Setting and participants
The design of the two-arm randomised controlled PACT study has been published elsewhere [12]. In short, the present study was conducted in seven hospitals (one academic and six general hospitals) in the Netherlands between 2010 and 2013. Participants were invited by their clinician or oncological nurse during a regular outpatient clinic visit. The inclusion criteria were a definitive full histological breast cancer diagnosis <6 weeks before recruitment; stage M0 (i.e., no distant metastasis); scheduled for chemotherapy (as part of the treatment regime); aged 25 to 75 years; not treated for any cancer in the preceding 5 years (except basal skin cancer); able to read and understand the Dutch language; Karnovsky Performance Status of ≥60; and no contra-indications for physical activity. Inclusion was irrespective of the patients’ current physical activity level. The 6-week period was extended to 10 weeks if patients had a mastectomy with immediate reconstruction involving the use of tissue expander (n = 19). In the Netherlands, if indicated, patients usually receive radiotherapy for 3 to 4.5 weeks before chemotherapy if they are at low risk of distant metastases (less than four positive lymph nodes). Otherwise radiotherapy is scheduled after chemotherapy. By starting the intervention within 6 weeks post-diagnosis, we made sure that all patients participated in the 18-week exercise program during (part of their) chemotherapy.
The study was approved by the Medical Ethics Committee of the University Medical Centre Utrecht and the local Ethical Boards of the participating hospitals (i.e., St. Antonius Hospital, Nieuwegein; Diakonessenhuis Hospital, Utrecht; Meander Medical Centre, Amersfoort; Rivierenland Hospital, Tiel; Orbis Medical Centre, Sittard; Zuwe Hofpoort Hospital, Woerden).
Breast cancer patients willing to participate were asked to visit the study centre to confirm eligibility and sign informed consent. A concealed computer-generated randomisation, following a 1:1 ratio, stratified per age, adjuvant treatment (radiotherapy yes/no before chemotherapy), use of tissue expander, and hospital by sequential balancing, was used to allocate participants to study groups. Blinding of participants was not possible due to the nature of the study, but outcome measures were assessed by researchers not involved with the participants. Colon cancer patients were also included in the PACT study. Results for colon cancer patients will be presented separately to be able to address site-specific issues. Further, results of a formal cost-effectiveness analysis will be reported elsewhere.
Intervention
An 18-week exercise programme was offered to patients randomised to the intervention group in addition to usual care. The programme included two aerobic and strength exercise sessions per week, supervised by a physiotherapist and incorporating cognitive behavioural principles of social Bandura’s cognitive theory [13]. The 60-min exercise classes included a warming-up (5 min), aerobic and muscle strength training (25 min each), and a cooling down (5 min) period. The exercise program was individualized to the patients’ preferences inventoried during the first exercise session and fitness level assessed by means of a cardiopulmonary exercise test and 1-repetition maximum muscle strength tests.
Intensity of the aerobic training was based on the heart rate at the ventilatory threshold as determined during baseline cardiopulmonary exercise test. The aerobic training included interval training of alternating intensity performed with a heart rate at (3 × 2 min increasing to 2 × 7 min) or below (3 × 4 min decreasing to 1 × 7 min) ventilatory threshold. Heart rate and the Borg scale of perceived exertion were monitored during the aerobic training.
Muscle strength training was performed for all major muscle groups: arms, legs, shoulder, and trunk. The training started with 2 × 10 repetitions (65 % one-repetition maximum) and gradually increased to reach 1 × 10 repetitions (75 % one-repetition maximum) and 1 × 20 repetitions (45 % one-repetition maximum) by the end of the programme. Training intensity was re-evaluated every four weeks by a submaximal cardiopulmonary exercise test and by repeating the 1-repetition maximum muscle strength tests. In addition, the participants of the intervention group were encouraged to be physically active for at least 30 min on at least three other days as recommended by the Dutch guidelines for physical activity [14]. This should include an aerobic component of moderate intensity in agreement with the participants’ fitness and desires.
Participants randomised to control received usual care and were asked to maintain their habitual physical activity pattern up to week 18. Then, they were allowed, for ethical reasons, to participate in exercise programmes, offered in the Netherlands to cancer patients after completion of primary treatment for over 10 years and are thus part of usual care.
Outcome measures
Participants visited the study centre for outcome assessment at baseline, post-intervention (18 weeks), and after 36 weeks.
Fatigue, the primary outcome (at 18 weeks), was assessed using the Multidimensional Fatigue Inventory (MFI) and the Fatigue Quality List (FQL). The validated MFI is a 20-item questionnaire designed to measure general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue [15]. Scores range from 4 to 20, with higher scores indicating more fatigue. The FQL consists of 28 adjectives, clustered in four subscales: frustrating, exhausting, pleasant, and frightening, addressing the perception of fatigue [16]. Participants were asked to indicate the adjectives that fit their experienced fatigue.
Quality of life (QoL) was assessed using the validated 30-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [17] and the 36-item Short Form Health Survey (SF-36) [18, 19]. Anxiety and depression were assessed using the validated Dutch language version of the 20-items Hospital Anxiety and Depression Scale [20].
Aerobic capacity was determined using a cardiopulmonary exercise test with continuous breathing gas analysis. After a 1-min warm-up at 20 W, cycling workload was increased every minute by a predetermined 10, 15, or 20 W until exhaustion or symptom limitation (dyspnoea and/or fatigue). Objective criteria for exhaustion were peak heart rate >85 % of age-predicted maximal HR, and respiratory exchange ratio >1.10. The load for each patient was defined according to the patient’s condition in order to reach exhaustion in about 10 min. The test was terminated on the basis of the patient’s symptoms or at the physician’s discretion. Peak oxygen uptake (VO2peak) was determined by taking the mean of VO2 values of the last 30 s before exhaustion. In addition, VO2 and power output were assessed at ventilatory threshold [21].
Thigh muscle strength was evaluated using a Cybex dynamometer at angular velocities of 60°/s and 180°/s. The highest peak torque of three repetitions was calculated for both velocities and both legs.
Handgrip strength was obtained taking the best score of two attempts provided by a mechanical handgrip dynamometer for both hands.
Body weight and height were measured to the nearest 0.5 kg and 0.5 cm, respectively, with patients wearing light clothes and no shoes.
Physical activity level was evaluated using the validated Short QUestionnaire to ASsess Health enhancing physical activity (SQUASH) [22]. This questionnaire contains questions on commuting activities, leisure-time and sports activities, household activities, and activities at work, and consists of three main queries: days per week, average time per day, and intensity referring to a normal week in the past months. We calculated the minutes per week of moderate to high intensity total physical activity and leisure and sport activity.
Adherence
The attendance rate for the exercise sessions and the compliance with the protocol of the exercise sessions were recorded in a Case Record Form. Adherence to the exercise recommendation was recorded by the patients in an exercise log.
Sample size calculation and statistical analysis
In order to detect a between-group change in fatigue of 2 units (±4 SD) at 18 weeks, corresponding to a medium effect size [23], we needed 75 participants in the intervention and control group (alpha = 0.05, power = 0.80) anticipating a drop-out of 10 %. With the current number of participants (n = 204) we are even able to detect smaller effect sizes.
Intention-to-treat mixed linear regression models were used to model the different outcome measures at 18 and 36 weeks. These models were adjusted for baseline values of the outcome, hospital, age, adjuvant radiotherapy, use of tissue expander, and tumour receptor status (triple negative/Her2Neu+, ER+ or PR+/Her2Neu+, ER– and PR–/Her2Neu–, ER+ or PR+). Between-group effects were modelled using outcome measurements obtained at 18 and/or 36 weeks; participants with only baseline data were not included in this analysis.
Within-group changes were modelled using outcome measurements obtained at the three time points (i.e., at baseline, and at 18 and/or 36 weeks) so all patients with at least one measurement were included in this analysis.
A sensitivity analysis was performed to assess whether having started chemotherapy before randomisation modified the intervention effect on fatigue. Standardized effect sizes (ES) were calculated by dividing the adjusted between-group difference of the post-intervention means by the pooled baseline standard deviation. According to Cohen, effect sizes <0.2 indicate ‘no difference’, effect sizes of 0.2 to 0.5 indicate ‘small differences’, effect sizes of 0.5 to 0.8 indicate ‘moderate differences’, and effect sizes ≥0.8 indicate ‘considerable differences’ [23].
We performed per-protocol analyses among adherent participants, i.e., excluding intervention and control participants reporting physical activity levels, respectively, below or above the 210 min of moderate-to-vigorous physical activity per week as assessed by the SQUASH questionnaire expected from participation in the intervention.