Effects of heavy-load strength training during (neo-)adjuvant chemotherapy on muscle strength, muscle fiber size, myonuclei, and satellite cells in women with breast cancer.

To investigate the effects of heavy-load strength training during (neo-)adjuvant chemotherapy in women with breast cancer on muscle strength, body composition, muscle fiber size, satellite cells, and myonuclei. Women with stage I-III breast cancer were randomly assigned to a strength training group (ST, n = 23) performing supervised heavy-load strength training twice a week during chemotherapy, or a usual care control group (CON, n = 17). Muscle strength and body composition were measured and biopsies from m. vastus lateralis collected before the first cycle of chemotherapy (T0) and after chemotherapy and training (T1). Muscle strength increased significantly more in ST than in CON in chest-press (ST: +10 ± 8%, p < .001, CON: -3 ± 5%, p = .023) and leg-press (ST: +11 ± 8%, p < .001, CON: +3 ± 6%, p = .137). Both groups reduced fat-free mass (ST: -4.9 ± 4.0%, p < .001, CON: -5.2 ± 4.9%, p = .004), and increased fat mass (ST: +15.3 ± 16.5%, p < .001, CON: +16.3 ± 19.8%, p = .015) with no significant differences between groups. No significant changes from T0 to T1 and no significant differences between groups were observed in muscle fiber size. For myonuclei per fiber a non-statistically significant increase in CON and a non-statistically significant decrease in ST in type I fibers tended (p = .053) to be different between groups. Satellite cells tended to decrease in ST (type I: -14 ± 36%, p = .097, type II: -9 ± 55%, p = .084), with no changes in CON and no differences between groups. Strength training during chemotherapy improved muscle strength but did not significantly affect body composition, muscle fiber size, numbers of satellite cells, and myonuclei compared to usual care.

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/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 >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.

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 [ß = -.33], physical fatigue [ß = -.53] and reduced activity [ß = -.37]), higher cardiorespiratory fitness (ß = .34) and less sedentary time (ß = -.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 [ß = -1.77], physical fatigue [ß = -3.36] and reduced activity [ß = -1.58]), higher HRQoL (ß = 6.84) and had less sedentary time (ß = -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. TRIAL REGISTRATION: NCT02473003 (10/10/2014).

How many days of continuous physical activity monitoring reliably represent time in different intensities in cancer survivors.

BACKGROUND: Physical activity (PA) monitoring is applied in a growing number of studies within cancer research. However, no consensus exists on how many days PA should be monitored to obtain reliable estimates in the cancer population. The objective of the present study was to determine the minimum number of monitoring days required for reliable estimates of different PA intensities in cancer survivors when using a six-days protocol. Furthermore, reliability of monitoring days was assessed stratified on sex, age, cancer type, weight status, and educational level. METHODS: Data was obtained from two studies where PA was monitored for seven days using the SenseWear Armband Mini in a total of 984 cancer survivors diagnosed with breast, colorectal or prostate cancer. Participants with ≥22 hours monitor wear-time for six days were included in the reliability analysis (n = 736). The intra-class correlation coefficient (ICC) and the Spearman Brown prophecy formula were used to assess the reliability of different number of monitoring days. RESULTS: For time in light PA, two monitoring days resulted in reliable estimates (ICC >0.80). Participants with BMI ≥25, low-medium education, colorectal cancer, or age ≥60 years required one additional monitoring day. For moderate and moderate-to-vigorous PA, three monitoring days yielded reliable estimates. Participants with BMI ≥25 or breast cancer required one additional monitoring day. Vigorous PA showed the largest within subject variations and reliable estimates were not obtained for the sample as a whole. However, reliable estimates were obtained for breast cancer survivors (4 days), females, BMI ≥30, and age <60 years (6 days). CONCLUSION: Shorter monitoring periods may provide reliable estimates of PA levels in cancer survivors when monitored continuously with a wearable device. This could potentially lower the participant burden and allow for less exclusion of participants not adhering to longer protocols.

Cost-effectiveness of different exercise intensities during oncological treatment in the Phys-Can RCT.

BACKGROUND: Cost-effectiveness is important in the prioritisation between interventions in health care. Exercise is cost-effective compared to usual care during oncological treatment; however, the significance of exercise intensity to the cost-effectiveness is unclear. In the present study, we aimed to evaluate the long-term cost-effectiveness of the randomised controlled trial Phys-Can, a six-month exercise programme of high (HI) or low-to-moderate intensity (LMI) during (neo)adjuvant oncological treatment. METHODS: A cost-effectiveness analysis was performed, based on 189 participants with breast, colorectal, or prostate cancer (HI: n = 99 and LMI: n = 90) from the Phys-Can RCT in Sweden. Costs were estimated from a societal perspective, and included cost of the exercise intervention, health care utilisation and productivity loss. Health outcomes were assessed as quality-adjusted life-years (QALYs), using EQ-5D-5L at baseline, post intervention and 12 months after the completion of the intervention. RESULTS: At 12-month follow-up after the intervention, the total cost per participant did not differ significantly between HI (€27,314) and LMI exercise (€29,788). There was no significant difference in health outcome between the intensity groups. On average HI generated 1.190 QALYs and LMI 1.185 QALYs. The mean incremental cost-effectiveness ratio indicated that HI was cost effective compared with LMI, but the uncertainty was large. CONCLUSIONS: We conclude that HI and LMI exercise have similar costs and effects during oncological treatment. Hence, based on cost-effectiveness, we suggest that decision makers and clinicians can consider implementing both HI and LMI exercise programmes and recommend either intensity to the patients with cancer during oncological treatment to facilitate improvement of health.

Reallocating sedentary time to physical activity: effects on fatigue and quality of life in patients with breast cancer in the Phys-Can project.

PURPOSE: We aimed to investigate the effects of reallocating sedentary time to an equal amount of light (LPA) or moderate-to-vigorous intensity physical activity (MVPA) on cancer-related fatigue and health-related quality of life (HRQoL) in patients with breast cancer. We also aimed to determine the daily amount of sedentary time needed to be reallocated to LPA or MVPA to produce minimal clinically important changes in these outcomes. METHODS: Pooled baseline data from three studies were used, including women with breast cancer who participated in the Phys-Can project. Fatigue was assessed with the Multidimensional Fatigue Inventory questionnaire (MFI; five dimensions, 4-20 scale) and HRQoL with the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30; 0-100 scale). Sedentary time and physical activity were measured with accelerometry. Isotemporal substitution modelling was used for the analyses. RESULTS: Overall, 436 participants (mean age 56 years, fatigue 11 [MFI], HRQoL 66 [EORTC QLQ-C30], LPA 254 min/day, MVPA 71 min/day) were included. Fatigue significantly decreased in two MFI dimensions when reallocating 30 min/day of sedentary time to LPA: reduced motivation and reduced activity (ß = - 0.21). Fatigue significantly decreased in three MFI dimensions when reallocating 30 min/day of sedentary time to MVPA: general fatigue (ß = - 0.34), physical fatigue (ß = - 0.47) and reduced activity (ß = - 0.48). To produce minimal clinically important changes in fatigue (- 2 points on MFI), the amount of sedentary time needed to be reallocated to LPA was ≈290 min/day and to MVPA was ≥ 125 min/day. No significant effects were observed on HRQoL when reallocating sedentary time to LPA or MVPA. CONCLUSIONS: Our results suggest that reallocating sedentary time to LPA or MVPA has beneficial effects on cancer-related fatigue in patients with breast cancer, with MVPA having the greatest impact. In relatively healthy and physically active breast cancer populations, a large amount of time reallocation is needed to produce clinically important changes. Future studies are warranted to evaluate such effects in broader cancer populations. TRIAL REGISTRATION: NCT02473003 (10/10/2014) and NCT04586517 (14/10/2020).

Does inflammation markers or treatment type moderate exercise intensity effects on changes in muscle strength in cancer survivors participating in a 6-month combined resistance- and endurance exercise program? Results from the Phys-Can trial.

BACKGROUND: Resistance exercise has a beneficial impact on physical function for patients receiving oncological treatment. However, there is an inter-individual variation in the response to exercise and the tolerability to high-intensity exercise. Identifying potential moderating factors, such as inflammation and treatment type, for changes in muscle strength is important to improve the effectiveness of exercise programs. Therefore, we aimed to investigate if inflammation and type of oncological treatment moderate the effects of exercise intensity (high vs. low-moderate) on muscular strength changes in patients with breast (BRCA) or prostate cancer (PRCA). METHODS: Participants with BRCA (n = 286) and PRCA (n = 65) from the Physical training and Cancer study (Phys-Can) were included in the present study. Participants performed a combined resistance- and endurance exercise program during six months, at either high or low-moderate intensity. Separate regression models were estimated for each cancer type, with and without interaction terms. Moderators included in the models were treatment type (i.e., neo/adjuvant chemotherapy-yes/no for BRCA, adjuvant androgen deprivation therapy (ADT)-yes/no for PRCA)), and inflammation (interleukin 6 (IL6) and tumor necrosis factor-alpha (TNFα)) at follow-up. RESULTS: For BRCA, neither IL6 (b = 2.469, 95% CI [- 7.614, 12.552]) nor TNFα (b = 0.036, 95% CI [- 6.345, 6.418]) levels moderated the effect of exercise intensity on muscle strength change. The same was observed for chemotherapy treatment (b = 4.893, 95% CI [- 2.938, 12.724]). Similarly, for PRCA, the effect of exercise intensity on muscle strength change was not moderated by IL6 (b = - 1.423, 95% CI [- 17.894, 15.048]) and TNFα (b = - 1.905, 95% CI [- 8.542, 4.732]) levels, nor by ADT (b = - 0.180, 95% CI [- 11.201, 10.841]). CONCLUSIONS: The effect of exercise intensity on muscle strength is not moderated by TNFα, IL6, neo/adjuvant chemotherapy, or ADT, and therefore cannot explain any intra-variation of training response regarding exercise intensity (e.g., strength gain) for BRCA or PRCA in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02473003.

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

BACKGROUND: Chemotherapy efficacy is largely dependent on treatment adherence, defined by the relative dose intensity (RDI). Identification of new modifiable 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 inflammation. 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, defined 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 significant 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, inflammatory cytokines were significant 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. Clinical trial number NCT02473003 (registration: June 16, 2015).

Effects of High and Low-To-Moderate Intensity Exercise During (Neo-) Adjuvant Chemotherapy on Muscle Cells, Cardiorespiratory Fitness, and Muscle Function in Women With Breast Cancer: Protocol for a Randomized Controlled Trial.

BACKGROUND: (Neo-)adjuvant chemotherapy for breast cancer is effective but has deleterious side effects on muscle tissue, resulting in reduced skeletal muscle mass, muscle function, and cardiorespiratory fitness. Various exercise regimens during cancer treatment have been shown to counteract some of these side effects. However, no study has compared the effect of high-intensity training versus low-to-moderate intensity training on muscle tissue cellular outcomes and physical function in patients with breast cancer during chemotherapy. OBJECTIVE: The aim of this substudy within the Physical Training in Cancer (Phys-Can) consortium is to evaluate and compare the effects of high and low-to-moderate intensity exercise on muscle cellular outcomes, muscle function, and cardiorespiratory fitness in women with breast cancer undergoing (neo-)adjuvant chemotherapy. We further aim to investigate if the effects of chemotherapy including taxanes on muscles will be different from those of taxane-free chemotherapy. METHODS: Eighty women recently diagnosed with breast cancer scheduled to start (neo-)adjuvant chemotherapy will be randomized to a combination of strength and endurance training, either at high intensity or at low-to-moderate intensity. Testing of muscle function and cardiorespiratory fitness and collection of muscle biopsies from the vastus lateralis muscle will be performed before the first cycle of chemotherapy (or after 1 week, when not possible) (T0), halfway through chemotherapy (T1), and after completion of chemotherapy (T2). It is estimated that approximately 50% of the participants will be willing to undergo muscle biopsies. To separate the effect of the treatment itself, a usual care group with no supervised training will also be included, and in this group, testing and collection of muscle biopsies will be performed at T0 and T2 only. RESULTS: This study is funded by Active Against Cancer (Aktiv mot kreft) (May 2013) and the Norwegian Cancer Society (December 2018). Inclusion started in December 2016 and the last participant is expected to be recruited in December 2022. As of June 2022, we enrolled 38 (19 with biopsies) participants to the high-intensity training group, 36 (19 with biopsies) participants to the low-to-moderate intensity training group, and 17 (16 with biopsies) participants to the usual care group. Data analyses will start in fall 2022. The first results are expected to be published in spring 2024. CONCLUSIONS: This study will generate new knowledge about the effects of different training intensities for women with breast cancer during chemotherapy treatment. It will give further insight into how chemotherapy affects the muscle tissue and how physical training at different intensities may counteract the treatment side effects in muscles. The results of this study will inform the development and refinement of exercise programs that are effective and compatible with the multidisciplinary management of breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT05218876; https://tinyurl.com/ysaj9dhm. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40811.

Patterns and determinants of adherence to resistance and endurance training during cancer treatment in the Phys-Can RCT.

BACKGROUND: Knowledge regarding adherence is necessary to improve the specificity of exercise interventions during cancer treatment. We aimed to determine adherence to resistance and endurance training interventions in parallel; identify subgroups with similar adherence characteristics; and examine determinants of these subgroups. METHODS: In the Phys-Can randomised controlled trial, participants (n = 577, 81% women, mean(SD) age 59(12) years, and 50% with BMI ≥ 25 kg/m2) starting (neo-) adjuvant treatment for breast, colorectal or prostate cancer were randomized to 6-month of high (HI) or low-to-moderate intensity (LMI) supervised, group-based resistance training and individual home-based endurance training, with or without behavior change support. Adherence was calculated as performed exercise volume as a proportion of prescribed exercise volume (0-100%), overall (HI and LMI groups) and for frequency, intensity, type and time (FITT principles) (HI group). Adherence to resistance training was plotted against adherence to endurance training overall and for each FITT principle. K-means cluster analysis was used to identify subgroups with similar adherence characteristics. Potential determinants of subgroup membership were examined using multinomial logistic regression. RESULTS: We found a positive curvilinear correlation between adherence to resistance and endurance training overall. A similar correlation was seen for adherence to frequency of resistance vs. endurance training in the HI group. In the HI group, adherence to resistance training intensity and time was > 80% for almost all participants. For endurance training adherence ranged from 0 to 100% for each of the FITT principles. Three clusters were identified, representing low, mixed, and high adherence to resistance and endurance training overall. Participants with higher age (Relative risk ratio [95% CI]; LMI: 0.86[0.77-0.96], HI: 0.83[0.74-0.93]), no behaviour change support (LMI: 0.11[0.02-0.56], HI: 0.20[0.05-0.85]), higher cardiorespiratory fitness (LMI: 0.81[0.69-0.94], HI: 0.80[0.69-0.92]), more fatigue (according to the reduced activity subscale of the MFI questionnaire) (LMI: 0.48[0.31-0.73], HI: 0.69[0.52-0.93]) or higher quality of life (LMI: 0.95[0.90-1.00], HI: 0.93[0.88-0.98]) were less likely to be in the low than the high adherence cluster whether randomised to LMI or HI training. Other determinants were specific to those randomised to LMI or HI training. CONCLUSIONS: In an exercise intervention during cancer treatment, adherence to resistance and endurance training were positively correlated. Personalisation of interventions and additional support for some subgroups of participants may improve adherence. Trial registration NCT02473003 (clinicaltrials.gov, Registered 16/06/2015).

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 < 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 < or > 58% based on median, moderated the effect of HI vs. LMI on CRF (B = -0.08, 95% CI [-0.16, 0.01], p interaction = 0.06, and B = 1.63, 95% CI [-0.12, 3.38], p interaction = 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.

Immediate increase in perceived energy after exercise during the course of chemotherapy treatment for breast cancer.

PURPOSE: Exercise during chemotherapy has beneficial long-term effects on women with breast cancer, but short-term beneficial changes have been less investigated. Though short-term changes may be important as a encouraging factor, this study aimed to investigate immediate changes in self-reported energy, stress, nausea and pain following a single exercise session during chemotherapy. METHODS: Forty-six women who were exercising while undergoing adjuvant chemotherapy for breast cancer were included between October 2016 and April 2018. Self-reported energy and stress were assessed before, immediately after and 3 h after exercise sessions by the Stress-Energy Questionnaire. On the same questionnaire nausea and pain were assessed by a Visual Analog Scale. The measurements were completed at four time points during cycles 2 and 5 of the 6-cycle chemotherapy course. RESULTS: Energy level increased immediately after a single exercise session for three out of four periods during the chemotherapy course (p < 0.01), with a larger increase when energy was lower before the session (p < 0.01). Three hours after the exercise session, the energy was about the same level as before the exercise session. Stress decreased immediately after the session during cycle two (p < 0.01) but not cycle five. There were no changes in nausea or pain. CONCLUSIONS: Patients undergoing chemotherapy should be informed not only about the long-term advantages of exercise, but also immediate benefits in terms of increased energy. The energy increase both while exercise in the beginning and toward the end of the chemotherapy course, this short-term advantageous consequence may strengthen patients' motivation to exercise. Clinicians should also inform patients that exercise does not seem to worsen nausea and pain.

Long-term resource utilisation and associated costs of exercise during (neo)adjuvant oncological treatment: the Phys-Can project.

BACKGROUND: Exercise during oncological treatment is beneficial to patient health and can counteract the side effects of treatment. Knowledge of the societal costs associated with an exercise intervention, however, is limited. The aims of the present study were to evaluate the long-term resource utilisation and societal costs of an exercise intervention conducted during (neo)adjuvant oncological treatment in a randomised control trial (RCT) versus usual care (UC), and to compare high-intensity (HI) versus low-to-moderate intensity (LMI) exercise in the RCT. METHODS: We used data from the Physical Training and Cancer (Phys-Can) project. In the RCT, 577 participants were randomised to HI or to LMI of combined endurance and resistance training for 6 months, during oncological treatment. The project also included 89 participants with UC in a longitudinal observational study. We measured at baseline and after 18 months. Resource utilisation and costs of the exercise intervention, health care, and productivity loss were compared using analyses of covariance (RCT vs. UC) and t test (HI vs. LMI). RESULTS: Complete data were available for 619 participants (RCT HI: n = 269, LMI: n = 265, and UC: n = 85). We found no difference in total societal costs between the exercise intervention groups in the RCT and UC. However, participants in the RCT had lower rates of disability pension days (p < .001), corresponding costs (p = .001), and pharmacy costs (p = .018) than the UC group. Nor did we find differences in resource utilisation or costs between HI and LMI exercise int the RCT. CONCLUSION: Our study showed no difference in total societal costs between the comprehensive exercise intervention and UC or between the exercise intensities. This suggests that exercise, with its well-documented health benefits during oncological treatment, produces neither additional costs nor savings.

The Phys-Can study: meaningful and challenging - supervising physical exercise in a community-based setting for persons undergoing curative oncological treatment.

Introduction: Supervised exercise may improve physical function and quality of life during oncological treatment. Providing supervised exercise to all patients at hospitals may be impractical, with community-based settings (e.g. public gyms) as a possible alternative. To facilitate implementation, knowledge about the experiences of professionals who deliver exercise programs in community-based settings is crucial.Objective: To explore how physical therapists and personal trainers experience supervising exercise in a community-based setting for persons undergoing curative oncological treatment. Methods: Nine physical therapists and two personal trainers (coaches) were interviewed individually. The semi-structured interviews lasted 33-67 minutes and were analyzed using thematic analysis. Results: Two main themes emerged: "A meaningful task" and "A challenging task," with nine sub-themes. The coaches experienced supervising exercise for persons undergoing treatment as meaningful, as they became a link between oncology care and health promotion. They grew more confident in the role and ascertained that exercising during treatment was feasible. Challenges included managing side effects of treatment and contradictory information from oncology care staff at hospitals, advising patients not to exercise.Conclusion: Supervising exercise for persons undergoing oncological treatment in a community-based setting may be highly rewarding for professionals who deliver exercise programs, which is promising for implementation. However, patients receive contradictory information about exercise, which may prevent physical activity. Also, supervising exercise for persons undergoing oncological treatment requires skills training; this is suggested for inclusion in educational programs for physical therapists and others. Future research should focus on strategies for cooperation between oncology care and health promotion.

Who makes it all the way? Participants vs. decliners, and completers vs. drop-outs, in a 6-month exercise trial during cancer treatment. Results from the Phys-Can RCT.

PURPOSE: To compare sociodemographic, health- and exercise-related characteristics of participants vs. decliners, and completers vs. drop-outs, in an exercise intervention trial during cancer treatment. METHODS: Patients with newly diagnosed breast, prostate, or colorectal cancer were invited to participate in a 6-month exercise intervention. Background data for all respondents (n = 2051) were collected at baseline by questionnaire and medical records. Additional data were collected using an extended questionnaire, physical activity monitors, and fitness testing for trial participants (n = 577). Moreover, a sub-group of decliners (n = 436) consented to additional data collection by an extended questionnaire . Data were analyzed for between-group differences using independent t-tests and chi2-tests. RESULTS: Trial participants were younger (59 ± 12yrs vs. 64 ± 11yrs, p < .001), more likely to be women (80% vs. 75%, p = .012), and scheduled for chemotherapy treatment (54% vs. 34%, p < .001), compared to decliners (n = 1391). A greater proportion had university education (60% vs 40%, p < .001), reported higher anxiety and fatigue, higher exercise self-efficacy and outcome expectations, and less kinesiophobia at baseline compared to decliners. A greater proportion of trial participants were classified as 'not physically active' at baseline; however, within the group who participated, being "physically active" at baseline was associated with trial completion. Completers (n = 410) also reported less kinesiophobia than drop-outs (n = 167). CONCLUSION: The recruitment procedures used in comprehensive oncology exercise trials should specifically address barriers for participation among men, patients without university education and older patients. Individualized efforts should be made to enroll patients with low exercise self-efficacy and low outcome expectations of exercise. To retain participants in an ongoing exercise intervention, extra support may be needed for patients with kinesiophobia and those lacking health-enhancing exercise habits at baseline.

Effect of self-regulatory behaviour change techniques and predictors of physical activity maintenance in cancer survivors: a 12-month follow-up of the Phys-Can RCT.

BACKGROUND: Current knowledge about the promotion of long-term physical activity (PA) maintenance in cancer survivors is limited. The aims of this study were to 1) determine the effect of self-regulatory BCTs on long-term PA maintenance, and 2) identify predictors of long-term PA maintenance in cancer survivors 12 months after participating in a six-month exercise intervention during cancer treatment. METHODS: In a multicentre study with a 2 × 2 factorial design, the Phys-Can RCT, 577 participants with curable breast, colorectal or prostate cancer and starting their cancer treatment, were randomized to high intensity exercise with or without self-regulatory behaviour change techniques (BCTs; e.g. goal-setting and self-monitoring) or low-to-moderate intensity exercise with or without self-regulatory BCTs. Participants' level of PA was assessed at the end of the exercise intervention and 12 months later (i.e. 12-month follow-up), using a PA monitor and a PA diary. Participants were categorized as either maintainers (change in minutes/week of aerobic PA ≥ 0 and/or change in number of sessions/week of resistance training ≥0) or non-maintainers. Data on potential predictors were collected at baseline and at the end of the exercise intervention. Multiple logistic regression analyses were performed to answer both research questions. RESULTS: A total of 301 participants (52%) completed the data assessments. A main effect of BCTs on PA maintenance was found (OR = 1.80, 95%CI [1.05-3.08]) at 12-month follow-up. Participants reporting higher health-related quality-of-life (HRQoL) (OR = 1.03, 95%CI [1.00-1.06] and higher exercise motivation (OR = 1.02, 95%CI [1.00-1.04]) at baseline were more likely to maintain PA levels at 12-month follow-up. Participants with higher exercise expectations (OR = 0.88, 95%CI [0.78-0.99]) and a history of tobacco use at baseline (OR = 0.43, 95%CI [0.21-0.86]) were less likely to maintain PA levels at 12-month follow-up. Finally, participants with greater BMI increases over the course of the exercise intervention (OR = 0.63, 95%CI [0.44-0.90]) were less likely to maintain their PA levels at 12-month follow-up. CONCLUSIONS: Self-regulatory BCTs improved PA maintenance at 12-month follow-up and can be recommended to cancer survivors for long-term PA maintenance. Such support should be considered especially for patients with low HRQoL, low exercise motivation, high exercise expectations or with a history of tobacco use at the start of their cancer treatment, as well as for those gaining weight during their treatment. However, more experimental studies are needed to investigate the efficacy of individual or combinations of BCTs in broader clinical populations. TRIAL REGISTRATION: NCT02473003 (10/10/2014).

Lifestyle and Empowerment Techniques in Survivorship of Gynaecologic Oncology (LETSGO study): a study protocol for a multicentre longitudinal interventional study using mobile health technology and biobanking.

INTRODUCTION: The number of gynaecological cancer survivors is increasing and there is a need for a more sustainable model of follow-up care. Today's follow-up model is time-consuming and patients have reported unmet needs regarding information about their cancer and strategies for managing the consequences of treatment. The main aim of this study is to assess health-related empowerment-in terms of patient education, psychosocial support, and promotion of physical activity-in a new follow-up model by comparing it to standard follow-up in a quasi-randomised study involving intervention hospitals and control hospitals. METHODS AND ANALYSIS: At the intervention hospitals, patients will be stratified by risk of recurrence and late effects to either 1 or 3 years' follow-up. Nurses will replace doctors in half of the follow-up visits and focus in particular on patient education, self-management and physical activity. They will provide patients with information and guide them in goal setting and action planning. These measures will be reinforced by a smartphone application for monitoring symptoms and promoting physical activity. At the control hospitals, patients will be included in the standard follow-up programme. All patients will be asked to complete questionnaires at baseline and after 3, 6, 12, 24 and 36 months. Blood samples will be collected for biobanking at 3, 12 and 36 months. The primary outcome is health-related empowerment. Secondary outcomes include health-related quality of life, adherence to physical activity recommendations, time to recurrence, healthcare costs and changes in biomarkers. Changes in these outcomes will be analysed using generalised linear mixed models for repeated measures. Type of hospital (intervention or control), time (measurement point), and possible confounders will be included as fixed factors. ETHICS AND DISSEMINATION: The study is approved by the Regional Committee for Medical Research Ethics (2019/11093). Dissemination of findings will occur at the local, national and international levels. TRIAL REGISTRATION NUMBER: NCT04122235.

Effects of heavy-load resistance training during (neo-)adjuvant chemotherapy on muscle cellular outcomes in women with breast cancer.

INTRODUCTION: (Neo-)adjuvant chemotherapy for breast cancer has a deleterious impact on muscle tissue resulting in reduced cardiorespiratory fitness, skeletal muscle mass and function. Physical exercise during treatment may counteract some of these negative effects. However, the effects of resistance training (RT) alone have never been explored. The present study aims to investigate if heavy-load RT during (neo-)adjuvant chemotherapy counteracts deleterious effects on skeletal muscle in women diagnosed with breast cancer. We hypothesize that (neo-)adjuvant treatment with chemotherapy will reduce muscle fiber size, impair mitochondrial function, and increase indicators of cellular stress and that RT during treatment will counteract these negative effects. We also hypothesize that RT during (neo-)adjuvant chemotherapy will increase muscle and blood levels of potential antitumor myokines and reduce treatment-related side effects on muscle strength and cardiorespiratory fitness. METHODS: Fifty women recently diagnosed with breast cancer scheduled to start (neo-)adjuvant chemotherapy will be randomized to either randomized to either intervention group or to control group.The intervention group will perform supervised heavy-load RT twice a week over the course of chemotherapy (approximately 16-weeks) whereas the control group will be encouraged to continue with their usual activities. Muscle biopsies from m. vastus lateralis will be collected before the first cycle of chemotherapy (T0), after chemotherapy (T1), and 6 months later (T2) for assessment of muscle cellular outcomes. The primary outcome for this study is muscle fiber size. Secondary outcomes are: regulators of muscle fiber size and function, indicators of cellular stress and mitochondrial function, myokines with potential antitumor effects, muscle strength, and cardiorespiratory fitness. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Regional Ethical Review Board in Uppsala, Sweden (Dnr:2016/230/2). Results will be disseminated through presentations at scientific meetings, publications in peer-reviewed journals, social media, and patient organizations. TRIAL REGISTRATION NUMBER: NCT04586517.

Exercise intensity and markers of inflammation during and after (neo-) adjuvant cancer treatment.

Exercise training has been hypothesized to lower the inflammatory burden for patients with cancer, but the role of exercise intensity is unknown. To this end, we compared the effects of high-intensity (HI) and low-to-moderate intensity (LMI) exercise on markers of inflammation in patients with curable breast, prostate and colorectal cancer undergoing primary adjuvant cancer treatment in a secondary analysis of the Phys-Can randomized trial (NCT02473003). Sub-group analyses focused on patients with breast cancer undergoing chemotherapy. Patients performed 6 months of combined aerobic and resistance exercise on either HI or LMI during and after primary adjuvant cancer treatment. Plasma taken at baseline, immediately post-treatment and post-intervention was analyzed for levels of interleukin 1 beta (IL1B), IL6, IL8, IL10, tumor-necrosis factor alpha (TNFA) and C-reactive protein (CRP). Intention-to-treat analyses of 394 participants revealed no significant between-group differences. Regardless of exercise intensity, significant increases of IL6, IL8, IL10 and TNFA post-treatment followed by significant declines, except for IL8, until post-intervention were observed with no difference for CRP or IL1B. Subgroup analyses of 154 patients with breast cancer undergoing chemotherapy revealed that CRP (estimated mean difference (95% CI): 0.59 (0.33; 1.06); P = 0.101) and TNFA (EMD (95% CI): 0.88 (0.77; 1); P = 0.053) increased less with HI exercise post-treatment compared to LMI. Exploratory cytokine co-regulation analysis revealed no difference between the groups. In patients with breast cancer undergoing chemotherapy, HI exercise resulted in a lesser increase of CRP and TNFA immediately post-treatment compared to LMI, potentially protecting against chemotherapy-related inflammation.

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.