The Alberta physical activity and breast cancer prevention trial: Quality of life outcomes1

Preventive Medicine 52 (2011) 26–32

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Preventive Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y p m e d

The Alberta physical activity and breast cancer prevention trial: Quality of life outcomes1 Kerry S. Courneya a,⁎, Ame-Lia Tamburrini b, Christy G. Woolcott c, Margaret L. McNeely d, Kristina H. Karvinen e, Kristin L. Campbell f, Anne McTiernan g, Christine M. Friedenreich b a

Faculty of Physical Education and Recreation, University of Alberta, Edmonton, Alberta, Canada T6G 2H9 Alberta Health Services, Calgary, Alberta, Canada T2N 4N2 Departments of Obstetrics & Gynecology and Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada B3K 6R8 d Departments of Physical Therapy and Oncology, University of Alberta, Edmonton, Alberta, Canada T6G 2G4 e Department of Exercise and Sports Science, East Carolina University, Greenville, NC 27858, USA f Department of Physical Therapy, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3 g Prevention Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA b c

a r t i c l e

i n f o

Available online 8 November 2010 Keywords: Exercise Physical activity Breast cancer Quality of life

a b s t r a c t Objective. Interventions for disease prevention should also be evaluated for quality of life (QoL) effects. Few exercise trials have examined QoL in the context of primary disease prevention. Here, we report the QoL outcomes from the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial. Methods. The ALPHA trial was a randomized controlled trial in Calgary and Edmonton, Canada between May 2003 and July 2007 that compared an exercise intervention to a sedentary lifestyle among 320 sedentary, postmenopausal women. The exercise group was asked to perform moderate-to-vigorous intensity aerobic exercise 45 min/day, 5 days/week for 1 year. QoL was assessed by the short form-36 health survey. Results. Compared to the control group, the exercise group maintained significantly better physical functioning (p b 0.001), general health (p b 0.001), vitality (p = 0.002), and bodily pain (p = 0.020) by 4–5 points which exceeds the 3.0 minimally important difference for these scales. Changes in body composition partially mediated the intervention effects. Antidepressant use and the presence of comorbidities moderated some intervention effects. Conclusions. A 1-year moderate-to-vigorous aerobic exercise program prevents declines in the physical aspects of QoL in postmenopausal women. Exercise may have a potentially important advantage for breast cancer prevention compared to other lifestyle or biomedical interventions. © 2010 Elsevier Inc. All rights reserved.

Quality of life (QoL) is a critical outcome in clinical trials testing interventions for disease prevention. Any improvements in disease prevention must be weighed against potential effects on QoL. Most exercise trials have examined QoL in the context of clinical or elderly populations where rehabilitation or disease management is the primary goal (Bize et al., 2007; Gillison et al., 2009). In the primary prevention setting, most exercise studies have used cross-sectional or prospective observational designs with the attendant difficulties of assigning causality (Bize et al., 2007; Martin et al., 2009). With few exceptions (Bowen et al., 2006; Martin et al., 2009), the small number of randomized controlled trials in the primary prevention setting have been limited by modest adherence, short term interventions, small sample sizes, and unsupervised exercise. Moreover, few exercise trials

⁎ Corresponding author. Faculty of Physical Education and Recreation, University of Alberta, E-488 Van Vliet Center, Edmonton, Alberta, Canada T6G 2H9. Fax: + 1 780 492 8003. E-mail address: [email protected] (K.S. Courneya). 1 Trial registration clinicaltrials.gov identifier: NCT00522262. 0091-7435/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2010.10.014

have examined potential mediators or moderators of QoL. The demonstration of a causal effect of exercise on QoL in the primary prevention setting may provide an important proximal benefit that can sustain motivation while achieving the longer term disease prevention effects. Moreover, such a positive effect on QoL from an exercise intervention may be contrasted against potential negative or null effects from biomedical or other lifestyle interventions designed to target disease prevention. In this paper, we report the QoL outcomes from the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial (Friedenreich et al., 2010). The ALPHA Trial was a primary prevention trial designed to determine the effects of a 1-year exercise intervention on biologic markers hypothesized to mediate the inverse association between physical activity and breast cancer risk. The primary endpoints of the trial were sex hormones and adiposity. We previously reported an excellent adherence rate, a low attrition rate, and changes in sex hormones and adiposity that were consistent with a reduced risk of breast cancer (Friedenreich et al., 2010, in press). In the present paper, we hypothesized significant improvements in QoL,

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especially for the physical health components of QoL. Moreover, we expected that these improvements would be mediated by both improved body composition and cardiorespiratory fitness. Finally, we explored common demographic and health factors as potential moderators of the intervention effects, and also tested for a dose–response association with exercise adherence. Methods Setting and participants The design and methods for the ALPHA Trial have been reported elsewhere (Friedenreich et al., 2010). In brief, the ALPHA Trial was a two-center, randomized controlled trial involving postmenopausal women living in Calgary and Edmonton, Alberta, Canada. Women were recruited through mailings to participants in the Alberta Breast Screening Program, posters and brochures distributed to family physicians, and media campaigns. Eligibility criteria included: age 50–74 years, postmenopausal, no previous cancer diagnosis, sedentary (b 90 min of weekly exercise), able to do unrestricted physical activity (BCMH/CSEP, 2002), normal blood lipid and hormone levels, body mass index (BMI) between 22 and 40 kg/m2, nonsmoker, no medications or exogenous hormones that might influence estrogen metabolism, and not planning to undertake a weight loss program. A telephone screen identified eligible women who then attended an information session in which the study was explained and informed consent obtained. Further screening occurred based on questionnaires, a mammogram, physician approval, a blood draw, and a submaximal fitness test. Participants were then randomized to either a 1-year exercise intervention or a control group.

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scores indicating better QoL (Ware et al., 2002). The health transition item remained in its original format with “1” indicating that health was “much better than 1 year ago” and “5” indicating that health was “much worse than 1 year ago.”

Covariates and proposed moderators Standard items on demographics, medical, and reproductive history were obtained from a self-administered questionnaire at baseline and have been reported elsewhere (Friedenreich et al., 2010). Past year dietary intake was assessed using the National Cancer Institute's 124-item Diet History Questionnaire previously adapted for use in Canada (Csizmadi et al., 2007) and occupational, household and recreational physical activity were assessed using the validated Past Year Total Physical Activity Questionnaire (PYTPAQ) (Friedenreich et al., 2006).

Proposed mediators Assessments of body composition and cardiorespiratory fitness have been reported elsewhere (Friedenreich et al., 2010, in press). Briefly, a modified Balke treadmill protocol was used to estimate maximum oxygen consumption (VO2max) from submaximal exercise intensities (ACSM, 2006). Weight and height measurements were made using a balance beam scale and a stadiometer. Body mass index (BMI) was calculated as weight/height (kg/m2). Waist and hip circumferences were measured to the nearest 0.1 cm using a metal tape measure. Total body fat and body fat percentage were assessed using whole body dual energy x-ray absorptiometry (DXA) scans.

Randomization The randomization sequence was created by the study biostatistician using a random number program in S-plus®. Stratification was done by center (Calgary, Edmonton) and BMI (b 27.5, ≥ 27.5 m/kg2) with blocks randomly sized between four and six within strata. Sealed opaque envelopes containing randomized numbers were only opened by the Study Coordinator in Calgary at the time of randomization. Exercise and control interventions Participants randomized to the exercise intervention were asked to perform moderate-to-vigorous intensity aerobic exercise for at least 45 min on 5 days/week for 1 year (i.e., 225 min/week). At least three sessions/week were supervised at a fitness facility with on-site exercise trainers and the remaining sessions were unsupervised. Participants wore heart rate monitors (Polar® A3) to ensure an intensity of 70–80% of their heart rate reserve. The exercise prescription increased gradually over the first 3 months. The program was individualized to the age and fitness level of each participant. Several methods were used to increase exercise adherence including scheduling of all facility-based sessions, telephone follow-up of missed sessions, plans for vacations, group sessions, an educational package, incentives, and regular newsletters. Adherence was monitored by weekly exercise logs completed by the participants (all exercise) and the trainers (facility-based exercise). Women in the control group were asked to maintain their current exercise levels and were offered a 1-month supervised exercise program after their postintervention assessments. Both the exercise and control participants were asked not to change their diet or attempt weight loss. Outcome measures The outcome of interest in the present paper was QoL, which was assessed by the Medical Outcomes Study short form survey (SF-36) (Ware et al., 2002). This survey contains 36 questions covering eight health scales: general health (personal evaluation of health), physical and social function (ability to take part in physical and social activities), role-physical and emotional (barriers to work or daily activities due to physical or emotional health problems), bodily pain (feeling of pain and limitation due to pain), vitality (feeling energetic or fatigued), and mental health (daily feeling of nervousness, depression, peacefulness, happiness or calm). A single item assesses perceived change in health (how much better or worse your health is now compared to 1 year ago). The eight subscales were transformed into 0–100 scales with higher

Power calculation and statistical analyses Sample size for the trial was based on the primary endpoints of sex hormones and body composition. For the present report, we estimate that our planned sample size of 320 (160 per group) would allow us to detect between group differences on the QoL scales of about 0.33 standard deviations with a power of 0.80 and two-tailed alpha of 0.05. To evaluate the effect of the exercise intervention on QoL, general linear models were used. We computed the mean change from baseline to 12 months in each QoL subscale by group assignment. The differences between the exercise and control groups were tested with two-sample t-tests. In subsequent general linear models, we included the baseline value of the QoL variable and examined the effect of covariates that may have been different between exercisers and controls by chance. The following covariates were explored for their confounding effects: site (Calgary, Edmonton), age, marital status (married, other), education (≤ high school, ≥some college education), BMI, presence of comorbidities (0 or ≥1 comorbidity), and use of antidepressants (yes, no). We used intention-to-treat analyses that included all participants with 12 month data regardless of their protocol adherence. We also conducted a sensitivity analysis using baselineobservation-carried-forward for the 14 participants (4.4%) with missing 12 month QoL data. Multiple regression was used to test the mediating role of cardiovascular fitness and body composition (i.e., weight loss, waist circumference, and % body fat) on QoL outcomes where we observed a significant intervention effect (Baron and Kenny, 1986). This approach requires that the outcome of interest (QoL) be regressed on the proposed mediator (cardiorespiratory fitness, body composition) and the intervention (group assignment coded as “0” = control and “1” = aerobic exercise). Mediation is present when the proposed mediator maintains a significant relationship with the outcome whereas group assignment becomes nonsignificant. We also used general linear models to assess effect modification by our proposed moderators in an interaction test. Proposed moderators included age (b 60 vs. ≥ 60), marital status (yes/no), education (≤ high school vs. N high school), site (Calgary vs. Edmonton), BMI (b 27.5 vs. ≥ 27.5 m/kg2), use of antidepressants (yes/no), and presence of comorbidities (yes/no). We analyzed the dose–response association between exercise adherence and QoL using trend analyses with adherence as a continuous variable followed by independent t-tests comparing the controls to three prespecified levels of exercise adherence (b150 min per week vs. 150–225 min per week vs. N 225 min per week). All statistical tests were two-sided with a level of significance set at 0.05. The analyses were conducted in SAS (Version 9.1, SAS Institute, Inc., Cary NC).

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covariates and moderators examined in the present report (Table 1). QoL data were obtained at postintervention (12 months) from 153 controls (96%) and 153 exercisers (96%). Adherence to the intervention has been reported elsewhere (Friedenreich et al., 2010). Briefly, the exercise group completed an average of 3.6 (SD=1.3) sessions/week for a mean duration of 178.5 (SD=76.1) minutes. As assessed with the PYTPAQ at 12 months, the exercise group increased their recreational activity by 20.2 MET-hours/ week compared to 3.2 MET-hours/week in the control group (p b 0.01). Changes in the proposed mediators of QoL have also been reported elsewhere (Friedenreich et al., 2010, in press). Briefly, cardiorespiratory fitness increased by 3.9 ml/kg/min (14.2%) in the exercise group compared to 0.7 ml/kg/min (2.6%) in the control group (p b 0.01). Moreover, the exercise group lost 2.3 kg of body weight compared to 0.5 kg for the controls (pb 0.01) and 2.0% body fat compared to 0.2% (p b 0.01).

Table 1 Baseline covariates and proposed moderators for the randomized participants in the ALPHA Trial, Alberta, Canada, 2003–2007. Baseline characteristic

Exercise group (n = 160)

Age (years), n (%) ≤60 N60 Site, n (%) Calgary Edmonton Education, n (%) ≤High school ≥College/trade, undergraduate degree Marital status, n (%) Married, common-law Divorced, separated, widowed Body mass index (kg/m2), n (%) ≤27.5 N27.5 Use of antidepressants, n (%) Yes No Presence of comorbidities,⁎ n (%) Yes No

Control group (n = 160)

73 (46) 87 (54)

82 (51) 78 (49)

77 (48) 83 (52)

78 (49) 82 (51)

48 (30) 112 (70)

58 (36) 102 (64)

113 (70) 47 (30)

125 (78) 35 (22)

63 (39) 97 (61)

62 (39) 98 (61)

18 (11) 142 (89)

14 (9) 146 (91)

100 (63) 59 (37)

90 (56) 70 (44)

Main effects of the exercise intervention on quality of life Table 2 reports the main effects of the exercise intervention on QoL. In general, the exercise group maintained QoL compared to declines in the control group. Specifically, the exercise group significantly maintained physical functioning (adjusted mean group difference = +5.2; 95% CI = 2.1–8.2; p b 0.01), general health (adjusted mean group difference = +4.1; 95% CI= 1.6–6.6; p b 0.01), vitality (adjusted mean group difference = +5.2; 95% CI= 1.9–8.5; p b 0.01), and bodily pain (adjusted mean group difference = +5.1; 95% CI = 0.8–9.4; p = 0.02); and borderline significantly maintained mental health (adjusted mean group difference = +2.2; 95% CI = −0.2 to 4.5; p = 0.07). No statistically significant differences were found for role-physical (p = 0.21), social functioning (p = 0.23), or role-emotional QoL (p = 0.62). Results were unchanged when using baseline-observation-carried-forward for the 14 participants with missing 12 month QoL data. The exercise group also reported a significantly more positive health transition from 1 year ago (p b 0.01). Specifically, 109 of 153 (71%) participants in the exercise

⁎ Comorbidities include having been diagnosed with angina, arthritis, MI, stroke, thyroid disease, blood clots in the leg or lung, or hypercholesterolemia.

Results Flow of participants through the trial has been reported elsewhere (Friedenreich et al., 2010). Briefly, recruitment began in May 2003 and was completed in June 2006. Postintervention assessments were completed by July 2007. Of 3454 women assessed for eligibility, 1965 did not meet the inclusion criteria, 274 were excluded for other reasons, 895 refused participation, and 320 women were randomized. Baseline characteristics of the two groups were similar including the

Table 2 Main effects of the exercise intervention on quality of life outcomes in the ALPHA Trial, Alberta, Canada, 2003–2007. Baseline Mean General health Exercise group Control group Physical functioning Exercise group Control group Role–physical Exercise group Control group Bodily pain Exercise group Control group Vitality Exercise group Control group Social functioning Exercise group Control group Role–emotional Exercise group Control group Mental health Exercise group Control group

a

Postintervention SD

a

Mean

SD

81.6 83.8

13.7 12.4

82.0 79.8

15.1 13.3

88.4 86.1

9.7 15.1

88.6 83.2

14.4 14.7

91.0 94.1

21.0 17.4

87.3 84.9

27.4 30.1

80.0 81.8

17.7 16.5

77.2 73.5

21.6 20.0

68.1 69.3

15.5 16.2

69.5 65.5

18.2 18.4

92.0 96.2

15.5 9.2

91.7 90.7

15.8 16.7

90.0 93.9

23.6 19.7

88.2 88.9

26.9 26.2

83.2 84.6

11.9 10.7

84.6 83.5

11.7 12.5

Baseline adjusted difference in mean change b

Mean

95% CI

Fully adjustedc difference in mean change

p-value

Meanb

95% CI

p-value

3.7

1.2–6.2

b0.01

4.1

1.6–6.6

b0.01

4.5

1.4–7.6

b0.01

5.2

2.1–8.2

b0.01

3.1

−3.4 to 9.5

0.35

4.0

−2.3 to 10.4

0.21

4.6

0.3–8.9

0.04

5.1

0.8–9.4

0.02

4.9

1.5–8.2

b0.01

5.2

1.9–8.5

b0.01

1.7

−1.9 to 5.4

0.35

2.2

−1.4 to 5.8

0.23

0.8

−4.9 to 6.5

0.79

1.5

−4.2 to 7.2

0.62

1.9

−0.5 to 4.2

0.13

2.2

−0.2 to 4.5

0.07

a Means are based on available data. bMean change may not precisely reflect differences between means as they are calculated based on generalized linear model. Difference is based on between group. cAdjusted for baseline value and presence of comorbidities (having been diagnosed with angina, arthritis, MI, stroke, thyroid, blood clot in leg, blood clot in lung, and/or hypercholesterolemia. Abbreviations: CI, confidence interval; SD, standard deviation. n = 153 exercisers and 153 controls. Scales range from 0 to 100 with higher scores indicating better quality of life.

Percentage With Each Response

K.S. Courneya et al. / Preventive Medicine 52 (2011) 26–32

100 90

Control

80

Exercise

29

(p b 0.01) compared to a 1.4 point advantage for participants with one or more comorbidities (p = 0.64). No other proposed moderators significantly moderated the intervention effects.

70

Dose–response association between exercise adherence and quality of life

60 50 40

There was an association between exercise adherence and QoL for all eight QoL outcomes (Table 3). The general pattern was for a threshold association that occurred with 150–225 min of exercise/ week (Figs. 2a to h).

30 20 10 0 Much worse

Worse

Same

Better

Discussion

Much better

The effects of the exercise intervention on the physical QoL subscales in our trial were about 4–5 points which exceeds the 3.0 minimal important difference (MID) for these scales (Ware et al., 2007). Moreover, the standardized effect sizes ranged from about 0.30 to 0.40 which would be considered small-to-moderate and of potential clinical importance. A recent systematic review located 56 randomized controlled trials of exercise and QoL but only 11 involved well participants (i.e., disease prevention) (Gillison et al., 2009). The findings for the well participants showed no effect of exercise on measures of overall QoL but significant small standardized effects of around 0.20 on specific measures of physical and psychological health. The main moderator of the findings in that review was exercise intensity with light intensity exercise resulting in better overall and psychological QoL and moderate intensity exercise resulting in better physical QoL. The moderate-to-vigorous intensity nature of the exercise intervention in the ALPHA trial may partly explain our significant effects on physical QoL but not mental QoL. Two other primary prevention trials are noteworthy and directly comparable to the ALPHA trial. Bowen et al. (2006) compared a similar 1-year aerobic exercise intervention to a stretching control group in 173 postmenopausal women at high risk for breast cancer and, consistent with the present study, found significant positive effects on general health and physical functioning at 12 months. An effect on mental health was present at 3 months but not 12 months. In the ALPHA trial, we did not complete an assessment of QoL during the trial and, therefore, cannot address the issue concerning the timing of QoL changes. In the Dose–Response to Exercise in Women (DREW) trial, Martin et al. (2009) examined the effects of a 6-month, moderate intensity exercise program performed at three different exercise volumes (75, 150, and 225 min weekly) compared to a no intervention group in 430 postmenopausal women at high risk for cardiovascular disease. Results showed a general dose–response effect on all QoL subscales except bodily pain. Our trial showed some evidence that changes in body composition, especially percent body fat and waist circumference, partially mediated the effects of the exercise intervention on physical QoL. We found no

Fig. 1. Effects of the exercise intervention on general health transition from 1 year ago in the ALPHA Trial, Alberta, Canada, 2003–2007.

group reported that their general health was much better (n = 57; 37%) or somewhat better (n = 52; 34%) than a year ago compared to 22 of 153 (14%) participants in the control group reporting that their general health was much better (n = 6; 4%) or somewhat better (n = 16; 10%) than a year ago (Fig. 1). Tests of mediation Change in percent body fat partially mediated the effect of the exercise intervention on change in bodily pain (% body fat: β = −0.19, p b 0.01; group assignment: β = 0.08, p = 0.17) and change in physical functioning (% body fat: β = −0.21, p b 0.01; group assignment: β = 0.10, p = 0.06). Change in waist circumference also partially mediated the effect of the intervention on change in bodily pain (waist circumference: β = −0.19, p b 0.01; group assignment: β = 0.09, p = 0.09). No other variables significantly mediated the effects of the exercise intervention; however, the general pattern was for the body composition variables to slightly attenuate the effects with no such attenuation for cardiorespiratory fitness. Tests of moderation Antidepressant use moderated the effect of the exercise intervention on role-emotional QoL (p for interaction = 0.04). Specifically, exercise resulted in an 18.3 point advantage for participants using antidepressants (p = 0.11) compared to a −1.1 point disadvantage for participants not using antidepressants (p = 0.72). The presence of comorbidities moderated the effect of the exercise intervention on bodily pain (p for interaction = 0.04). Specifically, exercise resulted in a 10.4 point advantage for participants with no comorbidities

Table 3 Changes in quality of life from baseline to postintervention by exercise adherence in the ALPHA Trial, Alberta, Canada, 2003–2007. QOL variable

General Health Physical function Role-physical Bodily pain Vitality Social function Role-emotional Mental health

Control group

≤ 150 min/week

Mean (95% CI)

Mean (95% CI)

p

−3.5 −3.5 −7.9 −7.7 −3.6 −3.6 −3.7 −0.7

−6.7 ( −10.1 to −3.3) −3.5 (−7.7 to 0.8) −10.9 (−19.9 to −2.0) −9.7 (−15.7 to −3.7) −6.8 (−11.3 to −2.3) −6.3 (−11.4 to −1.3) −8.8 (−16.8 to −0.8) 1.1 (−2.3 to 4.4)

0.09 0.97 0.54 0.56 0.21 0.35 0.26 0.36

(−5.2 to −1.8) (−5.7 to −1.4) (−12.3 to −3.4) (−10.7 to −4.7) (−5.9 to −1.4) (−6.2 to −1.1) (−7.7 to 0.3) (−2.3 to 1.0)

N225 min/week

150–225 min/week ‡

p for trend

Mean (95% CI)

p‡

Mean (95% CI)

P‡

1.7 0.9 −5.7 −2.4 2.7 −1.7 −0.7 0.9

0.01 0.02 0.60 0.06 0.01 0.43 0.43 0.31

4.7 (1.7–7.6)** 6.9 (3.0–10.7)** 4.7 (−3.4 to 12.7)* 2.9 (−2.5 to 8.3)* 6.8 (2.7–10.9)** 2.9 (−1.6 to 7.5)* 1.0 (−6.3 to 8.2)* 2.7 (−0.4 to 5.7)

b0.01 b0.01 b0.01 b0.01 b0.01 0.02 0.27 0.06

(−0.8 to 4.3)** (−2.3 to 4.1) (−12.5 to 1.1) (−7.0 to 2.1) (−0.8 to 6.1)* (−5.6 to 2.1) (−6.9 to 5.4) (−1.6 to 3.5)

b 0.01 b 0.01 0.02 b 0.01 b 0.01 0.02 0.21 0.05

Means and confidence intervals (CI) presented are adjusted for the baseline QOL values and presence of comorbidities. n = 153, 40, 66, and 47 for controls and three exercise adherence levels ≤150, 150–225, N 225 min/week, respectively. ‡ p value for comparing the adherence group to controls. * Significantly different (p b 0.05) from ≤ 150 min group. ** Significantly different (p b .001) from ≤150 min group. Trend test for the quality of life changes across controls and three adherence groups. Abbreviation: CI, confidence interval. n = 153 exercisers and 153 controls.

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a

b

Change in general health score between baseline and 12 months by controls and three adherence groups

Change in physical function score between baseline and 12 months by controls and three adherence groups 8

4.7

4 1.7

2 0 -2 -4

-3.5

-6 -6.7

Adjusted mean change (QOL units)

Adjusted mean change (QOL units)

6

-8

6.9

6 4 2 0.9

0 -2 -4

Control

<150

150-225

>225

c 4.7

4 2 0 -2 -4 -6

-5.7 -7.9

-10

4

-10.9

-12 Control

<150

150-225

0 -2 -2.4

-4 -6 -8

-7.7

-10

-9.7

Control

<150

150-225

>225

f 6.8

6 4

2.7

2 0 -2 -3.6

-6 -6.8

-8 Control

<150

Change in social function score between baseline and 12 months by controls and three adherence groups 4

Adjusted mean change (QOL units)

8

Adjusted mean change (QOL units)

2.9

2

>225

Change in vitality score between baseline and 12 months by controls and three adherence groups

2.9

2 0 -2 -4

-1.7

-3.6

-6 -6.3

-8 150-225

>225

Control

g

<150

150-225

>225

h

Change in role-emotional score between baseline and 12 months by controls and three adherence groups 1.0

0 -0.7

-2

-3.7

-6 -8 -8.8

-10

Change in mental health score between baseline and 12 months by controls and three adherence groups 4

Adjusted mean change (QOL units)

2

Adjusted mean change (QOL units)

>225

-12

e

-4

150-225

Change in bodily pain score between baseline and 12 months by controls and three adherence groups Adjusted mean change (QOL units)

Adjusted mean change (QOL units)

6

-4

-3.5

<150

d Change in role-physical score between baseline and 12 months by controls and three adherence groups

-8

-3.5

Control

3

2.7

2 1.1

1

0.9

0 -1

-0.7

-2 Control

<150

150-225

>225

Control

<150

150-225

>225

Fig. 2. Associations between exercise adherence and: (a) general health, (b) physical functioning, (c) role-physical, (d) bodily pain, (e) vitality, (f) social function, (g) role-emotional, and (h) mental health in the ALPHA Trial, Alberta, Canada, 2003–2007.

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evidence of mediation by cardiorespiratory fitness or body weight. Anecdotally, many of the women commented that they noticed changes in their body composition (i.e., fat loss and muscle gain) despite the modest weight loss. This observation may have improved their physical QoL. It is also possible that improvements in functional ability from fat loss and muscle gain may also have improved physical QoL. Few trials have examined mediators of QoL changes in the context of disease prevention. In the DREW trial, Martin et al. (2009) reported that controlling for body weight and cardiorespiratory changes did not substantively alter the effects of their interventions on QoL. Bowen et al. (2006) reported that change in cardiorespiratory fitness predicted change in physical functioning in the intervention group but they did not statistically test for mediation. In disease management trials, improvements in cardiovascular fitness have mediated improvements in physical QoL, but not mental QoL, in breast cancer patients (Courneya et al., 2003) and lymphoma patients (Courneya et al., 2009). It is also possible that psychosocial aspects of the intervention may explain the improved physical health outcomes (e.g., increased social interaction, positive social support, distraction from daily worries), although we did not measures such aspects. Future trials may consider assessing potential mediating psychosocial outcomes such as self-efficacy, social support, self-esteem, and enjoyment. Exercise adherence was associated with QoL improvements in the ALPHA trial. The general pattern was a threshold association that occurred between 150 and 225 exercise minutes per week which is consistent with current public health recommendations (USDHHS, 2008). There were further gains in QoL by exceeding this goal and, if anything, participants falling short of the 150 min reported worse QoL than the control group. In the ALPHA trial, the dose–response analysis is a nonrandomized comparison and participants that achieved the exercise prescription are likely different than those who did not achieve the exercise prescription. The DREW trial (Martin et al., 2009) examined the dose–response issue using randomized comparisons and observed a general dose–response effect across 75, 150, and 225 min of exercise per week. Use of antidepressant medication modified the effect of the exercise intervention on role-emotional QoL but not other QoL subscales. Specifically, participants using antidepressant medications experienced significant benefit from the exercise intervention, whereas participants not using antidepressants experienced no benefit. Moreover, the existence of comorbidities also modified the effects of the intervention on bodily pain with participants reporting no comorbidities experiencing significant benefit from the intervention compared to participants reporting one or more comorbidities. Given the large number of analyses, it is possible that these interactions are a chance finding. Nevertheless, the DREW trial (Martin et al., 2009) also reported antidepressant use to modify the effect of the exercise interventions on QoL including the mental QoL scales of role-emotional, social functioning, and vitality. It is also well established that exercise can improve depressive symptoms in patients with clinical depression (Perraton et al., 2009). Future trials should continue to monitor the effects of antidepressant medications and comorbidities on the QoL effects of exercise. Our results were not modified by age, marital status, education, location, or BMI suggesting benefits across a wide-cross section of postmenopausal women. The strengths of our trial include the 1-year exercise intervention, the mostly supervised exercise protocol, excellent adherence, minimal loss-to-follow-up, a large sample size, a valid measure of QoL, and statistically and clinically meaningful effects on physical QoL. The limitations of our trial include some contamination in the control group (23% reported N150 min of exercise/week during the intervention), some changes to dietary energy intake in both groups (20% of exercisers and 31% of controls decreased their caloric intake N300 kcal/day), the inherent social interaction of a supervised exercise intervention that may influence QoL, and the large number of analyses which increases the chances of false positive findings. Nevertheless, given the overall pattern of our results, it is unlikely that the effects of our intervention on QoL are due entirely to chance.

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Our efficacy trial is further limited by the use of a select population and a supervised exercise intervention that restrict its generalizability and its potential for dissemination. The women in our trial had relatively high baseline QoL and it is unclear if women with lower QoL would benefit as much from an exercise intervention (Gillison et al., 2009). Moreover, the high level of baseline QoL, along with the sedentary older sample and year-long intervention, may explain why our intervention effect was largely derived from the prevention of decline in physical QoL. In terms of dissemination, the ALPHA trial intervention could probably be implemented at community-based fitness centers with qualified staff among highly motivated women. Given its sophistication in terms of exercise training principles and its demanding nature, it is unclear if such a program could be self-directed by most women with minimal or no supervision. Future pragmatic trials are needed to test exercise interventions that may be more feasible and have greater potential for dissemination. In summary, our trial provides strong evidence that a moderateto-vigorous aerobic exercise intervention performed over a 1 year period has beneficial effects on physical QoL in postmenopausal women. Our mediation analyses suggest that improvements in body composition may partially explain these benefits but other mechanisms are likely at work. These data suggest a potentially important additional benefit from using exercise for disease prevention compared to no QoL benefit from diet (Hislop et al., 2006) and no QoL benefit or even a worsening of QoL from pharmacological interventions (Day et al., 1999). Additional research on QoL effects of exercise in the context of disease prevention is warranted. Conflict of interest statement The authors declare that there are no conflicts of interest.

Acknowledgment Funding/support This study was funded by a research grant (#017468) from the Canadian Breast Cancer Research Alliance which played no role in the conduct, analysis, or interpretation of the study. Dr. Courneya is supported by the Canada Research Chairs Program. Dr Friedenreich was funded by career awards from Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. Study set-up: Kim van der Hoek and Marla Orenstein; Study Coordinators: Rosemary Crosby, Fitness Centre Managers: Ben Wilson, Lisa Workman, Diane Cook; Exercise Trainers: Shannon Hutchins, Kathy Traptow; Shannon Brown, Susan Daniel, Parissa Gillani, Stephanie Sanden, Karen Mackay, Sandra Olsen; Data analysis: Qinggang Wang. Author contributions Drs. Courneya and Friedenreich, as co-Principal Investigators of this study, had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analyses. Study concept and design: Courneya, McTiernan, Friedenreich. Acquisition of data: Courneya, Woolcott, McNeely, Karvinen, Campbell, Friedenreich. Analysis and interpretation of data: Courneya, Tamburrini, Woolcott, McNeely, Karvinen, Campbell, McTiernan, Friedenreich. Drafting of the manuscript: Courneya, Tamburrini, Friedenreich. Critical revision of the manuscript for important intellectual content: Courneya, Tamburrini, Woolcott, McNeely, Karvinen, Campbell, McTiernan, Friedenreich. Statistical expertise: Tamburrini. Obtained funding: Courneya, McTiernan, Friedenreich. Administrative, technical or material support: Courneya, Tamburrini, Woolcott, McNeely, Karvinen, Campbell, McTiernan, Friedenreich, Study supervision: Courneya, Friedenreich.

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Appendix A. Supplementary data Supplementary data to this article can be found online at doi:10.1016/j.ypmed.2010.10.014.

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