Drug Evaluation

The emerging role of anamorelin hydrochloride in the management of patients with cancer anorexia-cachexia

*Author for correspondence:

E-mail Address: David.Currow@uts.edu.au

ImPACCT – Faculty of Health, University of Technology Sydney, Sydney, New South Wales, Australia

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Richard JE Skipworth

Clinical Surgery, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK

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Published Online:16 Jun 2017https://doi.org/10.2217/fon-2017-0141

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Abstract

Cancer cachexia affects many patients with advanced cancer. This multifactorial syndrome, which involves loss of muscle mass and body weight, profoundly affects patients’ physical functioning and quality of life. Pharmacologic interventions that target weight loss and also improve patient-reported measures are required. Anamorelin hydrochloride is an oral ghrelin receptor agonist for the treatment of cancer anorexia-cachexia that stimulates release of growth hormone and insulin-like growth factor 1, and improves food intake and body weight. Phase II and III trials have demonstrated that anamorelin increases body muscle and fat composition, and improves patient-reported appetite and quality of life. Anamorelin shows promise as an anabolic agent with benefits maintained over time, without the virilizing side effects of other anabolic medications.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1 Kumar NB, Kazi A, Smith T et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr. Treat. Options Oncol. 11(3–4), 107–117 (2010).
MedlineGoogle Scholar
2 von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J. Cachexia Sarcopenia Muscle 1(1), 1–5 (2010).
MedlineGoogle Scholar
3 Fearon K, Strasser F, Anker SD et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 12(5), 489–495 (2011). •• Key paper that provides a consensus definition of cancer cachexia.
MedlineGoogle Scholar
4 Fearon KC, Voss AC, Hustead DS, Cancer Cachexia Study Group. Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. Am. J. Clin. Nutr. 83(6), 1345–1350 (2006).
Medline CASGoogle Scholar
5 Evans WJ, Morley JE, Argilés J et al. Cachexia: a new definition. Clin. Nutr. 27(6), 793–799 (2008).
Medline CASGoogle Scholar
6 Muscaritoli M, Molfino A, Lucia S, Rossi Fanelli F. Cachexia: a preventable comorbidity of cancer. A T.A.R.G.E.T. approach. Crit. Rev. Oncol. Hematol. 94(2), 251–259 (2015).
MedlineGoogle Scholar
7 Tisdale MJ. Mechanisms of cancer cachexia. Physiol. Rev. 89(2), 381–410 (2009). • Provides a comprehensive overview of the mechanisms underlying cancer cachexia.
Medline CASGoogle Scholar
8 Argilés JM, Anker SD, Evans WJ et al. Consensus on cachexia definitions. J. Am. Med. Dir. Assoc. 11(4), 229–230 (2010).
MedlineGoogle Scholar
9 Van Cutsem E, Arends J. The causes and consequences of cancer-associated malnutrition. Eur. J. Oncol. Nurs. 9(Suppl. 2), S51–S63 (2005).
MedlineGoogle Scholar
10 Dahele M, Skipworth RJ, Wall L, Voss A, Preston T, Fearon KC. Objective physical activity and self-reported quality of life in patients receiving palliative chemotherapy. J. Pain Symptom Manage. 33(6), 676–685 (2007).
MedlineGoogle Scholar
11 Ferriolli E, Skipworth RJ, Hendry P et al. Physical activity monitoring: a responsive and meaningful patient-centered outcome for surgery, chemotherapy, or radiotherapy? J. Pain Symptom Manage. 43(6), 1025–1035 (2012).
MedlineGoogle Scholar
12 Arrieta O, Michel Ortega RM, Villanueva-Rodríguez G et al. 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 (2010).
MedlineGoogle Scholar
13 Aapro M, Arends J, Bozzetti F 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. 25(8), 1492–1499 (2014).
Medline CASGoogle Scholar
14 Andreyev HJN, Norman AR, Oates J, Cunningham D. Why do patients with weight loss have worse outcomes when undergoing chemotherapy for gastrointestinal malignancies? Eur. J. Cancer 34(4), 503–509 (1998).
Medline CASGoogle Scholar
15 Costa G, Donaldson SS. Current concepts in cancer: effects of cancer and cancer treatment on the nutrition of the host. N. Engl. J. Med. 300(26), 1471–1474 (1979).
Medline CASGoogle Scholar
16 Maltoni M, Nanni O, Pirovano M et al. Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care. J. Pain Symptom Manage. 17(4), 240–247 (1999).
Medline CASGoogle Scholar
17 Currow DC, Abernethy AP. Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome. Future Oncol. 10(5), 789–802 (2014).
CASGoogle Scholar
18 International Alliance of Patients’ Organizations. What is Patient-Centred Healthcare? A Review of Definitions and Principles. International Alliance of Patients’ Organizations, London, UK, 1–34 (2007).
Google Scholar
19 Hopkinson JB. Psychosocial impact of cancer cachexia. J. Cachexia Sarcopenia Muscle 5(2), 89–94 (2014). •• Provides an overview of the impact of cancer cachexia on patients and their carers from a social, as opposed to clinical, perspective, highlighting the potential importance of psychosocial interventions in cancer.
MedlineGoogle Scholar
20 Wheelwright SJ, Johnson CD. Patient-reported outcomes in cancer cachexia clinical trials. Curr. Opin. Support. Palliat. Care 9(4), 325–332 (2015). • Discusses the importance of patient-reported outcomes in clinical trials and some of the instruments that can be used to measure such outcomes.
MedlineGoogle Scholar
21 Kluetz PG, Slagle A, Papadopoulos EJ et al. Focusing on core patient-reported outcomes in cancer clinical trials: symptomatic adverse events, physical function, and disease-related symptoms. Clin. Cancer Res. 22(7), 1553–1558 (2016).
Medline CASGoogle Scholar
22 Robinson DW, Eisenberg DF, Cella D et al. The prognostic significance of patient-reported outcomes in pancreatic cancer cachexia. J. Support. Oncol. 6(6), 283–290 (2008).
MedlineGoogle Scholar
23 Hopkinson JB. Carers’ influence on diets of people with advanced cancer. Nurs. Times 104(12), 28–29 (2008).
Google Scholar
24 Deshpande PR, Rajan S, Sudeepthi BL, Abdul Nazir CP. Patient-reported outcomes: a new era in clinical research. Perspect. Clin. Res. 2(4), 137–144 (2011).
MedlineGoogle Scholar
25 Fearon KC, Skipworth RJ. A critical assessment of the outcome measures and goals of intervention in cancer cachexia. In: Cachexia and Wasting: A Modern Approach. Mantovani G (Ed.). Springer, Milan, Italy, 619–630 (2006).
Google Scholar
26 Blauwhoff-Buskermolen S, Ruijgrok C, Ostelo RW et al. The assessment of anorexia in patients with cancer: cut-off values for the FAACT-A/CS and the VAS for appetite. Support. Care Cancer 24(2), 661–666 (2016).
Medline CASGoogle Scholar
27 Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J. Natl Cancer Inst. 85(5), 365–376 (1993).
Medline CASGoogle Scholar
28 Ribaudo JM, Cella D, Hahn EA et al. Re-validation and shortening of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Qual. Life Res. 9(10), 1137–1146 (2000).
Medline CASGoogle Scholar
29 LeBlanc TW, Samsa GP, Wolf SP, Locke SC, Cella DF, Abernethy AP. Validation and real-world assessment of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) scale in patients with advanced non-small cell lung cancer and the cancer anorexia-cachexia syndrome (CACS). Support. Care Cancer 23(8), 2341–2347 (2015).
MedlineGoogle Scholar
30 Fearon K, Argiles JM, Baracos VE et al. Request for regulatory guidance for cancer cachexia intervention trials. J. Cachexia Sarcopenia Muscle 6(4), 272–274 (2015).
MedlineGoogle Scholar
31 Mantovani G, Maccio A, Madeddu C et al. Randomized Phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Oncologist 15(2), 200–211 (2010).
Medline CASGoogle Scholar
32 Baldwin C, Spiro A, Ahern R, Emery PW. Oral nutritional interventions in malnourished patients with cancer: a systematic review and meta-analysis. J. Natl Cancer Inst. 104(5), 371–385 (2012).
MedlineGoogle Scholar
33 Gould DW, Lahart I, Carmichael AR, Koutedakis Y, Metsios GS. Cancer cachexia prevention via physical exercise: molecular mechanisms. J. Cachexia Sarcopenia Muscle 4(2), 111–124 (2013).
MedlineGoogle Scholar
34 Grande AJ, Silva V, Maddocks M. Exercise for cancer cachexia in adults: executive summary of a Cochrane Collaboration systematic review. J. Cachexia Sarcopenia Muscle 6(3), 208–211 (2015).
MedlineGoogle Scholar
35 Berenstein G, Ortiz Z. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst. Rev. (2), CD004310 (2005).
MedlineGoogle Scholar
36 Lee SJ, Glass DJ. Treating cancer cachexia to treat cancer. Skelet. Muscle 1(1), 2 (2011).
MedlineGoogle Scholar
37 Loprinzi CL, Kugler JW, Sloan JA et al. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J. Clin. Oncol. 17(10), 3299–3306 (1999).
Medline CASGoogle Scholar
38 Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J. Exp. Med. 173(3), 699–703 (1991).
Medline CASGoogle Scholar
39 Gordon JN, Goggin PM. Thalidomide and its derivatives: emerging from the wilderness. Postgrad. Med. J. 79(929), 127–132 (2003).
Medline CASGoogle Scholar
40 Lundholm K, Daneryd P, Körner U, Hyltander A, Bosaeus I. Evidence that long-term COX-treatment improves energy homeostasis and body composition in cancer patients with progressive cachexia. Int. J. Oncol. 24(3), 505–512 (2004).
Medline CASGoogle Scholar
41 Mantovani G, Macciò A, Madeddu C et al. Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia. J. Mol. Med. (Berl.) 88(1), 85–92 (2010).
Medline CASGoogle Scholar
42 Fearon KC, Barber MD, Moses AG et al. Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J. Clin. Oncol. 24(21), 3401–3407 (2006).
Medline CASGoogle Scholar
43 McCarthy HD, Crowder RE, Dryden S, Williams G. Megestrol acetate stimulates food and water intake in the rat: effects on regional hypothalamic neuropeptide Y concentrations. Eur. J. Pharmacol. 265(1–2), 99–102 (1994).
Medline CASGoogle Scholar
44 Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst. Rev. (3), CD004310 (2013).
MedlineGoogle Scholar
45 Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J. Clin. 52(2), 72–91 (2002).
MedlineGoogle Scholar
46 Gordon JN, Trebble TM, Ellis RD et al. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut 54(4), 540–545 (2005).
Medline CASGoogle Scholar
47 Davenport AP, Bonner TI, Foord SM et al. International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol. Rev. 57(4), 541–546 (2005).
Medline CASGoogle Scholar
48 Lundholm K, Gunnebo L, Körner U et al. Effects by daily long term provision of ghrelin to unselected weight-losing cancer patients: a randomized double-blind study. Cancer 116(8), 2044–2052 (2010).
Medline CASGoogle Scholar
49 Temel JS, Abernethy AP, Currow DC et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, Phase III trials. Lancet Oncol. 17(4), 519–531 (2016). •• Primary results of two pivotal Phase III trials demonstrating the efficacy of anamorelin in patients with cancer cachexia and non-small-cell lung cancer.
Medline CASGoogle Scholar
50 Arends J, Bachmann P, Baracos V et al. ESPEN guidelines on nutrition in cancer patients. Clin. Nutr. 36(1), 11–48 (2017).
MedlineGoogle Scholar
51 Dev R, Del Fabbro E, Bruera E. Association between megestrol acetate treatment and symptomatic adrenal insufficiency with hypogonadism in male patients with cancer. Cancer 110(6), 1173–1177 (2007).
Medline CASGoogle Scholar
52 Anker SD, Coats AJ, Morley JE. Evidence for partial pharmaceutical reversal of the cancer anorexia-cachexia syndrome: the case of anamorelin. J. Cachexia Sarcopenia Muscle 6(4), 275–277 (2015).
MedlineGoogle Scholar
53 Macciò A, Madeddu C, Mantovani G. Current pharmacotherapy options for cancer anorexia and cachexia. Expert Opin. Pharmacother. 13(17), 2453–2472 (2012).
Medline CASGoogle Scholar
54 Currow DC, Temel JS, Giorgino R, Abernethy AP, Friend J, Fearon K. Anamorelin in cachectic patients with non-small cell lung cancer (NSCLC) and low BMI (<20 kg/m²): a pooled efficacy data analysis of two Phase III studies. J. Clin. Oncol. 34(Suppl.), Abstract 10119 (2016).
Google Scholar
55 Pietra C, Takeda Y, Tazawa-Ogata N et al. Anamorelin HCl (ONO-7643), a novel ghrelin receptor agonist, for the treatment of cancer anorexia-cachexia syndrome: preclinical profile. J. Cachexia Sarcopenia Muscle 5(4), 329–337 (2014).
MedlineGoogle Scholar
56 Nakazato M, Murakami N, Date Y et al. A role for ghrelin in the central regulation of feeding. Nature 409(6817), 194–198 (2001).
Medline CASGoogle Scholar
57 Williams DL, Cummings DE. Regulation of ghrelin in physiologic and pathophysiologic states. J. Nutr. 135(5), 1320–1325 (2005).
Medline CASGoogle Scholar
58 Delporte C. Structure and physiological actions of ghrelin. Scientifica (Cairo) 2013, 518909 (2013).
MedlineGoogle Scholar
59 Arnold M, Mura A, Langhans W, Geary N. Gut vagal afferents are not necessary for the eating-stimulatory effect of intraperitoneally injected ghrelin in the rat. J. Neurosci. 26(43), 11052–11060 (2006).
Medline CASGoogle Scholar
60 Takaya K, Ariyasu H, Kanamoto N et al. Ghrelin strongly stimulates growth hormone release in humans. J. Clin. Endocrinol. Metab. 85(12), 4908–4911 (2000).
Medline CASGoogle Scholar
61 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402(6762), 656–660 (1999).
Medline CASGoogle Scholar
62 Akazimu T, Kangawa K. Ghrelin for cachexia. J. Cachexia Sarcopenia Muscle. 1(2), 169–176 (2010).
MedlineGoogle Scholar
63 Zhang H, Garcia JM. Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC. Expert Opin. Pharmacother. 16(8), 1245–1253 (2015).
Medline CASGoogle Scholar
64 Jeffery PL, Herington AC, Chopin LK. The potential autocrine/paracrine roles of ghrelin and its receptor in hormone-dependent cancer. Cytokine Growth Factor Rev. 14(2), 113–122 (2003).
Medline CASGoogle Scholar
65 Sever S, White DL, Garcia JM. Is there an effect of ghrelin/ghrelin analogs on cancer? A systematic review. Endocr. Relat. Cancer 23(9), R393–R409 (2016).
MedlineGoogle Scholar
66 Northrup R, Kuroda K, Duus EM et al. Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model. Support. Care Cancer 21(9), 2409–2415 (2013).
Medline CASGoogle Scholar
67 Legakis I, Stathopoulos J, Matzouridis T, Stathopoulos GP. Decreased plasma ghrelin levels in patients with advanced cancer and weight loss in comparison to healthy individuals. Anticancer Res. 29(10), 3949–3952 (2009).
MedlineGoogle Scholar
68 Huang Q, Fan YZ, Ge BJ, Zhu Q, Tu ZY. Circulating ghrelin in patients with gastric and colorectal cancer. Dig. Dis. Sci. 52(3), 803–809 (2007).
Medline CASGoogle Scholar
69 Mansson JV, Alves FD, Biolo A, Souza GC. Use of ghrelin in cachexia syndrome: a systematic review of clinical trials. Nutr. Rev. 74(11), 659–669 (2016).
MedlineGoogle Scholar
70 Su J, Geng J, Bao J et al. Two ghrelin receptor agonists for adults with malnutrition: a systematic review and meta-analysis. Nutr. J. 15(1), 97 (2016).
MedlineGoogle Scholar
71 Laviano A, Meguid MM, Inui A, Muscaritoli M, Rossi-Fanelli F. Therapy insight: cancer anorexia-cachexia syndrome--when all you can eat is yourself. Nat. Clin. Pract. Oncol. 2(3), 158–165 (2005).
Medline CASGoogle Scholar
72 Dewys WD, Begg C, Lavin PT et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am. J. Med. 69(4), 491–497 (1980).
Medline CASGoogle Scholar
73 Garcia JM, 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(1), 129–137 (2013).
MedlineGoogle Scholar
74 Garcia JM, Boccia RV, Graham CD et al. Anamorelin for patients with cancer cachexia: an integrated analysis of two Phase II, randomised, placebo-controlled, double-blind trials. Lancet Oncol. 16(1), 108–116 (2015). •• Primary results of two Phase II trials and some of the first clinical evidence demonstrating the efficacy of anamorelin.
Medline CASGoogle Scholar
75 Temel J, Bondarde S, Jain M, Allen S, Mann W. Efficacy and safety of anamorelin HCl in NSCLC patients: results from a randomized, double-blind, placebo-controlled, multicentre Phase II study. Eur. J. Cancer 49(Suppl. 2), Abstract 1308 (2013).
Google Scholar
76 Blum R, Polvino W. Pharmacokinetic (PK) profile of RC-1291, a novel oral ghrelin mimetic for the treatment of cancer anorexia/cachexia. Support. Care Cancer 14(6), Abstract 03–010 (2006).
Google Scholar
77 Kumor K, Polvino W. Biologic activity of RC-1291, a novel oral ghrelin mimetic for cancer anorexia/cachexia: results from a Phase I randomized, double-blind, placebo-controlled trial in healthy volunteers. Support. Care Cancer 14(6), Abstract 03–009 (2006).
Google Scholar
78 Garcia JM, Yan Y, Duus E, Friend J. Anamorelin’s effects on appendicular lean body mass in cancer patients with cachexia: results from a Phase II randomized, double blind, multicenter study. Ann. Oncol. 23(Suppl. 9), Abstract 1588P (2012).
Google Scholar
79 Takayama K, Katakami N, Yokoyama T et al. Anamorelin (ONO-7643) in Japanese patients with non-small cell lung cancer and cachexia: results of a randomized Phase II trial. Support. Care Cancer 24(8), 3495–3505 (2016).
MedlineGoogle Scholar
80 Kurihara M, Shimizu H, Tsuboi K et al. Development of quality of life questionnaire in Japan: quality of life assessment of cancer patients receiving chemotherapy. Psychooncology 8(4), 355–363 (1999).
Medline CASGoogle Scholar
81 Okuyama T, Wang XS, Akechi T et al. Japanese version of the MD Anderson Symptom Inventory: a validation study. J. Pain Symptom Manage. 26(6), 1093–1104 (2003).
MedlineGoogle Scholar
82 Currow D, Temel J, Fearon K, Friend J, Yan Y, Abernethy A. ROMANA 3: a safety extension study of anamorelin in advanced non-small cell lung cancer (NSCLC) patients with cachexia. Eur. J. Cancer 51(Suppl. 3), Abstract 1603 (2015).
Google Scholar
83 Currow D, Temel J, Abernethy A, Friend J, Giorgino R, Fearon KC. Pooled efficacy data from ROMANA 1 and ROMANA 2, two Phase III trials of anamorelin in advanced non-small cell lung cancer (NSCLC) patients with cachexia. Support. Care Cancer 24(Suppl. 1), Abstract PS006 (2016).
MedlineGoogle Scholar
84 Currow D, Temel J, Abernethy A, Friend J, Giorgino R, Fearon KC. Anamorelin in cachectic patients with non-small cell lung cancer (NSCLC) and acute phase protein reaction (APPR): pooled analysis of two Phase III trials (ROMANA 1 and ROMANA 2). Ann. Oncol. 27(Suppl. 6), Abstract 1446P (2016).
Google Scholar
85 Fearon K, Currow D, Temel J, Giorgino R, Friend J, Abernethy A. Body composition in non-small cell lung cancer (NSCLC) patients with cachexia and improved anorexia-cachexia symptoms: anamorelin Phase III trials pooled analysis. Clin. Nutr. 35(Suppl. 1), Abstract OR45 (2016).
Google Scholar
86 Jahn P, Currow D, Temel J et al. Effects of anamorelin on anorexia-cachexia in advanced non-small cell lung cancer patients: pooled analysis of two Phase III trials (ROMANA 1 and ROMANA 2). Eur. J. Oncol. Nurs. (Suppl.), Abstract (Ahead of print).
Google Scholar
87 Heppner KM, Tong J. Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions. Eur. J Endocrinol. 171(1), R21–R32 (2014).
Medline CASGoogle Scholar
88 Bai Y, Hu Y, Zhao Y et al. Anamorelin for cancer anorexia-cachexia syndrome: a systematic review and meta-analysis. Support. Care Cancer 25(5), 1651–1659 (2017).
MedlineGoogle Scholar
89 Hopkinson JB, Richardson A. A mixed-methods qualitative research study to develop a complex intervention for weight loss and anorexia in advanced cancer: the family approach to weight and eating. Palliat. Med. 29(2), 164–176 (2015).
MedlineGoogle Scholar

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Published online 16 June 2017

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Financial & competing interests disclosure

R Skipworth has received research funding from Novartis. D Currow has participated as an unpaid advisory board member for Helsinn. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Editorial support and medical writing assistance was provided by J Franklin, PhD, CMPP (TRM Oncology, The Hague, The Netherlands), funded by Helsinn Healthcare SA (Lugano, Switzerland). The authors are fully responsible for all content and editorial decisions for this manuscript.

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