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Abstract

Introduction:

Anxiety and dyspnea are 2 common symptoms for lung cancer survivors. Although research suggests decreasing respiration rate can reduce anxiety in several populations, potential benefits of device-guided breathing have not been studied in lung cancer survivors. This feasibility study (WF-01213) provides estimates of accrual, adherence, retention, and preliminary efficacy of 2 doses of a device-guided breathing intervention versus a usual breathing control group for improving self-reported anxiety and dyspnea in post-treatment lung cancer survivors.

Methods:

Stage I-IV lung cancer survivors were recruited through the NCI Community Oncology Research Program (NCORP) and randomized to 12 weeks of a device-guided breathing intervention (high dose vs. low dose) or control device. Self-reported outcomes (anxiety, depression, dyspnea, cancer-related worry, fatigue) were assessed at baseline, mid-intervention (Week-6), and post-intervention (Week-12).

Results:

Forty-six participants (ages 41-77, median = 65; 78% White) were randomized to the high-dose intervention (n = 14), low-dose intervention (n = 14), or control (n = 18) groups between July 2015 and September 2019. Study accrual rate was 0.92 per month for 50 months (projected accrual was 6.3/month). Fourteen participants (30%) withdrew early from the study, with almost half of those discontinuing at or immediately following baseline assessment. No participants were adherent with the intervention per protocol specifications. The proportion minimally adherent (using device at least 1x/week) was 43% (6/14), 64% (9/14), and 61% (11/18) for high-dose, low-dose, and control groups, respectively. Anxiety significantly decreased from baseline for all groups at Week 12. Adherence to the intervention was low across all treatment groups.

Conclusions:

This study did not establish feasibility of a community-based randomized trial of 2 doses of device-guided breathing and a control group using an identical-looking device for lung cancer survivors. In both the high-dose and control groups, there were significant improvements from baseline for anxiety and dyspnea. In the low-dose group, there were significant improvements from baseline for anxiety and depression. Ratings and feedback on the intervention were mixed (although leaned in a positive direction). Participants reported liking the feeling of relaxation/calm, helping others, breathing awareness, and music. Participants reporting liking least finding/making time to use the device, frustration with the device, and completing study forms.

Trial Registration: Clinical Trials ID:

NCT02063828, clinicaltrials.gov.

Keywords

anxiety dyspnea emotional distress lung cancer NCORP symptom management

Introduction

Anxiety is a significant and common problem for post-treatment lung cancer survivors,^1-6 significantly more so than depressive symptoms.^7,8 Compared with other cancer types, lung cancer survivors have the highest rates of psychological distress^9,10 and report a higher number of unmet psychological needs, including fears of recurrence, physical disability, or deterioration, difficulty making long-term plans, feeling dependent and helpless, and preoccupation with being ill.^10-12 Anxiety often increases in the year after lung cancer surgery,¹³ and studies have reported rates of clinically significant anxiety symptoms among lung cancer patients and post-treatment survivors ranging from 9% to 65%.^14-17

Anxiety commonly co-occurs with distressing physical symptoms in lung cancer survivors.^18-21 The correlation between self-reported anxiety and dyspnea (shortness of breath) is estimated at 0.30.²⁰ This relationship is bidirectional, reflecting affective and physiological processes.^19,22-25 The number of lung cancer patients reporting dyspnea at some stage in their illness ranges from 55% to 90%.^19,20,25-28 Estimates of dyspnea in post-treatment early stage lung cancer (ESLC) survivors range from 40% to 60%.^29,30 Thus, dyspnea commonly occurs with anxiety after lung cancer treatment and is associated with worse functioning in multiple domains, greater distress, and lower quality of life.^22,25,31-34

Breathing interventions have been effective at reducing anxiety and distress in several populations. Interventions focused on slow, deep breathing have decreased anxiety, stress symptoms, and physiological arousal in various groups including healthy adults, adults with elevated anxiety, and adults with chronic physical health issues (eg, chronic pain, cardiac disorders).^35-39 Relaxation training interventions (that include deep breathing components) show promise for relieving anxiety in cancer survivors.^4,40,41 Breathing exercises have also been incorporated into multi-modal interventions to address dyspnea in lung cancer survivors.^42,43 Such interventions have yielded limited, but promising results for anxiety and distress related to breathlessness in post-treatment lung cancer survivors.^44,45 Importantly, anxiety level has not been a criterion for study entry.

The present study sought to build on growing evidence for the efficacy of breathing interventions in cancer survivors through the use of the RESPeRATE device, which guides the user to reduce respiration rate and increase exhalation time.⁴⁶ RESPeRATE has FDA approval as an adjunctive treatment for hypertension. Positive outcomes, including improved cardiorespiratory fitness and quality of life, have been observed in heart failure patients, particularly in groups receiving longer treatment and in participants who were successful at increasing their inhalation/exhalation ratio (deemed “responders”).^47,48 However, these studies did not assess anxiety or other psychological outcomes.

This study was conducted through the Wake Forest National Cancer Institute Community Oncology Research Program (NCORP) Research Base (1UG1CA189824), a national network designed to increase community participation in cancer trials. This feasibility study aimed: (1) to estimate accrual, retention, and adherence to a device-guided breathing intervention versus a usual breathing control group in lung cancer survivors; and (2) to obtain intervention feedback and preliminary estimates of the variability and efficacy of 2 doses of a device-guided breathing intervention for reducing anxiety and improving dyspnea, cancer-related worry, and fatigue in lung cancer survivors.

Methods

Study Design

In this parallel, randomized, 3-arm feasibility study, participants with clinically significant anxiety symptoms were stratified by baseline self-reported dyspnea score and randomized with equal probability to a 12-week high-dose (2x/day) or low-dose (1x/day) device-guided breathing intervention versus a usual breathing control group (1x/day), using variable length permuted block randomization. The study was blinded at the participant and assessor level via color-coding the intervention devices. Measures were obtained at baseline (Week 0), mid-intervention (Week 6), and immediately post-intervention (Week 12). Institutional Review Boards at Wake Forest Baptist Health and the participating NCORP sites approved this study (WF-01213; NCT02063828). The study was registered with ClinicalTrials.gov (NCT02063828).

Eligibility Criteria

Eligibility included: (1) past history of any lung cancer; (2) 2 to 24 months post-completion of surgery, radiation therapy and/or chemotherapy with no further planned treatment during the 12-week study and no evidence of disease (Stage I-III) OR receiving no treatment or receiving maintenance treatment with a targeted agent, chemotherapy, or immunotherapy provided the most recent imaging did not demonstrate progressive disease (Stage IV); (3) score ≥8 on the anxiety subscale of the HADS-Anxiety/Depression Scale or score ≥4 on the Distress Thermometer or score ≥5 on the Modified Cancer Acceptance Scale; (4) ECOG performance status 0 to 2; (5) willing and able to attend a brief introductory session and use assigned device for the assigned period of time (15 minutes once or twice per day), at least 5 days/week for 12 weeks; (6) age ≥18; and (7) had a telephone. Participants were excluded if they: (1) did not understand English; (2) had an active lung infection; (3) had progressive cancer; (4) had any change in psychotropic medications in the past 30 days; or (5) had hearing loss that would preclude participating in interventions.

Recruitment

This study was conducted through the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base. Research staff across the participating NCORP sites tailored recruitment activities for clinic workflow and requirements. We have limited data about exactly which recruitment strategies were employed at each site, as the primary purpose of the trial was not to test recruitment strategies. Generally, they identified potentially eligible participants via screening registries/chart records or provider referrals. Recruitment posters and letters were also provided to sites to encourage participant inquiry. Participants were approached at time of appointment or by phone for anxiety/distress eligibility screening and to confirm other eligibility criteria. Incentives were not provided for participating in this study.

Data Collection

All questionnaires were administered and collected by a research staff person blinded to group assignment at each site. Patient-reported outcomes were collected from participants at baseline, Week 6, and Week 12. Each week, site coordinators contacted participants by phone to assess use of the device, collect device data and pre-post session ratings, and answer questions/troubleshoot. At Week 12, participants were seen in clinic to collect final device data and return the device.

RESPeRATE Intervention

Site coordinators were trained to use the RESPeRATE devices at in-person annual meetings or site calls as needed. Detailed instructions were given to each site coordinator on how to use the device, how to view and record the values saved on the device and clear its memory. Telephone and e-mail support were offered in addition to bi-monthly site calls. At the baseline visit, the site coordinator provided a demonstration on how to use the device and assist the participant with its first use. Detailed device instructions with pictures and troubleshooting were also given to each participant based on group assignment (ie, RESPeRATE intervention or control group). The participant was also given the site coordinator name and contact information for assistance, if needed.

The RESPeRATE device constantly synchronizes and automatically adjusts the melody/tones to the person’s breathing pattern detected via a sensor around the mid-section to reduce breaths per minute by prolonging exhalation (device pictured at www.resperate.com). Respiration rate is reduced by asking the person to breathe in conjunction with the gentle tones audible through earphones; the rate of the tones starts at the person’s initial respiration rate and then gradually slows down. For the low-dose group, participants were instructed to use the RESPeRATE device for 15 minutes once a day, 5 days/week for 12 weeks, based on previous research that found this dose to be effective in reducing blood pressure.^49-51 For the high-dose group, participants were instructed to use the RESPeRATE device for 15 minutes twice a day, 5 days/week for 12 weeks, similar to the dose used in previous research conducted with other clinical populations with significant respiratory symptoms.^47,48 The device automatically records use, initial respiration rate, and final respiration rate. Information from the devices was retrieved to measure intervention adherence.

Usual Breathing Control Group

For the control group, participants used an identical control device (with non-rhythmical tones that do not gradually slow down to reduce respiration rate) for 15 minutes once per day, at least 5 days/week over 12 weeks.

Measures

Demographic information collected at baseline included age, race/ethnicity, marital/partner status, education, and income. Clinical information obtained from medical records included date and stage of lung cancer diagnosis, treatment regimen, and current medications.

Feasibility measures calculated at the end of the trial included: (1) accrual, calculated by the number of participants accrued divided by the months of accrual. (2) Retention was obtained by tracking the number of participants who completed the final assessment divided by the number randomized. (3) Adherence was calculated as the number of sessions completed divided by the number prescribed, with successful adherence defined as completing ≥75% of prescribed sessions. (4) Minimally adherent, defined as the proportion of participants who used the RESPeRATE device to reach specified breathing parameters at least once a week for 5 out of 6-week intervals or 9 out of the 12 weeks of the total study intervention.

Patient-reported outcome measures collected at baseline, 6, and 12 weeks included: (1) Hospital Anxiety and Depression Scale-Anxiety (HADS),^52-54 a 14-item self-report measure of cognitive and behavioral symptoms of anxiety and depression; clinically significant symptoms are indicated by a total score of ≥8 for the anxiety and depression subscales. (2) Cancer Dyspnea Scale (CDS)^20,55 is a 12-item self-report measure of multidimensional (subscales include sense of effort, sense of anxiety, discomfort) nature of dyspnea that is reliable and valid in lung cancer survivors. Total score indicating clinically significant dyspnea is ≥8. The CDS was selected as an optimal measure of dyspnea since it assesses multiple symptom components and is validated for use in cancer survivors. (3) The Cancer Worry Scale (CWS)⁵⁶ is an 8-item measure used to assess concerns about developing cancer or developing cancer again and how these concerns impact daily functioning among at-risk individuals. Items are rated on a 4-point Likert scale from “never” to “almost always” with scores ranging from 8 to 32. Higher scores indicate more worry/concern.⁵⁶ (4) The PROMIS Fatigue – Short Form 7a⁵⁷ is a 7-item self-report measure of fatigue rated 1 = never, 2 = rarely, 3 = sometimes, 4 = often, and 5 = always. The 7 items measure both experience of fatigue and how fatigue impacts daily activities over the past week. Scores range from 7 to 35, with higher scores indicating greater fatigue. (5) Visual Analog Scales (VAS) for anxiety, distress, and dyspnea^58-60 are symptom intensity ratings using scales from 0 (none) to 10 (extreme). VAS ratings are quick and simple for repeated measurement of acute intervention effects. By comparing VAS ratings before and after an intervention, a VAS change score can be calculated and interpreted with a range from −10 (largest possible improvement) to 10 (worst possible decline).

Intervention feedback

Participants provided feedback regarding the intervention at Week 12 and rated their experience with the device from 0 = not at all to 4 = very much for the following items: (1) I liked using the breathing device; (2) The breathing device was helpful to me; (3) I plan to start or continue to practice another type of relaxation technique; (4) The instructions were easy to understand; and (5) Using the breathing device was enjoyable. Participants also responded to the following open-ended items to provide feedback on their experience: (1) What did you like best about participating in this study and using the breathing device?; (2) What did you like least about participating in this study and using the breathing device?; (3) What did you learn from using the breathing device?; (4) What other suggestions would you make to improve this program?; and (5) Please share any other thoughts and comments about your participation in the study. Responses to these open-ended questions (ie, likes, dislikes, and skills learned as a result of using the breathing device) were grouped by common themes in the responses.

Statistical Considerations

Sample size was based on statistical selection theory and was designed to pick the “best” regimen based on the outcome of self-reported anxiety.⁶¹ Simulations showed 20 participants per group provided 90% probability that the best regimen to move forward to a phase III trial would be chosen if the mean in that group was at least 0.5 SD lower than the mean in the control arm. Assuming a 20% dropout, the study planned to enroll a total of 75 participants. Assuming no effect of the RESPeRATE device, there is a 90% probability of stopping with the phase II trial and not moving on to a larger trial.

Baseline characteristics were summarized using median (range) and count (percent) for continuous and categorical variables respectively. Distributions by low-dose, high-dose, and control groups were contrasted using χ² test (Fischer’s Exact Test, when appropriate) for baseline variables and overall rates of retention and adherence. Patient-reported outcomes of anxiety, dyspnea, cancer worry, and fatigue were calculated as the change from baseline. These change outcomes were assessed by repeated measure linear models adjusting for baseline dyspnea stratification, baseline outcome score, intervention group, repeated assessments at Weeks 6 and 12, and the interaction of group by time with an assumed unstructured covariance. All analyses were conducted as intention to treat. Adherence and compliance outcomes assumed if data were missing that the participant was not compliant or adherent for that given period of time; differences in these outcomes were assessed by Kruskal Wallis tests. Due to the pilot nature of this study, significant differences from baseline and by group were considered for P < .05. All analyses were conducted using SAS v9.4.

Results

Participant Characteristics

Forty-six participants were accrued between July 30, 2015 and June 11, 2019, and the trial was discontinued in December 2019 due to slow accrual. A total of 14 participants were randomized to the high-dose group, 14 participants were randomized to the low-dose group, and 18 to the control group (Figure 1). Table 1 summarizes baseline characteristics of the sample. Ages ranged from 41 to 77 (median = 65) years. The majority were White (78%), non-Hispanic (100%), married (63%), and non-smokers (78%). Slightly half of the participants (56%) were stage III or IV lung cancer survivors, and most had an ECOG status of 0 or 1 (89%). There were no significant group differences across any demographic or clinical characteristics.

Figure 1.

CONSORT diagram.

Table 1.

Baseline Characteristics of Participants with Lung Cancer and Anxiety Enrolling on a Device-Guided Breathing Intervention Trial (N = 46).

Characteristic	High dose (n = 14)	Low dose (n = 14)	Control (n = 18)
Characteristic	n (%)	n (%)	n (%)
Female sex	12 (86)	10 (71)	13 (72)
Age
Median (range)	64 (41-77)	63 (45-76)	66 (43-74)
≥50 years, %	11 (79)	13 (93)	17 (94)
Dyspnea ≥8, %^a	8 (57)	8 (57)	9 (50)
Race
White	12 (86)	10 (71)	14 (78)
Black	1 (7)	3 (21)	2 (11)
Asian	0 (0)	0 (0)	1 (6)
Mixed	1 (7)	0 (0)	1 (6)
Unknown	0 (0)	1 (7)	0 (0)
Marital status
Single	0 (0)	0 (0)	0 (0)
Married	8 (57)	8 (57)	13 (72)
Separated/Divorced/Widowed	6 (43)	6 (43)	2 (11)
Household income
Under $20k	2 (14)	4 (29)	6 (33)
$20K-$49 999	5 (36)	5 (36)	8 (44)
$50K+	5 (36)	2 (14)	2 (11)
Unknown	2 (14)	3 (21)	2 (11)
Education
High school or less	0 (0)	2 (14)	1 (6)
BA/BS/some college	9 (64)	10 (71)	13 (72)
Post college work	5 (36)	2 (14)	4 (22)
Stage of disease
I	6 (43)	2 (14)	7 (39)
II	1 (7)	2 (14)	2 (11)
III	4 (29)	3 (21)	1 ( 6)
IV	3 (21)	7 (50)	8 (44)
ECOG performance status
0	6 (43)	6 (43)	6 (33)
1	7 (50)	8 (57)	8 (44)
2	1 ( 7)	0 ( 0)	4 (22)
Current smoker	4 (29)	2 (14)	4 (22)

Total score on the Cancer Dyspnea Scale of ≥8 indicates clinically significant dyspnea symptoms.^20,55

Feasibility Measures

Accrual

The accrual plan was to recruit 75 lung cancer survivors through at least 12 study sites. Accrual was estimated to be completed in 12 months with an accrual rate of 6.3 participants accrued/month. Overall, 205 subjects were screened between July 2015 and September 2019 at 11 study sites. Of the 205 screened, 76 (37%) were deemed eligible, with 46 (22%) enrolled into the study at an accrual rate of 0.92 per month over 50 months.

Retention

Fourteen participants (30%) withdrew from the study (Table 2), with 6 (13%) discontinuing at or immediately after baseline assessment. Overall retention did not statistically differ by group (P = .45). Six (43%) high-dose participants did not complete the study (n = 3 at/immediately after baseline assessment; n = 2 before Week 6; n = 1 before Week 12). Three were lost to follow-up, 2 had feelings of being overwhelmed, and one did not have time after a death in the family. Four (29%) low-dose participants withdrew from the study (n = 2 at/immediately after baseline assessment; n = 1 before Week 6; n = 1 before Week 12). Of the four, two felt overwhelmed and 2 reported increased anxiety. Four (22%) control participants did not complete the study (n = 1 at baseline; n = 3 before Week 6). Of the four, two were non-compliant, one did not like the study assessment. One participant enrolled and then subsequently died before any baseline activities occurred and never started using the device.

Table 2.

Retention of Participants With Lung Cancer by Device-Guided Breathing Treatment Group over 12 Weeks (N = 46).

Adherence

Protocol specified adherence was calculated as the actual number of times the device was used divided by the prescribed times with successful adherence defined as completing ≥75% of prescribed sessions. No participants in any group had successful adherence with the intervention. Minimally adherent was defined by reaching specified breathing parameters at least once a week for 5 out of 6-week intervals or 9 out of the 12-week total study intervention. The low-dose group had the largest proportion of adherent participants (12/14; 86%) for Weeks 1 to 6. The high-dose group had the lowest proportion adherent (7/14; 50%). During Weeks 7 to 12, no participant met the pre-defined minimally adherent definition regardless of randomized group. Across all weeks, the low-dose had the highest proportion of minimally adherent participants (9/14; 64%). The proportions in the high-dose and control groups were 43% (6/14) and 61% (11/18), respectively. There was no significant difference in the proportion adherent between the arms (P = .46).

Patient-Reported Outcomes

For the patient-reported outcomes (Table 3), change from baseline at Weeks 6 and 12 was calculated within each group. Negative changes in scores from baseline represent an improvement in the outcome of interest. Several outcomes had a statistically significant within-group difference from baseline (P < .05). For the high-dose group, there were significant improvements in HADS-Anxiety from baseline at Weeks 6 (mean −2.38) and 12 (mean −2.10), CDS total dyspnea (Week 6 = −6.38; Week 12 = −5.78), CWS at Week 12 only (−3.16), and PROMIS fatigue at Week 12 (−4.29). For the low-dose group, there were improvements from baseline at Week 12 for HADS-Anxiety (−2.27) and HADS-Depression (−2.32). For controls, there were significant improvements in HADS-Anxiety at both time points (Week 6 = −1.75; Week 12 = −1.89) and CDS total dyspnea at Week 6 (−2.81).

Table 3.

Patient-reported Outcomes among Participants with Lung Cancer by Device-Guided Breathing Intervention Group.

	Week	Baseline (Week 0) andChange from Baseline (Weeks 6, 12)
	Week	High-Dose	Low-Dose	Control
HADS Anxiety	Baseline	12.23 (4.3)	7.86 (4.1)	8.28 (3.0)
	Change from baseline at Week 6	−2.38* (−4.34,−0.43)	−1.22 (−2.90,0.45)	−1.75* (−3.21,−0.29)
	Change from baseline at Week 12	−2.10* (−3.74,−0.45)	−2.27* (−3.55,−0.99)	−1.89* (−3.01,−0.77)
HADS Depression	Baseline	8.85 (4.8)	6.43 (3.2)	5.50 (3.1)
	Change from baseline at Week 6	−0.71 (−2.89,1.46)	−1.75 (−3.65,0.15)	0.23 (−1.46,1.92)
	Change from baseline at Week 12	−1.88 (−4.02,0.26)	−2.32* (−4.07,−0.58)	−0.41 (−1.97,1.14)
CDS (total dyspnea)	Baseline	11.79 (9.4)	9.07 (5.6)	10.22 (10.7)
	Change from baseline at Week 6	−6.38* (−9.92,−2.84)	0.15 (−3.10,3.41)	−2.81* (−5.61,−0.008)
	Change from baseline at Week 12	−5.78* (−9.83,−1.74)	−1.68 (−5.37,2.01)	−2.67 (−5.77,0.43)
Cancer Worry Scale (CWS)	Baseline	23.82 (5.2)	18.45 (6.1)	18.63 (6.2)
	Change from baseline at Week 6	−0.80 (−3.16,1.55)	−0.41 (−2.61,1.80)	−0.53 (−2.37,1.31)
	Change from baseline at Week 12	−3.16* (−5.40,−0.91)	−0.83 (−2.95,1.29)	−1.18 (−2.85,0.50)
PROMIS Fatigue	Baseline	21.25 (2.9)	19.31 (3.8)	21.65 (5.8)
	Change from baseline at Week 6	−0.76 (−3.33,1.81)	0.42 (−1.93,2.78)	−1.71 (−3.75,0.34)
	Change from baseline at Week 12	−4.29* (−6.79,−1.80)	0.63 (−1.67,2.93)	−0.28 (−2.19,1.64)

Baseline scores reported as M (SD) and were adjusted as a covariate in each model. Change and difference scores reported as least-squares mean (95% CI). Number of available data at each time point by group is displayed in Figure 1. Sample sizes may vary slightly (no more than 1) due to missing data of specific outcomes at each time point.

Indicates statistically significant within-group difference from baseline.

Considering between-group contrasts among the patient-reported outcomes, PROMIS Fatigue was the only outcome with significant differences by group (P = .008). The high-dose group improved significantly more than both the low-dose and control groups at Week 12 for PROMIS Fatigue (high = −4.29, low = 0.63, control = −0.28, pairwise comparisons both P < .01).

Comparing average change in pre-post VAS measures across the groups (Table 4), only VAS Emotional Distress across Weeks 1 to 6 showed a significant difference (P = <.01) with the high-dose group showing larger improvements. There were not adequate data beyond Week 6 for comparison.

Table 4.

Average Change in Pre/Post Visual Analog Scale (VAS) Outcomes among Device Guided Breathing Intervention Trial Participants (N = 37).

Measure	Weeks	Average Change in Pre-PostN (median) (min, max)			P-value
Measure	Weeks	High Dose	Low Dose	Control	P-value
VAS anxiety	Weeks 1-6	10 (−2.33) (−5.00,0.17)	12 (−0.92) (−1.83,1.00)	15 (−0.83) (−4.17,0.00)	.07
VAS dyspnea	Weeks 1-6	10 (−1.25) (−3.33,0.00)	12 (−0.67) (−3.00,3.00)	15 (−0.33) (−2.33,0.67)	.07
VAS emotional distress	Weeks 1-6	10 (−1.04) (−3.50,−0.08)	12 (−0.11) (−1.17,5.00)	15 (−0.19) (−2.00,0.00)	<.01

A negative difference in a specific VAS outcome represents an improvement in anxiety, dyspnea, or emotional distress for the outcome of interest.

Intervention Ratings and Feedback

On all rated items, more than 47% of participants in all groups provided favorable ratings of “quite a bit” or “very much.” Unfavorable (“not at all”/“a little bit”) participant ratings were rare and comparable between groups with all rated items receiving <28% negative ratings. Participants in the high and low dose intervention groups were less likely to report favorable ratings than control participants for “I liked using the breathing device.” (25%, 25%, and 50%, respectively), but more likely to report favorable ratings for “Using the breathing device was enjoyable” (62.5%, 62.5%, and 35.7%, respectively). Responses to open-ended feedback questions are summarized in Table 5. The most common responses for what participants liked best were the feeling of relaxation/calm, helping others, breathing awareness, and music. The most common responses for what they liked least were finding/making time to use the device, frustration with the device, and completing study forms. The responses re: frustration with the device included comments about the elastic belt that needed to be positioned around the abdomen, having to “hook everything up” to use it, and having to reposition the sensor due to the “touchiness” of the device.

Table 5.

Intervention Feedback From Open-Ended Questions (n = 33 Completed This Form).

	# Reporting	High-dose	Low-dose	Control
What did you like best about participating in this study and using the breathing device?
Relaxation/calm	13 (38.2)	3 (42.9)	3 (30.0)	7 (41.2)
Helping others	5 (14.7)	0 (0)	2 (20.0)	3 (17.6)
Breathing shift/awareness	3 (8.8)	1 (14.3)	0 (0)	2 (11.8)
Music	3 (8.8)	0 (0)	1 (10.0)	2 (11.8)
Doing something useful for myself	2 (5.9)	0 (0)	1 (10.0)	1 (5.9)
Help with anxiety	2 (5.9)	1 (14.3)	1 (10.0)	0 (0)
Clear mind	1 (2.9)	0 (0)	0 (0)	1 (5.9)
Learning about the device	1 (2.9)	0 (0)	1 (10.0)	0 (0)
Time to be still	1 (2.9)	0 (0)	0 (0)	1 (5.9)
What did you like least about participating in this study and using the breathing device?
Finding/making time	14 (41.2)	4 (44.4)	3 (30.0)	7 (46.7)
Struggle/irritation with device	8 (23.5)	2 (22.2)	2 (20.0)	4 (26.7)
Study forms	2 (5.9)	2 (22.2)	0 (0)	0 (0)
Boring	1 (2.9)	0 (0)	1 (10.0)	0 (0)
Chore	1 (2.9)	0 (0)	0 (0)	1 (6.7)
Music	1 (2.9)	0 (0)	0 (0)	1 (6.7)
What did you learn from using the breathing device?
Relaxation/calm	16 (41.0)	6 (60.0)	5 (35.7)	5 (33.3)
Breathing shift/awareness	11 (28.2)	2 (20.0)	4 (28.6)	5 (33.3)
Importance of taking time	6 (15.4)	1 (10.0)	1 (7.1)	4 (26.7)

Discussion

This study did not establish feasibility of a community-based randomized trial of 2 doses of device-guided breathing and a control group (using an identical-looking device) for lung cancer survivors. The accrual target was 60 participants; this study accrued 46 participants over a nearly 4-year period (0.92 participants/month). Despite a large research network, it was very challenging to accrue participants to this study. Estimates from study sites suggested that they anticipated being able to enroll at least 1 participant every 1 to 2 months. To be conservative, our accrual target was at the low end of this estimate (6/month). Coordinators reported that it was difficult to identify lung cancer survivors who likely met screening criteria. Several eligibility criteria are not easily queried from the electronic medical record (eg, completion of treatment, no evidence of or stable disease, clinically significant distress), which made chart screening laborious. Identifying cancer survivors with clinically meaningful symptoms for intervention research is also challenging in the absence of routine patient-reported outcome monitoring.

We also saw difficulties with adherence and retention; 30% of participants withdrew from the study early. There were no participants who used the device at a rate that would be considered adherent as defined in the protocol (using the device ≥75% of the prescribed sessions). Minimal adherence defined as reaching specified breathing parameters at least once a week for 9 of 12 weeks, was limited at 43%, 64%, and 65% of participants for high-dose, low-dose, and control groups, respectively. Data from the device proved difficult to interpret. The bottom line is that adherence was quite poor. Similarly, another study intervening on caregivers of allogeneic hematopoietic stem cell transplant patients, showed that only 16% of caregivers had consistent weekly use of the RESPeRATE device throughout the intervention phase.⁶²

The impact of the intervention arms on patient-reported outcomes was mixed. We observed decreases in anxiety for all 3 groups at Week 12, suggesting a lack of specific treatment effects. Improvements in dyspnea, worry, fatigue, and VAS emotional distress appeared to favor the high-dose group compared to the low-dose and control groups. Intervention feedback was also mixed, yet trended toward more positive than negative feedback. Approximately half of participants in all groups provided favorable ratings of their randomly assigned intervention. Clearly, many participants (per their ratings and comments) found the intervention useful, yet a substantial minority did not. Interestingly, despite the adherence challenges, many of the comments were quite positive. Observationally, if participants used the device, many of them really liked it. It is possible that pre-intervention behavioral session(s) providing more guidance about using the device and identifying facilitators/barriers to its use would be immensely helpful.

A strength of this randomized feasibility study is inclusion of a control group that offered an inactive intervention using a device that looked identical to the actual intervention devices and blinding of study staff who collected outcomes data to group assignment. A primary limitation of this study is the small sample size and great difficulty with recruitment. As a feasibility study, it lacked power to make definitive conclusions about intervention efficacy for lung cancer survivors. Another limitation is the lack of a usual-care control group. The control device also encouraged participants to sit quietly and focus on their breathing and thus may have had some active effects. Including such a group in future research would help to determine whether the interventions prevented an exacerbation of symptoms and to estimate non-specific intervention effects. The relatively low rates of device use across the 3 study groups also make it challenging to interpret the findings, especially between the high- and low-dose groups. Additionally, we did not collect comorbidity data as part of this protocol so cannot speak to how many had chronic obstructive pulmonary disease (COPD) in the cohort, which could also contribute to dyspnea and fatigue. Importantly, accrual for this study largely happened prior to widespread uptake of immunotherapy.

Future research should carefully consider strategies for identifying potentially eligible cancer survivors that minimize burden on research staff and referring providers. Future studies may also consider expanding eligibility criteria to which this approach may also be beneficial (eg, lung cancer patients undergoing active treatment). Additional strategies to support cancer survivors in using the RESPERATE device successfully are likely needed. A stronger supportive component might include helping participants plan when and how to use the device, discussing potential barriers to using it, and offering a designated person “on call” to assist with device difficulties so participants can address any frustrations in real time. Additionally, creative strategies to boost interest and engagement in the device may include developing introductory materials (eg, brief video) that incorporates positive testimonials from other lung cancer survivors who have benefited from the device or sending brief text reminders to use the device. Further, incorporating feedback from patient stakeholders into the design and conduct of future studies would be extremely helpful to address issues with recruitment and adherence. It may also be important to compare various deep breathing strategies (device vs recorded instruction) to compare acceptability. Also, ensuring that there is a straightforward way to reliably capture adherence data is critical. There was much interest in this study and use of the devices from oncology clinicians, some of whom suggested that targeting other types of cancer survivors would likely yield much greater feasibility.

Conclusions

The mixed feedback on the device-guided breathing intervention, low adherence to prescribed sessions, and modest enrollment rates of eligible lung cancer survivors (61%) suggest a lack of fit of the device-guided breathing intervention with the lung cancer survivor population. The lung cancer survivors enrolled in this trial likely had more distress and overall emotional and physical symptoms compared with the patients with hypertension enrolled on prior RESPERATE trials.^46-51 While the trial did not reach pre-specified feasibility metrics, it is possible that more intensive efforts to support lung cancer survivors in successfully using the device and overcoming schedule and other barriers might improve adherence, retention, and intervention feedback. It is not known whether an enhanced intervention might prove to be more successful in a different population of cancer survivors.

Footnotes

Acknowledgements

We are grateful to the cancer survivors who participated in this study and the staff members at each participating NCORP site. This work would not have been possible without them. We acknowledge the following NCORP sites and PIs for their participation: Delaware/Christiana Care NCORP, Metro Minnesota Community Oncology Research Consortium, NCORP of the Carolinas (Greenville Health System NCORP), Southeast Clinical Oncology Research Consortium NCORP, Wake Forest NCORP Research Base, Wichita NCORP, and Upstate Carolina Consortium Community Oncology Research Program. Additionally, we would like to thank Wake Forest NCORP Research Base staff members Karen Craver, Tammy Vogler, and Rhonda Kimball for their efforts on behalf of this study and study participants.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this project was provided by the National Cancer Institute [5R21CA182111-02, PI: Danhauer] and [1UG1CA189824, MPIs: Lesser & Weaver].

ORCID iDs

Suzanne C. Danhauer

Chandylen L. Nightingale

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Reducing Anxiety and Dyspnea via Device-Guided Breathing (RELAX): A Multi-Site Feasibility Study in Post-Treatment Lung Cancer Survivors at Community Cancer Clinics (WF-01213)

Abstract

Introduction:

Methods:

Results:

Conclusions:

Trial Registration: Clinical Trials ID:

Keywords

Introduction

Methods

Study Design

Eligibility Criteria

Recruitment

Data Collection

RESPeRATE Intervention

Usual Breathing Control Group

Measures

Intervention feedback

Statistical Considerations

Results

Participant Characteristics

Feasibility Measures

Accrual

Retention

Adherence

Patient-Reported Outcomes

Intervention Ratings and Feedback

Discussion

Conclusions

Footnotes

Acknowledgements

Declaration of Conflicting Interests

Funding

ORCID iDs

References