Treating cancer patients with cancer anorexia-cachexia syndrome

Introduction

Cachexia is described as a wasting disorder associated with dramatic weight reduction due to the loss of skeletal muscle and body fat. The syndrome affects patients in the later stages of various diseases including congestive heart failure, HIV/AIDS, chronic obstructive pulmonary disease (COPD), kidney failure and importantly in cancer.

Cachexia is intimately associated with anorexia, which is a loss of appetite for food or desire to eat, with a defined reduction of at least five percent of body weight. The combination of cachexia and anorexia is referred to as cancer anorexia-cachexia syndrome (CACS).¹

Among hospitalised patients, cancer sufferers present with the highest prevalence of suboptimal dietary intake, with 30 to 50 percent found to be malnourished or at risk of malnutrition.^2,3 Cachexia reduces the quality of patients’ lives, compromises therapy and can hasten the end of life. The prevalence increases from 50 percent to more than 80 percent before death and in more than 20 percent of patients, cachexia is noted as the main cause of death.⁴

Despite its apparent prevalence, CACS remains under-recognised and under-treated in clinical settings, because definitions, diagnostic criteria, classification schemes and licensed therapies have not yet been fully established.^5,6 A patient’s nutritional state is usually evaluated with a combination of clinical assessment and anthropometric tests, such as body weight, skin fold thickness and mid-arm circumference, but most clinicians rely mainly on body weight as the major measure of nutritional status, often using usual adult weights as a potentially inappropriate reference.⁷

Pathophysiology

The causes of CACS are many and various, being broadly divided into those of peripheral or central origin.⁸ In addition to the disease process itself, treatments, particularly chemotherapy, can markedly contribute to the syndrome.

Peripheral causes may be due to the direct effects of tumours causing dysphagia or interference with gastrointestinal function, tumour-derived substances that reduce appetite (eg, lactate, tryptophan or parathormone-related peptide)⁹ and tumour-induced inflammation causing cytokine release. Proinflammatory cytokines such as tumour necrosis factor (TNFα), interleukin-1 (IL-1) and interleukin-6 (IL-6) are elevated in many cancers¹⁰ and cause sickness behaviour with fatigue, weakness, hyperalgesia and anorexia.¹¹ A related molecule, human growth differentiation factor 15 (GDF15) has also been implicated in cancer cachexia and serum levels of GDF15 correlate with body weight loss in patients with prostate cancer.³⁹

Chemotherapy commonly causes nausea and vomiting, abdominal cramps and ileus and altered taste perception. Alteration in taste and smell (dysgeusia), is also present in approximately 40 percent of chemotherapy patients.¹³

Central causes include cancer-related depression and pain with associated changes in central neurotransmitters; notably, the monoamines (5-hydroxytryptamine (5HT) and noradrenaline) and corticotrophin-releasing factor (CRF)¹² leading to anorexia.

Treatment

An obvious way to treat anorexia is to improve nutrition, although the evidence supporting the success of this seemingly straightforward approach is lacking.¹⁴ Nutritional care and therapy in cancer patients include dietary counselling by dieticians to improve food consumption, oral supplementation with nutritional supplements, enteral nutrition and parenteral nutrition.¹⁵ There is no one-size fits all solution and the success of the various approaches varies depending upon the type of cancer and its stage of progression.^16,17

Pharmacological approaches

To date there are no licensed medicines to treat CACS. However, there are medicines that are used off-license or are currently under clinical development for treating CACS. These therapies can be divided into four major groups dependant on their mode of action.¹⁸ These are; appetite stimulants, cytokine modulators, anabolic agents and combination therapies. The progestin megestrol acetate also stands alone outside of these currently, due to its unknown mode of action.

Appetite stimulants

Leptin and ghrelin are two hormones that have important but contradictory influences on energy balance.¹⁹ Leptin mediates regulation of energy balance, suppressing food intake and inducing weight loss whilst ghrelin is a fast-acting hormone that controls meal initiation. It is therefore unsurprising that ghrelin-like compounds have been investigated as a potential benefit in CACS therapy.

Anamorelin is an orally available, selective ghrelin receptor agonist. Meta-analysis showed a consistent positive effect of anamorelin on lean body mass and quality of life among cancer patients, although there was no effect on survival.^20,21 However, in a number of studies, there was an increased frequency of nausea, hyperglycaemia, skin rash, first degree atrioventricular block and increased liver enzymes.²²

Cannabinoids have been used as an appetite stimulant for many centuries, but reliable data concerning potential benefits of individual cannabinoids are still lacking. One study reported the effects of Cannabis sativa and its components, including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with placebo, in patients with advanced cancer and greater than five percent weight loss. However, there were no significant differences between groups with respect to appetite, body weight or quality of life.²³ Similarly, a study with nabilone, a synthetic analogue of the major cannabis component Δ-9 THC, showed no benefit in a lung cancer cohort.²⁴ A recent small pilot study of controlled-release cannabis capsules in advanced cancer patients demonstrated a body weight increase of more than 10 percent, without significant side effects in 17 percent of patients who were able to complete the trial.²⁵ In non-cancer settings, the synthetic cannabinoid Dronabinol has been shown to cause significant weight in both HIV-positive patients,⁴² and young anorexic women.⁴³

Synthetic cannabinoids also hold promise in CACS therapy. ART27.13 (Artelo Biosciences), a peripherally selective, high-affinity, full agonist of CB₁ and CB₂ receptors, has been demonstrated in a Phase I multiple ascending dose study, to increase body weight. There is a well-known link between peripheral CB₁ receptor activation and appetite, food storage and weight gain and given the role of proinflammatory cytokines in CACS, ART27.13’s attenuation of immune function through CB₂ activation might well play a part in its anti-anorectic action. A further advantage of this synthetic, peripherally-restricted agent is its lack of any psychoactivity, which is an unwanted side effect of many less selective cannabinoids.

More extensive trials, evaluating the synthetic cannabinoids and the individual components of Cannabis sativa and other modulators of the endocannabinoid signalling system are clearly needed.

Melatonin has been reported to produce increased appetite in advanced lung or gastrointestinal (GI) cancer patients although there were no significant effects on body weight or other end points.²⁶

Cytokine modulators

Trials in various cancers have been conducted with etanercept (a fusion protein TNFα inhibitor), infliximab (an anti-TNFα monoclonal antibody), pentoxifylline and thalidomide (small molecule TNFα inhibitors), but none have shown significant positive effects on any clinical endpoints related to CACS and unwanted side effects are relatively common.^27-31 GDF15-induced weight loss is mediated by a glial cell line-derived neurotrophic factor (GDNF) family receptor-α-like (GFRAL)-RET proto-oncogene (RET) signalling complex in brainstem neurons. Studies in mice have indicated that antibody-mediated inhibition of GDF15-GFRAL can reverse cancer cachexia.⁴⁰ Pfizer’s Ponsegromab (PF-06946860) is a GDF15 inhibitor currently in Phase II trials to assess efficacy in cancer cachexia and anorexia.⁴¹

Anabolic agents

Insulin has been studied, largely on the basis of its anti-lipolytic effects, in advanced GI cancer patients suffering from CACS.³² There were no effects on appetite, body weight or quality of life, although, interestingly, there was some improvement in survival in the insulin-treated group.  

Enobosarm (also known as ostarine or MK-2866) is a selective androgen receptor modulator (SARM) developed for the treatment of osteoporosis and muscle wasting, although it is also employed (illegally) as a performance-enhancing drug by some athletes. In a trial of advanced cancer patients with CACS, enobosarm increased lean body mass by 1-1.5kg compared with placebo with some improvement in physical activity measures.³³

Megestrol acetate (MA) is a progestin (synthetic progesterone) originally developed for birth control, but also used to treat breast cancer and endometrial cancer. It was approved by the US Food and Drug Administration (FDA) in 1993 for patients with a diagnosis of acquired immunodeficiency syndrome, although its mechanism is unknown. Meta-analysis³⁴ showed that MA stimulated an overall average increase of 2.5kg in body weight in CACS patients, although quality of life was not improved.

Combination therapies

Given the, at best, equivocal benefits of individual pharmacological agents, it is not surprising that there have been a number of attempts to combine compounds in CACS patients. Among these trials, some increased body weight was seen due to a combination of MA, the non-steroidal anti-inflammatory agent meloxicam and the omega-3 fatty acid eicosapentaenoic acid (EPA).³⁵ In another rather complex trial³⁶ which studied various combinations of MA, EPA, L-carnitine and thalidomide, there were some benefits to CACS patients in relation to body weight, resting energy expenditure, appetite and fatigue, although the differences in doses and time intervals make between-group comparisons difficult.

Conclusions

CACS is a difficult syndrome that exacerbates the consequences of many cancers and the heterogeneous nature of the different disease types makes it unsurprising that treatments reversing the muscle and adipose wasting have been challenging to develop. Given the lack of currently licensed therapies in this active field of research, the future of treatment may lie with drugs in development offering a mechanistic approach, such as the benzimidazole derivative ART27.13 and the GDF15 inhibitor Ponsegromab. Additionally, consistency regarding diagnostic criteria is essential within the clinical speciality to be able to effectively compare treatment options and their measured outcomes. In addition to the approaches listed above, there are also some clues from pre-clinical studies that novel or repurposed therapies might be effective. For example, antimyostatin peptides³⁷ have produced significant benefits in mouse models of CACS and the positive effects of beta-adrenergic blockers in cardiac cachexia patients might indicate some potential value in CACS. Equally important will be the necessity of optimising clinical trials with the staging of patients in relation to the severity of their disease, types of anticancer interventional treatment and combining various pharmacological approaches with targeted nutritional and exercise protocols.

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