Abstract
Purpose
Cachexia in cancer adversely affects patients' perception of symptoms, well-being, and response to therapy, and shortens survival. Anamorelin, an oral mimetic of ghrelin, has been shown to increase body weight and anabolic hormone levels in healthy volunteers and is being investigated to treat cancer cachexia.
Methods
This multicenter, double-blind, placebo-controlled, crossover study evaluated the effects of anamorelin in 16 patients with different cancers and cachexia. Patients were randomly assigned to anamorelin 50 mg/day or placebo for 3 days. A 3- to 7-day washout period followed and then treatments were switched. Assessments included body weight, appetite, food intake, growth hormone (GH) levels, patient-reported symptom assessments (e.g., the Anderson Symptom Assessment Scale [ASAS] and also an inclusion criterion), and safety.
Results
Anamorelin significantly increased body weight compared with placebo (0.77 kg vs. −0.33 kg). Food intake increased compared with placebo, but not significantly. GH significantly increased at all time points (0.5–4 h postdose). Insulin-like growth factor-1 (IGF-1) significantly increased by 54.09 ng/mL with anamorelin treatment compared with −3.56 ng/mL for placebo; significant changes in insulin-like growth factor-binding protein 3 (IGFBP-3) were 0.75 μg/mL vs. −0.19 μg/mL, respectively. Patient-reported symptoms, including appetite as measured by ASAS, significantly improved with anamorelin (8.1 vs. 1.0 for placebo). Adverse events (AEs) in four patients were possibly or probably related to anamorelin: hyperglycemia (two patients), nausea (one patient), and dizziness (one patient). Most AEs were mild; no patients withdrew due to AEs.
Conclusions
Anamorelin showed significant metabolic, clinical, and patient-rated effects in cancer cachexia. Further studies are warranted.
Similar content being viewed by others
References
Lasheen W, Walsh D (2010) The cancer anorexia–cachexia syndrome: myth or reality? Support Care Cancer 18:265–272
Tisdale MJ (2009) Mechanisms of cancer cachexia. Physiol Rev 89:381–410
Adamopoulos S, Parissis JT, Georgiadis M et al (2002) Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy. Am Heart J 144:359–364
Arrieta O, Michel Ortega RM, Villanueva-Rodríguez G et al (2010) Association of nutritional status and serum albumin levels with development of toxicity in patients with advanced non-small cell lung cancer treated with paclitaxel–cisplatin chemotherapy: a prospective study. BMC Cancer 10:50. doi:10.1186/1471-2407-10-50
Dewys WD, Begg C, Lavin PT et al (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 69:491–497
Davidoff AJ, Tang M, Seal B, Edelman MJ (2010) Chemotherapy and survival benefit in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 28:2191–2197. doi:10.1200/JCO.2009.25.4052
Mantovani G, Madeddu C (2010) Cancer cachexia: medical management. Support Care Cancer 18:1–9. doi:10.1007/s00520-009-0722-3
Neary NM, Small CJ, Wren AM et al (2004) Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 89:2832–2836. doi:10.1210/jc.2003-031768
Fouladiun M, Körner U, Bosaeus I, Daneryd P, Hyltander A, Lundholm KG (2005) Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care: correlations with food intake, metabolism, exercise capacity, and hormones. Cancer 103:2189–2198. doi:10.1002/cncr.21013
Morley JE, Thomas DR, Wilson M-MG (2006) Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 83:735–743
Crown AL, Cottle K, Lightman SL et al (2002) What is the role of the insulin-like growth factor system in the pathophysiology of cancer cachexia, and how is it regulated? Clin Endocrinol (Oxf) 56:723–733. doi:10.1046/j.1365-2265.2002.01540.x
Strasser F, Lutz TA, Maeder MT et al (2008) Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study. Br J Cancer 98:300–308. doi:10.1038/sj.bjc.6604148
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660
Wren AM, Seal LJ, Cohen MA et al (2001) Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992. doi:10.1210/jc.86.12.5992
Garcia JM, Polvino WJ (2007) Effect on body and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers. Oncologist 12:594–600
Garcia JM, Polvino WJ (2009) Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers. Growth Horm IGF Res 19:267–273. doi:10.1016/j.ghir.2008.12.003
Nass R, Pezzoli SS, Oliveri MC et al (2008) Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med 149:601–611
Akamizu T, Takaya K, Irako T et al (2004) Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur J Endocr 150:447–455. doi:10.1530/eje.0.1500447
World Medical Association: The World Medical Association: policy: World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Amendments through 55th WMA General Assembly, Tokyo; 2004. Available at: 40news/20archives/2004/2004_24/index.html. Accessed February 8, 2011
United States Food and Drug Administration, Department of Health and Human Services: FDA Good Clinical Practice Program. Available at http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm155713.htm. Accessed February 8, 2011
European Union Directive 91/507/EEC: Commission Directive 91/507/EEC of 19 July 1991: modifying the Annex to Council Directive 75/318/EEC on the approximation of the laws of member states relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products. Available at http://eur-lex.europa.eu/smartapi/cgi/sga_doc?smartapi!celexplus!prod!DocNumber&lg=en&type_doc=Directive&an_doc=1991&nu_doc=507. Accessed February 8, 2011
Oken MM, Creech RH, Tormey DC et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655
Hesketh PJ (1999) Defining the emetogenicity of cancer chemotherapy regimens: relevance to clinical practice. Oncologist 4:191–196
Chang VT, Hwang SS, Feuerman M (2000) Validation of the Edmonton Symptom Assessment Scale. Cancer 88:2164–2171
Palmer JL, Fisch MJ (2005) Association between symptom distress and survival in outpatients seen in a palliative care cancer center. J Pain Symptom Manag 29:565–571. doi:10.1016/j.jpainsymman.2004.11.007
Robinson DW Jr, Eisenberg DF, Cella D et al (2008) The prognostic significance of patient-reported outcomes in pancreatic cancer cachexia. J Support Oncol 6:283–290
Cella DF, VonRoenn J, Lloyd S, Browder HP (1995) The Bristol-Myers Anorexia/Cachexia Recovery Instrument (BACRI): a brief assessment of patients' subjective response to treatment for anorexia/cachexia. Qual Life Res 4:221–231
McMillan DC (2009) Systemic inflammation, nutritional status, and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 12:223–226
Garcia JM, Garcia-Touza M, Hijazi RA et al (2005) Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia. J Clin Endocrinol Metab 90:2920–2926. doi:10.1210/jc.2004-1788
Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518
Rowlands MA, Gunnell D, Harris R, Vatten LJ, Holly JM, Martin RM (2009) Circulating insulin-like growth factor peptides and prostate cancer risk: a systematic review and meta-analysis. Int J Cancer 124:2416–2429
Han J, Jogie-Brahim S, Harada A, Oh Y (2011) Insulin-like growth factor-binding protein-3 suppresses tumor growth via activation of caspase-dependent apoptosis and cross-talk with NF-κB signaling. Cancer Lett 307:200–210. doi:10.1016/j.canlet.2011.04.004
Kim JH, Choi DS, Lee OH, Oh SH, Lippman SM, Lee HY (2011) Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1-mediated transcriptional events. Blood 118:2622–2631. doi:10.1182/blood-2010-08-299784
Wolf RF, Ng B, Weksler B, Burt M, Brennan MF (1994) Effect of growth hormone on tumor and host in an animal model. Ann Surg Oncol 1:314–320
Hanada T, Toshinai K, Kajimura N et al (2003) Anti-cachectic effect of ghrelin in nude mice bearing human melanoma cells. Biochem Biophys Res Commun 301:275–279
Bartlett DL, Charland S, Torosian MH (1994) Growth hormone, insulin, and somatostatin therapy of cancer cachexia. Cancer 73:1499–1504
Bartlett DL, Stein TP, Torosian MH (1995) Effect of growth hormone and protein intake on tumor growth and host cachexia. Surgery 117:260–267
Rohrmann S, Linseisen J, Becker S et al (2011) Concentrations of IGF-I and IGFBP-3 and brain tumor risk in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 20:2174–2182
Lundholm K, Gunnebo L, Korner U et al (2010) Effects by daily long term provision of ghrelin to unselected weight-losing cancer patients: a randomized double-blind study. Cancer 116:2044–2052. doi:10.1002/cncr.24917
Ghigo E, Arvat E, Broglio F et al (1999) Endocrine and non-endocrine activities of growth hormone secretagogues in humans. Horm Res 51(suppl 3):9–15
Fearon KC (2011) Cancer cachexia and fat-muscle physiology. N Engl J Med 365:565–567
American Thoracic Society/American College of Chest Physicians (2003) Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167:211–277
Jakobsen LH, Rask IK, Kondrup J (2010) Validation of handgrip strength and endurance as a measure of physical function and quality of life in healthy subjects and patients. Nutrition 26:542–550
Acknowledgments
Support for developing this manuscript was provided by Helsinn Therapeutics (US), Inc., and copyediting, editorial assistance, and production assistance was provided by Paul V. Shea and The Curry Rockefeller Group, LLC (Tarrytown, NY). The authors thank Wei Du, Ph.D. (Norristown, PA) for reviewing the statistical methods and verifying data.
Funding
This research was sponsored by Helsinn Therapeutics (US), Inc.
Disclosure
José M. Garcia has received research funding from Helsinn Therapeutics (US), Inc. and Aeterna Zentaris Inc., and receives research support from the Department of Veterans Affairs (MERIT awards BX000507 and CX00174). John Friend and Suzan Allen are employees of Helsinn Therapeutics (US), Inc.
Author information
Authors and Affiliations
Corresponding author
Additional information
Declaration
The authors declare that they have full control of the primary data and agree to allow the journal to review these data if requested.
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(PDF 64.8 kb)
Rights and permissions
About this article
Cite this article
Garcia, J.M., Friend, J. & Allen, S. Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study. Support Care Cancer 21, 129–137 (2013). https://doi.org/10.1007/s00520-012-1500-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00520-012-1500-1