To our knowledge, this systematic review and meta-analysis is the first to date characterizing the lasting effects of combined exercise interventions on physical fitness and mental wellbeing during adjuvant therapy using the factors investigated herein.
These meta-analyses show interventions consisting of both resistance and endurance exercise elicit significant long-lasting improvements in global fatigue (SMD = -0.26, 95% CI = [-0.46; -0.07], I^2 = 0%, P = 0.008). This finding is supported by Carayol et al.  who also finds exercise interventions consisting of resistance, aerobic, and yoga exercise significantly improve fatigue in breast cancer patients receiving adjuvant therapy (P < 0.0001). This is of importance because high levels of fatigue during adjuvant treatment have been significantly linked to decreased adherence to treatment. This is demonstrated by Kidwell et al.  who show patients that were feeling tired/fatigued had significantly decreased adherence to aromatase inhibitor adjuvant therapy compared to patients without this symptom (OR = 1.76). This is also supported by Ruddy et al.  who show cyclophosphamide-methotrexate-5-fluorouracil (CMF) treatment attrition rates were significantly linked to patient fatigue (P = 0.025). Therefore, this finding is of clinical value to reducing fatigue, enhancing treatment adherence and therefore efficacy, and improving disease prognosis.
A lack of studies investigating the effects of combined interventions on muscular endurance and social functioning meant complete statistical analysis could not be completed. This finding therefore warrants further research into these areas in future randomised controlled trials.
The four remaining factors showed non-significant lasting improvements following interventions consisting of both resistance and endurance exercise. This means there are overall, no statistically significant lasting effects of combined resistance and endurance interventions on physical fitness and mental wellbeing in female breast cancer patients (≥ 18 years old) undergoing adjuvant therapy compared to adjuvant therapy alone, which is summarised in Table 3 in the appendix.
Despite being non-significant, these findings indicate there are still clinical benefits of combined exercise interventions to these adjuvant therapy side effects. Firstly, these findings show combined interventions elicit small improvements in cardiorespiratory fitness which is supported by other meta-analyses such as Furmaniak, Menig and Markes  and Lahart et al.  who show exercise interventions during and after adjuvant therapy non-significantly and significantly improve cardiorespiratory fitness respectively. This is reinforced by Wiestad et al.  and Møller et al.  who found exercise interventions elicit significant long-lasting improvements in cardiorespiratory fitness following adjuvant therapy. The present finding therefore implies combined exercise interventions enhance cardiorespiratory fitness which may contribute to enduring amelioration of physical fitness following adjuvant therapy. This is however modulated by ethnicity as shown by Dieli-Conwright et al.  who found that patients of Hispanic origin had lower baseline cardiorespiratory fitness following adjuvant treatment so would have lower overall cardiorespiratory fitness after completing combined exercise interventions compared to other ethnic groups. This suggests exercise interventions should be tailored accordingly during adjuvant therapy to maximise the lasting clinical benefits to cardiorespiratory fitness and therefore physical fitness.
Secondly, the present findings indicate there to be clinical benefits of combined interventions to muscular strength (shown by the 0.47 effect size) despite being non-significant. Support for this is provided by two recent meta-analyses conducted by Lahart et al.  and Møller et al.  who both found combined exercise interventions elicit significant enduring improvements in muscular strength following adjuvant therapy. Thus, combined exercise interventions may offer long-lasting clinical amelioration of muscular strength when completed during adjuvant treatment contributing to enhanced physical functioning and clinical outcome.
This research also shows there to be enduring clinical benefits of combined interventions to ameliorating depression demonstrated with an effect size of -0.42. Meta-analyses by Carayol et al. ; Furmaniak, Menig and Markes  and Lahart et al.  support this by finding significant enduring improvements in depression in response to combined exercise interventions during adjuvant treatment. These effects may also be applied if the exercise interventions are completed after adjuvant therapy –.
Ameliorating global fatigue, cardiorespiratory fitness, muscular strength and depression may collectively contribute to enhanced physical fitness and mental wellbeing and therefore improved QOL as demonstrated by these meta-analyses. The beneficial effects of exercise interventions on QOL are confirmed by additional meta-analyses such as research by Lee and Lee ; Carayol et al. ; Furmaniak, Menig and Markes  and Lahart et al.  who all found significant improvements in QOL following exercise interventions. This is also demonstrated on a singular basis by randomised controlled trials conducted by Kirkham et al.  and Dieli-Conwright et al. . The present findings in conjunction with previous research therefore clearly show the lasting benefits of combined exercise interventions to side effects harming physical fitness and mental wellbeing during adjuvant therapy when treating breast cancer.
Depression leading to decreased QOL and mental wellbeing may arise from adjuvant therapy such as chemotherapy through a disruption in monoamine homeostasis (monoamine hypothesis). Smith  explains this by suggesting that since chemotherapy is non-specific during treatment, damage associated molecular patterns may arise from both tumourigenic and healthy cells. These subsequently bind to pattern recognition receptors such as Toll-like receptors (TLRs) to stimulate pro-inflammatory pathways, including NF-κB. Resulting from this, secreted pro-inflammatory cytokines such as TNF-α may increase the reuptake of several neurotransmitters including serotonin, dopamine, noradrenaline and bone-derived neurotrophic factor (BDNF) resulting in lower serum levels leading to symptoms of depression. Therefore, a mechanistic basis for these findings in improving mental wellbeing after exercise may lie in biochemical alterations to these monoamines in response to exercise. Research by Helmich et al.  and Basso and Suzuki  show exercise induces serum increases in serotonin, dopamine, norepinephrine and BDNF . Therefore, it may be postulated that serum increases in monoamine levels following exercise interventions during chemotherapy may work to restore monoamine homeostasis alleviating depressive symptoms thus improving QOL.
A mechanism for why combined exercise interventions improve muscular strength and therefore physical fitness may lie in leukocyte alterations following exercise. Generally, the role of leukocytes in muscle repair and hypertrophy is well characterised: in response to acute myotrauma, a pro-inflammatory response occurs, establishing a chemotactic gradient for leukocyte invasion. These leukocytes augment this inflammation by secreting growth factors and cytokines to stimulate satellite cell recruitment for repair . Alongside satellite cells, M2 macrophages assist in repair and hypertrophy by modulating inflammation and aiding in the formation of novel myofibers and myonuclei –. In healthy individuals, leukocyte levels are within the normal range meaning muscle regeneration after exercise occurs normally, however chemotherapy regimens in breast cancer patients can significantly decrease blood leukocyte counts . This may result in impaired muscle repair following exercise, leading to decreased muscular strength and hypertrophy after completing daily tasks during adjuvant treatment. Over time since repair is impaired, muscular strength and health may decline leading to decreased physical fitness during adjuvant treatment. This would not only account for why chemotherapy has detrimental effects on physical fitness but also why exercise interventions may improve muscular strength following adjuvant treatment. To elaborate on this, following exercise bouts, leukocyte counts significantly increase  which may improve muscular regeneration and hypertrophy after exercise. In addition to this, recent research shows in response to exercise, epigenetic alterations occur in leukocytes favouring the demethylation and activation of anabolic pathways such as growth hormone-releasing hormone improving muscular hypertrophy and regeneration . Thus, the beneficial effects of exercise interventions on muscular strength may be mediated by increased leukocyte counts and alterations in the leukocyte epigenetic landscape favouring hypertrophy and repair. To complement this, exercise interventions such as endurance exercise are well characterised to improve oxygen uptake, enhancing cardiorespiratory fitness, which may in turn result in higher muscle oxygenation and therefore enhanced performance, leading to enhanced physical strength and fitness following adjuvant therapy. Holistically, improving muscular strength and health is of clinical importance to avoid the development of sarcopenia which may be augmented by adjuvant therapies, preventing the deterioration of physical fitness, QOL and mental wellbeing , .
The present findings also show interventions consisting of solely resistance exercise have an enduring, albeit non-significant, effect on improving each of the factors, apart from depression where there is little/no effect. These findings align with previous meta-analyses , . The findings also suggest endurance interventions improve each factor excluding muscular strength in which it has a small negative impact. A rationale behind this unexpected result could be that endurance interventions elicit high levels of autophagy resulting in muscle protein breakdown exceeding synthesis leading to loss of muscle mass and strength . However, the current paradigm based on an array of research suggests the opposite in that autophagy is key for muscle maintenance and homeostasis. Therefore, an alternative mechanism may be that endurance interventions induce transient muscle fiber type transitions from type II to type I fibers over the intervention period, increasing muscular endurance at the expense of muscular strength . This rationale aligns with the present results.
These findings indicate that overall, resistance exercise interventions are more effective than endurance exercise to lastingly improve these adjuvant therapy side effects when performed alone. This is evident in both the separate meta-analyses and the resistance and endurance vs endurance meta-analysis in which adding resistance to endurance is more effective than endurance alone.
Despite deploying methodology to minimise bias, there are still some important limitations to consider. Firstly, some of these meta-analyses are negatively impacted by studies with small sample sizes. Alongside this, multiple analyses suffer from high heterogeneity which together, may lead to low statistical power as shown by some of these analyses. This may leave these analyses prone to type 2 errors and bias leading to the possibility of misinformed conclusions. In addition, some of these meta-analyses are limited by study availability due to authors not replying with the required information and due to a lack of research in these areas. The possibility of missed papers during study selection also cannot be ruled out, although rigorous measures were taken to minimise this risk. In addition, the future direction provided by some prediction intervals were not clear, possibly impeding conclusions. These limitations therefore warrant further research into some of these adjuvant therapy factors to further inform clinical recommendations during adjuvant therapy.
4.2 Future research
These findings indicate that due to a lack of studies, more research is required in the following areas: the effects of combined interventions on depression, muscular endurance and social functioning, the effects of resistance interventions on cardiorespiratory fitness, depression and muscular endurance, and the effects of endurance exercise on cardiorespiratory fitness, depression, muscular endurance, muscular strength and social functioning. Additionally, due to a lack of power and non-definitive prediction intervals, further research is warranted in the following areas: the effects of combined interventions on QOL, the effects of resistance interventions on QOL and social functioning and finally, the effects of endurance interventions on global fatigue and QOL.
In conclusion, these findings show combined exercise interventions elicit significant enduring benefits to global fatigue during adjuvant therapy. They also suggest there to be lasting clinical benefits of combined interventions to improving the remaining factors thus improving physical fitness and mental wellbeing. When performed separately, these results suggest both types of interventions are beneficial in improving physical fitness and mental wellbeing. Finally, in the event combined interventions cannot take place, interventions consisting of solely resistance exercise elicit higher clinical benefits than endurance interventions.