Cachexia: Current and New Approaches to A Deleterious Syndrome in Oncology

By April 27, 2020 No Comments

Although many consider cachexia to be a pathology, the truth is that cachexia is defined as a metabolic disorder caused secondarily by some underlying disease, which brings various consequences to our body such as loss of muscle mass, fat, immune deficit, infections, etc.

Although there are many causes, it is usually associated with serious diseases such as AIDS, tuberculosis, severe autoimmune diseases, etc. However, the one that worries doctors the most (and is the first thing that comes to mind when we talk about cachexia is cancer, a “consumer” disease, closely related to the abnormal and unhealthy weight loss that accompanies this disorder.

What happens in Cachexia

In principle, there is a “consuming” pathology that attacks your body from within. Imagine that one day you do not eat the amount of food necessary to support all the energy expenditure of those 24 hours. What does your body do? It begins to take energy from other sources housed in reservoirs that you have in various sectors of your body.

Fats, proteins, carbohydrates, all come from your own body to maintain the expenditure of the metabolism. Something similar is what happens with consuming pathologies, such as cancer. Cellular turnover and tumor growth require the use of a lot of energy that has to come from somewhere. Because of the physiopathology and the development of the disease, it usually comes from your body.

In principle, it is only weight loss, however, as it progresses disorders begin to appear that stem from the metabolic alterations caused by cachexia, such as Anorexia, insulin resistance, problems with protein degradation, chronic inflammation, etc. Your body does not know how to respond to a permanent energy deficit. It’s like if you have an engine running without gasoline, it eventually breaks down or explodes, right?

Also, it is necessary to emphasize that cachexia is not just “starving”, it is a complex clinical syndrome, which is accompanied by the release of multiple cytokines and millions of other pro-inflammatory factors, which ends up affecting the muscle metabolism and causing anorexia.

Although being hungry triggers various responses, the hormonal involvement is not as severe, nor are the alterations in the metabolism of lipids, carbohydrates, and proteins, which are crucial for life. Cachexia stems from this alteration in the regulation of cytokines, which alter specific regions of our body that control both orexigenic and anorexigenic signals.

Our brain understands (mistakenly) that it must limit food intake and increase energy expenditure at rest (something illogical and anomalous), causing weight loss and altering various systems in our body.

What is a Cachectic Appearance?

A person with cachexia will appear thin, excessively thin. With difficulty moving, slow thinking, speech problems, inability to stay awake (drowsiness), with bones protruding over thin, dry skin. Most cases are associated with difficulty breathing or maintaining some other basic vital functions, but this depends on the patient’s overall condition and how advanced the cachexia is.

Is Cachexia a sign of dying?

Cachexia is a sign that your body is doing its best to stand up and fight a disease that overcomes it. Cachexia is best thought of as a syndrome that indicates that you have a serious illness or a major commitment, but not one that causes imminent death. Some malignancies are curable with proper treatment.

The question should be: How long can you live with Cachexia? And it’s hard to answer. It depends on what pathology is behind the cachexia, how severe it is and how much time you have with it. Those will be the real determinants of your life after cachexia.

Overcoming Cachexia: New Treatments and Options

The best management for cachexia will always be to treat the underlying cause. For example, if you have cancer, then treating cancer will be the way to reverse the syndrome completely. However, many adults with advanced disease or in palliative treatments do not have this option, so the solution is to try to reverse and counteract the cachexia without altering the underlying cause along the way.

There are several approaches, some try to adjust their measures to counteract the weight loss by improving the nutritional intake, however, in almost all patients the nutritional part is only one side of the problem. Others try multiple approach therapies trying to control certain variables at the same time, but not all have been successful.

Many studies have been based on interventions involving the use of drugs in conjunction with nutritional changes. Some even seek to manipulate the development of cachexia (despite that progress) to decrease symptoms and improve health status. However, success has not been unequivocal and this is due to the multifactorial pathogenesis of cachexia.

We will discuss the most effective options and science’s approach to new treatments and therapies for cachexia:

Effective Treatments Approved for Use

  1. Progestogens

Both Medroxyprogesterone Acetate and megestrol Acetate (progestins) are considered the best available therapy for the cachexia syndrome associated with cancer. There is evidence confirming how it stimulates the appetite through the release of certain specific neuropeptides, as well as downregulating the synthesis and release of proinflammatory cytokines.

There are various presentations of these drugs (oral solution, pills, powder, etc.), and almost all have been shown to have a positive effect. The FDA is evaluating them for approval as a treatment for other types of cachexia, such as AIDS-derived cachexia.

  1. Corticosteroids

Corticosteroids are the most widely used or known of the orexigenic agents. Not only for cachexia but for other states associated with nutritional disorders. This drug has been shown to cause a radical and significant increase in appetite.

Still, it can alter other effects such as protein metabolism, insulin resistance, water retention, and even cause adrenal infarction. The only way to use them as therapy is under the strict supervision of doctors and in the short term, as complications are worse in the long term.

Emerging Drugs with Effective Results

  1. Thalidomide

As mentioned above, cachexia is a syndrome characterized by the abnormal release of cytokines, pro-inflammatory molecules capable of altering the body’s metabolic regulation. Thalidomide is an immunomodulator capable of regulating inflammatory processes through effects on certain key molecules of our immune system, such as IL-6 and TNF-alpha.

  1. Selective COX-2 Inhibitors

Nonsteroidal anti-inflammatories are abundant in our home and are used in various aspects of neoplastic pathologies. Several scientific studies have been conducted on various drugs, and one of the ones that have provided better results is Celecoxib, which suppresses the systemic inflammatory response, improving the weight and body mass of patients.

Several animal studies have been conducted previously with this drug and all have yielded positive results, which encourage the formal indication of Celecoxib in patients with cachexia, although more studies are needed.

  1. Ghrelin

This drug is a peptide of only 28 amino acids capable of regulating the secretion of certain hormones and neuropeptides, which promote appetite and food intake. Besides, it appears to have some interaction with the sympathetic nervous system, promoting muscle wasting and functional capacity in cancer patients, crucial markers for anyone with severe body involvement.

  1. Insulin

Insulin has also been considered as a possible drug affecting the hormonal and metabolic system. According to available studies, it attenuates the progression of cancer-associated cachexia and improves metabolic and physical parameters in patients in palliative stages.

Thousands of studies have focused on this hormone, which also appears to significantly stimulate carbohydrate intake and promote the development of body fat, especially in the trunk and legs.

Also, let us remember that there is insulin resistance in cachexia patients, which prevents glucose absorption in the muscles and promotes the general disorder. Using insulin increases the number of nutrients and energy that tissues in general receive, promoting body weight gain, and regulation of metabolic balance.

  1. Branched-Chain Amino Acids (BCAA)

This is one of the more recent alternatives, which could be listed as food for cachexia associated with cancer. Its metabolic effects are quite interesting. They seem to intervene with the release of appetite-related neurotransmitters and inhibit the expression of molecules that favor muscle proteolysis, improving the condition of patients with cachexia.

BCAA has been proposed as a potential regulator of the antianorexic and anti-cachexic quality of our body. Recently, several studies have been conducted that support this premise, based on the objective decrease in weight loss and the regulation and increase of muscle mass.

  1. Oxanlodrone

Several recent scientific studies have determined that this drug, a steroidal anabolic agent, improves body composition and quality of life in palliative care patients with solid tumors. This information is relevant because these patients in addition to having cancer were under chemotherapy, which also acts as “consumption pathologies”. Achieving that effect is remarkable.

The Future Therapy

Many drugs are under research or development currently. One of these may be the anti-IL-6 humanized monoclonal antibody, which appears to inhibit cachexia directly, although only the one related to cancer has been studied.

Other compounds that may also be on this list of novel drugs are IL-16, formoterol, new classes of nonsteroidal MRSA, Ostarine, Melanocortin MC4 antagonists, among others. The future is quite promising, but it is directed towards only one aspect: treating cachexia as an immune-compromised syndrome.

Regulation of abnormal cytokine release may be the secret to overcoming cachexia, however, many scientific studies need to be conducted and a thorough investigation of how this syndrome works and what the ultimate solution might be.