Amino Acids and Protein Nutrition for Cancer Cachexia

Virtually all forms of cancer induce a condition called cachexia, a weakening and wasting away of the body during serious illness. The effects of cancer cachexia have become recognized as a major factor in determining the effectiveness of cancer therapy and ultimately mortality. And amino acids are an important nutritional therapy for combating it.

There are many forms of cancer, from pancreatic cancer to non-small cell lung cancer to colorectal cancer. And each has specific and unique characteristics. However, virtually all forms of cancer, especially advanced cancers, induce a condition called cachexia—a weakening and wasting away of the body during serious illness that shouldn’t be confused with sarcopenia, which refers to the loss of muscle mass and function commonly seen with aging. While cachexia is known to occur during the course of a number of serious illnesses, including acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), and heart failure, when it occurs as a side effect of cancer, it’s known as cancer cachexia. And the effects of cancer-related cachexia have become recognized as a major factor in determining both the effectiveness of cancer therapy and, ultimately, mortality.

What Is Cancer Cachexia?

An international consensus regarding the definition of cachexia wasn’t reached until 2011, when a panel of experts convened for a formal consensus process.

According to the authors—including Kenneth Fearon and Stefan Anker—of the report, which appeared in The Lancet Oncology (Lancet Oncol), the definition of cancer cachexia that emerged was this: “A multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. The pathophysiology is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism.”

The international panel also emphasized the importance of additional factors related to cancer cachexia, including tumor progression, systemic inflammation, reduced muscle mass and function, and psychosocial difficulties, and set forth a classification of cancer cachexia that included three stages:

  1. Precachexia
  2. Cachexia
  3. Refractory cachexia

In addition, and as noted in a 2011 systematic review, this wasting syndrome is associated with both metabolic changes in the body that render normal nutrition ineffective and cancer-related anorexia, or loss of appetite that reduces food intake and thus energy intake, which is why cancer cachexia is sometimes called cancer anorexia-cachexia syndrome.

Moreover, a 2015 study found higher levels of pro-inflammatory cytokines (like tumor necrosis factor) and lower levels of anti-inflammatory cytokines within the cancer tumors and adipose tissue (body fat) of patients with cancer cachexia.

Regardless of the name used, the end result is malnutrition and loss of lean body mass, which lead to muscle atrophy and changes in body composition. And this can have a number of detrimental effects, including:

  • Significant weight loss
  • Skeletal muscle loss
  • Loss of heart muscle
  • Weakness
  • Fatigue
  • Depression
  • Anxiety

Every single one of these consequences can impair a patient’s ability to recover from cancer.

A 2013 study conducted at a cancer center in Alberta, Canada, sought to determine the degree to which muscle loss contributes to cancer mortality. And results showed that, regardless of weight, cachectic patients (characterized by involuntary weight loss, muscle depletion, and low muscle attenuation, or decreased muscle quality) had a poor prognosis, while patients who maintained more lean muscle mass lived nearly 2 years longer.

A 2017 study determined that low muscle mass and muscle attenuation contribute to a poor outcome for metastatic breast cancer patients as well.

Is it possible to do anything about the devastating effects of cancer cachexia on muscle?

The answer is yes, but to determine the appropriate treatment, we must first understand what causes the onset of cachexia.

Unfortunately, this can be difficult because, at a molecular level, scientists don’t fully understand the precise mechanisms involved. However, we do understand, as demonstrated in a 2006 study by Vickie Baracos, that, at the physiological level, nutritional therapy is key to tackling cancer cachexia.

The Stress Response in Cancer

Cancer places the body under physiological stress. As a result, appetite is reduced and food intake falls. Thus, during the stress response, there’s a greater need than ever for amino acid nutrition.

And this is because amino acids are required to produce the new proteins needed to help battle the cancer—such as the proteins involved with immune function and the proteins in tissues and organs like the liver and brain, whose uninterrupted function is absolutely essential for survival.

While nonessential amino acids can be produced in the body, the nine essential amino acids must be obtained through diet. And since the body’s main reservoir of amino acids is muscle tissue, an insufficient quantity of these building blocks of life means that muscle protein starts to break down at an accelerated rate to maintain a steady supply of both nonessential and essential amino acids for the other tissues and organs.

Muscle is the primary tissue that can afford to lose some of its protein mass without affecting normal physiology. However, the stress response is adaptive for only a few days—continued loss of muscle protein for longer than that will begin to adversely affect many normal physiological responses. Thus, continued and accelerated loss of muscle protein is the physiological basis for the development of cancer cachexia.

Consequences of Malnutrition and Lean Tissue Loss

Conventional Treatment of Cancer Cachexia

Scientists and oncologists have been searching for a treatment for cancer cachexia for many years but have yet to produce a successful solution. The most current recommendations for treatment of cancer cachexia come from the European Society of Parenteral and Enteral Nutrition (ESPEN).

These recommendations focus on the early diagnosis of nutritional risk and call for the use of a variety of nutritional interventions as well as efforts to decrease inflammation and increase physical activity. Unfortunately, several factors may lead to significant problems implementing the ESPEN recommendations.

Although increased activity is the most effective way to reverse muscle protein breakdown, a cancer patient usually doesn’t feel like doing a lot of activity. And while reducing inflammation with nutrients (such as the omega-3 fatty acids found in fish oil) is useful for mild cases, the level of systemic inflammation in cancer cachexia is so great that dietary approaches often have little impact.

Further, the suppression of appetite seen in cancer cachexia limits how much adequate nutrition can actually be consumed. In fact, it’s often necessary to provide nutritional support via tube or intravenous feedings.

In addition, the normal effectiveness of dietary protein in reversing the breakdown of muscle protein is limited in cancer cachexia.

Anabolic Resistance and Cancer Cachexia

The term anabolism refers to the building up of muscle. This can be contrasted with catabolism, which refers to the breakdown of muscle via protein degradation.

Dietary protein is normally anabolic because it stimulates the production of new muscle protein. However, in cancer cachexia, muscle becomes resistant to the normal anabolic effect of dietary protein via a process called anabolic resistance.

A 2011 double-blind clinical trial published in the journal Clinical Nutrition (Clin Nutr) demonstrated that feeding a nutritional supplement containing proteins, carbohydrates, and fats designed specifically for cancer cachexia was completely ineffective in stimulating the production of new muscle protein.

The problem in anabolic resistance is that the molecular machinery in the muscle that must be triggered to initiate the process of protein synthesis is in an inactive state and can’t be activated by normal nutrition.

However, a high dose of the amino acid leucine can activate these intracellular factors.

For example, when a high dose of leucine was added to the nutritional supplement in the study described above, the supplement became an active stimulator of muscle protein synthesis.

Essential Amino Acids and Muscle Protein Synthesis

The effectiveness of a nutritional supplement that’s been enhanced with leucine for the treatment of cancer cachexia can be further increased by using a balanced mixture of essential amino acids to stimulate muscle protein synthesis.

A balanced mixture of essential amino acids—with a relatively high proportion of leucine—not only activates the initiation of muscle protein synthesis but also provides all the amino acids necessary for the synthesis of muscle protein since the body supplies ample quantities of nonessential amino acids.

Essential amino acids also have the great advantage of being effective in very small amounts. For instance, a dose as small as 3 grams can effectively stimulate muscle protein synthesis, thereby reversing the loss of muscle protein.

Do Essential Amino Acids Stimulate Tumor Growth?

The notion that providing nutrition to cancer patients feeds the tumor and accelerates growth has been kicked around for more than 40 years. And studies done on mice support this perspective, as feeding mice specific amino acids can indeed stimulate tumor growth. However, one must be extremely cautious when extrapolating results from mice to humans.

Experimental cancer in mice usually involves the implantation of tumors that become much larger, relative to body weight, than any tumor in humans. Further, mice have very little muscle. Thus, a big tumor without much muscle means that the tumor isn’t getting all the amino acids it needs for optimal growth from muscle protein breakdown.

Therefore, dietary amino acids can stimulate tumor growth in mice—but this doesn’t accurately reflect the response seen in humans.

In humans, muscle mass is large relative to tumor load, so muscle protein breakdown provides the tumor with all the amino acids necessary for rapid growth.

Consequently, dietary protein won’t stimulate tumor growth, as the tumor is already getting all the amino acids it needs. Rather, the absorbed amino acids will start to replete the muscle protein that’s been lost due to the cachexia response.

Essential Amino Acid Supplementation for Cancer Patients

The muscle wasting seen in cancer cachexia contributes directly to mortality and should be treated nutritionally. But because of anabolic resistance and decreased appetite, normal dietary intake is generally insufficient to combat the rapid loss of muscle.

Thus, treatment of cachexia that incorporates the use of dietary supplements containing essential amino acids, including a relatively high dose of leucine, is a reasonable approach to slowing the rate of muscle protein loss, preventing skeletal muscle wasting, and improving nutritional status, weight gain (and thus body mass index), performance status, response to cancer treatment, and quality of life.