Current therapeutic options for cachexia

[madman]

Pharmacotherapy in Cachexia: A Review of Endocrine Abnormalities and Steroid Pharmacotherapy (2022)
Magdalena Celichowska, Miłosz Miedziaszczyk & Katarzyna Lacka


ABSTRACT

Cachexia is a state of increased metabolism associated with high morbidity and mortality. Dysregulation of cytokines and hormone activity causes reduced protein synthesis and excessive protein breakdown. Various treatments are available, depending on the primary disease and the patient’s state. Besides pharmacological treatment, crucial is nutritional support as well as increasing physical activity. The main purpose of pharmacological treatment is to diminish inflammation, improve appetite and decrease muscle wasting. Therefore a lot of medications aim at proinflammatory cytokines such as Interferon-α or Tumor Necrosis Factor-β, but because of the complicated mechanism of cachexia, the range of targets is very wide. in cachexia treatment, the use of corticosteroids is common, which improve appetite, diminish inflammation, inhibit prostaglandin metabolism, Interleukin-1 activity. They can also decrease protein synthesis and increase protein degradation, which can be prevented by resveratrol. Estrogen analogs, progesterone analogs, testosterone analogs, Selective Androgen Receptor Modulators (SARM), Angiotensin-Converting-Enzyme Inhibitors (ACEI), Nonsteroidal anti-inflammatory drugs (NSAIDs), thalidomide, melatonin, Growth Hormone Releasing Peptide-2 (GHRP-2) may play important role in wasting syndrome treatment as well. However, for the usage of some of them, evidence-based recommendations are not available. This review highlights current therapeutic options for cachexia with a specific focus on steroid therapy.




Introduction

Cachexia, also known as wasting syndrome is a state of increased metabolism, which cannot be compensated by daily caloric intake in the setting of ongoing disease. It manifests with increased muscle mass loss (with or without loss of body fat) and usually fatigue, lack of appetite, apathy, weakness, sleep disturbances, depression, anemia, and early satiety. Furthermore noticed should be problems with food intake from xerostomia stomatitis or inflammatory condition in the oral cavity, pain, nausea, emesis, diarrhea, and depression. Cachexia is very often underestimated as a potential cause of death and also is hard to treat. Proper management of patients with cachexia is crucial to achieving therapeutic success. With the increasing age of society as well as the increasing number of patients with cancer, the incidence of cachexia may also increase (1–4).

*The aim of this review is to summarize current data on the pathophysiology and treatment of cachexia, especially about the endocrinological aspect of that state and steroid therapy. This review will also highlight pharmacologic therapeutic strategies which could be helpful in managing wasting syndromes and also those which need further study. Although nutritional interventions are also important in the management of cachexia, these strategies are outside of the scope of this review.




Pathophysiology of cachexia

There are various conditions, which lead to cachexia, but the most common ones are cancer, AIDS, chronic heart failure (CHF), rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), chronic kidney disease, liver cirrhosis, cystic fibrosis, Crohn’s disease, stroke, degenerative neurological disorders, sepsis, states after spinal cord injuries, malaria or tuberculosis (5).




Pharmacological treatment

Treatment

*Non-steroid pharmacological treatment

*Steroid therapy
Adrenocortical corticosteroids
Progesterone analogs
Testosterone analogs
Estrogens analogs


Non-pharmacological therapy




Conclusion

The range of drugs used in the treatment of cachexia has grown significantly in recent years. The knowledge of the treatment of cachexia is essential for the therapy of patients, which should be selected individually. Dexamethasone and megestrol acetate are the most commonly used steroids for wasting syndromes, and current guidelines support their use in patients with cancer cachexia. Other steroid and non-steroid medications may be used in appropriate patients; however, further studies are needed to recommend their use in cancer cachexia (Table 4).

 

[madman]

Figure 1. Endocrine changes in cachectic patients (4–6,12–17). AgRP - orexigenic peptide associated with agouti; NPY - neuropeptide Y; POMC - pro-opiomelanocortin peptide; alpha-MSH - melanocyte-stimulating hormone; MC4R - melanocortin 4 receptors; CRF - corticotropin-releasing factor; GH - growth hormone; IGF-1 - insulin growth hormone 1.]

 

[madman]

Table 1. Cachexia underlying conditions and their pathophysiologic elements (5–9,18–24).

 

[madman]

Table 2. Stages of wasting syndrome (3,4,6).

 

[Nelson Vergel]

Dexamethasone and megestrol acetate are the most commonly used steroids for wasting syndromes, and current guidelines support their use in patients with cancer cachexia.

The worst thing to give anyone. Both increase fat mass (not lean body mass, which is what keep you alive), decrease bone density, cause ED, and many other problems.

Megestrol is a progesterone based product used in the treatment of advanced cancer of the breast and endometrium. When given in relatively high doses, Megestrol can substantially increase appetite in most individuals, even those with advanced cancer. It is also used to boost appetite in individuals with other cancers or HIV/AIDS.

Megace is the worst drug to use for weight gain. It increases mostly fat mass, hyperglycemia, risks of blood clots and joint bone death.

Here is a chapter of my book "Built to Survive" about the Megace:

Megace The Wrong Drug

By James Brockman (Reprinted with permission)

One of the most commonly used drugs for treatment of AIDS-related weight loss is megestrol acetate, which is sold as the brand name Megace by Bristol-Myers Squibb. Megace is a synthetic drug categorized as a gestagen, which is a class of drugs that mimic the actions of the naturally occurring female hormone progesterone. Originally the drug was developed to be an injectable contraceptive for women, but the drug has now found a role as a chemotherapeutic agent in the treatment of several cancers in women and men, such as cancers of the breast, uterus, and prostate. Two commonly observed side effects of Megace, increased appetite and weight gain, prompted its current use for AIDS-wasting.

The effects of progesterone and other gestagens, like Megace, on appetite and energy metabolism, are well known. Gestagens induce increased food intake by direct stimulation of the appetite centers in the brain. They also improve the efficiency of food energy used to produce new tissue; this effect of gestagens on increasing weight is seen even when gestagen-induced increase in food intake is prevented by restricting calories to maintenance levels.10 So much for the good points.


What Kind Of Weight Gain?

The problem with the weight gained from Megace is that it is primarily fat and water weight, with little lean tissue increase. , Through interactions with mineral corticoid receptors in the kidneys, specific metabolites of Megace promote retention of water. In addition some studies have shown that Megace increases the number of fat cells as well as their size. This is exactly what someone who is wasting or have lipodystrophy doesn't want. We should be clear that the focus of just putting weight on HIV(+) individuals is inappropriate. Studies are conclusive that survival is correlated with lean body mass, not total weight or fat weight. So if you want to be fat and hungry, take Megace, but do not expect to gain much muscle or live any longer.

Many Side Effects

Megace has almost too many side effects to list. For both men and women the most commonly observed side effect is loss of libido. When Megace was used as a female contraceptive, it worked too well. All the women lost their fertility, but they lost their normal sex drive too! Megace interacts with the progesterone receptors in the hypothalamus to inhibit gonadotropin release in both sexes. Gonadotropins stimulate testosterone production, and testosterone is necessary for a healthy sex drive in both men and women. The end-result of lower gonadotropins in men is not only lower testosterone production, and lower libido, but also testicular atrophy. In other words, the testicles shrivel up. Finally, low plasma testosterone levels are bad for HIV(+) men and women because they are associated with a weakened immune system and the loss of muscle tissue.


Because Megace and/or its metabolites have glucocorticoid activity, 9 Megace is also potentially immunosuppressive. Glucocorticoids are well known to inhibit proliferation of white blood cells including T cells, and weaken the body's response to infection, as well as slowing the healing process. Furthermore, a glucocorticoid responsive element has been identified in the RNA of the HIV virus, so it is possible that Megace could have a direct effect on stimulating viral replication. Other side effects related to the cortisol-like activity of Megace are glucose intolerance, full-blown diabetes, and suppression of the hypo-thalamic-pituitary-adrenal (HPA) axis.9 Resist-ance to cortisol is common in HIV, and with-drawal from Megace therapy could result in a dangerous state of adrenal deficiency. These conditions are associated with the later stages of HIV in cytokine-related wasting, so it makes little sense to use a drug that has the potential to make the complications of HIV infection even worse. Other problems seen with Megace include thrombosis (blood clots), carpal tunnel syndrome, and peripheral neuropathy.

Conclusions

When it comes to gaining muscle to rebuild a body weakened by AIDS, Megace cannot begin to stack up to anabolic steroids. While some people assert that Megace has a role as an appetite stimulant, there are other substances, like Marinol, that work with far fewer side effects. If your doctor is not yet aware of the benefits of Marinol and anabolic steroids and the problems associated with Megace, work to educate them, and be sure to ask questions if they tell you they would like to prescribe Megace for you. After all, your choice of therapies is up to you.

https://www.thebody.com/article/megace-gain-weight

 

[madman]

Table 3. Division of adrenocortical corticosteroids depending on their biological activity.

 

[madman]

Table 4. The methods of cachexia treatment (project prepared by authors).

 

[Nelson Vergel]

"The goal of a supplemental intervention is ultimately to improve quality of life, performance status, and chance of survival of the patient beyond that which is achieved with standard of care chemotherapy alone. Concomitant treatment of oral amino acids and testosterone may be a viable therapeutic option for fighting cachexia and improving body composition and quality of life during chemotherapeutic treatment of recurrent cervical cancer. In the case study we present here, we utilized a combination therapy approach of oral whey protein plus testosterone to improve muscle mass and quality of life during chemotherapy in a patient with recurrent cervical cancer. Clearly, a larger cohort is needed to determine whether such supplemental treatment approaches are efficacious over the long-term in improving body composition, physical function, quality of life, and cancer survival of cachectic patients when compared to standard of care alone. "

Cancer cachexia and anabolic interventions: a case report - PMC

Standard-of-care (SOC) cancer treatments are primarily aimed at reducing size and progression of a tumor. There is a need for successful supplemental anabolic therapies to combat cancer cachexia in addition to these SOC treatment modalities. ...

www.ncbi.nlm.nih.gov

 

[Nelson Vergel]

Oral Anabolic Steroid Effective for Cancer Cachexia : Oncology Times

An abstract is unavailable.

journals.lww.com

 

[madman]

The worst thing to give anyone. Both increase fat mass (not lean body mass, which is what keep you alive), decrease bone density, cause ED, and many other problems.

Megestrol is a progesterone based product used in the treatment of advanced cancer of the breast and endometrium. When given in relatively high doses, Megestrol can substantially increase appetite in most individuals, even those with advanced cancer. It is also used to boost appetite in individuals with other cancers or HIV/AIDS.

Megace is the worst drug to use for weight gain. It increases mostly fat mass, hyperglycemia, risks of blood clots and joint bone death.

Here is a chapter of my book "Built to Survive" about the Megace:

Megace The Wrong Drug

By James Brockman (Reprinted with permission)

One of the most commonly used drugs for treatment of AIDS-related weight loss is megestrol acetate, which is sold as the brand name Megace by Bristol-Myers Squibb. Megace is a synthetic drug categorized as a gestagen, which is a class of drugs that mimic the actions of the naturally occurring female hormone progesterone. Originally the drug was developed to be an injectable contraceptive for women, but the drug has now found a role as a chemotherapeutic agent in the treatment of several cancers in women and men, such as cancers of the breast, uterus, and prostate. Two commonly observed side effects of Megace, increased appetite and weight gain, prompted its current use for AIDS-wasting.

The effects of progesterone and other gestagens, like Megace, on appetite and energy metabolism, are well known. Gestagens induce increased food intake by direct stimulation of the appetite centers in the brain. They also improve the efficiency of food energy used to produce new tissue; this effect of gestagens on increasing weight is seen even when gestagen-induced increase in food intake is prevented by restricting calories to maintenance levels.10 So much for the good points.


What Kind Of Weight Gain?

The problem with the weight gained from Megace is that it is primarily fat and water weight, with little lean tissue increase. , Through interactions with mineral corticoid receptors in the kidneys, specific metabolites of Megace promote retention of water. In addition some studies have shown that Megace increases the number of fat cells as well as their size. This is exactly what someone who is wasting or have lipodystrophy doesn't want. We should be clear that the focus of just putting weight on HIV(+) individuals is inappropriate. Studies are conclusive that survival is correlated with lean body mass, not total weight or fat weight. So if you want to be fat and hungry, take Megace, but do not expect to gain much muscle or live any longer.

Many Side Effects

Megace has almost too many side effects to list. For both men and women the most commonly observed side effect is loss of libido. When Megace was used as a female contraceptive, it worked too well. All the women lost their fertility, but they lost their normal sex drive too! Megace interacts with the progesterone receptors in the hypothalamus to inhibit gonadotropin release in both sexes. Gonadotropins stimulate testosterone production, and testosterone is necessary for a healthy sex drive in both men and women. The end-result of lower gonadotropins in men is not only lower testosterone production, and lower libido, but also testicular atrophy. In other words, the testicles shrivel up. Finally, low plasma testosterone levels are bad for HIV(+) men and women because they are associated with a weakened immune system and the loss of muscle tissue.


Because Megace and/or its metabolites have glucocorticoid activity, 9 Megace is also potentially immunosuppressive. Glucocorticoids are well known to inhibit proliferation of white blood cells including T cells, and weaken the body's response to infection, as well as slowing the healing process. Furthermore, a glucocorticoid responsive element has been identified in the RNA of the HIV virus, so it is possible that Megace could have a direct effect on stimulating viral replication. Other side effects related to the cortisol-like activity of Megace are glucose intolerance, full-blown diabetes, and suppression of the hypo-thalamic-pituitary-adrenal (HPA) axis.9 Resist-ance to cortisol is common in HIV, and with-drawal from Megace therapy could result in a dangerous state of adrenal deficiency. These conditions are associated with the later stages of HIV in cytokine-related wasting, so it makes little sense to use a drug that has the potential to make the complications of HIV infection even worse. Other problems seen with Megace include thrombosis (blood clots), carpal tunnel syndrome, and peripheral neuropathy.

Conclusions

When it comes to gaining muscle to rebuild a body weakened by AIDS, Megace cannot begin to stack up to anabolic steroids. While some people assert that Megace has a role as an appetite stimulant, there are other substances, like Marinol, that work with far fewer side effects. If your doctor is not yet aware of the benefits of Marinol and anabolic steroids and the problems associated with Megace, work to educate them, and be sure to ask questions if they tell you they would like to prescribe Megace for you. After all, your choice of therapies is up to you.

https://www.thebody.com/article/megace-gain-weight

Adrenocortical corticosteroids.

To treat cachexia crucial is managing inflammation. Therefore basic treatment includes steroids. Adrenocortical hormones are steroids produced and released by the adrenal cortex under corticotropin (ACTH) control. That group is divided into a few subgroups depending on their biological activity (Table 3) (44).

Corticosteroids, such as dexamethasone (2-4 mg/day), prednisolone (15-30 mg/day), or methylprednisolone (8-24 mg/day), are used to treat cachexia (3,4). Their main mechanism of action is increased appetite and diminishing inflammation (4,36). Additionally, they inhibit prostaglandin metabolism and IL-1 activity (22). With higher steroid doses, the probability of important adverse effects increases, particularly when dexamethasone dose is above 3mg (in mice studies) or when serum levels increase in stressful situations. Corticosteroids can decrease protein synthesis and increase protein degradation, due to activation of the ubiquitin-proteasome system and muscle ring finger 1 (MuRF1) inhibition, reducing muscle strength (10,45). Because of corticosteroids’ side effect profile, they are indicated only for short-term treatment – less than 4weeks. That side effects include osteoporosis, steroid-induced myopathy, osteonecrosis, suppression of the hypothalamic-pituitary-adrenal (HPA) axis, diabetes, cushingoid features, infections, fluid retention, edema, weight gain, hypertension, and arrhythmias by increasing renal excretion of potassium, calcium, and phosphate, cataract, open-angle glaucoma, skin thinning and atrophy (46).




Progesterone analogs

Progesterone, another steroid hormone, is a natural progestin synthesized by the ovary, testis, and adrenal cortex from circulating cholesterol, also by the placenta during pregnancy (44). In wasting syndrome treatment we use synthetic progestin, which increases appetite and reduces inflammation – Megestrol Acetate, Medroxyprogesterone Acetate, and Fluoxymesterone.

Megestrol Acetate is often used in the treatment of patients with metastatic breast cancer patients as well as in anorexia. Its mechanism may involve IL-1α and β, IL-2, IL-6, and TNF-α serum levels reduction. Megestrol acetate causes weight gain, but mainly fat tissue, not muscle (22,52,53). The dose range is 400-800 mg/day (higher doses do not bring benefits and increase the risk of adverse effects, mainly thromboembolic events and adrenal cortex suppression). Maximal weight gain is normally achieved within 8 weeks (54). In 2019 was published by Cochran Database Systemic Review, which included 35 trials comprising 3963 patients for effectiveness and 3180 for safety. Meta-analysis showed a benefit of megestrol acetate (MA) compared with placebo, especially regarding appetite improvement and weight gain in cancer, AIDS, and other underlying conditions. According to this review, MA does not improve quality of life, and in patients treated with MA side effects are more frequent. The most common adverse effect is increased risk of blood clots, therefore swelling, pain or redness of one extremity and not the other, severe headache, sudden dyspnea or vision changes, as well as fluid retention, which can lead to swelling of the feet or hands, and death (55). According to Loprinzi et al clinical trial, there is no significant distinction between dexamethasone and megestrol acetate's effectiveness on appetite stimulation as well as their influence on nonfluid weight status. However there were differences in their side effects – dexamethasone caused corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity or patient's refusal, and megestrol acetate had a higher rate of deep venous thrombosis. A randomized, double-blind, placebo-controlled trial of megestrol acetate or dexamethasone in treating symptomatic anorexia in people with advanced cancer also showed, that there are no significant differences between treatment effects including weight, performance status (AKPS), and appetite score of megestrol acetate 480 mg or dexamethasone 4 mg compared to placebo daily. However, the study lasted only 4weeks (56). Other analogs, which is fluoxymesterone (testosterone analog), according to Loprinzi et al studies, are definitely less effective in appetite enhancement than dexamethasone or MA (57).

 

[Nelson Vergel]

Most doctors are so afraid of anabolic steroids that they would rather give the patient a drug that has no survival benefits.

 

[madman]

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