Many patients with cancer experience muscle wasting and weakness. Muscle wasting in patients with cancer can be caused by cachexia and sarcopenia. Both cachexia and sarcopenia involve inflammation and oxidative stress. However, they differ in the underlying mechanisms that lead to muscle wasting. Cachexia involves the release of inflammatory cytokines due to cancer, while sarcopenia involves inflammation due to aging. Physical exercise has shown effectiveness for improving physical function, ability, and quality of life (QOL) in patients with cancer cachexia. On the other hand, no studies have investigated the relationship between physical exercise and sarcopenia in elderly patients with cancer. Previous studies showed effectiveness for improving physical function in elderly patients with cancer. In the future, more studies are required on physical exercise in sarcopenic elderly patients with cancer.
- physical exercise
- quality of life
- patients with cancer
Muscle wasting and weakness are common in many disease states and conditions including aging and cancer . Muscle wasting in advanced cancer is related to age, sex, tumor type, and inflammation . It can be caused by inflammation and malnutrition in patients with cancer . Patients with cancer have problems including anorexia, weight loss, negative nitrogen balance, and skeletal muscle wasting . The loss of muscle and fat tissue due to chronic illness is referred to as cachexia, and the general loss of muscle mass with advancing age is referred to as sarcopenia . Sarcopenia diagnosis requires documentation of low muscle mass along with either low muscle strength or low physical performance . Cachexia and sarcopenia share some pathological muscle wasting mechanisms characterized by inflammation and oxidative stress [7, 8]. In both cachexia and sarcopenia, muscle loss can lead to frailty and adversely affect various clinical outcomes . Many oncologists and rehabilitation staffs confuse cancer cachexia with simple starvation or physiological processes such as sarcopenia. Since cancer cachexia and sarcopenia can both involve muscle wasting, we speculate that the two conditions can be confused in patients with cancer. However, sarcopenia and cachexia should not be confused in patients with cancer (Figure 1). Instead, it should be understood that the loss of skeletal muscle mass occurs in patients with cancer (cachexia) as well as during aging (sarcopenia). Cachexia involves muscle wasting and weakness as a result of cancer-related inflammation, while sarcopenia involves muscle wasting and weakness as a result of age-related inflammation. Thus, the underlying pathological processes leading to muscle wasting and weakness differ between the two conditions.
Cachexia is associated with cancer and other chronic diseases, and cachexia patients lose weight and experience a decline in their overall health. The mechanism of cancer cachexia is known to involve inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 . Cancer cachexia is a complex syndrome that describes the progressive muscle wasting and weakness observed in many patients with cancer and accounts for at least 20% of cancer deaths [11, 12]. It is caused by numerous complex interactions of tumor and host factors [13, 14], and results in anorexia, wasting syndrome, and subsequent related issues . It is a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support . A panel of experts has also defined consensus criteria for diagnosing cachexia in patients with cancer : (1) weight loss > 5% over the past 6 months (in the absence of simple starvation); (2) BMI < 20 kg/m2 and any degree of weight loss > 2%; or (3) appendicular skeletal muscle index consistent with sarcopenia (males < 7.26 kg/m2; females < 5.45 kg/m2), and any degree of weight loss > 2%. A defining feature of cancer cachexia is the loss of muscle, but fat may also be lost . Weight loss is involuntary, meaning that there is no desire or attempt to lose weight. Cancer cachexia usually worsens over time, and as weight loss increases, cancer cachexia patients also experience difficulties in daily activities.
Cancer cachexia has three clinical stages: precachexia, cachexia, and refractory cachexia . The condition may occur in stages that are defined by differences in food intake, weight loss, and ability to function. In addition to muscle wasting and appetite loss, patients who have cancer anorexia–cachexia have a poor overall quality of life (QOL) and experience fatigue. They find it difficult to perform regular daily activities , and experience a significant symptom burden [19, 20]. Patients with cancer cachexia have significant decrease in physical function [21, 22], with low grip strength, and shorter walking distance even when controlling for muscle wasting [23, 24]. Also, cancer cachexia patients demonstrate lower physical activity [25–27]. In the early or mild stage, patients with cancer may only notice a slight loss of appetite. At the moderate stage, patients will notice more weight loss and often eat less than at the early and mild stages. In the severe stage, muscle wasting becomes markedly increased compared to the moderate stage, and the condition may be resistant to normal treatments such as dietary supplementation and nutritional support. Patients with cancer do not experience weight gain. Furthermore, patients may also have great difficulties in performing routine activities [16, 28]. Cachexia can reduce the physical activities of daily living (ADL) in patients with cancer . Many patients with cancer cachexia experience decrease in physical function and ADL after muscle wasting. Thus, in addition to nutritional support, physical exercise may also contribute to improve the physical function in patients with cancer cachexia.
Sarcopenia, derived from a Greek word meaning “poverty of flesh,” is characterized by the triad of progressive loss of skeletal muscle mass, muscle strength, and physical performance . It is defined as age-related muscle wasting; thus, sarcopenia frequently occurs in elderly people. European Working Group on Sarcopenia in Older People (EWGSOP) recommends that the diagnosis of sarcopenia in elderly patients should be based on the presence of both low muscle mass and low muscle function (strength or performance) . EWGSOP uses these characteristics to further classify the condition into the stages of presarcopenia, sarcopenia, and severe sarcopenia . Sarcopenia has emerged as an important prognostic factor in elderly advanced patients with cancer . Modalities used to assess sarcopenia include magnetic resonance imaging, computed tomography, dual-energy X-ray absorptiometry, and bioelectrical impedance analysis . Sarcopenia is associated with poor performance status, toxicity from chemotherapy, and short time of tumor control [32, 33].
Sarcopenia is now recognized as a multifactorial geriatric syndrome [34, 35], and is a common clinical symptom of elderly patients with cancer . It has been reported to serve as an independent risk factor for poor prognosis indicative of disease and death . It typically co-occurs with cachexia in patients with cancer . However, changes in muscle mass and physical performance may occur before clinically overt cachexia in patients with cancer . In recent years, clinical research on the application of exercise, nutritional support, and drugs, as well as other comprehensive interventions in sarcopenia patients have demonstrated good results . A significant proportion of elderly patients with cancer are at risk of sarcopenia development. However, despite its potential impact on their quality of life [2, 40], limited data are available regarding the factors associated with sarcopenia in elderly patients with cancer, who might have more problems such as malnutrition than non sarcopenic patients.
4. Physical exercise
Physical exercise has the potential to help maintain or slow the loss of physical function  as well as sustain and build muscle mass . Aerobic and resistance exercise have been found to better improve upper and lower body strength than usual care in patients with cancer . Aerobic exercise training for skeletal muscles improves wasting in cardiac and cancer cachexia patients . Resistance exercise attenuates muscle wasting associated with a variety of catabolic conditions . Physical exercise has been shown to be effective in improving physical activity levels in cancer survivors . Physical activity intervention significantly improved quality of life for cancer cachexia patients [46, 47]. A systematic review found that physical activity has benefits including improvement in physical activity levels, aerobic fitness, muscle strength, functional quality of life, anxiety, and self-esteem  (Figure 2).
Physical activity correlated with maximum exercise capacity, weight loss, blood hemoglobin concentration, C-reactive protein, and QOL-related factors of physical functioning and bodily pain in patients with cancer with progressive cachexia . Physical exercise may promote a disruption in the cycle of events leading to cachexia advancement (i.e. muscle tissue loss via anorexigenic proinflammatory cytokines) and, in turn, enhanced functionality and thus, improved QOL in patients with cancer . It has been suggested to counteract sustained disease-related inflammation and the effect of exercise training in cancer cachexia . Furthermore, it has been shown an association with the reduced levels of C-reactive protein in patients with cancer .
In patients with cancer, physical exercise represents a function-preserving, anti-inflammatory, and metabolism-modulating strategy with a low cost . It may reverse protein degradation while increasing protein synthesis and lean body mass, thus counteracting the wasting seen in cachexia . It is necessary to develop a better understanding of how to support patients with cancer in starting and maintaining physical activity and exercise programs. It is uncertain whether physical activity during and following cancer treatment has the same benefits in the weight-stable and weight-losing patients. The question also remains as to whether physical exercise has any health benefit in people with cancer cachexia or those at risk of cancer cachexia. Research investigating physical exercise in patients with cancer undergoing treatment has demonstrated improvements in physical performance, fatigue, and functional quality of life. It is unclear whether these benefits are experienced by patients with cancer cachexia. There is insufficient evidence to establish the safety and effectiveness of physical exercise in cancer cachexia patients, and future trials on exercise and supportive care interventions are required in this population. Aerobic and resistance exercise regimens may have positive effects on decreasing cancer-related fatigue and muscle wasting in patients with cancer cachexia.
To date, no studies have shown a relationship between physical exercise and cancer sarcopenia. In elderly patients with cancer, physical exercise has several benefits including improving immune function , hemoglobin and red blood cell count , and physical activity , not but VO2peak, 1 repetition maximum, functional capacity, anxiety level, or emotional well-being . Physical exercise seems to improve physical function and immune function in elderly patients with cancer . However, it has not shown effectiveness for sarcopenic patients with cancer.
5. Summary and conclusion
Muscle wasting is often encountered in patients with cancer. Both cachexia and sarcopenia lead to muscle wasting in patients with cancer. However, the different mechanisms of muscle wasting in patients with cancer should be recognized. Physical exercise might be effective for improving physical function, physical activity, ADL, and QOL in patients with cancer cachexia. In the future, more studies are required on physical exercise in sarcopenic elderly patients with cancer. Studies investigating the combined effect of physical exercise and nutritional therapies such as branched chain amino acids in cancer rehabilitation are required to improve patient outcomes in the future.
Lynch GS, Schertzer JD, Ryall JG: Therapeutic approaches for muscle wasting disorders. Pharmacol Ther2007, 113(3):461–487.
Wallengren O, Iresjö BM, Lundholm K, Bosaeus I: Loss of muscle mass in the end of life in patients with advanced cancer. Support Care Cancer2015, 23(1):79–86.
Argilés JM, López-Soriano FJ, Busquets S: Muscle wasting in cancer: The role of mitochondria. Curr Opin Clin Nutr Metab Care2015, 18(3):221–225.
Fearon KC, Baracos VE: Cachexia in pancreatic cancer: New treatment options and measures of success. HPB (Oxford)2010, 12(5):323–324.
Muscaritoli M, Anker SD, Argilés J, Aversa Z, Bauer JM, Biolo G, Boirie Y, Bosaeus I, Cederholm T, Costelli P et al: Consensus definition of sarcopenia, cachexia and pre-cachexia: Joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin Nutr2010, 29(2):154–159.
Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM et al: Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing2010, 39(4):412–423.
Bowen TS, Schuler G, Adams V: Skeletal muscle wasting in cachexia and sarcopenia: Molecular pathophysiology and impact of exercise training. J Cachexia Sarcopenia Muscle2015, 6(3):197–207.
Argilés JM, Busquets S, Stemmler B, López-Soriano FJ: Cachexia and sarcopenia: Mechanisms and potential targets for intervention. Curr Opin Pharmacol2015, 22:100–106.
Rolland Y, Abellan van Kan G, Gillette-Guyonnet S, Vellas B: Cachexia versus sarcopenia. Curr Opin Clin Nutr Metab Care2011, 14(1):15–21.
Argilés JM, Busquets S, López-Soriano FJ: Cytokines as mediators and targets for cancer cachexia. Cancer Treat Res2006, 130:199–217.
Shum AM, Polly P: Cancer cachexia: Molecular targets and pathways for diagnosis and drug intervention. Endocr Metab Immune Disord Drug Targets2012, 12(3):247–259.
Murphy KT, Lynch GS: Update on emerging drugs for cancer cachexia. Expert Opin Emerg Drugs2009, 14(4):619–632.
Tisdale M: Cancer cachexia. Curr Opin Gastroenterol2010, 26(2):146–151.
Tisdale M: Mechanisms of cancer cachexia. Physiol Rev2009, 89(2):381–410.
Fearon K, Arends J, Baracos V: Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol2013, 10(2):90–99.
Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G et al: Definition and classification of cancer cachexia: An international consensus. Lancet Oncol2011, 12(5):489–495.
Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G et al: Cachexia: A new definition. Clin Nutr2008, 27(6):793–799.
Vaughan VC, Martin P, Lewandowski PA: Cancer cachexia: Impact, mechanisms and emerging treatments. J Cachexia Sarcopenia Muscle2013, 4(2):95–109.
LeBlanc TW, Nipp RD, Rushing CN, Samsa GP, Locke SC, Kamal AH, Cella DF, Abernethy AP: Correlation between the international consensus definition of the Cancer Anorexia-Cachexia Syndrome (CACS) and patient-centered outcomes in advanced non-small cell lung cancer. J Pain Symptom Manage2015, 49(4):680–689.
Tarricone R, Ricca G, Nyanzi-Wakholi B, Medina-Lara A: Impact of cancer anorexia-cachexia syndrome on health-related quality of life and resource utilisation: A systematic review. Crit Rev Oncol Hematol2016, 99:49–62.
Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, Morton RA, Steiner MS: The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: Results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle2011, 2(3):153–161.
Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, Johnston MA, Steiner MS: Effects of enobosarm on muscle wasting and physical function in patients with cancer: A double-blind, randomised controlled phase 2 trial. Lancet Oncol2013, 14(4):335–345.
Wallengren O, Lundholm K, Bosaeus I: Diagnostic criteria of cancer cachexia: Relation to quality of life, exercise capacity and survival in unselected palliative care patients. Support Care Cancer2013, 21(6):1569–1577.
Mantovani G: Randomised phase III clinical trial of 5 different arms of treatment on 332 patients with cancer cachexia. Eur Rev Med Pharmacol Sci2010, 14(4):292–301.
Maddocks M, Byrne A, Johnson CD, Wilson RH, Fearon KC, Wilcock A: Physical activity level as an outcome measure for use in cancer cachexia trials: A feasibility study. Support Care Cancer2010, 18(12):1539–1544.
Johns N, Greig C, Fearon KC: Is tissue cross-talk important in cancer cachexia? Crit Rev Oncog2012, 17(3):263–276.
Fearon KC: The 2011 ESPEN Arvid Wretlind lecture: Cancer cachexia: The potential impact of translational research on patient-focused outcomes. Clin Nutr2012, 31(5):577–582.
Tan BH, Fearon KC: Cachexia: Prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care2008, 11(4):400–407.
Massa E, Madeddu C, Lusso MR, Gramignano G, Mantovani G: Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy. Crit Rev Oncol Hematol2006, 57(2):175–182.
Iannuzzi-Sucich M, Prestwood KM, Kenny AM: Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol A Biol Sci Med Sci2002, 57(12):M772–M777.
Cruz-Jentoft AJ, Landi F, Schneider SM, Zúñiga C, Arai H, Boirie Y, Chen LK, Fielding RA, Martin FC, Michel JP et al: Prevalence of and interventions for sarcopenia in ageing adults: A systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing2014, 43(6):748–759.
Peng PD, van Vledder MG, Tsai S, de Jong MC, Makary M, Ng J, Edil BH, Wolfgang CL, Schulick RD, Choti MA et al: Sarcopenia negatively impacts short-term outcomes in patients undergoing hepatic resection for colorectal liver metastasis. HPB (Oxford)2011, 13(7):439–446.
Miyamoto Y, Baba Y, Sakamoto Y, Ohuchi M, Tokunaga R, Kurashige J, Hiyoshi Y, Iwagami S, Yoshida N, Watanabe M et al: Negative impact of skeletal muscle loss after systemic chemotherapy in patients with unresectable colorectal cancer. PLoS One2015, 10(6):e0129742.
Cruz-Jentoft AJ, Landi F, Topinková E, Michel JP: Understanding sarcopenia as a geriatric syndrome. Curr Opin Clin Nutr Metab Care2010, 13(1):1–7.
Collins JT, Noble S, Chester J, Davies HE, Evans WD, Lester J, Parry D, Pettit RJ, Byrne A: Association of sarcopenia and observed physical performance with attainment of multidisciplinary team planned treatment in non-small cell lung cancer: An observational study protocol. BMC Cancer2015, 15:544.
Gibson DJ, Burden ST, Strauss BJ, Todd C, Lal S: The role of computed tomography in evaluating body composition and the influence of reduced muscle mass on clinical outcome in abdominal malignancy: A systematic review. Eur J Clin Nutr2015, 69(10):1079–1086.
Zhuang CL, Huang DD, Pang WY, Zhou CJ, Wang SL, Lou N, Ma LL, Yu Z, Shen X: Sarcopenia is an independent predictor of severe postoperative complications and long-term survival after radical gastrectomy for gastric cancer: Analysis from a large-scale cohort. Medicine (Baltimore)2016, 95(13):e3164.
Evans WJ: Skeletal muscle loss: Cachexia, sarcopenia, and inactivity. Am J Clin Nutr2010, 91(4):1123S–1127S.
Burton LA, Sumukadas D: Optimal management of sarcopenia. Clin Interv Aging2010, 5:217–228.
Ugolini G, Pasini F, Ghignone F, Zattoni D, Bacchi Reggiani ML, Parlanti D, Montroni I: How to select elderly colorectal cancer patients for surgery: A pilot study in an Italian academic medical center. Cancer Biol Med2015, 12(4):302–307.
Maddocks M, Murton AJ, Wilcock A: Therapeutic exercise in cancer cachexia. Crit Rev Oncog2012, 17(3):285–292.
Stene GB, Helbostad JL, Balstad TR, Riphagen II, Kaasa S, Oldervoll LM: Effect of physical exercise on muscle mass and strength in cancer patients during treatment–A systematic review. Crit Rev Oncol Hematol2013, 88(3):573–593.
Alves CR, da Cunha TF, da Paixão NA, Brum PC: Aerobic exercise training as therapy for cardiac and cancer cachexia. Life Sci2015, 125:9–14.
al-Majid S, McCarthy DO: Cancer-induced fatigue and skeletal muscle wasting: The role of exercise. Biol Res Nurs2001, 2(3):186–197.
Bourke L, Homer KE, Thaha MA, Steed L, Rosario DJ, Robb KA, Saxton JM, Taylor SJ: Interventions for promoting habitual exercise in people living with and beyond cancer. Cochrane Database Syst Rev2013, 9:CD010192.
Lowe SS: Physical activity and palliative cancer care. Recent Results Cancer Res2011, 186:349–365.
Aapro M, Arends J, Bozzetti F, Fearon K, Grunberg SM, Herrstedt J, Hopkinson J, Jaquelin-Ravel N, Jatoi A, Kaasa S et al: Early recognition of malnutrition and cachexia in the cancer patient: A position paper of a European School of Oncology Task Force. Ann Oncol 2014, 25(8):1492–9.
Speck RM, Courneya KS, Mâsse LC, Duval S, Schmitz KH: An update of controlled physical activity trials in cancer survivors: A systematic review and meta-analysis. J Cancer Surviv2010, 4(2):87–100.
Fouladiun M, Körner U, Gunnebo L, Sixt-Ammilon P, Bosaeus I, Lundholm K: Daily physical-rest activities in relation to nutritional state, metabolism, and quality of life in cancer patients with progressive cachexia. Clin Cancer Res2007, 13(21):6379–6385.
Battaglini CL, Hackney AC, Goodwin ML: Cancer cachexia: Muscle physiology and exercise training. Cancers (Basel)2012, 4(4):1247–1251.
Lira FS, Neto JC, Seelaender M: Exercise training as treatment in cancer cachexia. Appl Physiol Nutr Metab2014, 39(6):679–686.
Maddocks M, Jones LW, Wilcock A: Immunological and hormonal effects of exercise: Implications for cancer cachexia. Curr Opin Support Palliat Care2013, 7(4):376–382.
Lira FS, Antunes BeM, Seelaender M, Rosa Neto JC: The therapeutic potential of exercise to treat cachexia. Curr Opin Support Palliat Care2015, 9(4):317–324.
Gould DW, Lahart I, Carmichael AR, Koutedakis Y, Metsios GS: Cancer cachexia prevention via physical exercise: Molecular mechanisms. J Cachexia Sarcopenia Muscle2013, 4(2):111–124.
Bigley AB, Spielmann G, LaVoy EC, Simpson RJ: Can exercise-related improvements in immunity influence cancer prevention and prognosis in the elderly? Maturitas2013, 76(1):51–56.
Mohamady HM, Elsisi HF, Aneis YM: Impact of moderate intensity aerobic exercise on chemotherapy-induced anemia in elderly women with breast cancer: A randomized controlled clinical trial. J Adv Res2017, 8(1):7–12.
Ying H, Wang Y, Ning X, Zhou J, Zhao L, Shao Y, Bai C, Chen S: Changes of exercise and the clinical effects among eldly non-small cell lung cancer survivors. Zhongguo Fei Ai Za Zhi2010, 13(1):64–68.
Quist M, Adamsen L, Rørth M, Laursen JH, Christensen KB, Langer SW: The impact of a multidimensional exercise intervention on physical and functional capacity, anxiety, and depression in patients with advanced-stage lung cancer undergoing chemotherapy. Integr Cancer Ther2015, 14(4):341–349.
Miki E, Kataoka T, Okamura H: Feasibility and efficacy of speed-feedback therapy with a bicycle ergometer on cognitive function in elderly cancer patients in Japan. Psychooncology2014, 23(8):906–913.