Pilot study of a multimodal intervention: mixed-type exercise ... - Nature

Bone Marrow Transplantation (2007) 40, 793–800 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00

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ORIGINAL ARTICLE

Pilot study of a multimodal intervention: mixed-type exercise and psychoeducation in patients undergoing allogeneic stem cell transplantation M Jarden1,2, D Hovgaard1, E Boesen3, M Quist2 and L Adamsen2,4 1 Department of Haematology, The University Hospital of Copenhagen, Copenhagen, Denmark; 2The University Hospital’s Centre for Nursing and Care Research, The University Hospital of Copenhagen, Copenhagen, Denmark; 3Department of Psychosocial Cancer Research, Danish Cancer Society, Copenhagen, Denmark and 4University of Copenhagen Faculty of Health Sciences, Copenhagen, Denmark

Substantial physical and functional deconditioning and diminished psychological wellbeing are all potential adverse effects of allogeneic stem cell transplantation (allo-HSCT). The aim of this study was to evaluate the feasibility, safety and benefits (physical and functional capacity) of a 4–6 week supervised and structured mixedtype exercise, progressive relaxation and psychoeducation programme in patients undergoing allo-HSCT. Nineteen patients were randomized to an intervention or a conventional care group (CC) and were tested for physical and functional capacity before admission and upon hospital discharge. In all, 14 patients completed all study requirements (74%) and no adverse reactions that could be attributed to the intervention were observed. At the time of discharge, the intervention group showed significant improvements in several muscle strength scores as compared to the CC group; chest press (P ¼ 0.023), leg extension (P ¼ 0.007) and isometric right knee flexor (P ¼ 0.033). The intervention proved feasible, safe and well tolerated in this small sample of patients undergoing allo-HSCT. An intervention of this type may be a useful strategy for maintaining or improving muscle strength, and minimizing loss of physical and functional capacity in patients undergoing allo-HSCT. Bone Marrow Transplantation (2007) 40, 793–800; doi:10.1038/sj.bmt.1705807; published online 20 August 2007 Keywords: allogeneic stem cell transplantation; cancer; exercise; physical and functional capacity; multimodal intervention

Introduction More than 15 000 myeloablative allogeneic stem cell transplants (allo-HSCT) are performed worldwide each

Correspondence: Ms M Jarden, The University Hospital’s Centre for Nursing and Care Research, The University Hospital of Copenhagen, Department 7331, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark. E-mail: [email protected] Received 15 January 2007; revised 24 June 2007; accepted 4 July 2007; published online 20 August 2007

year mainly for malignant haematological disorders and it is predicted that transplantation rates for allo-HSCT will continue at the same or higher level in the immediate future.1 Owing to advancements in the treatment and care, survival rates have continued to improve over the last two decades, reaching a 20–70% cure rate.1 The standard procedure for myeloablative allo-HSCT entails a conditioning regime of high-dose chemotherapy often in combination with total-body irradiation (TBI), then infusion of stem cells harvested from a donor’s bone marrow or peripheral blood.1 This procedure is followed by a 2- to 4-week period of severe leucopenia and thrombocytopenia while hospitalized in a single bed isolation room for a period of 4–6 weeks. The severely depressed bone marrow function increases the risk of bleeding, infection and anaemia, subsequently resulting in weakness, fatigue, shortness of breath and insomnia.2 Furthermore, side effects related to severe mucositis and gastrointestinal complications induce nausea, emesis, diarrhoea and eventually a compromised nutritional intake.2 The principle complication of allo-HSCT is graft vs host disease (GvHD), where prophylaxis and treatment include immune suppression and glucocorticoids, both associated with muscle atrophy.3,4 Allo-HSCT can lead to substantial physical and functional deconditioning and diminished psychological wellbeing.5,6 Fatigue is one of the most frequent side effect reported by patients who have undergone an HSCT in quality-of-life evaluations.7 Thus, there is a continued need for the development and testing of intervention strategies that address the specific physical and psychological impairments experienced by patients undergoing allo-HSCT. Lately, there has been an increasing interest in examining exercise, relaxation and psychoeducational interventions with the goal of preventing and reducing impairments experienced as a result of HSCT. The majority of research has focused on exercise interventions following allo-HSCT or autologous peripheral blood stem cell transplantations (PBST). To our knowledge, exercise initiated before transplantation and then throughout hospitalization has not been tested. One exercise trial in patients undergoing allo-HSCT, started after infusion of donor stem cells, with treadmill and range

Multimodal intervention M Jarden et al

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of motion exercises, and found significant improvements in muscle strength after 6 weeks.8 Three other exercise programmes reported improvements in aerobic capacity and fatigue measurements,9 aerobic fitness, fatigue severity and physical well-being;6,10 however, these programmes were home-based and were initiated after alloHSCT. Similarly, only a few exercise interventions have been tested in patients after autologous peripheral blood stem cell transplantations (PBST). This procedure involves high-dose chemotherapy followed by re-infusion of the patient’s own stem cells. Courneya et al.11 found in their explorative study of patients after PBST, a significant correlation between exercise and physical and psychological wellbeing. Hayes’ aerobic and resistance exercise programmes showed a positive correlation between peak aerobic capacity and quality of life.6 Dimeo’s bed ergometer aerobic intervention following PBST minimized loss of physical performance and found fewer medical complications.12 These findings, despite the small sample sizes and lack of randomized design, suggest that there are preliminary positive physiological and psychological benefits from exercise in patients after PBST and allo-HSCT. But due to lack of evidence, no recommendation can be issued for patients during treatment and hospitalization for allo-HSCT. In cancer patients experiencing multiple and complex illness and treatment-related side effects, intervention studies that combined different types of exercise with psychosocial interventions have shown to improve physical capacity, reduce treatment-related side effects and improve quality of life.13 Clinically controlled trials using psychoeducation interventions based on cognitive-behavioural theory, decreased emotional distress and enhanced coping skills14 and reduced pain and fatigue.15 Furthermore, progressive relaxation is shown to have a positive impact on cancer treatment-related side effects.16 This body of research provides evidence that exercise, psychoeducation and progressive relaxation can each positively have an impact on physical and functional capacity and psychological indices in cancer patients. We chose to test a programme integrating these elements, deemed a multimodal intervention, to support the patient’s complex situation during allo-HSCT. The objective of the present study is to investigate the feasibility, safety and possible benefits (physical and functional capacity) of a supervised and structured multimodal intervention programme in patients undergoing myeloablative allo-HSCT. To our best knowledge, this is a first time study that examines a multimodal intervention in an allo-HSCT patient group, initiated before allo-HSCT and carried out throughout hospitalization.

Patients and methods Design This pilot study is a prospective, randomized pre- and post-test clinically controlled trial comparing an intervention group to a control group receiving conventional care. Bone Marrow Transplantation

Patients and procedures Coordination and treatment of allo-HSCT in Denmark is centrally carried out at The University Hospital of Copenhagen. Patients between the ages of 18–65 years were eligible for the study if they were to undergo a standard myeloablative allo-HSCT and met the eligibility criteria. The exclusion criteria included recent cardiovascular or pulmonary disease, an abnormal electrocardiogram, psychiatric disorder, motor function, musculoskeletal or neurological disturbances requiring walking aids and bony metastasis. If before the pre- and post-tests, the patients showed signs of infection (T4381C), anaemia (haemoglobin Hbgo5 g/dl), neutropenia (absolute neutrophil count ANCo0.05 109/l) or thrombocytopenia (plateletso20 109/l) they were disqualified or testing postponed. Patients were randomized and stratified by gender and age to an intervention or control group. All patients signed a written informed consent and the study was approved by the Scientific Committees of the Copenhagen and Frederiksberg municipalities (J.no. 01-173/04) and by the Danish Data Protection Agency (J.no. 2004-41-4266). Assessment instruments Demographic data and leisure time physical activity level were collected at baseline.17 Disease and treatment variables were obtained through patient chart review. Patients were tested at baseline during their pre-transplantation admission (test 1) and repeated on the day of hospital discharge 71 day (test 2). All tests were performed between 9:00 a.m. and 12:00 noon by the same research investigator (MJ). The patients were instructed on proper technique for all tests, and advised to stop if they experienced pain or extreme discomfort, nausea or dizziness. The battery of tests included: (1) physical capacity measured by an estimated oxygen uptake (VO2max), one-repetition maximum (1RM) and maximal isometric voluntary strength (Newton), (2) functional capacity measured by a 2 min stair-climbing test, (3) four questionnaires (EORTC-QLQC30, FACT-An, HADS and Mini Mac), (4) a body and training logbook, (5) a project journal and (6) interviews. Owing to the small sample size in this pilot study only data from (1) the physical, (2) functional capacity tests, (4) body and training logbook and (5) project journal are presented here. Physical capacity Aerobic capacity. A single-stage 6 min submaximal exercise test; the Aastrand-Rhyming cycle ergometer test was used to predict VO2max values.18 The test is based on the linear relationship between VO2 and heart rate. The patients pulse was continuously monitored using a wireless heart rate transmitter. Resistance (Watt) was increased to elicit a steady-state heart rate between 125 and 170 beats/ min at a speed between 60 and 65 r.p.m. If after 6 min the HR was above 125 beats/min and stable, not fluctuating more then 5 beats/min, the test was terminated. VO2max was determined using a nomogram with an age and body weight correction factor.18 VO2max is stated in ml/kg/min.


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Isotonic muscular strength. Estimated 1 RM tests were used to evaluate upper and lower body strength potential.19 The two tests (1) chest press and (2) leg extension, measured performance on technogym variable resistance equipment and targeted the large muscle groups. 1 RM is stated in kilograms. Maximal isometric voluntary strength test. The right elbow and knee flexors were tested for maximal isometric strength.19 Placed in a sitting position with flexion of the right shoulder at 451 and 901 at the right elbow, the patient pulled a non-elastic strap placed in the right hand exerting the maximum strength sustained for 3 s. For the right knee flexors, the patient was placed on a sitting position with flexion in the right hip and knee at 901. The patient kicked a non-elastic strap secured on the right ankle exerting the maximum strength sustained for 3 s. The measuring unit is stated in Newtons (N).

Functional performance The 2 min stair-climbing test was used to assess the patient’s functional capacity and capability of performing everyday activities like stair climbing and walking in a controlled setting.20 The patient climbed and descended two flights of standardized stairs for two consecutive minutes with the goal of covering the maximal number of steps. Body and training logbook All components of the intervention performed were recorded daily by the study investigator (MJ); including exercise mode, frequency, intensity, duration and progression as well as subjective exercise response and heart rate. Screening criteria and observations for adverse effects were documented in the project journal. Components performed above and beyond that prescribed in the intervention programme, that is weekends or evenings, were documented by the patient. The control group received a modified logbook and were asked to register exercise mode, frequency and duration during hospitalization. Multimodal intervention The multimodal intervention programme (Table 1) was designed using principles and recommendations for cancer patients21 combined with psychoeducation, an ongoing and structured supportive and educational intervention.22

Table 1

This programme took place in the patient’s hospital room and each session was 1 h710 min, 5 days weekly during hospitalization between 9 a.m. and 12 noon beginning the first day of admission (day 7) until the day of discharge. The same research investigator (MJ) administered and supervised all sessions. The patients were continuously monitored with a digital heart rate monitor (Polar Model). If one or more of the following criteria was present before the intervention, the session was either postponed or modified on that specific day; diastolic blood pressure o45 or 495 mm Hg, pulse at rest 4100/min, signs of infection (temp4381C); respiration frequency at rest 420/ min; ongoing bleeding, fresh petecchiae; bruises; thrombocytopenia (platelets o20 109/l) and anaemia (haemoglobin o5 g/dl). During the sessions, patients were observed for sudden pain or discomfort, nausea or dizziness in which the intervention would be stopped immediately. Aerobic exercise. After a 4 min warm up, stationary cycling was initiated for a period of 15–30 min daily. Individual rest intervals were allowed and training did not exceed 75% of the maximal heart rate calculated by Karvonen’s equation (220-age-HR basal þ 50/75%).23 The subjective intensity of effort was evaluated by using the Borg Rate of Perceived Exertion scale (RPE), a visual analogue scale ranging from 6 (light effort) to 20 (very hard effort).24 Intensity effort during training ranged between 10 and 13 (somewhat hard). Patient’s performance varied due to changes in clinical status and tolerance, therefore mean pedal frequency ranged between 30 and 70 cycles/min and a mean work load of 50 W (range 30–75 W) was readjusted daily to achieve the heart rate goal, and then kept constant during each session. Since patients cycled 5 days/week, the main goal of aerobic progression was to gradually increase exercise duration and intensity. Cycling alternated with the following dynamic, stretching and resistance exercises: Daily dynamic exercises included neck movements, shoulder rotations, hip flexion/extension, standing calf raise, ankle dorsi and plantar flexion and performed in 1–2 sets of 12 repetitions and daily stretching exercises included chest expansion, back expansion, hamstring stretch, quad stretch and double calf-stretch, holding positions between 15 and 30 s. Stretching exercises were performed after cycle training. Resistance training was performed three times weekly using free hand and ankle weights; bicep curl, shoulder press, triceps extension, chest press, flyer, squat, hip flexion, knee extension and leg curl

Multimodal intervention: mixed-type exercise and psycho-education

Mode

Frequency

Intensity

Duration

Progression

Stationary cycling

5 days/week 5 days/week

15–30 min/session with or without rest intervals 15–20 min/session

Increase intensity and duration

Dynamic and stretching exercises Resistance training

3 days/week

Progressive relaxation Psychoeducation

2 days/week Ongoing

Low to moderate 50–75% HR max RPE 10–13 Dynamic: 1–2 sets, 10–12 reps Static: 1 set, hold for 15–30 s Low to moderate 1–2 sets of 10–12 reps RPE 10–13 Low RPE 6–9

15–20 min/session 20 min/session

Abbreviations: HR: heart rate maximum; Reps: repetitions; RPE: rate of perceived exertion.

Bone Marrow Transplantation


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and extension. Daily core exercises for abdominal and back muscles were added. All exercises were performed in 1–2 sets of 10–12 repetitions. Weight was adjusted so that the patient was able to perform 2 sets and up to 12 repetitions. Exercises were modified so they could be performed lying, sitting or standing according to the patient’s clinical status and tolerance level. Progressive relaxation training was performed twice weekly for 20 min. Patients alternated between muscle tensing (5 s) and muscle relaxation (30 s) for each muscle group, while lying supine in bed and following audio-recorded instructions.25 Psychoeducation was individual and based on behavioural and cognitive therapy techniques,22 incorporated 5 days per week to help the patients adjust to diagnosis and treatment. The aim was to foster a fighting spirit and a sense of personal control, to increase motivation and self-efficacy.

Control group Patients randomized to the control group received the departments’ standard of care for physical activity while undergoing allo-HSCT. All patients were advised to remain active during their hospitalization and physiotherapy was offered individually, 2–3 days (range 1–112 h) per week following allo-HSCT (day þ 1). Physiotherapy varied from patient to patient in mode, frequency, intensity and duration and therefore not considered a consistent, structured programme. A stationary cycle was available, if requested by the patient. Setting Patients were restricted to a single-bed room with laminar airflow allowing a germ-free environment upon initiation of chemotherapy and until evidence of bone marrow recovery (ANCX0.5 109/l). The criteria for hospital discharge were trilinear haematopoietic reconstitution, transfusion independency, temp.o381C resolution of stomatitis and able to meet daily nutritional requirements.

Data analysis Feasibility of the study is evaluated from the criteria of acceptability, attrition and adherence.10 Acceptability is measured by the percentage of eligible patients who agreed to participate in the study. Attrition is calculated by the percentage of patients who did not complete the study. For each individual component in the programme, adherence to the intervention is measured by calculating the percentage of recommended exercise sessions performed by the patient (number of sessions performed/number of sessions prescribed). Adherence calculations only include the prescribed sessions.

Safety and tolerability Daily evaluation of adverse effects related to the training sessions was assessed before and during each session. Exclusion days from the intervention programme due to adverse reactions are considered a parameter of safety and tolerability, as well as increased rate of infection measured Bone Marrow Transplantation

in days with elevated temperature (4381C), and reconstitution time measured in days from stem cell infusion (day 0) to bone marrow engraftment (ANC X0.5 109/l for two consecutive days). Benefits of the intervention were measured by pre- and post-testing for physical and functional capacity. To test for comparability of groups, the physical and functional capacity data was first examined by conducting a Kolmogorov–Smirnov and Shapiro–Wilk test. Being normally distributed, independent samples tests were thereafter applied to compare the difference between the pre- and post-tests within each group and then between the two groups. Calculations for statistical analysis were performed using SPSS and a value of Po0.05 was accepted as statistically significant.

Results Patient characteristics Baseline descriptive data for the 14 of 19 patients who completed all study requirements are summarized in Table 2. Feasibility Acceptance and attrition. During the inclusion period, 36 patients were registered, of which 22 were found eligible, two declined participation. The study enrolled 20 patients, an acceptance of 91%. One patient became ineligible due to cancellation of allo-HSCT. Fourteen of nineteen patients (74%) completed all study requirements. In the intervention group, six of the nine patients completed all study requirements, representing a 33% attrition rate. From the intervention group, one patient became ineligible shortly after the initiation of the intervention due to medical reasons. Two patients left the study, one after one week due to lack of interest in exercising, and one did not complete the post-tests due to travel and scheduling constraints. Two patients from the control group refused the post-tests due to complaints of tiredness. Of the 14 patients who completed all study requirements, 6 patients were from the intervention group and 8 from the control group. Adherence. Patients in the intervention group trained mean 94% (89–100%) of the total expected training days. These training sessions included at least one of the physical training components. Six of the nine days where patients did not train were due to constraints related to the day of admission or discharge. The three other reasons were central venous catheter discomfort, elevated temperature and an incident of emesis before training. When considering the different components of the intervention, patients participated in mean 86% (60–96%) of the expected cycling sessions, mean 88% (65–97%) of the expected dynamic and stretching exercise sessions and 100 and 100% of the expected resistance and relaxation training sessions, respectively. The control group reported engaging in different modes of exercise (dynamic exercises, cycle) varying in frequency (0–1.5 h/week) and intensity from day þ 1.


797 Table 2 Demographic and clinical characteristics of study participants Demographic and clinical characteristics of study participants (n ¼ 14) Control group Intervention (n ¼ 8) group (n ¼ 6) Age (18–65 years) Body mass index (BMI)

Gender Male Female Baseline level of physical activity I Sedentary II Walking or bicycling for pleasure—less than 3 h/week III Regular physical exercise—at least 3 h/week IV Athletic—more than 4 h/week Diagnosis Chronic myelogenous leukaemia Acute myelogenous leukaemia Acute lymphocytic (lymphoblastic) leukaemia Aplastic anaemia Multiple myeloma Non-Hodgkin’s lymphoma Paroxysmal nocturnal hemoglobinuria Myelofibrosis Conditioning regime Total-body irradiation and Cyclophosphamide Total-body irradiation and Etopofos Busulphan and Cyclophosphamide ATG and Cyclophosphamide

37a 18–53 range 22.1a 20.1–30.5 range

34a 18–58 range 27.0a 24.2–41.4 range

4 4

4 2

1 4

5

3

1

2 2 1

1 1 1 2

1 1 1 1

4

3

2 2

1 1 1

Donor Matched related donor Matched unrelated donor

4 4

3 3

Source of stem cell Bone marrow Peripheral stem cell

4 4

4 2

a

Median.

Safety and tolerability. No adverse reactions or injuries were observed as a result of the testing or exercise programme. Days with elevated temperature (4381C) was mean 5 days (2–12 days) and 6 days (0–12 days), and number of days to bone marrow engraftment was mean 27 days (22–29 days) and 29 days (22–34 days) for control and intervention groups, respectively; which indicates that the intervention group did not have an interruption in reconstitution time nor was there an increase of infection. Benefits. At baseline, no statistical difference was found between the physical and functional capacity measures, allowing comparability of the two groups. The point of pretesting (test 1) was the same for both groups, while the post-test (test 2) was carried out on the day of discharge.

Admission days and therefore the point in time for test 2 were mean 34 days (range 30–37) and 40 days (range 28– 43), respectively. The difference in mean scores for muscle strength reached statistical significance for the chest press (P ¼ 0.023), leg extension (P ¼ 0.007) and the isometric right knee flexor test (P ¼ 0.033). The difference in mean scores for the isometric right elbow (0.098), stair climbing (P ¼ 0.118) and estimated VO2max (P ¼ 0.273) did not reach statistical significance, though indicated a positive trend in the intervention group (Table 3).

Discussion This study provides data concerning the feasibility, safety and possible benefits of a multimodal intervention designed to minimize the loss of physical and functional capacity in patients undergoing allo-HSCT. Furthermore, it makes specific contributions to the growing literature on supportive interventions in patients undergoing stem cell transplantations. The study participants were concurrently undergoing allo-HSCT treatment; the conditioning phase (high-dose chemotherapy, total-body irradiation), infusion of stem cells, myelosuppression and reconstitution while engaging in the study. This intervention was a supervised, structured and individual programme of a 4–6 week duration that involved mixed-type exercise, progressive relaxation and psychoeducation. Other exercise studies with allo-HSCT, initiated exercise programmes at later points in time than our study. One study began after blood and marrow infusion, with muscle strength as the only outcome.8 Other published studies with allo-HSCT were initiated after hospital discharge and were home-based.9,10 Dimeo12 and Courneya11 reported the effect of exercise in patients undergoing autologous PBST, initiated after infusion of stem cells. Autologous PBST is different from allo-HSCT in that, the myeloablative treatment is less intense and hospitalization is considerably shorter (2–3 weeks) than can be expected for allo-HSCT (4–6 week hospitalization). In addition, patients are not at risk of experiencing side effects associated with donor transplantations, that is immune suppressants, GvHD. Treatment differences must be considered when comparing interventions and outcomes. An acceptability rate of 94% was achieved, indicating that patients were very interested in being physically active during hospitalization. This is significant because it was not clear that we would be able to recruit this treatment population into an exercise protocol, let alone effectively retain them in the programme. Because allo-HSCT’ are performed only at The University Hospital of Copenhagen, acceptability rates reflect all patients recruited to this treatment in Denmark. The acceptability rate may be partially due to patients viewing physical activity as a means of achieving a positive medical outcome through active participation. During hospitalization, all patients undergoing allo-HSCT experience severe treatment-related side effects, however, despite this, fourteen of nineteen patients (74%) completed all study requirements, a retention rate similar to that of other studies.8 The attrition rate for control and intervention groups were comparable. The Bone Marrow Transplantation


798 Table 3

Pre- and post-physical and functional capacity scores Mean pre-scores (s.d.)

Mean post-scores (s.d.)

Mean change D ¼ (T2-T1)

P-value

Chest press (kg 1 RM)

55.83 (721.8) 46.25 (714)

55.83 (719.3) 39.38 (713.1)

0 6.8

0.023*

1 2

Leg extension (kg 1 RM)

67.92 (723) 56 (715)

72.08 (720.3) 46.88 (79.2)

4.1 9.1

0.007*

1 2

Right elbow (N)

2.58 (71.1) 2.48 (772)

2.72 (70.84) 2.04 (70.54)

0.14 0.44

0.098

1 2

4.89 (71.9) 4.07 (71.5)

4.9 (71.8) 3.48 (71.2)

0.1 0.59

0.033*

1 2

Right knee flex (N) Estimated VO2max (ml/kg/min)

2.3 (791) 1.82 (747)

2.21 (70.62) 1.4 (70.58)

0.09 0.42

0.273

1 2

Stair test (number of steps)

Group

Test

1 2

210.23 (736) 216.63 (748)

171.33 (736) 141.63 (735)

39 75

0.118

Group 1 intervention n ¼ 6, *P ¼ o0.05. Group 2 control n ¼ 8, s.d. ¼ standard deviation.

post-tests for physical and functional capacity were a challenge for patients who felt weakened and there were time constraints due to the discharge procedure. We must also consider that losing patients between pre- and posttesting can potentially influence test outcomes in that, refusal of post-testing by severely de-conditioned patients might imply that only the ‘most fit’ were able to complete the study. Since two patients from the control group refused post-testing due to weakness, perhaps this would have revealed an even greater effect difference between groups. The intervention groups adherence rate is slightly higher (94%) than in studies with structured and supervised training during standard cancer treatment (78%)8,13,26 and following treatment in home-based programmes (62%).9,10 This positive overall intervention adherence rate and individual component adherence rates (86% aerobic, 88% exercise, 100% resistance and 100% relaxation) can be attributed to the sessions taking place during hospitalization, being individualized with a psycho-education component that took the patient’s specific needs and preferences into account. Furthermore, the continuity factor of the same research investigator providing and supervising a consistent structured programme resulted in the patient experiencing the necessary security and confidence in their own ability to perform physically, thus motivating and increasing efforts made. The intervention group even reported self-training on weekends (mean 4.5 days, range 2–12 days) throughout hospitalization. Gaining insight and knowledge in the importance of staying active can be initiated during the treatment phase and may be the key to understanding and dealing with physical and psychological symptoms experienced during and following allo-HSCT. It is found that up to 78% of stem cell transplantation survivors experience fatigue,7 a multidimensional concept often accompanied by lack of motivation and inactivity.27 No adverse reactions were noted due to the multimodal intervention. In addition to the programme being safe and well tolerated, it addresses the concern about the special Bone Marrow Transplantation

problems associated with exercising patients during alloHSCT, that is low platelet counts, infection. Despite the small sample size, we found a statistically significant positive effect difference in three of four muscle strength tests (lower and upper body strength). This has also been reported in Mello when exercising patients following allo-HSCT.8 VO2max levels were maintained in the intervention group, though statistical significance was not attained. However, this trend is comparable to Dimeo’s findings, where partial prevention in loss of physical performance was attained in patients following PBST.26 The clinical significance of the results lies not only in the difference in mean change scores between groups, but in the fact that patients were able to safely participate in a 5 days/ week programme. Even though, the control group engaged in some physical activity, they showed a larger loss of physical and functional capacity on all outcome tests. The loss of VO2max measured in the control group can partly represent loss of muscle strength, but we can also assume that it reflects actual loss of physical condition. Convertino28 showed that even healthy persons placed on 3–4 weeks of bed rest resulted in a reduction of VO2max by 20%. Furthermore, based on the knowledge that the largest loss of physical capacity occurs during the first 10 days of inactivity,28 may be one explanation why the intervention group showed a larger loss of VO2max. In addition, both the frequency of the intervention and the combination of components may have contributed to the positive effects. Training patients who experience multiple and concurrent side effects demand frequent rest intervals; therefore, the length of the sessions may have enabled adequate time to complete the programme. More importantly, patients were capable of remaining active during their hospital stay. What affect this active behaviour has on quality of life and other clinical parameters during and after hospitalization will be addressed in a subsequent article. The gold standard of maximal oxygen uptake requires patients to perform a maximal stress test, however, wearing a mask is uncomfortable for patients recovering from


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severe stomatitis, as reported by Dimeo.29 Therefore, oxygen uptake in this study was estimated by a submaximal cycle test, requiring a work intensity that was realistic for weakened patients at both pre- and post-test points. The selection of the stair-climbing test to measure functional capacity, though not a standard test method, was validated by Harding et al.20 Patients in the intervention group were unable to maintain their performance level, though they were able to minimize loss of functional capacity, as compared to the control group. Studies have shown, that the number of stairs climbed correlates well with pulmonary function, but that performance on the stairs may be explained by other factors like cardiac function, selfdetermination, cooperation and motivation.30 The methodological strengths of the present randomized, controlled pilot study are the homogeneous patient sample (allo-HSCT) and the objective evaluation of physical and functional capacity at pre- and post-test points. Furthermore, an advantage of the applied study design is the steady recruitment of all patients admitted for allo-HSCT in a small country. All diagnostic procedures, treatment schedules and study conditions are standardized, reducing variations in outcomes. However, a range of methodological limitations are recognized, including the small sample size, a limitation seen in studies in similar settings.8–10 The inclusion and exclusion criteria took safety and ethical factors into consideration, excluding all patients under 18 years and those presenting with concurring medical problems. The attrition rate is also in line with similar studies,8 where competing schedule and travel restraints, challenges in coordinating study requirements and withdrawal due to side effects were all reasons why achieving a larger sample size is a major challenge. Although the study sample is deemed homogeneous (allo-HSCT), there were variations in baseline characteristics and other concomitant factors, such as attitudes towards exercising and life experiences with handling adversity; factors that could potentially affect outcomes. However, no consistent pattern that can explain the difference in the two groups can be identified and due to the small sample, it is difficult to predict the influence these factors had on the outcome of this study. Owing to ethical considerations, the control group was not a non-exercising group and despite being given reasonable conditions to be active during admission, patients were considerably less active, which Courneya also found in patients following PBST.11 A further limitation of the study is the point in time of post-testing, which was dependent upon the discharge date and therefore varied between patients. Despite the limitations, we find these preliminary data to be encouraging as part of a growing literature supporting the use of mixed-exercise, progressive relaxation and psychoeducation in treatment regimes for patients undergoing allo-HSCT. With continued improvements in alloHSCT outcome and survival rates, this type of intervention can be an important component of complementary treatment in preventing or counteracting debilitating side effects. It is, however, too early to conclude how the elements of the intervention individually or in interaction may be responsible for the observed changes. It is possible

that subsequent studies will explain some of these mechanisms and help to define the exact role of the intervention. In addition, there is a need to examine the effects of the intervention on intermediate and long-term health benefits (side effects, hospitalization days, quality of life and survival time). We conclude that this multimodal intervention during hospitalization proved to be feasible, safe and well tolerated with possible benefits in this small sample of patients undergoing allo-HSCT.

Acknowledgements We gratefully acknowledge the study participants, the staff and administration at the Department of Haematology, University Hospital of Copenhagen. This research was supported by grants from The Lundbeck Foundation, The Novo Nordic Foundation, The Danish Cancer Society, The Copenhagen Hospital Corporation and The Danish Nursing Society.

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