Changes in exercise capacity, quality of life and fatigue in cancer patients during an intervention

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1 bs_bs_banner Original article Changes in exercise capacity, quality of life and fatigue in cancer patients during an intervention W. BANZER, MD, PHD, PROFESSOR, Department of Sports Medicine, Goethe-University, Frankfurt am Main, M. BERNHÖRSTER, MD, Department of Sports Medicine, Goethe-University, Frankfurt am Main, K. SCHMIDT, MA, Department of Sports Medicine, Goethe-University, Frankfurt am Main, D. NIEDERER, MSC, Department of Sports Medicine, Goethe-University, Frankfurt am Main, A. LUNGWITZ, MA, Department of Sports Medicine, Goethe-University, Frankfurt am Main, C. THIEL, PHD, Department of Sports Medicine, Goethe-University, Frankfurt am Main, E. JÄGER, MD, PROFESSOR, Department of Haematology and Oncology, Krankenhaus Nordwest, Frankfurt am Main, & L. VOGT, PHD, PROFESSOR, Department of Sports Medicine, Goethe-University, Frankfurt am Main, Germany BANZER W., BERNHÖRSTER M., SCHMIDT K., NIEDERER D., LUNGWITZ A., THIEL C., JÄGER E. & VOGT L. (2014) European Journal of Cancer Care 23, Changes in exercise capacity, quality of life and fatigue in cancer patients during an intervention The study explored the interdependence of changes in oxygen uptake, quality of life and cancer-related side-effect fatigue during a 4-month exercise intervention. Participants were during adjuvant (curative) or palliative therapy and post-adjuvant therapy (finished within the previous 12 months). Aerobic exercise capacity (VO 2peak), quality of life and fatigue symptom (EORTC QLQ-C30) were obtained in 101 cancer patients (30 77 years). After initial examination, patients participated in supervised and/or home-based training interventions. Patients were re-examined after weeks and stratified into 3 subgroups (terciles) with respect to the absolute change in VO 2peak. The ANCOVA, with significant covariate effect for pretest fatigue score (F (5,101) = 8.150, P < 0.001), indicated significant differences between groups in outcome measures (P < 0.001). Based on the absolute change of VO 2peak (1.9 ± 1.7; 1.8 ± 0.8; 5.7 ± 2.8 ml/kg/min) there were significant differences in the quality of life improvement (17.2 ± 15.1 vs. 4.8 ± 22.0 points, P < 0.05) and cancer-related fatigue reduction ( 6.1 ± 30.7; 11.5 ± 20.9; 21.2 ± 21.4 points) between upper and lower tercile. The findings point towards a relationship of exercise capacity enhancement, quality of life improvement and fatigue symptom reduction during and shortly after cancer treatment. Keywords: cancer-related fatigue, cancer, exercise capacity, oxygen uptake, quality of life. INTRODUCTION While physical activity and exercise during cancer treatment have been neglected for many years, there is strong evidence that being physically active is beneficial during and post cancer treatment (Schmitz et al. 2010; Mishra Correspondence address: Daniel Niederer, Department of Sports Medicine, Goethe-University Frankfurt, Ginnheimer Landstrasse 39, Frankfurt/Main, Germany ( Niederer@sport.uni-frankfurt.de). Accepted 26 March 2014 DOI: /ecc European Journal of Cancer Care, 2014, 23, et al. 2012a,b). Several studies and reviews point out that exercise may improve muscle strength and aerobic endurance capacity as well as physical and social functioning in cancer patients (Schmitz et al. 2010; Speck et al. 2010; Spence et al. 2010; Jones et al. 2011; Fong et al. 2012). Furthermore, aerobic exercise is considered to be valuable in the management of cancer- and treatment-related side-effects such as cancer-related fatigue (CRF) (Cramp & Byron-Daniel 2012) and may as well contribute to improvements in quality of life (QoL). Moderate intensity aerobic interventions lasting 3 5 months have been reported to result in changes in aerobic 2014 John Wiley & Sons Ltd

2 VO 2, quality of life and fatigue in cancer capacity and CRF ranging from +0.9 to +3.3 ml/kg/min (Jones et al. 2011) and +9 to 42 points (EORTC QLQ-C30 subscale; points) (Mishra et al. 2012a,b respectively). These comparatively wide ranges in exercise induced changes warrant further exploration in relation to their association and the underlying mechanisms. Resulting findings might help to evaluate aerobic intervention effects more accurately. Therefore, the present longitudinal study aims to elucidate exercise induced adaptions of QoL and CRF in relation to the initial performance capacity and its changes during intervention in cancer patients. METHODS Ethical approval The experiments were conducted in accordance to the current laws of Germany. The study was designed to be consistent with the revised Helsinki Declaration (Helsinki, 1964; Seoul, 2008). All participants provided informed consent to the protocol that had been approved by the local ethics committee. Participants Participants were considered eligible if they fulfilled the following criteria: (1) a histological confirmed cancer diagnosis (within the last 3 years) with any tumour site and disease stage; (2) during adjuvant (curative) or palliative therapy or post-adjuvant therapy (finished within the previous 12 months); (3) eastern cooperative oncology group (ECOG) performance status 0 II (0: Able to carry on all pre-disease performance without restriction, I: Restricted in physical activity but able to carry out work of a light or sedentary nature, II: Unable to carry out any work activities but capable of all self-care); and (4) ability to perform short bouts of adapted exercise. Exclusion criteria were brain or bone metastases, haemoglobin concentration <8 g/dl, chronic infection, uncontrolled hypertension (diastolic pressure >95 mmhg), and any condition precluding participation in exercise. Patients who were unable to stay in a stable supine position for the duration of the ergometer-based measurement were also excluded. Study participants were informed by oncologists and consecutively recruited from a local clinic for haematology and oncology, after receiving physicians approval for aerobic endurance exercise participation. Initially, 204 cancer patients (84 male, years; 120 female, years) were referred to the study. With a retention rate of almost 50%, 101 patients were able to participate in the re-examination (aerobic exercise performance, QoL and CRF) scheduled 16 weeks after study inclusion. Thus, the present evaluation reports the findings of 101 cancer patients (41 male, years; 60 female, years), who completed the trial (Table 1). Reasons for drop-out were clinic admission due to therapy side-effects, disease progression and infection. Lack of interest was mentioned in a single case. Patients who dropped out did not differ in sex, age and clinical characteristics as tumour site and treatment from participants who completed the trial (P > 0.05). Experimental design All participants underwent baseline and follow-up evaluation of socio-demographic data, aerobic exercise performance (VO 2peak), QoL and CRF (interval of 16 weeks). The investigations were carried out under constant conditions (temperature C, comparable time of day). In between evaluations, patients participated in an aerobic exercise intervention. According to their absolute change in VO 2peak, patients were afterward stratified into three subgroups to reveal differences in QoL and CRF during aerobic endurance exercise. Exercise capacity Aerobic exercise capacity was determined by a physiciansupervised cardiopulmonary exercise test (CPET), a safe and effective method to assess functional capacity in cancer patients (Klika et al. 2009, 2011). Participants were asked to refrain from alcohol or caffeine use and strenuous physical activity for 24 h, from light physical activity for 4 h, and from eating 2 h before CPET. Body weight and height in light clothing were measured using standard techniques. On an electrically braked cycle ergometer (custo control, customed GmbH, Munich, Germany) the initial workload of 0 watt was increased by 25 watt every 3 min until exhaustion. Heart rate, electrocardiogram data (ECG) and VO 2 [open-circuit indirect spirometry (Cortex Metalizer 3B, Leipzig, Germany)] were registered continuously. Stringent quality protocols were followed to control for activities, mechanical and environment related influences like relative humidity, mask fitting, sampling lines, as well as the metabolic system, which was calibrated using standard ventilatory volumes (0.2 and 2 l air/min) and gases (outside air and 5% CO 2, 16% O 2) after sufficient warm-up before each use. Ratings of perceived exertion (RPE; Borg-scale) and lactate concentration (Lactate Pro LT-1710, ARKAY, Japan) were measured at the end of each stage and after CPET termination. Patients were 2014 John Wiley & Sons Ltd 625

3 BANZER ET AL. Table 1. Patients demographics and clinical characteristics Total Tercile low Tercile med Tercile up No. % No. % No. % No. % Sex (n) Male Female Age (years) Median Range BMI (kg/m 2 ) Median Range VO 2peak (ml/kg/min) (baseline) Median Range Tumour (n) Brain Breast Colorectal Haematological Lung Lymphoma Melanoma Mesothelioma Myeloma Pancreatic Prostate Renal cell Urothelial carcinoma Other Treatment (n) Chemo Radiation Hormone Finished N/A Time post diagnosis (months) Median Range BMI, body mass index; VO 2peak, aerobic exercise performance. strongly encouraged throughout the test. Criteria for test cessation were volitional exhaustion (cadence below 60 rev/min) or symptom limitation. For data analysis, peak oxygen uptake (VO 2peak) was defined as the highest of all 30-s averages elicited during CPET. QoL and cancer-related symptoms Health-related QoL as well as cancer- and treatmentrelated symptoms (particularly CRF) were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 version 3.0), a widely applied and well-validated cancerspecific instrument (Aaronson et al. 1993). It consists of 30 items measuring multiple dimensions of QoL on different functioning scales (physical, role, emotional, social 626 and cognitive), symptom scales (fatigue, pain, nausea/ vomiting, dyspnoea, appetite loss, insomnia, constipation, diarrhoea and financial difficulties) and a global QoL scale. All scores were calculated and linearly transformed to a scale, according to the EORTC manual. Higher scores in the CRF scale (0 100, based on three items) indicate more severe complaints, whereas higher scores in QoL (0 100, based on two items) represent a higher QoL. Exercise intervention Following the initial examination, patients were counselled how to exercise adapted to their disease status and treatment. Recommendations for frequency (three to five times per week), intensity (moderate, heart-rate controlled), time ( min) and type of exercise (hiking, 2014 John Wiley & Sons Ltd

4 VO 2, quality of life and fatigue in cancer Table 2. Pre-, post-measures (mean ± SD, range) and P-values of quality of life (QoL) and cancer-related fatigue in relation to tercile groups of change in aerobic capacity QoL score (%) Fatigue score (%) Change in VO 2peak (ml/min/kg) Baseline Follow-up Baseline Follow-up lower tercile (<0.5), n = ± ± ± ± 24.8 ( ) ( ) ( ) ( ) middle tercile ( ), n = ± ± ± ± 22.4 ( ) ( ) ( ) ( ) Upper tercile (>3.2), n = ± ± ± ± 18.1 ( ) ( ) ( ) ( ) P-values P > 0.05 P > 0.05 VO 2peak, aerobic exercise performance. walking, running, bicycle and/or swimming) followed the FITT principle (Barisic et al. 2011). According to validated general lactate threshold assumptions (Faude et al. 2009) moderate exercise intensity was 70 90% of individual anaerobic threshold (IAT) derived from the CPET and RPE (rates of perceived exertion) target score of on the Borg (6 20) scale. Thereby, IAT, shown to be helpful in establishing training intensities in cancer populations (Klika et al. 2009, 2011), was defined as the workload corresponding to a lactic acid concentration at the aerobic threshold plus 1.5 mmol/l, according to Dickhuth et al. (1999). Additionally, the opportunity to participate in a supervised exercise programme consisting of a 60-min Nordic Walking training session once a week was given. To monitor home training compliance, all subjects were asked to fill in an exercise log in accordance to the physical activity assessment components of FITT (Barisic et al. 2011). All patients had to attend a second exercise counselling session after 4 weeks to adjust their home-based exercise to their condition, side-effect status and exercise readiness. Subjects were encouraged to contact their exercise counsellor by phone, or in person at any time during the intervention in case of any questions. Statistical methods Patients who did not undertake reassessment and participants with complete data sets values were compared using unpaired t-tests for all dependent variables. Overall effects were analysed (complete data sets, diagnosis and time since diagnosis as covariate) using unpaired t-tests. Participants with complete data were afterwards stratified into three subgroups (terciles) according to their absolute change in VO 2peak. Tercile split and statistical computations were made with a commercial statistics package (SPSS 18, SPSS Inc., USA). Dependent variables (primary outcome: QoL) testing was performed using analysis of covariance (pretest fatigue and VO 2peak scores, age and treatment as covariates), followed by post-hoc parametric testing to determine differences in outcome measures over time (paired sample t-test) and between subgroups (unpaired sample t-test, χ 2 -test). The a priori level of significance was set at 95% (P < 0.05). RESULTS Patients were active (hiking, walking, running, bicycle and swimming) 3 6 (4.0 ± 1.0) times per week for (169 ± 68) min at % of individual anaerobic threshold and at RPE scores of Patients without reassessment and participants with complete data sets differed significantly in baseline QoL (50.5 ± 20.6 vs. 58 ± 18.4; P < 0.05) but not in CRF nor VO 2peak (P > 0.05). Concerning all patients with complete data sets, analysis revealed a significant increase in VO 2peak and QoL from 22.2 ± 5.0 to 24.0 ± 5.8 ml/kg/min (P < 0.001) and from 58.0 ± 18.4 to 69.4 ± 17.9 points (P < 0.001) respectively. Fatigue decreased significantly from 46.4 ± 24.2 to 33.6 ± 22.5 on the 100-point scale (P < 0.001). No significant effect for diagnosis nor time since diagnosis as covariates occurred (P > 0.05). Cut-offs for participants tercile placement (subgroups based on VO 2peak changes) were calculated at <0.5 (lower tercile), (middle tercile) and >3.2 (upper tercile) ml/kg/min. The average change in VO 2peak (over 16 weeks) within subgroup was 1.9 ± 1.7, 1.8 ± 0.8 and 5.7 ± 2.8 ml/kg/min. Baseline and follow-up outcome measures (QoL and CRF) for the tercile subgroups based on absolute VO 2peak-changes are given in Table 2. The ANCOVA indicated significant differences between subgroups regarding all outcome measures (P < 0.001). Thereby, a significant effect for pretest fatigue score as covariate (F (5,101) = 8150, P < 0.00l), but neither for pretest VO 2peak, age nor treatment (P > 0.05) occurred. Post-hoc analysis revealed no significant differences between subgroups at baseline and follow-up (Table 2). Nevertheless, patients in the upper tercile demonstrated a significantly higher QoL increase compared with patients 2014 John Wiley & Sons Ltd 627

5 BANZER ET AL. 16-week change in fatigue symptom [score] (mean: 95% confidence interval) in the lower tercile (17.2 ± 15.1 vs. 4.8 ± 22.0 points, P < 0.05). Additionally, significant differences in fatigue score reduction between subgroups ( 6.1 ± 30.7; 11.5 ± 20.9; 21.2 ± 21.4 points) occurred (Fig. 1). Based on point estimation, participants who achieved a minimum increase of 10% in VO 2peak within 16 weeks had a 2.6 times (95% confidence interval: ) higher chance to obtain a fatigue symptom reduction of at least 20%. Effect size calculation (ANCOVA, primary outcome: QoL) revealed an effect size of DISCUSSION < > week change in VO2peak [ml/min/kg] (terciles) Figure 1. Fatigue symptom reduction in dependence of aerobic exercise performance (VO 2peak) terciles. *P < Patients of the mixed diagnosis cancer population improved exercise capacity and QoL during the 16-week guided and home-based moderate aerobic exercise intervention. These results are in agreement with actual findings stating that cancer patients both during and after cancer treatment can benefit from exercise interventions (Schmitz et al. 2010; Speck et al. 2010; Spence et al. 2010; Jones et al. 2011; Fong et al. 2012). The calculated terciles are in agreement with previous findings, stating that mean * VO 2peak improvements from 0.9 to 3.3 (represented by the middle tercile) can be reached during a 16-week moderate aerobic intervention (Jones et al. 2011). Thus, present studies middle tercile cancer patients can be classified as patients with a mean (in comparison with actual research) achievable VO 2peak increase, whereas patients in the lower tercile are below and those in the upper tercile over the mean reported increases in VO 2peak. The present findings point towards an interdependence of exercise capacity enhancement, QoL improvements and fatigue symptom reduction during cancer treatment. While only a slight increase in QoL and a reduction in CRF were observed in participants with small or no changes in aerobic capacity (lower tercile), a higher QoL improvement and fatigue-symptom reduction occurred in participants who achieved higher VO 2peak enhancements (upper tercile). Thus, improvements in both exercise capacity and QoL/CRF seems to be interdependent. Nevertheless, it remains unclear, whether QoL and CRF levels were modulated by the improvement of exercise capacity or by physical activity itself. First hints suggest a negative impact of CRF on QoL and daily functioning (Ahlberg et al. 2003; Knobel et al. 2003; National Comprehensive Cancer Network 2010) as well as on physical function (Given et al. 2007). Thus, a reverse impact of exercise capacity on CRF might be suggested. Especially in terms of side-effects (Cramp & Daniel 2008), the present findings once more underline the potential and postulate the prescription of exercise training during the treatment of cancer patients. Some methodological and clinical limitations of the present study have to be taken into consideration. Although the EORTC QLQ-C30 is common and often used in clinical settings, a more specific multidimensional instrument may be used in future studies to confirm the present findings. In Addition, the observational analysis is not capable to demonstrate causal dose response relationships. Therefore, future studies should further explore the association of oxygen capacity and more specific variables of the CRF symptom complex as well as the underlying mechanisms through which exercise influences these symptoms. ACKNOWLEDGEMENTS This work was partly supported by the Stiftung Leben mit Krebs. REFERENCES Aaronson N.K., Ahmedzai S., Bergman B., Bullinger M., Cull A., Duez N.J., Filiberti A., Flechtner H., Fleishman S.B. & de Haes J.C. (1993) The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. Journal of the National Cancer Institute 85, John Wiley & Sons Ltd

6 VO 2, quality of life and fatigue in cancer Ahlberg K., Ekman T., Gaston-Johansson F. & Mock V. (2003) Assessment and management of cancer-related fatigue in adults. Lancet 362, 9384, Barisic A., Leatherdale S.T. & Kreiger N. (2011) Importance of frequency, intensity, time and type (FITT) in physical activity assessment for epidemiological research. Canadian Journal of Public Health 102, Cramp F. & Byron-Daniel J. (2012) Exercise for the management of cancer-related fatigue in adults. Cochrane Database of Systematic Reviews (11), CD Cramp F. & Daniel J. (2008) Exercise for the management of cancer-related fatigue in adults. Cochrane Database of Systematic Reviews (2), CD Dickhuth H.H., Yin L., Niess A., Röcker K., Mayer F., Heitkamp H.C. & Horstmann T. (1999) Ventilatory, lactate-derived and catecholamine thresholds during incremental treadmill running: relationship and reproducibility. International Journal of Sports Medicine 20, Faude O., Kindermann W. & Meyer T. (2009) Lactate threshold concepts: how valid are they? Sports medicine 39, Fong D.Y.T., Ho J.W.C., Hui B.P.H., Lee A.M., Macfarlane D.J., Leung S.S.K., Cerin E., Chan W.Y.Y., Leung I.P.F., Lam S.H.S., Taylor A.J. & Cheng K.-K. (2012) Physical activity for cancer survivors: meta-analysis of randomised controlled trials. BMJ (Clinical Research Ed.) 344, 70. Given B.A., Given C.W., Sikorskii A. & Hadar N. (2007) Symptom clusters and physical function for patients receiving chemotherapy. Seminars in Oncology Nursing 23, Jones L.W., Liang Y., Pituskin E.N., Battaglini C.L., Scott J.M., Hornsby W.E. & Haykowsky M. (2011) Effect of exercise training on peak oxygen consumption in patients with cancer: a metaanalysis. The Oncologist 16, Klika R.J., Callahan K.E. & Drum S.N. (2009) Individualized 12-week exercise training programs enhance aerobic capacity of cancer survivors. The Physician and Sports Medicine 37, Klika R.J., Golik K.S., Drum S.N., Callahan K.E. & Thorland W.G. (2011) Comparison of physiological response to cardiopulmonary exercise testing among cancer survivors and healthy controls. European Journal of Applied Physiology 111, Knobel H., Loge J.H., Brenne E., Fayers P., Hjermstad M.J. & Kaasa S. (2003) The validity of EORTC QLQ-C30 fatigue scale in advanced cancer patients and cancer survivors. Palliative Medicine 17, Mishra S.I., Scherer R.W., Geigle P.M., Berlanstein D.R., Topaloglu O., Gotay C.C. & Snyder C. (2012a) Exercise interventions on health-related quality of life for cancer survivors. Cochrane Database of Systematic Reviews (8), CD Mishra S.I., Scherer R.W., Snyder C., Geigle P.M., Berlanstein D.R. & Topaloglu O. (2012b) Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database of Systematic Reviews (8), CD National Comprehensive Cancer Network (2010) Clinical Practice Guidelines in Oncology. Cancer-related fatigue version 1. Available at: Schmitz K.H., Courneya K.S., Matthews C., Demark-Wahnefried W., Galvão D.A., Pinto B.M., Irwin M.L., Wolin K.Y., Segal R.J., Lucia A., Schneider C.M., von Gruenigen V.E. & Schwartz A.L. (2010) American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Medicine and Science in Sports and Exercise 42, Speck R.M., Courneya K.S., Mâsse L.C., Duval S. & Schmitz K.H. (2010) An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Journal of Cancer Survivorship Research and Practice 4, Spence R.R., Heesch K.C. & Brown W.J. (2010) Exercise and cancer rehabilitation: a systematic review. Cancer Treatment Reviews 36, John Wiley & Sons Ltd 629

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