Hematopoietic cell transplantation (HCT) is a potentially curative but rigorous therapy for hematologic malignancies with significant morbidity and risk of mortality. Common adverse effects of HCT include nausea, diarrhea, anorexia, cognitive changes, mucositis, mood disturbance, and loss of muscle mass [ 1 ]. While many of these resolve within the initial weeks after HCT, functional recovery tends to occur slowly over 6–12 months [ 2 ]. It is typically a year or longer before patients can return to work or resume a more normal schedule of activities, assuming a good outcome [ 3 ].
Insomnia, fatigue, and depression are among the most prevalent and distressing concerns after HCT, and these symptoms can persist for many months and even years after transplant [ [3] , [4] , [5] , [6] , [7] ]. Research from our lab and others has shown that up to 69% of HCT patients experience clinically significant sleep disruption during the acute recovery period, and recent research indicates that 24% meet criteria for a clinical insomnia diagnosis [ 6 , 8 ]. Further, 43–48% continue to experience clinically significant sleep disruption at 1 year post-transplant [ 6 , 7 ]. Fatigue is even more common, with 81% of HCT patients reporting moderate to severe fatigue in the early recovery period [ 9 ]. A large study of long-term HCT survivors who were an average of 7 years post-transplant reported continued problems with sleep, depression, and fatigue [ 4 ]. Insomnia, fatigue, and depression tend to co-occur as a “cluster” among cancer patients due to shared mechanisms, including inflammation and alterations in sleep and circadian rhythms [ 6 , [10] , [11] , [12] ]. The translational implication is that a single intervention targeting this cluster may be an efficient and effective means for improving multiple quality of life concerns [ 13 ].
Restoration of normal circadian rest-activity patterns has been proposed to be one of the most promising intervention strategies for this symptom cluster [ 10 , [12] , [13] , [14] ]. Circadian rhythms have a biological and behavioral basis; they are orchestrated endogenously by the central clock in the suprachiasmatic nucleus in the hypothalamus and are sensitive to external input including light-dark exposure, social patterns, physical activity, and sleep timing [ 15 ]. Stress and changes in daily routines are known to disrupt circadian rhythms among cancer patients [ 14 , [16] , [17] , [18] , [19] , [20] , [21] , [22] ]. Alterations in circadian rhythms may be even more marked for HCT recipients due to extended hospitalizations, the adverse physical side effects of the intensive therapeutic regimen that limit activity, and routine use of medications such as steroids and narcotics that are known to disrupt sleep ( Fig. 1 ). Fig. 1 Biobehavioral model informing the intervention. Fig. 1
Interventions that optimize sleep or activity patterns have been demonstrated to be effective treatments for insomnia, fatigue, and depression in other cancer populations. Two randomized trials have shown that cognitive behavior therapy for insomnia (CBT-I) was highly effective for insomnia occurring in the context of cancer treatment, with secondary analyses showing reduced fatigue and depression [ 10 , 23 , 24 ]. A Cochrane review found that the most effective interventions for cancer-related fatigue incorporated activity management—a set of strategies to optimally schedule and pace daytime activity—as a central component [ 20 , [25] , [26] , [27] , [28] , [29] ]. The combination of behavioral techniques to optimize both sleep and daytime activity across the 24-h cycle may be even more powerful than focusing selectively on nighttime or daytime patterns. Attention to the 24-h rest-activity rhythm is the basis of a well-established treatment for mood disorders, Interpersonal and Social Rhythm Therapy [ 30 , 31 ]. Despite the promise and potential, none of these interventions have been tested in the HCT context.
Aims and objectives
The present study will examine the feasibility and acceptability of a novel behavioral intervention for cancer patients recovering from HCT, Restoring Sleep and Energy after Transplant (ReSET). ReSET uses behavioral strategies to enhance the quality of nighttime sleep and increase engagement in daytime activity. Participants will learn and apply well-established cognitive-behavioral techniques for insomnia and activity management strategies. The techniques will be delivered in an individual format tailored to each patient. These non-pharmacologic approaches are safe, inexpensive, and have no significant side effects. The approach emphasizes scalable implementation and minimal patient burden; the intervention is delivered in a few brief sessions that can easily be incorporated in routine clinical care.
Given the novelty of the proposed intervention and the unique implementation challenges of the HCT context, the aims of the current study are centered on establishing the feasibility and acceptability of both the ReSET intervention and the trial protocol. The specific objectives are to:
ReSET Intervention. 1. Determine participant satisfaction with and acceptability of the behavioral techniques 2. Evaluate facilitator fidelity and participant uptake of key intervention components
Trial Protocol. 1. Assess the ability to recruit, retain, and collect complete data from participants 2. Assess participant willingness to be randomized and acceptability of the usual care condition 3. Evaluate acceptability and validity of the assessment strategy with a particular focus on actigraphy and patient reported outcome measures
Method
Study design
We will conduct a Stage 1b randomized controlled trial (RCT) to compare a novel biobehavioral intervention with usual care. In the intervention, cancer patients who were treated with HCT will learn behavioral techniques to improve sleep and increase daytime activity with the goal of alleviating insomnia, fatigue, and depression. Participants will be enrolled at least one week prior to admission to the hospital for HCT. After successfully completing baseline assessments and infusion of stem cells (HCT), participants will be randomized to the intervention ( n = 24) or standard care ( n = 12). The University of Wisconsin Health Sciences Institutional Review Board (IRB) reviewed and approved all study procedures.
Participants
Participants will include 36 adults undergoing autologous or allogeneic HCT at the University of Wisconsin Carbone Cancer Center between the ages of 18–74 years. Autologous transplant recipients with multiple myeloma or lymphoma (both Hodgkin's and Non-Hodgkin's types) and allogeneic transplant recipients undergoing ablative transplants will be eligible to participate in the study. Autologous transplant recipients with other disease types will be excluded, as will allogeneic transplant recipients undergoing non-ablative regimens due to different treatment trajectories and side-effect profiles. As this is a feasibility study, we are purposefully including participants with a range of symptom severities.
Demographic information and previous experience with psychotherapy or complementary and alternative therapies will be collected at baseline. Information regarding diagnosis, disease stage, conditioning regimen, medications, physician-rated performance status [ 32 ], comorbid medical conditions [ 33 ], and psychiatric diagnoses will be abstracted from patient records. Incidence of post-treatment complications and disease recurrence will also be tracked during the study period.
Study procedure
Recruitment
Eligible patients will be identified by transplant coordinators and HCT physicians. Study personnel will meet with patients who express interest and agree to be contacted at a pre-HCT clinic visit. Those wishing to participate will be asked to sign the informed consent document.
Assessment timing
Participants will be asked to complete self-report and actigraphy assessments prior to hospitalization for HCT (baseline) and approximately 9 (mid-intervention) and 18 weeks (post-intervention) post-HCT. Study investigators will conduct one telephone interview to assess satisfaction and acceptability at approximately 18 weeks (post-intervention). See Fig. 2 . Fig. 2 Participant Flow Note. Self-report, sleep log, and actigraphy measures will be collected at each assessment point. Phone interviews will be conducted at the final T2 Assessment (Week 18) timepoint. Fig. 2
Randomization
Randomization to trial condition will occur approximately 3–4 weeks post-transplant prior to hospital discharge. The study will use a 2:1 allocation ratio to randomize participants to the intervention (n = 24) or usual care (n = 12) conditions. Participants allocated to the ReSET intervention will receive the first treatment session on the same day as randomization when possible. Randomization will be stratified by allogeneic versus autologous graft type due to differences in disease, conditioning regimen, post-HCT complications, and recovery trajectories, with the randomization sequence generated via blocked randomization by the study biostatistician.
The ReSET intervention
Timing
The intervention will be delivered in three 45–60 min face-to-face sessions at approximately 3–4, 8, and 12 weeks post-HCT with follow-up phone calls scheduled at the mid-point between sessions (see Fig. 1 ). The initial session will occur just prior to discharge from the hospital to allow patients to begin to practice the strategies as they return home. The final session occurs around 12 weeks post-transplant, an important clinical milestone during which disease outcomes are assessed and patients are beginning to re-establish more normal routines. Participants will be encouraged to use the behavioral strategies from hospital discharge through 18 weeks post-HCT. The timing of the sessions may be modified up to 2 weeks to accommodate timing with post-transplant clinic visits and hospital discharge. A major aim of this study is to develop an intervention that can be delivered as part of routine clinical care, so the timing is purposely flexible.
Administration
The intervention will be administered by a clinical or counseling psychology graduate student with at least 2 years of clinical training experience. Interventionists will use a treatment manual to guide the intervention sessions. In addition, they will have a weekly supervision session with a licensed clinical psychologist, at which time all study sessions will be reviewed and discussed to ensure correct delivery of the intervention components and adherence to the treatment manual and to address any problems that may arise. All intervention sessions will be audio-recorded. A selection of the audio-recorded intervention sessions for each time point will be evaluated using a fidelity checklist. In addition, the lead investigators will track any problems with delivery or lack of adherence to the treatment manual noted during weekly supervision sessions with the study interventionists.
The intervention will be adapted to the individual needs of the patient. While all participants will receive base modules of the primary intervention components, additional instruction and strategies will be implemented based on a brief assessment of sleep and activity patterns at the start of each session. For example, if a patient is already sleeping well but is having trouble sustaining activity during the day, additional coaching in activity management strategies would occur during the session and follow-up call. The proposed intervention attempts to strike a balance between patient burden and sufficient dose. We have timed the face-to-face sessions so that they can be conducted during the inpatient hospital stay and routine follow-up clinic visits to reduce burden and increase participation. Additional coaching will occur by phone so that participants do not need to make additional trips to the clinic.
The study has a formal plan for monitoring and reporting adverse events (AE) to ensure participant safety that includes notifying the participant's medical provider if concerning symptoms are noted. Participants will be specifically instructed to stop strategies and inform research staff if symptoms worsen and/or increasingly interfere with daily activities. Regular contacts between research staff and participants for study activities will provide frequent opportunities to assess and address any symptoms or unanticipated problems.
Intervention strategies
Improve nighttime sleep quality . Participants will receive an abbreviated, modified form of CBT-I with a primary focus on stimulus control, a set of techniques to strengthen the association between one's bed and sleep and weaken its association with stimulating behaviors. Stimulus control is a well-established stand-alone treatment for insomnia [ 34 , 35 ]. Sleep restriction will not be used due to the increased need for sleep in this population. Participants will also receive instruction in sleep hygiene, with cognitive restructuring utilized as needed. CBT-I is an established, evidence-based treatment for insomnia that has been effective in other cancer populations and has been shown to improve fatigue and mood [ 10 , 23 , 29 , 35 ]. Moreover, abbreviated CBT-I can be effective in doses as small as one session [ 36 ]. Nightiime sleep intervention components are described in Table 1 . Table 1 Intervention components. Table 1 Nighttime sleep Stimulus control Techniques to strengthen the association between bed and sleep and weaken the association between bed and stimulating behaviors. For example, patients are asked to only use the bed for sleeping, go to bed only when sleepy, set a regular morning rise time, and leave the bed when unable to fall asleep. Sleep hygiene Techniques to avoid behaviors that interfere with sleep and optimize the environment for sleep. For example, patients are encouraged to avoid stimulants such as caffeine before bed, establish a relaxing bedtime routine, and ensure the bedroom is dark, cool, and quiet. Cognitive restructuring Techniques to correct maladaptive beliefs and attitudes about sleep (e.g., “Tomorrow will be terrible and I won't be able to function if I don't sleep well.”). Patients learn to recognize and correct problematic thought patterns with accurate information. Daytime activity Prioritizing and planning Techniques to optimize energy resources and prevent energy depletion. For example, patients are assisted with prioritizing activities that are most fundamental to well-being, activities are planned at times of peak energy, and high-energy or non-essential activities are delegated or deferred. Activity pacing Techniques to increase ability to sustain activity over the day and to avoid either prolonged rest or over-activity. Patients learn to alternate between planned, manageable periods of activity and rest. Pedometer Pedometers facilitate accurate self-monitoring of activity and increase motivation for activity. Patients wear a basic step-count pedometer and learn strategies for monitoring and tracking activity across the day and over time.
Table 1
Intervention components.
| Nighttime sleep | Stimulus control | Techniques to strengthen the association between bed and sleep and weaken the association between bed and stimulating behaviors. For example, patients are asked to only use the bed for sleeping, go to bed only when sleepy, set a regular morning rise time, and leave the bed when unable to fall asleep. |
| Sleep hygiene | Techniques to avoid behaviors that interfere with sleep and optimize the environment for sleep. For example, patients are encouraged to avoid stimulants such as caffeine before bed, establish a relaxing bedtime routine, and ensure the bedroom is dark, cool, and quiet. | |
| Cognitive restructuring | Techniques to correct maladaptive beliefs and attitudes about sleep (e.g., “Tomorrow will be terrible and I won't be able to function if I don't sleep well.”). Patients learn to recognize and correct problematic thought patterns with accurate information. | |
| Daytime activity | Prioritizing and planning | Techniques to optimize energy resources and prevent energy depletion. For example, patients are assisted with prioritizing activities that are most fundamental to well-being, activities are planned at times of peak energy, and high-energy or non-essential activities are delegated or deferred. |
| Activity pacing | Techniques to increase ability to sustain activity over the day and to avoid either prolonged rest or over-activity. Patients learn to alternate between planned, manageable periods of activity and rest. | |
| Pedometer | Pedometers facilitate accurate self-monitoring of activity and increase motivation for activity. Patients wear a basic step-count pedometer and learn strategies for monitoring and tracking activity across the day and over time. |
Optimize daytime activity . Participants will receive instruction in activity management strategies including prioritizing activities, planning activities during times of peak energy, activity pacing, and alternating between rest and activity with the goal of increasing ability to engage in non-sedentary, valued activities. In addition, participants will be provided with a basic step-counting pedometer to enhance ability to self-monitor activity across the day and over time and increase motivation for activity. These approaches have been shown to be among the most effective strategies for treating cancer-related fatigue [ [25] , [26] , [27] , [28] , [29] ]. Increasing engagement in meaningful activities is also a central component of established, evidence-based behavioral treatments for depression that are typically comparable or superior to other psychotherapeutic and medication strategies [ [37] , [38] , [39] ]. Daytime activity intervemtion components are described in Table 1 .
Session breakdown
Each session will begin with a brief, semi-structured assessment of current sleep and activity patterns. Questions will focus on ability to fall asleep, nighttime sleep disturbance, napping, and extent and patterns of engagement in activities of daily living, work inside or outside of the home, family and social activities, and hobbies. Sessions will incorporate all intervention components but will focus on areas of concern. A sample session outline is shown in Table 2 . Session 1 (prior to hospital discharge) will include instruction in basic stimulus control and sleep hygiene strategies for re-establishing good sleep patterns after hospital discharge, introduction of the principles of activity management, and instruction on use of the pedometer. Session 2 will review progress with Session 1 components, introduce additional stimulus control and cognitive restructuring techniques for sleep if needed, and incorporate planning and goal setting for daytime activities. Session 3 will focus on the use and maintenance of strategies learned in previous sessions as participants begin to re-establish daily routines. Participants will receive educational handouts and worksheets at each in-person session outlining and personalizing key strategies and a 3-ring binder to store the materials for easy reference between sessions. All sessions will be followed with a scheduled phone call approximately 2 weeks later for additional coaching and troubleshooting focused on problem areas. Participants will also be asked to keep a daily checklist of sleep and activity strategies used between sessions. Table 2 Sample session outline. Table 2 5–10 min Greeting, brief assessment of current sleep and activity patterns and concerns. 5–10 min Review progress on behavioral strategies already introduced. Provide additional instruction and coaching as needed. 10–15 min Instruction in new behavioral strategies in base module. Review patient take-home materials. 10–15 min Instruction and coaching in additional behavioral strategies as needed based on assessment. 5–10 min Planning and goal setting for incorporating strategies into daily life. 5–10 min Address questions and concerns. Schedule interview and phone coaching sessions.
Table 2
Sample session outline.
| 5–10 min | Greeting, brief assessment of current sleep and activity patterns and concerns. |
| 5–10 min | Review progress on behavioral strategies already introduced. Provide additional instruction and coaching as needed. |
| 10–15 min | Instruction in new behavioral strategies in base module. Review patient take-home materials. |
| 10–15 min | Instruction and coaching in additional behavioral strategies as needed based on assessment. |
| 5–10 min | Planning and goal setting for incorporating strategies into daily life. |
| 5–10 min | Address questions and concerns. Schedule interview and phone coaching sessions. |
Usual care condition
Participants randomized to usual care will complete outcome measures. They will undergo the typical post-transplant medical care at the cancer center. The cancer center does not provide systematic education about symptom management but provides education and referrals to community support groups and health psychology as needed.
Measures
Actigraphy
The Actiwatch-2 (Philips Respironics), a wrist-worn actigraphy device, will be used to objectively quantify circadian rest-activity patterns over a continuous 7-day period at three time points: prior to hospital admission for HCT and 9 weeks (mid-intervention) and 18 weeks (post-intervention) post-HCT [ 40 ]. Data processing will yield the following indices: mesor (mean activity level), amplitude (rhythm height), acrophase (time of day the rhythm peaks), and R-squared (goodness-of-fit or robustness of the rhythm), as described in Rumble et al., 2015 [ 41 ]. These rest-activity indices will be the primary actigraphy outcomes of interest. However, we will also collect additional measures of sleep and daytime activity. Specifically, participants will complete a concurrent nightly sleep log, and traditional sleep parameters will be calculated from both the logs and actigraphy, including total sleep time, sleep onset latency, wake time after sleep onset, and sleep efficiency. For daytime activity, calibration thresholds will be used to aggregate activity data into steps and minutes spent in sedentary, light, moderate, and vigorous activity [ 42 ].
Patient-reported outcomes
Participants will complete well-validated self-report assessments at the same three time points: prior to hospital admission and 9 and 18 weeks post-HCT. The sleep disturbance, fatigue, and depression modules of NIH Patient Reported Outcomes Measurement Information System (PROMIS) will be the primary outcomes [ [43] , [44] , [45] ]. The anxiety, pain, and physical functioning modules will also be used. We will compare performance with more established instruments that our team has previously used, including the Insomnia Severity Index (ISI), Fatigue Symptom Inventory (FSI), and Inventory of Depression and Anxiety Symptoms Depression Scale (IDAS) [ [46] , [47] , [48] ]. In addition, we will report PROMIS sleep, fatigue, and depression scores relative to population norms, and we will report the percent of the sample with of mild, moderate, and severe insomnia symptoms on the ISI to estimate prevalence and severity to inform a future trial.
Patient interviews
Study investigators will conduct a semi-structured interview at the end of the intervention (approximately 18 weeks post-HCT) to determine participant satisfaction with and acceptability of a) the behavioral strategies, timing, and delivery mode of the intervention and b) the assessment strategy and time commitment of the RCT. Two trained research assistants will administer this interview; one will ask questions, the other will take notes and the interview will be audiorecorded. Participants will be asked about barriers to participation and problems encountered as well as areas of satisfaction. They will be cued to report both problems and satisfaction with each of the aforementioned elements. Notes and recordings will be reviewed to generate a list of barriers and facilitators of participation in the intervention. Details from participant narratives will be used to determine the significance of the issues and potential means to address them.
Data analysis
The primary outcomes will focus on feasibility and acceptability of the intervention and the trial protocol.
Feasibility and acceptability of the intervention
The goals are to determine the following:
Participant satisfaction with and acceptability of the behavioral techniques . Interview data will be examined to determine participant satisfaction with the intervention and behavioral techniques. We will also evaluate this indirectly through examining participant attrition.
Intervention fidelity. All intervention sessions will be audio-recorded. A selection of the audio-recorded intervention sessions for each time point will be evaluated using a fidelity checklist. In addition, the lead investigators will track any problems with delivery or lack of adherence to the treatment manual noted in weekly supervision sessions with the study interventionists.
Intervention uptake. Participants will be asked to complete a daily checklist to indicate which behavioral strategies they used each day.
Feasibility and acceptability of the trial protocol
The goals are to determine the following:
Ability to recruit, retain, and collect complete data from participants. These will be evaluated by tracking recruitment rate and reasons for non-participation. Retention rates and those contributing complete data will be tracked at milestones of 4, 8, 9, 12, and 18 weeks. Woolf's method will provide confidence intervals for these rates [ 49 ].
Participant willingness to be randomized and acceptability of the usual care condition. Participant willingness to be randomized will be evaluated by examining attrition between enrollment and the first intervention session as well as attrition between randomization and the mid-point assessment. Participant willingness to be randomized and acceptability of the usual care condition will also be evaluated by examining responses to a semi-structured interview of usual care participants at 18 weeks post-transplant.
Acceptability and validity of the assessment strategy. Acceptability will be assessed by examining interview data and rates of completion of actigraphy, logs, and self-report measures. To address validity, we will assess the ability to predict PROMIS measures with the legacy measures of the same symptoms we have previously used successfully with this patient population. Strong prediction ( r > 0.5) will imply that the PROMIS measures are a statistically valid approach to quantifying the effects of our intervention.
Determination of estimates of variance and effect sizes
The exploratory goal is to conduct a preliminary test of the efficacy of the intervention to determine estimates of variance and effect sizes for determination of power and sample size. The primary outcomes will be PROMIS sleep disturbance, fatigue, and depression scores. Actigraphy index scores (mesor, amplitude, acrophase, R-squared) will also be compared to determine the effects of the intervention on rest-activity patterns. We will use linear regression to compare groups, and we will obtain mean differences and within-group standard deviations. It is important to emphasize that this is an exploratory analysis only as we are likely underpowered to test the efficacy of the intervention. Our sample size will provide 80% power to detect a group difference of 1.0 within-group standard deviations (a large effect). In sum, we will have sufficient information to gain a sense of whether there is an effect and to quantify within-group standard deviations. These within-group standard deviations will be essential for study planning for a full-fledged 2-arm larger, confirmatory RCT.
Finally, we will examine the extent to which actigraphy index scores are associated with—i.e., predictive of—the patient-reported outcomes listed above. For outcomes that are highly skewed, ordinal logistic regression will be used to model the data. For more continuous or symmetrically distributed outcomes, we will use linear regression models.
Discussion
Despite the prevalence and persistence among HCT survivors, insomnia, fatigue, and depression are undertreated in this population [ 1 ], and a key barrier is the lack of practical, evidence-based strategies for addressing these concerns in the HCT setting. ReSET was designed to address this gap and optimize recovery from HCT with a brief, non-invasive intervention that can be implemented as a part of routine clinical care.
Strengths of ReSET include the attention to scalability and minimizing patient burden by integrating face-to-face sessions into existing clinical care and using telephone coaching. To increase benefits and efficiency, ReSET will target sleep and rest-activity patterns across the 24-h cycle. While similar approaches have been established in the treatment of mood disorders, prior research in cancer has focused selectively on either sleep or management of daytime activity, but not both. This approach also applies emerging models of biobehavioral symptoms in cancer to treat prevalent and debilitating symptoms occurring in the context of HCT. Specifically, ReSET will capitalize on the shift in focusing on treating symptoms individually to developing interventions with the potential to alleviate multiple quality-of-life concerns [ 10 , 12 , 13 ]. Finally, while ReSET is manualized and includes standardized base content, it is also designed to be flexibly tailored to patient needs based on brief assessments at the start of each session. This flexible approach is designed to optimize engagement, efficiency, and benefits.
Strengths of the assessment approach include the use of both patient-reported outcome measures and the objective assessment with actigraphy, a sophisticated and non-invasive measure that uses a highly sensitive accelerometer to objectively quantify circadian rest-activity rhythms. These novel indices of circadian rest-activity patterns, in addition to more traditional sleep parameters, will be brought to bear on this project. Semi-structured interviews will further be utilized to evaluate patient satisfaction and acceptability.
There are also some limitations that should be noted. The protocol was specifically designed to assess feasibility and acceptability of ReSET. Therefore, the sample size is likely underpowered to test the efficacy of the intervention. However, the statistics generated will be key ingredients to power and sample size calculations that will be needed to plan a larger, confirmatory RCT.
Another potential limitation is the heterogeneity of the patients with respect to diagnosis, treatment, and stem cell source. We opted to include both allogeneic and autologous transplant recipients based on research from our laboratory and results from another large study showing comparable levels of fatigue, sleep disturbance, and depression in both groups [ 3 , 7 , 50 ]. We will stratify randomization based on transplant type. If findings are promising, subgroup analyses would be planned in a future trial.
While ReSET is designed to minimize patient burden, it is possible that the dose may not be sufficient to improve target symptoms. However, there is already evidence that behavioral interventions as short as one session can have a clinically meaningful impact on insomnia [ 36 ], and most activity management interventions are similarly brief [ 28 ]. Given barriers to implementing behavioral interventions in the cancer care setting, there is a high need for developing efficacious, brief interventions that can be successfully implemented under real world conditions. Preliminary effect sizes and participant feedback will guide optimization of ReSET for a future trial, which could increase number, frequency, or duration of sessions.
Finally, while it might be ideal to evaluate patients for a longer period of time, the 18-week follow-up will allow us to answer the critical questions concerning the feasibility and initial effects. The acquired data will lay the groundwork for a larger trial where a longer follow-up period can be employed.
All intervention research reflects a balance between practical considerations, burden and time constraints, and ethical concerns, when seeking to achieve desired goals. We believe our approach maximizes the potential gain and has high potential to make a meaningful contribution with respect to the care of HCT patients. The current protocol will focus on HCT recipients due to the severity and persistence of the quality-of-life impairments; however, if shown to be effective, this approach could easily be extended to other cancer populations.
While the overarching goal is to improve quality of life by minimizing the impact of distressing symptoms for HCT patients, our research group has recently demonstrated that insomnia, fatigue, and depression occurring pre-HCT and in the early post-HCT recovery period predict important clinical outcomes following HCT. Specifically, pre-HCT sleep disturbance, fatigue, and depression symptoms and post-HCT fatigue and depression symptoms predicted higher risk for mortality by 6 years post-HCT, after adjusting for known clinical risk factors. Similarly, pre-HCT sleep disturbance was a risk factor for disease relapse [ 6 ]. The findings underscore these symptoms as important targets for intervention and extend the possible benefits to improving the clinical outcome and extending survival.
Funding
This work was supported by the 10.13039/100000002 National Institutes of Health (NIH) 10.13039/100000054 National Cancer Institute [grant number K07 CA136966], 10.13039/100007923 University of Wisconsin Carbone Cancer Center Support Grant [grant number P30 CA014520], and the Clinical and Translational Science Award program through the 10.13039/100000002 NIH 10.13039/100006108 National Center for Advancing Translational Sciences [grant number UL1 TR002372]. These funding sources were not involved in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Author contributions
Kirvin-Quamme: Conceptualization, Writing – original draft. Rumble: Conceptualization, methodology, writing – review and editing. Cadmus-Bertram: Conceptualization, methodology, writing – review and editing. Juckett: Methodology, resources, writing – review and editing. Rathouz: Conceptualization, methodology, biostatistics, writing – review and editing. Schell: Methodology, project administration, writing – review and editing. Callander: Methodology, resources, writing – review and editing. Hematti: Methodology, resources, writing – review and editing. Costanzo: Conceptualization, funding acquisition, methodology, resources, supervision, writing – original draft.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
1 Syrjala K.L. Martin P.J. Lee S.J. Delivering care to long-term adult survivors of hematopoietic cell transplantation JCO 30 2012 3746 3751 10.1200/JCO.2012.42.3038 PMC3675679 23008296
2 Costanzo E.S. Juckett M.B. Coe C.L. Biobehavioral influences on recovery following hematopoietic stem cell transplantation Brain, Behavior, and Immunity 30 2013 S68 S74 10.1016/j.bbi.2012.07.005 22820408 PMC3493826
3 Syrjala K.L. Langer S.L. Abrams J.R. Storer B. Sanders J.E. Flowers M.E.D. Martin P.J. Recovery and long-term function after hematopoietic cell transplantation for leukemia or lymphoma JAMA 291 2004 2335 2343 10.1001/jama.291.19.2335 15150205
4 Andrykowski M.A. Bishop M.M. Hahn E.A. Cella D.F. Beaumont J.L. Brady M.J. Horowitz M.M. Sobocinski K.A. Rizzo J.D. Wingard J.R. Long-term health-related quality of life, growth, and spiritual well-being after hematopoietic stem-cell transplantation JCO 23 2005 599 608 10.1200/JCO.2005.03.189 15659507
5 Artherholt S.B. Hong F. Berry D.L. Fann J.R. Risk factors for depression in patients undergoing hematopoietic cell transplantation Biology of Blood and Marrow Transplantation 20 2014 946 950 10.1016/j.bbmt.2014.03.010 24650679 PMC4057950
6 Rentscher K.E. Carroll J.E. Juckett M.B. Coe C.L. Broman A.T. Rathouz P.J. Hematti P. Costanzo E.S. Sleep Disruption, Fatigue, and Depression as Predictors of 6-year Clinical Outcomes Following Allogeneic Hematopoietic Cell Transplantation, JNCI 2021 Journal of the National Cancer Institute 10.1093/jnci/djab032 PMC8633423 33693799
7 Nelson A.M. Coe C.L. Juckett M.B. Rumble M.E. Rathouz P.J. Hematti P. Costanzo E.S. Sleep quality following hematopoietic stem cell transplantation: longitudinal trajectories and biobehavioral correlates Bone Marrow Transplant 49 2014 1405 1411 10.1038/bmt.2014.179 25133898 PMC4221490
8 Boonstra L. Harden K. Jarvis S. Palmer S. Kavanaugh-Carveth P. Barnett J. Friese C. Sleep disturbance in hospitalized recipients of stem cell transplantation Clin J Oncol Nurs 15 2011 271 276 10.1188/11.CJON.271-276 21624862
9 Bevans M.F. Mitchell S.A. Marden S. The symptom experience in the first 100 days following allogeneic hematopoietic stem cell transplantation (HSCT) Support Care Cancer 16 2008 1243 1254 10.1007/s00520-008-0420-6 18322708 PMC2885854
10 Fleming L. Randell K. Harvey C.J. Espie C.A. Does Cognitive behaviour therapy for insomnia reduce clinical levels of fatigue, anxiety and depression in cancer patients? Psycho-Oncology 23 2014 679 684 10.1002/pon.3468 24458543
11 Kim H.J. Barsevick A.M. Fang C.Y. Miaskowski C. Common biological pathways underlying the psychoneurological symptom cluster in cancer patients Cancer Nursing 35 2012 E1 10.1097/NCC.0b013e318233a811 22228391
12 Miller A.H. Ancoli-Israel S. Bower J.E. Capuron L. Irwin M.R. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer JCO 26 2008 971 982 10.1200/JCO.2007.10.7805 PMC2770012 18281672
13 Kwekkeboom K.L. Cherwin C.H. Lee J.W. Wanta B. Mind-body treatments for the pain-fatigue-sleep disturbance symptom cluster in persons with cancer Journal of Pain and Symptom Management 39 2010 126 138 10.1016/j.jpainsymman.2009.05.022 19900778 PMC3084527
14 Grutsch J.F. Ferrans C. Wood P.A. Du-Quiton J. Quiton D.F.T. Reynolds J.L. Ansell C.M. Oh E.Y. Daehler M.A. Levin R.D. Braun D.P. Gupta D. Lis C.G. Hrushesky W.J. The association of quality of life with potentially remediable disruptions of circadian sleep/activity rhythms in patients with advanced lung cancer BMC Cancer 11 2011 193 10.1186/1471-2407-11-193 21605390 PMC3114794
15 Mohawk J.A. Green C.B. Takahashi J.S. Central and peripheral circadian clocks in mammals Annual Review of Neuroscience 35 2012 445 462 10.1146/annurev-neuro-060909-153128 PMC3710582 22483041
16 Ancoli-Israel S. Liu L. Marler M.R. Parker B.A. Jones V. Sadler G.R. Dimsdale J. Cohen-Zion M. Fiorentino L. Fatigue, sleep, and circadian rhythms prior to chemotherapy for breast cancer Support Care Cancer 14 2006 201 209 10.1007/s00520-005-0861-0 16010529 PMC1599708
17 Ancoli-Israel S. Liu L. Rissling M. Natarajan L. Neikrug A.B. Palmer B.W. Mills P.J. Parker B.A. Sadler G.R. Maglione J. Sleep, fatigue, depression, and circadian activity rhythms in women with breast cancer before and after treatment: a 1-year longitudinal study Support Care Cancer 22 2014 2535 2545 10.1007/s00520-014-2204-5 24733634 PMC4119484
18 Berger A.M. Hertzog M. Geary C.R. Fischer P. Farr L. Circadian rhythms, symptoms, physical functioning, and body mass index in breast cancer survivors J Cancer Surviv 6 2012 305 314 10.1007/s11764-012-0218-x 22484807
19 Dedert E. Lush E. Chagpar A. Dhabhar F.S. Segerstrom S.C. Spiegel D. Dayyat E. Daup M. McMasters K. Sephton S.E. Stress, coping, and circadian disruption among women awaiting breast cancer surgery Ann. Behav. Med. 44 2012 10 20 10.1007/s12160-012-9352-y 22450856
20 Eismann E.A. Lush E. Sephton S.E. Circadian effects in cancer-relevant psychoneuroendocrine and immune pathways Psychoneuroendocrinology 35 2010 963 976 10.1016/j.psyneuen.2009.12.011 20097011
21 Jim H.S.L. Jacobsen P.B. Phillips K.M. Wenham R.M. Roberts W. Small B.J. Lagged relationships among sleep disturbance, fatigue, and depressed mood during chemotherapy Health Psychol 32 2013 768 774 10.1037/a0031322 23437852 PMC3700563
22 Mormont M.C. Waterhouse J. Bleuzen P. Giacchetti S. Jami A. Bogdan A. Lellouch J. Misset J.L. Touitou Y. Lévi F. Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status Clin Cancer Res 6 2000 3038 3045 10955782
23 Espie C.A. Fleming L. Cassidy J. Samuel L. Taylor L.M. White C.A. Douglas N.J. Engleman H.M. Kelly H.L. Paul J. Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer JCO 26 2008 4651 4658 10.1200/JCO.2007.13.9006 18591549
24 Savard J. Simard S. Ivers H. Morin C.M. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: sleep and psychological effects JCO 23 2005 6083 6096 10.1200/JCO.2005.09.548 16135475
25 Armes J. Chalder T. Addington-Hall J. Richardson A. Hotopf M. A randomized controlled trial to evaluate the effectiveness of a brief, behaviorally oriented intervention for cancer-related fatigue Cancer 110 2007 1385 1395 10.1002/cncr.22923 17661342
26 Barsevick A.M. Dudley W. Beck S. Sweeney C. Whitmer K. Nail L. A randomized clinical trial of energy conservation for patients with cancer-related fatigue Cancer 100 2004 1302 1310 10.1002/cncr.20111 15022300
27 Gielissen M.F.M. Verhagen S. Witjes F. Bleijenberg G. Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial JCO 24 2006 4882 4887 10.1200/JCO.2006.06.8270 17050873
28 Goedendorp M.M. Gielissen M.F.M. Verhagen C. Bleijenberg G. Psychosocial interventions for reducing fatigue during cancer treatment in adults Cochrane Database Syst Rev 2009 10.1002/14651858.CD006953.pub2 CD006953 PMC7197415 19160308
29 Mustian K.M. Morrow G.R. Carroll J.K. Figueroa-Moseley C.D. Jean-Pierre P. Williams G.C. Integrative nonpharmacologic behavioral interventions for the management of cancer-related fatigue The Oncologist 12 2007 52 67 10.1634/theoncologist.12-S1-52 17573456
30 Ehlers C.L. Frank E. Kupfer D.J. Social zeitgebers and biological rhythms: a unified approach to understanding the etiology of depression Archives of General Psychiatry 45 1988 948 952 10.1001/archpsyc.1988.01800340076012 3048226
31 Swartz H.A. Frank E. O'Toole K. Newman N. Kiderman H. Carlson S. Fink J.W. Cheng Y. Maihoefer C.C. Wells K.F. Houck P.R. Painter T. Ortenzio S.H. Simon S.L. Henschke P. Ghinassi F. Implementing interpersonal and social rhythm therapy for mood disorders across a continuum of care PS 62 2011 1377 1380 10.1176/ps.62.11.pss6211_1377 PMC3387565 22211221
32 Karnofsky D. Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer Evaluation of Chemotherapeutic Agents 1949 Columbia University Press New York 196
33 Imamura K. McKinnon M. Middleton R. Black N. Reliability of a comorbidity measure: the index of Co-existent disease (ICED) Journal of Clinical Epidemiology 50 1997 1011 1016 10.1016/S0895-4356(97)00128-5 9363035
34 Bootzin R.R. Perlis M.L. Stimulus control therapy Perlis M. Aloia M. Kuhn B. Behavioral Treatments for Sleep Disorders 2011 Academic Press San Diego 21 30 10.1016/B978-0-12-381522-4.00002-X
35 Morin C.M. Bootzin R.R. Buysse D.J. Edinger J.D. Espie C.A. Lichstein K.L. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998–2004) Sleep 29 2006 1398 1414 10.1093/sleep/29.11.1398 17162986
36 Ellis J.G. Cushing T. Germain A. Treating acute insomnia: a randomized controlled trial of a “single-shot” of cognitive behavioral therapy for insomnia Sleep 38 2015 971 978 10.5665/sleep.4752 25515106 PMC4434564
37 Dimidjian S. Hollon S.D. Dobson K.S. Schmaling K.B. Kohlenberg R.J. Addis M.E. Gallop R. McGlinchey J.B. Markley D.K. Gollan J.K. Atkins D.C. Dunner D.L. Jacobson N.S. Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the acute treatment of adults with major depression Journal of Consulting and Clinical Psychology 74 2006 658 670 10.1037/0022-006X.74.4.658 16881773
38 Dimidjian S. Barrera M. Martell C. Muñoz R.F. Lewinsohn P.M. The origins and current status of behavioral activation treatments for depression Annual Review of Clinical Psychology 7 2011 1 38 10.1146/annurev-clinpsy-032210-104535 21275642
39 Ekers D. Webster L. Straten A.V. Cuijpers P. Richards D. Gilbody S. Behavioural activation for depression; an update of meta-analysis of effectiveness and sub group analysis PLOS ONE 9 2014 e100100 10.1371/journal.pone.0100100 PMC4061095 24936656
40 Littner M. Kushida C.A. Anderson W.M. Bailey D. Berry R.B. Davila D.G. Hirshkowitz M. Kapen S. Kramer M. Loube D. Wise M. Johnson S.F. Practice parameters for the role of actigraphy in the study of sleep and circadian rhythms: an update for 2002 Sleep 26 2003 337 341 10.1093/sleep/26.3.337 12749556
41 Rumble M.E. Rose S.L. White K.H. Moore A.H. Gehrman P. Benca R.M. Costanzo E.S. Circadian actigraphic rest–activity rhythms following surgery for endometrial cancer: a prospective, longitudinal study Gynecologic Oncology 137 2015 448 455 10.1016/j.ygyno.2015.04.001 25906914 PMC4452033
42 Troiano R.P. Berrigan D. Dodd K.W. Mâsse L.C. Tilert T. McDowell M. Physical activity in the United States measured by accelerometer Med Sci Sports Exerc 40 2008 181 188 10.1249/mss.0b013e31815a51b3 18091006
43 Cella D. Riley W. Stone A. Rothrock N. Reeve B. Yount S. Amtmann D. Bode R. Buysse D. Choi S. Cook K. DeVellis R. DeWalt D. Fries J.F. Gershon R. Hahn E.A. Lai J.S. Pilkonis P. Revicki D. Rose M. Weinfurt K. Hays R. The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005–2008 Journal of Clinical Epidemiology 63 2010 1179 1194 10.1016/j.jclinepi.2010.04.011 20685078 PMC2965562
44 Liu H. Cella D. Gershon R. Shen J. Morales L.S. Riley W. Hays R.D. Representativeness of the patient-reported outcomes measurement information System internet panel Journal of Clinical Epidemiology 63 2010 1169 1178 10.1016/j.jclinepi.2009.11.021 20688473 PMC2943555
45 Rothrock N.E. Hays R.D. Spritzer K. Yount S.E. Riley W. Cella D. Relative to the general US population, chronic diseases are associated with poorer health-related quality of life as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Journal of Clinical Epidemiology 63 2010 1195 1204 10.1016/j.jclinepi.2010.04.012 20688471 PMC2943571
46 Hann D.M. Denniston M.M. Baker F. Measurement of fatigue in cancer patients: further validation of the fatigue symptom inventory Qual Life Res 9 2000 847 854 10.1023/A:1008900413113 11297027
47 Okun M.L. Kravitz H.M. Sowers M.F. Moul D.E. Buysse D.J. Hall M. Psychometric evaluation of the Insomnia Symptom Questionnaire: a self-report measure to identify chronic insomnia Journal of Clinical Sleep Medicine 5 2009 41 51 10.5664/jcsm.27391 19317380 PMC2637165
48 Watson D. O'Hara M.W. Simms L.J. Kotov R. Chmielewski M. McDade-Montez E.A. Gamez W. Stuart S. Development and validation of the inventory of depression and anxiety symptoms (IDAS) Psychological Assessment 19 2007 253 268 10.1037/1040-3590.19.3.253 17845118
49 Woolf B. On estimating the relation between blood group and disease Annals of Human Genetics 19 1955 251 253 10.1111/j.1469-1809.1955.tb01348.x 14388528
50 Larson A.G. Morris K.J. Juckett M.B. Coe C.L. Broman A.T. Costanzo E.S. Mindfulness, experiential avoidance, and recovery from hematopoietic stem cell transplantation Annals of Behavioral Medicine 53 2019 886 895 10.1093/abm/kay097 30624541 PMC6736040