VOLUME
34
•
NUMBER
28
•
OCTOBER
1,
2016
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Efficacy of Mindfulness-Based Cognitive Therapy on Late
Post-Treatment Pain in Women Treated for Primary Breast
Cancer: A Randomized Controlled Trial
Maja Johannsen, Maja O’Connor, Mia Skytte O’Toole, Anders Bonde Jensen, Inger Højris, and Robert Zachariae
See accompanying editorial on page 3366
Maja Johannsen, Maja O’Connor, Mia
Skytte O’Toole, Anders Bonde Jensen,
Inger Højris, and Robert Zachariae, Aarhus
University Hospital; Anders Bonde
Jensen and Inger Højris, Aarhus
University, Aarhus, Denmark.
Published online ahead of print at
www.jco.org on June 20, 2016.
Supported by The Danish Cancer Society,
Aase & Ejnar Danielsens Fond, Einar
Willumsens Mindelegat, and
Radiumstationens Forskningsfond.
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.
Clinical trial information: NCT01674881.
Corresponding author: Maja Johannsen,
MSc, Unit for Psychooncology and Health
Psychology, Department of Oncology,
Aarhus University Hospital and
Department of Psychology, Aarhus
University, Bartholins Alle 9, Bld 1340,
DK-8000 Aarhus C, Denmark; e-mail:
[email protected].
© 2016 by American Society of Clinical
Oncology
0732-183X/16/3428w-3390w/$20.00
DOI: 10.1200/JCO.2015.65.0770
A
B
S
T
R
A
C
T
Purpose
To assess the efficacy of mindfulness-based cognitive therapy (MBCT) for late post-treatment pain
in women treated for primary breast cancer.
Methods
A randomized wait list–controlled trial was conducted with 129 women treated for breast cancer reporting
post-treatment pain (score $ 3 on pain intensity or pain burden assessed with 10-point numeric rating
scales). Participants were randomly assigned to a manualized 8-week MBCT program or a wait-list control
group. Pain was the primary outcome and was assessed with the Short Form McGill Pain Questionnaire 2
(SF-MPQ-2), the Present Pain Intensity subscale (the McGill Pain Questionnaire), and perceived pain
intensity and pain burden (numeric rating scales). Secondary outcomes were quality of life (World Health
Organization-5 Well-Being Index), psychological distress (the Hospital Depression and Anxiety Scale), and
self-reported use of pain medication. All outcome measures were assessed at baseline, postintervention,
and 3-month and 6-month follow-up. Treatment effects were evaluated with mixed linear models.
Results
Statistically significant time 3 group interactions were found for pain intensity (d = 0.61; P = .002),
the Present Pain Intensity subscale (d = 0.26; P = .026), the SF-MPQ-2 neuropathic pain subscale
(d = 0.24; P = .036), and SF-MPQ-2 total scores (d = 0.23; P = .036). Only pain intensity remained
statistically significant after correction for multiple comparisons. Statistically significant effects were
also observed for quality of life (d = 0.42; P = .028) and nonprescription pain medication use (d = 0.40;
P = .038). None of the remaining outcomes reached statistical significance.
Conclusion
MBCT showed a statistically significant, robust, and durable effect on pain intensity, indicating that
MBCT may be an efficacious pain rehabilitation strategy for women treated for breast cancer. In
addition, the effect on neuropathic pain, a pain type reported by women treated for breast cancer,
further suggests the potential of MBCT but should be considered preliminary.
J Clin Oncol 34:3390-3399. © 2016 by American Society of Clinical Oncology
INTRODUCTION
Breast cancer (BC) is the most common cancer
type among women, with . 1 million new cases
worldwide each year.1 Although survival rates are
increasing,2 patients with BC report high levels of
physical and psychological symptoms after
treatment,3,4 underscoring the need for effective rehabilitation programs. Persistent posttreatment pain is of particular concern because
of its high prevalence, with 16% to 20% of women
treated for BC experiencing moderate to severe
pain 5 to 9 years after surgery.5,6 Although women
3390
treated for BC rate pain among the 10 most
important quality of life (QoL) –related issues,7
pain remains undertreated.8,9
Although BC-related pain is often associated
with nervous system damage (ie, neuropathic
pain),10 it is generally accepted that pain is
multifaceted, consisting of sensory, cognitive, and
affective dimensions influencing the patients’
pain experience and their reactions to this experience.9 Targeting cognitive and affective dimensions of pain with psychosocial interventions
may, as supported by a recent meta-analysis,11
help patients with BC cope better with persisting
post-treatment pain. One type of intervention,
© 2016 by American Society of Clinical Oncology
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Efficacy of MBCT on Late Post-Treatment Pain
which recently has received considerable attention, is mindfulnessbased therapy (MBT).12 Mindfulness focuses on directing attention
to the experience that unfolds moment by moment in a nonjudgmental way, and MBT teaches ways of relating to bodily
sensations and emotional discomfort with a higher degree of
acceptance and openness.12 MBT has shown promising results in
cancer populations in reducing anxiety and depression and in
improving QoL.12-14 Although there are indications that MBT may
be effective in reducing pain in noncancer populations,15-17 a literature search for studies on MBT and pain in patients with BC
revealed only five studies published in six articles.18-23 Only one
study22 showed a statistically significant effect, and when calculating the inverse variance weighted pooled effect size of the five
studies, the effect failed to reach statistical significance (Cohen’s
d = 0.32; 95% CI, 20.18 to 0.83; P = .21). There may be several
reasons for the negative result. First, in all studies, pain was a secondary
outcome, and participant selection was not based on pain levels.
Second, only three studies were controlled trials,18,22,23 and three
studies had modest sample sizes (N = 17 to 42),19,20,22 compromising statistical power. Furthermore, in the three studies that
reported the timing of the intervention relative to treatment, the
time ranges varied considerably.18,19,23 Thus, the efficacy of MBT
on post-treatment pain in patients with BC and survivors remains
unclear. We therefore conducted a randomized controlled trial of
the effect of mindfulness-based cognitive therapy (MBCT) on late
post-treatment pain in women treated for primary BC.
METHODS
Study Design and Sample
MBCT was compared with a wait-list control condition in a final
sample of 129 women treated at the Department of Oncology, Aarhus
University Hospital. During control visits, the oncologists asked patients
about their current pain status and informed eligible patients about the
study. Inclusion criteria were: primary BC, $ 3 months after surgery,
completed chemotherapy and/or radiotherapy, a score $ 3 on perceived
pain intensity or pain burden on a 10-point numerical rating scale (NRS),
and ability to understand Danish. Exclusion criteria were: metastatic BC,
other cancers, male sex, serious psychiatric diagnoses (eg, psychosis), and
other severe medical conditions related to the musculoskeletal system (eg,
arthritis). The study was approved by the Regional Science Ethical
Committees (registration No.: 1-10-72-460-12) and preregistered at
clinicaltrials.gov (NCT01674881).
Procedures
Recruitment lasted from October 2012 through December 2013.
Eligible and interested participants were screened for possible additional
barriers to participation (eg, scheduling difficulties). After completing
consent forms and baseline questionnaires (T1), participants were randomly assigned to intervention or wait-list control. Randomization was
conducted independently using Power and Sample Size (PASS), v.12
(NCSS, Kaysville, UT). Additional questionnaires were mailed out immediately after (T2), 3 months after (T3), and 6 months after (T4) the
8-week intervention.
MBCT and Wait-List Control
The intervention generally adhered to the MBCT manual.24 Modifications adapting the program to the current study population25 included
slightly shorter 2-hour sessions, shorter meditation exercises (# 30 min),
more gentle yoga exercises, and omission of the whole-day session. MBCT
www.jco.org
was delivered in groups of 13 to 17 participants in weekly sessions over
8 consecutive weeks. The sessions consisted of formal mindfulness exercises
and psychoeducation, with main focus on the participants’ here-and-now
pain experiences. In addition, MBCT includes cognitive exercises, here
targeting pain catastrophizing. Daily 45-minute home practice was encouraged. Adherence was monitored using weekly homework records.
All sessions were facilitated by a mindfulness instructor with training
from Oxford University and 9 years of MBCT experience. The instructor
received supervision from Centre for Mindfulness Research and Practice,
Bangor University, UK, during the study. Wait-list participants were only
contacted during the study period when asked to complete the T2, T3, and
T4 questionnaires.
Measures
All patients provided sociodemographic information. Clinical and
comorbidity (Charlson Comorbidity Index)26 data were retrieved from the
Danish Breast Cancer Cooperative Group registry, which contains information on diagnosis and treatment reported by all national oncology
departments.27 Use of complementary and alternative treatments
(eg, massage, acupuncture) or psychological counseling during the previous year was assessed at T1 together with motivation for participating in
the program (5-point Likert scale, from “Not motivated” to “Very
motivated”).
Primary outcomes. All primary outcome measures were completed at
all four time points (T1 to T4). Because of the multifaceted nature of pain,9
we included several primary pain measures. Pain outcomes included the
Short Form McGill Pain Questionnaire 2 (SF-MPQ-2),28 yielding a total
score, three sensory subscale scores (continuous, intermittent, and neuropathic pain), and one affective subscale score (affective pain descriptors).
The SF-MPQ-2 has shown good psychometric properties in neuropathic
pain conditions.28 The Present Pain Intensity (PPI) from the original
McGill Pain Questionnaire was also included. The PPI is an overall present
pain intensity measure that is sensitive to the evaluative pain dimension.29
However, because the PPI is influenced by psychological factors at the
moment (eg, current mood),29 we also included an 11-point NRS, a valid
measure of pain intensity less influenced by present mood state.30 Finally,
we assessed perceived pain burden during the previous week (11-point
NRS).
Secondary outcomes. QoL was assessed with the World Health
Organization–5 Well-Being Index (WHO-5).31,32 A standardized percentage score is calculated, with higher scores indicating better QoL.
Psychological distress was assessed with the Hospital Anxiety and
Depression Scale (HADS),33 which has shown acceptable use in cancer
populations.34 The HADS total score has shown good psychometric
qualities as an overall measure of distress.35
Finally, participants reported their weekly use of (non)prescription
pain medications at T2 to T4 (“Have you used nonprescribed [prescribed]
pain medication during the last week?” with a 6-point response format
ranging from “no” to “more than 8 times”).
Adherence was assessed by number of MBCT sessions attended, total
number of minutes spent on homework during the 8-week program, and
total number of minutes spent on mindfulness practice during the previous week at T2 to T4.
Statistical Analysis
IBM SPSS statistics, v.21 (IBM, Chicago, IL) was used for all analyses.
Baseline group differences were explored with t tests or x2-tests. Statistically significant (P , .05) baseline differences were entered as covariates
in all main analyses and for statistically significant secondary outcomes.
Study dropouts were defined as participants discontinuing the intervention
and participants failing to return the questionnaires. Because of an unbalanced dropout between study groups at T2, dropout characteristics at
this time point were explored with t tests and x2 tests. At the scale level,
missing values were mean substituted with the respondent’s average response on the remaining scale items, if the respondent had completed
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3391
Johannsen et al
$ 50% of the items. For scales and subscales with internal consistencies
$ 0.70, this is considered an appropriate method.36
Mixed linear models (MLMs) were used to compare groups over time
on all outcome variables, all treated as continuous variables. MLMs tolerate
missing values and thus do not unnecessarily compromise statistical power.
All MLMs were estimated with the maximum likelihood method and were
based on the intent-to-treat sample. The data were hierarchically arranged
in two levels, with time at level 1 nested within individuals at level 2. Fixed
effects were specified for intercept, time, group, and the time 3 group
interaction. All models included a random intercept, and the slope was
specified as random if it improved the model fit as evaluated by a change in
the 22LL fit statistics.37 Because the steepest change is likely to occur at the
beginning of therapy,38 the time variable was log-transformed. In all
models, this function provided an equal or better fit than a linear function
of time. In post hoc analyses, using MLMs, the effects of adherence-related
variables were explored for the statistically significant outcomes. In addition, because of the unbalanced dropout at T2, sensitivity analyses were
performed testing the robustness of the results. The sensitivity analyses
were conducted using MLMs exploring the assumptions that dropouts had
reduced (50%) effect of the intervention and dropouts had zero effect of
the intervention (last observation carried forward from baseline).
An intervention effect was indicated by a statistically significant twoway interaction between treatment group and time. Post hoc corrections
for multiple comparisons were performed for the primary outcomes using
the Benjamin-Hochberg procedure with a 0.05 false-discovery rate.39
Effect sizes were expressed as Cohen’s d, with 0.2, 0.5, and 0.8
considered a small, medium, and large effect size, respectively.40 Cohen’s
d was derived from the F test calculated as d = 2 3 √(F/df).
RESULTS
Patients
Descriptive data are shown in Table 1. Generally, no baseline
group differences were found for any sociodemographic variables,
clinical characteristics, or outcome measures. The exception was
pain burden, with controls reporting higher pain burden than intervention group participants (P = .04; d = 0.36). Pain burden (T1)
was therefore adjusted for in a second set of analyses. This did not
change the results, except for SF-MPQ-2 total scores, which reached
statistical significance when adjusting for pain burden (Table 2).
Study flow is shown in Figure 1. In the intervention group,
dropout rates were higher (31.3% [T2], 37.3% [T3], and 41.8%
[T4]) than in controls (1.6% [T2] and 8.1% [T3, T4]).
Dropouts at T2 did not differ statistically significantly on any
primary outcome measures compared with participants returning the
questionnaires. However, dropouts were less motivated to participate
in the intervention (P = .009), reported more comorbidity (P = .01),
and had used more nonprescription pain medication (P = .03)
compared with participants returning the questionnaires (Table 1).
Primary Outcome
Pain. Statistically significant time 3 group effects were found
for pain intensity (d = 0.61), the PPI (d = 0.26), and neuropathic
pain (d = 0.24; Table 2; Figure 2). SF-MPQ-2 total scores reached
statistical significance when adjusting for pain burden (d = 0.23).
No other effects reached statistical significance. To explore the
durability of effect over time, we calculated the effect sizes for
changes from T1 to T2, T3, and T4, respectively. For SF-MPQ-2
(adjusted for pain burden) and neuropathic pain, the effects
(Cohen’s d) seemed to be relatively stable over time (SF-MPQ-2: T2,
3392
0.30; T3, 0.31; T4, 0.27; neuropathic pain: T2, 0.31; T3, 0.30; T4,
0.32). For the PPI and pain intensity, effects increased from T2 to
T3, after which the effects declined at T4 (PPI: T2, 0.31; T3, 0.52;
T4, 0.27; pain intensity: T2, 0.54; T3, 0.64; T4, 0.51). When
adjusting for comparisons of multiple outcomes, only pain intensity remained statistically significant (Table 2).
Sensitivity analyses. Sensitivity analyses were performed,
testing the robustness of the observed effect on pain intensity
(that is, the result that remained statistically significant after
correcting for multiple comparisons). The possible influence of
pain intensity at baseline on dropout at T2 was explored with
logistic regression. The result was statistically nonsignificant
(P = .69; odds ratio, 0.96). Two MLMs assuming that dropouts
experienced 50% of the effect observed in the main analysis and
that dropouts experienced zero effect (last observation carried
forward from baseline) were conducted. The time 3 group
effect for pain intensity remained statistically significant in both
the 50%-effect (P = .003; d = 0.56) and the zero-effect analysis
(P = .034; d = 0.39).
Secondary Outcomes
Statistically significant time 3 group effects were observed
for QoL (d = 0.42) and use of nonprescription pain medication
(d = 0.40; Table 2; Figure 3). When examining effects over time,
the effect on QoL at T2 (d = 0.44) and T4 (d = 0.42) were larger
than the effect at T3 (d = 0.31), whereas the effect on use of
nonprescription pain medication increased from T2 (d = 0.31)
to T3 (d = 0.53), followed by a decline at T4 (d = 0.34). The
time 3 group effects for psychological distress and use of
prescription pain medication did not reach statistical significance (Table 2).
Adherence-related effects. The mean number of MBCT sessions
attended in the intervention group was five (SD, 2.19). The mean
total time spent on mindfulness homework during the 8-week
program corresponded to an average of 24 min/d. At T2, mean time
spent on mindfulness during the previous week was 20 min/d,
decreasing to 9 min/d (T3) and 10 min/d (T4). More sessions
attended was associated with larger reductions in pain intensity
(P = .01; d = 0.44), SF-MPQ-2 total score (P = .03; d = 0.36), and
improved QoL (P = .02; d = 0.38) over time. Time spent on mindfulness
practice from T2 to T4 predicted improved QoL (P = .01; d = 0.49). No
further effects of mindfulness practice were found (P = .12 to .92).
DISCUSSION
To our knowledge, the current study is the first with the primary aim
of investigating the efficacy of MBCT on late post-treatment pain in
women treated for BC. MBCT significantly reduced pain intensity,
neuropathic pain, and the PPI (ie, the evaluative pain dimension). No
effect on the affective pain dimensions (ie, pain burden and affective
pain descriptors) or the two sensory pain dimensions of continuous
and intermittent pain were found. When testing the robustness of the
results, pain intensity remained statistically significant, suggesting
that MBCT may have a robust, durable effect on pain intensity in
women treated for BC. In terms of clinical significance, the minimum
clinically important difference on an 11-point NRS for pain intensity
© 2016 by American Society of Clinical Oncology
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JOURNAL OF CLINICAL ONCOLOGY
Efficacy of MBCT on Late Post-Treatment Pain
Table 1. Sociodemographic, Clinical, Pain-Related, and Psychological Characteristics of Study Sample at Baseline and Dropout Analyses
Patient Demographics and
Characteristics
Demographics
Age, mean (SD) [No.], years
Marital status, No. (%)
Married/cohabiting
Not cohabiting/single
Educational level, No. (%)b
Lower (, 2 years of further education)
Medium (2-4 years of further education)
Long ($ 5 years of further education)
Missing
Occupational status, No. (%)
Full- or part-time used
Unemployed or on sickness benefit
Retired
Missing
Participant motivation, mean (SD) [No.]
Use of psychological support during the
last year, No. (%)
Yes
No
Use of CAM treatment during the last
year, No. (%)
Yes
No
Clinical characteristics
Time since surgery, mean (SD) [No.], months
Relapse, No. (%)
Yes
No
Tumor size, No. (%), mm
# 20
. 20 to # 50
. 50
Not reported
Type of surgery, No. (%)
Mastectomy
Lumpectomy
Not reported
ALND, No. (%)
Yes
No
Not reported
Breast reconstruction, No. (%)
Yes
No
ER status, No. (%)c
Positive ($ 1%)
Negative (, 1%)
HER2 status, No. (%)
Positive
Negative
Not reported
Chemotherapy, No. (%)
Yes
No
Radiotherapy, No. (%)
Yes
No
Not reported
Endocrine treatment, No. (%)
Yes
No
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Pa
.96
.50
Intervention Group
(n = 67)
Control Group
(n = 62)
56.8 (9.99) [67]
56.7 (8.10) [62]
47 (70.1)
20 (29.9)
40 (64.5)
22 (35.5)
21
36
9
1
28
29
4
1
.18
58.6 (10.55) [22]
56.4 (8.77) [107]
16 (72.7)
6 (27.3)
71 (66.4)
36 (33.6)
(45.2)
(46.8)
(6.5)
(1.6)
10 (45.5)
11 (50.0)
1 (4.5)
—
39
54
12
2
(36.4)
(50.5)
(11.2)
(1.9)
.76
29
10
24
4
3.30
(43.3)
(14.9)
(35.8)
(6.0)
(0.86) [66]
45 (67.2)
22 (32.8)
22
8
28
4
3.44
(35.5)
(12.9)
(45.2)
(6.5)
(0.74) [62]
.009
.11
35 (56.5)
27 (43.5)
.93
8 (36.4)
3 (13.6)
11 (50.0)
—
3.00 (0.97) [21]
43
15
41
8
3.45
(40.2)
(14.0)
(38.3)
(7.5)
(0.74) [107]
17 (77.3)
5 (22.7)
63 (58.9)
44 (42.1)
7 (31.8)
15 (68.2)
30 (28.0)
77 (72.0)
.72
19 (28.4)
48 (71.6)
.54
.61
.39
.56
Respondents
(Returned Questionnaires;
n = 107)
.56
(31.3)
(53.7)
(13.4)
(1.5)
.53
.35
.21
Pa
Dropouts From
Baseline to
Postintervention
(T2; n = 22)
40.0 (24.56) [66]
18 (29.0)
44 (71.0)
43.2 (34.82) [62]
2 (3.0)
65 (97.0)
1 (1.6)
61 (98.4)
36
27
1
3
30
31
0
1
.42
.45
.45
45.9 (27.42) [22]
1 (4.5)
21 (95.5)
40.6 (30.43) [106]
2 (1.9)
105 (98.1)
.84
(53.7)
(40.3)
(1.5)
(4.5)
(48.4)
(50.0)
(0.0)
(1.6)
.26
12
9
0
1
(54.6)
(40.9)
(0.0)
(4.5)
54
49
1
3
(50.5)
(45.8)
(0.94)
(2.8)
.72
27 (40.3)
38 (56.7)
2 (3.0)
32 (51.6)
30 (48.4)
—
39 (58.2)
26 (38.8)
2 (3.0)
32 (51.6)
28 (45.2)
2 (3.2)
14 (20.9)
53 (79.1)
8 (12.9)
54 (87.1)
55 (82.1)
12 (17.9)
55 (88.7)
7 (11.3)
6 (9.0)
54 (9.0)
8 (11.9)
8 (12.9)
46 (74.2)
6 (9.7)
38 (56.7)
29 (43.3)
39 (62.9)
23 (37.1)
54 (80.6)
7 (10.4)
6 (9.0.)
48 (77.4)
12 (19.4)
2 (3.2)
.32
9 (40.9)
12 (54.6)
1 (4.6)
50 (46.7)
56 (52.3)
1 (0.94)
10 (45.5)
12 (54.5)
—
59 (55.1)
44 (41.1)
4 (3.7)
5 (22.7)
17 (77.3)
17 (15.9)
90 (84.1)
19 (86.4)
3 (13.6)
91 (85.0)
16 (15.0)
1 (4.6)
17 (77.3)
4 (18.2)
13 (12.2)
82 (76.6)
12 (11.2)
10 (45.5)
12 (54.5)
67 (62.6)
40 (37.4)
16 (72.7)
2 (9.1)
4 (18.2)
86 (80.4)
6 (5.6)
15 (14.0)
16 (72.7)
6 (27.3)
78 (73.0)
29 (27.0)
.88
.23
.44
.29
.87
.48
.57
.47
.14
.20
.49
.26
.99
46 (68.7)
48 (77.4)
21 (31.3)
14 (22.6)
(continued on following page)
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3393
Johannsen et al
Table 1. Sociodemographic, Clinical, Pain-Related, and Psychological Characteristics of Study Sample at Baseline and Dropout Analyses (continued)
Patient Demographics and
Characteristics
In active endocrine treatment during
study period, No. (%)
Yes
No
Comorbidity,d No. (%)
No comorbidity
Comorbidity ($ 1)
Not reported
Pain related to breast cancer, No. (%)
Yes
No
Missing
Primary outcome measures
McGill pain total score,e mean (SD) [No.]
McGill subscales,e mean (SD) [No.]
Continuous pain
Intermittent pain
Neuropathic pain
Affective descriptors
Pain intensity (11-point NRS), mean (SD) [No.]
Pain burden (11-point NRS), mean (SD) [No.]
McGill PPI,f mean (SD) [No.]
Secondary outcome measures
Quality of life (WHO-5),g mean (SD) [No.]
HADS total score,h mean (SD) [No.]
Self-reported use of nonprescription pain
medication during last week,
No. (%), times/wk
No use
1-2
3-4
5-6
7-8
.8
Missing
Self-reported use of prescription pain medication
during last week, No. (%), times/wk
0
1-2
3-4
5-6
7-8
.8
Missing
Pa
Intervention Group
(n = 67)
Control Group
(n = 62)
.42
Pa
Dropouts From
Baseline to
Postintervention
(T2; n = 22)
Respondents
(Returned Questionnaires;
n = 107)
.94
41 (61.2)
5 (7.5)
40 (64.5)
8 (12.9)
39 (58.2)
5 (7.5)
23 (34.3)
38 (61.3)
6 (9.7)
18 (29.0)
62 (92.5)
4 (6.0)
1 (1.5)
52 (83.9)
7 (11.3)
3 (4.8)
16 (72.7)
6 (27.3)
77 (72.0)
30 (28.0)
7 (31.8)
4 (18.2)
11 (50.0)
70 (72.0)
7 (6.5)
30 (28.0)
19 (86.4)
2 (9.1)
1 (4.6)
95 (88.8)
9 (8.4)
3 (2.8)
.01
.75
.27
.90
.25
2.90 (1.64) [65]
3.31 (2.10) [62]
.86
3.2 (2.13) [22]
3.1 (1.84) [105]
.08
.28
.86
.22
.57
.04
.12
3.24
2.91
3.08
2.43
5.5
5.8
2.6
3.96
3.37
3.01
2.89
5.3
6.5
2.9
.81
.88
.44
.82
.58
.44
.68
3.5
3.1
3.4
2.7
5.7
5.9
2.7
3.6
3.2
3.0
2.6
5.4
6.2
2.8
.31
.22
.52
46.4 (19.41) [67]
16.5 (6.66) [67]
18
17
6
10
6
9
1
(2.01)
(2.10)
(2.09)
(1.88)
(2.09)
(1.82)
(0.72)
[66]
[67]
[66]
[66]
[60]
[66]
[64]
(26.9)
(25.4)
(9.0)
(14.9)
(9.0)
(13.4)
(1.5)
(2.52)
(2.67)
(2.28)
(2.27)
(2.56)
(2.05)
(0.88)
[62]
[62]
[62]
[62]
[56]
[62]
[56]
42.0 (22.00) [61]
18.1 (7.47) [61]
20
16
9
5
2
9
1
.48
.53
.03
(32.3)
(25.8)
(14.5)
(8.1)
(3.2)
(14.5)
(1.6)
.29
(2.28)
(2.65)
(2.38)
(2.10)
(2.58)
(2.20)
(1.02)
[22]
[22]
[22]
[22]
[19]
[21]
[21]
47.1 (17.5) [22]
16.4 (6.6) [22]
(2.30)
(2.34)
(2.14)
(2.10)
(2.28)
(1.92)
(0.76)
[106]
[107]
[106]
[106]
[97]
[107]
[99]
43.7 (21.4) [106]
17.5 (7.2) [106]
4
4
4
6
3
1
(18.2)
(18.2)
(18.2)
(27.3)
(13.6)
(4.5)
—
34
29
11
9
5
17
2
(31.8)
(27.1)
(10.3)
(8.4)
(4.7)
(15.9)
(1.9)
13
4
2
2
1
0
(59.1)
(18.2)
(9.1)
(9.1)
(4.5)
(0.0)
—
71
9
5
2
7
12
1
(66.4)
(8.4)
(4.7)
(1.9)
(6.5)
(11.2)
(0.94)
.15
46
6
2
4
4
5
(68.7)
(9.0)
(3.0)
(6.0)
(6.0)
(7.5)
—
38
7
5
0
4
7
1
(61.3)
(11.3)
(8.1)
(0.0)
(6.5)
(11.3)
(1.6)
NOTE. The total sample consists of 129 women.
Abbreviations: ALND, Axillary Lymph Node Dissection; CAM, complementary and alternative; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2;
NRS, numerical rating scale; SD, standard deviation.
aStatistically significant group differences (P , .05) are shown in boldface.
bFurther education refers to years of education beyond high school.
cThe number of women with ER-positive tumors and the number of women receiving endocrine treatment differs slightly. The indication for endocrine treatment was
changed in 2010 (from $ 10% to $ 1% ER-positive tumor cells); thus, women with 1% to 9% ER-positive tumor cells treated before 2010 were not offered endocrine
treatment. Also, a number of patients declined receiving endocrine treatment or may have ended their endocrine treatment prematurely because of adverse effects.
dCharlson Comorbidity Index.26
eShort Form McGill Pain Questionnaire 2.28
fPresent Pain Intensity subscale from the McGill Pain Questionnaire.29
gWorld Health Organization–5 Well-Being Index.31,32
hHospital Anxiety and Depression Scale.33
has been proposed to correspond to a 2-point reduction.41 At T3, the
mean reduction in pain intensity in the intervention group reached
1.9, suggesting a clinically important effect.
Neuropathic pain is often reported by women treated for BC42
and has been found difficult to treat pharmacologically.43 Thus, the
observed reduction in neuropathic pain may be of possible clinical
3394
relevance. However, because of less robust results, the neuropathic
pain findings should be considered preliminary. In addition, a statistically significant effect on self-reported use of nonprescription pain
medication was detected, which has not previously been reported for
MBT with women treated for BC. However, as more women in the
intervention group than controls discontinued participation, and as
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JOURNAL OF CLINICAL ONCOLOGY
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Outcome
42.0 (22.00) [61]
18.1 (7.5) [61]
1.7 (1.8) [61]
2.1 (1.8) [61]
46.4 (19.4) [67]
16.5 (6.7) [67]
1.9 (1.8) [66]
1.9 (1.7) [67]
(2.52) [62]
(2.67) [62]
(2.28) [62]
(2.27) [62]
(0.9) [56]
(2.6) [56]
(2.1) [62]
3.96
3.37
3.01
2.89
2.9
5.3
6.5
3.24
2.91
3.08
2.43
2.6
5.5
5.8
(2.01) [66]
(2.09) [67]
(2.10) [66]
(1.88) [66]
(0.7) [64]
(2.1) [60]
(1.8) [66]
3.31 (2.10) [62]
Control
2.90 (1.64) [65]
Treatment
(1.78) [46]
(1.71) [46]
(1.93) [46]
(1.19) [46]
(0.9) [45]
(2.0) [43]
(1.8) [46]
2.1 (1.7) [46]
56.8 (16.6) [46]
15.7 (5.1) [46]
1.5 (1.6) [46]
2.63
2.25
2.39
1.47
2.1
4.02
4.4
2.19 (1.35) [46]
Treatment
(2.35) [61]
(2.66) [61]
(2.29) [61]
(2.12) [61]
(0.9) [53]
(2.5) [57]
(2.2) [59]
2.2 (1.9) [60]
45.5 (21.2) [60]
18.3 (6.4) [61]
1.8 (1.7) [59]
3.62
3.38
2.95
2.51
2.8
5.3
5.7
3.11 (2.04) [61]
Control
Postintervention
(1.77) [41]
(1.86) [42]
(1.75) [41]
(1.31) [40]
(1.0) [39]
(2.1) [39]
(2.2) [42]
1.8 (1.5) [42]
57.2 (19.9) [41]
14.4 (5.9) [41]
1.6 (1.7) [42]
2.83
2.18
2.41
1.42
2.0
3.6
4.1
2.16 (1.41) [40]
Treatment
(2.37) [57]
(2.62) [57]
(2.10) [57]
(2.14) [57]
(0.6) [53]
(2.4) [52]
(2.4) [57]
1.9 (1.8) [57]
46.9 (23.1) [57]
17.5 (6.5) [57]
2.0 (1.9) [56]
3.69
3.30
2.86
2.44
2.7
5.0
5.7
3.07 (2.03) [57]
Control
3-Month Follow-Up
Table 2. Primary and Secondary Outcomes and Estimates of Treatment Effects
(1.84) [39]
(1.87) [39]
(1.87) [39]
(1.44) [39]
(0.9) [36]
(1.9) [38]
(2.4) [39]
1.9 (1.7) [39]
56.2 (20.6) [39]
16.1 (6.4) [39]
1.6 (1.8) [39]
2.65
2.32
2.56
1.62
2.1
4.1
4.3
2.29 (1.48) [39]
Treatment
2.1 (1.9) [56]
45.1 (22.8) [56]
17.8 (6.4) [57]
1.9 (2.0) [56]
3.57 (2.51) [57]
3.51 (2.48) [57]
3.07 (2.34) [57]
2.59(2.07) [57]
2.6 (0.9) [50]
5.1 (2.5) [53]
5.8 (2.3) [52]
3.18 (2.06) [57]
Control
6-Month Follow-Up
.051
.036
.702
.111
.036
.140
.026
.002
.077
(0.22)
(0.23)d
(0.04)
(0.31)
(0.24)
(0.27)
(0.26)
(0.61)f
(0.34)
0.2, .662 (0.05)
4.9, .028 (0.42)
1.2, .275 (0.21)
4.4, .038 (0.40)
3.8,
4.4,
0.1,
2.6,
4.5,
2.2,
5.0,
9.9,
3.2,
Time 3 Group
Interactiona
F, P (Cohen’s d )b
NOTE. Data presented as mean (SD) [No.] unless otherwise noted.
Abbreviations: NRS, numerical rating scale; QoL, quality of life; SD, standard deviation.
aStatistically significant results (P , .05) are shown in boldface. Note that similar P values can yield different effect sizes because of the number of random parameters specified in the model.
bModels specifying a random slope in addition to a random intercept. Note that higher effect sizes may be nonsignificant depending on the degrees of freedom in the model as a result of the number of parameters
specified as random.
cShort Form McGill Pain Questionnaire 2.28
dSignificant when including NRS pain burden at baseline as a covariate
ePresent Pain Intensity subscale from the McGill Pain Questionnaire.29
fStatistically significant result after adjusting for multiple comparisons (Benjamin-Hockberg procedure).
gWorld Health Organization–5 Well-Being Index.31,32
hHospital Anxiety and Depression Scale.33
iPain medication was measured as self-reported use of (prescription) pain medication during the last week and was asked in a categorical format (see categories in Table 1). In the analyses, however, the variables were
entered as continuous variables (interval scale). Therefore, the reported means and SDs do not reflect actual use (i.e. number of times that pain medication was used).
Primary outcomes
SF-MPQ-2c
SF-MPQ-2 subscalesc
Continuous
Intermittent
Neuropathic
Affective
MPQ PPIe
Pain intensity
Pain burden
Secondary outcomes
QoLg
HADSh
Use of nonprescription
pain medicationi
Use of prescription
pain medicationi
Baseline
Efficacy of MBCT on Late Post-Treatment Pain
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3395
Johannsen et al
Patients screened for eligibility
(N = 1,546)
79.7%
Eligible patients
(n = 314; 20.3%)
7.4%
Eligible and interested patients
(n = 200; 12.9%)
4.4%
Informed consent received
(n = 132; 8.5%)
0.2%
Pain ≤ 2
No valid
pain assessment
Ineligible
Not interested
(no to contact)
(n = 1,162)
(n = 61)
(n = 9)
(n = 114)
Declined due to:
Transportation challenges
(n = 2)
Schedule conflict
(n = 34)
Lack of energy
(n = 2)
Use of other pain treatment (n = 2)
Reason unknown
(n = 28)
Withdrew consent
(reason unknown)
(n = 3)
Returned baseline questionnaires
(n = 129; 8.3%)
Randomly assigned
(n = 129)
Dropped out before the
intervention due to:
(n = 4)
(n = 1)
(n = 1)
Schedule conflict
Family concerns
Reason unknown
Allocated to MBCT
(n = 67)
Allocated to wait list control
(n = 62)
Dropped out during the
intervention due to:
Schedule conflict
Hearing and language
difficulties
Too emotionally
challenging
Lack of motivation
Lost to follow-up
(reason unknown)
Did not want to
be on the wait list
(n = 2)
(n = 1)
(n = 2)
(n = 7)
Post intervention (8 weeks)
Returned questionnaires
(n = 46; 68.7%)
Withdrew
(n = 1)
(n = 3)
Post intervention (8 weeks)
Returned questionnaires
(n = 61; 98.4%)
Death in family
Lost to follow-up
(reason unknown)
(n = 3)
Lost to follow-up
(reason unknown)
(n = 1)
Lost to follow-up
(reason unknown)
(n = 3)
3-month follow-up
Returned questionnaires
(n = 42; 62.7%)
3-month follow-up
Returned questionnaires
(n = 57; 91.9%)
6-month follow-up
Returned questionnaires
(n = 39; 58.2%)
6-month follow-up
Returned questionnaires
(n = 57; 91.9%)
Included in analyses
(Intent-to-treat sample)
(n = 67)
Included in analyses
(Intent-to-treat sample)
(n = 62)
(n = 1)
(n = 3)
Fig 1. CONSORT study flow diagram. MBCT, mindfulness-based cognitive therapy.
3396
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JOURNAL OF CLINICAL ONCOLOGY
[57]
2.5
[39]
[46]
2
[40]
1.5
T2
T3
Intermittent pain (SF-MPQ-2)
4
[61]
[57]
[57]
3 [67]
2.5
[39]
[46]
2
[42]
1.5
T1
T2
T3
Mean With Error Bars: 95% CI
Pain burden (11-point NRS)
[62]
6
[66]
[59]
[57]
[52]
5
[46]
4
[42]
[39]
3
T1
T2
T3
T4
[61]
[62]
[57]
[57]
[39]
2.5
[46]
[41]
2
1.5
T1
T2
T3
Affective pain descriptors (SF-MPQ-2)
3
[62]
2.5
[66]
[61]
[57]
[57]
2
[39]
1.5
[46]
[40]
1
0.5
T1
T2
T3
Continous pain (SF-MPQ-2)
5
4.5
4
T4
[62]
[61]
3.5
[57]
[57]
[66]
3
2.5
[46]
[41]
[39]
2
T1
T4
3.5
T4
8
7
[66]
3
T4
4.5
3.5 [62]
3.5
Mean With Error Bars: 95% CI
[57]
3 [65]
T1
Mean With Error Bars: 95% CI
[61]
Mean With Error Bars: 95% CI
[62]
Neuropathic pain (SF-MPQ-2)*
4
Mean With Error Bars: 95% CI
3.5
Mean With Error Bars: 95% CI
SF-MPQ-2 total score*
4
Mean With Error Bars: 95% CI
Mean With Error Bars: 95% CI
Efficacy of MBCT on Late Post-Treatment Pain
T2
T3
T4
Evaluative pain (PPI MPQ)*
3.5
3
[56]
[53]
2.5
[53]
[64]
[50]
[36]
2
[45]
[39]
1.5
T1
T2
T3
T4
Pain intensity (11-point NRS)*
6.5
Intervention
6
5.5
5
Control
No. of respondents appears in brackets
[60]
[57]
[52]
[56]
[53]
4.5
[38]
4
[43]
3.5
T1: Baseline
T2: Post-intervention
T3: 3-month follow-up
T4: 6-month follow-up
*Statistically significant effect (P < .05)
[39]
3
2.5
T1
T2
T3
T4
Fig 2. Raw scores on primary outcomes from baseline to 6-month follow-up. MPQ, McGill Pain Questionnaire; NRS, numerical rating scale; PPI, Present Pain Intensity;
SF-MPQ-2, Short Form McGill Pain Questionnaire 2.
dropouts had used more nonprescription pain medication at baseline
than completers, the effect could possibly be inflated by drop-out bias.
In contrast to previous reported effects of MBTs on anxiety
and depression,12,13,45 we found no statistically significant effects
on psychological distress. A possible explanation could be that
although the mean HADS distress score in the present sample
exceeded the suggested clinical cutoff,46 participants were included
on the basis of their pain experience and not their distress levels.
Furthermore, MBCT focuses on the here-and-now experience, and
the participants’ pain experiences as they unfolded during the
sessions were the main focus during the intervention. Although we
found no effect of MBCT on psychological distress, we did find an
effect on QoL, supporting the findings of a previous MBT study
with patients with BC that had included a 3-month follow-up.45
Our results extend these findings by reporting an effect that goes
beyond 3 months. The minimum clinically important difference
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for the WHO-5 has been suggested to be a 10% change in the total
score.45 At T3 and T4, the intervention group reported an improvement of 10.8% and 9.7%, respectively, suggesting a clinically
significant improvement in QoL.
The current study has several strengths, including a relatively
large sample, a randomized design, and long-term (6 months)
follow-up data. In addition, patient selection was based on initial
pain levels. However, some possible limitations should be noted.
Although the purpose of the current study was to investigate the
efficacy of MBCT on post-treatment pain, we used a wait-list
control group rather than an active treatment control group.
Thus, the present results offer no data on the possible superiority
of MBCT compared with other interventions or on how the
intervention may exert its effect. Research is needed investigating
various psychological mechanisms (eg, level of mindfulness, selfcompassion, and pain catastrophizing)47,48 by conducting mediation
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3397
Johannsen et al
22
[46]
[41]
[39]
55
50
[67]
[60]
[57]
[56]
[61]
40
35
3
20
18
16
[61]
[61]
[57]
[57]
[67]
[46]
14
[39]
[41]
T2
T3
T4
2.5
2
[56]
[66]
[56]
[59]
[61]
1.5
[39]
[46]
[42]
1
12
T1
Mean With Error Bars:
95% CI
60
Mean With Error Bars:
95% CI
Mean With Error Bars:
95% CI
65
45
Use of non prescription pain
medication*
Psychological distress (HADS)
Quality of life (WHO-5)*
T1
T2
T3
T4
T1
T2
T3
T4
Use of prescription pain
medication
Mean With Error Bars:
95% CI
3
Intervention
2.5
[60]
[61]
2
Control
No. of respondents appears in brackets
[67]
[57]
[46]
[56]
[39]
T1: Baseline
T2: Post intervention
T3: 3-month follow-up
T4: 6-month follow-up
[42]
*Statistically significant effect (P < .05)
1.5
1
T1
T2
T3
T4
Fig 3. Raw scores on secondary outcomes from baseline to 6-month follow-up. HADS, Hospital Anxiety and Depression Scale; WHO-5, World Health Organization–5
Well-Being Index.
analyses and including active control groups. Another issue
could be the unbalanced dropout at T2, with more dropouts in
the intervention group than in controls, possibly introducing
biased estimates. However, dropout analyses did not reveal
any baseline differences between dropouts and respondents on
any primary outcome measures, nor did baseline pain intensity
predict dropout at T2. In addition, the sensitivity analyses
conducted for pain intensity indicated that the results were
robust. Future studies are advised to include more assessment
time points to determine whether dropout is related to treatment
gain and should focus on strategies that may help retain more
participants (eg, booster sessions), especially because other MBT
studies with patients with BC report comparable dropout rates
(29% to 32%).13,19
Other limitations include that the current study is a single-center trial design with only one instructor. Furthermore,
although measuring several aspects of pain, we did not include
a specific measure of pain interference or targeted BC-specific
types of pain (eg, joint aches), nor did we ask participants to
indicate the duration of their pain. However, all women were
included $ 3 months post-treatment, which corresponds to
the chronic pain definition stated by the International Association for the Study of Pain. 49 Finally, although there were
generally no group differences at baseline, the difference
found for perceived pain burden could suggest a less than
optimal randomization. However, all primary outcome analyses were adjusted for this variable.
3398
In conclusion, statistically significant, robust, and clinically
relevant effects of MBCT were found for pain intensity, and the
effect seemed relatively stable over time. One out of every five
patients with BC continues to experience pain even several years
after ending treatment,5,6 and persistent pain generally seems to be
difficult to treat effectively pharmacologically. Our results suggest
that MBCT could be an efficacious treatment option for women
treated for BC with late post-treatment pain. Further research is
needed to determine the mechanisms of the effect and to explore
how the effects can be even better maintained over time.
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: Maja Johannsen, Maja O’Connor, Anders Bonde
Jensen, Robert Zachariae
Collection and assembly of data: Maja Johannsen, Maja O’Connor
Data analysis and interpretation: Maja Johannsen, Mia Skytte O’Toole,
Anders Bonde Jensen, Inger Højris, Robert Zachariae
Manuscript writing: All authors
Final approval of manuscript: All authors
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JOURNAL OF CLINICAL ONCOLOGY
Efficacy of MBCT on Late Post-Treatment Pain
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Johannsen et al
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Efficacy of Mindfulness-Based Cognitive Therapy on Late Post-Treatment Pain in Women Treated for Primary Breast Cancer: A Randomized
Controlled Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Maja Johannsen
No relationship to disclose
Maja O’Connor
No relationship to disclose
Mia Skytte O’Toole
No relationship to disclose
Anders Bonde Jensen
Honoraria: Amgen
Travel, Accommodations, Expenses: Amgen
Inger Højris
No relationship to disclose
Robert Zachariae
Research Funding: LEO Pharma
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JOURNAL OF CLINICAL ONCOLOGY
Efficacy of MBCT on Late Post-Treatment Pain
Acknowledgment
We thank all the participating women; the Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen University Hospital, for
providing the clinical data; professor and biostatistician Michael Væth for helpful suggestions concerning the dropout analyses; and Jacob
Piet for valuable discussions during the planning of the study.
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