Exercise Medicine for Cancer Cachexia : Targeted Exercise to Counteract Mechanisms and Treatment Side Effects

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY 4.0 https://creativecommons.org/licenses/by/4.0/ Exercise Medicine for Cancer Cachexia : Targeted Exercise to Counteract Mechanisms and Treatment Side Effects © The Author(s) 2022 Published version Mavropalias, Georgios; Sim, Marc; Taaffe, Dennis, R.; Galvão, Daniel A.; Spry, Nigel; Kraemer, William, J.; Häkkinen, Keijo; Newton, Robert, U. Mavropalias, G., Sim, M., Taaffe, D., Galvão, D. A., Spry, N., Kraemer, W., Häkkinen, K., & Newton, R. (2022). Exercise Medicine for Cancer Cachexia : Targeted Exercise to Counteract Mechanisms and Treatment Side Effects. Journal of Cancer Research and Clinical Oncology, 148(6), 1389-1406. https://doi.org/10.1007/s00432-022-03927-0 2022 Vol.:(0123456789) 1 3 Journal of Cancer Research and Clinical Oncology https://doi.org/10.1007/s00432-022-03927-0 REVIEW – CLINICAL ONCOLOGY Exercise medicine forcancer cachexia: targeted exercise tocounteract mechanisms andtreatment side effects GeorgiosMavropalias1,2 · MarcSim2,3,4· DennisR.Taaffe1,2· DanielA.Galvão1,2· NigelSpry1,2· WilliamJ.Kraemer1,2,5· KeijoHäkkinen6· RobertU.Newton1,2 Received: 6 December 2021 / Accepted: 13 January 2022 © The Author(s) 2022 Abstract Purpose Cancer-induced muscle wasting (i.e., cancer cachexia, CC) is a common and devastating syndrome that results in the death of more than 1 in 5 patients. Although primarily a result of elevated inflammation, there are multiple mechanisms that complement and amplify one another. Research on the use of exercise to manage CC is still limited, while exercise for CC management has been recently discouraged. Moreover, there is a lack of understanding that exercise is not a single medicine, but mode, type, dosage, and timing (exercise prescription) have distinct health outcomes. The purpose of this review was to examine the effects of these modes and subtypes to identify the most optimal form and dosage of exercise therapy specific to each underlying mechanism of CC. Methods The relevant literatures from MEDLINE and Scopus databases were examined. Results Exercise can counteract the most prominent mechanisms and signs of CC including muscle wasting, increased protein turnover, systemic inflammation, reduced appetite and anorexia, increased energy expenditure and fat wasting, insulin resistance, metabolic dysregulation, gut dysbiosis, hypogonadism, impaired oxidative capacity, mitochondrial dysfunction, and cancer treatments side-effects. There are different modes of exercise, and each mode has different sub-types that induce vastly diverse changes when performed over multiple sessions. Choosing suboptimal exercise modes, types, or dosages can be counterproductive and could further contribute to the mechanisms of CC without impacting muscle growth. Conclusion Available evidence shows that patients with CC can safely undertake higher-intensity resistance exercise programs, and benefit from increases in body mass and muscle mass. Keywords Cancer cachexia· Inflammation· Tumor· Exercise· Muscle wasting· Muscle atrophy Abbreviations CC Cancer cachexia CRP C-reactive protein HIIET Higher-intensity interval endurance training HOMA Homeostasis model assessment IGF-1 Insulin-like growth factor 1 LICET Low-intensity continuous endurance training mTORC1 MTOR complex 1 RET Resistance exercise training TNF-α Tumor-necrosis factor alpha Introduction Among the most detrimental side effects of cancer and treatment is cachexia, a multifactorial metabolic and immune system imbalance (Tisdale 2005). Cancer cachexia (CC) is the ongoing skeletal muscle loss (with or without fat mass * Georgios Mavropalias georgios.ma[email protected] 1 Exercise Medicine Research Institute, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA6027, Australia 2 School ofMedical andHealth Sciences, Edith Cowan University, Joondalup, Australia 3 Institute forNutrition Research, Edith Cowan University, Joondalup, Australia 4 Medical School, University ofWestern Australia, Perth, Australia 5 Department ofHuman Sciences, Ohio State University, Columbus, USA 6 Neuromuscular Research Center, Faculty ofSport andHealth Sciences, University ofJyväskylä, Jyvaskyla, Finland Journal of Cancer Research and Clinical Oncology 1 3 loss) during cancer manifestation and treatment, which cannot be reversed by conventional nutritional support, leading to progressive functional impairment and death (Fearon etal. 2011). Half of all cancer patients develop cachexia, and this estimate increases to 80% in hospitalized or advanced-stage patients (Tisdale 2003). Cachexia is observed in 80% of gastric, pancreatic, and esophageal, ~ 70% of head-and-neck, ~ 60% of lung, colorectal, lymphoma, and prostate, and 54% of malignant pleural mesothelioma cancer patients (Laviano and Meguid 1996). Moreover, CC is the immediate cause of death of at least 22% of all cancer patients (Argilés etal. 2014). Notably, aside from cancer, cachexia is observed in the late stages of almost every major chronic illness (Farkas etal. 2013), such as HIV/AIDS (prevalence 35%), chronic heart failure and chronic obstructive pulmonary disease (20%), chronic kidney disease (40%), and rheumatoid arthritis (10%) (von Haehling and Anker 2010). Despite the prevalence and severity, cachexia remains under-researched, while treatment options are limited, due to treatment inadequacy and inconsistency (Roeland etal. 2020). CC progression is often described as a continuum, advancing from pre-cachexia to cachexia, and finally to refractory cachexia, where the expected survival is less than 3months (Fearon etal. 2011). Even though its pathologic mechanisms are complex (see Fig.1), it is often mistakenly regarded as a uniform condition, with little understanding that the underlying causes can be heterogeneous. Causes of CC can be malnutrition/anorexia (Fredrix etal. 1990), elevated inflammation (Tisdale 2005; Argilés etal. 2014), or even treatments such as chemotherapy (Brierley etal. 2019). Due to the complexity and varying proportion of underlying causes, a one-size-fits-all approach cannot be assumed, and different treatment strategies must be employed to counteract the patient’s mechanism profile. While pharmacological interventions to reduce inflammation, stimulate appetite, or reduce muscle wasting already exist (Saeteaw etal. 2020), these should ideally be accompanied with adjunct non-pharmacological treatments, such as exercise, to amplify treatment effectiveness. Awareness that exercise as a medicine can be effective and reliable in cancer supportive care is well-established (Schmitz etal. 2019); however, there is a lack of understanding that exercise is not a single medicine, but mode, type, dosage, and timing (exercise prescription) have distinct effects on the components of health and fitness. For example, resistance exercise training (RET) consists of high-tension muscle contractions against a heavy external load and when performed regularly and in sufficient volume leads to increased muscle mass and strength (Grgic etal. 2019). On the other hand, endurance exercise consists of long durations of low-tension muscle contractions which result in increased respiration, cardiac output, and blood flow, leading to increased oxidative capacity, improved cardiovascular function, and fatigue resistance (Egan and Zierath 2013). Therefore, the different exercise modes will be reviewed to explore potential applications of targeted exercise medicine for CC management. Apart from different exercise modes, different types of each mode can also elicit distinct and clinically-relevant outcomes. For example, during RET, different contractions are performed, such as concentric, eccentric, and isometric. Eccentric (lengthening) contractions are performed when the force generated by the muscle is less than the external load, causing the muscle to lengthen while resisting the external load. In contrast, concentric (shortening) contractions in which the force is greater than the load, allows the muscle to shorten (Vogt and Hoppeler 2014). During exercise composed of eccentric contractions (eccentric RET), the same muscle work can be produced with only ~ 15% of the metabolic demand of equivalent concentric RET, which enables the performance of more contractions for the same effort (Lastayo etal. 1999). Similarly in endurance training, due to cancer-related fatigue and reduced physical capacity, non-continuous training (interval) with short bursts of work and longer rests might be more tolerable than a single continuous effort. Moreover, higher-intensity interval endurance training (HIIET) is as effective at increasing muscle oxidative capacity as lower-intensity continuous endurance training (LICET) (Gibala and McGee 2008). Recently, the American Society of Clinical Oncology published their guideline on the management of CC and concluded that exercise after the onset of CC is ineffective (Roeland etal. 2020), and therefore not recommended. These recommendations are particularly surprising, given that they were based on no trials (Roeland etal. 2020). Even in animal CC models, RET increases body (Donatto etal. 2013) and muscle mass (Hardee etal. 2016). Moreover, RET trials in cancer patients with particularly aggressive CC forms (e.g., pancreatic cancer) already exist (Table1). Notably, RET did not only preserve muscle mass in patients with pancreatic and lung CC (Naito etal. 2019), but even increased body (Wiskemann etal. 2019) and muscle mass (Kamel etal. 2020) in patients with pancreatic CC, and increased muscle mass in head and neck cancer patients undergoing radiotherapy with large (> 8.5%) body mass loss (Lønbro etal. 2013a). Therefore, CC patients may experience clinically-significant muscle mass and strength gains following supervised RET (Lønbro etal. 2013a; Naito etal. 2019; Wiskemann etal. 2019; Kamel etal. 2020). However, more trials are needed to examine the most effective RET type, and the specific exercise parameters (i.e., intensity, volume, time under tension) to simultaneously increase muscle mass and reduce inflammation. The purpose of this review is to examine the most prominent CC mechanisms, and provide a rationale for research recommendations on specific exercise modes (and types) that could be used as a targeted non-pharmacological therapy integrated with the patient’s clinical treatment plan to not only Journal of Cancer Research and Clinical Oncology 1 3 reduce the side effects of cancer treatments but also improve their effectiveness, and reduce disease severity by reversing the multiple physiological mechanisms driving CC. Muscle mass wasting andincreased protein turnover The most devastating symptom of CC is muscle wasting, which can result from a variety of mechanisms (Fig.1). Muscle mass is sustained by an intricate balance of protein breakdown and synthesis, known as protein turnover. Muscle proteins are in a constant state of turnover to maintain protein homeostasis, but CC disrupts this process, as there is simultaneously excessive protein breakdown and suppressed protein synthesis (White etal. 2013). Although increased body mass is desirable during CC, it is more important for the gained mass to be composed of muscle rather than fat. Specifically, skeletal muscle is an important resource for Fig. 1 Cachexia mechanisms. APR acute phase response, CRP C-reactive protein, ECM extracellular matrix, IGF-1 insulin growth factor 1, IL interleukin (1–11), INF-γ interferon gamma, LMF lipidmobilizing factor, PIF proteolysis-inducing factor, REE resting energy expenditure, TGF-β transforming growth factor beta, TNF-α tumor necrosis factor alpha Journal of Cancer Research and Clinical Oncology 1 3 Table 1 Exercise training trials involving humans with cancer cachexia Study Population Cachexia criteria Intervention Outcomes Bland etal. (2021) 162 cancer patients 6-month BM loss at baseline was 10.4%; 7 (4%) patients had precachexia, 83 (51%) had cachexia, and 29 (18%) had refractory cachexia Multidisciplinary clinical service for cancer cachexia; same as Vaughan etal. (2020) Stabilized BM between 6-week visits to the clinic, improved physical function, pain, nausea, appetite, anorexiacachexia symptoms, physical, emotional and functional wellbeing Capozzi etal. (2016) 60 head and neck cancer patients undergoing radiotherapy 12-week lifestyle intervention and progressive RET The program failed to reduce loss of lean BM (−5kg) but improved quality of life, depression, and nutritional scores Del Fabbro etal. (2011) 151 patients with cancer cachexia History of BM loss ≥ 5% (median was 9%) Dietary counseling by a dietician and standard exercise recommendations in an exercise clinic Increased appetite and BM for those who returned for a second visit Denehy etal. (2020) 45 patients with inoperable lung cancer 41% had CC 6-week biweekly home-based LICET Better physical strength in adherent than non-adherent group, without differences in quality of life and disease symptoms Grote etal. (2018) 12 head and neck cancer patients undergoing radiotherapy BM loss (7.1%) At least 13 sessions of RET (3 sets; 8–12 RM) Increases in muscle strength but difference between groups in lean BM was not significant (intervention: + 1%, usual-care: −3%) Kamel etal. (2020) Patients with pancreatic CC BM loss > 5% over the past 6months 12-week (2 week−1) whole-body RET (50–80% of the participant’s 1-RM; 3 sets; 8–12 repetitions) Improvements in mobility, muscle mass, and strength, of both upperand lower-limbs over a non-exercising group Lønbro etal. (2013b) 21 head and neck cancer patients undergoing radiotherapy Large BM loss > 8.5% in 2months 12-week (30 sessions) whole-body RET with or without creatine and protein supplementation 5% increase in lean BM for the supplementation and 2.8% for the exerciseonly group. Both increased strength Lønbro etal. (2013a) 36 head and neck cancer patients undergoing radiotherapy Large BM loss > 8.5% in 2months 12-week (30 sessions) whole-body RET (2–3 sets of 8–15 RM) 4.3% increase in lean BM and increased muscle strength Naito etal. (2019) Advanced pancreatic and lung cancer scheduled for chemotherapy BM loss of > 5% during the preceding 6months or > 2% in patients with a BM index < 20kg/m2; CC in 40% of patients 8weeks of nutritional counseling, supplementation (branched-chain amino acids, coenzyme Q10, and L-carnitine) home-based bodyweight RET 3 sets of 10 repetitions Body and skeletal muscle mass, and muscle function were maintained Niels etal. (2018) Case-study of stage IV pancreatic cancer patient undergoing chemotherapy Typically expected 30% BM loss in patient 12-week biweekly RET (8–12 repetitions and 2 sets with 70–80% of rep-max), and LICET (70–80% of maximum of watt) 16min, 2 sets Maintained BM, increased strength Rogers etal. (2013) 15 head and neck cancer patients undergoing radiotherapy BM loss 12-week RET (exercise bands); 6-week supervised; 6-week unsupervised Usual-care group lost 5.5kg of lean BM, while intervention group lost only 0.4 Journal of Cancer Research and Clinical Oncology 1 3 BM body mass, CC cancer cachexia, LICET low-intensity continuous endurance training, RET resistance exercise training, RM repetition maximum Table 1 (continued) Study Population Cachexia criteria Intervention Outcomes Kaasa etal. (2015), Solheim etal. (2017), Balstad etal. (2020) Pancreatic or lung cancer commencing chemotherapy BM index < 30kg/m2; and < 20% BM loss in the previous 6months 6weeks of (a) anti-inflammatory medication, (b) EPA supplementation, (c) nutritional counseling, (d) biweekly home-based LICET and RET Even though only control group lost BM, both lost muscle mass Storck etal. (2020) 52 advanced cancer patients 12-week leucine-rich supplementation, nutrition, and exercise program Increases in lean BM did not reach significance vs usual-care. Increases in handgrip strength, trend for improvement in nutritional status, dietary intake, fatigue, quality of life and clinical course Vaughan etal. (2020) 99 cancer patients 6% of patients were pre-cachectic (BM loss < 5%), 64% were cachectic (BM loss ≥ 5% or BMI < 20 with BM loss > 2%, systemic inflammation), and 30% had refractory cachexia (survival < 90days, BM loss ≥ 5% or BMI < 20 with weight loss > 2%) 6-week home-based RET (5 exercises; ~ 4 week−1), high energy and protein diets, supplementation of fish oil, zinc, and multi-vitamins 49% displayed positive outcomes with > 2-kg BM gain between two consecutive appointments, 54% increased mid-upper arm muscle circumference, and > 50% improved functional strength between two consecutive appointments Wiskemann etal. (2019) 65 patients with pancreatic cancer Half of the patients had BM loss (≥ 10% in last 6months) 6-months (2 week−1) whole-body RET either at home or performed under supervision in an exercise clinic (50–80% of 1-RM, 3 sets; 8–12 repetitions) Higher adherence when home-based (78.4%) versus clinic-based (64.1%), but only the clinic-based group significantly increased upperand lower-body strength, and BM (3.1%) over a non-exercising group Journal of Cancer Research and Clinical Oncology 1 3 cancer patients, not only for metabolic, hormonal, and physical capacity reasons, but also because low muscle mass significantly predicts chemotherapy-induced toxicity and survival (Pin etal. 2018). It is well established from a variety of studies that RET stimulates myofibrillar protein synthesis, whereas endurance training stimulates mitochondrial synthesis (Grgic etal. 2019). Consequently, endurance exercise training does not promote the same degree of skeletal muscle hypertrophy as RET (Grgic etal. 2019). However, recent reviews on exercise during CC have surprisingly recommended endurance over RET for preventing muscle wasting during CC (Aquila etal. 2020). In fact, when performing LICET concurrently with RET, it can result in smaller muscle growth compared to RET alone due to physiological interference (Wilson etal. 2012). For example, we have reported that prostate cancer patients who underwent androgen-deprivation therapy and RET, had greater increases in appendicular muscle mass versus those that included additional 20–30min of LICET (Newton etal. 2019). Nevertheless, studies with preclinical models showed that endurance exercise might prevent muscle loss (Jee etal. 2016), however, only the mice undergoing higher-intensity activity (90% of maximum heart rate, every second day exercise for 45min) preserved their muscle weight, while moderate intensities (70% of maximum heart rate) did not elicit the same effects (Jee etal. 2016). Moreover, lack of adequate intensity could have led to null findings in a study where patients with lung and pancreatic CC undergoing radiotherapy underwent 6-weeks of homebased exercise and supplementation (Solheim etal. 2017). The program consisted of twice-weekly LICET (30min) and thrice-weekly RET, however, the exercises performed were of very light loads, such as body-weight pushups against the wall, and failed to significantly reduce muscle wasting (Solheim etal. 2017). Overall, current evidence suggests that heavier muscle loading is preferable and likely to be essential for hypertrophy. During CC, metabolic and signaling pathways that increase protein synthesis are suppressed while pathways that decrease protein synthesis are activated, with this phenomenon considered the primary mechanism for muscle wasting (Tisdale 2009). Specifically, type II myofiber atrophy is particularly prevalent during CC, occurring to a greater degree than type I myofiber atrophy (Mendell and Engel 1971). Moreover, it is well-established that mTOR complex 1 (mTORC1) plays a central role in mechanical load-induced muscle growth by activating downstream substrates such as p70S6k, which is an integral pathway for muscle protein synthesis (Goodman etal. 2011). This pathway is regulated by signaling molecules such as insulin-like growth factor 1 (IGF-1), which is progressively decreased in tissue and blood during CC (White etal. 2013; Martins etal. 2018). However, it appears that this problem is multi-faceted, as exogenous IGF-1 treatment does not attenuate CC-induced muscle wasting (Costelli etal. 2006). Additionally, pathways that suppress protein synthesis, such as those involving AMPK, FoxO, STAT3, and myostatin are up-regulated during CC (White etal. 2013; Hardee etal. 2016, 2020). Previous investigations showed that eccentric RET stimulates pathways commonly affected during CC that cause muscle hypertrophy (IGF-1, mTORC1, p70S6k) and suppressed pathways that cause atrophy (FoxO, AMPK, STAT3, MuRF-1, myostatin) (Hardee etal. 2016, 2020; Tatebayashi etal. 2018; Martins etal. 2018), and those effects are often greater compared to equivalent concentric RET. Additionally, greater increases in type II myofiber size are observed from eccentric compared to concentric or even conventional RET (both concentric + eccentric), at least in healthy humans (Hather etal. 1991; Hortobágyi etal. 1996, 2000; Friedmann etal. 2004; Friedmann-Bette etal. 2010; English etal. 2014; Horwath etal. 2019). CC reduces muscle protein synthesis, partially through elevated IL-6 (Tisdale 2005; Argilés etal. 2014). Nevertheless, 14 sessions of maximal eccentric RET effectively increased protein synthesis (p70S6K and rpS6), reversed inhibitors of protein synthesis (MuRF-1), and reduced the CC-induced atrophy in mouse gastrocnemius (Tatebayashi etal. 2018). This was also verified by another group, as eight sessions of maximal eccentric RET improved oxidative metabolism, reduced muscle wasting, and increased basal muscle protein synthesis and mTORC1, and surprisingly, these improvements were positively correlated with plasma IL-6 levels (Hardee etal. 2020). These findings have significant implications for clinical practice due to the potential of repeated RET (particularly eccentric) in ‘exploiting’ elevated inflammation to proportionately increase muscle growth (see also “Systemic inflammation”). Apart from signaling factor changes, CC can induce long-term muscle composition changes. For example, in mice with CC, muscle non-contractile tissue (fibrosis) was ~ 2.1-fold greater compared to healthy controls, but 2weeks (4 week−1) of eccentric RET reduced fibrosis by 20% (Hardee etal. 2016). Another muscle-wasting mechanism during CC is dystrophin loss without an inherent genetic issue, leading to myofiber integrity impairments, muscle protein breakdown and wasting (Acharyya etal. 2005). In contrast, increased muscle integrin concentration can compensate for the lack of dystrophin in dystrophic animals by maintaining muscle mobility and structure and increasing muscle mass (Burkin etal. 2005). Integrin concentrations in humans increase after long-term eccentric RET (Mavropalias etal. 2021b), but there is a lack of information regarding the effects of concentric RET. We have recently reported that 20–30min of eccentric RET per week elicited large increases (in some cases > 30%) in muscle cross-sectional area in healthy men after only 8weeks (Mavropalias etal. Journal of Cancer Research and Clinical Oncology 1 3 2021b). Given that integrins sense mechanical tension and stimulate protein synthesis, increased integrin concentration following eccentric RET could enhance anabolic signaling, thereby further amplifying muscle growth (Burkin etal. 2005). Thus, eccentric RET appears to be specific and potent for counteracting the multiple causes of wasting at the myofiber level and could be very beneficial if incorporated as an additional brief component after a conventional RET program. Systemic inflammation Persistently elevated circulating levels of interleukins, C-reactive protein (CRP), tumor-necrosis factor alpha (TNFα), and interferon-γ are hallmark indicators and primary drivers of CC (Tisdale 2005; Argilés etal. 2009, 2014). These tumor-driven cytokines cause multiple health issues, such as anorexia, and increased metabolic rate, lipolysis, and proteolysis, among others (Tisdale 2005; Argilés etal. 2009, 2014). Therefore, controlling systemic inflammation is critical for CC prevention and management. Exercise is generally thought to induce a pro-inflammatory state for a few hours following a session and thus may seem contra-indicated in the presence of already exacerbated inflammation. However, pro-inflammatory cytokines, such as TNF-α and interleukin-1, do not markedly increase after exercise, suggesting that the exercise-induced inflammatory profile differs from that induced by disease. In fact, musclederived IL-6 following exercise may inhibit the effects of pro-inflammatory cytokines such as TNF-α (Pedersen etal. 2001). Therefore, acute (a few hours post-exercise) exercise-induced increases in cytokine levels do not exacerbate already high-inflammation states but may instead exert an inflammation-controlling effect. IL-6 is a critical cytokine for muscle metabolism, as it mediates muscle growth demonstrated by both in-vivo and in-vitro studies (Serrano etal. 2008). However, when chronically elevated, circulating IL-6 negatively correlates with myofiber cross-sectional area and protein synthesis (Hardee etal. 2020). Exercise training can lower elevated IL-6, as 12weeks (3 week−1) of either descending or ascending stair-walking in women decreased resting IL-6 levels (−24%) (Chow etal. 2020). In pre-clinical CC models, muscle growth induced by 2weeks (4 week−1) of eccentric RET positively correlated with circulating IL-6 (Hardee etal. 2020), such that higher serum IL-6 was associated with greater muscle protein synthesis. This suggests that in mice with CC, repeated eccentric RET might mediate muscle protein synthesis through inflammation (greater inflammation induces greater muscle protein synthesis), a finding which may hold potential for CC patients. It is currently unknown if this effect is induced by concentric or conventional RET, however, based on its ability to control IL-6 in healthy women (Chow etal. 2020), pathways that mediate protein synthesis through elevated IL-6 might also be activated during concentric RET. CRP is the most practical, cost-effective, and scientifically robust CC biomarker, with important roles in prognosis, and utility to predict quality of life in CC patients (Fearon etal. 2011; Laird etal. 2016). The results of one meta-analysis were that RET reduces CRP levels, but only when the programs included more than eight exercises, were performed at least 3 week−1, and for longer than 12weeks (Sardeli etal. 2018). However, 1year of biweekly RET was also effective in reducing CRP levels by ~ 10% in women (Olson etal. 2007). Regarding type, RET either with eccentric or concentric movements reduced CRP levels (25%) in sedentary humans, however, the authors reported that eccentric RET was significantly more efficient (~ 2.5 times) than concentric after adjusting for energy expenditure (Zeppetzauer etal. 2013). Specifically for cancer, a meta-analysis showed that a combination of RET and endurance training can reduce CRP levels (Khosravi etal. 2019). Regarding endurance exercise, patients with different cancer types had a 6% reduction in CRP levels after 12weeks (3 week−1) of HIIET, but this was significantly different to the LICET group who exhibited a 19% increase (Toohey etal. 2016). These findings show a clear beneficial effect of RET of all types in reducing CRP levels in both healthy and cancer patients, however, there appears to be a preference for HIIET over LICET in cancer patients, although the information at this stage is limited. Chronically elevated TNF-α, both circulating and in muscle, is a common symptom during CC, and has been also shown to be inversely associated with muscle protein synthesis (Greiwe etal. 2001; Argilés etal. 2009, 2014). However, 3months (3 week−1) of lower-body RET was effective in reducing TNF-α levels in the muscle of frail elderly individuals (Greiwe etal. 2001). In another study, 12weeks (3 week−1) of descending stair walking (eccentric exercise for knee extensors) was more effective (−40%) than ascending stair walking training (−24%) at decreasing TNF-α levels in women (Chow etal. 2020). While research on humans is limited, non-RET endurance training can precipitate decreased TNF-α levels, however, intensity matters, as 8weeks (5 week−1) of HIIET was more effective than LICET in reducing TNF-α in mouse renal tissue (Leite etal. 2021). Elevated circulating interferon-γ is another commonlyobserved disease sign during CC (Argilés etal. 2009). Interferon-γ is produced by activated T and natural killer cells, and animal studies have shown that increased interferon-γ production rapidly develops CC, and that CC can be reversed by blocking interferon-γ (Argilés etal. 2009). In elderly women, 12weeks (3 week−1) of wholebody light-load (elastic bands) RET reduced interferon-γ Journal of Cancer Research and Clinical Oncology 1 3 levels (12%) (Roh etal. 2020). Moreover, patients with prostate cancer decreased interferon-γ levels after only 8weeks (3 week−1) of RET (Papadopoulos etal. 2021). Although further information regarding responses to long-term exercise training is currently limited, these results are promising and suggest that even light-load RET might effectively reduce interferon-γ levels. Therefore, RET appears to be effective in reducing elevated TNF-α, CRP, and interferon-γ, while simultaneously ‘exploiting’ elevated IL-6, typically observed during CC, to increase muscle protein synthesis. When combined with HIIET, the inflammation-controlling effect may be potentiated. Reduced appetite andanorexia Reduced appetite and anorexia contribute greatly to CC, especially during head-and-neck, gastrointestinal, and colorectal cancer (Fredrix etal. 1990). In fact, the disease profile of CC can appear similar to starvation, however, muscle wasting often precedes decreased energy intake, and can occur even without anorexia, in both humans and animals (Tisdale 2001). Both acute sessions and 12weeks (3 week−1) of exercise involving eccentric RET decreased preference and implicit wanting for sweet foods, but increased preference for fatty foods (Thivel etal. 2020). This might be particularly beneficial during CC, as patients are urged to consume an energydense diet composed of high amounts of fat (Arends etal. 2021). Equivalent concentric RET increased hunger and desire to eat more than eccentric, even though both concentric and eccentric RET equally increased total energy consumption (Thivel etal. 2020). Speculatively, due to the lower energy expenditure of eccentric RET (Lastayo etal. 1999), the increased energy consumption might result in a higher net energy balance compared to concentric. These findings suggest that eccentric might be preferable to concentric RET in simultaneously increasing preference for energy-dense foods and energy consumption, however, it is unknown if this applies during CC. Regarding endurance training, post-exercise appetite or adlibitum energy consumption were unchanged after a single session of either LICET or HIIET (Poon etal. 2018). However, after 16weeks (5 week−1), both LICET and HIIET, when combined with RET, increased fasting hunger, desire to eat, and total energy consumption in adolescents (Miguet etal. 2020). In another study, 12weeks (3 week−1) of either HIIET or LICET increased fasting and postprandial feelings of hunger with no differences between type, however energy consumption was unchanged (Martins etal. 2017). One possible reason for this discrepancy is that the second study did not include RET (Martins etal. 2017). Even though more research is needed, especially during CC, these results suggest that a combination of RET and endurance training might increase hunger and total energy consumption. Increased energy expenditure andfat wasting Despite reduced physical activity, energy expenditure increases during CC (Fredrix etal. 1990). This hypermetabolic state is thought to occur from a combination of elevated inflammation and resting lipolysis (Fredrix etal. 1990). When combined with appetite reductions, it inevitably leads to fat and muscle wasting. Apart from being amplified by the increased energy expenditure, fat wasting is primarily induced by increased lipolysis, as there is an increased turnover of free fatty acids and glycerol, caused by elevated TNF-α (Mathur and Pedersen 2008; Tisdale 2009). Exercise increases energy expenditure; thus, CC management should include exercise modes that promote muscle growth with the lowest energy expended. Endurance training has almost double the energy expenditure compared to RET, when matched for relative intensity (Bloomer 2005). Moreover, due to its capacity to induce white adipose tissue browning, mitochondrial biogenesis, fat loss, and thermogenesis, which are existing problems during CC (Grgic etal. 2019), LICET is less optimal during CC. Surprisingly, recent reviews recommended endurance training over RET to reduce muscle wasting during CC (Aquila etal. 2020). However, due to the above-mentioned contra-indications, LICET may be suboptimal against muscle wasting during CC. Nevertheless, in some cases, even higher-intensity endurance training modalities of shorter durations may be beneficial. For example, in mice with CC, 10weeks of higher-intensity continuous endurance exercise (5 week−1, 30min/day, 85% VO2max) increased lifespan, reduced tumor mass, and prevented reductions in total body fat (Bacurau etal. 2007). However, there is a lack of information on endurance training interspaced with rest on energy expenditure in CC patients. Interestingly, in healthy runners replacing LICET with HIIET did not impair aerobic capacity or muscle oxidative capacity, but decreased energy expenditure during running (Iaia etal. 2009); however, these results may differ during CC. Therefore, HIIET could be beneficial during CC, but priority should be given to RET when aiming to increase muscle mass with lower energy expenditure. Regarding RET types, during eccentric RET the same muscle work can be produced with only ~ 15% of the metabolic demand, while cardiovascular demand is ~ 40% less when compared to concentric RET (Lastayo etal. 1999). 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