Impact of Protein Deficiency in Patients with Cancer

Introduction

Loss of skeletal muscle and body cell mass are often correlated with loss of strength, immune function, pulmonary function, as well as increased disability and mortality.^1-3 Protein is required for all components of the immune system and even moderate protein loss can negatively impact resistance to infection. Accordingly, in cancer, the loss of skeletal muscle may predict reduced quality of life and independence, as well as increased risk of morbidity and mortality.

Although the prevalence of inadequate intake and malnutrition varies across cancer types, poor nutritional status has been documented in more than 50% of patients at the time of diagnosis.⁴ Moreover, poor nutritional status is thought to be a significant contributor in 20% of all cancer deaths.⁵

Nutritional intervention may provide a means to decrease the rate at which muscle mass is lost. This paper will discuss protein metabolism, the mechanisms involved in the loss of muscle tissue in cancer, and the reported benefits of nutrition, most notably from dietary protein intake and energy in the form of carbohydrate and fat calories.

Protein Metabolism

Protein metabolism is the metabolism of lean body mass (LBM), consisting of all skeletal (muscle) protein and visceral (organ) protein. Skeletal muscle is the largest tissue in the body and accounts for half of LBM.6 The general factors regulating protein metabolism are reviewed in the simplified figure below.

Dietary protein

Adequate dietary protein must first and foremost be provided to build and maintain LBM. Adequate dietary protein ensures an adequate supply of all 21 amino acids (AA). Consequently, an inadequate dietary protein intake will result in breakdown of LBM to make the necessary concentrations of all 21 AA available. The analogy of a dog chasing his tail easily comes to mind when visualizing the scenario of inadequate protein intake.

Traditionally, amino acids have been nutritionally defined between two categories: essential (EAA) and nonessential (NEAA). See table below. Accordingly, EAA are those the body must obtain from the diet and NEAA, those the body can synthesize. Under this definition, dietary protein sources containing all EAA (high biological value proteins/HBV) have more value because EAA are rate limiting to net protein synthesis.

How much protein is needed?

Protein is the only nutrient that contains nitrogen (N₂) and therefore the only nutrient that may be exclusively used to synthesize LBM. In acute and study settings, this allows protein metabolism to be individually measured by calculating nitrogen balance.

In healthy people muscle tissues are constantly breaking down and being rebuilt; it is the dynamic balance between the synthesis of new muscle proteins (anabolism) versus degradation of current muscle proteins (catabolism) that is responsible for maintaining nitrogen balance.⁷ A N₂ balance of zero is a good thing and essentially means the body is in equilibrium. The term anabolism describes the net process of protein synthesis as well as a state of positive N₂ balance. Conversely, catabolism may be used to indicate the net process of protein degradation as well as a state of negative N₂ balance.

Given that nitrogen balance studies aren't usually available in the outpatient setting, guidelines are needed to help determine the amount of dietary protein a patient with cancer is likely to need. The Institute of Medicine cites the daily protein requirement to be 0.8g protein/kg^BW/day⁸, the majority of which is used to maintain muscle and other protein stores. The Recommended Dietary Allowance (RDA) in the US is also 0.8g protein/kg^BW/day, and is based on data from research in young healthy individuals, not the elderly and not those undergoing cancer treatment or recovery.

A reduced rate of protein synthesis and increased rate of protein degradation has been observed in muscle biopsies from cancer patients with weight loss.⁹ However, it's challenging to determine a guideline for dietary protein needs for persons suffering metabolic disturbances associated with cancer. The majority of protein metabolic research has focused on the requirement (read: minimum) for protein intake and not on optimal protein intake necessary to improve clinical and functional outcomes. The research which is outcome based has often focused on acute disease states, e.g. major burns, surgery, sepsis.

However, the progressive loss of muscle mass is a common phenomenon of old age^10-12 and referred to as sarcopenia. Muscle mass atrophies at a rate of 8% per decade starting at approximately age 40.^13-17 This continues until age 70 when the rate of muscle loss increases to 15% per decade.^13,14 Protein metabolic research focusing on the elderly may be somewhat helpful due to the higher incidence of cancer diagnoses in the elderly. It's also likely sarcopenia is compounded by loss of LBM associated with cancer.

Differences in digestion, metabolism, and circulation between the young and elderly would suggest that a higher value for protein needed may be more appropriate for the elderly. Research shows healthy, free-living elderly men and women accommodated to the RDA for protein of 0.8 g protein/kg^BW, with a continued decrease in urinary nitrogen excretion and reduced muscle mass. Accommodation is a survival response for short-term, acute protein deficiency and results in a net loss of LBM.¹⁸

The American College of Sports Medicine issued a 'Position Stand' on exercise in the elderly that discussed and also draws into question the RDA for protein.¹⁹ In 1985, the World Health Organization's (WHO) nitrogen-balance formula yielded an overall protein requirement estimate of 0.91g protein/kg^BW/day. Further research, conducted over a decade ago, suggests the elderly require an intake of 1.0g protein/kg^BW.²⁰ Experts in the field believe 1.0g protein/kg^BW may even be inadequate, and this amount needs to be increased to 1.2 -1.5 g protein/kg^BW. Another report showed dietary protein intake (up to 1.6 g protein/kg^BW) may enhance the anabolic response in elderly participating in a resistance exercise program.¹⁸ Increasing the amount of amino acids available to the tissues stimulates their incorporation into the muscle proteins of elderly individuals. This demonstrates that supplementing amino acids can stimulate muscle protein anabolism in elderly individuals with a reduced muscle mass.²¹ Further, we know that in the diets of healthy humans (elderly or otherwise), as dietary protein intake increases, stimulation of protein synthesis may increase in parallel to a ceiling of 1.5-1.7 g/kg of HBV protein.^22,23

What does that look like on the menu?

Although a hard and fast guideline does not exist for protein needs in the patient with cancer, the above data lends itself to a practical example. If an estimated protein intake of 1.3 g/kg is needed by a 70 kg (154 lbs) patient with cancer, that's 90 g of total protein, the majority which needs to come from HBV sources to support anabolism of LBM. By a simple move of the decimal place, 90 g translates into 9 oz of high quality protein foods per day.

Good sources of HBV protein are milk, cheese, eggs and meat/fish/poultry. Small amounts of lower quality proteins will come along with the consumption of breads/cereals/vegetables, but the important thing for the patient and caregiver to keep in mind as meals are prepared, served and eaten, is the number of ounces of HBV. Counting every gram of protein is neither necessary nor practical. See the chart below for approximate portion sizes of HBV protein foods.

Increasing the amount of dietary protein, as a percentage of total calories consumed, may support reducing the rate of muscle loss, whereas long-term consumption of inadequate protein will exacerbate the loss of muscle and other tissue protein.

What about vegan diets?

It's more difficult, but cancer patients following vegan diets can meet increased protein needs if nuts, seeds, legumes and cereal grain products are consumed in sufficient quantities. If all animal foods are excluded, supplementary vitamin B12 may be necessary, and supplemental vitamin D may also be a concern.⁴

Calories are needed to spare protein for synthesis

Each gram of protein synthesized to LBM requires 0.7 calories of energy.²⁴ In terms of energy value, dietary protein and carbohydrate each contain 4 calories/gram, whereas dietary fat has 9 calories/gram. Adequate caloric intake from carbohydrate and fat is critical to spare AA for use in protein synthesis and the maintenance of LBM, rather than to burn AA for energy. In this way, provision of energy in the form or carbohydrate and fat may serve to spare the body from additional protein catabolism.

In addition to energy, there is another important reason to provide carbohydrate in the form of supplemental calories. Carbohydrates stimulate the secretion of insulin which has anabolic properties. There is likely an optimal ratio of carbohydrate to protein that maximizes net anabolism for each individual according to age and cancer type/stage/therapy.

What causes LBM loss in cancer?

The loss of LBM in patients with cancer is aggressive and may occur in physically active individuals, even those consuming recommended amounts of protein and calories. Multiple metabolic factors are thought to be responsible for this condition, also known as cancer cachexia.

The role of the liver

The loss of LBM in patients with cancer is indicative of a shift in how the liver may be metabolizing protein. This, from a state of supplying amino acids and producing proteins for building muscle, to one of producing acute phase proteins such as opsonins, protease inhibitors, complement factors, apoproteins, fibrinogen and others. As a result, the synthesis of proteins needed to replace skeletal muscle may decrease sharply.^25-27

An inflammatory process is driving the shift in how the liver metabolizes protein in the patient with cancer. Therefore, in order to understand how nutrition can address the issue of muscle wasting, it is necessary to understand more about the inflammatory process.

Inflammation

Tumors cause inflammation and the resulting loss of LBM in two ways. One, the immune system may recognize and reject the foreign cell mass by increasing the inflammatory response. Two, tumor-derived compounds may also directly stimulate the production of inflammatory cytokines. Proteolysis inducing factor (PIF) is one such compound, and the mechanism by it works to disrupt protein balance is thought to also be two-fold. First, PIF is reported to increase protein degradation.²⁸ Second, PIF likely decreases protein synthesis, albeit indirectly. As a result of PIF's dual mechanism, a rapid loss of muscle protein may be induced when combined with maintenance of an inflammatory (catabolic) state.

Regardless of initiating cause, the result is elevated concentrations of the following pro-inflammatory cytokines: TNFα, IFN-γ, IL-1, IL-6, and IL-8, all of which promote the loss of muscle through upregulated protein breakdown. (See figure)²⁹

* Although appetite plays a significant role in LBM wasting, a discussion of the hormones and endogenous neuropeptides involved in appetite regulation are beyond the scope of this paper.

Altered protein metabolism in patients with cancer may stem from multiple causes including: inadequate dietary intake, increased uptake of amino acids by the tumor cells, decreased protein synthesis, increased protein degradation, and protein loss through fistulas or other gastrointestinal losses. However, an increase in the rate of muscle breakdown is the predominant mechanism.

Oxidative stress

Oxidative stress is an additional type of inflammation that may contribute to the loss of LBM in patients with cancer. Very simply, oxygen exists as two oxygen molecules bound together (O2), and is consumed by muscle cells during energy metabolism. If the two oxygen molecules become separated they form two 'singlet' oxygen (O•). The singlet oxygen molecule is called a reactive oxygen species (ROS) or free-radical. ROS that leak out of muscle cell mitochondrial membranes during aerobic respiration may have a significant degenerative effect on muscle fibers and degrade muscle proteins.^30-32 A low antioxidant status is associated with an inability to combat oxidative stress. As the damage progresses, muscle fibers release minerals, such as iron from myoglobin, which catalyze some of these oxidative processes and exacerbate muscle loss.³²

Examples of ROS include superoxide, hydrogen peroxide, and hydroxyl radicals. All aerobic respiratory tissues are exposed to ROS; however, oxidative stress occurs when the rate of forming ROS exceeds the rate of removal via endogenous antioxidants. Therefore, an accumulation of oxidative damage occurs as a result of either a decline in antioxidant defenses related to poor nutrition and/or each of the following: the excessive production of proinflammatory cytokines,^33,34 chemotherapeutic drugs (especially alkylating agents or cisplatin) and radiation therapy.³⁵

Bed Rest/Inactivity

Inactivity has a direct correlation to increased muscle loss, muscle weakness, and loss of total body nitrogen.^36-37 As recently stated, the rate of muscle protein breakdown is not increased by bed rest, but rather bed rest decreases the rate of protein synthesis.³⁸ However, the balance between these two mechanisms on overall protein loss remains controversial and more research is needed.³⁹

Decreased physical activity can lead not only to loss of LBM, but also to the development of metabolic abnormalities such as decreased glucose tolerance, peripheral insulin resistance and a possible decrease in skeletal muscle synthesis.⁵

Inactivity results in loss of both muscle and fat tissues. Bed rest study volunteers that were provided with 80% of their caloric requirements lost both fat and lean body mass as compared to ambulatory volunteers who maintained their lean mass. Evidence that inactivity blunts anabolism was provided by research where no postprandial anabolism was observed following prolonged bed rest.³⁶

The encouraging news is that individuals who maintain an active resistance training program have been able to slow and, for a period, stop the loss of lean muscle mass.⁴¹ Despite small sample sizes, existing evidence not only favors exercise as safe and feasible during cancer treatment, but that exercise may improve physical functioning and some aspects of quality of life.

Nutrition therapy for cancer

Nutritional therapy for patients with cancer needs to be initiated as early as possible to improve clinical outcomes and quality of life. Indeed, when nutritional intervention is provided proactively, the goals of nutritional therapy have a much better chance of being achieved. In a fairly recent study, a cancer treatment center took a proactive standardized approach to providing nutritional assessment and intervention to cancer patients (n=186) referred to the nutritional oncology service. All patients were managed by oral nutritional supplement intervention and aggressive management of treatment side effects during the 1 year duration of the study. The result was a 50% success rate in achieving weight maintenance or gain when all patients were accounted for, and an 80% success rate when those expected to live more than 6 weeks were exclusively considered.⁴²

Nutrition and quality of life

It has been suggested quality of life be utilized as the gold standard for an independent end point in clinical trials.^43,44 The interaction between nutritional status, dietary intake and treatment side effects are part of the disease- and treatment-related symptoms that factor into contributions from functional status and psychosocial well-being to ultimately determine quality of life for people with cancer.⁴⁵

A recent study looked at the interrelationships of disease-related and diet-related variables on quality of life in patients with head/neck, esophagus, stomach and colorectal cancer (n = 271) referred for radiation therapy (primary, adjuvant to surgery, chemoradiotherapy or palliative). Of interest, chemotherapy and surgery did not stand out as independent variables influencing quality of life.⁴⁵ The three main determinants for quality of life found in this study are described in the figure below.

Nutritional therapy may include dietary assessment and education, oral supplements, enteral tube feedings and/or parenteral nutrition. Given this paper's focus on protein metabolism and the maintenance of LBM, special emphasis will be placed on discussing the supplementation of dietary protein.

Dietary protein supplements

Dietary protein supplements are available in a variety of formats and derived from many sources. In addition, these supplements may be nutritionally complete, nutritionally-incomplete, or modular protein supplement products. The term 'complete nutritional supplement' refers to whether a product contains the macronutrients: protein, carbohydrate, and fat, as well as the vitamins and minerals essential for human health. The modular protein supplements lack one or more of the macronutrients and essential vitamins and minerals.

The amino acid profile of different protein sources and fractions determine the utility of the protein in nutrition. Commercially manufactured proteins used in supplements are either animal or vegetable in origin and most commonly derived from milk, soy, wheat, beans, or nuts. One of the most important differences between these sources, from a clinical standpoint, is their amino acid profile. Milk proteins are considered to be of the highest quality as a result of their rich indispensable amino acid content. If the intention of supplementing protein is to increase anabolism, then a protein with the highest BCAA and/or indispensable amino acid content, like whey protein isolate or concentrate, may be the best choice. Milk protein concentrate and higher quality caseinates are also excellent sources of BCAA. Soy protein isolates and concentrates typically contain less of these desirable amino acids. Although soy is considered an acceptable protein source, soy is less biologically valuable when compared to milk proteins.

Protein type matters with muscle wasting

As previously discussed, some dietary protein sources have greater value when evaluated biologically (e.g., complete indispensable amino acid profile, readily digestible, etc). (see chart below comparing whey, casein and soy protein)⁴⁶ Most sources of protein have been investigated for their ability to promote accretion of lean mass, but only some have been evaluated in the elderly and ill.

Whey and casein

Whey and casein proteins are high quality proteins considered to be quickly or slowly digested, respectively.^47-49 Protein source can significantly affect the appearance and concentration of plasma amino acids following a meal.^48,50,51 Ingestion of whey protein, as compared to casein, was reported to result in a greater postprandial concentration of plasma amino acids. The difference is thought to be related to the different rate of gastric emptying associated with their respective amino acid profiles. Gastric emptying, a major factor in milk protein absorption, is quicker with β-lactoglobulin (major constituent of whey) than casein.^52,53 As a result, casein is thought of as a slowly-digested protein while whey has been determined to be a 'fast' protein.^48-49

Dangin et al determined that in elderly subjects (≈72 years) there was a marked improvement in postprandial protein gain when given quickly digested whey protein as compared to more slowly digested casein. It is noteworthy that the difference in protein gain among the various dietary sources was only significant in elderly; no difference was observed in younger (≈24 years) adults. Dangin et al. hypothesized that AA availability between whey and casein was the rate limiting factor in protein gain. Other potential mechanisms offered to explain the difference included the higher leucine content found in whey as compared to casein.⁵⁴

Whey protein and cysteine

Whey protein is also an excellent source of cysteine, the rate limiting AA for synthesis of the body's central antioxidant, glutathione (GSH).^55-56

Glutathione is important for neutralizing the free radicals that can cause oxidative stress⁵⁷ and for supporting the inhibition of cytokine regulators that drive inflammatory processes earlier discussed.⁵⁸ Of interest, cysteine status has been found to be two times higher and disulfide cystine (another form of cysteine) status 30% lower in cancer wasting.^59,60

BCAA can aid in protein synthesis

BCAA have been given considerable attention in promoting protein synthesis in muscle. BCAA in human muscle have been shown to act as nutrient signals to activate messenger ribonucleic acid (mRNA) translation and protein synthesis.^61,62 Further, Stein et al supplemented BCAA into the diet of volunteers subjected to 6 days of bed rest who consumed a commercially available diet at 1.3X their resting energy expenditure (REE). The results of this work suggest that nitrogen balance can be improved by BCAA-supplementation as compared to a control diet supplemented with dispensable amino acids.⁶³

In particular, leucine has been reported to stimulate the translation of mRNA necessary for protein synthesis.⁶¹ Katsanos et al demonstrated that in elderly humans the ingestion of extra leucine with small amounts of amino acids reversed the attenuation of muscle protein synthesis.⁶⁴ This data emphasizes the role of leucine in the formulation of amino acid / protein nutritional supplements for the elderly.

Whey protein and BCAA

Whey protein isolate is rich in branched chain amino acids (BCAA) (up to 26%), and as a result receives interest as a nutritional method of promoting muscle synthesis.^65,66 Whey is also the richest leucine source available containing more than 12% of total protein. Other milk proteins, including milk protein concentrate and caseinates are also good sources, but contain less than 20% BCAA and thus less than 10% leucine.

Conclusion

The impact of protein deficiency and the associated loss of LBM for the patient with cancer are grave. A high percentage of cancer patients are also elderly and the underlying process of sarcopenic muscle loss and decreased mobility are already at play. Metabolic alterations by the liver, the inflammatory response driven by the tumor and a lack of physical activity combine to increase morbidity and mortality.

Clearly, supporting these patients to consume adequate amounts of HBV protein and calories is of paramount importance to improve outcomes. This support may come in the form of diet counseling, nutritional supplements, tube feeding or even parenteral nutrition. Whey protein in particular shows promise for supporting anabolism due to its concentration of BCAA and cysteine.

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