BREATH: Web-Based Self-Management for Psychological Adjustment After Primary Breast Cancer-Results of a Multicenter Randomized Controlled Trial

Abstract

Purpose:
Early breast cancer survivors (BCSs) report high unmet care needs, and easily accessible care is not routinely available for this growing population. The Breast Cancer E-Health (BREATH) trial is a Web-based self-management intervention to support the psychological adjustment of women after primary treatment, by reducing distress and improving empowerment.

Patients and methods:
This multicenter, randomized, controlled, parallel-group trial evaluated whether care as usual (CAU) plus BREATH is superior to CAU alone. BREATH is delivered in sixteen fully automated weekly modules covering early survivorship issues. Two to 4 months post-treatment, BCSs were randomly assigned to receive CAU + BREATH (n = 70) or CAU alone (n = 80) using a stratified block design (ratio 1:1). Primary outcomes were distress (Symptom Checklist-90) and empowerment (Cancer Empowerment Questionnaire), assessed before random assignment (baseline, T0) and after 4 (T1), 6 (T2), and 10 months (T3) of follow-up. Statistical (analysis of covariance) and clinical effects (reliable change index) were tested in an intention-to-treat analysis (T0 to T1). Follow-up effects (T0 to T3) were assessed in assessment completers.

Results:
CAU + BREATH participants reported significantly less distress than CAU-alone participants (-7.79; 95% CI, -14.31 to -1.27; P = .02) with a small-to-medium effect size (d = 0.33), but empowerment was not affected (-1.71; 95% CI, 5.20 to -1.79; P = .34). More CAU + BREATH participants (39 of 70 [56%]; 95% CI, 44.1 to 66.8) than CAU-alone participants (32 of 80 [40%]; 95% CI, 30.0 to 51.0) showed clinically significant improvement (P = .03). This clinical effect was most prominent in low-distress BCSs. Secondary outcomes confirmed primary outcomes. There were no between-group differences in primary outcomes during follow-up.

Conclusion:
Access to BREATH reduced distress among BCSs, but this effect was not sustained during follow-up.

Full text

BREATH: Web-Based Self-Management for Psychological
Adjustment After Primary Breast Cancer—Results of a
Multicenter Randomized Controlled Trial
Sanne W. van den Berg, Marieke F.M. Gielissen, José A.E. Custers, Winette T.A. van der Graaf,
Petronella B. Ottevanger, and Judith B. Prins
All authors: Radboud university medical
center, Nijmegen, the Netherlands.
Published online ahead of print at
www.jco.org on July 13, 2015.
Supported by Pink Ribbon, the Nether-
lands (Grant No. 2009-2013).
Presented at the International Psycho-
Oncology Society 15th World Congress
of Psycho-Oncology, Rotterdam, the
Netherlands, November 6-8, 2013; and
at the 13th International Congress of
Behavioral Medicine, Groningen, the
Netherlands, August 20-23, 2014.
The study sponsor had no role in the
study design, data collection, analysis
and interpretation of data, writing of the
report, or decision to submit the paper
for publication. The authors had full
access to all data and had final respon-
sibility for the decision to submit for
publication.
Authors’ disclosures of potential
conflicts of interest are found in the
article online at www.jco.org. Author
contributions are found at the end of
this article.
Corresponding author: Sanne W. van
den Berg, MSc, Radboud university
medical center, Department of Medical
Psychology (840), PO Box 9101, 6500
HB Nijmegen, the Netherlands; e-mail:
sanne.vandenberg@radboudumc.nl.
© 2015 by American Society of Clinical
Oncology
0732-183X/15/3399-1/$20.00
DOI: 10.1200/JCO.2013.54.9386
ABSTRACT
Purpose
Early breast cancer survivors (BCSs) report high unmet care needs, and easily accessible care is
not routinely available for this growing population. The Breast Cancer E-Health (BREATH) trial is a
Web-based self-management intervention to support the psychological adjustment of women
after primary treatment, by reducing distress and improving empowerment.
Patients and Methods
This multicenter, randomized, controlled, parallel-group trial evaluated whether care as usual (CAU)
plus BREATH is superior to CAU alone. BREATH is delivered in sixteen fully automated weekly
modules covering early survivorship issues. Two to 4 months post-treatment, BCSs were
randomly assigned to receive CAU ⫹BREATH (n ⫽70) or CAU alone (n ⫽80) using a stratified
block design (ratio 1:1). Primary outcomes were distress (Symptom Checklist-90) and empower-
ment (Cancer Empowerment Questionnaire), assessed before random assignment (baseline, T0)
and after 4 (T1), 6 (T2), and 10 months (T3) of follow-up. Statistical (analysis of covariance) and
clinical effects (reliable change index) were tested in an intention-to-treat analysis (T0 to T1).
Follow-up effects (T0 to T3) were assessed in assessment completers.
Results
CAU ⫹BREATH participants reported significantly less distress than CAU-alone participants
(⫺7.79; 95% CI, ⫺14.31 to ⫺1.27; P⫽.02) with a small-to-medium effect size (d⫽0.33), but
empowerment was not affected (⫺1.71; 95% CI, 5.20 to ⫺1.79; P⫽.34). More CAU ⫹BREATH
participants (39 of 70 [56%]; 95% CI, 44.1 to 66.8) than CAU-alone participants (32 of 80 [40%];
95% CI, 30.0 to 51.0) showed clinically significant improvement (P⫽.03). This clinical effect was
most prominent in low-distress BCSs. Secondary outcomes confirmed primary outcomes. There
were no between-group differences in primary outcomes during follow-up.
Conclusion
Access to BREATH reduced distress among BCSs, but this effect was not sustained during
follow-up.
J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
INTRODUCTION
Women diagnosed with breast cancer face chal-
lenges that do not end with treatment completion.
The first year after primary treatment, the so-called
re-entry phase,
1
is characterized by physical, emo-
tional, and social recovery.
2
Women report high
unmet care needs
3
and have to cope with lingering
physical and emotional symptoms of treatment, fear
of recurrence, decreasing social support, losing the
safety net of care providers, and resuming profes-
sional and recreational activities.
2,4-6
Approximately
70% of breast cancer survivors (BCSs; ie, women
who have completed primary breast cancer treat-
ment with no evidence of recurrence
7
) adjust well
during the re-entry phase, but a substantial propor-
tion report high levels of distress.
8,9
Better diagnosis and therapy mean that more
women survive breast cancer, and self-management
strategies
10
and e-health
11
have been proposed as
ways to support this growing population. Because
approximately half of all BCSs already search the
Internet for breast cancer–specific information,
12-15
the Internet is promising for providing psycho-
oncological interventions.
16
However, there are few
randomized controlled trials (RCTs) of Web-based
interventions to support re-entry adjustment. To
date, most Web-based interventions including
JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT
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women with breast cancer have not been either re-entry specific
17-20
or
breast cancer specific,
21,22
or have predominantly focused on peer
support groups
23-26
or informational support.
27
In a recent overview
advocating re-entry specific care, Stanton
2
reported promising but
inconclusive evidence from seven RCTs that psychoeducational inter-
ventions can be effective in BCSs.
We developed the Breast Cancer E-Health (BREATH) trial,
28
a
Web-based self-management intervention on the basis of cognitive
behavioral therapy that provides early BCSs with self-management
skills to enable them to take control of, and adjust to, post-treatment
survivorship. The intervention was developed using the transactional
model of stress
29
and the model of psychological well-being in cancer
survivors,
30
both of which describe negative and positive outcomes in
adapting to a stressor. Thus, the primary aim of this RCT was to study
whether care as usual (CAU) plus BREATH (CAU ⫹BREATH) can
effectively target negative and positive adjustment. We hypothesized
that CAU ⫹BREATH is superior to CAU alone in reducing distress
and improving empowerment. Because BCSs exhibit different levels
of distress during the re-entry phase, subhypotheses were that CAU ⫹
BREATH would reduce distress in high-distress BCSs, keep levels of
distress low in low-distress BCSs, and improve empowerment in both
distress groups.
PATIENTS AND METHODS
Study Design and Participants
The BREATH study protocol has been published elsewhere.
28
We conducted a multicenter, randomized, controlled, parallel-
group trial to evaluate the efficacy of a Web-based self-
management intervention in facilitating psychological adjustment
among BCSs. One university hospital and five regional hospitals in
the Netherlands participated (Fig 1). Female BSCs were eligible if
they had a histologically proven malignancy of the breast and had
completed curative-intent primary treatment (defined as surgery
plus adjuvant chemotherapy and/or radiotherapy) 2 to 4 months
before the baseline assessment. Participant characteristics are listed
in Table 1.
The local treatment team monitored patient recruitment and
eligibility and obtained informed consent. A researcher (S.v.d.B.)
contacted participants to check additional eligibility criteria: un-
derstanding the Dutch language, access to the Internet, and having
an e-mail address.
Study assessments covered the first year after breast cancer, with
baseline at 2 to 4 months after completion of primary treatment (T0),
and follow-up assessments at 4 (T1), 6 (T2), and 10 (T3) months after
Women with primary breast cancer were
referred from participating centers and met
eligibility criteria
(N = 170)
Completed baseline T0 and
were randomly allocated
(n = 151)
Excluded (metastases) (n = 1)
Lost to 4 months (n = 8) Lost to 4 months (n = 9)
Declined to participate
Intervention did not meet
participants’ needs
Time investment
Assessments too confronting
Web-based nature of intervention
Participation in other trials
Unknown
(n = 19)
(n = 6)
(n = 5)
(n = 4)
(n = 2)
(n = 1)
(n = 1)
(34 RUMC; 45 RS; 24 SL; 24 CWZ; 18 ZGV; 6 JBZ)
Randomly allocated to
CAU + BREATH
(n = 70)
Randomly allocated to
CAU alone
(n = 80)
Completed T1 assessment
at 4 months
(n = 62)
Intention-
to-treat analysis
(n = 150)
Completed T1 assessment
at 4 months
(n = 71)
Completed T2 assessment
at 6 months
(n = 62)
Completed T2 assessment
at 6 months
(n = 73)
Completed T3 assessment
at 10 months
(n = 63)
Assessment completers
analysis (58 CAU +
BREATH; 66 CAU)
(n = 124)
Completed T3 assessment
at 10 months
(n = 72)
Fig 1. Trial profile. BREATH, Breast
Cancer E-Health intervention; CAU, care
as usual; CWZ, Canisius-Wilhelmina Hos-
pital, Nijmegen; JBZ, Jeroen Bosch Hos-
pital, Den Bosch; RS, Rijnstate Hospital,
Arnhem and Zevenaar; RUMC, Radboud
university medical center, Nijmegen; SL,
Slingeland Hospital, Doetinchem; ZGV,
Hospital Gelderse Vallei, Ede.
van den Berg et al
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baseline. The Radboud University Medical Center Medical Review
Ethics Committee (file No. 2009/144) and the ethics boards of local
participating centers approved the study (Netherlands Trial Register
NTR2935).
Intervention
BREATH (Appendix Fig A1, online only) targets re-entry
issues relevant to BCSs during a fixed 16-week modular program
for four phases of adjustment to breast cancer (looking back,
emotional processing, strengthening, and looking ahead).
28
Inter-
vention components (104 total) are based on cognitive behavioral
therapy and include information (26 scripts), assignment (48 tasks,
or homework), assessment (10 self-tests followed by automated
feedback), and video (20 topics illustrated with clips extracted
from interviews). BREATH is a pure self-help program without
therapist contact (also known as self-administered therapy
31
).
Each week, new materials are released, accompanied by standard
e-mail reminders, in an attempt to maintain or improve adher-
ence. Access to BREATH was withdrawn after 16 weeks.
BCSs receiving CAU alone did not have access to BREATH. For
both conditions, CAU consisted of visits to an oncologist three times
per month and psychosocial care on demand or referral. No restric-
tions were made regarding use of Internet or psychological or other
self-help interventions.
Outcomes
Study assessments and random assignment were conducted on-
line using RadQuest software (Radboudumc Medical Psychology,
Nijmegen, the Netherlands). Baseline characteristics were obtained
with a medical checklist derived from the patient chart.
General psychological distress was assessed with the Symptom
Checklist-90 (SCL-90; range, 90-450), which has good psychometric
properties in healthy and patient populations.
32
The SCL-90 total
score showed good internal consistency at baseline (Cronbach’s
␣
⫽
.97). For the General Severity Index (GSI), which represents the mean
score of all responses, transformed item scores (0-4) were used. Gen-
eral psychological empowerment was assessed with the Cancer Em-
powerment Questionnaire (CEQ).
33
The CEQ presumes that patients
can derive strength from themselves (intrapersonal) and from their
social surroundings (interpersonal). Baseline internal consistency was
good (Cronbach’s
␣
⫽.92).
Secondary outcomes reflected negative adjustment (general
34,35
and cancer-specific distress,
36
fatigue,
37
helplessness,
38
and fear of
cancer recurrence
39,40
) and positive adjustment (self-efficacy,
41
rem-
oralization,
42
personal control,
43
quality of life,
44
fulfillment,
45
re-
evaluation,
45
new ways of living,
45
and valuing life
45
). For details of
secondary outcomes, see our study protocol
28
(or the legend of Table
2 with treatment effects).
Information about self-reported use of Internet and other re-
sources (individual support, peer support, rehabilitation support
groups) was collected at T1. General Internet use was assessed with the
question “Have you consulted the Internet for information on (learn-
ing to live with) breast cancer in the past 4 months?” Four-month
usage data of CAU ⫹BREATH participants were evaluated.
46
For the
current report, correlations were calculated between the mean differ-
ence (T0 to T1) in distress and the continuous usage variables of
frequency of log-ins, total duration (in minutes), and activity (number
of intervention components opened).
Random Assignment and Masking
BCSs were randomly assigned (allocation ratio 1:1) to receive
CAU ⫹BREATH or CAU alone. For each center, a randomized block
design with stratification by hormone therapy was generated. After
baseline assessment, a random number generator with variable block
sizes of 4, 6, and 8 automatically ensured blinded allocation until
intervention assignment. One researcher (S.v.d.B.) informed partici-
pants about treatment assignment by e-mail and was therefore not
blinded. In one case, a participant was told an incorrect treatment
assignment (CAU instead of CAU ⫹BREATH); this participant re-
ceived CAU alone and her data were analyzed accordingly.
Table 1. Baseline Characteristics of Study Participants (N ⫽150)
Characteristic
CAU ⫹
BREATH
(n ⫽70)
CAU alone
(n ⫽80)
No. of
Patients %
No. of
Patients %
Age, years
Mean 51.44 50.18
SD 8.30 9.15
Educational level
ⴱ
Low (ISCED 0-1-2) 14 20 13 16
Medium (ISCED 3-4-5) 32 46 48 60
High (ISCED 6-7-8) 24 34 19 24
Marital status
Married/cohabiting 58 83 61 76
Unmarried 5 7 5 6
Divorced 5 7 10 13
Widowed 2 3 4 5
Children (yes) 61 87 62 76
Employment†
Paid work outside home 30 43 32 40
Home management 21 30 18 23
Unemployed 3 4 8 10
Sick leave 30 43 42 53
Disability insurance act 3 4 5 6
Voluntary work 7 10 4 5
Student 0 0 1 1
Retired 3 4 3 4
Treatment type
Surgery ⫹chemotherapy ⫹radiotherapy 48 69 56 70
Surgery ⫹chemotherapy 19 27 22 28
Surgery ⫹radiotherapy 3 4 2 2
Hormone therapy 46 66 53 66
Low distress (GSI ⱕ0.57) 51 73 55 69
Frequency of Internet use‡
Daily 24 59 38 73
2 to 4 times a week 12 29 9 17
Weekly or less 5 12 5 10
NOTE. No significant differences were found between the two conditions
(P⬎.05). Pvalues were calculated using
␹
2
tests for categorical variables and
a two-tailed Students’s ttest (independent samples) for continuous variables.
Abbreviations: BREATH, Breast Cancer E-Health intervention; CAU, care as
usual; GSI, General Severity Index; ISCED, International Standard Classifica-
tion of Education; SD, standard deviation.
ⴱ
ISCED 2011.
†Percentages do not add up to 100% because more options are possible.
‡CAU ⫹BREATH (n ⫽41), CAU alone (n ⫽52).
Breast Cancer E-Health (BREATH) Trial
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Statistical Methods
All statistical analyses were performed with SPSS 20 (IBM, Ar-
monk, NY). The sample size calculation for the primary outcomes at
T1 was 170: 128 BCSs (64 in each group) at 80% power for differences
between CAU ⫹BREATH and CAU alone with a medium effect size
of 0.50, plus a 25% dropout rate.
28
The level of significance in the
sample size calculation was adjusted to Pⱕ.025 to keep the overall
chance of type I error at 5%. Inclusion was prematurely stopped at 151
participants, with approval of the ethics committee, because only 5%
(7 of 151) of the participants dropped out at T1.
Statistical Effect
The primary hypothesis was that CAU ⫹BREATH would be
superior to CAU alone in decreasing distress and increasing empow-
erment, and it was tested in an intention-to-treat (ITT) analysis of data
for T0 and T1. Missing data at T1 were imputed using last observation
carried forward. The significance of intervention effects on primary
and secondary outcomes was tested using one-way between-groups
analyses of covariance with group (CAU ⫹BREATH or CAU alone)
as a fixed factor. Because participants were not preselected before
inclusion, the analysis of covariance model corrected for baseline
differences. For primary outcome analyses, baseline distress (SCL-90)
and empowerment (CEQ) were used as covariates. For secondary
outcome analyses, baseline scores of corresponding questionnaires
were used as covariates. Interaction effects of mean adjusted differ-
ences between T0 and T1 by group are reported in Table 2, with SEs,
significance level, and 95% CI. Effect size Cohen’s dfor independent
groups was calculated using the pooled standard deviations and un-
adjusted means on T1.
Clinically Significant Change
Clinically significant change, assessed with the reliable change
index (RCI) of the GSI, was tested in ITT analysis (T0 to T1).
Following Jacobson and Truax,
47
Schauenburg and Strack
48
calcu-
lated the GSI cutoff 0.567 to discriminate between low and high
distress on the basis of normative and psychotherapy samples. The
magnitude of improvement (defined as RCI ⱕ⫺0.16 for low-
distress participants and RCI ⱕ⫺0.43 for high-distress partici-
pants) or deterioration (RCI ⱖ0.16 for low-distress participants
and RCI ⱖ0.43 for high-distress participants) was assessed using
one-sided
␹
2
tests.
33
Follow-Up Effect
Follow-up effects for primary and secondary outcomes were
evaluated with mixed within-between repeated-measures analysis of
variance, including data for participants who completed all four as-
sessments (T0 to T3). Because participants were randomly assigned at
each center, center was not included as a random effect. Baseline
variables were taken into account as within factors in the model.
Differences between CAU ⫹BREATH and CAU alone were tested
using independent samples ttests.
RESULTS
Between August 2010 and March 2012, 170 women were referred
and 151 (89%) underwent random assignment (Fig 1). Data col-
lection was finalized in February 2013. One woman was errone-
ously enrolled (metastatic disease) and excluded after the random
assignment,
49
leaving a final ITT sample of 150 BCSs (70 CAU ⫹
BREATH, 80 CAU alone). At baseline, the two groups did not
differ on demographic characteristics (Table 1) and study out-
comes (Table 2). Participants with missing data at T1 (n ⫽17) had
higher levels of baseline distress than participants with complete
data at T1 (mean difference, 23.57; 95% CI, 3.82 to 43.31; P⫽.02).
Levels of baseline empowerment were similar (P⫽.79). Missing
data at T1 were equally distributed between the two groups. Over-
all, 124 participants (58 CAU ⫹BREATH; 66 CAU alone) com-
pleted all four assessments, and their data were included in
follow-up analyses. No metastases or severe illnesses were reported
during the study. One woman was admitted to a psychiatric clinic;
this was reported as a serious adverse event.
Statistical Effect
The decrease in distress at T1 was significantly greater in
CAU ⫹BREATH participants than in CAU-alone participants, with a
small-to-medium effect size (d⫽0.33; Table 2). Baseline distress
explained 53% of the variance in distress at T1 (P⬍.005). No such
difference in empowerment was found.
Secondary outcome analyses (Table 2) revealed that CAU⫹
BREATH led to significant improvements in five of seven negative
adjustment variables (general and cancer-specific distress, fatigue, and
two fear of cancer recurrence outcomes) with small-to-medium effect
sizes (d⫽0.37 to 0.55), and in 3 of 10 positive adjustment variables
(self-efficacy, remoralization, new ways of living) with small-to-
medium effect sizes (d⫽0.26 to 0.39).
Clinically Significant Change
More CAU ⫹BREATH participants (39 of 70 [56%]; 95% CI,
44.1 to 66.8) than CAU-alone participants (32 of 80 [40%]; 95% CI,
30.0 to 51.0) showed a clinically significant improvement (P⫽.03).
We had hypothesized that more high-distress BCSs would show a
clinically significant improvement after CAU ⫹BREATH than after
CAU alone, but this was not the case (10 of 21 [48%]; 95% CI, 28.3 to
67.6 v14 of 27 [52%]; 95% CI, 34.0 to 69.3, respectively; P⫽.39). Post
hoc analysis revealed that there was no difference in the proportion of
high-distress BCSs showing clinical deterioration (5 of 21 [24%] v2of
27 [7%], respectively; P⫽.06). Of the low-distress BCSs, more
CAU ⫹BREATH participants than CAU-alone participants showed
clinical improvement or no change (41 of 49 [84%]; 95% CI, 71.0 to
91.5 v35 of 53 [66%]; 95% CI, 52.6 to 77.3 respectively; P⫽.02).
Moreover, explorative post hoc analyses of low-distress BCSs revealed
that, compared with CAU-alone participants, CAU ⫹BREATH par-
ticipants showed more clinically significant improvement (29 of 49
[59%] v18 of 53 [34%], respectively; P⫽.006) and less deterioration
(8 of 49 [16%] v18 of 53 [34%], respectively; P⫽.02). The empow-
erment hypothesis was not tested, because empowerment was not
significantly different between CAU ⫹BREATH and CAU alone.
Follow-Up Effect
At T2 and T3, distress was significantly reduced regardless of
group assignment (F[3, 120] ⫽5.88; P⫽.001; Fig 2). This was also
true for the secondary negative adjustment outcomes of fear of cancer
recurrence (Cancer Worry Scale; F[3, 120] ⫽5.954; P⫽.001), fatigue
(F[3, 120] ⫽4.40; P⫽.006), and helplessness (F[3, 120] ⫽11.964;
P⫽.000). A significant time ⫻group interaction effect was found for
van den Berg et al
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Table 2. Effect of Treatment (intention-to-treat analysis) on Primary and Secondary Outcomes After 4 Months (N ⫽150)
Treatment Effect
Mean (SD/SE)
Mean Difference (95% CI) PEffect Size (Cohen’s d)
CAU ⫹BREATH
(n ⫽70)
CAU Alone
(n ⫽80)
Primary outcomes
Distress (SCL-90
ⴱ32
)
T0 135.44 (37.532) 140.33 (41.045)⫺4.882 (⫺17.640 to 7.875) .451
T1 (unadjusted) 124.90 (26.956) 135.84 (37.975)
T1 (adjusted) 126.676 (2.412) 134.463 (2.250) ⫺7.788 (⫺14.308 to ⫺1.267) <.05 0.33
Empowerment (CEQ†
33
)
T0 156.90 (13.222) 154.06 (15.133) 2.838 (⫺1.779 to 7.454) .226
T1 (unadjusted) 159.13 (15.116) 155.45 (13.639)
T1 (adjusted) 157.946 (1.293) 156.240 (1.206) 1.706 (⫺1.787 to 5.200) .336 0.16
Secondary outcomes
Negative adjustment variables
General (distress [HADS-total score]
ⴱ35
)
T0 9.07 (6.710) 10.01 (7.259) ⫺0.941 (⫺3.208 to 1.326) .413
T1 (unadjusted) 7.67 (6.033) 9.89 (6.129)
T1 (adjusted) 8.052 (0.461) 9.621 (0.431) ⫺1.569 (⫺2.815 to ⫺0.322) <.05 0.37
General (Distress Thermometer
ⴱ
)
T0 3.89 (2.505) 4.53 (2.516) ⫺0.639 (⫺1.451 to 0.173) .122
T1 (unadjusted) 3.46 (2.506) 4.00 (2.408)
T1 (adjusted) 3.662 (0.249) 3.858 (0.232) ⫺0.196 (⫺0.868 to 0.477) .566 0.22
General (fatigue [CIS]
ⴱ37
)
T0 33.29 (12.530) 33.38 (12.627)⫺0.089 (⫺4.159 to 3.980) .965
T1 (unadjusted) 28.57 (12.913) 32.77 (13.309)
T1 (adjusted) 28.602 (1.205) 32.746 (1.127) ⫺4.144 (⫺7.404 to ⫺0.884) <.05 0.32
Cancer specific (fear of recurrence [CWS]
ⴱ39
)
T0 14.31 (4.454) 15.36 (3.892) ⫺1.048 (⫺2.395 to 0.298) .126
T1 (unadjusted) 13.13 (3.310) 15.19 (4.119)
T1 (adjusted) 13.452 (0.296) 14.799 (0.277) ⫺1.347 (⫺2.149 to ⫺0.545) <.001 0.55
Cancer specific (fear of recurrence [CAS]
ⴱ40
)
T0 5.11 (1.584) 5.45 (1.630) ⫺0.336 (⫺0184 to 0.856) .204
T1 (unadjusted) 4.90 (1.395) 5.51 (1.567)
T1 (adjusted) 5.015 (0.120) 5.398 (0.112) ⫺0.383 (⫺0.707 to ⫺0.059) <.05 0.41
Cancer specific (helplessness [ICQ]
ⴱ38
)
T0 10.36 (3.301) 10.21 (3.133) 0.145 (⫺0.894 to 1.184) .784
T1 (unadjusted) 9.39 (2.975) 9.45 (3.023)
T1 (adjusted) 9.335 (0.274) 9.488 (0.256) ⫺0.153 (⫺0.894 to 0.589) .685 0.02
Cancer specific [distress (IES-total score]
ⴱ36
)
T0 18.11 (15.098) 18.88 (15.730)⫺0.761 (⫺5.754 to ⫺4.232) .764
T1 (unadjusted) 11.81 (12.240) 17.35 (14.371)
T1 (adjusted) 12.024 (1.244) 17.143 (1.164) ⫺5.119 (⫺8.486 to ⫺1.752) <.01 0.42
Positive adjustment variables
General (self-efficacy [SES]†
41
)
T0 19·97 (2·756) 20·30 (2·655) ⫺0.329 (⫺1.203 to 0.545) .459
T1 (unadjusted) 21.03 (3.217) 20.23 (2.556)
T1 (adjusted) 21.130 (0.290) 20.133 (0.271) 0.997 (0.213 to 1.781) <.05 0.28
General (remoralization [RS12]†
42
)
T0 3.09 (0.512) 3.06 (0.569) 0.022 (⫺0.153 to 0.198) .802
T1 (unadjusted) 3.28 (0.495) 3.08 (0.540)
T1 (adjusted) 3.275 (0.051) 3.081 (0.047) 0.195 (0.058 to 0.332) <.01 0.39
General (personal control [Mastery]†)
T0 23.93 (4.604) 23.64 (4.653) 0.291 (⫺1.206 to 1.789) .701
T1 (unadjusted) 24.74 (4.548) 23.58 (4.957)
T1 (adjusted) 24.655 (0.435) 23.677 (0.407) 0.977 (⫺0.199 to 2.154) .103 0.24
General (acceptance [ICQ]†)
T0 16.17 (3.996) 16.14 (3.525) 0.034 (⫺1.180 to 1.247) .956
T1 (unadjusted) 17.60 (4.109) 16.94 (3.509)
T1 (adjusted) 17.586 (0.313) 16.948 (0.293) 0.637 (⫺0.209 to 1.1484) .139 0.17
(continued on following page)
Breast Cancer E-Health (BREATH) Trial
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fear of cancer recurrence (Cancer Worry Scale; F[3, 120] ⫽4.563; P⫽
.005), with CAU ⫹BREATH participants reporting less fear than
CAU-alone participants at T2 (⫺1.459; 95% CI, ⫺2.743 to ⫺0.175).
Of the positive adjustment outcomes, acceptance significantly im-
proved in both groups (ICQ; F[3, 120] ⫽8.531; P⫽.000). Time
effects and time ⫻group interactions were not significant for all
remaining outcomes, including empowerment (Fig 3).
Use of BREATH and Other Resources
Use of the BREATH intervention varied considerably. Frequency
of logins ranged from 0 to 45, total duration ranged from 0 to 2,324
minutes, and activity ranged from 0 to 104 intervention components
opened. The mean difference in distress (SCL-90, T0 to T1) was not
correlated with frequency (r⫽⫺0.007; P⫽.96), total duration (r⫽
0.000; P⫽1.00), or activity (r⫽⫺1.072; P⫽.55).
At T1, similar proportions of women in CAU ⫹BREATH and
CAU alone had consulted the Internet in the previous 4 months on a
monthly (24% v34%), weekly (13% v8%), or daily (0% v2%) basis,
or not at all (61% v58%). There were also no significant differences
(n ⫽126; P⫽.27) between CAU ⫹BREATH and CAU-alone par-
ticipants in the use of individual support (eg, psychologist; 12% v25%,
respectively), peer and rehabilitation support groups (14% v12%,
respectively), or combined individual and group support (21% v13%,
respectively). Half of the participants in both groups did not make use
of other support (53% v50%, respectively).
DISCUSSION
At the start of the re-entry phase, 4-month access to BREATH in
addition to CAU resulted in a statistically and clinically significant
distress reduction compared with CAU alone. However, this small-to-
medium effect was not sustained, and levels of distress were similar at
6 and 10 months. CAU ⫹BREATH participants also showed a greater
decrease than CAU-alone participants in fear of cancer recurrence,
fatigue, and general and cancer-related distress. The effect of BREATH
on fear of cancer recurrence was sustained during follow-up. Access to
BREATH did not influence empowerment or clinical distress im-
provement in high-distress BCSs. Low-distress BCSs showed a greater
clinical improvement and less deterioration with CAU ⫹BREATH
than with CAU alone.
The RCT was designed according to quality standards
(CONSORT for parallel group,
50
nonpharmacologic treatment,
51
and eHealth trials).
52,53
Statistically and clinically significant
changes were evaluated in ITT analyses, with missing data imputed
using a conservative method (last observation carried forward)
Table 2. Effect of Treatment (intention-to-treat analysis) on Primary and Secondary Outcomes After 4 Months (N ⫽150) (continued)
Treatment Effect
Mean (SD/SE)
Mean Difference (95% CI) PEffect Size (Cohen’s d)
CAU ⫹BREATH
(n ⫽70)
CAU Alone
(n ⫽80)
General (perceived benefits [ICQ]†)
T0 15.09 (4.169) 15.86 (3.801) ⫺0.777 (⫺2.063 to 0.509) .235
T1 (unadjusted) 15.66 (4.584) 16.21 (4.541)
T1 (adjusted) 16.042 (0.363) 15.926 (0.339) 0.116 (⫺0.866 to 1.098) .816 0.12
Cancer specific (quality of life [EORTC QLQ-C30]†
40
)
T0 66.79 (16.575) 69.79 (17.906) ⫺3.006 (⫺8.601 to 2.589) .290
T1 (unadjusted) 72.50 (18.572) 70.52 (15.231)
T1 (adjusted) 73.295 (1.784) 69.882 (1.666) 3.413 (⫺1.411 to 8.236) .164 0.12
Cancer specific (fulfillment [PAQ]†
45
)
T0 38.30 (6.686) 39.80 (6.934) ⫺1.500 (⫺3.706 to 0.706) .181
T1 (unadjusted) 40.89 (6.728) 40.10 (7.289)
T1 (adjusted) 41.284 (0.759) 39.788 (0.708) 1.496 (⫺0.55 to 3.548) .152 0.11
Cancer specific (re-evaluation [PAQ]†)
T0 38.39 (6.160) 40.01 (6.407) ⫺1.627 (⫺3.662 to 0.409) .116
T1 (unadjusted) 38.81 (6.493) 39.44 (7.107)
T1 (adjusted) 39.380 (0.611) 38.835 (0.570) 0.545 (⫺1.107 to 2.197) .516 0.09
Cancer specific (new ways of living [PAQ]†)
T0 41.19 (5.279) 41.34 (7.488) ⫺0.152 (⫺2.271 to 1.967) .888
T1 (unadjusted) 42.94 (6.230) 41.07 (8.012)
T1 (adjusted) 43.001 (0.709) 41.032 (0.663) 1.969 (0.051 to 3.886) <.05 0.26
Cancer specific (valuing life [PAQ]†)
T0 34.06 (5.778) 34.51 (4.963) ⫺0.455 (⫺2.188 to 1.278) .604
T1 (unadjusted) 34.40 (6.087) 34.11 (5.972)
T1 (adjusted) 34.595 (0.545) 33.971 (0.510) 0.623 (⫺0.853 to 2.100) .405 0.05
NOTE. All Pvalues were calculated using an analysis of covariance with adjustment for baseline value. (Unadjusted) means unadjusted for baseline covariates.
(Adjusted) means adjusted for baseline value of the corresponding questionnaire. Bold font indicates significant effect and corresponding effect size.
Abbreviations: BREATH, Breast Cancer E-Health intervention; CAS, Cancer Acceptance Scale; CAU, care as usual; CEQ, Cancer Empowerment Questionnaire; CIS,
Checklist Individual Strength; CWS, Cancer Worry Scale; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life
Questionnaire Core 30 items; HADS, Hospital Anxiety and Depression Scale; ICQ, Illness Cognition Questionnaire; IES, Impact of Event Scale; PAQ, Positive
Adjustment Questionnaire; RS12, Remoralization Scale-12 items; SCL-90, Symptom Checklist-90 items; SD, standard deviation; SES, Self-Efficacy Scale.
ⴱ
Increase represents worsening; decrease represents improvement.
†Increase represents improvement; decrease represents worsening.
van den Berg et al
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because the patients in our sample were expected to improve on
distress over the study period.
8,9
The multicenter recruitment
strategy guaranteed referrals from both secondary and tertiary care
centers. The recruitment procedure, which ensured minimal in-
volvement of the research team, and lack of assistance regarding
intervention use and adherence support the ecological validity of
BREATH. In the absence of RCTs evaluating similar unguided
Web-based interventions for BCSs, the effect size of BREATH is
consistent with that of two recent meta-analyses of guided face-to-
face (effect size range 0.26 to 0.38)
54
and Web-based (effect size
range, 0.17 to 0.21)
55
interventions for people with cancer
54
and
chronic somatic conditions.
55
The secondary outcomes revealed that CAU ⫹BREATH de-
creased general and cancer-specific distress, fatigue, and fear of cancer
recurrence, which may reflect the multicomponent nature of distress
in cancer patients.
56
The clinical relevance of these outcomes needs to
be addressed in future research.
CAU ⫹BREATH did not significantly change empowerment
relative to the effect of CAU alone and had inconsistent effects on the
secondary positive adjustment variables. The study of positive adjust-
ment is a new research area and poses multiple challenges. Although
new models of survivorship care stress patient empowerment,
57,58
there is no consensus about the empowerment construct. Conse-
quently, positive adjustment questionnaires, such as the CEQ, are
new, but not extensively validated in BCSs and lack information on
sensitivity to change. Furthermore, in psycho-oncology, resource-
oriented therapeutic models
59
are lacking, and interventions are tra-
ditionally aimed at diminishing deficits instead of enhancing
strengths. It is possible that BREATH does not include a sufficient
number of empowerment modules (only 4 of the 16 weekly modules
targeted empowerment).
Results should be considered with caution for several reasons.
Consistent with the scarce literature on Web-based interventions
for cancer patients,
60
BREATH did not have a sustained effect on
distress. This may be because access to the Web site was for 4
months only. Although the limited access enabled accurate postin-
tervention assessments, in retrospect it might have been better to
allow participants to retain access, especially because information
often remains available with other psychoeducational interven-
tions or self-help books. Another explanation for lack of a sus-
tained effect may be the small-to-medium effect size, which might
not have been enough to compensate for the natural course of
emotional recovery. The missing-at-random assumption for im-
putation was violated. BCSs with missing data for the 4-month
assessment had significantly higher levels of distress at baseline.
Although not significant, more high-distress BCSs in the CAU ⫹
BREATH group showed a clinical deterioration. This leads to a
cautious interpretation of the results regarding high-distress BCSs,
and suggests that these women may need a more intensive inter-
vention than BREATH.
The limited data on BREATH use means it is not possible to
draw firm conclusions about how often the intervention should be
used to have an effect. Further investigations with larger samples,
mediation analyses, or usage pattern are needed to gain insight into
determinants of intervention use and to study a possible dose-
response relationship.
61
Data for BCSs who declined to participate
were not recorded. Although it was not feasible to recruit patients
consecutively, our sample seemed homogeneous and representa-
tive, because the mean age, treatment type, education, and work
situation of participants were comparable to those of other studies
evaluating the Dutch breast cancer population.
3,9,62,63
The study
sample also proved representative with regard to psychological
10 Months6 Months4 MonthsBaseline
SCL-90 Total Score
145
140
135
130
125
120
115
110
CAU + BREATH (n = 58)
CAU alone (n = 66)
CAU + BREATH (n = 58)
CAU alone (n = 66)
Fig 2. Psychological distress (Symptom Checklist-90 [SCL-90]) at baseline and
4, 6, and 10 months after baseline (n ⫽124 assessment completers). Vertical
bars represent the 95% CI of the mean SCL-90 at each time point. BREATH,
Breast Cancer E-Health intervention;; CAU, care as usual.
10 Months6 Months4 MonthsBaseline
CEQ Total Score
170
165
160
155
150
145
140
135
130
CAU + BREATH (n = 58)
CAU alone (n = 66)
CAU + BREATH (n = 58)
CAU alone (n = 66)
Fig 3. Psychological empowerment (Cancer Empowerment Questionnaire
[CEQ]) at baseline and 4, 6, and 10 months after baseline (n ⫽124 assessment
completers). Vertical bars represent the 95% CI of the mean CEQ at each time
point. BREATH, Breast Cancer E-Health intervention; CAU, care as usual.
Breast Cancer E-Health (BREATH) Trial
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functioning during the first year after treatment. As in other studies
of patients with breast
8,9
or other
64
cancer, most patients experi-
enced low levels of distress (n ⫽102 [68%]).
To the best of our knowledge, this is the first RCT to demonstrate an
additional effect of a self-management intervention specifically designed
to support BCSs in the year after treatment completion. Although small,
the primary effect on distress was statistically robust and clinically relevant.
Moreover, the intervention does not necessarily require a lot of user
commitment. Future research should focus on replicating the current
findings, using more valid questionnaires for the positive adjustment
variables, and evaluating the follow-up effect beyond 4 months of access.
The magnitude of the effect in BCSs with low and high distress should be
investigated further. BREATH demonstrated its potential as a feasible first
step in a matched supportive care model providing evidence-based and
easily accessible re-entry care.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Sanne W. van den Berg, Petronella B.
Ottevanger, Judith B. Prins
Administrative support: Sanne W. van den Berg
Provision of study materials or patients: Petronella B. Ottevanger
Collection and assembly of data: Sanne W. van den Berg
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
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Breast Cancer E-Health (BREATH) Trial
www.jco.org © 2015 by American Society of Clinical Oncology 9
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Acknowledgment
We thank all patients who gave their time to participate and the oncologists, radiotherapists, and research nurses of the participating hospitals:
Radboud university medical center, Nijmegen; Rijnstate, Arnhem and Zevenaar; Slingeland, Doetinchem; Hospital Gelderse Vallei, Ede;
Canisius-Wilhelmina Hospital, Nijmegen; and Jeroen Bosch, Den Bosch.
Appendix
Fig A1. Screenshot of the BREATH (Breast Cancer E-Health intervention) Web site (in Dutch) with four-phase structure.
van den Berg et al
10 © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org by Winette T.A. Van Der Graaf on July 13, 2015 from 84.80.216.31
Copyright © 2015 American Society of Clinical Oncology. All rights reserved.