85 Review Article Prokinetics and ghrelin for the management of cancer cachexia syndrome Jimi S. Malik, Sriram Yennurajalingam Department of Palliative Care, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Contributions: (I) Conception and design: All authors; (II) Administrative support: S Yennurajalingam; (III) Provision of study materials or patients: S Yennurajalingam; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Sriram Yennurajalingam, MD. Department of Palliative Care, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1414, Houston, TX 77030, USA. Email: [email protected]. Abstract: Cancer cachexia (CC) is one of the most distressing syndromes for both patients and their families. CC can have an impact on patient reported quality of life and overall survival. It is often associated with symptoms such as fatigue, depressed mood, early satiety, and anorexia. Prokinetic agents have been found to improve chronic nausea and early satiety associated with CC. Among the prokinetic agents, metoclopramide is one of the best studied medications. The role of the other prokinetic agents, such as domperidone, erythromycin, haloperidol, levosulpiride, tegaserod, cisapride, mosapride, renzapride, and prucalopride is unclear for use in cachectic cancer patients due to their side effect profile and limited efficacy studies in cancer patients. There has been an increased interest in the use of ghrelin-receptor agonists for the treatment of CC. Anamorelin HCl is a highly selective, novel ghrelin receptor agonist. A meta-analysis was conducted of the recent randomized trials using anamorelin (daily dose of 50 and 100 mg daily). Results show that both total body weight and lean body mass were significantly increased from baseline in the anamorelin group. Anamorelin did not improve overall survival or hand grip strength, and there were no significant differences between groups for frequency or severity of any adverse events. In this review, the authors discuss the available evidence for the use of prokinetics such as metoclopramide and ghrelin receptor agonists for the treatment of CC. Keywords: Cancer; cachexia; ghrelin receptor agonists; anamorelin; metoclopramide Submitted Jul 14, 2018. Accepted for publication Oct 02, 2018. doi: 10.21037/apm.2018.11.01 View this article at: http://dx.doi.org/10.21037/apm.2018.11.01 Introduction associated with serious debility in patients with advanced cancer (1). Moreover, it is also associated with a reduction Cancer cachexia (CC) is a “multifactorial syndrome in physical function, tolerance to anticancer therapy, and defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by survival (2,3). The field of cachexia management has seen conventional nutritional support and leads to progressive rapid growth since the definition of cachexia in 2011; functional impairment” (1). CC is often associated with however, there is limited published data on the management symptoms such as fatigue, depressed mood, early satiety, of debilitating symptoms associated with CC, especially and anorexia. Pathophysiology of CC is characterized early satiety and anorexia (4-6). In this review, the authors by a negative protein and energy balance driven by a discuss the available evidence for the use of the prokinetic variable combination of reduced food intake and abnormal metoclopramide and ghrelin receptor agonists for the metabolism (1). CC is a frequent syndrome, and it is treatment of CC. © Annals of Palliative Medicine. All rights reserved. apm.amegroups.com Ann Palliat Med 2019;8(1):80-85 Annals of Palliative Medicine, Vol 8, No 1 January 2019 81 Prokinetics metoclopramide with other prokinetic agents for the treatment of nausea, anorexia, or early satiety. Additionally, CC is associated with secondary symptoms such as anorexia, the association of improved motility and symptom relief early satiety, and chronic nausea (7,8). Often, management with prokinetics is poor in functional bowel syndrome of the secondary cachexia symptoms will significantly benefit and non-existent in cancer. Therefore, further research is these types of patients (9,10). In regards to anorexia and needed. early satiety, both autonomic dysfunction and gastroparesis can contribute to a worsening of symptoms (11,12). While medications such as opioids can induce chronic constipation Ghrelin and ghrelin receptor agonists leading to nausea (12), prokinetic agents have been found to Ghrelin is a natural ligand of the growth hormone (GH) improve chronic nausea and early satiety related to cachexia secretagogue receptor (17). It is produced primarily in the (13,14). Among the prokinetic agents, metoclopramide is stomach (oxyntic mucosa) and its levels increase during a well-studied dopamine receptor antagonist (7,10,15) that anorexia, fasting or starvation (18). Ghrelin stimulates acts centrally as well as peripherally as an antiemetic and appetite and regulates energy balance by down-regulating also has gastric emptying properties (10,16). This medication thermogenesis (19-22). It modulates pro-inflammatory can help treat issues such as autonomic dysfunction related cytokine synthesis, including IL-6 and TNF-α, by to advanced cancer and impaired gastric emptying due to downregulating leptin-induced expression of the cytokines, opioids (10). In patients with chronic nausea and dyspepsia and expression of cytokines by monocytes and T cells (23). from advanced cancer, the use of metoclopramide can result Ghrelin promotes growth of adipose tissue by activation of in the improvement of nausea, vomiting, and bloating (10). lipogenic pathways and can influence regulation of skeletal Side effects that can be dose-limiting include extrapyramidal muscle mass (24) by stimulation of insulin-like growth symptoms such as akathisia (restlessness and motor agitation) factor 1 (IGF-1) production. and tremor. These side effects are more severe when co- Because of its unique properties, recent research has administered in combination with neuroleptics such as focused to evaluate how ghrelin can influence inflammatory haloperidol (15). Of note, metoclopramide can contribute and metabolic pathways by its effects on the GH receptor, to prolonging the QTc interval, and in the case of complete and lead to both improvement of muscle mass and reduction bowel obstruction, the drug is contraindicated. Table 1 in the rate of muscle atrophy in CC (24). While the data is shows the mechanism of actions, the starting dose, and the promising to support the therapeutic use of ghrelin in CC, side effects of metoclopramide and other commonly used drawbacks of the treatment that limit clinical use include a prokinetic agents. short half-life and the need for parenteral administration. There are limited studies that evaluate the efficacy These limitations of ghrelin led to the investigation of of metoclopramide for the treatment of CC symptoms. an orally-available ghrelin agonist for the treatment of Metoclopramide was found to be superior to placebo in CC; ONO-7643, or anamorelin, is one such promising two of three small controlled studies. In a double-blind, treatment. crossover study lasting four days, Bruera et al. compared controlled-release metoclopramide with placebo for the Anamorelin chronic nausea and dyspepsia in patients with advanced cancer. The results of this preliminary study were suggestive Anamorelin HCl is an orally active ghrelin receptor that metoclopramide may reduce nausea in advanced agonist being investigated as part of the treatment cancer patients (10). In another trial comparing extended for CC. Two early phase studies were conducted to release to immediate release metoclopramide for cancer- evaluate the safety and efficacy profile of anamorelin. related nausea in thirty-four advanced cancer patients, the A phase 1 study by Kumor et al. found oral anamorelin same investigators found improvement in nausea with both (25 and 50 mg daily) to be associated with a significant extended release metoclopramide and immediate release increase in appetite and food intake (25). In a separate metoclopramide, though the extended release was slightly phase 1 study, a significant change in body weight better when nausea was assessed using a visual analogue was noted with the use of oral anamorelin (26). scale (13). At present, there are no comparative effectiveness The drug was well-tolerated with no dose-limiting adverse studies in advanced cancer patients with CC comparing effects. © Annals of Palliative Medicine. All rights reserved. apm.amegroups.com Ann Palliat Med 2019;8(1):80-85 82 Malik and Yennurajalingam. CC management with prokinetics and ghrelin Table 1 Prokinetic agents, their starting doses Prokinetics Starting dose, and routes of use Side-effects and comments Metoclopramide First-line agent. Mechanism 5–10 mg orally, tablet, liquid Common side effects include fatigue, anxiety, and of action: dopamine 2 or intravenous preparation; depressed mood. Restlessness, hyperprolactinemia, antagonist, 5HT4 and weak Recommended to use 15 minutes prior QT- interval prolongation, extrapyramidal symptoms such 5HT3 receptor antagonist. to meals and bedtime. Short term use, dystonia and tardive dyskinesia have frequently been Gastric