Tackling the Conundrum of Cachexia in Cancer
By some estimates, nearly one-third of cancer deaths can be attributed to a wasting syndrome called cachexia that can be devastating for patients and their families. Characterized by a dramatic loss of skeletal muscle mass and often accompanied by substantial weight loss, cachexia (pronounced kuh-KEK-see-uh) is a form of metabolic mutiny in which the body overzealously breaks down skeletal muscle and adipose tissue, which stores fat. Patients suffering from cachexia are often so frail and weak that walking can be a Herculean task.
Cachexia occurs in many cancers, usually at the advanced stages of disease. It is most commonly seen in a subset of cancers, led by pancreatic and gastric cancer, but also lung, esophageal, colorectal, and head and neck cancer.
Defining Cancer Cachexia
The international consensus statement on the definition and classification of cancer cachexia, published in May 2011 in Lancet Oncology, established these criteria for diagnosing cachexia in patients with cancer:
- Weight loss greater than 5 percent over the past 6 months; or
- BMI less than 20 and any degree of weight loss greater than 2 percent;
- Appendicular skeletal muscle index consistent with sarcopenia (another wasting syndrome) and weight loss of more than 2 percent
The stages of cancer cachexia agreed upon by the panel are:
- Precachexia: weight loss of less than 5 percent, along with other symptoms such as impaired glucose tolerance or anorexia
- Cachexia: Weight loss greater than 5 percent or other symptoms and conditions consistent with the diagnostic criteria for cachexia
- Refractory cachexia: Patients experiencing cachexia who are no longer responsive to cancer treatment, have a low performance score, and have a life expectancy of less than 3 months
Despite cachexia's impact on mortality and data strongly suggesting that it hinders treatment responses and patients' ability to tolerate treatment, researchers who study muscle wasting say it has not received the attention it deserves. No effective therapies have been developed to prevent or hamper its progression. Even for patients who are able to eat—appetite suppression or anorexia is a common cachexia symptom—improved nutrition often offers no respite.
And yet, over the last few years, researchers have begun to better understand the underlying biology of cancer-related cachexia. Findings from several studies point to potentially powerful therapeutic approaches, and a number of clinical trials of investigational drugs and drugs approved for other uses have been conducted or are under way.
"It's exciting to see several avenues of investigation coming to the forefront and trials moving forward," said Dr. Aminah Jatoi, a medical oncologist at the Mayo Clinic Comprehensive Cancer Center.
"It's important that oncologists be aware of these trials and offer participation to their patients," said Dr. Jatoi, a member of an international group of clinicians and researchers who earlier this year published a consensus statement to more precisely define cancer-related cachexia. The publication also provided a preliminary classification system for the condition—akin in some respects to the staging system used for tumors. (See the sidebar.)
Cachexia isn't limited to cancer. It is commonly seen in people with AIDS and chronic forms of kidney disease and heart failure, among other conditions, as well as in those who have suffered severe trauma and burns, said Dr. Alfred Goldberg of the Harvard University School of Medicine, whose research on muscle wasting and protein degradation eventually led to the development of the cancer drug bortezomib (Velcade). With so many potential clinical applications, Dr. Goldberg said, "There really is an enormous therapeutic opportunity here."
Why and How Cachexia Happens
The consensus statement is a good beginning, according to another co-author, Dr. Mellar Davis of the Cleveland Clinic Taussig Cancer Center. But researchers still need to dig deeper into how cachexia develops in patients with cancer, Dr. Davis continued, and how its course is influenced by everything from nutrition and physical activity to disease-specific factors, such as reduced testosterone levels caused by cancer therapy or opioids to treat pain.
Multiple factors are clearly at play in cachexia development and progression, Dr. Goldberg explained. He believes that at its core cachexia is "more of a host response that's evolved to fight fasting, injury, or disease," he said. During this response, the body is trying to obtain additional energy stores from muscle, in the form of amino acids, to convert into glucose to keep the brain functioning. The problem, he continued, "is that we can't turn off this response to the cancer, even when we can provide the patient with essential nutrients."
Many studies suggest that inflammation "is a unifying theme of cachexia across many diseases, including cancer," said Dr. Teresa Zimmers of the Jefferson Kimmel Cancer Center in Philadelphia.
There really is an enormous therapeutic opportunity here.
The inflammation is caused in part by the body's immune response to the tumor, which results in the production of pro-inflammatory cytokines, explained Dr. Konstantin Salnikow, of NCI's Division of Cancer Biology (DCB). Although these cytokines can help to kill tumor cells, some also appear to tilt the body's metabolism toward catabolism, the breakdown of muscle proteins and fat.
Elevated levels of several cytokines in particular have been closely associated with cachexia and mortality in cancer patients. In NCI-supported mouse model studies, for example, Dr. Zimmers has shown that elevated levels of the cytokine IL-6 can induce cachexia. She and others have begun to unravel some of the potential mechanisms by which IL-6 may do this.
Searching for Treatments
Despite the incomplete understanding of the underlying biology of cancer-related cachexia, a few potential therapies are moving into early human trials.
More than one drug will likely be needed to successfully combat cachexia, particularly if it's at an advanced stage, said Dr. Barbara Spalholz, also of DCB. "We may have to hit different combinations of targets, depending on the type of cancer and other factors," she said.
The agent that appears to be the furthest along is the selective androgen receptor modulator GTx-024 (Ostarine), developed by GTx Inc., based in Memphis, TN. In August, GTx launched two phase III clinical trials of the investigational agent, dubbed POWER1 and POWER2, for the prevention or treatment of cachexia in patients with advanced non-small cell lung cancer.
Researchers and several pharmaceutical and biotechnology companies have increasingly trained their sights on agents that target several members of a family of growth regulators that appear to have an outsized influence on muscle growth, in particular the proteins activin and myostatin. Myostatin's primary function is to serve as a brake on muscle growth. Sheep, mice, dogs, and cattle with mutations in the gene that produces myostatin are excessively brawny. A case report published in 2004 found that a German child who at birth "appeared extraordinarily muscular, with protruding muscles in his thighs and upper arms" had a genetic mutation in the myostatin gene.
Two mouse-model studies published last year, one led by Dr. Zimmers and the other by Dr. H.Q. Han at the biotechnology company Amgen, provided strong proof of principle that blocking the activity of myostatin and activin can have a significant impact on cachexia. Both studies used different versions of an investigational agent—an engineered form of a cellular receptor for myostatin and activin called ActRIIB—that acts as a decoy, mopping up these proteins in the circulatory system.
Dr. Zimmers' study showed that the drug could potently reverse cachexia in a mouse model of colon cancer. Working with a similar mouse model, Dr. Han and his colleagues showed that the treatment not only reversed cachexia but, in a finding that Dr. Goldberg, a study co-author, called "quite remarkable," allowed treated mice to live substantially longer than untreated mice, even as their tumors continued to grow normally. The study was also the first to demonstrate that targeting myostatin and activin could reverse cachexia-induced heart muscle loss.
An Uphill Climb
Despite the enticing results in mice, unanswered questions and challenges remain, stressed Dr. Se-Jin Lee of Johns Hopkins University, who discovered myostatin and co-developed the first form of the ActRIIB agent in 2005, in collaboration with scientists from the pharmaceutical company Wyeth, now part of Pfizer.
"One of the most informative studies would be to get muscle samples from patients experiencing wasting and see if the pathway [regulated by activin and myostatin] has been activated," Dr. Lee said.
The ActRIIB agent may need to be refined for use in humans, he continued, because it binds other proteins besides myostatin and activin (one of the reasons it is so potent in mice), which could produce unanticipated and unwelcome side effects.
If we can identify the early switch to cachexia, we could really prevent the extended cachexic effects and improve patients' ability to withstand therapy.
At least one company, Massachusetts-based Acceleron, has an ActRIIB-targeted agent in two human phase II trials for the treatment of a form of muscular dystrophy. The trials were stopped earlier this year because of treatment-related bleeding issues in patients. Amgen representatives did not respond to inquiries about the developmental status of the agent used in its previous mouse model studies.
"The appeal of targeting this pathway," Dr. Lee said, "is that even if it's not playing a causative role [in muscle wasting], hitting it could have a major clinical benefit in terms of preserving muscle mass."
Dr. Salnikow noted that targeting cachexia could have a spillover effect on the tumor, perhaps robbing cancer cells of molecules they use for energy that are produced by the excess breakdown of muscle. He has other hopes as well.
"If we can identify the early switch to cachexia, we could really prevent the extended cachexic effects and improve patients' ability to withstand therapy," he said.