Top

Published in:

01-02-2007

Cancer Cachexia: It’s Time for More Clinical Trials

Authors: Maurizio Bossola, Fabio Pacelli, Antonio Tortorelli, Giovan Battista Doglietto

Published in: Annals of Surgical Oncology | Issue 2/2007

Abstract

Cancer cachexia (CC) is a multifactorial paraneoplastic syndrome characterized by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, accounting for at least 20% of deaths in neoplastic patients. CC significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of CC and the principal cause of function impairment, fatigue and respiratory complications, mainly related to a hyperactivation of muscle proteolytic pathways. Most current therapeutic strategies to counteract CC have proven to be only partially effective. In the last decade, the correction of anorexia, the inhibition of catabolic processes and the stimulation of anabolic pathways in muscle have been attempted pharmacologically with encouraging results in animal models and through preliminary clinical trials. However, data in the clinical setting are still scanty and non definitive. It is time to start prospective, randomized, controlled trials to evaluate which drugs are effective in counteracting the loss of lean of muscle mass and in improving nutritional status and quality of life in patients affected by cancer-related cachexia.

Muscaritoli M, Bossola M, Aversa Z, et al. Prevention and treatment of cancer cachexia: new insights into and old problem. Eur J Cancer 2006; 42:31–41PubMedCrossRef

MacDonald N, Easson AM, Mazurak VC, et al. Understanding and managing cancer cachexia. J Am Coll Surg 2003; 197:143–161PubMedCrossRef

Falconer JS, Fearon KC, Plester CE, et al. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 1994; 219:325–331PubMedCrossRef

Laviano A, Meguid MM, Rossi Fanelli F. Cancer anorexia: clinical implications, pathogenesis, and therapeutic strategies. Lancet Oncol 2003; 4:686–694PubMedCrossRef

Dempsey DT, Knox LS, Mullen JL, et al. Energy expenditure in malnourished patients with colorectal cancer. Arch Surg 1996; 121:789–795

Gibney E, Elia M, Jebb SA, et al. Total energy expenditure in patients with non small-cell lung cancer: results of a validated study using the bicarbonate-urea method. Metabolism 1997; 46:1412–1417PubMedCrossRef

Jeevanandam M, Horowitz GD, Lowry SF, et al. Cancer cachexia and protein metabolism. Lancet 1984; 1:1423–1426PubMedCrossRef

Fearon KCH. The mechanisms and treatment of weight loss in cancer. Proc Nutr Soc 1992; 51:251–265PubMedCrossRef

Tisdale MJ. The cancer cachectic factor. Support Care Cancer 2003; 11:73–78PubMed

10.

Todorov PT, Mc Devitt TM, Meyer DJ, et al. Purification and characterization of a tumor lipid-mobilizing factor. Cancer Res 1998; 58:2353–2358PubMed

11.

Hirai K K, Hussey HJ, Barber MD, et al. Biological evaluation of a lipid mobilizing factor isolated from the urine cancer patients. Cancer Res 1998; 58:2359–2365PubMed

12.

Khan S, Tisdale M. Catabolism of adipose tissue by a tumor-produced lipid mobilising factor. Int J Cancer 1999; 29:444–447CrossRef

13.

Costelli P, Baccino FM. Mechanisms of skeletal muscle depletion in wasting syndromes: role of ATP-ubiquitin-dependent proteolysis. Curr Opin Clin Nutr Metab Care 2003; 6:407–412PubMedCrossRef

14.

Costelli P, Tullio RD, Baccino FM, et al. Activation of Ca²⁺-dependent proteolysis in skeletal muscle and heart in cancer cachexia. Br J Cancer 2001; 84:946–950PubMedCrossRef

15.

Costelli P, Bossola M, Muscaritoli M, et al. Anticytokine treatment prevents the increase in the activity of ATP-ubiquitin- and Ca²⁺-dependent proteolytic systems in the muscle of tumour-bearing rats. Cytokine 2002; 19:1–5PubMedCrossRef

16.

Bossola M, Muscaritoli M, Costelli P, et al. Increased muscle ubiquitin mRNA levels in gastric cancer patients. Am J Physiol Regul Integr Comp Physiol 2001; 280:R1518–R1523PubMed

17.

Bossola M, Muscaritoli M, Costelli P, et al. Increased muscle proteasome activity correlates whit disease severity in gastric cancer patients. Ann Surg 2003; 237:384–389PubMedCrossRef

18.

Bodine SC, Latres E, Baumhueter S, et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 2001; 294:1704–1708PubMedCrossRef

19.

Lecker SH, Jagoe T, Gilbert M, et al. Multiple types of skeletal muscle atrophy involve a common program of changes in genes expression. FASEB J 2004; 18:39–51PubMedCrossRef

20.

Guttridge DC, Mayo MW, Madrid LV, et al. NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 2000; 289:2363–2366PubMedCrossRef

21.

Costelli P, Muscaritoli M, Bossola M, et al. Skeletal muscle wasting in tumour-bearing rats is associated with MyoD down-regulation. Int J Oncol 2005; 26:1663–1668PubMed

22.

Kambadur R, Sharma M, Smith TP, Bass JJ. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res 1997; 7:910–916PubMed

23.

McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 1997; 94:12457–12461PubMedCrossRef

24.

Szabo G, Dallmann G, Muller G, et al. A deletion in the myostatin gene causes the compact (Cmpt) hypermuscular mutation in mice. Mamm Genome 1998; 9:671–672PubMedCrossRef

25.

Ma K, Mallidis C, Bhasin S, et al. Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression. Am J Physiol Endocrinol Metab 2003; 285:E363–E371PubMed

26.

Zimmers TA, Davies MV, Koniaris LG, et al. Induction of cachexia in mice by systemically administered myostatin. Science 2002; 296:1486–1488PubMedCrossRef

27.

McCroskery S, Thomas M, Maxwell L, et al. Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol 2003; 162:1135–1147PubMedCrossRef

28.

Langley B, Thomas M, Bishop A, et al. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem 2002; 277:49831–49840PubMedCrossRef

29.

Gonzales-Cadavid NF, Bhasin S. Role of myostatin in metabolism. Curr Opin Clin Nutr Metab Care 2004; 7:451–457CrossRef

30.

Lopez AP, Roque Figuls M, Cuchi GU, et al. Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. J Pain Sympt Manag 2004; 27:360–369CrossRef

31.

Klein T.W, Lane B, Newton CA, et al. The cannabinoid system and cytokine network. Proc Soc Exp Biol Med 2000; 225:1–8PubMedCrossRef

32.

Fide E, Bregman T, Kirkham TC, et al. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med 2005; 230:225–234

33.

Jatoi A, Windschiltl HE, Loprinzi CL, et al. Dronabinol versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment study. J Cin Oncol 2002; 20:567–573CrossRef

34.

Baldwin C, Parsons T, Logan S. Dietary advice for illness-related malnutrition in adults. Cochrane Database Syst Rev 2001; 2:CD002008

35.

Milne AC, Potter J, Avenell A. Protein and energy supplementation in elderly people at risk of malnutrition. Cochrane database Syst Rev 2002; 3:CD003288

36.

Stratton RJ, Elia M. Are oral nutritional supplements of benefits in patients in the community? Findings from a systematic review. Curr Opin Clin Nutr Metab Care 2000; 3:311–315PubMedCrossRef

37.

Bozzetti F. Rationale and indications for preoperative feeding of malnourished surgical cancer patients. Nutrition 2002; 18:953–959PubMedCrossRef

38.

American Gastroenterological Association. Medical position statement: parenteral nutrition. Gastroeneterology 2001; 121:966–969CrossRef

39.

American Society for Parenteral and Enteral Nutrition Board of Directors. Guidelines for the use of parenteral and enteral nutrition in adult pediatric patients. JPEN J Parenter Enteral Nutr 2002; 26:SA1–S138

40.

Arends J, Bodoky G, Bozzetti F, et al. ESPEN guidelines on enteral nutrition: non-surgical oncology. Clin Nutr 2006, May 11; Epub ahead of print

41.

Mirhosseini N, Fainsinger RL, Baracos V. Pareneteral nutrition in advanced cancer: indications and clinical practice guidelines. J Pall Med 2005; 8:914–918CrossRef

42.

Lundholm K, Daneryd P, Bosaeus I, Komer Ulla, Lindholm E. 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

43.

Schattner M. Enteral nutritional support of the patient with cancer. J Clin Gastroenterol 2003; 36:297–302PubMedCrossRef

44.

Bozzetti F, Gavazzi C, Mariani L, et al. Artificial nutrition in cancer patients: which route, what composition? World J Surg 1999; 23:577–583PubMedCrossRef

45.

Mercadante S. Parenteral versus enteral nutrition in cancer patients: indications and practice. Support Care Cancer 1998; 6:85–93PubMedCrossRef

46.

Whitehouse AS, Smith HJ, Drake JL, et al. Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer Res 2001; 61:3604–3609PubMed

47.

Wigmore SJ, Barber MD, Ross JA. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 2000; 36:177–184PubMedCrossRef

48.

Fearon KC, von Meyenfeldt MF, Moses AG, et al. Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut 2003; 52:1479–1486PubMedCrossRef

49.

Moses AWG, 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; 90:996–1002PubMedCrossRef

50.

Jatoi A, Kendrith R, Loprinzi CL, et al. An eicosapentaenoic acid supplement versus megestrol acetate versus both patients with cancer-associated wasting: a north central cancer treatment group and national cancer institute of Canada collaborative efforts. J Clin Oncol 2004; 22:2469–2476PubMedCrossRef

51.

Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci 2005; 8:571–578PubMedCrossRef

52.

Foster AC, Chen C, Markison S, Marks DL. MC4 receptor antagonists: a potential treatment for cachexia. IDrugs 2005; 8:314–319PubMed

53.

Markison S, Foster AC, Chen C, et al. The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology 2005; 146:2766–2773PubMedCrossRef

54.

Nicholson JR, Kohler G, Schaerer F, et al. Peripheral administration of a melanocortin4-receptor inverse agonist prevents loss of a lean body mass in tumor-bearing mice. J Pharmacol Exp Ther 2006, Jan 25; Epub ahead of print

55.

Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Endocrinol Metab 2001; 86:5992–5995CrossRef

56.

Druce MR, Neary NM, Small CJ, et al. Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. Int J Obes 2006; 30:293–296CrossRef

57.

Neary NM, Small CJ, Wren AM, et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrin Metab 2004; 89:2832–2836CrossRef

58.

Combaret L, Ralliere C, Taillandier D, et al. Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of the 20S and 26S proteasomes in muscles from tumour bearing rats. Mol Biol Rep 1999; 26:95–101PubMedCrossRef

59.

Peuckmann V, Fisch M, Bruera E. Potential novel uses of thalidomide: focus on palliative care. Drugs 2000; 60:273–292PubMedCrossRef

60.

Lundholm K, Daneryd P, Korner U, et al. Evidence that long-term COX-treatment improves energy homeostasis and body composition in cancer patients with progressive cachexia. Int J Oncol 2004; 24:505–512PubMed

61.

Davis TW, Zweifel BS, O’Neal JM, et al. Inhibition of cyclooxygenase by celecoxib reverses tumour-2 induced wasting. J Pharmacol Exp Ther 2004; 308:929–934PubMedCrossRef

62.

Muscaritoli M, Costelli P, Bossola M, et al. Effects of simvastatin administration in an experimental model of cancer cachexia. Nutrition 2003; 19:936–940PubMedCrossRef

63.

Strassmann G, Fong M, Freter CE, et al. Suramin interfers with interleukin-6 receptor binding in vitro and inhibits colon-26-mediated experimental cancer cachexia in vivo. J Clin Invest 1993; 92:2152–2159PubMedCrossRef

64.

Mori K, Fujimoto-Ouchi K, Ishikawa T, et al. Murine interleukin-12 prevents the development of cancer cachexia in a murine model. Int J Cancer 1996; 67:849–855PubMedCrossRef

65.

Quinn LS, Haugk KL, Grabstein KH. Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology 1995; 136:3669–3672PubMedCrossRef

66.

Goldberg RM, Loprinzi CL, Maillard JA, et al. Pentoxiphylline for treatment of cancer anorexia and cachexia? A randomised, double-bind, placebo-controlled trial. J Clin Oncol 1995; 13:2856–2859PubMed

67.

Bruera E, Neumann CM, Pituskin E, Calder K, Ball G, Hanson J. Thalidomide in patients with cachexia due to terminal cancer: preliminary report. Ann Oncology 1999; 10:857–859CrossRef

68.

Khan ZH, Simpson EJ, Cole AT, et al. Oesophageal cancer and cachexia: the effect of short term treatment with thalidomide on weight loss and lean body mass. Aliment Pharmacol Ther 2003; 17:677–683PubMedCrossRef

69.

Gordon JN, Trebble TM, Ellis RD, et al. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut 2005; 54:540–545PubMedCrossRef

70.

Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336:186–195PubMedCrossRef

71.

Lissoni P, Paolorossi F, Tancini G, et al. Is there a role for melatonin in treatment of neoplastic cachexia? Eur J Cancer 1996; 32:340–1343CrossRef

72.

Pearson C, Glimelius B, Ronnelid J, et al. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomised pilot study. Nutrition 2005; 21:170–178CrossRef

73.

Mc Millan DC, O’Gorman P, Fearon KC, et al. A pilot study of megestrol acetate and ibuprofen in the treatment of cachexia in gastrointestinal cancer patients. Br J cancer 1997; 76:788–790

74.

Langer CJ, Hoffman JP, Ottery FD, et al. Clinical significance of weight loss in cancer patients: rationale for the use of anabolic agents in the treatment of cancer-related cachexia. Nutrition 2001; 17(Suppl):S1–S20PubMedCrossRef

75.

Sheffield Moore M. Androgens and the control of skeletal muscle protein synthesis. Ann Med 2000; 32:181–186PubMedCrossRef

76.

Demling RH, DeSanti L. Oxandrolone induced lean mass gain during recovery from severe burns is maintained after discontinuation of the anabolic steroid. Burns 2003; 29:793–797PubMedCrossRef

77.

Earthman CP, Reid PM, Harper IT, et al. Body cell mass repletion and improved quality of life in HIV-infected individuals receiving oxandrolone. JPEN J Parenteral Enteral Nutr 2002; 26:357–365CrossRef

78.

Creutzberg EC, Wouters EF, Mostert R, et al. A role for anabolic steroids in therehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial. Chest 2003; 104:1733–1742CrossRef

79.

Chlebowski RT, Herrold J, Ali I, et al. Influence of nandrolone decanoate on weight loss in advanced non-small cell lung cancer. Cancer 1986; 58:183–186PubMedCrossRef

80.

Tchekmedyian S, Fesen M, Price LM, et al. Ongoing placebo-controlled study of oxandrolone in cancer-related weight loss. Int J Radiat Oncol Biol Phys 2003; 57 Suppl: S283–S284

81.

Bogdanovich S, Krag TOB, Barton ER, et al. Functional improvement of dystrophic muscle by myostatin blockade. Nature 2002; 420:418–421PubMedCrossRef

82.

Wagner KR, McPherron AC, Winik N, et al. Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann Neurol 2002; 52:832–836PubMedCrossRef

83.

Jatoi A, Jett JR, Sloan J, et al. A pilot study on safety and pharmacokinetics of infliximab for the cancer anorexia/weight loss syndrome in non-small-cell lung cancer patients. Support Care Cancer 2004; 12:859–863PubMedCrossRef

84.

Monk JP, Phillips G, Waite R, et al. Assessment of tumor necrosis factor-alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. J Clin Oncol 2006; 24:1852–1859PubMedCrossRef

Title: Cancer Cachexia: It’s Time for More Clinical Trials
Authors: Maurizio Bossola
Fabio Pacelli
Antonio Tortorelli
Giovan Battista Doglietto
Publication date: 01-02-2007
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 2/2007
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-006-9179-5

At a glance: The STEP trials

Springer Medicine

Cancer Cachexia: It’s Time for More Clinical Trials

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2007

Neoadjuvant Chemoradiation Versus Hyperfractionated Accelerated Radiotherapy in Locally Advanced Rectal Cancer

Perioperative Interstitial Brachytherapy for Soft Tissue Sarcomas: Prognostic Factors and Long-Term Results of 155 Patients

Timing of Adjuvant Radioimmunotherapy after Cytoreductive Surgery in Experimental Peritoneal Carcinomatosis of Colorectal Origin

Amelioration of Operation-Induced Suppression of Marginating Pulmonary NK Activity using Poly IC: A Potential Approach to Reduce Postoperative Metastasis

Cancer Cells Cause Vascular Endothelial Cell (vEC) Retraction via 12(S)HETE Secretion; The Possible Role of Cancer Cell Derived Microparticle

Incidence Pattern and Survival for Gallbladder Cancer Over Three Decades—An Analysis of 10301 Patients