Design of a randomized controlled trial of physical training and cancer (Phys-Can) – the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome

Background: Cancer-related fatigue is a common problem in persons with cancer, influencing health-related quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment, activities of daily living after treatment completion and return to work, and behaviour change techniques effect on exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue and health related quality of life. Methods/design: Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing adjuvant therapy will be randomized in a 2 × 2 factorial design to following conditions; A) individually tailored low-to-moderate intensity exercise with or without behaviour change techniques or B) individually tailored high intensity exercise with or without behaviour change techniques. The training consists of both resistance and endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance, adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment, return to work as well as inflammatory markers, cytokines and gene expression. Discussion: The study will contribute to our understanding of the value of exercise and exercise intensity in reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in persons with cancer will be evaluated

Exploring moderators of the effect of high vs. low-to-moderate Intensity exercise on cardiorespiratory fitness during breast cancer treatment – Analyses of a subsample from the phys-can RCT

Introduction The results from the physical training and cancer randomized controlled trial (Phys-Can RCT) indicate that high intensity (HI) strength and endurance training during (neo-)adjuvant cancer treatment is more beneficial for cardiorespiratory fitness (CRF, measured as peak oxygen uptake [VO2peak]) than low-to-moderate intensity (LMI) exercise. Adherence to the exercise intervention and demographic or clinical characteristics of patients with breast cancer undergoing adjuvant treatment may moderate the exercise intervention effect on VO2peak. In this study, the objective was to investigate whether baseline values of VO2peak, body mass index (BMI), time spent in moderate- to vigorous-intensity physical activity (MVPA), physical fatigue, age, chemotherapy treatment, and the adherence to the endurance training moderated the effect of HI vs. LMI exercise on VO2peak. Materials and Methods We used data collected from a subsample from the Phys-Can RCT; women who were diagnosed with breast cancer and had a valid baseline and post-intervention VO2peak test were included (n = 255). The exercise interventions from the RCT included strength and endurance training at either LMI, which was continuous endurance training at 40 – 50 % of heart rate reserve (HRR), or at HI, which was interval training at 80–90% of HRR, with similar exercise volume in the two groups. Linear regression analyses were used to investigate moderating effects using a significance level of p \u3c 0.10. Statistically significant interactions were examined further using the Johnson–Neyman (J-N) technique and regions of significance (for continuous variables) or box plots with adjusted means of post-intervention VO2peak (for binary variables). Results Age, as a continuous variable, and adherence, dichotomized into \u3c or \u3e 58% based on median, moderated the effect of HI vs. LMI on CRF (B = −0.08, 95% CI [−0.16, 0.01], pinteraction = 0.06, and B = 1.63, 95% CI [−0.12, 3.38], pinteraction = 0.07, respectively). The J-N technique and regions of significance indicated that the intervention effect (HI vs. LMI) was positive and statistically significant in participants aged 61 years or older. Baseline measurement of CRF, MVPA, BMI, physical fatigue, and chemotherapy treatment did not significantly moderate the intervention effect on CRF. Conclusion Women with breast cancer who are older and who have higher adherence to the exercise regimen may have larger effects of HI exercise during (neo-)adjuvant cancer treatment on CRF

The clinical course of low back pain: a meta-analysis comparing outcomes in randomised clinical trials (RCTs) and observational studies.

BACKGROUND: Evidence suggests that the course of low back pain (LBP) symptoms in randomised clinical trials (RCTs) follows a pattern of large improvement regardless of the type of treatment. A similar pattern was independently observed in observational studies. However, there is an assumption that the clinical course of symptoms is particularly influenced in RCTs by mere participation in the trials. To test this assumption, the aim of our study was to compare the course of LBP in RCTs and observational studies. METHODS: Source of studies CENTRAL database for RCTs and MEDLINE, CINAHL, EMBASE and hand search of systematic reviews for cohort studies. Studies include individuals aged 18 or over, and concern non-specific LBP. Trials had to concern primary care treatments. Data were extracted on pain intensity. Meta-regression analysis was used to compare the pooled within-group change in pain in RCTs with that in cohort studies calculated as the standardised mean change (SMC). RESULTS: 70 RCTs and 19 cohort studies were included, out of 1134 and 653 identified respectively. LBP symptoms followed a similar course in RCTs and cohort studies: a rapid improvement in the first 6 weeks followed by a smaller further improvement until 52 weeks. There was no statistically significant difference in pooled SMC between RCTs and cohort studies at any time point:- 6 weeks: RCTs: SMC 1.0 (95% CI 0.9 to 1.0) and cohorts 1.2 (0.7to 1.7); 13 weeks: RCTs 1.2 (1.1 to 1.3) and cohorts 1.0 (0.8 to 1.3); 27 weeks: RCTs 1.1 (1.0 to 1.2) and cohorts 1.2 (0.8 to 1.7); 52 weeks: RCTs 0.9 (0.8 to 1.0) and cohorts 1.1 (0.8 to 1.6). CONCLUSIONS: The clinical course of LBP symptoms followed a pattern that was similar in RCTs and cohort observational studies. In addition to a shared 'natural history', enrolment of LBP patients in clinical studies is likely to provoke responses that reflect the nonspecific effects of seeking and receiving care, independent of the study design

The Role of Long-Term Physical Activity in Relation to Cancer-Related Health Outcomes: A 12-Month Follow-up of the Phys-Can RCT

Purpose: While moderate-to-vigorous intensity physical activity (MVPA) is associated with various health improvements shortly after completion of exercise interventions, it remains unclear which health benefits can be expected when MVPA levels are maintained in the long term in cancer survivors. We aimed to assess the associations of (1) MVPA level at 12-month follow-up and (2) long-term MVPA patterns (from immediately post-intervention to 12-month follow-up) with different cancer-related health outcomes. Methods: In the Physical training and Cancer (Phys-Can) RCT, 577 participants diagnosed with breast (78%), prostate (19%), or colorectal (3%) cancer were randomized to 6 months of exercise during curative cancer treatment. Accelerometer-assessed physical activity and outcome data (ie, cancer-related fatigue, health-related quality of life [HRQoL], anxiety and depression, functioning in daily life, cardiorespiratory fitness, sedentary time and sleep) were collected immediately post-intervention and at 12-month follow-up. Based on the sample’s median of MVPA immediately post-intervention (65 minutes/day) and the changes between the 2 measurement points, 4 categories with different long-term MVPA patterns were created: High & Increasing, High & Decreasing, Low & Increasing, and Low & Decreasing. Multiple linear regression analyses were performed for the analyses. Results: A total of 353 participants were included in the analyses. At 12-month follow-up, a higher MVPA level was significantly associated with lower fatigue in 3 domains (general fatigue [β = −.33], physical fatigue [β = −.53] and reduced activity [β = −.37]), higher cardiorespiratory fitness (β = .34) and less sedentary time (β = −.35). For long-term MVPA patterns, compared to the participants in the “Low & Decreasing” category, those in the “High & Increasing” category reported significantly lower fatigue in 3 domains (general fatigue [β = −1.77], physical fatigue [β = −3.36] and reduced activity [β = −1.58]), higher HRQoL (β = 6.84) and had less sedentary time (β = −1.23). Conclusion: Our results suggest that long-term physical activity is essential for improving health outcomes post-intervention in cancer survivors. Cancer survivors, including those who reach recommended MVPA levels, should be encouraged to maintain or increase MVPA post-intervention for additional health benefits.publishedVersio

Pre-treatment levels of inflammatory markers and chemotherapy completion rates in patients with early-stage breast cancer

Author's accepted manuscriptBackground Chemotherapy efficacy is largely dependent on treatment adherence, defned by the relative dose intensity (RDI). Identifcation of new modifable risk factors associated with low RDI might improve chemotherapy delivery. Here, we evaluated the association between low RDI and pre-chemotherapy factors, including patient- and treatment-related characteristics and markers of infammation. Methods This exploratory analysis assessed data from 267 patients with early-stage breast cancer scheduled to undergo (neo-)adjuvant chemotherapy included in the Physical training and Cancer (Phys-Can) trial. The association between low RDI, defned as<85%, patient-related (age, body mass index, co-morbid condition, body surface area) and treatment-related factors (cancer stage, receptor status, chemotherapy duration, chemotherapy dose, granulocyte colony-stimulating factor) was investigated. Analyses further included the association between RDI and pre-chemotherapy levels of interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP) and Tumor Necrosis Factor-alpha (TNF-α) in 172 patients with available blood samples. Results An RDI of<85% occurred in 31 patients (12%). Univariable analysis revealed a signifcant association with a chemotherapy duration above 20 weeks (p<0.001), chemotherapy dose (p=0.006), pre-chemotherapy IL-8 (OR 1.61; 95% CI (1.01; 2.58); p=0.040) and TNF-α (OR 2.2 (1.17; 4.53); p=0.019). In multivariable analyses, infammatory cytokines were signifcant association with low RDI for IL-8 (OR: 1.65 [0.99; 2.69]; p=0.044) and TNF-α (OR 2.95 [1.41; 7.19]; p=0.007). Conclusions This exploratory analysis highlights the association of pre-chemotherapy IL-8 and TNF-α with low RDI of chemotherapy for breast cancer. IL-8 and TNF-α may therefore potentially help to identify patients at risk for experiencing dose reductions.acceptedVersio

Dropout from exercise trials among cancer survivors—An individual patient data meta-analysis from the POLARIS study

Introduction: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. Methods: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. Results: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI &gt;28.4 kg/m2, performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI &gt;28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. Conclusions: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.</p

Does exercise intensity matter for fatigue during (neo‐)adjuvant cancer treatment? The Phys‐Can randomized clinical trial

Exercise during cancer treatment improves cancer‐related fatigue (CRF), but the importance of exercise intensity for CRF is unclear. We compared the effects of high‐ vs low‐to‐moderate‐intensity exercise with or without additional behavior change support (BCS) on CRF in patients undergoing (neo‐)adjuvant cancer treatment. This was a multicenter, 2x2 factorial design randomized controlled trial (Clinical Trials NCT02473003) in Sweden. Participants recently diagnosed with breast (n = 457), prostate (n = 97) or colorectal (n = 23) cancer undergoing (neo‐)adjuvant treatment were randomized to high intensity (n = 144), low‐to‐moderate intensity (n = 144), high intensity with BCS (n = 144) or low‐to‐moderate intensity with BCS (n = 145). The 6‐month exercise intervention included supervised resistance training and home‐based endurance training. CRF was assessed by Multidimensional Fatigue Inventory (MFI, five subscales score range 4‐20), and Functional Assessment of Chronic Illness Therapy‐Fatigue scale (FACIT‐F, score range 0‐52). Multiple linear regression for main factorial effects was performed according to intention‐to‐treat, with post‐intervention CRF as primary endpoint. Overall, 577 participants (mean age 58.7 years) were randomized. Participants randomized to high‐ vs low‐to‐moderate‐intensity exercise had lower physical fatigue (MFI Physical Fatigue subscale; mean difference −1.05 [95% CI: −1.85, −0.25]), but the difference was not clinically important (ie <2). We found no differences in other CRF dimensions and no effect of additional BCS. There were few minor adverse events. For CRF, patients undergoing (neo‐)adjuvant treatment for breast, prostate or colorectal cancer can safely exercise at high‐ or low‐to‐moderate intensity, according to their own preferences. Additional BCS does not provide extra benefit for CRF in supervised, well‐controlled exercise interventions

Dropout from exercise trials among cancer survivors-An individual patient data meta-analysis from the POLARIS study

INTRODUCTION: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. METHODS: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. RESULTS: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m 2 , performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m 2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m 2 exercising during (5.2%) or post (9.5%) treatment. CONCLUSIONS: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects

Behaviours, Beliefs and Back Pain : Prognostic Factors for Disability in the General Population and Implementation of Screening in Primary Care Physiotherapy

Aim: The overall aim of this thesis was to study prognostic factors for prolonged disability in back pain in the general population and physiotherapists’ screening for prolonged disability, applying a social cognitive learning perspective. Methods and results: Studies I and II were based on a survey in the general population in Sweden. Study I included 1024 individuals aged 20-50 years, reporting non-specific back pain. Four groups (n = 100, 215, 172 and 537) based on duration and recurrence of back pain were formed and compared. After controlling for pain intensity, catastrophising and expectations of future pain were positively correlated to pain duration. Perceived social support was negatively correlated to pain duration. Study II was longitudinal over 12 months and analysed one group reporting first-episode back pain (n = 77), and one group reporting long-term back pain (n = 302). Future pain intensity and disability were predicted by initial levels of pain and disability and pain-related cognitions in both groups. Study III examined the inter-rater reliability of a research protocol for assessment of physiotherapists’ telephone screening for prolonged disability. The results demonstrated sufficient inter-rater reliability. Study IV evaluated the effect of a tailored skills training intervention on physiotherapists’ screening for prolonged disability in back pain. Four physiotherapists in primary care participated in four quasi-experimental single-subject studies. Effects were seen in all participants, with increased screening of prognostic factors and less time spent on detailed discussions about back pain. Conclusions: The identification of mainly cognitive explanatory variables indicates the relevance of a social cognitive perspective of back pain-related disability (studies I and II). Physiotherapists’ telephone screening for prolonged disability in back can be reliably assessed (study III). It is suggested that interventions based on social cognitive theory are effective in producing change in specified clinical behaviours in physiotherapists (study IV)