Interventions in the Treatment and Prevention of Adult Cancer Cachexia

CANCER CACHEXIA is perhaps one of the most vexing of the myriad of challenges cancer patients face. Cachexia, which affects not only cancer patients but those in the end stages of other chronic diseases, causes the body’s lean and fat mass to deteriorate, leading to an eventual inability to tolerate lifesaving chemotherapy due to its toxicity, thus hastening mortality. Depending on the data, cachexia affects approximately onethird to 80 percent of cancer patients and is implicated in approximately 20 percent to 30 percent of their deaths. Among its many symptoms are an extremely high metabolism, endocrine dysfunction, compromised appetite control and impaired immune function. Cachexia is perplexing because, while its effects are devastating, its cause is only beginning to be understood, and successful treatment options are largely elusive. While simply increasing nutrient content would seem a reasonable response, it is ineffective as a unimodal therapy. In addition, many promising drug trials have shown to have negative or ineffective results. The complexity of the syndrome is a major factor, explains Vickie Baracos, PhD, specializing in palliative care medicine in the department of oncology at the University of Alberta, Cross Cancer Institute: “Nutrition support, pain and symptom management, as well as therapies to reduce excess catabolism and concurrently increase anabolism, appear to be required. Any of these alone, may have limited efficacy.”

Cachexia’s effects are both physical and financial, with longer inpatient stays and higher costs compared with noncachectic patients. Inpatient death rates attributed to cachexia are also higher. That being said, Dr. Baracos says the medical industry is now beginning to understand cachexia. Ten years ago, there were no Phase III clinical trials looking at cachexia, and no matter the form the current trials take, thereis great learning potential. “The aim of preventing or reversing cachexia seems tangentially achievable,” she explains.

Cachexia Classification

Although there is some disagreement about how cancer cachexia should be characterized, the current international consensus is that there are three clinically relevant stages:

• precachectic (less than 5 percent weight loss during the previous six months in combination with reduced food intake)
• cachectic (weight loss of greater than 5 percent)
• refractory cachexia (patients no longer responding to treatment with less than three months to live)

Currently, there are no biomarkers identified with cancer cachexia. However, researchers are looking at the complex multifactorial relationship of proinflammatory cytokines. Previously, specific inflammatory biomarkers were thought to be involved (i.e., interleukin 1 or 6, commonly known as IL-1, IL-6 and TNF-a), but more recently, they have shown to be inconsistent in some cancer cachexias. Researchers now question if IL-6 is the best predictive cytokine, particularly in advanced cancer patients, or if other cytokines such as IL-1b are better associated.¹

When assessing and characterizing a patient’s weight loss, a body mass index (BMI) of less than 20 and evidence of sarcopenia must be considered (see Defining Cancer Cachexia). And, as cachexia is explored, the severity of weight loss in relation to the rate of weight loss should be considered. This is because each patient’s weight and BMI differ upon diagnosis, so looking at raw numbers in terms of weight loss or percentage of loss does not necessarily take into consideration the severity of the reduction. In addition, today’s prevalence of upwardly trending body weights suggests the need to consider new definitions in cachexia weight-loss risk classifications, which also take BMI into consideration. Indeed, the international community is exploring the consideration of a revised classification of cancer cachexia in relation to treatment toxicity and mortality to gain more meaningful criteria.²

Causes of Cachexia

Although the specific causes of cancer cachexia are not fully understood, several studies are attempting to gain a better appreciation of contributing factors. Unfortunately, cancer cachexia is not a high priority for cancer research agencies or pharmaceutical companies, explains Dr. Baracos, so trials are difficult to fund. And, while there have been many drug trials with potential applications to cancer cachexia, the drugs’ limited scope make them financially unattractive to pharmaceutical companies.

Major strides are now being made in understanding the basic biology of cancer cachexia; however, most studies involve rodent models, and there is still little known about what signals the initiation of cachexia in humans. For instance, some, but not all, cancers overproduce catabolic processes at a very intense rate. Yet, other patients have dramatic weight loss exacerbated by not only their cancer but other lifestyle factors such as poor nutrition or an inability to care for themselves.

A common school of thought is that cachexia may be associated with the administration of chemotherapy. In one study, mice receiving five weeks of treatments for colorectal cancer exhibited MAPK-dependent muscle atrophy, mitochondrial depletion and alterations of sarcomeric units, suggesting chemotherapy potentially plays a causative role. The study also found that testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs could identify those for whom strategies aimed at preventing chemotherapy-associated muscle atrophy may be helpful.³

Another study looked at the Pax7 muscle stem cell factor that, in normal circumstances, would develop into mature cells that bind to damaged muscle fibers to help repair them. In cancer cachexia, an overexpression of Pax7, controlled by NF-kappa B (NF-kB), inhibits the normal binding and leads to muscle wasting.⁴ The researchers postulated that inhibition of Pax7 may provide an alternative therapy.

Scientists also suspect that the gene USP19 may play a role in the development of cachexia, because studies in mice show that suppressing the gene may protect against it. Scientists are looking at two factors leading to muscle wasting: nerve loss leading to muscle atrophy (as in the case of a bedridden patient) and increased levels of cortisol. In mice in which USP19 was suppressed, muscle wasting happened much more slowly, suggesting protection against both causes of muscle wasting. If so, inhibiting the USP19 gene in the early stages of cancer could potentially have an impact on a patient’s quality of life, and perhaps positively impact mortality.⁵

Researchers are also looking at the role of inflammation as a cause of white fat turning to brown fat in cancer patients. Brown fat is more calorically active, resulting in more heat production, calorie burning and organ wasting. It’s possible that identifying brown fat in the early stages could predict which cancer patients will develop cachexia and benefit from preventive treatment. In mice studies, a nonsteroidal anti-inflammatory drug (NSAID) was found to be effective as preventive treatment.⁶

More recently, scientists looked at the AMP-activated protein kinase (AMPK), an enzyme that protects fat cells from energy deficiency in healthy people. They found that the inhibition of AMPK in mice with cancer caused white fat-cell wasting. Therefore, by manipulating the AMPK-stabilizing peptide (ACIP), which prevents the interaction between AMPK and the AMPK-interacting protein (CIDEA), increased fat breakdown could be halted.⁷

Treatment Options

Pharmacological treatments. There are no approved pharmacological treatments for cancer cachexia approved in the U.S. However, there are some approved in Europe. These treatments are considered palliative, and of those, progestogens (a class of steroid hormones) are considered the most effective.

Treatments for refractory cancer cachexia such as corticosteroids or progestins can provide short-term benefit. Earlier-stage therapies are “increasingly based on distinct molecular targets such as the skeletal muscle androgen receptor, myostatin, ghrelin, interleukin 6, and interleukin 1α,” according to Dr. Baracos. Researchers are also assessing the success of a combination of exercise, nutritional supplementation and pharmacological intervention.⁸

The appetite stimulant Megestrol acetate (MA), approved to treat anorexia, cachexia or unexplained weight loss in patients with AIDS, and medroxyprogesterone acetate (MPA), used to treat breast, womb and kidney cancers, are showing promise for helping to improve cancer patients’ nutritional status. MA is the most widely used drug for treating cancer cachexia. In clinical trials, patients showed a decreased level of IL-1, IL-6 and TNF-α after MA or MPA treatment. 9 While the mechanism by which these work against cancer cachexia is not fully understood, it is thought to be similar to corticosteroids: They may stimulate appetite and regulate the synthesis of and release of cytokines. MA and MPA have also shown to be effective in increasing body weight, primarily through water and fat mass. Unfortunately, they do not appear to be effective against increasing muscle mass.¹⁰

More than 100 randomized clinical trials have been conducted of potential therapies for cancer cachexia. Unfortunately, many have produced either negative results or they were not approved for treatment in the U.S. Part of the problem is a lack of consensus on what exactly should be tested. To demonstrate reversal or prevention of cancer cachexia, explains Dr. Baracos, the first endpoint is proof using dual energy X-ray or some other highly precise measure. The second endpoint must demonstrate the benefits of the therapy. However, because there is no clear guidance on what trials should be looking for, the challenge is defining exactly what success looks like. Examples of this are four Phase III trials. Two trials assessed treatment with anamorelin, a novel, orally active, selective ghrelin receptor, to improve lean body mass and handgrip strength. And, two assessed treatment with enobosarm, an investigational selective androgen receptor modulator, to improve lean body mass and power and speed via stair climbing. While all showed significant improvements in lean muscle mass, they did not improve strength.

In the first two randomized, double-blind Phase III trials of anamorelin (Romana 1 and 2), sponsored by Helsinn of Switzerland, results showed that over a 12-week period, “ghrelin mimic” stimulated appetite and regulated rate of energy usage in combating muscle wasting and increasing lean body mass in certain advanced non-small cell lung cancer patients; however, there was no difference in handgrip strength. Also, survival improved for those who either maintained or increased lean body mass. The results are exciting because the retention and gain of lean muscle mass in those with advanced lung cancer, without any exercise or nutrient intervention, is remarkable progress. Helsinn has requested approval of anamorelin from the European Medicines Agency (EMA), and discussions are underway with the U.S. Food and Drug Administration for further trials to gain approval in the U.S.¹⁰

In search of a different definition of clinical benefit, two Phase III trials (POWER 1 and POWER 2) of GTX Inc.’s enobosarm assessed the molecule’s ability to treat and prevent cancer cachexia in patients with advanced small cell lung cancer. They also tested power and speed via the patient’s ability to climb stairs. Enobosarm, which binds to the same receptor as testosterone, showed improvements in participants’ ability to maintain or prevent loss of lean body mass in both trials; however, it showed no absolute increase in stair climbing power. After the disappointing results, GTX stopped testing enobosarm to treat cancer cachexia and is instead focusing on the possibility as a treatment for breast cancer.¹⁰ It has been hypothesized that a higher dosage of enobosarm might have overcome the effects of the cancer and demonstrated improvement.

Another Phase IIb trial (ACT ONE) of espindolol, a combined anabolic and anticatabolic therapy, resulted in the largest efficacy rate in any placebo‐controlled clinical trial in cancer‐related cachexia. Results of the 16-week study, sponsored by PsiOxus Therapeutics, showed significant positive effects on fat‐free mass, body weight, relevant functional measure and hand grip strength in patients with colorectal and non-small cell lung cancer, two types of cancer that have high rates of cachexia. Inspired by the results of earlier Phase III trials of enobosarm and anamorelin and a smaller study of L‐carnitine supplementation, which also showed positive effects on weight loss and BMI, a Phase III trial of espindolol is being designed.¹¹

According to Dr. Baracos, these trials are the closest ever to changing clinical practice: “It is an encouraging time. We are taking baby steps, but we are going forward.”

The exercise effect. Exercise is being explored as a means to prevent and counter the effects of cancer cachexia. Even though fewer than 5 percent of studies have included exercise, the positive effects of activity on inflammation, muscle strength and endurance are well-documented, particularly if exercise intervention is begun soon after the cancer diagnosis.

Mild endurance exercise reduces oxidative capacity, insulin resistance and inflammatory response. In studies of patients with breast and prostate cancers, resistance exercise had positive results against cachexia. Even high-intensity resistance training showed positive results in patients undergoing chemotherapy, with an average increase in muscle strength of 41.3 percent and a body weight increase of 1 percent. While these studies had small population sizes, making it difficult to generalize the results, they do indicate a positive relationship between appropriate exercise interventions and mitigating cancer cachexia’s devastating effects.¹²

Andrew Wolf, MS, ED, exercise physiologist at Miraval Spa in Tucson, Ariz., explains that the release of myostatin by cancer cells results in negative effects on muscle mass. However, positive results of resistance training by cancer patients are two-fold. “First, our muscles secrete less myostatin in response to the increased use of the muscles in order to produce force,” he says. “Second, the muscles actively produce a chemical called decorin. What decorin can do is sequester the myostatin produced by the cancer cells and keep that downward regulation of muscle tissue from occurring. The beauty of this two-fold effect is that we can now give real cause-and-effect rationale to cancer patients instead of simply talking about correlations between resistance training and better posttreatment outcomes.”

Nutritional interventions. Few oncologists fully understand cancer cachexia, and their recommendations for increased caloric intake are met with so-so results. This is because using nutrition as a unimodal mechanism against cachexia is insufficient. Nonetheless, studies show that nutritional support and increasing caloric intake in the form of liquid or solid nutritional supplements can reverse the effects of weight loss in the short term and may enable patients to live longer and benefit from cancer treatments. Yet, other studies showed that while fat mass was improved in cachectic patients receiving nutritional support, longevity was not.

Generally encouraged are smaller, more frequent meals, which include fat and protein to support muscle synthesis, and proper hydration. In patients unable to tolerate eating, parenteral and enteral nutrition may be prescribed, although infection rates using these methods are higher. The Society for Critical Care Management and the American Society for Parenteral and Enteral Nutrition (ASPEN) recently updated their guidelines.¹³ Also available is an article titled “A.S.P.E.N. Guidelines for Nutrition Support Therapy During Adult Anticancer Treatment.”¹⁴

Because a review of randomized studies showed no real difference in either mobility or mortality post-op when comparing parenteral nutrition, enteral nutrition and oral diets, ASPEN does not recommend nutritional support for routine use in patients undergoing major cancer operations. And, after concluding no real benefit but an increased risk of infection in immunocompromised patients, it also does not recommend nutritional support to patients undergoing chemotherapy or head, neck, abdominal or pelvic radiation therapy. Studies do show there may be some pre-operative benefit to moderately or severely malnourished patients, and ASPEN does recommend nutritional support for “patients receiving active anticancer treatment who are malnourished and who are anticipated to be unable to ingest and/or absorb adequate nutrients for a prolonged period of time.” There is also emerging evidence supporting the use of omega-3 fatty acids as a preserver of lean body mass in advanced cancer patients undergoing chemotherapy.

One confusion concerning nutrition and cancer care is patients’ understanding of what constitutes a “healthy” diet and the possibly erroneous reporting of their own eating habits. While a diet high in fruits and vegetables has shown a positive effect in preventing a variety of cancers, those micronutrients may have little impact on those with advanced stage cancer. Still, good nutritional intake in the presence of cancer cachexia is valuable, especially when considering the costs of other treatments.¹⁵

It is important to note that nutritional support does not work for all cancer patients. It has had mixed results in some studies, and it has not been validated through rigorous clinical trials. For example, some studies show that while nutritional support can stabilize weight and reduce the side effects of cancer therapy, it may also have the unintended consequence of decreasing the therapy’s effectiveness.

“In the case of a cancer diagnosis, the more levers that you can pull in order to tamp down harmful inflammatory responses that may accelerate or exacerbate your situation, the better,” says Wolf. “Be that traditional medicine, complementary therapies, nutritional therapies or exercise, the more positives you can integrate the better. In addition, the proactive feeling that you are doing something to help yourself while letting experts help you cannot be overstated.”

Multimodal therapies. Multimodal therapies combining pharmaceutical therapies, exercise and diet are being explored and have potential for great promise in treating cancer cachexia. A Phase III trial currently recruiting participants will assess exercise with activity directed by a physical therapist, nutrition directed by a registered dietician and pharmacologic interventions with NSAIDs. The Multimodal Exercise/Nutrition/Anti-Inflammatory Treatment for Cachexia trial is recruiting patients with lung cancer, pancreatic cancer or cholangiocarcinoma at multiple sites in Europe, Canada and Australia.

Hope Is on the Horizon

While cancer cachexia continues to confound researchers, some enlightening findings in the search for prevention and treatment are coming to light. From pharmacological treatments currently under investigation to exercise and nutrition, hope is on the horizon for this devastating condition.

Though the specifics on cancer cachexia are not yet well understood, the complexities and importance of this condition are evidenced by the well-deserved attention to this multifactorial syndrome. With conferences focusing on cancer cachexia (cancercachexia2016.com/index.html); the Society on Sarcopenia, Cachexia and Wasting Disorders, an international, nonprofit scientific organization devoted to increasing awareness, education and research about cachexia (society-scwd.org/scwd); and the Journal of Cachexia Sarcopenia and Muscle (www.jcsm.info/ index.php/en/), excellent resources are available today.