High-intensity interval training in combination with aerobic or resistance training for patients with breast cancer : a HIIT to counteract detrimental effects of chemotherapy

With the increasing number of individuals that enter cancer survivorship there is a growing need for interventions that can alleviate treatment-related adverse effects such as fatigue, and that can improve and restore physical functioning and health-related quality of life during and after treatment. After a breast cancer diagnosis, patients with breast cancer show significantly reduced physical activity levels, especially during the adjuvant treatment phase. Today, there is evidence supporting the efficacy of exercise, particularly combined resistance and aerobic training, to improve physiological and health-related outcomes in patients with breast cancer. However, most evidence is based on findings from studies conducted after chemotherapy. The training modality high-intensity interval training (HIIT) has been proven time effective and beneficial for various physiological outcomes. Despite this, data on the effects of HIIT during chemotherapy is limited. Moreover, few of the trials that have assessed exercise training during chemotherapy have included longer follow-ups, especially on objectively measured physiological outcomes, and no trials for patients with breast cancer during chemotherapy have evaluated the effects of exercise on objectively measured pain sensitivity or molecular outcomes in skeletal muscle. To meet the needs that follow the increasingly aggressive treatments for patients with breast cancer, equally progressive countermeasures are needed. Therefore, assessment of the influence of HIIT is highly justified. In this thesis, the aim was to examine and compare the effects of two different supervised exercise programs that included the training modality HIIT with focus on objectively measured physiological and self-reported health-related outcomes over the course of chemotherapy, and 12 months into survivorship. Two hundred and forty women with early stage breast cancer were randomized to 16 weeks of twice weekly supervised resistance combined with high-intensity interval training (RT-HIIT), moderate-intensity continuous aerobic training (AT-HIIT), or usual care (UC). The results of this thesis showed that compared to the deteriorations found in the UC group over the 16-week intervention, RT-HIIT was effective to counteract fatigue and pain sensitivity and showed improvements in muscle strength, while both exercise groups were effective to prevent declines in cardiorespiratory fitness, gains in body mass, and were effective to alleviate symptom burden. Moreover, exercise-induced specific morphological and functional improvements were found in skeletal muscle. At 12 months, both exercise groups were effective to counteract fatigue, and displayed improved muscle strength compared to deteriorations in the UC group. Additionally, AT-HIIT was effective to maintain body mass, and displayed lower symptom burden, as well as lower sick leave rates compared to the UC group. Taken together, this thesis shows that adding high-intensity interval training to resistance or aerobic training during chemotherapy in women with breast cancer was feasible, and was shown to be a powerful strategy to manage or prevent many of the short-and long-term adverse effects of treatment and inactivity, as well as to potentially minimize significant societal costs associated with high sick leave rates

Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

Funder: Vetenskapsrådet; FundRef: http://dx.doi.org/10.13039/501100004359Funder: Cancerfonden; FundRef: http://dx.doi.org/10.13039/501100002794Funder: Barncancerfonden; FundRef: http://dx.doi.org/10.13039/501100006313Funder: Svenska Läkaresällskapet; FundRef: http://dx.doi.org/10.13039/501100007687Funder: Cancer Research UK; FundRef: http://dx.doi.org/10.13039/501100000289Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. We show here that in mice, exercise-induced reduction in tumor growth is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted into plasma at high levels during exertion in both mice and humans enhance the effector profile of CD8+ T-cells. We found that activated murine CD8+ T cells alter their central carbon metabolism in response to exertion in vivo, and that immune cells from trained mice are more potent antitumor effector cells when transferred into tumor-bearing untrained animals. These data demonstrate that CD8+ T cells are metabolically altered by exercise in a manner that acts to improve their antitumoral efficacy

Doxorubicin-induced skeletal muscle atrophy:Elucidating the underlying molecular pathways

AIM: Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta-analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin-induced muscle atrophy in both human and animal models. METHODS: A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE's risk of bias tool. RESULTS: Twenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross-sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin-induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin-proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin-induced muscle atrophy, the activation of the ubiquitin-proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway. CONCLUSION: The results of the meta-analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose-response, separate the effects of doxorubicin from tumour-induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches

Physical Activity During and After Adjuvant Treatment for Breast Cancer : An Integrative Review of Women's Experiences

Background: In oncology, physical activity (PA) is recognized to improve psychological and physiological functions. Motivating women with breast cancer to sustain a physically active lifestyle is important for promoting positive health after diagnosis. To review and synthesize what is known about how women with breast cancer experience supervised and unsupervised PA during and after adjuvant treatment. PubMed, PsycINFO, and CINAHL were searched, yielding 994 citations. The final review included 17 articles published between 2004 and 2014 in English. The CASP (Critical Appraisal Skills Programme) instrument was used to appraise quality. Results: Exercise is experienced as a positive element with multiple benefits. However, maintaining a physically active lifestyle during and after chemotherapy is sometimes challenging. Reported benefits of PA include feeling empowered, and improving and reclaiming health. Facilitators to PA comprised exercising with peers and skilled instructors. Barriers included social factors and lack of information. Conclusions: Findings highlight the importance of incorporating PA programs from a patient experience perspective as routine treatment. Health care professionals play a crucial gateway role in providing information on implementation and benefits of PA. Providing support and educated advice about how to safely start or continue regular PA to minimize symptoms, reduce morbidity, and increase well-being during or after treatment is vital for women with breast cancer. Implications for Practice: Health care professionals need increased knowledge of the breast cancer patients' perspectives on facilitators and barriers to PA during and after treatment, in order to provide sufficient support for women to stay physically active during a breast cancer illness.CC BY-NC 3.0</p

Distance-based delivery of exercise for people treated for breast, prostate or colorectal cancer : a study protocol for a randomised controlled trial of EX-MED Cancer Sweden.

BACKGROUND: Regular exercise has been shown to have beneficial health effects in cancer survivors, including improving quality of life and other important health outcomes. However, providing people with cancer with easily accessible, high-quality exercise support and programs is a challenge. Therefore, there is a need to develop easily accessible exercise programs that draw upon the current evidence. Supervised, distance-based exercise programs have the benefit of reaching out to many people whilst providing the support of an exercise professional. The aim of the EX-MED Cancer Sweden trial is to examine the effectiveness of a supervised, distance-based exercise program, in people previously treated for breast, prostate, or colorectal cancer, on health-related quality of life (HRQoL), as well as other physiological and patient-reported health outcomes. METHODS: The EX-MED Cancer Sweden trial is a prospective randomised controlled trial including 200 people that have completed curative treatment for breast, prostate, or colorectal cancer. Participants are randomly allocated to an exercise group or a routine care control group. The exercise group will participate in a supervised, distanced-based exercise program delivered by a personal trainer who has undertaken specialised exercise oncology education modules. The intervention consists of a combination of resistance and aerobic exercises with participants completing two 60-min sessions per week for 12 weeks. The primary outcome is HRQoL (EORTC QLQ-C30) assessed at baseline, 3- (end of intervention and primary endpoint) and 6-months post-baseline. Secondary outcomes are physiological (cardiorespiratory fitness, muscle strength, physical function, body composition) and patient-reported outcomes (cancer-related symptoms, fatigue, self-reported physical activity), and self-efficacy of exercise. Furthermore, the trial will explore and describe the experiences of participation in the exercise intervention. DISCUSSION: The EX-MED Cancer Sweden trial will provide evidence regarding the effectiveness of a supervised, distance-based exercise program for survivors of breast, prostate, and colorectal cancer. If successful, it will contribute to the implementation of flexible and effective exercise programs as part of the standard of care for people following cancer treatment, which is likely to contribute to a reduction in the burden of cancer on the individual, health care system and society. CLINICALTRIALS: gov NCT05064670. Registered on October 1, 2021

Adding high-intensity interval training to conventional training modalities : optimizing health-related outcomes during chemotherapy for breast cancer: the OptiTrain randomized controlled trial

PURPOSE: Exercise training is an effective and safe way to counteract cancer-related fatigue (CRF) and to improve health-related quality of life (HRQoL). High-intensity interval training has proven beneficial for the health of clinical populations. The aim of this randomized controlled trial was to compare the effects of resistance and high-intensity interval training (RT-HIIT), and moderate-intensity aerobic and high-intensity interval training (AT-HIIT) to usual care (UC) in women with breast cancer undergoing chemotherapy. The primary endpoint was CRF and the secondary endpoints were HRQoL and cancer treatment-related symptoms. METHODS: Two hundred and forty women planned to undergo chemotherapy were randomized to supervised RT-HIIT, AT-HIIT, or UC. Measurements were performed at baseline and at 16 weeks. Questionnaires included Piper Fatigue Scale, EORTC-QLQ-C30, and Memorial Symptom Assessment Scale. RESULTS: The RT-HIIT group was superior to UC for CRF: total CRF (p = 0.02), behavior/daily life (p = 0.01), and sensory/physical (p = 0.03) CRF. Role functioning significantly improved while cognitive functioning was unchanged for RT-HIIT compared to declines shown in the UC group (p = 0.04). AT-HIIT significantly improved emotional functioning versus UC (p = 0.01) and was superior to UC for pain symptoms (p = 0.03). RT-HIIT reported a reduced symptom burden, while AT-HIIT remained stable compared to deteriorations shown by UC (p &lt; 0.01). Only RT-HIIT was superior to UC for total symptoms (p &lt; 0.01). CONCLUSIONS: 16 weeks of resistance and HIIT was effective in preventing increases in CRF and in reducing symptom burden for patients during chemotherapy for breast cancer. These findings add to a growing body of evidence supporting the inclusion of structured exercise prescriptions, including HIIT, as a vital component of cancer rehabilitation. TRIAL REGISTRATION: Clinicaltrials.gov Registration Number: NCT02522260.CC BY 4.0</p

Highly favorable physiological responses to concurrent resistance and high-intensity interval training during chemotherapy: the OptiTrain breast cancer trial

Advanced therapeutic strategies are often accompanied by significant adverse effects, which warrant equally progressive countermeasures. Physical exercise has proven an effective intervention to improve physical function and reduce fatigue in patients undergoing chemotherapy. Effects of high-intensity interval training (HIIT) in this population are not well established although HIIT has proven effective in other clinical populations. The aim of the OptiTrain trial was to examine the effects of concurrent resistance and high-intensity interval training (RT-HIIT) or concurrent moderate-intensity aerobic and high-intensity interval training (AT-HIIT), to usual care (UC) on pain sensitivity and physiological outcomes in patients with breast cancer during chemotherapy.Two hundred and forty women were randomized to 16\ua0weeks of RT-HIIT, AT-HIIT, or UC.cardiorespiratory fitness, muscle strength, body mass, hemoglobin levels, and pressure-pain threshold.Pre- to post-intervention, RT-HIIT (ES\ua0=\ua00.41) and AT-HIIT (ES\ua0=\ua00.42) prevented the reduced cardiorespiratory fitness found with UC. Handgrip strength (surgery side: RT-HIIT vs. UC: ES\ua0=\ua00.41, RT-HIIT vs.ES\ua0=\ua00.28; non-surgery side: RT-HIIT vs. UC: ES\ua0=\ua00.35, RT-HIIT vs.ES\ua0=\ua00.22) and lower-limb muscle strength (RT-HIIT vs. UC: ES\ua0=\ua00.66, RT-HIIT vs.ES\ua0=\ua00.23) were significantly improved in the RT-HIIT. Increases in body mass were smaller in RT-HIIT (ES\ua0=\ua0-\ua00.16) and AT-HIIT (ES\ua0=\ua0-\ua00.16) versus UC. RT-HIIT reported higher pressure-pain thresholds than UC (trapezius: ES\ua0=\ua00.46, gluteus: ES\ua0=\ua00.53) and AT-HIIT (trapezius: ES\ua0=\ua00.30).Sixteen\ua0weeks of RT-HIIT significantly improved muscle strength and reduced pain sensitivity. Both exercise programs were well tolerated and were equally efficient in preventing increases in body mass and in\ua0preventing declines in cardiorespiratory fitness. These results highlight the importance of implementing a combination of resistance and high-intensity interval training during chemotherapy for women with breast cancer