Muscle strength characteristics following megaprosthetic knee reconstruction for bone sarcoma.

OBJECTIVE: To assess muscle strength characteristics in patients with resection and megaprosthetic reconstruction of the knee for bone sarcoma compared to age- and sex-matched controls. METHODS: This was a cross-sectional, case-control study. Muscle strength characteristics for knee extension and -flexion were assessed isokinetically at three different joint velocities: 60, 120 and 180°/s, and by the rate of force development (RDFmax) in knee extension. The Toronto Extremity Salvage Score (TESS) was used in patients. RESULTS: Eighteen patients (91.6 months postop.) and 18 controls were included. Relative to controls, patients generated maximal torques of 19%, 23% and 23% in knee extension at 60, 120 and 180°/s, respectively. For knee flexion, patients generated maximal torques of 58%, 53% and 60% at 60, 120, and 180°/s, relative to the controls. RDFmax of the operated leg was 2.75 ± 2.13 N/ms, 7.16 ± 4.78 N/ms for the non-operated leg, and 7.95 ± 4.29 N/ms for the controls. The mean TESS score was 84.0. CONCLUSION: Patients reached approximately 20% of the maximal knee extension torque. In isometric assessments, they used double the amount of time to generate one-third of the maximal force compared to the controls despite good TESS scores.

Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival.

Cancer survivors suffer impairments in skeletal muscle in terms of reduced mass and function. Interestingly, human skeletal muscle possesses an epigenetic memory of earlier stimuli, such as exercise. Long-term retention of epigenetic changes in skeletal muscle following cancer survival and/or exercise training has not yet been studied. We, therefore, investigated genome-wide DNA methylation (methylome) in skeletal muscle following a 5-month, 3/week aerobic-training intervention in breast cancer survivors 10-14 years after diagnosis and treatment. These results were compared to breast cancer survivors who remained untrained and to age-matched controls with no history of cancer, who undertook the same training intervention. Skeletal muscle biopsies were obtained from 23 females before(pre) and after(post) the 5-month training period. InfiniumEPIC 850K DNA methylation arrays and RT-PCR for gene expression were performed. The breast cancer survivors displayed a significant retention of increased DNA methylation (i.e., hypermethylation) at a larger number of differentially methylated positions (DMPs) compared with healthy age-matched controls pre training. Training in cancer survivors led to an exaggerated number of DMPs with a hypermethylated signature occurring at non-regulatory regions compared with training in healthy age-matched controls. However, the opposite occurred in important gene regulatory regions, where training in cancer survivors elicited a considerable reduction in methylation (i.e., hypomethylation) in 99% of the DMPs located in CpG islands within promoter regions. Importantly, training was able to reverse the hypermethylation identified in cancer survivors back toward a hypomethylated signature that was observed pre training in healthy age-matched controls at 300 (out of 881) of these island/promoter-associated CpGs. Pathway enrichment analysis identified training in cancer survivors evoked a predominantly hypomethylated signature in pathways associated with cell cycle, DNA replication/repair, transcription, translation, mTOR signaling, and the proteosome. Differentially methylated region (DMR) analysis also identified genes: BAG1, BTG2, CHP1, KIFC1, MKL2, MTR, PEX11B, POLD2, S100A6, SNORD104, and SPG7 as hypermethylated in breast cancer survivors, with training reversing these CpG island/promoter-associated DMRs toward a hypomethylated signature. Training also elicited a largely different epigenetic response in healthy individuals than that observed in cancer survivors, with very few overlapping changes. Only one gene, SIRT2, was identified as having altered methylation in cancer survivors at baseline and after training in both the cancer survivors and healthy controls. Overall, human skeletal muscle may retain a hypermethylated signature as long as 10-14 years after breast cancer treatment/survival. Five months of aerobic training reset the skeletal muscle methylome toward signatures identified in healthy age-matched individuals in gene regulatory regions.

Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials.

Background: Low muscle in cancer is associated with an increase in treatment-related toxicities and is a predictor of cancer-related and all-cause mortality. The mechanisms of cancer-related muscle loss are multifactorial, including anorexia, hypogonadism, anaemia, inflammation, malnutrition, and aberrations in skeletal muscle protein turnover and metabolism. Methods: In this narrative review, we summarise relevant literature to (i) review the factors influencing skeletal muscle mass regulation, (ii) provide an overview of how cancer/treatments negatively impact these, (iii) review factors beyond muscle signalling that can impact the ability to participate in and respond to an exercise intervention to counteract muscle loss in cancer, and (iv) provide perspectives on critical areas of future research. Results: Despite the well-known benefits of exercise, there remains a paucity of clinical evidence supporting the impact of exercise in cancer-related muscle loss. There are numerous challenges to reversing muscle loss with exercise in clinical cancer settings, ranging from the impact of cancer/treatments on the molecular regulation of muscle mass, to clinical challenges in responsiveness to an exercise intervention. For example, tumour-related/treatment-related factors (e.g. nausea, pain, anaemia, and neutropenia), presence of comorbidities (e.g. diabetes, arthritis, and chronic obstructive pulmonary disease), injuries, disease progression and bone metastases, concomitant medications (e.g., metformin), can negatively affect an individual's ability to exercise safely and limit subsequent adaptation. Conclusions: This review identifies numerous gaps and oppportunities in the area of low muscle and muscle loss in cancer. Collaborative efforts between preclinical and clinical researchers are imperative to both understanding the mechanisms of atrophy, and develop appropriate therapeutic interventions.

Does Androgen Deprivation for Prostate Cancer Affect Normal Adaptation to Resistance Exercise?

BACKGROUND: Loss of muscle mass and muscle function is a common side effect from androgen deprivation therapy (ADT) for prostate cancer (PCa). Here, we explored effects of heavy-load resistance training (RT) on lean body mass and muscle strength changes reported in randomized controlled trials (RCTs) among PCa patients on ADT and in healthy elderly men (HEM), by comparison of results in separate meta-analysis. METHODS: RCTs were identified through databases and reference lists. RESULTS: Seven RCTs in PCa patients (n = 449), and nine in HEM (n = 305) were included. The effects of RT in lean body mass change were similar among PCa patients (Standardized mean difference (SMD): 0.4, 95% CI: 0.2, 0.7) and HEM (SMD: 0.5, 95% CI: 0.2, 0.7). It is noteworthy that the within group changes showed different patterns in PCa patients (intervention: 0.2 kg; control: -0.6 kg) and HEM (intervention: 1.2 kg; control: 0.2 kg). The effects of RT on change in muscle strength (measured as 1 RM) were similar between PCa patients and HEM, both for lower body- (PCa: SMD: 1.9, 95% CI: 1.2, 2.5; HEM: SMD: 2.2, 95% CI: 1.0, 3.4), and for upper body exercises (PCa: SMD: 2.0, 95% CI: 1.3, 2.7; HEM: SMD: 1.9, 95% CI: 1.3, 2.6). CONCLUSIONS: The effects of RT on lean body mass and 1 RM were similar in PCa patients on ADT and HEM, but the mechanism for the intervention effect might differ between groups. It seems that RT counteracts loss of lean body mass during ADT in PCa patients, as opposed to increasing lean body mass in HEM.

Reporting of Resistance Training Dose, Adherence, and Tolerance in Exercise Oncology.

PURPOSE: While general guidelines (such as CONSORT or Consensus on Exercise Reporting Template) exist to enhance the reporting of exercise interventions in the field of exercise science, there is inadequate detail facilitating the standardized reporting of resistance training adherence in the oncology setting. The purpose of this study was to apply a novel method to report resistance training dose, adherence, and tolerance in patients with cancer. METHODS: A total of 47 prostate cancer patients (70.1 ± 8.9 yr, body mass index, 28.6 ± 4.0) with bone metastatic disease completed an exercise program for 12 wk. We assessed traditional metrics of adherence (attendance and loss to follow-up), in addition to novel proposed metrics (exercise-relative dose intensity, dose modification, and exercise interruption). Total training volume in kilograms (repetitions × sets × training load (weight)) was calculated for each patient. RESULTS: Attendance assessed from traditional metrics was 79.5% ± 17.0% and four patients (9%) were lost to follow-up. The prescribed and actual cumulative total dose of resistance training was 139,886 ± 69,150 kg and 112,835 ± 83,499 kg, respectively, with a mean exercise-relative dose intensity of 77.4% ± 16.6% (range: 19.4% -99.4%). Resistance training was missed (1-2 consecutive sessions) or interrupted (missed ≥3 consecutive sessions) in 41 (87%) and 24 (51%) participants, respectively. Training dose was modified (reduction in sets, repetitions, or weight) in 40 (85%) of patients. Importantly, using attendance as a traditional metric of adherence, these sessions would have all counted as adherence to the protocol. CONCLUSIONS: Traditional reporting metrics of resistance training in exercise oncology may overestimate exercise adherence. Our proposed metrics to capture resistance training dose, adherence, and tolerance may have important applications for future studies and clinical practice.

Efficacy of Exercise Therapy on Cardiorespiratory Fitness in Patients With Cancer: A Systematic Review and Meta-Analysis.

Purpose To evaluate the effects of exercise therapy on cardiorespiratory fitness (CRF) in randomized controlled trials (RCTs) among patients with adult-onset cancer. Secondary objectives were to evaluate treatment effect modifiers, safety, and fidelity. Methods A systematic search of PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library was conducted to identify RCTs that compared exercise therapy to a nonexercise control group. The primary end point was change in CRF as evaluated by peak oxygen consumption (VO2peak; in mL O2 × kg-1 × min-1) from baseline to postintervention. Subgroup analyses evaluated whether treatment effects differed as a function of exercise prescription (ie, modality, schedule, length, supervision), study characteristics (ie, intervention timing, primary cancer site), and publication year. Safety was defined as report of any adverse event (AE); fidelity was evaluated by rates of attendance, adherence, and loss to follow-up. Results Forty-eight unique RCTs that represented 3,632 patients (mean standard deviation age, 55 ± 7.5 years; 68% women); 1,990 (55%) and 1,642 (45%) allocated to exercise therapy and control/usual care groups, respectively, were evaluated. Exercise therapy was associated with a significant increase in CRF (+2.80 mL O2 × kg-1 × min-1) compared with no change (+0.02 mL O2 × kg-1 × min-1) in the control group (weighted mean differences, +2.13 mL O2 × kg-1 × min-1; 95% CI, 1.58 to 2.67; I2, 20.6; P < .001). No statistical significant differences were observed on the basis of any treatment effect modifiers. Thirty trials (63%) monitored AEs; a total of 44 AEs were reported. The mean standard deviation loss to follow-up, attendance, and adherence rates were 11% ± 13%, 84% ± 12%, and 88% ± 32%, respectively. Conclusion Exercise therapy is an effective adjunctive therapy to improve CRF in patients with cancer. Our findings support the recommendation of exercise therapy for patients with adult-onset cancer.

Association of Exercise With Mortality in Adult Survivors of Childhood Cancer.

Importance: Adult survivors of childhood cancer are at excess risk for mortality compared with the general population. Whether exercise attenuates this risk is not known. Objective: To examine the association between vigorous exercise and change in exercise with mortality in adult survivors of childhood cancer. Design, Setting, and Participants: Multicenter cohort analysis among 15 450 adult cancer survivors diagnosed before age 21 years from pediatric tertiary hospitals in the United States and Canada between 1970 and 1999 enrolled in the Childhood Cancer Survivor Study, with follow-up through December 31, 2013. Exposures: Self-reported vigorous exercise in metabolic equivalent task (MET) hours per week. The association between vigorous exercise and change in vigorous exercise and cause-specific mortality was assessed using multivariable piecewise exponential regression analysis to estimate rate ratios. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary end points were cause-specific mortality (recurrence/progression of primary malignant neoplasm and health-related mortality). Outcomes were assessed via the National Death Index. Results: The 15 450 survivors had a median age at interview of 25.9 years (interquartile range [IQR], 9.5 years) and were 52.8% male. During a median follow-up of 9.6 years (IQR, 15.5 years), 1063 deaths (811 health-related, 120 recurrence/progression of primary cancer, 132 external/unknown causes) were documented. At 15 years, the cumulative incidence of all-cause mortality was 11.7% (95% CI, 10.6%-12.8%) for those who exercised 0 MET-h/wk, 8.6% (95% CI, 7.4%-9.7%) for 3 to 6 MET-h/wk, 7.4% (95% CI, 6.2%-8.6%) for 9 to 12 MET-h/wk, and 8.0% (95% CI, 6.5%-9.5%) for 15 to 21 MET-h/wk (P < .001). There was a significant inverse association across quartiles of exercise and all-cause mortality after adjusting for chronic health conditions and treatment exposures (P = .02 for trend). Among a subset of 5689 survivors, increased exercise (mean [SD], 7.9 [4.4] MET-h/wk) over an 8-year period was associated with a 40% reduction in all-cause mortality rate compared with maintenance of low exercise (rate ratio, 0.60; 95% CI, 0.44-0.82; P = .001). Conclusions and Relevance: Vigorous exercise in early adulthood and increased exercise over 8 years was associated with lower risk of mortality in adult survivors of childhood cancer.

Feasibility, safety, and efficacy of aerobic training in pretreated patients with metastatic breast cancer: A randomized controlled trial.

BACKGROUND: The investigation of exercise training in metastatic breast cancer has received minimal attention. This study determined the feasibility and safety of aerobic training in metastatic breast cancer. METHODS: Sixty-five women (age, 21-80 years) with metastatic (stage IV) breast cancer (57% were receiving chemotherapy, and >40% had ≥ 2 lines of prior therapy) were allocated to an aerobic training group (n = 33) or a stretching group (n = 32). Aerobic training consisted of 36 supervised treadmill walking sessions delivered thrice weekly between 55% and 80% of peak oxygen consumption (VO2peak ) for 12 consecutive weeks. Stretching was matched to aerobic training with respect to location, frequency, duration, and intervention length. The primary endpoint was aerobic training feasibility, which was a priori defined as the lost to follow-up (LTF) rate (<20%) and attendance (≥70%). Secondary endpoints were safety, objective outcomes (VO2peak and functional capacity), and patient-reported outcomes (PROs; quality of life). RESULTS: One of the 33 patients (3%) receiving aerobic training was LTF, whereas the mean attendance rate was 63% ± 30%. The rates of permanent discontinuation and dose modification were 27% and 49%, respectively. Intention-to-treat analyses indicated improvements in PROs, which favored the attention control group (P values > .05). Per protocol analyses indicated that 14 of 33 patients (42%) receiving aerobic training had acceptable tolerability (relative dose intensity ≥ 70%), and this led to improvements in VO2peak and functional capacity (P values < .05). CONCLUSIONS: Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of patients with metastatic breast cancer. The acceptable feasibility and promising benefit for select patients warrant further evaluation in a dose-finding phase 1/2 study. Cancer 2018;124:2552-60. © 2018 American Cancer Society.

Exercise Therapy and Cardiovascular Toxicity in Cancer.

Cardio-oncology is an emerging discipline focused predominantly on the detection and management of cancer treatment-induced cardiac dysfunction (cardiotoxicity), which predisposes to development of overt heart failure or coronary artery disease. The direct adverse consequences, as well as those secondary to anticancer therapeutics, extend beyond the heart, however, to affect the entire cardiovascular-skeletal muscle axis (ie, whole-organism cardiovascular toxicity). The global nature of impairment creates a strong rationale for treatment strategies that augment or preserve global cardiovascular reserve capacity. In noncancer clinical populations, exercise training is an established therapy to improve cardiovascular reserve capacity, leading to concomitant reductions in cardiovascular morbidity and its attendant symptoms. Here, we overview the tolerability and efficacy of exercise on cardiovascular toxicity in adult patients with cancer. We also propose a conceptual research framework to facilitate personalized risk assessment and the development of targeted exercise prescriptions to optimally prevent or manage cardiovascular toxicity after a cancer diagnosis.

Novel Methods for Reporting of Exercise Dose and Adherence: An Exploratory Analysis.

PURPOSE: The purpose of this study was to explore whether methods adapted from oncology pharmacological trials have utility in reporting adherence (tolerability) of exercise treatment in cancer. METHODS: Using a retrospective analysis of a randomized trial, 25 prostate cancer patients received an aerobic training regimen of 72 supervised treadmill walking sessions delivered thrice weekly between 55% and 100% of exercise capacity for 24 consecutive weeks. Treatment adherence (tolerability) was assessed using conventional (lost to follow-up and attendance) and exploratory (e.g., permanent discontinuation, dose modification, and relative dose intensity) outcomes. RESULTS: The mean total cumulative "planned" and "completed" dose was 200.7 ± 47.6 and 153.8 ± 68.8 MET·h, respectively, equating to a mean relative dose intensity of 77% ± 24%. Two patients (8%) were lost to follow-up, and mean attendance was 79%. A total of 6 (24%) of 25 patients permanently discontinued aerobic training before week 24. Aerobic training was interrupted (missing ≥3 consecutive sessions) or dose reduced in a total of 11 (44%) and 24 (96%) patients, respectively; a total 185 (10%) of 1800 training sessions required dose reduction owing to both health-related (all nonserious) and non-health-related adverse events. Eighteen (72%) patients required at least one session to be terminated early; a total of 59 (3%) sessions required early termination. CONCLUSIONS: Novel methods for the conduct and reporting of exercise treatment adherence and tolerability may provide important information beyond conventional metrics in patients with cancer.

Effects of strength training on body composition, physical functioning, and quality of life in prostate cancer patients during androgen deprivation therapy.

BACKGROUND: Androgen deprivation therapy (ADT) increases survival rates in prostate cancer (PCa) patients with locally advanced disease, but is associated with side effects that may impair daily function. Strength training may counteract several side effects of ADT, such as changes in body composition and physical functioning, which in turn may affect health-related quality of life (HRQOL). However, additional randomised controlled trials are needed to expand this knowledge. MATERIAL AND METHODS: Fifty-eight PCa patients on ADT were randomised to either 16 weeks of high-load strength training (n = 28) or usual care (n = 30). The primary outcome was change in total lean body mass (LBM) assessed by dual x-ray absorptiometry (DXA). Secondary outcomes were changes in regional LBM, fat mass, and areal bone mineral density (aBMD) measured by DXA; physical functioning assessed by 1-repetition maximum (1RM) tests, sit-to-stand test, stair climbing test and Shuttle walk test; and HRQOL as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. RESULTS AND CONCLUSION: No statistically significant effect of high-load strength training was demonstrated on total LBM (p = 0.16), but significant effects were found on LBM in the lower and upper extremities (0.49 kg, p < 0.01 and 0.15 kg, p < 0.05, respectively). Compared to usual care, high-load strength training showed no effect on fat mass, aBMD or HRQOL, but beneficial effects were observed in all 1RM tests, sit-to-stand test and stair climbing tests. Adherence to the training program was 88% for lower body exercises and 84% for upper body exercises. In summary, high-load strength training improved LBM in extremities and physical functioning, but had no effect on fat mass, aBMD, or HRQOL in PCa patients on ADT.

A randomized controlled trial on the effectiveness of strength training on clinical and muscle cellular outcomes in patients with prostate cancer during androgen deprivation therapy: rationale and design.

BACKGROUND: Studies indicate that strength training has beneficial effects on clinical health outcomes in prostate cancer patients during androgen deprivation therapy. However, randomized controlled trials are needed to scientifically determine the effectiveness of strength training on the muscle cell level. Furthermore, close examination of the feasibility of a high-load strength training program is warranted. The Physical Exercise and Prostate Cancer (PEPC) trial is designed to determine the effectiveness of strength training on clinical and muscle cellular outcomes in non-metastatic prostate cancer patients after high-dose radiotherapy and during ongoing androgen deprivation therapy. METHODS/DESIGN: Patients receiving androgen deprivation therapy for 9-36 months combined with external high-dose radiotherapy for locally advanced prostate cancer are randomized to an exercise intervention group that receives a 16 week high-load strength training program or a control group that is encouraged to maintain their habitual activity level. In both arms, androgen deprivation therapy is continued until the end of the intervention period.Clinical outcomes are body composition (lean body mass, bone mineral density and fat mass) measured by Dual-energy X-ray Absorptiometry, serological outcomes, physical functioning (muscle strength and cardio-respiratory fitness) assessed with physical tests and psycho-social functioning (mental health, fatigue and health-related quality of life) assessed by questionnaires. Muscle cellular outcomes are a) muscle fiber size b) regulators of muscle fiber size (number of myonuclei per muscle fiber, number of satellite cells per muscle fiber, number of satellite cells and myonuclei positive for androgen receptors and proteins involved in muscle protein degradation and muscle hypertrophy) and c) regulators of muscle fiber function such as proteins involved in cellular stress and mitochondrial function. Muscle cellular outcomes are measured on muscle cross sections and muscle homogenate from muscle biopsies obtained from muscle vastus lateralis. DISCUSSION: The findings from the PEPC trial will provide new knowledge on the effects of high-load strength training on clinical and muscle cellular outcomes in prostate cancer patients during androgen deprivation therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00658229.