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Editorial

Evidence for partial pharmaceutical reversal of the cancer anorexia-cachexia syndrome: the case of anamorelin

Stefan D. Anker1,*, Andrew J. S. Coats2,3, John E. Morley4

How to Cite

Anker, S. D., Coats, A. J. S., and Morley, J. E. (2015) Evidence for partial pharmaceutical reversal of the cancer anorexia–cachexia syndrome: the case of anamorelin. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12063.

Author Information

1

Division of Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen (UMG), Göttingen, Germany

2

Monash University, Melbourne, Australia

3

University of Warwick, Coventry, UK

4

Divisions of Geriatric Medicine and Endocrinology, Saint Louis University School of Medicine, St Louis, MO, USA


Abstract

A major component of the cancer anorexia-cachexia syndrome is a decline in food intake. Up until now none of the drugs that improve appetite also improve skeletal muscle. Recent studies have suggested that the oral ghrelin-analog, anamorelin, increased food intake and muscle mass. Unfortunately, it does not increase muscle power. Its regulatory future is uncertain, although it has important clinical effects.

Article

Loss of muscle and fat mass and anorexia are the key components of the cancer anorexia–cachexia syndrome.[1] This syndrome plays a key role in the end stage ‘suffering’ of persons dying from cancer. While nutritional intervention can reverse some components of this syndrome, it is insufficient to make a major impact on the outcomes in most patients with cancer.[2, 3] This has led to a search for drugs that will increase food intake and muscle mass quality in persons with cancer.[4, 5] While megestrol acetate, dronabinol and corticosteroids increase appetite, they have not been shown to alter muscle mass.[6] Anabolic steroids increase muscle mass but have no effect on appetite.[7]

Ghrelin, a 28-amino acid hormone, discovered in 1999, is produced from the fundus of the stomach. It increases food intake, growth hormone release and enhances memory.[8, 9] The effects of ghrelin on food intake and growth hormone release are mediated through the nitric oxide-AMP kinase food regulatory system.[10]

Anamorelin is a ghrelin receptor agonist that can be administered orally. Recently, two-phase two multicentre studies involving 82 persons treated for 12 weeks have been published.[11] Anamorelin increased lean body mass compared with placebo and improved non-dominant handgrip strength. This was correlated with an increase with insulin-like growth factor 1. In addition, anamorelin administration led to an increase in quality of life.

However, the Phase III trials (ROMANA 1 and ROMANO 2) presented at the 2014 European Oncology Congress in Madrid were somewhat less exciting. In these studies, a total of 979 patients with non-small cell lung cancer were studied. In this study, body weight was increased compared with placebo, but there was no improvement in handgrip strength. In addition, anamorelin improved the Functional Assessment of Anorexia Cachexia Treatment scores.

The results are not unsurprising as ghrelin increases muscle mass by increasing growth hormone. Growth hormone increases muscle mass but not muscle strength.[12] It is now well recognized that muscle quality is not directly related to muscle mass.[13] This has led to the definitions for sarcopenia requiring the older person not only to have a decrease in lean mass but also in a functional measure (either walking speed/distance or handgrip strength).[14, 15]

The question now arises whether or not a drug that improves appetite and muscle mass, but not muscle function, can be approved for the treatment of the cancer/anorexia syndrome. Both megestrol acetate and dronabinol are approved in the USA as appetite stimulants for anorexia in cancer. This precedent suggests that the approval for anamorelin could be for improving appetite. Improving anorexia is a major quality of life issue in the cancer anorexia–cachexia syndrome. And if the aforementioned question is answered in the affirmative, can such an approval be based on secondary rather than primary endpoints of pivotal trials? Maybe at least one more trial is needed to confirm these clinically important results.

There are some data suggesting that muscle and/or fat loss in persons with cachexia is protective against early mortality.[16, 17] In addition, prevention of weight loss may improve the ability of persons with cancer to tolerate chemotherapy.[18] Obviously, if anamorelin could be shown to clearly support either of these two concepts, it could become a very important often used drug.

For those scientists who are interested in muscle wasting disease,[19] this is an exciting time as a number of drugs with potential positive effects on muscle wasting are under development and are coming closer to possible approval by the European and American Drug Agencies. We hope that the therapeutic developments will not only affect outcomes in cancer[20-22] but also in chronic kidney disease and heart failure,[23, 24] stroke,[25] COPD,[26] and frailty due to aging.[27, 28] From 4 to 6 December 2015 in Paris, we will organize the eighth Cachexia Conference (for details, see www.society-scwd.org), and hope for many participants and more news on many new therapeutic developments, combining effective drugs with good nutrition.

Acknowledgements

The authors of this paper certify that they comply with the principles of ethical publishing in the Journal of Cachexia, Sarcopenia and Muscle 2010;1:7–8 (von Haehling S, Morley JE, Coats AJ and Anker SD).

References


1
Argiles JM
, Anker SD, Evans WJ, Morley JE, Fearon KC, Strasser F, et al. Consensus on cachexia definitions. J Am Med Dir Assoc 2010; 11: 229230.

CrossRef |
PubMed |
Web of Science® Times Cited: 55
2
Bauer J
, Biolo G, Cederholm T, Cesari M, Cruz-Jentoft AJ, Morley JE, et al. Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE study group. J Am Med Dir Assoc 2013; 14: 542559.

CrossRef |
PubMed |
Web of Science® Times Cited: 85
3
Omlin A
, Blum D, Wierecky J, Haile SR, Ottery FD, Strasser F. Nutrition impact symptoms in advanced cancer patients: frequency and specific interventions, a case–control study. J Cachexia Sarcopenia Muscle 2013; 4: 5561.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 4
4
Morley JE
, von Haehling S, Anker SD. Are we closer to having drugs to treat muscle wasting disease? J Cachexia Sarcopenia Muscle 2014; 5: 8387.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 9
5
von Haehling S
, Anker SD. Treatment of cachexia: an overview of recent developments. J Am Med Dir Assoc 2014; 15: 866872.

CrossRef |
PubMed |
Web of Science®
6
Morley JE
. Pathophysiology of the anorexia of aging. Curr Opin Clin Nutr Metab Care 2013; 16: 2732.

CrossRef |
PubMed |
CAS |
Web of Science® Times Cited: 14
7
Dobs AS
, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomized controlled phase 2 trial. Lancet Oncol 2013; 14: 335345.

CrossRef |
PubMed |
CAS |
Web of Science® Times Cited: 34
8
Müller TD
, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab 2015; 4: 437460.

CrossRef |
PubMed |
CAS
9
Diano S
, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 2006; 9: 382388.

CrossRef |
CAS |
Web of Science® Times Cited: 374
10
Gaskin FS
, Farr SA, Banks WA, Kumar VB, Morley JE. Grhelin-induced feeding is dependent on nitric oxide. Peptides 2003; 24: 913918.

CrossRef |
PubMed |
CAS |
Web of Science® Times Cited: 79
11
Garcia JM
, Boccia RV, Graham CD, Yan Y, Duus EM, Allen S, et al. Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomized, placebo-controlled, double-blind trials. Lancet Oncol 2015; 16: 108116.

CrossRef |
PubMed |
CAS |
Web of Science® Times Cited: 2
12
Morley JE
. Scientific overview of hormone treatment used for rejuvenation. Fertil Steril 2013; 99: 18071813.

CrossRef |
PubMed |
CAS |
Web of Science® Times Cited: 4
13
Barbat-Artigas S, Rolland Y, Vellas B, Aubertin-Leheudre M. Muscle quantity is not synonymous with muscle quality. J Am Med Dir Assoc 2013; 14: 852.e1852.e7.
CrossRef |
Web of Science®
14
Woo J
, Leung J, Morley JE. Validating the SARC-F: a suitable community screening tool for sarcopenia? J Am Med Dir Assoc 2014; 15: 630634.

CrossRef |
PubMed |
Web of Science® Times Cited: 14
15
Chen LK
, Liu LK, Woo J, Assantachai P, Auyeung TW, Bahyah KS, et al. Sarcopenia in Asia: consensus report of the Asian working group for sarcopenia. J Am Med Dir Assoc 2014; 15: 95101.

CrossRef |
PubMed |
Web of Science® Times Cited: 46
16
Veasey Rodrigues H
, Baracos VE, Wheler JJ, Parsons HA, Hong DS, Naing A, et al. Body composition and survival in the early clinical trials setting. Eur J Cancer 2013; 49: 30683075.

CrossRef |
PubMed |
Web of Science®
17
Kalantar-Zadeh K
, Rhee C, Sim JJ, Stenvinkel P, Anker SD, Kovesdy CP. Why cachexia kills: examining the causality of poor outcomes in wasting conditions. J Cachexia Sarcopenia Muscle 2013; 4: 8994.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 12
18
Cousin S
, Hollebecque A, Koscielny S, Mir O, Varga A, Baracos VE, et al. Low skeletal muscle is associated with toxicity in patients included in phase I trials. Invest New Drugs 2014; 32: 382387.

CrossRef |
PubMed |
CAS |
Web of Science® Times Cited: 1
19
Anker SD
, Coats AJ, Morley JE, Rosano G, Bernabei R, von Haehling S, et al. Muscle wasting disease: a proposal for a new disease classification. J Cachexia Sarcopenia Muscle 2014; 5: 13.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 8
20
Toledo M
, Springer J, Busquets S, Tschirner A, López-Soriano FJ, Anker SD, et al. Formoterol in the treatment of experimental cancer cachexia: effects on heart function. J Cachexia Sarcopenia Muscle 2014; 5: 315320.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 2
21
Fogelman DR, Holmes H, Mohammed K, Katz MH, Prado CM, Lieffers J, et al. Does IGFR1 inhibition result in increased muscle mass loss in patients undergoing treatment for pancreatic cancer? J Cachexia Sarcopenia Muscle 2014; 5: 307313.
Wiley Online Library |
PubMed |
Web of Science® Times Cited: 3
22
de Campos-Ferraz PL, Andrade I, das Neves W, Hangai I, Alves CR, Lancha AH Jr. An overview of amines as nutritional supplements to counteract cancer cachexia. J Cachexia Sarcopenia Muscle 2014; 5: 105110.
Wiley Online Library |
PubMed |
Web of Science® Times Cited: 2
23
Rattanasompattikul M
, Molnar MZ, Lee ML, Dukkipati R, Bross R, Jing J, et al. Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial. J Cachexia Sarcopenia Muscle 2013; 4: 247257.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 5
24
Khawaja T
, Chokshi A, Ji R, Kato TS, Xu K, Zizola C, et al. Ventricular assist device implantation improves skeletal muscle function, oxidative capacity, and growth hormone/insulin-like growth factor-1 axis signaling in patients with advanced heart failure. J Cachexia Sarcopenia Muscle 2014; 5: 297305.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 2
25
Knops M
, Werner CG, Scherbakov N, Fiebach J, Dreier JP, Meisel A, et al. Investigation of changes in body composition, metabolic profile and skeletal muscle functional capacity in ischemic stroke patients: the rationale and design of the Body Size in Stroke Study (BoSSS). J Cachexia Sarcopenia Muscle 2013; 4: 199207.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 4
26
Scott IC
, Tomlinson W, Walding A, Isherwood B, Dougall IG. Large-scale isolation of human skeletal muscle satellite cells from post-mortem tissue and development of quantitative assays to evaluate modulators of myogenesis. J Cachexia Sarcopenia Muscle 2013; 4: 157169.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 5
27
Pötsch MS
, Tschirner A, Palus S, von Haehling S, Doehner W, Beadle J, et al. The anabolic catabolic transforming agent (ACTA) espindolol increases muscle mass and decreases fat mass in old rats. J Cachexia Sarcopenia Muscle 2014; 5: 149158.

Wiley Online Library |
PubMed |
Web of Science®
28
Morley JE
, von Haehling S, Anker SD, Vellas B. From sarcopenia to frailty: a road less traveled. J Cachexia Sarcopenia Muscle 2014; 5: 58.

Wiley Online Library |
PubMed |
Web of Science® Times Cited: 17