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Why hormones matter in Cancer Cachexia: the Endocrinologist's perspective

Background

Over 1,500,000 new diagnoses of cancer are made in the U.S. every year1 and in the vast majority of these patients,  this condition will have a devastating impact in the individuals’ quality of life (QoL) and ultimately in their survival. Cancer Cachexia is a multifactorial syndrome that affects up to 80% of cancer patients depending on the tumor type2 and it is characterized by a decrease in appetite, severe body weight, fat and muscle loss due to an underlying illness3. Typically, it is associated with increased catabolism and it cannot be reversed by mere nutritional support. Losses of adipose tissue and muscle and lean body mass in patients with cancer are strongly associated with mortality2,4, and they may be the direct cause of death in some patients5. Recently, a decrease in muscle mass has been associated with poor response to therapy and increased toxicity from chemotherapy6. Cancer Cachexia is commonly caused by the cancer itself and worsened by the drugs used for its treatment. Regardless of the specific etiology, Cancer Cachexia extracts a heavy toll psychologically and physically on the cancer patient.

Despite the significant burden that cachexia represents to cancer patients, this condition often remains undiagnosed and untreated. To date, no drug has been approved by regulatory agencies in the U.S. for the treatment of Cancer Cachexia. Moreover, off-label treatments used for cancer-related cachexia such as appetite stimulants (i.e. megestrol acetate) are largely ineffective, increasing only fat mass, and are associated with potentially serious side effects (i.e. adrenal insufficiency, hypogonadism, deep venous thrombosis, etc).

Several hormonal axes are known to play a key role in the regulation of food intake, body weight, adipose tissue metabolism and muscle mass and function. Also, several hormones have been reported to be altered in the setting of Cancer Cachexia. Here we will review some of these alterations, their clinical implications and the potential therapeutic role of hormonal manipulations in this setting.

Growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis alterations in Cancer Cachexia

Cancer Cachexia  is usually associated with high levels of GH but low levels of IGF-17,8 and, hence, it has been postulated to represent a "GH resistant" state. These changes have been described in patients with Cancer Cachexia due to different tumor types and when compared to cancer patients without cachexia and to patients without cancer matched by age and BMI. Moreover, this "GH resistance" is not unique to Cancer Cachexia and it has also been described in other acute or chronic diseases.

The clinical relevance of this decrease in IGF-1 levels has not been well established in Cancer Cachexia but given that IGF-1 is a potent stimulus of muscle growth, it is possible that these changes contribute to the decrease in muscle mass and strength seen in this setting. Whether this "resistance" can be overcome by exogenous administration of GH is not known. On the other hand, stimulation of the GH/IGF-1 axis carries the theoretical concern of tumor growth with GH or IGF-1 administration. Growth hormone administration is contraindicated in individuals with active cancer and blocking the IGF-1 receptor is being tested as a therapeutic strategy for small cell lung cancer9. Individuals with GH excess or acromegaly have an increased risk of developing colonic polyps10. Because of this theoretical concern, the hypothesis that GH administration can increase anabolism and prevent wasting has only been tested preliminarily. Tayek et al. administered GH to a small cohort of individuals with active cancer and found that GH treatment increased IGF-1 levels and reversed the negative nitrogen balance, although this was only present in those patients without preexisting severe malnutrition. Given that this was an acute study, tumor progression was not assessed11. Activation of the GH/IGF-1 axis can also be achieved by administering GH secretagogues. This is discussed separately below.

Gonadal axis alterations in Cancer Cachexia

There is a high prevalence of hypogonadism in men with Cancer Cachexia with estimations ranging between 70-90%12-15. This condition is also very prevalent in male cancer survivors in remission, including those treated for childhood cancer, suggesting that these changes are permanent16,17. The etiology of hypogonadism in this setting is likely to be multifactorial in most patients with Cancer Cachexia. For instance, it is well-known that opioids are potent suppressors of LH and FSH secretion in the pituitary18 and morphine equivalent daily dose is inversely correlated with serum testosterone levels in patients with advanced cancer15. Aging per se is associated with lower testosterone levels, although the prevalence of hypogonadism is higher in Cancer Cachexia patients even when compared to age-matched, non-cancer controls12. Also, decreased caloric intake and malnutrition also suppress LH and FSH production probably through a decrease in leptin. Chemotherapy, surgery or radiation to the pelvic area or the gonads can also contribute to a decrease in testosterone levels. Brain irradiation is also linked to hypopituitarism and central hypogonadism.

This decrease in testosterone levels in the setting of patients with Cancer Cachexia is also associated with decreased muscle mass, fatigue, sexual dysfunction and mood alterations13. This phenotype is also seen in men without cancer suffering from hypogonadism and, more importantly, is responsive to testosterone replacement therapy19. However, Cancer Cachexia patients are often not evaluated for hypogonadism and even those that are, may not be offered treatment. Testosterone circulates in men either tightly bound to a hepatic protein known as sex hormone binding globulin (SHBG,~60%), free (~2%), loosely bound to albumin (~38%). The fraction of testosterone that is free or bound to albumin is readily available to bind to the androgen receptor in target tissues and is referred to as "bioavailable testosterone", whereas the fraction of testosterone bound to SHBG remains bound, and is not available to bind to the receptor. Given that SHBG is increased in Cancer Cachexia13,14, this is potentially a significant confounder in this setting and bioavailable testosterone measured by either tandem mass spectrometry/liquid chromatography or by ammonia sulfate precipitation or calculated using the Vermeulen formula20 should be assessed early morning on two separate occasions to establish the diagnosis of hypogonadism21.

Although the relative contribution of hypogonadism to Cancer Cachexia in women is not known, it is likely to be smaller than in men and this may be the cause for a gender dimorphism in this setting22. Chemotherapeutic agents and radiation therapy to the pelvic area may lead to a decrease in estradiol levels and infertility in premenopausal women. As mentioned before opioids and malnutrition are also likely to contribute to hypogonadism in woman with Cancer Cachexia.

With regards to the therapeutic potential of androgens in the setting of Cancer Cachexia, a small pilot study suggested that testosterone replacement therapy may improve fatigue and sexual function scores and performance status in men with fatigue, hypogonadism and advanced cancer23. However, a large randomized placebo controlled trial will be needed to establish the efficacy and safety of this approach.

Selective androgen receptor modulators (SARMS) are also in development for the treatment of Cancer Cachexia. They offer the advantage of being orally available agonists of the androgen receptor that, compared with testosterone, have more potent anabolic effects in muscle and less potent effects on the prostate and other tissues (i.e. hair follicle and skin). Enobosarm, one of these agents, shows positive results on a phase II study in patients with Cancer Cachexia24 showing increases in fat free mass and muscle power. However, two recently completed phase III studies in men and women with advanced non-small cell lung cancer failed to confirm these findings. These two trials (named POWER1 and 2), did not meet the overall criteria for the co-primary responder endpoints of lean body mass and physical function as agreed on with the US FDA; the responder endpoints showed mixed results (for POWER1 and POWER2, p values at Day 84 for fat free mass were 0.036 and 0.113, respectively; p values at Day 84 for stair climbing power were 0.315 and 0.289, respectively).

Hypothalamic-pituitary – adrenal (HPA) alterations in Cancer Cachexia

Latrogenic alterations of the HPA axis are commonly seen cancer patients. Patients often receive high doses of steroids in pulses along with chemotherapy or continuously for brain metastases. Also, the progestational agent megestrol acetate, often used off-label for the treatment of anorexia, in spite of only having been shown to increase appetite and fat mass without affecting muscle mass or quality of life, is known to induce adrenal insufficiency in the setting of cancer cachexia 25,26.

In patients with advanced cancer, elevated random cortisol levels were associated with pain and opioid use, although abnormally low levels of cortisol were found to be infrequent. Patients on higher opioid therapy (MEDD >30) had increased cortisol levels, and male patients had lower testosterone levels27.

Animal data also suggest a role for glucocorticoids in cachexia as in mice lacking glucocorticoid receptor expression in skeletal muscle, chemotherapy-induced muscle atrophy was shown to be blocked. This suggests that cytotoxic chemotherapy causes muscle wasting at least in part through the production of endogenous glucocorticoids and that glucocorticoid therapy, often given with chemotherapy, may play a role in exacerbating muscle wasting28.

Insulin resistance in Cancer Cachexia

Insulin resistance has been reported in cancer patients 29,30; however, this may not be linked to cachexia per se. For instance, insulin resistance was increased in men with cancer but without cachexia but not in age- and gender-matched patients with Cancer Cachexia when both groups were compared to non-cancer controls. The authors postulated that the cancer-associated insulin resistance can be at least partially reversed by the weight loss and decreased food intake seen in Cancer Cachexia, although additional studies are needed to prove this hypothesis8.

In subjects with diabetes, the development of cancer and Cancer Cachexia may alter the goals of treatment as well as the regimen use for diabetes management. Dietary restrictions are usually lifted and a certain level of hyperglycemia may be tolerated, especially in patients with short life expectancy or frequent hypoglycemia. Also, the increase in insulin resistance mentioned above can be exacerbated by the administration of glucocorticoids as these usually worsen hyperglycemia. Frequent glucose monitoring is recommended because adjustments in medication doses may be needed. Changes in body weight, steroid doses, food intake or other intercurrent illnesses may make glucose control erratic and precipitate hypoglycemic events or severe hyperglycemia. Especially for patients receiving insulin, a consultation with an endocrinologist should be considered.

Ghrelin, and GHSR-1a agonists in Cancer Cachexia

Ghrelin is a hormone that is primarily secreted from the stomach. In 1999, it was discovered to be the endogenous ligand for the -until then orphan- growth hormone secretagogue receptor 1-a (GHSR-1a)31,32. This receptor had been identified in 199633 but agonists of this receptor had been in development since 198134. Ghrelin, through activation of the GHSR1a receptor, causes an increase in appetite and food intake as well as a decrease in energy expenditure in humans and rodents. It also induces a rapid increase in circulating GH levels. Notably this receptor is not present in liver, adipose tissue or skeletal muscle35. Although ghrelin binds to the GHSR1a and signals through this receptor to exert many of its endocrine effects, including the release of GH, mounting evidence suggest that there is an alternative ghrelin receptor. Ghrelin has a number of actions in cell types that do not express the GHSR1a, and these effects must be mediated through the hypothesized alternative receptor36,37.

The appetite-enhancing and anabolic effects of ghrelin in healthy volunteers made it a potential therapeutic option in various catabolic states including Cancer Cachexia. Ghrelin was shown in two pilot studies to increase appetite and food intake and to be well-tolerated after a single dose administration38,39. In a different study daily administration of ghrelin for 8 weeks improved appetite scores and decreased loss of adiposity without affecting tumor progression40. Hiura et al. recently showed that ghrelin infused twice daily increases food intake, and appetite and decreased nausea in a group of esophageal cancer patients treated with cisplatin-based neoadjuvant chemotherapy. Also, ghrelin treatment led to less toxicity from chemotherapy (as assessed by need to have dose modification) and reduced length of hospital stay41.

Although early results using ghrelin for Cancer Cachexia treatment were encouraging, the fact that it is a peptide with a short half life, and so has to be given parenterally, has moved investigators to develop agonists of the GHSR1a receptor (also known as GH secretagogues [GHS]) that can be given orally and have a longer half-life that would allow for daily administration. GHS also have been evaluated in the setting of Cancer Cachexia. In a multi centre phase II study, patients with Cancer Cachexia gained approximately 1 Kg of weight when treated with the oral GHS anamorelin 50 mg once daily vs. placebo for 3 days. Patient-reported quality of life (QOL) scores were also significantly improved by anamorelin42. In an unpublished phase II study of patients with advanced NSCLC, anamorelin given for 3 months increased body weight, fat-free mass, grip strength and QOL compared with placebo. Phase III studies have recently been completed and results are expected soon.

Safety of Ghrelin and GHS in the Setting of Cancer. A potential concern regarding use of ghrelin in cancer patients is that ghrelin may cause tumor progression via its GH/IGF-1 stimulatory effect or through other unidentified mechanisms as discussed above (see section on GH/IGF1). Although in-vitro experiments have given conflicting results showing an increase or a decrease in cell proliferation with ghrelin43-44, whole-animal models and human studies where ghrelin or GHS have been used, have not shown an increase in tumor proliferation, although none of these animal models have reported survival and all human studies were not designed or adequately powered to address this question45-48. Larger clinical trials with extended follow-up to determine long-term safety will be needed to establish safety of ghrelin or GHS in this setting.

Conclusion

Several hormonal abnormalities have been reported in the setting of Cancer Cachexia and are likely to contribute to the progression of the syndrome. Given that there is an urgent need for new and effective therapies for the prevention and treatment of the Cancer Cachexia, this may represent an opportunity for increasing our understanding of the syndrome and thus our ability to help patients suffering from Cancer Cachexia.

Jose M. Garcia
Assistant Professor, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College

References

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