 
intervention for symptom management over time.  Family involvement has been a missing 
link in sustaining home-based symptom management.  Many interventions require delivery by a 
provider outside of the home and can be expensive. This research creatively utilizes a 
multistage intervention that builds on evidence established in our work that friend or family 
caregivers can successfully learn to deliver reflexology and can also participate and/or support 
patients with their meditative practices over time in nonclinical environments such as the 
patient’s home.  
2. Rigorous investigation of combinations and sequencing of therapies. Past research on 
complementary interventions often bundled several therapies together, and the resulting 
outcomes could not be attributed to specific therapies.74,115-118 The proposed study takes a new 
approach to the rigorous testing of the value added by a second therapy if the first one does not 
achieve outcomes. The step-up approach with the second randomization provides a design 
where the effect of intensifying an intervention with a second therapy versus giving a single 
therapy more time (higher dose) can be isolated.  
3. Dynamic delivery model and cutting-edge statistical methods. The innovative SMART 
design allows us to investigate the sequencing of interventions based on their success with 
individual patients. Designs similar to SMART have begun to be implemented in chronic 
conditions119-122 including cancer,123,124 and their use for optimizing behavioral interventions has 
been suggested in PA-13-165125that we are responding to. To our knowledge, this research 
is the first to use the SMART design for symptom management in cancer patients. This 
innovative dynamic delivery model is ideally suited for the temporal nature of symptoms that 
present challenges to symptom management science.11,126-128 The exploratory Aim 5 analyses 
use a Q-learning algorithm to determine optimal decision rules for choosing intervention 
sequences for individual patients in the future, based on their characteristics and the 
characteristics of the caregivers who will be providing these home-based interventions or 
practicing them with the patients.  The Q-learning algorithm allows for inclusion of time-varying 
covariates,129 such as repeated measures of symptom severity at baseline and over the first 4 
weeks, to determine if adding another intervention during weeks 5-8 is warranted. The resulting 
new clinical decision rules and algorithms have the potential to optimize the delivery of 
supportive care interventions given individual dyadic profiles. 
 
D. Approach 
1. Justification and feasibility 
1a. Preliminary Work with Patient Selection of Therapy. In preliminary work, our team 
administered a 25-item complementary therapy survey to 27 cancer survivors. Strong interest 
was shown for both mind-body therapies such as meditative practices and body-based physical 
touch therapies such as reflexology.130  

 
 
We then conducted a quasi-experimental study with 100 mixed cancer patients in active 
treatment to participate over eight weeks with a family caregiver. Results demonstrated 
acceptability and feasibility of caregiver participation in complementary supportive therapies.131   
1b. Preliminary Work with Reflexology. In our recently completed reflexology RCT with 385 
women in treatment for breast cancer, no adverse events were reported, and > 89% of women 
in the reflexology group completed three or four sessions of the four session protocol. 
Longitudinal comparisons revealed significant improvements in physical functioning for the 
reflexology group compared to the control group (p=.04). Dyspnea severity was reduced 
compared with the control (p < .01) and lay foot manipulation (LFM) groups (p = .02). The 
effects sizes for the improvements in dyspnea and physical function in the reflexology group 
compared to controls and LFM were medium to large (between 0.41 and 0.87 for average 
differences between groups over time). No differences were found for depressive symptoms or 
state anxiety. The LFM  group had a significant improvement in fatigue compared to controls 
(p=.01).5  
1c. Preliminary Work with Reflexology and Caregivers. In the principal investigators’ (PIs) 
ongoing R01, both patients and their friend or family caregivers are enrolled as dyads in a 
reflexology study for symptom support and reduction of unscheduled health services used.132  
We have been successful in maintaining scheduled dyad enrollment (N=240 consented and 190 
randomized after completing baseline interview as of February, 2015). Friend and family 
caregivers have been able to achieve protocol proficiency at 90% immediately after training and 
at the follow-up quality assurance check a week later.132  
After caregiver training, the rate 
of protocol completion is high for 
more than one session per week 
(69%, 89%, 82%, and 83% by 
week). Virtually all dyads that 
completed at least one session 
actually did 2 or more, which 
indicates the willingness and 
interest of caregivers in 
delivering reflexology sessions 
to patients. Outcomes are measured at baseline, week 5 (post 4-week intervention) and at 11 
week follow-up. Analysis included group comparisons at weeks 5 and 11 using  linear mixed 
effects models and estimation of the effect sizes (Cohen’s d) for average group differences over 
time expressed in standard deviation units. The results from N=140 dyads who completed the 5 
and/or 11 week interview to date are summarized in Table 1. P-values <.05 and clinically 
significant effects sizes >0.33 are bolded. The significant improvements due to caregiver-
delivered reflexology are seen in severity of fatigue, pain, and summed symptom severity and 
interference (MDASI).   
1d. Preliminary work with meditative practices. To develop our meditative practices intervention, 
we first conducted focus groups with cancer patients who had undergone radiation (RT) and 
chemotherapy.14  
Table 1. Preliminary Work: Reflexology and Caregivers 
 
Caregiver-
delivered 
reflexology 
LS Mean (SE) 
N=72 
Attention 
control  
LS Mean 
(SE) N=68 
P-
value 
Effect 
size 
Fatigue severity  
3.64 (0.23) 
4.32 (0.23) 
.04 
.46 
Insomnia severity 
2.95 (0.26) 
3.57 (0.27) 
.10 
.31 
Pain severity 
2.25 (0.23) 
3.21 (0.24) 
<.01 
.49 
MDASI total symptom 
severity 
25.07 (1.59) 
30.63 (1.63) 
.02 
.48 
MDASI total symptom 
interference 
12.15 (1.15) 
16.08 (1.17) 
.02 
.48 
Table 2. Preliminary work with Meditative Practices  

 
 
Based on the findings from 
these focus groups, we 
developed a shortened home-
based intervention responsive 
to the needs of vulnerable 
cancer patients who are in 
treatment. The adapted 
meditative practices protocol 
was tested with 40 patients with 
lung cancer [mean age: 
66.2+9.4 years; sex: 27(67.5%) females, 13(32.5%) males; disease stage: III, 10(25%); IV, 
30(75%)] receiving radiation and/or chemotherapy. Patients were randomized to receive weekly 
meditative practice sessions (N=20) or an attention control condition (N=20). Outcomes were 
measured at baseline, post intervention and at 11 weeks.  Table 2 summarizes  the least 
squares (LS) means, their standard errors (SE), p-values and adjusted effect sizes for group 
comparisons. Due to relatively small sample size, statistical significance was not reached for all 
outcomes; however the effect sizes indicate clinically significant improvements and the 
magnitude of the effect sizes is similar to those seen in Table 1 for the reflexology intervention. 
The study demonstrated feasibility of our adapted meditative practices program, and early 
efficacy with respect to symptom reduction.32 
2. Team. Our team is led by Co-PIs Drs. Gwen Wyatt and Alla Sikorskii. Dr. Wyatt is a professor 
in the College of Nursing, whose research program focuses on testing complementary therapies 
as supportive care interventions for cancer patients to lessen symptoms and enhance 
HRQOL.130,131,133-142 She is currently PI on a NCI 1R01 (CA 157459-01) involving reflexology 
and a friend or family caregiver; she is also Co-I on an acupressure study with breast cancer 
survivors (1R01 CA151445-03); and has completed a reflexology RCT (1R01 CA104883-01A1) 
with breast cancer patients. Dr.  Sikorskii is an associate professor in the Department of 
Statistics and Probability, statistician and methodologist who has collaborated with Dr. Wyatt 
since 2004 and is currently a Co-Investigator (Co-I) on the ongoing reflexology R01. In addition 
to the ongoing reflexology RCT, Dr. Sikorskii has served as a Co-I on 10 NIH funded R01 grants 
and one large CDC-funded study. The multiple PI leadership is essential to the proposed project 
that requires expertise in symptom management and complementary interventions as well as 
expertise in design and methodology of intervention testing. Co-I Dr. Rebecca Lehto is an 
assistant professor and expert oncology clinician who investigates meditative practices in 
cancer patients to facilitate improvement of cognitively-mediated symptoms. Our team 
consultants are: Elizabeth Marazita, a Doctor of Oriental Medicine and reflexology expert; and 
Denise Kozikowski, PhD who is a psychologist and certified expert in meditative practices.  
Other Personnel. Recruiters will be located at each site. Interviewers will contact participants via 
telephone at baseline and week 12 from the main research office. Intervention experts will train 
and QA the study reflexologists and meditative practices teachers; study reflexologists will train 
caregivers in reflexology and meditative practices teachers will train caregivers in meditative 
practices. The Education Coordinator (EC) will schedule and coordinate all training, and make 
weekly calls to caregivers. 
3. Setting. We will begin with 3-4 oncology clinics in the Midwest, and open additional sites if 
needed to maintain enrollment. All dyad therapy sessions will be done in the home. 
 
Meditative 
practices  
LS Mean (SE) 
Attention 
control  
LS Mean (SE) 
P-
value 
Effect 
size 
SF-36 Vitality (lack of 
fatigue) 
47.92 (2.19) 
44.15 (2.06) 
0.24 
0.45 
Total Dyspnea Score 
3.64 (1.07) 
7.60 (0.99) 
0.02 
0.96 
SF-36 Bodily Pain  
48.89 (2.39) 
44.93 (2.25) 
0.26 
0.41 
Cancer Worry 
6.17 (0.53) 
8.07 (0.49) 
0.02 
0.85 
Depressive symptoms 
(CESD) 
7.84 (1.80) 
12.76 (1.68) 
0.07 
0.70 
Sleep Quality Problems 
8.38 (1.87) 
11.76 (1.75) 
0.22 
0.45 

 
 
4. Sample. Patients will be approached at the participating oncology clinics. Inclusion criteria 
are: 1) age 21 or older; 2) solid tumor cancer diagnosis; 3) able to perform basic activities of 
daily living; 4) undergoing chemotherapy, hormonal therapy, or targeted therapy; 5) reporting 
severity of >3 on fatigue using a 0-10 standardized scale at intake; 6) able to speak and 
understand English; 7) have telephone access; and 8) able to hear normal conversation. 
Exclusion criteria are: 1) diagnosis of major mental illness in medical record and verified by the 
recruiter; 2) nursing home resident; 3) bedridden; 4) currently involved with reflexology or 
meditative practices; or 5) deep vein thrombosis or painful foot neuropathy.  
Solid tumors have been selected because fatigue can be effectively managed with the two 
interventions based on existing evidence, and this symptom is prevalent during cancer 
treatment.5,143,144 The cut-off of >3  indicates a moderate level of fatigue based on established 
interference-based cut-points.145 Virtually all solid tumor cancer patients on chemotherapy reach 
a threshold of 2 or higher on fatigue at some point, and the cut-off of 3 was found to be optimal 
in past work for balancing sensitivity and specificity in the prediction of the need for symptom 
management in the future 8 weeks.146  
Friends/family caregivers will participate with each patient and will complete a consent form. 
Their inclusion criteria are: 1) age 18 or older; 2) able to speak and understand English; 3) 
access to a telephone; 4) able to hear normal conversation; 5) cognitively oriented to time, place 
and person (determined via recruiter); and 6) willing to be trained in reflexology and meditative 
practices.  
4a. Sample size. To determine the sample size for this study, we started at the right end of the 
schematic in Figure 1 (the second randomization) and moved from right to left to determine the 
needed number of consenting patients. To power the comparisons for the value added by 
reflexology or meditative practices, we used the effect size of 0.45, the smaller of the two effects 
sizes for fatigue from Tables 1 and 2 to conservatively estimate sample size requirements. The 
effect size of 0.45 corresponded to 2 repeated measures in past work, and the design of this 
study includes 4 repeated measures at each phase. Assuming a correlation of 0.4 among 
repeated measures seen in past work, the adjusted effect size for the longitudinal analysis of 4 
time points is 0.54, which results in the sample size requirement of N=55 per group being 
compared (far right of Figure 1), for power of .80 or greater in two-tailed tests at 0.05 level of 
significance.  These 55 patients from 4 groups (220 total) created by the second randomization 
will be non-responders from the first intervention stage. Assuming that these 220 are 80% of the 
total number of patients in the first stage (i.e., that there is a 20% response rate to fatigue during 
the first 4 weeks), we will need 276 patients to be randomized to interventions. The size of the 
control group was selected to be 55 to maximize power in the comparisons with intervention 
subgroups. Therefore the total required post-attrition sample size is N=331. To account for 23% 
attrition seen in past work5,147 with solid tumor cancer patients, we will need to have 430 patients 
consent. 
4b. Strategies to minimize sample attrition. 1) Recruiters will emphasize the importance of 
participating in the full intervention and the weekly calls; 2) patients will be asked to mark their 
home calendar for intervention days and study calls; and 3) weekly calls to patients maintain 
contact for the entire study duration. These strategies have worked well in our completed and 
ongoing trials.  

 
 
Participants will be assured of the confidentiality of all information and that refusing to 
participate will not alter their care. Patients will continue to receive standard medical care, so if 
any healthcare problems arise, they may seek care from their health providers. For patients who 
refuse, the recruiter will seek consent to review their record for demographics and ask the 
reason for refusal. These data help us understand who declines and contribute to external 
validity and generalizability of the findings. 
5. Recruitment. Our team has an existing relationship with 14 oncology clinics in the Midwest. 
Even with recruitment challenges,148 we are confident of achieving the recruitment target of 430 
before attrition, and a post-attrition sample size of 331. In our recently completed reflexology 
R01 (N=385 breast cancer patients), we were able to remain within 10% of recruitment goals for 
the four years of enrollment and had a consent rate of 74%. In our current R01 with both cancer 
patients and their caregivers (planned N=200 patients; 200 caregivers post-attrition), we are 
having similar enrollment rates during year four. As of February 2015, N=190 dyads have 
completed baseline interview and were randomized. Our samples are representative of the 
cancer patient populations in the Midwest. In the most recent reflexology trial, 14% of patients 
and 13% of caregivers were African American, and 4% were Hispanic.33  
5a. Accrual. Recruiters have research roles and do not provide direct care at the sites. They will 
approach patients during clinic visits and explain the study. Patients can choose to consent at 
that time if their caregiver is present, or take the packet home to discuss with their caregiver. 
Recruiters will follow up during a clinic visit or by phone to further explain the study, answer 
questions, and discuss the study with caregivers. If verbal consent is obtained over the phone 
for either the patient or caregiver, the consent forms in the packet can be signed and returned in 
the stamped envelope. If the consent forms are not returned within one week, the recruiter will 
call as a reminder to mail the consent forms if they wish to participate.  
5b. Recruiter training includes didactic information, role-playing, problem cases and return-
demonstration conducted by the study Education Coordinator at sites. Recruiters will use a 
script to introduce the study to patients including: 1) initial randomization to reflexology, 
meditative practices for symptom management or a usual care control group, and the possibility 
of the two active groups being re-randomized after 4 weeks of using the first therapy to either 
continue the same therapy or to also add the other therapy; 2) weekly intervention sessions 
provided by their caregiver in the two active groups (following training by a reflexologist and/or a 
meditative practices teacher) in their home; 3) there is no cost; 4) the complete study lasts 12 
weeks to include all data collection (i.e., weekly calls and two 30-45 minute phone interviews); 
5) both therapies are designed to help reduce symptoms and improve HRQOL; and 6) a review 
of potential risks/benefits. 
6. Randomization. Following the baseline interview, patients will be randomized to reflexology, 
meditative practices or standard care control. Randomization will be completed using a 
computer minimization algorithm programmed by Dr. Sikorskii that balances arms by 
recruitment location, site of cancer, stage of cancer (early versus late) type of treatment 
(chemotherapy, hormonal therapy or targeted therapy, and their combinations), patient sex and 
relationship to the caregiver (spouse vs non-spouse).149 The second randomization will occur for 
those who do not respond on fatigue to the therapy received after the first 4 weeks of therapy. 
The second randomization will be implemented using the same approach as the first, with the 
same balancing factors, except that randomization will allocate patients into 2 groups: 
continuing the same therapy or adding the other one. 

 
 
7. Intervention Components 
7a. Active Group Caregiver Intervention Procedures. Caregivers will: 1) be trained by a study 
reflexologist or meditation teacher in the therapy their patient is initially randomized to; 2) after 4 
weeks of delivering the therapy, caregivers will be trained in the second therapy if their patient is 
re-randomized to receive the other therapy; 3) receive weekly calls over 8 weeks to maintain 
fidelity and inquire about the number of sessions completed in the past 7 days. At least one 
weekly session is required per protocol. The number of additional sessions per week is not 
restricted in a home-based intervention, and the number of sessions delivered is tracked weekly 
(see 7d, Protocol Fidelity).  
7b. Intervention Protocols. As recommended by the NCCAM, complementary therapy 
investigators should partner with therapy experts, while acknowledging that the investigator role 
requires very different preparation than that of the practitioner.150 Our team has successfully 
maintained this role delineation and will again engage leading experts to assure protocol fidelity 
and delivery. Consultant Dr. Elizabeth Marazita, reflexology expert, will oversee the protocol via 
start up and annual consultation with Dr. Wyatt and our training reflexologists. Consultant Dr. 
Denise Kozikowski, meditative practices expert, will oversee the protocol via start up and annual 
consultation with Co-I Dr. Lehto and our training meditation teacher (see experts & trainers 
letters of support). The consultants and trainer for each therapy will have no direct contact with 
participants; this further assures protection against contamination of roles.   
7c. Common Elements to Study Provider Training. The intervention trainers will train the study 
providers who will work directly with patients and caregivers. Study provider reflexologists will 
be practicing reflexologists, who will be trained in the study specific protocol. Study meditation 
providers will be health professionals, e.g., nurses. Training for both therapies will include 
didactic information, written steps of the protocol, role-playing, demonstrations, and return-
demonstrations based on our study-specific criteria. All study providers must demonstration 
protocol proficiency > 90% to begin and continue (QA checks) with participants (proficiency 
check list in appendix). Both therapies have written instructions with diagrams that will be left 
with caregivers. In addition, to enhance the utilization of technology, a DVD demonstrating the 
instructions will be offered to all dyads.  Each study provider will be in the home approximately 
45-60 minutes during the first two weeks of the caregiver using the therapy. The first visit is for 
training and the second to observe and smooth out any errors. This method of caregiver 
involvement is working well in our ongoing R01.132 All caregivers will be expected to involve the 
patient in a minimum of one session per week. Study providers will help the patient and 
caregiver select a day and time each week for the home-based session.  
7d. Protocol Fidelity and Number of Sessions Per Week. Intervention protocol fidelity will be 
assured through established methods outlined by the NIH Treatment Fidelity Workgroup on 
consistency in dose, providers, delivery, receipt and enactment of the intervention.151  
Consultants, Drs. Marazita and Kozikowski will assure fidelity through maintenance of the 
protocol and its delivery. If questions or concerns arise regarding protocol fidelity, the respective 
expert will be consulted for assistance and advice. Dose Consistency. Initially all patients 
randomized to intervention groups will have four weeks of either reflexology or meditative 
practices with their caregiver. Weekly sessions for each of the two therapies will be 
approximately 45-60 minutes long. Symptom data from the first four weeks will then be 
evaluated to determine which therapy the dyads will continue with through week 8. Provider 
Consistency. All study providers will pass a demonstration of > 90% proficiency as judged by 

 
 
the trainers’ score on the checklist for both therapies before beginning with caregivers. 
Caregivers must also achieve 90% accuracy. Delivery Consistency. There will be a QA check 
and booster session conducted biannually for each study provider (those who teach caregivers 
one or both therapies), with a 90% proficiency in delivery of the therapies. Caregivers are taught 
and evaluated during intervention weeks 1 and 2. If taught the second therapy after week 4, 
training and evaluation occurs again at weeks 5 and 6. Receipt and Enactment Consistency. 
The caregiver will also be called by the Education Coordinator every seven days and asked the 
number of completed sessions since the last weekly call seven days ago. A minimum of 1 
session is required, but the exact number of sessions reported by the caregiver will be recorded 
weekly. Thus, fidelity of the receipt and enactment of each therapy will be documented weekly 
over the 8-week intervention period.  
7e. Incentives.  All participants will be mailed a thank-you letter and a local complementary 
therapy directory after the week 12 data collection. Control caregivers will be offered a 
complimentary training session of their choice (reflexology or meditative practices). This 
therapy-based incentive has worked well in the past.132,152 
8. Data Collection 
8a. Interviews. All patients and caregivers in intervention and control groups will have data 
collected twice via telephone interviews: baseline and study week 12 to capture post-
intervention effects. Study measures have published evidence of reliability and validity with 
samples of cancer patients and caregivers. The interviews will take 30-45 minutes. If a 
participant becomes fatigued, we will divide the telephone interview into two phone calls within 
the same week.  
8b. Interviewer Training. The interviewers will call both members of the dyad at intake and week 
12. Interviewers will be blinded to the dyad’s group assignments. The Education Coordinator will 
train interviewers via didactic information, written steps, role-playing for difficult interview 
questions, and return-demonstrations based on our study-specific criteria. In addition, 10% of all 
interviews will be recorded for QA. 
8c. Weekly Calls to Patients. The interviewers will make the weekly calls to all patients to 
assess symptoms using MDASI (fatigue included) during the 8-week intervention period or an 
equivalent time frame for the control group. Therefore the attention of asking patients about their 
symptoms will be equalized across groups. When a symptom is rated at a 7 or higher on the 0-
10 scale, patients will be asked to contact their oncology office.  For patients randomized to 
reflexology or meditative practices, weeks 1-4 call data will be used to assess response on 
fatigue (see definition of symptom response below). If response is not achieved; the patient and 
caregiver will be re-randomized and weekly calls will continue for weeks 5-8 in the intervention 
and control groups. The weekly calls will provide documentation of the process of change in 
symptoms.  
8d. Weekly calls to Caregivers. Each intervention caregiver will be called by the Education 
Coordinator every 7 days to assess the number of  sessions conducted with the patient since 
the last call 7 days ago, as described under Fidelity (section 7b). During weeks 5-8, if re-
randomized to add another therapy, the number of sessions will be recorded for the initial and 
added therapies. The Education Coordinator will make these calls because interviewers need to 
be blinded to dyad’s group assignments. 

 
 
9. Measures of Primary Symptom Outcome - Fatigue  
9a. Brief Fatigue Inventory (BFI) 153 (Patients; baseline & week 12). Physical and emotional 
components of fatigue will be measured with the Brief Fatigue Inventory for rapid assessment of 
fatigue severity and interference with daily life. The instrument consists of nine items. The first 
three items ask respondents to rate 
the severity of fatigue “right now,” at 
its “usual” level during the past 24 
hours and at its “worst” level during 
the past 24 hours. Answer choices are 
on a scale of 0 to 10, where 0=no 
fatigue and 10=as bad as you can 
imagine. The remaining six items 
assess how fatigue affected the 
following during the past 24 hours: 
general activity, mood, walking ability, 
normal work (including work outside 
the home and daily chores), relations 
with other people, and enjoyment of 
life. Responses are on a 0 to 10 scale 
where 0=does not interfere and 
10=completely interferes. Alpha 
coefficients exceeded .95.  
9b. Attentional Function Index (AFI) 
(Patients; baseline & week 12).154 The 
cognitive component of fatigue will be 
assessed with the 13-item AFI which 
measures perceived effectiveness in 
essential daily challenges that require 
optimal cognition, and has shown 
consistent reliability in adults with 
breast cancer.154,155 In our previous 
studies with lung cancer, alpha 
reliabilities were .89 and .91 
respectively.156 
10. Measures of Secondary 
Symptom Outcomes.  
10a. Symptom Inventory (Patients; 
baseline & week 12 & weekly calls).157 The expanded M.D. Anderson Symptom Inventory 
(MDASI) evaluates severity of 19 symptoms experienced by cancer patients (i.e., fatigue, pain, 
nausea, disturbed sleep, distress, shortness of breath, difficulty remembering, decreased 
appetite, drowsiness, dry mouth, sadness, vomiting, numbness/tingling, diarrhea, constipation, 
sore mouth, rash, hair loss, and cough, and the interference of these symptoms with daily life on 
the scale from 0=symptom not present to 10=worst imaginable. This instrument has established 
evidence of reliability and validity in samples of cancer patients.158 It has been recently updated 
to include the most common symptoms experienced by patients undergoing modern cancer 
Table 3: Measures 
Patient Measures 
Week 
1 
Week 
12 
Weekly 
calls 
1.a Primary Outcome 
 
 
 
• Physical and Emotional Fatigue (Brief Fatigue Inventory) 
X 
X 
 
• Cognitive Fatigue (Attentional Function Index) 
X 
X 
 
1.b  Secondary Outcomes 
 
 
 
• MDASI minus fatigue to avoid redundancy with BFI 
X 
X 
 
• PROMIS Depression & Anxiety SF 4   
X 
X 
 
1.c  Weekly Calls 
 
 
 
•   MDASI with fatigue, since no BFI  or AFI in brief weekly calls 
 
 
X 
2. Potential Covariates 
 
 
 
• Patient Demographics 
X 
 
 
• Bayliss Tool (Chronic Conditions) 
X 
 
 
• Medical Chart: Symptoms & Conditions 
 
X 
 
• Complementary Therapy Expectancy Scale 
X 
 
 
• Complementary Therapy Utilization 
X 
X 
 
• Satisfaction with Caregiver Involvement Survey 
 
X 
 
Caregiver Measures  
 
 
 
1. Potential Covariates 
 
 
 
• PROMIS Profile 29 
X 
X 
 
• Caregiver Demographics 
X 
 
 
• Caregiver Reaction Assessment Tool 
X 
X 
 
• Complementary Therapy Expectancy Scale 
X 
 
 
• Number of Weekly Sessions Completed 
 
 
X 

 
 
treatments.25 A single summed symptom severity score across 18 symptoms (without fatigue, 
since it is measured in more detail by the BFI and AFI as described in item 9 above) will be 
used as a secondary outcome in study Aims 1-4 and in building optimal decision rules in 
exploratory Aim 5. 
10b. & c. Measures of Secondary Outcomes of Depression and Anxiety. PROMIS-short forms 4: 
depression and anxiety (Patients; baseline and week 12).159-162 These two symptoms are not 
directly covered by MDASI, which includes related items of distress and sadness. Therefore, we 
include the additional PROMIS measures for these symptoms. PROMIS measures were 
developed using sophisticated measurement techniques, including Item Response Theory 
(IRT).159,163 Testing in more than 21,000 individuals from the U.S. general population has 
resulted in individual item calibrations that produce t-scores for the general population. The 
available short forms have evidence of reliability and validity, and have high correlations with 
IRT-derived scores obtained from extensive item banks. We chose 4-item short forms to 
minimize respondent burden while maintaining measurement precision. 
11. Determination of Response on Fatigue during Weeks 1-4 for the Purpose of Re-
randomization (Patient; weekly calls). Fatigue response will be assessed based on the fatigue 
item from MDASI administered in weekly calls to patients. First, we define symptom onset as 
the date of the weekly call when a symptom for the first time is reported by the patient as 
moderate or severe according to established and validated cut-points.145 The cut-points mark 
the places on a 1-10 severity scale where largest increases in symptom interference occur as 
severity increases between successive integers ranging from 1 to 10. Thus, the cut-points are 
anchored in symptom interference with patient’s lives. For fatigue, the mild category 
corresponds to a severity score of 1, moderate category corresponds to scores 2-4, and scores 
of 5-10 fall into the severe category. Note that the cut-off score of 3 or higher in the inclusion 
criteria means that at intake patients experience fatigue at a moderate or severe level. Patients 
who started at severe at onset and ended at moderate or mild by the 4 week observation, and 
patients who started at moderate and ended at mild, will be called responders on fatigue.164 
Since responders demonstrate a substantial improvement anchored to fatigue interference with 
daily life after 4 weeks, they will continue with the intervention for another 4 weeks. Patients who 
remain at moderate levels or move to severe at week 4  will be classified as non-
responders.145,165,166  These patients will be re-randomized to either continue with the same 
therapy, or add the second therapy, in order to rigorously test the value added by the second 
therapy in Aims 2 and 3.  
12. Measures of Dyad Characteristics (Potential Covariates) 
12a. Demographics (Dyads; baseline). Demographics include age, education, work, ethnicity, 
race, religious affiliation, marital status, and relationship between patient and the friend or family 
caregiver.   
12b. Chronic Conditions (Patients; baseline). The Bayliss tool queries the presence of  20 
comorbidities.167 
12c. Medical Treatment (Patients; eligibility & week 12).  Chart data include radiation, surgery, 
chemotherapy (dose, type, dates received), co-morbidities, cancer stage, and medications (e.g., 
supportive agents for pain control, nausea, anxiety, or depressive symptoms) corresponding 
with the time-on-study. In addition, the Common Terminology Criteria for Adverse Events 
(CTCAE) data will be collected on side effects and toxicities including anemia and neutropenia. 

 
 
12d. Complementary Therapy Expectancy Scale (Dyads; baseline).168 This tool has items on 
logical thinking and feelings related to complementary therapy use.  
12e. Complementary Therapy Utilization (Patients; baseline & week 12).169 Assesses the use of 
24 therapies.  
12f. Caregiver Reaction Assessment Tool (Caregiver; baseline and week 12).170 Caregiver 
burden will be measured with this tool developed and validated with caregivers of patients with 
chronic conditions. It has 5 subscales: impact on schedule, caregiver’s esteem, family support, 
impact on health, and impact on finances. 
12g. PROMIS Profile-29 (Caregivers; baseline & week 12).159,171 The PROMIS profile 
instruments are a collection of profile short forms, containing items from one of seven primary 
PROMIS domains (depression, anxiety, physical function, pain interference, fatigue, sleep 
disturbance, and satisfaction with participation in social roles). The PROMIS Profile-29 includes 
four items from each primary domain plus a single pain intensity rating. The instrument was 
developed for the general population and is particularly suitable for the assessment of caregiver 
health, including symptoms and functioning. Since interventions will be delivered by or practiced 
with the caregivers, caregiver health may influence the optimal decision rules explored in Aim 5. 
12h. Patient Satisfaction with Friend or Family Caregiver Involvement. (Patients; week 12).172 
This survey consists of 5 items that query patient satisfaction with their caregiver involvement. 
Since the week 12 patient survey is unique for the purposes of this study, it has not been 
validated with other samples previously. Formal psychometric evaluation will be performed 
during analysis by Co-PI Dr. Sikorskii who has extensive expertise in measurement.173-176 
13. Protocol Integrity Assessments 
13a. Therapy Protocol adherence will be evaluated by the number of completed sessions per 
week. The Education Coordinator will call the caregiver every seven days and fills out a session 
form at the end of each weekly call which includes adherence and number of completed 
sessions during the past seven days. 
13b. Attrition Data will be documented when it occurs in association with data collection 
interviews, including being unable to reach the patient or the patient stating she/he wishes to 
discontinue. The date and reason, when possible, will be documented. Interviewers will make 
three attempts for each call.  
13c. Training Forms for proficiency will be completed at each training and refresher. The 
trainers for the reflexologist and meditative practices providers will use a scored proficiency 
checklist to test study providers accuracy initially and at QA checks every 6 months. Study 
providers will also use the proficiency checklist when training caregivers at weeks 1 & 2 and if a 
second therapy is added at weeks 5 & 6. 
14. Analytic Methods 
Data management, tracking and analyses. All data for patients will be entered into the secure 
web-based database that will be accessible to recruiters and interveners at multiple recruitment 
sites. To maintain security, data will be stored within a server different from the server of web 
application. Periodic quality assurance checks of the data will be performed.  De-identified data 
will be transferred into SAS 9.4 for analyses. 

 
 
14a. Baseline Comparisons and Regression Techniques. To check the baseline  equivalence of 
groups created by the first randomization and the equivalence of subgroups created by the 
second randomization, the outcome values at baseline and potential covariates will be 
compared using t-tests, chi-square or Fisher’s exact tests. The latter variables include 
recruitment location, age, sex, site and stage of cancer, type of treatment (e.g., chemotherapy 
and/or radiation, hormonal therapy, targeted therapy), administration of supportive agents, 
comorbid conditions, relationship to the caregiver, and living arrangements. If systematic 
differences are discovered, then the appropriate variables will be included as covariates in 
further analyses. Outliers will be investigated by inspecting the residuals, and models described 
below will be fit with and without outliers to examine their influence on the results. Two-sided 
tests of hypotheses stated below will be performed to determine the superiority of one group 
versus another as created by first and second randomizations. 
14b. Attrition Analyses and Handling of Missing Data. We will compare dyadic characteristics of 
those who drop out between consent and first randomization to those who continue 
participation. Following the first randomization, attrition analyses will compare those who drop 
out according to the second randomization. In addition, we will compare characteristics of those 
who completed the study with those who did not within their designated group to inform the 
generalizability of findings. The regression techniques described below allow for missing at 
random (MAR) mechanisms.177 If patterns of missing data indicate potential not missing at 
random (NMAR) mechanisms, then models describing missing mechanisms will be considered 
(e.g., pattern-mixture models).178,179 Since NMAR or MAR assumptions are not directly testable, 
we will employ sensitivity analyses to investigate the robustness of the results under pattern-
mixture or other  models.  
Primary Analysis outcomes: severity of fatigue (primary, physical and emotional from BFI, 
cognitive from AFI), summed severity index of other symptoms (secondary, from MDASI), 
depression (secondary, from PROMIS), anxiety (secondary, from PROMIS).  
Aim 1, part a), relative effectiveness of reflexology and meditative practices. 
Hypothesis 1. Patients randomized to the reflexology group will report lower severity of fatigue 
and lower summed severity score from the MD Anderson symptom inventory at weeks 1-4. 
This hypothesis will be tested using statistical model #1 that relates the outcome y  at weeks 1-4 
to the group assignment variable 
(reflexology, meditative practices or control), outcome at 
baseline
, and other covariates (see baseline comparisons). Additional covariates will include 
variables used in randomization, due to their potential impact on outcomes. If errors are 
normally distributed, this model will be fit as a linear mixed effects model (LME), which 
generalizes classical analysis of repeated measures.  Generalized linear mixed effects (GLME) 
modeling will be used with the appropriate link function and error distribution (e.g., gamma) if 
the symptom severity outcome is not normally distributed and cannot be normalized using 
transformations. We are primarily interested in the additive effect of the group variable, and 
differences in the least square (LS) means will be tested according to the levels of variable 
.  
Aim 1, part b), characteristics of responders and non-responders. Patients who are responders 
or non-responders on fatigue will be defined as described in measures. The characteristics of 
1x
2x
1x

 
 
responders and their caregivers will be compared to those of non-responders using t-tests, chi-
square or Fisher’s exact tests.  
Aim 2, Hypothesis 2. Patients who do not respond to reflexology on fatigue during weeks 1-4 
(1st intervention stage) and have the meditative practices added during weeks 5-8 (2nd 
intervention stage), will report lower severity of fatigue and improved 3 secondary outcomes: 
summed severity index of other symptoms, depression and anxiety, as compared to those who 
are re-randomized to continue with reflexology alone.  
The analytic strategy described under the analyses for Aim 1 will be implemented for the 
comparison of two groups created by the second randomization. The repeated severity 
measures during weeks 5-8 and week 12 will be related to study group (reflexology alone 
versus reflexology and meditative practices), symptom severity during week 4, and covariates 
(see preliminary analyses). The test of the significance of the coefficient for the group variable 
will yield a formal test of Hypothesis 2 for the severity of fatigue and other symptoms. PROMIS 
measures of depression and anxiety obtained in the week 12 interview will be analyzed using 
general or generalized linear models, and the test of Hypothesis 2 for these 2 secondary 
outcomes will come from the significance of the coefficient for group assignment in the second 
randomization. 
Aim 3, Hypothesis 3. Patients who do not respond to meditative practices on fatigue during the 
weeks 1-4 (1st intervention stage) and have the reflexology added during the 2nd intervention 
stage (weeks 5-8), will report lower severity of fatigue and improved 3 secondary outcomes: 
summed severity index of other symptoms, depression and anxiety as compared to those re-
randomized to continue with meditative practices alone.  
The analysis for this aim is the same as the analysis for Aim 2, but will be performed among 
those who did not respond to meditative practices during weeks 1-4. 
Aim 4, Hypothesis 4: Patients randomized to intervention sequences beginning with 
reflexology or meditative practices will report lower severity of fatigue and improved 3 secondary 
outcomes: summed severity of other symptoms at weeks 1-8 and week 12, depression and 
anxiety at week 12 compared to controls. 
The LME model described under analysis for Aim 1 will be extended to include 8 repeated 
measures of symptom severity (from weekly calls) and an additional measure from week 12 
interview. The test of significance of the explanatory variable reflecting the results of the first 
randomization will yield a formal test of Hypothesis 4. PROMIS depression and anxiety 
measures from week 12 interview will be analyzed using generalized linear models with the 
following explanatory variables: group assignment at first randomization, depression or anxiety 
(respectively) at baseline, and balancing variables from randomization. 
Exploratory Analysis: Aim 5.  
To explore which dyadic characteristics observed during weeks 1-4 are associated with optimal 
patient symptom outcomes at weeks 5-8 and week 12, so as to determine additional tailoring 
variables for the decision rules of selecting the first intervention stage and switching from the 
first intervention stage to the second. 

 
 
The analyses for this aim will help build optimal intervention sequences by determining the 
optimal decision rule 
 specifying best first and second intervention stage. This 
determination is not as simple as determining the best intervention at each stage ignoring future 
interventions. Such simplistic approaches would ignore longer-term effects of the intervention 
which was inferior at stage 1, but produced better outcomes in a longer term if simply continued 
versus combined with another intervention. The analysis approach to this aim therefore follows 
the maximization method called Q-learning.167,180-182 The Q-learning algorithm proceeds from 
right to left in Figure 1, i.e. backwards from the last decision to the first. Two Q-functions will be 
considered. The function 𝑄!(𝐻!) = 𝐸[𝑌!|𝐻!] is the expectation of the second stage outcome 𝑌!  
given history after 2 stages, denoted by 𝐻!: dyadic characteristics, outcomes observed during 
weeks 1-8 and week 12, and interventions received. The function 𝑄"(𝐻") = 𝐸[𝑌" + max 𝑄!(𝐻!)] 
uses history through the first intervention stage 𝐻".The conditional expectations in the Q-
functions will be estimated from regression analyses for the outcomes of severity of fatigue, 
summed severity of other symptoms, depression & anxiety, and the optimal decision rule will be 
found using backward induction by maximizing these functions.183,184  Due to caregiver 
involvement in intervention delivery, caregiver characteristics including measures of symptoms 
(described in the measures section) will be explored, as the optimal decision rules may be 
based on both patient and caregiver factors. The Q-learning method will be implemented in SAS 
PROC QLEARN129 developed by Murphy and colleagues.185 The procedure uses a 
generalization of Q-learning, which allows treatments and covariates to vary over time, a feature 
especially relevant to this trial that has weekly symptom assessments. Using this procedure, we 
will identify tailoring variables that can be used to operationalize the decision rules of selecting 
the first intervention and switching from the first intervention stage to the second. These 
decision rules can then undergo testing in a future confirmatory RCT.  
15. Potential Difficulties/Limitations and Alternative Approaches 
Since randomizations may not account for all possible error sources, we will adjust for baseline 
values of outcomes in the analysis to provide added control over possible confounding pre-
intervention influences.  One primary (fatigue), 3 secondary outcomes (summed severity of 
other symptoms, depression & anxiety) and the hypotheses are all stated a priori. In the 
exploratory analyses, the issue of multiple testing will be addressed by employing the 
Benjamini-Hochberg or Hochberg adjustment186-188  to control for the false discovery rate. 
Because multiplicity adjustments are controversial, all results will be presented both adjusted 
and unadjusted. 
Table 4. Timeline 
Months 
1-6 
7-12 
13-18 19-24 25-30 31-36 37-42 43-48 
Contracts, site IRBs, manuals, training, database 
programming 
X 
 
 
 
 
 
 
 
Enrollment,  interviews, interventions, medical record audits 
 
X 
X 
X 
X 
X 
X 
 
Conduct QA, data safety and attrition monitoring 
 
X 
X 
X 
X 
X 
X 
 
Set up for analysis, conduct analysis, report 
 
X 
 
X 
 
X 
 
X 
16. Data Sharing 
)
,
(
2
1 d
d

 
 
Findings from this study will be available to other researchers under the following conditions: 1) 
appropriate human subjects protection is in place; 2) data have been de-identified; and 3) study 
investigators have publicly presented and published key findings. 
 
 
 
 
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