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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.

BackgroundIn the earlier randomized controlled Physical Activity during Cancer Treatment (PACT) study, we found beneficial effects of an 18-week supervised exercise program on fatigue in patients with newly diagnosed breast or colon cancer undergoing adjuvant treatment. The present study assessed long-term effects of the exercise program on levels of fatigue and physical activity 4 years after participation in the PACT study.MethodsThe original study was a two-armed, multicenter randomized controlled trial comparing an 18-week supervised exercise program to usual care among 204 breast cancer patients and 33 colon cancer patients undergoing adjuvant treatment. Of the 237 PACT participants, 197 participants were eligible and approached to participate in the 4-year post-baseline measurements, and 128 patients responded. We assessed fatigue and physical activity levels at 4 years post-baseline and compared this to levels at baseline, post-intervention (18 weeks post-baseline), and at 36 weeks post-baseline.ResultsIntention-to-treat mixed linear effects model analyses showed that cancer patients in the intervention group reported significantly higher moderate-to-vigorous total physical activity levels (141.46 min/week (95% confidence interval (CI) 1.31, 281.61, effect size (ES) = 0.22) after 4 years compared to the usual care group. Furthermore, cancer patients in the intervention group tended to experience less physical fatigue at 4 years post-baseline compared to the usual care group (− 1.13, 95% CI –2.45, 0.20, ES = 0.22), although the result was not statistically significant.ConclusionPatients with breast or colon cancer who participated in the 18-week exercise intervention showed significant higher levels of moderate-to-vigorous total physical activity levels and a tendency towards lower physical fatigue levels 4 years post-baseline. Our result indicate that exercising during chemotherapy is a promising strategy for minimizing treatment-related side effects, both short and long term.Trial registrationCurrent Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on 9 December 2009.

Background This study investigated whether a supervised exercise programme improves quality of life (QoL), fatigue and cardiorespiratory fitness in patients in the first year after oesophagectomy. Methods The multicentre PERFECT trial randomly assigned patients to an exercise intervention (EX) or usual care (UC) group. EX patients participated in a 12-week moderate- to high-intensity aerobic and resistance exercise programme supervised by a physiotherapist. Primary (global QoL, QoL summary score) and secondary (QoL subscales, fatigue and cardiorespiratory fitness) outcomes were assessed at baseline, 12 and 24 weeks and analysed as between-group differences using either linear mixed effects models or ANCOVA. Results A total of 120 patients (mean(s.d.) age 64(8) years) were included and randomized to EX (61 patients) or UC (59 patients). Patients in the EX group participated in 96 per cent (i.q.r. 92–100 per cent) of the exercise sessions and the relative exercise dose intensity was high (92 per cent). At 12 weeks, beneficial EX effects were found for QoL summary score (3.5, 95 per cent c.i. 0.2 to 6.8) and QoL role functioning (9.4, 95 per cent c.i. 1.3 to 17.5). Global QoL was not statistically significant different between groups (3.0, 95 per cent c.i. –2.2 to 8.2). Physical fatigue was lower in the EX group (–1.2, 95 per cent c.i. –2.6 to 0.1), albeit not significantly. There was statistically significant improvement in cardiorespiratory fitness following EX compared with UC (peak oxygen uptake (1.8 ml/min/kg, 95 per cent c.i. 0.6 to 3.0)). After 24 weeks, all EX effects were attenuated. Conclusions A supervised exercise programme improved cardiorespiratory fitness and aspects of QoL. Trial registration Dutch Trial Register NTR 5045 (www.trialregister.nl/trial/4942).

BackgroundAdiposity increases endometrial cancer (EC) risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); interleukin-6, interleukin-1-receptor antagonist, TNF-receptor-1 and -2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); free estradiol and estrone (estrogen biomarkers) in the adiposity-EC link in postmenopausal women. MethodsWe used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition. Eligible women had not had cancer, hysterectomy, diabetes, did not use oral contraceptives or hormone therapy, and were postmenopausal at recruitment. Mediating pathways from adiposity to EC were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis. ResultsThe study included 163 cases and 306 controls. The adjusted odds ratio (OR) for EC for BMI≥30vs.18.5≤BMI<25kg/m 2 was 2.51 (95%CI 1.26-5.02). The ORs NIE were 1.95 (1.01-3.74) through all biomarkers (72% proportion mediated (PM)) decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33%PM); 1.13 (0.71-1.80) through inflammation beyond [the potential influence of] adiponectin (13%PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5%PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21%PM). The OR NDE not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results. ConclusionReduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated ~70% of increased odds of EC in women with obesity vs. normal weight. ImpactIf replicated, these results could have implications for identifying targets for intervention to reduce EC risk in women with obesity.

Purpose This study examined the Sense of Coherence (SOC) of patients participating in the randomized controlled 'Optimal Training for Women with Breast Cancer' (OptiTrain) study and assessed how patient characteristics were associated with SOC. Secondary aims were to assess the association between SOC and patients' participation in this study and to determine whether SOC moderates the effect of the 16-week exercise intervention on fatigue, quality of life (QoL), and symptom burden in women with breast cancer undergoing chemotherapy. Methods Modified Poisson regression analyses were conducted to determine the relative risk of weak-normal SOC versus strong SOC in terms of exercise session attendance, study and intervention dropout, and long absence rates. Analyses of covariance were performed to assess whether SOC moderated the effect of the exercise intervention (p interaction ≤ 0.10). Results Two hundred and forty women with early breast cancer (mean age 53 ± 10) participated in the OptiTrain study. Women with strong SOC reported less fatigue, lower symptom burden, and higher QoL. Women with weak-normal SOC were significantly more likely to drop out from the OptiTrain study and tended to have slightly poorer exercise session attendance. Women with breast cancer and weaker SOC benefitted as much from the exercise intervention, in terms of fatigue and QoL, as those with stronger SOC (p interaction > 0.10). Conclusions Strong SOC appears to be associated with a more positive subjective state of health. Women with weak-normal SOC may need additional support to encourage participation and adherence in exercise trials. Assessing SOC may assist clinicians to identify and provide extra support for participants with weak SOC, who may be less inclined to participate in exercise programs.

Background: Paclitaxel is a taxane-based chemotherapeutic agent used as a treatment in breast cancer. There is no effective prevention or treatment strategy for the most common side effect of peripheral neuropathy. In this manuscript, we reviewed the molecular mechanisms that contribute to paclitaxel-induced peripheral neuropathy (PIPN) with an emphasis on immune-related processes. Methods: A systematic search of the literature was conducted in PubMed, EMBASE and Cochrane Library. The SYRCLE's risk of bias tool was used to assess internal validity. Results: 156 studies conducted with rodent models were included. The risk of bias was high due to unclear methodology. Paclitaxel induces changes in myelinated axons, mitochondrial dysfunction, and mechanical hypersensitivity by affecting ion channels expression and function and facilitating spinal transmission. Paclitaxel-induced inflammatory responses are important contributors to PIPN. Conclusion: Immune-related processes are an important mechanism contributing to PIPN. Studies in humans that validate these mechanistic data are highly needed to facilitate the development of therapeutic strategies.

Background Having a physically active lifestyle after cancer diagnosis is beneficial for health, and this needs to be continued into survivorship to optimize long-term benefits. We found that patients, who participated in an 18-week exercise intervention, reported significant higher physical activity (PA) levels 4 years after participation in a randomized controlled trial of supervised exercise delivered during chemotherapy (PACT study). This study aimed to identify social-ecological correlates of PA levels in breast and colon cancer survivors 4 years after participation in the PACT study. Methods Self-reported PA levels and potential correlates (e.g. physical fitness, fatigue, exercise history, and built environment) were assessed in 127 breast and colon cancer survivors shortly after diagnosis (baseline), post-intervention and 4 years later. Multivariable linear regression analyses were performed to identify social-ecological correlates of PA 4 years postbaseline. Results The final model revealed that lower baseline physical fatigue (β =-0.25, 95% CI-0.26;-0.24) and higher baseline total PA (0.06, 95% CI, 0.03; 0.10) were correlated with higher total PA levels 4 years post-baseline. Higher baseline leisure and sport PA (0.02, 95% CI 0.01; 0.03), more recreational facilities within a buffer of 1 km (4.05, 95% CI = 1.28; 6.83), lower physical fatigue at 4-year follow-up (-8.07, 95% CI-14.00;-2.13), and having a