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

This is a sel -a chi ed e sion o an o iginal a icle. This e sion may di e om he o iginal in pagina ion and ypog aphic de ails. Au ho (s): Ti le: Yea : Ve sion: Copy igh : Righ s: Righ s u l: Please ci e he o iginal e sion: CC BY 4.0 h ps://c ea i ecommons.o g/licenses/by/4.0/ Exe cise Medicine o Cance Cachexia : Ta ge ed Exe cise o Coun e ac Mechanisms and T ea men Side E ec s © The Au ho (s) 2022 Published e sion Ma opalias, Geo gios; Sim, Ma c; Taa e, Dennis, R.; Gal ão, Daniel A.; Sp y, Nigel; K aeme , William, J.; Häkkinen, Keijo; New on, Robe , U. Ma opalias, G., Sim, M., Taa e, D., Gal ão, D. A., Sp y, N., K aeme , W., Häkkinen, K., & New on, R. (2022). Exe cise Medicine o Cance Cachexia : Ta ge ed Exe cise o Coun e ac Mechanisms and T ea men Side E ec s. Jou nal o Cance Resea ch and Clinical Oncology, 148(6), 1389-1406. h ps://doi.o g/10.1007/s00432-022-03927-0 2022 Vol.:(0123456789) 1 3 Jou nal o Cance Resea ch and Clinical Oncology h ps://doi.o g/10.1007/s00432-022-03927-0 REVIEW – CLINICAL ONCOLOGY Exe cise medicine o cance cachexia: a ge ed exe cise ocoun e ac mechanisms and ea men side e ec s Geo giosMa opalias1,2 · Ma cSim2,3,4· DennisR.Taa e1,2· DanielA.Gal ão1,2· NigelSp y1,2· WilliamJ.K aeme 1,2,5· KeijoHäkkinen6· Robe U.New on1,2 Recei ed: 6 Decembe 2021 / Accep ed: 13 Janua y 2022 © The Au ho (s) 2022 Abs ac Pu pose Cance -induced muscle was ing (i.e., cance cachexia, CC) is a common and de as a ing synd ome ha esul s in he dea h o mo e han 1 in 5 pa ien s. Al hough p ima ily a esul o ele a ed in lamma ion, he e a e mul iple mechanisms ha complemen and ampli y one ano he . Resea ch on he use o exe cise o manage CC is s ill limi ed, while exe cise o CC managemen has been ecen ly discou aged. Mo eo e , he e is a lack o unde s anding ha exe cise is no a single medicine, bu mode, ype, dosage, and iming (exe cise p esc ip ion) ha e dis inc heal h ou comes. The pu pose o his e iew was o examine he e ec s o hese modes and sub ypes o iden i y he mos op imal o m and dosage o exe cise he apy speci ic o each unde lying mechanism o CC. Me hods The ele an li e a u es om MEDLINE and Scopus da abases we e examined. Resul s Exe cise can coun e ac he mos p ominen mechanisms and signs o CC including muscle was ing, inc eased p o- ein u no e , sys emic in lamma ion, educed appe i e and ano exia, inc eased ene gy expendi u e and a was ing, insulin esis ance, me abolic dys egula ion, gu dysbiosis, hypogonadism, impai ed oxida i e capaci y, mi ochond ial dys unc ion, and cance ea men s side-e ec s. The e a e di e en modes o exe cise, and each mode has di e en sub- ypes ha induce as ly di e se changes when pe o med o e mul iple sessions. Choosing subop imal exe cise modes, ypes, o dosages can be coun e p oduc i e and could u he con ibu e o he mechanisms o CC wi hou impac ing muscle g ow h. Conclusion A ailable e idence shows ha pa ien s wi h CC can sa ely unde ake highe -in ensi y esis ance exe cise p o- g ams, and bene i om inc eases in body mass and muscle mass. Keywo ds Cance cachexia· In lamma ion· Tumo · Exe cise· Muscle was ing· Muscle a ophy Abb e ia ions CC Cance cachexia CRP C- eac i e p o ein HIIET Highe -in ensi y in e al endu ance aining HOMA Homeos asis model assessmen IGF-1 Insulin-like g ow h ac o 1 LICET Low-in ensi y con inuous endu ance aining mTORC1 MTOR complex 1 RET Resis ance exe cise aining TNF-α Tumo -nec osis ac o alpha In oduc ion Among he mos de imen al side e ec s o cance and ea - men is cachexia, a mul i ac o ial me abolic and immune sys em imbalance (Tisdale 2005). Cance cachexia (CC) is he ongoing skele al muscle loss (wi h o wi hou a mass * Geo gios Ma opalias geo gios.ma[email p o ec ed] 1 Exe cise Medicine Resea ch Ins i u e, Edi h Cowan Uni e si y, 270 Joondalup D i e, Joondalup, WA6027, Aus alia 2 School o Medical andHeal h Sciences, Edi h Cowan Uni e si y, Joondalup, Aus alia 3 Ins i u e o Nu i ion Resea ch, Edi h Cowan Uni e si y, Joondalup, Aus alia 4 Medical School, Uni e si y o Wes e n Aus alia, Pe h, Aus alia 5 Depa men o Human Sciences, Ohio S a e Uni e si y, Columbus, USA 6 Neu omuscula Resea ch Cen e , Facul y o Spo andHeal h Sciences, Uni e si y o Jy äskylä, Jy askyla, Finland Jou nal o Cance Resea ch and Clinical Oncology 1 3 loss) du ing cance mani es a ion and ea men , which can- no be e e sed by con en ional nu i ional suppo , leading o p og essi e unc ional impai men and dea h (Fea on e al. 2011). Hal o all cance pa ien s de elop cachexia, and his es ima e inc eases o 80% in hospi alized o ad anced-s age pa ien s (Tisdale 2003). Cachexia is obse ed in 80% o gas- ic, panc ea ic, and esophageal, ~ 70% o head-and-neck, ~ 60% o lung, colo ec al, lymphoma, and p os a e, and 54% o malignan pleu al meso helioma cance pa ien s (La iano and Meguid 1996). Mo eo e , CC is he immedia e cause o dea h o a leas 22% o all cance pa ien s (A gilés e al. 2014). No ably, aside om cance , cachexia is obse ed in he la e s ages o almos e e y majo ch onic illness (Fa kas e al. 2013), such as HIV/AIDS (p e alence 35%), ch onic hea ailu e and ch onic obs uc i e pulmona y disease (20%), ch onic kidney disease (40%), and heuma oid a h i- is (10%) ( on Haehling and Anke 2010). Despi e he p e a- lence and se e i y, cachexia emains unde - esea ched, while ea men op ions a e limi ed, due o ea men inadequacy and inconsis ency (Roeland e al. 2020). CC p og ession is o en desc ibed as a con inuum, ad ancing om p e-cachexia o cachexia, and inally o e ac o y cachexia, whe e he expec ed su i al is less han 3mon hs (Fea on e al. 2011). E en hough i s pa ho- logic mechanisms a e complex (see Fig.1), i is o en mis- akenly ega ded as a uni o m condi ion, wi h li le unde - s anding ha he unde lying causes can be he e ogeneous. Causes o CC can be malnu i ion/ano exia (F ed ix e al. 1990), ele a ed in lamma ion (Tisdale 2005; A gilés e al. 2014), o e en ea men s such as chemo he apy (B ie ley e al. 2019). Due o he complexi y and a ying p opo ion o unde lying causes, a one-size- i s-all app oach canno be assumed, and di e en ea men s a egies mus be employed o coun e ac he pa ien ’s mechanism p o ile. While pha macological in e en ions o educe in lam- ma ion, s imula e appe i e, o educe muscle was ing al eady exis (Sae eaw e al. 2020), hese should ideally be accompanied wi h adjunc non-pha macological ea - men s, such as exe cise, o ampli y ea men e ec i eness. Awa eness ha exe cise as a medicine can be e ec i e and eliable in cance suppo i e ca e is well-es ablished (Schmi z e al. 2019); howe e , he e is a lack o unde - s anding ha exe cise is no a single medicine, bu mode, ype, dosage, and iming (exe cise p esc ip ion) ha e dis- inc e ec s on he componen s o heal h and i ness. Fo example, esis ance exe cise aining (RET) consis s o high- ension muscle con ac ions agains a hea y ex e nal load and when pe o med egula ly and in su icien ol- ume leads o inc eased muscle mass and s eng h (G gic e al. 2019). On he o he hand, endu ance exe cise con- sis s o long du a ions o low- ension muscle con ac ions which esul in inc eased espi a ion, ca diac ou pu , and blood low, leading o inc eased oxida i e capaci y, imp o ed ca dio ascula unc ion, and a igue esis ance (Egan and Zie a h 2013). The e o e, he di e en exe cise modes will be e iewed o explo e po en ial applica ions o a ge ed exe cise medicine o CC managemen . Apa om di e en exe cise modes, di e en ypes o each mode can also elici dis inc and clinically- ele an ou comes. Fo example, du ing RET, di e en con ac ions a e pe - o med, such as concen ic, eccen ic, and isome ic. Eccen ic (leng hening) con ac ions a e pe o med when he o ce gen- e a ed by he muscle is less han he ex e nal load, causing he muscle o leng hen while esis ing he ex e nal load. In con- as , concen ic (sho ening) con ac ions in which he o ce is g ea e han he load, allows he muscle o sho en (Vog and Hoppele 2014). Du ing exe cise composed o eccen ic con ac ions (eccen ic RET), he same muscle wo k can be p oduced wi h only ~ 15% o he me abolic demand o equi a- len concen ic RET, which enables he pe o mance o mo e con ac ions o he same e o (Las ayo e al. 1999). Simi- la ly in endu ance aining, due o cance - ela ed a igue and educed physical capaci y, non-con inuous aining (in e al) wi h sho bu s s o wo k and longe es s migh be mo e ole - able han a single con inuous e o . Mo eo e , highe -in ensi y in e al endu ance aining (HIIET) is as e ec i e a inc easing muscle oxida i e capaci y as lowe -in ensi y con inuous endu - ance aining (LICET) (Gibala and McGee 2008). Recen ly, he Ame ican Socie y o Clinical Oncology published hei guideline on he managemen o CC and concluded ha exe cise a e he onse o CC is ine ec i e (Roeland e al. 2020), and he e o e no ecommended. These ecommenda ions a e pa icula ly su p ising, gi en ha hey we e based on no ials (Roeland e al. 2020). E en in animal CC models, RET inc eases body (Dona o e al. 2013) and muscle mass (Ha dee e al. 2016). Mo eo e , RET ials in cance pa ien s wi h pa icula ly agg essi e CC o ms (e.g., panc ea ic cance ) al eady exis (Table1). No ably, RET did no only p ese e muscle mass in pa ien s wi h panc ea ic and lung CC (Nai o e al. 2019), bu e en inc eased body (Wiskemann e al. 2019) and muscle mass (Kamel e al. 2020) in pa ien s wi h panc ea ic CC, and inc eased muscle mass in head and neck cance pa ien s unde going adio he apy wi h la ge (> 8.5%) body mass loss (Lønb o e al. 2013a). The e- o e, CC pa ien s may expe ience clinically-signi ican muscle mass and s eng h gains ollowing supe ised RET (Lønb o e al. 2013a; Nai o e al. 2019; Wiskemann e al. 2019; Kamel e al. 2020). Howe e , mo e ials a e needed o examine he mos e ec i e RET ype, and he speci ic exe cise pa ame e s (i.e., in ensi y, olume, ime unde ension) o simul aneously inc ease muscle mass and educe in lamma ion. The pu pose o his e iew is o examine he mos p omi- nen CC mechanisms, and p o ide a a ionale o esea ch ecommenda ions on speci ic exe cise modes (and ypes) ha could be used as a a ge ed non-pha macological he apy in e- g a ed wi h he pa ien ’s clinical ea men plan o no only Jou nal o Cance Resea ch and Clinical Oncology 1 3 educe he side e ec s o cance ea men s bu also imp o e hei e ec i eness, and educe disease se e i y by e e sing he mul iple physiological mechanisms d i ing CC. Muscle mass was ing andinc eased p o ein u no e The mos de as a ing symp om o CC is muscle was ing, which can esul om a a ie y o mechanisms (Fig.1). Muscle mass is sus ained by an in ica e balance o p o ein b eakdown and syn hesis, known as p o ein u no e . Mus- cle p o eins a e in a cons an s a e o u no e o main ain p o ein homeos asis, bu CC dis up s his p ocess, as he e is simul aneously excessi e p o ein b eakdown and supp essed p o ein syn hesis (Whi e e al. 2013). Al hough inc eased body mass is desi able du ing CC, i is mo e impo an o he gained mass o be composed o muscle a he han a . Speci ically, skele al muscle is an impo an esou ce o Fig. 1 Cachexia mechanisms. APR acu e phase esponse, CRP C- eac i e p o ein, ECM ex acellula ma ix, IGF-1 insulin g ow h ac o 1, IL in e leukin (1–11), INF-γ in e e on gamma, LMF lipid- mobilizing ac o , PIF p o eolysis-inducing ac o , REE es ing ene gy expendi u e, TGF-β ans o ming g ow h ac o be a, TNF-α umo nec osis ac o alpha Jou nal o Cance Resea ch and Clinical Oncology 1 3 Table 1 Exe cise aining ials in ol ing humans wi h cance cachexia S udy Popula ion Cachexia c i e ia In e en ion Ou comes Bland e al. (2021) 162 cance pa ien s 6-mon h BM loss a baseline was 10.4%; 7 (4%) pa ien s had p e- cachexia, 83 (51%) had cachexia, and 29 (18%) had e ac o y cachexia Mul idisciplina y clinical se ice o cance cachexia; same as Vaughan e al. (2020) S abilized BM be ween 6-week isi s o he clinic, imp o ed physical unc- ion, pain, nausea, appe i e, ano exia- cachexia symp oms, physical, emo ional and unc ional wellbeing Capozzi e al. (2016) 60 head and neck cance pa ien s unde going adio he apy 12-week li es yle in e en ion and p og essi e RET The p og am ailed o educe loss o lean BM (−5kg) bu imp o ed qual- i y o li e, dep ession, and nu i ional sco es Del Fabb o e al. (2011) 151 pa ien s wi h cance cachexia His o y o BM loss ≥ 5% (median was 9%) Die a y counseling by a die ician and s anda d exe cise ecommenda ions in an exe cise clinic Inc eased appe i e and BM o hose who e u ned o a second isi Denehy e al. (2020) 45 pa ien s wi h inope able lung cance 41% had CC 6-week biweekly home-based LICET Be e physical s eng h in adhe en han non-adhe en g oup, wi hou di - e ences in quali y o li e and disease symp oms G o e e al. (2018) 12 head and neck cance pa ien s unde going adio he apy BM loss (7.1%) A leas 13 sessions o RET (3 se s; 8–12 RM) Inc eases in muscle s eng h bu di e - ence be ween g oups in lean BM was no signi ican (in e en ion: + 1%, usual-ca e: −3%) Kamel e al. (2020) Pa ien s wi h panc ea ic CC BM loss > 5% o e he pas 6mon hs 12-week (2 week−1) whole-body RET (50–80% o he pa icipan ’s 1-RM; 3 se s; 8–12 epe i ions) Imp o emen s in mobili y, muscle mass, and s eng h, o bo h uppe - and lowe -limbs o e a non-exe cis- ing g oup Lønb o e al. (2013b) 21 head and neck cance pa ien s unde going adio he apy La ge BM loss > 8.5% in 2mon hs 12-week (30 sessions) whole-body RET wi h o wi hou c ea ine and p o ein supplemen a ion 5% inc ease in lean BM o he supple- men a ion and 2.8% o he exe cise- only g oup. Bo h inc eased s eng h Lønb o e al. (2013a) 36 head and neck cance pa ien s unde going adio he apy La ge BM loss > 8.5% in 2mon hs 12-week (30 sessions) whole-body RET (2–3 se s o 8–15 RM) 4.3% inc ease in lean BM and inc eased muscle s eng h Nai o e al. (2019) Ad anced panc ea ic and lung cance scheduled o chemo he apy BM loss o > 5% du ing he p eceding 6mon hs o > 2% in pa ien s wi h a BM index < 20kg/m2; CC in 40% o pa ien s 8weeks o nu i ional counseling, supplemen a ion (b anched-chain amino acids, coenzyme Q10, and L-ca ni ine) home-based body- weigh RET 3 se s o 10 epe i ions Body and skele al muscle mass, and muscle unc ion we e main ained Niels e al. (2018) Case-s udy o s age IV panc ea ic cance pa ien unde going chemo- he apy Typically expec ed 30% BM loss in pa ien 12-week biweekly RET (8–12 epe i- ions and 2 se s wi h 70–80% o ep-max), and LICET (70–80% o maximum o wa ) 16min, 2 se s Main ained BM, inc eased s eng h Roge s e al. (2013) 15 head and neck cance pa ien s unde going adio he apy BM loss 12-week RET (exe cise bands); 6-week supe ised; 6-week unsu- pe ised Usual-ca e g oup los 5.5kg o lean BM, while in e en ion g oup los only 0.4 Jou nal o Cance Resea ch and Clinical Oncology 1 3 BM body mass, CC cance cachexia, LICET low-in ensi y con inuous endu ance aining, RET esis ance exe cise aining, RM epe i ion maximum Table 1 (con inued) S udy Popula ion Cachexia c i e ia In e en ion Ou comes Kaasa e al. (2015), Solheim e al. (2017), Bals ad e al. (2020) Panc ea ic o lung cance commenc- ing chemo he apy BM index < 30kg/m2; and < 20% BM loss in he p e ious 6mon hs 6weeks o (a) an i-in lamma o y medica ion, (b) EPA supplemen a- ion, (c) nu i ional counseling, (d) biweekly home-based LICET and RET E en hough only con ol g oup los BM, bo h los muscle mass S o ck e al. (2020) 52 ad anced cance pa ien s 12-week leucine- ich supplemen a- ion, nu i ion, and exe cise p og am Inc eases in lean BM did no each signi icance s usual-ca e. Inc eases in handg ip s eng h, end o imp o emen in nu i ional s a us, die a y in ake, a igue, quali y o li e and clinical cou se Vaughan e al. (2020) 99 cance pa ien s 6% o pa ien s we e p e-cachec ic (BM loss < 5%), 64% we e cachec- ic (BM loss ≥ 5% o BMI < 20 wi h BM loss > 2%, sys emic in lam- ma ion), and 30% had e ac o y cachexia (su i al < 90days, BM loss ≥ 5% o BMI < 20 wi h weigh loss > 2%) 6-week home-based RET (5 exe - cises; ~ 4 week−1), high ene gy and p o ein die s, supplemen a ion o ish oil, zinc, and mul i- i amins 49% displayed posi i e ou comes wi h > 2-kg BM gain be ween wo con- secu i e appoin men s, 54% inc eased mid-uppe a m muscle ci cum e - ence, and > 50% imp o ed unc ional s eng h be ween wo consecu i e appoin men s Wiskemann e al. (2019) 65 pa ien s wi h panc ea ic cance Hal o he pa ien s had BM loss (≥ 10% in las 6mon hs) 6-mon hs (2 week−1) whole-body RET ei he a home o pe o med unde supe ision in an exe cise clinic (50–80% o 1-RM, 3 se s; 8–12 epe i ions) Highe adhe ence when home-based (78.4%) e sus clinic-based (64.1%), bu only he clinic-based g oup signi ican ly inc eased uppe - and lowe -body s eng h, and BM (3.1%) o e a non-exe cising g oup Jou nal o Cance Resea ch and Clinical Oncology 1 3 cance pa ien s, no only o me abolic, ho monal, and physi- cal capaci y easons, bu also because low muscle mass sig- ni ican ly p edic s chemo he apy-induced oxici y and su - i al (Pin e al. 2018). I is well es ablished om a a ie y o s udies ha RET s imula es myo ib illa p o ein syn hesis, whe eas endu - ance aining s imula es mi ochond ial syn hesis (G gic e al. 2019). Consequen ly, endu ance exe cise aining does no p omo e he same deg ee o skele al muscle hype ophy as RET (G gic e al. 2019). Howe e , ecen e iews on exe - cise du ing CC ha e su p isingly ecommended endu ance o e RET o p e en ing muscle was ing du ing CC (Aquila e al. 2020). In ac , when pe o ming LICET concu en ly wi h RET, i can esul in smalle muscle g ow h compa ed o RET alone due o physiological in e e ence (Wilson e al. 2012). Fo example, we ha e epo ed ha p os a e cance pa ien s who unde wen and ogen-dep i a ion he apy and RET, had g ea e inc eases in appendicula muscle mass e sus hose ha included addi ional 20–30min o LICET (New on e al. 2019). Ne e heless, s udies wi h p eclinical models showed ha endu ance exe cise migh p e en mus- cle loss (Jee e al. 2016), howe e , only he mice unde go- ing highe -in ensi y ac i i y (90% o maximum hea a e, e e y second day exe cise o 45min) p ese ed hei mus- cle weigh , while mode a e in ensi ies (70% o maximum hea a e) did no elici he same e ec s (Jee e al. 2016). Mo eo e , lack o adequa e in ensi y could ha e led o null indings in a s udy whe e pa ien s wi h lung and panc ea ic CC unde going adio he apy unde wen 6-weeks o home- based exe cise and supplemen a ion (Solheim e al. 2017). The p og am consis ed o wice-weekly LICET (30min) and h ice-weekly RET, howe e , he exe cises pe o med we e o e y ligh loads, such as body-weigh pushups agains he wall, and ailed o signi ican ly educe muscle was ing (Solheim e al. 2017). O e all, cu en e idence sugges s ha hea ie muscle loading is p e e able and likely o be essen ial o hype ophy. Du ing CC, me abolic and signaling pa hways ha inc ease p o ein syn hesis a e supp essed while pa hways ha dec ease p o ein syn hesis a e ac i a ed, wi h his phenomenon conside ed he p ima y mechanism o mus- cle was ing (Tisdale 2009). Speci ically, ype II myo ibe a ophy is pa icula ly p e alen du ing CC, occu ing o a g ea e deg ee han ype I myo ibe a ophy (Mendell and Engel 1971). Mo eo e , i is well-es ablished ha mTOR complex 1 (mTORC1) plays a cen al ole in mechanical load-induced muscle g ow h by ac i a ing downs eam subs a es such as p70S6k, which is an in eg al pa hway o muscle p o ein syn hesis (Goodman e al. 2011). This pa hway is egula ed by signaling molecules such as insu- lin-like g ow h ac o 1 (IGF-1), which is p og essi ely dec eased in issue and blood du ing CC (Whi e e al. 2013; Ma ins e al. 2018). Howe e , i appea s ha his p oblem is mul i- ace ed, as exogenous IGF-1 ea men does no a enua e CC-induced muscle was ing (Cos elli e al. 2006). Addi ionally, pa hways ha supp ess p o ein syn hesis, such as hose in ol ing AMPK, FoxO, STAT3, and myos a in a e up- egula ed du ing CC (Whi e e al. 2013; Ha dee e al. 2016, 2020). P e ious in es iga ions showed ha eccen ic RET s imula es pa hways commonly a ec ed du ing CC ha cause muscle hype ophy (IGF-1, mTORC1, p70S6k) and supp essed pa hways ha cause a ophy (FoxO, AMPK, STAT3, MuRF-1, myos a in) (Ha dee e al. 2016, 2020; Ta ebayashi e al. 2018; Ma ins e al. 2018), and hose e ec s a e o en g ea e compa ed o equi alen concen ic RET. Addi ionally, g ea e inc eases in ype II myo ibe size a e obse ed om eccen ic compa ed o concen ic o e en con en ional RET (bo h concen ic + eccen ic), a leas in heal hy humans (Ha he e al. 1991; Ho obágyi e al. 1996, 2000; F iedmann e al. 2004; F iedmann-Be e e al. 2010; English e al. 2014; Ho wa h e al. 2019). CC educes muscle p o ein syn hesis, pa ially h ough ele a ed IL-6 (Tisdale 2005; A gilés e al. 2014). Ne e heless, 14 sessions o maximal eccen ic RET e ec i ely inc eased p o ein syn hesis (p70S6K and pS6), e e sed inhibi o s o p o ein syn hesis (MuRF-1), and educed he CC-induced a ophy in mouse gas ocnemius (Ta ebayashi e al. 2018). This was also e i ied by ano he g oup, as eigh sessions o maximal eccen ic RET imp o ed oxida i e me abolism, educed muscle was ing, and inc eased basal muscle p o ein syn hesis and mTORC1, and su p isingly, hese imp o e- men s we e posi i ely co ela ed wi h plasma IL-6 le els (Ha dee e al. 2020). These indings ha e signi ican impli- ca ions o clinical p ac ice due o he po en ial o epea ed RET (pa icula ly eccen ic) in ‘exploi ing’ ele a ed in lam- ma ion o p opo iona ely inc ease muscle g ow h (see also “Sys emic in lamma ion”). Apa om signaling ac o changes, CC can induce long- e m muscle composi ion changes. Fo example, in mice wi h CC, muscle non-con ac ile issue ( ib osis) was ~ 2.1- old g ea e compa ed o heal hy con ols, bu 2weeks (4 week−1) o eccen ic RET educed ib osis by 20% (Ha - dee e al. 2016). Ano he muscle-was ing mechanism du - ing CC is dys ophin loss wi hou an inhe en gene ic issue, leading o myo ibe in eg i y impai men s, muscle p o ein b eakdown and was ing (Acha yya e al. 2005). In con as , inc eased muscle in eg in concen a ion can compensa e o he lack o dys ophin in dys ophic animals by main- aining muscle mobili y and s uc u e and inc easing mus- cle mass (Bu kin e al. 2005). In eg in concen a ions in humans inc ease a e long- e m eccen ic RET (Ma opa- lias e al. 2021b), bu he e is a lack o in o ma ion ega ding he e ec s o concen ic RET. We ha e ecen ly epo ed ha 20–30min o eccen ic RET pe week elici ed la ge inc eases (in some cases > 30%) in muscle c oss-sec ional a ea in heal hy men a e only 8weeks (Ma opalias e al. Jou nal o Cance Resea ch and Clinical Oncology 1 3 2021b). Gi en ha in eg ins sense mechanical ension and s imula e p o ein syn hesis, inc eased in eg in concen a ion ollowing eccen ic RET could enhance anabolic signaling, he eby u he ampli ying muscle g ow h (Bu kin e al. 2005). Thus, eccen ic RET appea s o be speci ic and po en o coun e ac ing he mul iple causes o was ing a he myo ibe le el and could be e y bene icial i inco po a ed as an addi- ional b ie componen a e a con en ional RET p og am. Sys emic in lamma ion Pe sis en ly ele a ed ci cula ing le els o in e leukins, C- eac i e p o ein (CRP), umo -nec osis ac o alpha (TNF- α), and in e e on-γ a e hallma k indica o s and p ima y d i e s o CC (Tisdale 2005; A gilés e al. 2009, 2014). These umo -d i en cy okines cause mul iple heal h issues, such as ano exia, and inc eased me abolic a e, lipolysis, and p o eolysis, among o he s (Tisdale 2005; A gilés e al. 2009, 2014). The e o e, con olling sys emic in lamma ion is c i ical o CC p e en ion and managemen . Exe cise is gene ally hough o induce a p o-in lamma- o y s a e o a ew hou s ollowing a session and hus may seem con a-indica ed in he p esence o al eady exace ba ed in lamma ion. Howe e , p o-in lamma o y cy okines, such as TNF-α and in e leukin-1, do no ma kedly inc ease a e exe cise, sugges ing ha he exe cise-induced in lamma o y p o ile di e s om ha induced by disease. In ac , muscle- de i ed IL-6 ollowing exe cise may inhibi he e ec s o p o-in lamma o y cy okines such as TNF-α (Pede sen e al. 2001). The e o e, acu e (a ew hou s pos -exe cise) exe - cise-induced inc eases in cy okine le els do no exace ba e al eady high-in lamma ion s a es bu may ins ead exe an in lamma ion-con olling e ec . IL-6 is a c i ical cy okine o muscle me abolism, as i media es muscle g ow h demons a ed by bo h in- i o and in- i o s udies (Se ano e al. 2008). Howe e , when ch oni- cally ele a ed, ci cula ing IL-6 nega i ely co ela es wi h myo ibe c oss-sec ional a ea and p o ein syn hesis (Ha - dee e al. 2020). Exe cise aining can lowe ele a ed IL-6, as 12weeks (3 week−1) o ei he descending o ascend- ing s ai -walking in women dec eased es ing IL-6 le els (−24%) (Chow e al. 2020). In p e-clinical CC models, muscle g ow h induced by 2weeks (4 week−1) o eccen ic RET posi i ely co ela ed wi h ci cula ing IL-6 (Ha dee e al. 2020), such ha highe se um IL-6 was associa ed wi h g ea e muscle p o ein syn hesis. This sugges s ha in mice wi h CC, epea ed eccen ic RET migh media e muscle p o ein syn hesis h ough in lamma ion (g ea e in lamma ion induces g ea e muscle p o ein syn hesis), a inding which may hold po en ial o CC pa ien s. I is cu - en ly unknown i his e ec is induced by concen ic o con en ional RET, howe e , based on i s abili y o con ol IL-6 in heal hy women (Chow e al. 2020), pa hways ha media e p o ein syn hesis h ough ele a ed IL-6 migh also be ac i a ed du ing concen ic RET. CRP is he mos p ac ical, cos -e ec i e, and scien i i- cally obus CC bioma ke , wi h impo an oles in p og- nosis, and u ili y o p edic quali y o li e in CC pa ien s (Fea on e al. 2011; Lai d e al. 2016). The esul s o one me a-analysis we e ha RET educes CRP le els, bu only when he p og ams included mo e han eigh exe cises, we e pe o med a leas 3 week−1, and o longe han 12weeks (Sa deli e al. 2018). Howe e , 1yea o biweekly RET was also e ec i e in educing CRP le els by ~ 10% in women (Olson e al. 2007). Rega ding ype, RET ei he wi h eccen- ic o concen ic mo emen s educed CRP le els (25%) in seden a y humans, howe e , he au ho s epo ed ha eccen- ic RET was signi ican ly mo e e icien (~ 2.5 imes) han concen ic a e adjus ing o ene gy expendi u e (Zeppe - zaue e al. 2013). Speci ically o cance , a me a-analysis showed ha a combina ion o RET and endu ance aining can educe CRP le els (Khos a i e al. 2019). Rega ding endu ance exe cise, pa ien s wi h di e en cance ypes had a 6% educ ion in CRP le els a e 12weeks (3 week−1) o HIIET, bu his was signi ican ly di e en o he LICET g oup who exhibi ed a 19% inc ease (Toohey e al. 2016). These indings show a clea bene icial e ec o RET o all ypes in educing CRP le els in bo h heal hy and cance pa ien s, howe e , he e appea s o be a p e e ence o HIIET o e LICET in cance pa ien s, al hough he in o ma ion a his s age is limi ed. Ch onically ele a ed TNF-α, bo h ci cula ing and in muscle, is a common symp om du ing CC, and has been also shown o be in e sely associa ed wi h muscle p o ein syn hesis (G eiwe e al. 2001; A gilés e al. 2009, 2014). Howe e , 3mon hs (3 week−1) o lowe -body RET was e ec i e in educing TNF-α le els in he muscle o ail elde ly indi iduals (G eiwe e al. 2001). In ano he s udy, 12weeks (3 week−1) o descending s ai walking (eccen ic exe cise o knee ex enso s) was mo e e ec i e (−40%) han ascending s ai walking aining (−24%) a dec easing TNF-α le els in women (Chow e al. 2020). While esea ch on humans is limi ed, non-RET endu ance aining can p e- cipi a e dec eased TNF-α le els, howe e , in ensi y ma e s, as 8weeks (5 week−1) o HIIET was mo e e ec i e han LICET in educing TNF-α in mouse enal issue (Lei e e al. 2021). Ele a ed ci cula ing in e e on-γ is ano he commonly- obse ed disease sign du ing CC (A gilés e al. 2009). In e e on-γ is p oduced by ac i a ed T and na u al kille cells, and animal s udies ha e shown ha inc eased in e e on-γ p oduc ion apidly de elops CC, and ha CC can be e e sed by blocking in e e on-γ (A gilés e al. 2009). In elde ly women, 12weeks (3 week−1) o whole- body ligh -load (elas ic bands) RET educed in e e on-γ Jou nal o Cance Resea ch and Clinical Oncology 1 3 le els (12%) (Roh e al. 2020). Mo eo e , pa ien s wi h p os- a e cance dec eased in e e on-γ le els a e only 8weeks (3 week−1) o RET (Papadopoulos e al. 2021). Al hough u he in o ma ion ega ding esponses o long- e m exe - cise aining is cu en ly limi ed, hese esul s a e p omis- ing and sugges ha e en ligh -load RET migh e ec i ely educe in e e on-γ le els. The e o e, RET appea s o be e ec i e in educing ele a ed TNF-α, CRP, and in e e on-γ, while simul ane- ously ‘exploi ing’ ele a ed IL-6, ypically obse ed du ing CC, o inc ease muscle p o ein syn hesis. When combined wi h HIIET, he in lamma ion-con olling e ec may be po en ia ed. Reduced appe i e andano exia Reduced appe i e and ano exia con ibu e g ea ly o CC, especially du ing head-and-neck, gas oin es inal, and colo- ec al cance (F ed ix e al. 1990). In ac , he disease p o- ile o CC can appea simila o s a a ion, howe e , muscle was ing o en p ecedes dec eased ene gy in ake, and can occu e en wi hou ano exia, in bo h humans and animals (Tisdale 2001). Bo h acu e sessions and 12weeks (3 week−1) o exe cise in ol ing eccen ic RET dec eased p e e ence and implici wan ing o swee oods, bu inc eased p e e ence o a y oods (Thi el e al. 2020). This migh be pa icula ly bene i- cial du ing CC, as pa ien s a e u ged o consume an ene gy- dense die composed o high amoun s o a (A ends e al. 2021). Equi alen concen ic RET inc eased hunge and desi e o ea mo e han eccen ic, e en hough bo h concen- ic and eccen ic RET equally inc eased o al ene gy con- sump ion (Thi el e al. 2020). Specula i ely, due o he lowe ene gy expendi u e o eccen ic RET (Las ayo e al. 1999), he inc eased ene gy consump ion migh esul in a highe ne ene gy balance compa ed o concen ic. These indings sugges ha eccen ic migh be p e e able o concen ic RET in simul aneously inc easing p e e ence o ene gy-dense oods and ene gy consump ion, howe e , i is unknown i his applies du ing CC. Rega ding endu ance aining, pos -exe cise appe i e o adlibi um ene gy consump ion we e unchanged a e a sin- gle session o ei he LICET o HIIET (Poon e al. 2018). Howe e , a e 16weeks (5 week−1), bo h LICET and HIIET, when combined wi h RET, inc eased as ing hunge , desi e o ea , and o al ene gy consump ion in adolescen s (Migue e al. 2020). In ano he s udy, 12weeks (3 week−1) o ei he HIIET o LICET inc eased as ing and pos p an- dial eelings o hunge wi h no di e ences be ween ype, howe e ene gy consump ion was unchanged (Ma ins e al. 2017). One possible eason o his disc epancy is ha he second s udy did no include RET (Ma ins e al. 2017). E en hough mo e esea ch is needed, especially du ing CC, hese esul s sugges ha a combina ion o RET and endu ance aining migh inc ease hunge and o al ene gy consump ion. Inc eased ene gy expendi u e and a was ing Despi e educed physical ac i i y, ene gy expendi u e inc eases du ing CC (F ed ix e al. 1990). This hype - me abolic s a e is hough o occu om a combina ion o ele a ed in lamma ion and es ing lipolysis (F ed ix e al. 1990). When combined wi h appe i e educ ions, i ine i- ably leads o a and muscle was ing. Apa om being ampli ied by he inc eased ene gy expendi u e, a was ing is p ima ily induced by inc eased lipolysis, as he e is an inc eased u no e o ee a y acids and glyce ol, caused by ele a ed TNF-α (Ma hu and Pede sen 2008; Tisdale 2009). Exe cise inc eases ene gy expendi u e; hus, CC manage- men should include exe cise modes ha p omo e muscle g ow h wi h he lowes ene gy expended. Endu ance aining has almos double he ene gy expendi- u e compa ed o RET, when ma ched o ela i e in ensi y (Bloome 2005). Mo eo e , due o i s capaci y o induce whi e adipose issue b owning, mi ochond ial biogenesis, a loss, and he mogenesis, which a e exis ing p oblems du ing CC (G gic e al. 2019), LICET is less op imal du - ing CC. Su p isingly, ecen e iews ecommended endu - ance aining o e RET o educe muscle was ing du ing CC (Aquila e al. 2020). Howe e , due o he abo e-men ioned con a-indica ions, LICET may be subop imal agains mus- cle was ing du ing CC. Ne e heless, in some cases, e en highe -in ensi y endu ance aining modali ies o sho e du a ions may be bene icial. Fo example, in mice wi h CC, 10weeks o highe -in ensi y con inuous endu ance exe - cise (5 week−1, 30min/day, 85% VO2max) inc eased li es- pan, educed umo mass, and p e en ed educ ions in o al body a (Bacu au e al. 2007). Howe e , he e is a lack o in o ma ion on endu ance aining in e spaced wi h es on ene gy expendi u e in CC pa ien s. In e es ingly, in heal hy unne s eplacing LICET wi h HIIET did no impai ae obic capaci y o muscle oxida i e capaci y, bu dec eased ene gy expendi u e du ing unning (Iaia e al. 2009); howe e , hese esul s may di e du ing CC. The e o e, HIIET could be bene icial du ing CC, bu p io i y should be gi en o RET when aiming o inc ease muscle mass wi h lowe ene gy expendi u e. Rega ding RET ypes, du ing eccen ic RET he same muscle wo k can be p oduced wi h only ~ 15% o he me a- bolic demand, while ca dio ascula demand is ~ 40% less when compa ed o concen ic RET (Las ayo e al. 1999). These cha ac e is ics a e a ac i e o implemen a ion du - ing CC, as eccen ic RET can s imula e muscle hype ophy bu wi h much lowe ene gy expendi u e. Jou nal o Cance Resea ch and Clinical Oncology 1 3 Capozzi LC, McNeely ML, Lau HY e al (2016) Pa ien - epo ed ou - comes, body composi ion, and nu i ion s a us in pa ien s wi h head and neck cance : esul s om an explo a o y andomized con olled exe cise ial. Cance 122:1185–1200. h ps:// doi. o g/ 10. 1002/ cnc . 29863 Chasland LC, Yeap BB, Maio ana AJ e al (2021) Tes os e one and exe cise: e ec s on i ness, body composi ion and s eng h in middle- o-olde aged men wi h low-no mal se um es os e one le els. Am J Physiol Hea Ci c Physiol. h ps:// doi. o g/ 10. 1152/ ajphe a . 00010. 2021 Chen TC, Hsieh C-C, Tseng K-W e al (2017a) E ec s o descending s ai walking on heal h and i ness o elde ly obese women. Med Sci Spo s Exe c 49:1614–1622. h ps:// doi. o g/ 10. 1249/ MSS. 00000 00000 001267 Chen TC-C, Tseng W-C, Huang G-L e al (2017b) Supe io e ec s o eccen ic o concen ic knee ex enso esis ance aining on physical i ness, insulin sensi i i y and lipid p o iles o elde ly men. F on Physiol. h ps:// doi. o g/ 10. 3389/ phys. 2017. 00209 Choi MH, Yoon SB, Lee K e al (2018) P eope a i e sa copenia and pos -ope a i e accele a ed muscle loss nega i ely impac su i al a e esec ion o panc ea ic cance . J Cachexia Sa copenia Mus- cle 9:326–334. h ps:// doi. o g/ 10. 1002/ jcsm. 12274 Chow BC, Li S, Zhu X e al (2020) E ec s o descending o ascend- ing s ai exe cise on body composi ion, insulin sensi i i y, and in lamma o y ma ke s in young Chinese women wi h obesi y: a andomized con olled ial. J Spo s Sci. h ps:// doi. o g/ 10. 1080/ 02640 414. 2020. 18293 62 Cos elli P, Musca i oli M, Bossola M e al (2006) IGF-1 is down egu- la ed in expe imen al cance cachexia. Am J Physiol Regul In eg Comp Physiol 291:R674-683. h ps:// doi. o g/ 10. 1152/ ajp e gu. 00104. 2006 Dehghan F, Hajiaghaalipou F, Yuso A e al (2016) Sa on wi h esis - ance exe cise imp o es diabe ic pa ame e s h ough he GLUT4/ AMPK pa hway in- i o and in- i o. Sci Rep 6:25139. h ps:// doi. o g/ 10. 1038/ s ep2 5139 Del Fabb o E, Hui D, Dalal S e al (2011) Clinical ou comes and con- ibu o s o weigh loss in a cance cachexia clinic. J Pallia Med 14:1004–1008. h ps:// doi. o g/ 10. 1089/ jpm. 2011. 0098 Denehy L, G ange C, Edb ooke L (2020) Who is able o adhe e o exe cise du ing non-su gical ea men o lung cance ? Eu Respi J. h ps:// doi. o g/ 10. 1183/ 13993 003. cong ess- 2020. 3237 Dona o FF, Ne es RX, Rosa FO e al (2013) Resis ance exe cise mod- ula es lipid plasma p o ile and cy okine con en in he adipose issue o umou -bea ing a s. Cy okine 61:426–432. h ps:// doi. o g/ 10. 1016/j. cy o. 2012. 10. 021 Egan B, Zie a h JR (2013) Exe cise me abolism and he molecula egula ion o skele al muscle adap a ion. Cell Me ab 17:162–184. h ps:// doi. o g/ 10. 1016/j. cme . 2012. 12. 012 English KL, Loeh JA, Lee SMC, Smi h SM (2014) Ea ly-phase mus- culoskele al adap a ions o di e en le els o eccen ic esis - ance a e 8weeks o lowe body aining. Eu J Appl Physiol 114:2263–2280. h ps:// doi. o g/ 10. 1007/ s00421- 014- 2951-5 Fa kas J, on Haehling S, Kalan a -Zadeh K e al (2013) Cachexia as a majo public heal h p oblem: equen , cos ly, and deadly. J Cachexia Sa copenia Muscle 4:173–178. h ps:// doi. o g/ 10. 1007/ s13539- 013- 0105-y Fea on K, S asse F, Anke SD e al (2011) De ini ion and classi ica- ion o cance cachexia: an in e na ional consensus. Lance Oncol 12:489–495. h ps:// doi. o g/ 10. 1016/ S1470- 2045(10) 70218-7 Fe nandez-Gonzalo R, De Paz JA, Rod iguez-Miguelez P e al (2014) TLR4-media ed blun ing o in lamma o y esponses o eccen- ic exe cise in young women. Media In lamm 2014:e479395. h ps:// doi. o g/ 10. 1155/ 2014/ 479395 F ed ix EW, Soe e s PB, Wou e s EF e al (1990) Ene gy balance in ela ion o cance cachexia. Clin Nu 9:319–324. h ps:// doi. o g/ 10. 1016/ 0261- 5614(90) 90004-c F iedmann B, Kinsche R, Vo wald S e al (2004) Muscula adap a- ions o compu e -guided s eng h aining wi h eccen ic o e - load. Ac a Physiol Scand 182:77–88. h ps:// doi. o g/ 10. 1111/j. 1365- 201X. 2004. 01337.x F iedmann-Be e B, Baue T, Kinsche R e al (2010) E ec s o s eng h aining wi h eccen ic o e load on muscle adap a ion in male a hle es. Eu J Appl Physiol 108:821–836. h ps:// doi. o g/ 10. 1007/ s00421- 009- 1292-2 Gal ão DA, Sp y NA, Taa e DR e al (2008) Changes in muscle, a and bone mass a e 36weeks o maximal and ogen blockade o p os a e cance . BJU In 102:44–47. h ps:// doi. o g/ 10. 1111/j. 1464- 410X. 2008. 07539.x Gibala MJ, McGee SL (2008) Me abolic adap a ions o sho - e m high-in ensi y in e al aining: a li le pain o a lo o gain? Exe c Spo Sci Re 36:58–63. h ps:// doi. o g/ 10. 1097/ jes. 0b013 e3181 68ec1 Gibala MJ, Li le JP, an Essen M e al (2006) Sho - e m sp in in e - al e sus adi ional endu ance aining: simila ini ial adap a- ions in human skele al muscle and exe cise pe o mance. J Phys- iol 575:901–911. h ps:// doi. o g/ 10. 1113/ jphys iol. 2006. 112094 Goodman CA, F ey JW, Mab ey DM e al (2011) The ole o skele al muscle mTOR in he egula ion o mechanical load-induced g ow h. J Physiol 589:5485–5501. h ps:// doi. o g/ 10. 1113/ jphys iol. 2011. 218255 G eiwe JS, Cheng B, Rubin DC e al (2001) Resis ance exe cise dec eases skele al muscle umo nec osis ac o alpha in ail elde ly humans. FASEB J 15:475–482. h ps:// doi. o g/ 10. 1096/ j. 00- 0274c om G gic J, Mcll enna LC, Fy e JJ e al (2019) Does ae obic aining p omo e he same skele al muscle hype ophy as esis ance aining? A sys ema ic e iew and me a-analysis. Spo s Med 49:233–254. h ps:// doi. o g/ 10. 1007/ s40279- 018- 1008-z G ossmann M, Hamil on EJ, Gil illan C e al (2011) Bone and me a- bolic heal h in pa ien s wi h non-me as a ic p os a e cance who a e ecei ing and ogen dep i a ion he apy. Med J Aus 194:301–306 G o e M, Maihö e C, Weigl M e al (2018) P og essi e esis ance aining in cachec ic head and neck cance pa ien s unde go- ing adio he apy: a andomized con olled pilo easibili y ial. Radia Oncol 13:215. h ps:// doi. o g/ 10. 1186/ s13014- 018- 1157-0 Ha dee JP, Mangum JE, Gao S e al (2016) Eccen ic con ac ion- induced myo ibe g ow h in umo -bea ing mice. J Appl Physiol 120:29–37. h ps:// doi. o g/ 10. 1152/ jappl physi ol. 00416. 2015 Ha dee JP, Fix DK, Koh H-J e al (2020) Repea ed eccen ic con ac- ions posi i ely egula e muscle oxida i e me abolism and p o- ein syn hesis du ing cance cachexia in mice. J Appl Physiol 128:1666–1676. h ps:// doi. o g/ 10. 1152/ jappl physi ol. 00908. 2019 Ha he BM, Tesch PA, Buchanan P, Dudley GA (1991) In luence o eccen ic ac ions on skele al muscle adap a ions o esis ance aining. Ac a Physiol Scand 143:177–185. h ps:// doi. o g/ 10. 1111/j. 1748- 1716. 1991. b092 19.x Ho obágyi T, Hill JP, Houma d JA e al (1996) Adap i e esponses o muscle leng hening and sho ening in humans. J Appl Physiol 80:765–772 Ho obágyi T, Dempsey L, F ase D e al (2000) Changes in muscle s eng h, muscle ib e size and myo ib illa gene exp ession a e immobiliza ion and e aining in humans. J Physiol 524:293–304. h ps:// doi. o g/ 10. 1111/j. 1469- 7793. 2000. 00293.x Ho wa h O, Paulsen G, Esping T e al (2019) Isokine ic esis ance aining combined wi h eccen ic o e load imp o es a hle ic pe - o mance and induces muscle hype ophy in young ice hockey playe s. J Sci Med Spo 22:821–826. h ps:// doi. o g/ 10. 1016/j. jsams. 2018. 12. 017 Iaia FM, Hells en Y, Nielsen JJ e al (2009) Fou weeks o speed endu - ance aining educes ene gy expendi u e du ing exe cise and Jou nal o Cance Resea ch and Clinical Oncology 1 3 main ains muscle oxida i e capaci y despi e a educ ion in ain- ing olume. J Appl Physiol 106:73–80. h ps:// doi. o g/ 10. 1152/ jappl physi ol. 90676. 2008 Jee H, Chang J-E, Yang EJ (2016) Posi i e p ehabili a i e e ec o in ense eadmill exe cise o amelio a ing cance cachexia symp- oms in a mouse model. J Cance 7:2378–2387. h ps:// doi. o g/ 10. 7150/ jca. 17162 Jiménez-Jiménez R, Cue as MJ, Alma M e al (2008) Eccen ic aining impai s NF-kappaB ac i a ion and o e -exp ession o in lamma ion- ela ed genes induced by acu e eccen ic exe cise in he elde ly. Mech Ageing De 129:313–321. h ps:// doi. o g/ 10. 1016/j. mad. 2008. 02. 007 Johnsson A, Demmelmaie I, Sjö all K e al (2019) A single exe cise session imp o es side-e ec s o chemo he apy in women wi h b eas cance : an obse a ional s udy. BMC Cance 19:1073. h ps:// doi. o g/ 10. 1186/ s12885- 019- 6310-0 Kaasa S, Solheim T, Lai d BJA e al (2015) A andomised, open-label ial o a mul imodal in e en ion (exe cise, nu i ion and an i- in lamma o y medica ion) plus s anda d ca e e sus s anda d ca e alone o p e en /a enua e cachexia in ad anced cance pa ien s unde going chemo he apy. J Clin Oncol 33:9628–9628. h ps:// doi. o g/ 10. 1200/ jco. 2015. 33. 15_ suppl. 9628 Kamel FH, Basha MA, Alsha idah AS, Salama AB (2020) Resis ance aining impac on mobili y, muscle s eng h and lean mass in panc ea ic cance cachexia: a andomized con olled ial. Clin Rehabil 34:1391–1399. h ps:// doi. o g/ 10. 1177/ 02692 15520 941912 Khos a i N, S one L, Fa aji a a V, Hanson ED (2019) Exe cise ain- ing, ci cula ing cy okine le els and immune unc ion in cance su i o s: a me a-analysis. B ain Beha Immun 81:92–104. h ps:// doi. o g/ 10. 1016/j. bbi. 2019. 08. 187 Kim J, Shin ES, Kim JE e al (2015) Neck muscle a ophy and so - is- sue ib osis a e neck dissec ion and pos ope a i e adio he apy o o al cance . Radia Oncol J 33:344–349. h ps:// doi. o g/ 10. 3857/ oj. 2015. 33.4. 344 Kim S-H, Ko YJ, Baek S-S (2021) Resis ance exe cise imp o es sho - e m memo y h ough inac i a ion o NF-κB pa hway in mice wi h Pa kinson disease. J Exe c Rehabil 17:81–87. h ps:// doi. o g/ 10. 12965/ je . 21421 88. 094 K aeme RR, Hollande DB, Ree es GV e al (2006) Simila ho monal esponses o concen ic and eccen ic muscle ac ions using ela- i e loading. Eu J Appl Physiol 96:551–557. h ps:// doi. o g/ 10. 1007/ s00421- 005- 0094-4 Lai d BJA, Fallon M, Hje ms ad MJ e al (2016) Quali y o li e in pa ien s wi h ad anced cance : di e en ial associa ion wi h pe o mance s a us and sys emic in lamma o y esponse. J Clin Oncol 34:2769–2775. h ps:// doi. o g/ 10. 1200/ JC O. 2015. 65. 7742 Las ayo PC, Reich TE, U quha M e al (1999) Ch onic eccen ic exe cise: imp o emen s in muscle s eng h can occu wi h li le demand o oxygen. Am J Physiol 276:R611-615. h ps:// doi. o g/ 10. 1152/ ajp e gu. 1999. 276.2. R611 La iano A, Meguid MM (1996) Nu i ional issues in cance manage- men . Nu i ion 12:358–371. h ps:// doi. o g/ 10. 1016/ s0899- 9007(96) 80061-x Lee WJ, Thompson RW, McClung JM, Ca son JA (2003) Regula ion o and ogen ecep o exp ession a he onse o unc ional o e load in a plan a is muscle. Am J Physiol Regul In eg Comp Physiol 285:R1076–R1085. h ps:// doi. o g/ 10. 1152/ ajp e gu. 00202. 2003 Lei e AB, Lima HN, Flo es CO e al (2021) High-in ensi y in e al aining is mo e e ec i e han con inuous aining o educe in lamma ion ma ke s in emale a s wi h cispla in neph o ox- ici y. Li e Sci 266:118880. h ps:// doi. o g/ 10. 1016/j. l s. 2020. 118880 Lønb o S, Dalgas U, P imdahl H e al (2013a) P og essi e esis ance aining ebuilds lean body mass in head and neck cance pa ien s a e adio he apy— esul s om he andomized DAHANCA 25B ial. Radio he Oncol 108:314–319. h ps:// doi. o g/ 10. 1016/j. adonc. 2013. 07. 002 Lønb o S, Dalgas U, P imdahl H e al (2013b) Feasibili y and e i- cacy o p og essi e esis ance aining and die a y supplemen s in adio he apy ea ed head and neck cance pa ien s— he DAHANCA 25A s udy. Ac a Oncol 52:310–318. h ps:// doi. o g/ 10. 3109/ 02841 86X. 2012. 741325 Ma ins C, Aschehoug I, Lud iksen M e al (2017) High-in ensi y in e al aining, appe i e, and ewa d alue o ood in he obese. Med Sci Spo s Exe c 49:1851–1858. h ps:// doi. o g/ 10. 1249/ MSS. 00000 00000 001296 Ma ins DF, Ma ins TC, Ba is i AP e al (2018) Long- e m egula eccen ic exe cise dec eases neu opa hic pain-like beha io and imp o es mo o unc ional eco e y in an axono mesis mouse model: he ole o insulin-like g ow h ac o -1. Mol Neu obiol 55:6155–6168. h ps:// doi. o g/ 10. 1007/ s12035- 017- 0829-3 Ma hu N, Pede sen BK (2008) Exe cise as a mean o con ol low-g ade sys emic in lamma ion. Media In lamm 2008:109502. h ps:// doi. o g/ 10. 1155/ 2008/ 109502 Ma inhomaee H, Banaei J, Aza bayjani MA, Zolak a V (2014) E ec s o 12-week high-in ensi y in e al aining on plasma is a in concen a ion and insulin esis ance in o e weigh men. J Exe c Sci Fi 12:20–25. h ps:// doi. o g/ 10. 1016/j. jes . 2014. 01. 001 Ma opalias G, Koeda T, Ba ley OR e al (2020) Compa ison be ween high- and low-in ensi y eccen ic cycling o equal mechani- cal wo k o muscle damage and he epea ed bou e ec . Eu J Appl Physiol 120:1015–1025. h ps:// doi. o g/ 10. 1007/ s00421- 020- 04341-5 Ma opalias G, Calap e L, Mo ici M e al (2021a) Changes in plasma hyd oxyp oline and plasma cell- ee DNA concen a ions a e highe - e sus lowe -in ensi y eccen ic cycling. Eu J Appl Phys- iol 121:1087–1097. h ps:// doi. o g/ 10. 1007/ s00421- 020- 04593-1 Ma opalias G, Wu Y-F, Boppa MD e al (2021b) Inc eases in in eg- in-ILK-RICTOR-Ak p o eins, muscle mass, and s eng h a e eccen ic cycling aining. Med Sci Spo s Exe c. h ps:// doi. o g/ 10. 1249/ MSS. 00000 00000 002778 McKie GL, W igh DC (2020) Biochemical adap a ions in whi e adi- pose issue ollowing ae obic exe cise: om mi ochond ial bio- genesis o b owning. Biochem J 477:1061–1081. h ps:// doi. o g/ 10. 1042/ BCJ20 190466 Mendell JR, Engel WK (1971) The ine s uc u e o ype II muscle ibe a ophy. Neu ology 21:358–365. h ps:// doi. o g/ 10. 1212/ wnl. 21.4. 358 Migue M, Fea nbach NS, Me z L e al (2020) E ec o HIIT e - sus MICT on body composi ion and ene gy in ake in die a y es ained and un es ained adolescen s wi h obesi y. Appl Physiol Nu Me ab 45:437–445. h ps:// doi. o g/ 10. 1139/ apnm- 2019- 0160 Mo on RW, Sa o K, Gallaughe MPB e al (2018) Muscle and o- gen ecep o con en bu no sys emic ho mones is associa ed wi h esis ance aining-induced skele al muscle hype ophy in heal hy, young men. F on Physiol. h ps:// doi. o g/ 10. 3389/ phy s. 2018. 01373 Munukka E, Ah iainen JP, Puigbó P e al (2018) Six-week endu ance exe cise al e s gu me agenome ha is no e lec ed in sys emic me abolism in o e -weigh women. F on Mic obiol 9:2323. h ps:// doi. o g/ 10. 3389/ micb. 2018. 02323 Nai o T, Mi sunaga S, Miu a S e al (2019) Feasibili y o ea ly mul i- modal in e en ions o elde ly pa ien s wi h ad anced panc ea ic and non-small-cell lung cance . J Cachexia Sa copenia Muscle 10:73–83. h ps:// doi. o g/ 10. 1002/ jcsm. 12351 New on RU, Gal ão DA, Sp y N e al (2019) Exe cise mode speci ic- i y o p ese ing spine and hip bone mine al densi y in p os a e cance pa ien s. Med Sci Spo s Exe c 51:607–614. h ps:// doi. o g/ 10. 1249/ MSS. 00000 00000 001831 Jou nal o Cance Resea ch and Clinical Oncology 1 3 New on RU, Ma opalias G, F agala MS e al (2021) Radio he apy be o e o du ing and ogen-dep i a ion he apy does no blun he exe cise-induced body composi ion p o ec i e e ec s in p os- a e cance pa ien s: a seconda y analysis o wo andomized con olled ials. Exp Ge on ol 151:111427. h ps:// doi. o g/ 10. 1016/j. exge . 2021. 111427 Niels T, Tomanek A, Schneide L e al (2018) Exe cise imp o es pa ien ou comes in ad anced panc ea ic cance pa ien du ing medical ea men . Panc ea Diso d The . h ps:// doi. o g/ 10. 4172/ 2165- 7092. 10001 93 Olson TP, Dengel DR, Leon AS, Schmi z KH (2007) Changes in in lamma o y bioma ke s ollowing one-yea o mode a e esis - ance aining in o e weigh women. In J Obes 31:996–1003. h ps:// doi. o g/ 10. 1038/ sj. ijo. 08035 34 Papadopoulos E, Gillen JB, Moo e DR e al (2021) High-in ensi y in e al aining o esis ance aining e sus usual ca e in men wi h p os a e cance on ac i e su eillance: a h ee-a m easibil- i y andomized con olled ial. Appl Physiol Nu Me ab. h ps:// doi. o g/ 10. 1139/ apnm- 2021- 0365 Paschalis V, Nikolaidis MG, Theodo ou AA e al (2011) A weekly bou o eccen ic exe cise is su icien o induce heal h-p omo ing e ec s. Med Sci Spo s Exe c 43:64–73. h ps:// doi. o g/ 10. 1249/ MSS. 0b013 e3181 e91d90 Pede sen BK, S eensbe g A, Schje ling P (2001) Muscle-de i ed in e - leukin-6: possible biological e ec s. J Physiol 536:329–337. h ps:// doi. o g/ 10. 1111/j. 1469- 7793. 2001. 0329c. xd Pin F, Couch ME, Bone o A (2018) P ese a ion o muscle mass as a s a egy o educe he oxic e ec s o cance chemo he apy on body composi ion. Cu Opin Suppo Pallia Ca e 12:420–426. h ps:// doi. o g/ 10. 1097/ SPC. 00000 00000 000382 Poon ET-C, Sun F-H, Chung AP-W, Wong SH-S (2018) Pos -exe cise appe i e and adlibi um ene gy in ake in esponse o high-in en- si y in e al aining e sus mode a e- o igo ous-in ensi y con- inuous aining among physically inac i e middle-aged adul s. Nu ien s 10:1408. h ps:// doi. o g/ 10. 3390/ nu101 01408 Puppa MJ, Mu phy EA, Fayad R e al (2014) Cachec ic skele al muscle esponse o a no el bou o low- equency s imula ion. J Appl Physiol 116:1078–1087. h ps:// doi. o g/ 10. 1152/ jappl physi ol. 01270. 2013 Roeland EJ, Bohlke K, Ba acos VE e al (2020) Managemen o cance cachexia: ASCO guideline. J Clin Oncol 38:2438–2453. h ps:// doi. o g/ 10. 1200/ JCO. 20. 00611 Roge s LQ, An on PM, Fogleman A e al (2013) Pilo , andomized ial o esis ance exe cise du ing adia ion he apy o head and neck cance . Head Neck 35:1178–1188. h ps:// doi. o g/ 10. 1002/ hed. 23118 Roh H-T, Cho S-Y, So W-Y (2020) A c oss-sec ional s udy e alua ing he e ec s o esis ance exe cise on in lamma ion and neu o- ophic ac o s in elde ly women wi h obesi y. J Clin Med 9:842. h ps:// doi. o g/ 10. 3390/ jcm90 30842 Sae eaw M, Sanguanboonyaphong P, Yoodee J e al (2020) E icacy and sa e y o pha macological cachexia in e en ions: sys ema ic e iew and ne wo k me a-analysis. BMJ Suppo Pallia Ca e. h ps:// doi. o g/ 10. 1136/ bmjsp ca e- 2020- 002601 Sa deli AV, Tomele i CM, Cy ino ES e al (2018) E ec o esis - ance aining on in lamma o y ma ke s o olde adul s: a me a- analysis. Exp Ge on ol 111:188–196. h ps:// doi. o g/ 10. 1016/j. exge . 2018. 07. 021 Sa o S, Gao S, Puppa MJ e al (2019) High- equency s imula ion on skele al muscle main enance in emale cachec ic mice. Med Sci Spo s Exe c 51:1828–1837. h ps:// doi. o g/ 10. 1249/ MSS. 00000 00000 001991 Schmi z KH, Campbell AM, S ui e MM e al (2019) Exe cise is medicine in oncology: engaging clinicians o help pa ien s mo e h ough cance . CA Cance J Clin 69:468–484. h ps:// doi. o g/ 10. 3322/ caac. 21579 Se ano AL, Baeza-Raja B, Pe digue o E e al (2008) In e leukin-6 is an essen ial egula o o sa elli e cell-media ed skele al muscle hype ophy. Cell Me ab 7:33–44. h ps:// doi. o g/ 10. 1016/j. cme . 2007. 11. 011 Singh F, New on RU, Bake MK e al (2017) Feasibili y o p esu gical exe cise in men wi h p os a e cance unde going p os a ec omy. In eg Cance The 16:290–299. h ps:// doi. o g/ 10. 1177/ 15347 35416 666373 Solheim TS, Lai d BJA, Bals ad TR e al (2017) A andomized phase II easibili y ial o a mul imodal in e en ion o he managemen o cachexia in lung and panc ea ic cance . J Cachexia Sa copenia Muscle 8:778–788. h ps:// doi. o g/ 10. 1002/ jcsm. 12201 S o ck LJ, Ruehlin M, Gaeumann S e al (2020) E ec o a leucine- ich supplemen in combina ion wi h nu i ion and physical exe cise in ad anced cance pa ien s: a andomized con olled in e en- ion ial. Clin Nu 39:3637–3644. h ps:// doi. o g/ 10. 1016/j. clnu. 2020. 04. 008 Ta ebayashi D, Himo i K, Yamada R e al (2018) High-in ensi y eccen- ic aining amelio a es muscle was ing in colon 26 umo -bea - ing mice. PLoSOne 13:e0199050. h ps:// doi. o g/ 10. 1371/ jou n al. pone. 01990 50 Thi el D, Julian V, Migue M e al (2020) In oducing eccen ic cycling du ing a mul idisciplina y weigh loss in e en ion migh p e en adolescen s wi h obesi y om inc easing hei ood in ake: he TEXTOO s udy. Physiol Beha 214:112744. h ps:// doi. o g/ 10. 1016/j. physb eh. 2019. 112744 Tisdale MJ (2001) Cance ano exia and cachexia. Nu i ion 17:438– 442. h ps:// doi. o g/ 10. 1016/ s0899- 9007(01) 00506-8 Tisdale MJ (2003) The “cance cachec ic ac o .” Suppo Ca e Cance 11:73–78. h ps:// doi. o g/ 10. 1007/ s00520- 002- 0408-6 Tisdale MJ (2005) Molecula pa hways leading o cance cachexia. Physiology 20:340–348. h ps:// doi. o g/ 10. 1152/ physi ol. 00019. 2005 Tisdale MJ (2009) Mechanisms o cance cachexia. Physiol Re 89:381–410. h ps:// doi. o g/ 10. 1152/ phys e . 00016. 2008 Toohey K, Pumpa KL, A nolda L e al (2016) A pilo s udy examining he e ec s o low- olume high-in ensi y in e al aining and con inuous low o mode a e in ensi y aining on quali y o li e, unc ional capaci y and ca dio ascula isk ac o s in cance su - i o s. Pee J 4:e2613. h ps:// doi. o g/ 10. 7717/ pee j. 2613 Vande Veen BN, Fix DK, Ca son JA (2017) Dis up ed skele al mus- cle mi ochond ial dynamics, mi ophagy, and biogenesis du ing cance cachexia: a ole o in lamma ion. Oxid Med Cell Longe 2017:3292087. h ps:// doi. o g/ 10. 1155/ 2017/ 32920 87 Vaughan VC, Fa ell H, Lewandowski PA e al (2020) De ining a new model o in e disciplina y cance cachexia ca e in egional Vic- o ia, Aus alia. Suppo Ca e Cance 28:3041–3049. h ps:// doi. o g/ 10. 1007/ s00520- 019- 05072-w Vog M, Hoppele HH (2014) Eccen ic exe cise: mechanisms and e ec s when used as aining egime o aining adjunc . J Appl Physiol 116:1446–1454. h ps:// doi. o g/ 10. 1152/ jappl physi ol. 00146. 2013 on Haehling S, Anke SD (2010) Cachexia as a majo unde es ima ed and unme medical need: ac s and numbe s. J Cachexia Sa co- penia Muscle 1:1–5. h ps:// doi. o g/ 10. 1007/ s13539- 010- 0002-6 Whi e JP, Puppa MJ, Gao S e al (2013) Muscle mTORC1 supp ession by IL-6 du ing cance cachexia: a ole o AMPK. Am J Physiol Endoc inol Me ab 304:E1042–E1052. h ps:// doi. o g/ 10. 1152/ ajpen do. 00410. 2012 Wilson JM, Ma in PJ, Rhea MR e al (2012) Concu en aining: a me a-analysis examining in e e ence o ae obic and esis ance exe cises. J S eng h Cond Res 26:2293–2307. h ps:// doi. o g/ 10. 1519/ JSC. 0b013 e3182 3a3e2d Wiskemann J, Clauss D, Tjaden C e al (2019) P og essi e esis ance aining o impac physical i ness and body weigh in panc ea ic Jou nal o Cance Resea ch and Clinical Oncology 1 3 cance pa ien s: a andomized con olled ial. Panc eas 48:257– 266. h ps:// doi. o g/ 10. 1097/ mpa. 00000 00000 001221 W igh TJ, Dillon EL, Du ham WJ e al (2018) A andomized ial o adjunc es os e one o cance - ela ed muscle loss in men and women. J Cachexia Sa copenia Muscle 9:482–496. h ps:// doi. o g/ 10. 1002/ jcsm. 12295 Zeppe zaue M, D exel H, Vonbank A e al (2013) Eccen ic endu ance exe cise economically imp o es me abolic and in lamma o y isk ac o s. Eu J P e Ca diol 20:577–584. h ps:// doi. o g/ 10. 1177/ 20474 87312 444236 Publishe 's No e Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in published maps and ins i u ional a ilia ions.