Cancer cachexia: Developing multimodal therapy for a multidimensional problem

  • K.C.H. Fearon
    Tel.: +44 (0) 131 242 3615; fax: +44 (0) 131 242 3617.
    Clinical and Surgical Sciences (Surgery), School of Clinical Sciences and Community Health, University of Edinburgh, Royal Infirmary, 51 Little France Crescent, Edinburgh EH16 4SA, United Kingdom
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Published:March 31, 2008DOI:


      Cancer cachexia is a multi-factorial syndrome that encompasses a spectrum from early weight loss (pre-cachexia) to a state of severe incapacity incompatible with life. The molecular basis of the syndrome in animal models (based on host–tumour cell interaction, the neuro-hormonal control of appetite and the hypertrophy/atrophy pathways that govern muscle-wasting) has provided a new raft of biomarkers and therapeutic targets. Key defining features of cachexia in humans (weight loss, reduced food intake and systemic inflammation) now provide not only a framework for classification but also a rationale for targets for therapeutic intervention. The role of age and immobility in muscle-wasting also provides a rationale for the nature of nutritional support in cachexia. There is now a substantive evidence that multimodal approaches that address these key issues can stabilise and even improve the nutritional status, function and quality of life of at least a proportion of advanced cancer patients. Novel biomarkers for patient stratification and more specific techniques for the estimation of muscle mass and physical activity level herald a new era in trial design. The current evidence-base justifies new enthusiasm for the design of complex intervention studies in the management of cancer cachexia.


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        • Fearon K.C.
        • Voss A.C.
        • Hustead D.S.
        Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis.
        Am J Clin Nutr. 2006; 83: 1345-1350
        • Skipworth R.J.
        • Stewart G.D.
        • Dejong C.H.
        • et al.
        Pathophysiology of cancer cachexia: much more than host–tumour interaction?.
        Clin Nutr. 2007; 26: 667-676
        • Stewart G.D.
        • Skipworth R.J.
        • Fearon K.C.
        Cancer cachexia and fatigue.
        Clin Med. 2006; 6: 140-143
        • Dewys W.D.
        • Begg C.
        • Lavin P.T.
        • et al.
        Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group.
        Am J Med. 1980; 69: 491-497
        • Teunissen S.C.
        • Wesker W.
        • Kruitwagen C.
        • et al.
        Symptom prevalence in patients with incurable cancer: a systematic review.
        J Pain Symptom Manage. 2007; 34: 94-104
        • Deans D.A.
        • Wigmore S.J.
        • de Beaux A.C.
        • et al.
        Clinical prognostic scoring system to aid decision-making in gastro-oesophageal cancer.
        Br J Surg. 2007; 94: 1501-1508
        • Cleveland R.J.
        • Eng S.M.
        • Abrahamson P.E.
        • et al.
        Weight gain prior to diagnosis and survival from breast cancer.
        Cancer Epidemiol Biomarkers Prev. 2007; 16: 1803-1811
        • Hinsley R.
        • Hughes R.
        ‘The reflections you get’: an exploration of body image and cachexia.
        Int J Palliat Nurs. 2007; 13: 84-89
        • McClement S.
        Cancer anorexia-cachexia syndrome: psychological effect on the patient and family.
        J Wound Ostomy Continence Nurs. 2005; 32: 264-268
        • Baracos V.E.
        Cancer-associated cachexia and underlying biological mechanisms.
        Annu Rev Nutr. 2006; 26: 435-461
        • Argiles J.M.
        • Busquets S.
        • Moore-Carrasco R.
        • et al.
        Targets in clinical oncology: the metabolic environment of the patient.
        Front Biosci. 2007; 12: 3024-3051
        • Fouladiun M.
        • Korner U.
        • Gunnebo L.
        • et al.
        Daily physical-rest activities in relation to nutritional state, metabolism, and quality of life in cancer patients with progressive cachexia.
        Clin Cancer Res. 2007; 13: 6379-6385
        • Dahele M.
        • Fearon K.C.H.
        Research methodology: cancer cachexia syndrome.
        Palliat Med. 2004; 18: 409-417
        • Fearon K.C.
        • Skipworth R.J.E.
        A critical assessment of the outcome measures and goals of intervention in cancer cachexia.
        in: Cachexia and wasting: a modern approach. Springer, Milan2006 ([p. 619–30. chapter 10.6])
        • Dahele M.
        • Skipworth R.
        • Wall L.
        • et al.
        Objective physical activity and self-reported quality of life in patients receiving palliative chemotherapy.
        J Pain Symptom Man. 2007; 33: 676-685
        • Ross P.J.
        • Ashley S.
        • Norton A.
        • et al.
        Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers?.
        Br J Cancer. 2004; 90: 1905-1911
        • Nixon D.W.
        • Lawson D.H.
        • Kutner M.
        • et al.
        Hyperalimentation of the cancer patient with protein-calorie undernutrition.
        Cancer Res. 1981; 41: 2038-2045
        • Laviano A.
        • Meguid M.M.
        • Rossi-Fanelli F.
        Cancer anorexia: clinical implications, pathogenesis, and therapeutic strategies.
        Lancet Oncol. 2003; 4: 686-694
        • Deans D.A.
        • Wigmore S.J.
        • Gilmour H.
        • et al.
        Elevated tumour interleukin-1beta is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer.
        Br J Cancer. 2006; 95: 1568-1575
        • Hirai K.
        • Hussey H.J.
        • Barber M.D.
        • et al.
        Biological evaluation of a lipid-mobilizing factor isolated from the urine of cancer patients.
        Cancer Res. 1998; 58: 2359-2365
        • Todorov P.
        • Cariuk P.
        • McDevitt T.
        • et al.
        Characterization of a cancer cachectic factor.
        Nature. 1996; 379: 739-742
        • Acharyya S.
        • Butchbach M.E.
        • Sahenk Z.
        • et al.
        Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia.
        Cancer Cell. 2005; 8: 421-432
        • Tisdale M.J.
        Cancer cachexia: metabolic alterations and clinical manifestations.
        Nutrition. 1997; 13: 1-7
        • Argiles J.M.
        • Busquets S.
        • Lopez-Soriano F.J.
        Cytokines in the pathogenesis of cancer cachexia.
        Curr Opin Clin Nutr Metab Care. 2003; 6: 401-406
        • Rosenberg I.H.
        Sarcopenia: origins and clinical relevance.
        J Nutr. 1997; 127: 990S-991S
        • Cuthbertson D.
        • Smith K.
        • Babraj J.
        • et al.
        Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle.
        FASEB J. 2005; 19: 422-424
        • Tessari P.
        • Inchiostro S.
        • Biolo G.
        • et al.
        Differential effects of hyperinsulinemia and hyperaminoacidemia on leucine–carbon metabolism in vivo. Evidence for distinct mechanisms in regulation of net amino acid deposition.
        J Clin Invest. 1987; 79: 1062-1069
        • Rennie M.J.
        • Bohe J.
        • Wolfe R.R.
        Latency, duration and dose response relationships of amino acid effects on human muscle protein synthesis.
        J Nutr. 2002; 132: 3225S-3227S
        • Rennie M.J.
        • Edwards R.H.
        • Halliday D.
        • et al.
        Muscle protein synthesis measured by stable isotope techniques in man: the effects of feeding and fasting.
        Clin Sci. 1982; 63: 519-523
        • Moses A.W.
        • Slater C.
        • Preston T.
        • et al.
        Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n−3 fatty acids.
        Br J Cancer. 2004; 90: 996-1002
        • Mollinger L.A.
        • Spurr G.B.
        • el Ghatit A.Z.
        • et al.
        Daily energy expenditure and basal metabolic rates of patients with spinal cord injury.
        Arch Phys Med Rehabil. 1985; 66: 420-426
        • Biolo G.
        • Ciocchi B.
        • Stulle M.
        • et al.
        Metabolic consequences of physical inactivity.
        J Ren Nutr. 2005; 15: 49-53
        • Biolo G.
        • Ciocchi B.
        • Lebenstedt M.
        • et al.
        Short-term bed rest impairs amino acid-induced protein anabolism in humans.
        J Physiol. 2004; 558: 381-388
        • Preston T.
        • Slater C.
        • McMillan D.C.
        • et al.
        Fibrinogen synthesis is elevated in fasting cancer patients with an acute phase response.
        J Nutr. 1998; 128: 1355-1360
        • Barber M.D.
        • Fearon K.C.
        • McMillan D.C.
        • et al.
        Liver export protein synthetic rates are increased by oral meal feeding in weight-losing cancer patients.
        Am J Physiol Endocrinol Metab. 2000; 279: E707-E714
        • Reeds P.J.
        • Fjeld C.R.
        • Jahoor F.
        Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states?.
        J Nutr. 1994; 124: 906-910
        • Khal J.
        • Hine A.V.
        • Fearon K.C.
        • et al.
        Increased expression of proteasome subunits in skeletal muscle of cancer patients with weight loss.
        Int J Biochem Cell Biol. 2005; 37: 2196-2206
        • Jatoi A.
        • Alberts S.R.
        • Foster N.
        • et al.
        Is bortezomib, a proteasome inhibitor, effective in treating cancer-associated weight loss? Preliminary results from the North Central Cancer Treatment Group.
        Support Care Cancer. 2005; 13: 381-386
        • Falconer J.S.
        • Fearon K.C.
        • Ross J.A.
        • et al.
        Acute-phase protein response and survival duration of patients with pancreatic cancer.
        Cancer. 1995; 75: 2077-2082
        • Mahmoud F.A.
        • Rivera N.I.
        The role of C-reactive protein as a prognostic indicator in advanced cancer.
        Curr Oncol Rep. 2002; 4: 250-255
        • Wigmore S.J.
        • Plester C.E.
        • Ross J.A.
        • et al.
        Contribution of anorexia and hypermetabolism to weight loss in anicteric patients with pancreatic cancer.
        Br J Surg. 1997; 84: 196-197
        • Barton B.E.
        IL-6-like cytokines and cancer cachexia: consequences of chronic inflammation.
        Immunol Res. 2001; 23: 41-58
        • Pfitzenmaier J.
        • Vessella R.
        • Higano C.S.
        • et al.
        Elevation of cytokine levels in cachectic patients with prostate carcinoma.
        Cancer. 2003; 97: 1211-1216
        • Tracey K.J.
        • Cerami A.
        Tumor necrosis factor, other cytokines and disease.
        Annu Rev Cell Biol. 1993; 9: 317-343
        • Pisters P.W.
        • Cersosimo E.
        • Rogatko A.
        • et al.
        Insulin action on glucose and branched-chain amino acid metabolism in cancer cachexia: differential effects of insulin.
        Surgery. 1992; 111: 301-310
        • Schaur R.J.
        • Fellier H.
        • Gleispach H.
        • et al.
        Tumour host relations. I. Increased plasma cortisol in tumor bearing humans compared with patients with benign surgical diseases.
        J Cancer Res Clin Oncol. 1979; 93: 281-285
        • Chlebowski R.T.
        • Heber D.
        Hypogonadism in male patients with metastatic cancer prior to chemotherapy.
        Cancer Res. 1982; 42: 2495-2498
        • Sanders P.M.
        • Russell S.T.
        • Tisdale M.J.
        Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia.
        Br J Cancer. 2005; 93: 425-434
        • Shimizu Y.
        • Nagaya N.
        • Isobe T.
        • et al.
        Increased plasma ghrelin level in lung cancer cachexia.
        Clin Cancer Res. 2003; 9: 774-778
        • Wolf I.
        • Sadetzki S.
        • Kanely H.
        • et al.
        Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients.
        Cancer. 2006; 106: 966-973
        • Sacheck J.M.
        • Hyatt J.P.
        • Raffaello A.
        • et al.
        Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases.
        FASEB J. 2007; 21: 140-155
        • Skipworth R.J.
        • Stewart G.D.
        • Ross J.A.
        • et al.
        The molecular mechanisms of skeletal muscle wasting: implications for therapy.
        Surgeon. 2006; 4: 273-283
        • Lecker S.H.
        • Solomon V.
        • Mitch W.E.
        • et al.
        Muscle protein breakdown and the critical role of the ubiquitin–proteasome pathway in normal and disease states.
        J Nutr. 1999; 129: 227S-237S
        • Jagoe R.T.
        • Goldberg A.L.
        What do we really know about the ubiquitin–proteasome pathway in muscle atrophy?.
        Curr Opin Clin Nutr Metab Care. 2001; 4: 183-190
        • Attaix D.
        • Aurousseau E.
        • Combaret L.
        • et al.
        Ubiquitin–proteasome dependent proteolysis in skeletal muscle.
        Reprod Nutr Dev. 1998; 38: 153-165
        • DeJong C.H.
        • Busquets S.
        • Moses A.G.
        • et al.
        Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia.
        Oncol Rep. 2005; 14: 257-263
        • Barber M.D.
        • Powell J.J.
        • Lynch S.F.
        • et al.
        A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer.
        Br J Cancer. 2000; 83: 1443-1447
        • Barber M.D.
        • Powell J.J.
        • Lynch S.F.
        • et al.
        Two polymorphisms of the tumour necrosis factor gene do not influence survival in pancreatic cancer.
        Clin Exp Immunol. 1999; 117: 425-429
        • Deans C.
        • Rose-Zerilli M.
        • Wigmore S.
        • et al.
        Host cytokine genotype is related to adverse prognosis and systemic inflammation in gastro-oesophageal cancer.
        Ann Surg Oncol. 2007; 14: 329-339
        • Zhang D.
        • Zheng H.
        • Zhou Y.
        • et al.
        Association of IL-1beta gene polymorphism with cachexia from locally advanced gastric cancer.
        BMC Cancer. 2007; 7: 45
        • McPherron A.C.
        • Lee S.J.
        Double muscling in cattle due to mutations in the myostatin gene.
        Proc Natl Acad Sci USA. 1997; 94: 12457-12461
        • Prado C.M.
        • Baracos V.E.
        • McCargar L.J.
        • et al.
        Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity.
        Clin Cancer Res. 2007; 13: 3264-3268
        • Berenstein E.G.
        • Ortiz Z.
        Megestrol acetate for the treatment of anorexia-cachexia syndrome.
        Cochrane Database Syst Rev. 2005; 2: CD004310
        • Willox J.C.
        • Corr J.
        • Shaw J.
        • et al.
        Prednisolone as an appetite stimulant in patients with cancer.
        Br Med J. 1984; 288: 27
        • Ovesen L.
        • Allingstrup L.
        • Hannibal J.
        • et al.
        Effect of dietary counseling on food intake, body weight, response rate, survival, and quality of life in cancer patients undergoing chemotherapy: a prospective, randomized study.
        J Clin Oncol. 1993; 11: 2043-2049
        • Fearon K.C.
        • von Meyenfeldt M.
        • Moses A.G.W.
        • et al.
        An energy and protein dense, high n-3 fatty acid oral supplement promotes weight gain in cancer cachexia: a randomised double blind trial.
        Gut. 2003; 52: 1479-1486
        • McMillan D.C.
        • Wigmore S.J.
        • Fearon K.C.H.
        • et al.
        A prospective randomised study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss.
        Br J Cancer. 1999; 79: 495-500
        • Lundholm K.
        • Daneryd P.
        • Bosaeus I.
        • et al.
        Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: effects on survival, metabolism, and function.
        Cancer. 2004; 100: 1967-1977
        • Lundholm K.
        • Korner U.
        • Gunnebo L.
        • et al.
        Insulin treatment in cancer cachexia: effects on survival, metabolism, and physical functioning.
        Clin Cancer Res. 2007; 13: 2699-2706
      1. Bosaeus I. Nutritional support in multimodal therapy for cancer cachexia. Support Care Cancer, in press.