Effects of Physical Exercise on Muscle Wasting in Cancer Patients

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Introduction:

Cachexia, meaning bad condition in Greek (4), is defined as “ a loss of lean tissue mass, involving a weight loss greater than 5% of body weight in 12 months or less in the presence of chronic illness”, like cancer (2,4,15,17,18,19,20,22,30,31). To be classified in a state of cachexia, 3 of the 5 criteria must be met along with a 5% weight loss in 12 months. Those criteria include; fatigue, the decline in muscle strength, low serum albumin levels, low fat-free mass index, and changes in biochemistry markers (4,15). There are 3 stages of muscle wasting: pre-cachexia, cachexia, and refractory (2,6). Pre-cachexia is deﬁned as weight loss ≤ 5% with anorexia and metabolic changes (17). Refractory is known as the “terminal stage of cachexia… it is also the stage at which interventions are the least likely to be effective, and it predicts limited survival” (10). While there are stages in this process, not every patient experiences cachexia from pre-cachexic to refractory. Although cachexia may not be able to be fully reversed, a multidimensional treatment approach should be implemented early to help prevent or delay the progression of cachexia (6). Death in these patients is dependent on the amount of weight loss which is why maintaining weight and muscle mass is an important factor (8,29). Prevention will not only help the survival rate but can also help the tolerance of anti-cancer treatments and help increase the patient’s quality of life (5). Research suggests that a combination of nutritional, pharmacological methods and physical activity show the greatest benefit to a patient with cachexia (2).

Significance of Problem:

With any health condition, there are risks that could cause the problem to worsen. Addressing the issue early and being proactive, could help prevent many negative outcomes that stem from health problems like cachexia (6). If preventative measures are not taken early on, the severity and rate of progression could be more severe than they would be if the correct precautions were taken (6). Without prevention, the patient is at higher risk to develop many other health conditions that are associated with the illness (6). Chemotherapy toxicity, shorter time to tumor progression, increased risk of poor surgical outcome, physical impairment, and shorter survival rate are just a few outcomes that could stem from cachexia (6). If cachexia is taken control of early on after diagnosis, a patient’s quality of life could enhance, and this is also important in treatment and recovery (6). Poor quality of life can cause a patient to become depressed and this can create a barrier to a patient’s outlook on life and see the condition as only negative (31).

According to Alves et. Al. (2015), eighty percent of people with advanced cancer will develop cachexia (1). Muscle wasting is more prone to happen in individuals who suffer from pancreatic, stomach, or esophageal cancers (24). Of the eighty percent who develop it, twenty to thirty percent of cancer-related deaths are due to a large amount of body weight loss (1,5,16). While aging humans are predominately disposed to a five to ten percent muscle mass loss every decade after the age of fifty, cachexia can show a five percent loss in less than 12 months (27). While muscle mass loss from aging is normal, certain health conditions that arise later in life such as cancer can exacerbate the decline of muscle mass, but treatments can help reduce these negative effects (8, 29).

Review Of Literature:

Exercise in General

Exercise is defined as a “planned structured and repetitive bodily movement done to maintain or improve one or more components of physical fitness” (17). Exercise, in general, has many positive outcomes for both healthy individuals and also someone who is suffering from cancer cachexia. Exercise can increase the quality of life in more ways than one, such as muscle hypertrophy, lessening fatigue related to cancer, helping inflammatory response, and increasing muscle strength just to name a few. (6, 29). Due to these responses, it was found that physical exercise needs to be implemented in a patient’s daily regime as a complementary treatment to other cancer treatments (22, 25).

One factor that comes from cancer itself is cancer-related fatigue, which could pose a problem in completing an exercise plan. Cancer-related fatigue has effects on many aspects, including quality of life. A study by Dimeo showed that exercise, when tailored to the individual, can increase energy in the patient, as well as, physical and mental benefits, increased functional capacity, improved quality of life, and decreased depression and anxiety (9,14). While trying to find a treatment for fatigue that stems from cancer, the theory of planned behavior by Icek Ajzen in 1985, was introduced into helping cancer patients. The theory of planned behavior was introduced to a group of patients that were experiencing cancer-related fatigue (31). The theory proposed that the motivation or lack thereof, would come from the potential of enjoyment, expected benefit or harm the task could bring, anticipated difficulty, and also a sense of support from others around them (31). It was found in a study by Brown, Huedo-Medina, Pescatello, Pesctello, Ferrer, and Johnson, that patients with cancer who were active, experienced multiple mental and physical benefits, increased quality of life, improved functional capacity, and a decrease in depression and anxiety (9).

Fatigue is different in every individual (9). These levels differ in each individual, it was proposed that each plan needs to be individualized so that each patient feels comfortable with the task before them (9). As stated, every patient is on different levels of the condition, whether it be disease progression or level of energy, which is why physicians are to individualize each exercise plan so they are tailored to the individual needs and energy levels (9). Fatigue, after diagnosis of the disease, is one of the first symptoms that need to be treated to help the patient progress through their treatment plan. This can also help increase the survival rate, as well as, delay the progression of cancer cachexia (14).

There are many negative symptoms and outcomes with cancer cachexia. It causes weight loss, a decrease in exercise capacity, as well a decreased survival rate (17). These are major factors that need to be dealt with to ensure survival and recovery. The loss of skeletal muscle that stems from cancer cachexia causes a decrease in protein synthesis and also an increase in protein degradation (7,15). Protein synthesis is a mechanism in the body that is used to build protein molecules while protein degradation is the process by which cells see the damaged and faulty cells and deteriorate them (7, 15). When these two body mechanisms are working against each other, there are no new proteins being made so muscle starts to waste away (7, 15). In Cancer Cachexia Prevention via Physical Exercise, it was shown that exercise is “shown to be effective at counteracting the muscle catabolism by increasing protein synthesis and reducing protein degradation, thus successfully improving muscle strength, physical function, and quality of life” (16). Physical exercise has the potential to balance protein turnover to anabolic versus catabolic reactions, making it so that there is no loss of protein synthesis and protein degradation only (8).

Cancer cachexia puts the body in a starvation-like state. It produces changes in weight, muscle, and adipose tissue wasting, anorexia, anemia, change in energy balance, and changes in the way the body metabolizes carbohydrates, lipids, and protein (8). In all health conditions, weight loss and starvation halt the recovery process (8). Exercise in any form can promote a disturbance in this cycle (8). It was found in the investigation by Battaglini, Hackney, and Goodwin that these disruptions can help with the promotion of muscle mass retention and hypertrophy of the muscle tissues (8). These disruptions can help lead to improved bodily functions and quality of life in a patient suffering from cachexic conditions (22).

When trying to increase skeletal muscle and muscle mass that has been lost, physical exercise is the only therapeutic method that has been shown to do just that (16). Skeletal muscle makes up to fifty percent of someone’s total body weight and consists of over six hundred separate muscles. When there is an imbalance of catabolism and anabolism, patients start to see a decline in muscle mass and muscle strength (19). Exercise is known to have an anabolic effect, especially when resistance methods are used (5). While there are no concrete ways to help prevent and lessen the effects of cancer cachexia it has been researched that endurance and resistance both show positive benefits. It’s been found that “exercise training can induce an increase in protein synthesis” (28). “In addition, increased protein synthesis depends on exercise intensity. Therefore, high-intensity exercise training is effective in increasing protein synthesis. However, it is difficult for cancer patients with cachexia to perform high-intensity endurance exercises. Low-intensity endurance exercises is an effective countermeasure” (28). In a study by Strasser, Steindorf, Wiskemann, and Ulrich, it was shown that patients’ muscle strength was improved after low volume, moderate volume, and high volume exercises (28). It is known that these all make positive impacts on strength. When dealing with patients suffering from cancer, especially cancer cachexia, it needs to be known that these patients are not as capable to perform at the same levels as healthy individuals (11). Individuals suffering from cancer cachexia can’t always perform at the same level as healthy individuals, individualized plans are the most successful way to reduce the effects of cancer cachexia (9). An example of an exercise prescription recommendation for someone battling cancer would be: after treatment exercise would be 3-5 days per week along with resistance training 2-3 days per week (11). Those that are still going through treatment can increase exercise over the span of a month (11). It was found in a recent study that when the low-load high volume was compared to high-load low volume, both being completed to failure, low-load high volume was more effective when increasing muscle protein synthesis (28). With this information, it may be thought that when trying to increase protein synthesis, the intensity is not the dependent factor as it is the volume of the exercise.

Exercise in general has a positive effect on the inflammatory response. Inflammation is a defensive shield for many different things, such as injuries, diseases, and cancers (13). Chronic inflammation can cause an increase in a person’s risk for cancer (13). Cancer and some of its associated treatments can promote the negative cytokines that promote the pro-inflammatory factor that is not wanted in cancer patients (8). Exercise, in the correct quantities, without pushing the patients over their limit is known to promote upregulation of anti-inflammatory cytokines and can also down-regulate the detrimental cytokines that induce pro-inflammation (8). The anti-inflammatory cytokines help to counteract the catabolism of muscles, it also increases protein synthesis, and helps to reduce the degradation of proteins, this will also help to improve muscle strength, physical function, and his/her quality of life (16). “Acute exercise is known to induce immune response with greatly enhanced production of both cytokines involved in the acute-phase inflammatory response and those that limit the inflammatory response”(16). This anti-inflammatory response has the ability to reduce systemic inflammation that is stemmed from cancer because of this process, it was found that it can relieve the wasting process brought on by cachexia (16). Repeated exercise would be more beneficial to produce anti-inflammatory cytokines if implemented in the early stages of cancer (17). Systemic inflammation that is brought on by cancer cachexia is associated with reduced weight, reduced exercise capacity, and reduced survival (17). “Incorporation of exercise training as a part of the therapeutic regime of cancer treatment can result in these anti-inflammatory cytokines mitigating some of the effects of the pro-inflammatory and through increased androgenic hormonal actions skeletal muscle protein synthesis is enhanced leading to a reduction in the muscle tissue and net protein losses within the cancer patient” (8).

Exercise is beneficial in so many ways. It can increase muscle mass, help a person’s overall mental and personal health, and muscle strength, reduce fatigue, increase metabolic changes, decrease inflammation, and many more. The processes within a body keep it going and help fight against infections and diseases. Even if a person did not exercise before they developed cancer cachexia, it is shown to help during the treatment process (28). The effects of exercise outweigh many treatment methods, but it is best to be used with other treatments for optimal success.

Resistance

Most people know a resistance exercise is a form of exercise that gains muscle and strength. Knowing that this is the outcome of resistance training and knowing that cancer cachexia produces a loss of muscle as well as weakens an individual. This regime of exercise seems a perfect combination to help combat the negative outcomes of cachexia.

Resistance training provides an increase in muscle fibers, which in turn helps gain muscle mass and also helps increase body weight, which is needed in patients suffering from cancer cachexia (18). Cancer cachexia treatments need to be a multifaceted approach. When individuals are on a positive basis on certain aspects such as nutritional status, pharmacological method, and exercise training, there is potential for a positive outcome to be reached (2,18). Resistance exercise can go farther past just building muscle and building strength. It can also help build confidence in the patient to ease their mind (21). Wondering if they can withstand having to do daily tasks of living can put a toll on individuals’ quality of life (21). Resistance can also improve the daily function of patients (21). With all the benefits of resistance training, it seems to be a viable option when treating to prevent, delay or reverse muscle wasting (21).

In a study by Little and Phillips, it was found that in a 12-week program of resistance training that both type I and type II muscle fiber size increased and also improved muscle strength by 25-30% in patients with renal disease muscle wasting (16,21). In an 8-week study, conducted on patients with HIV muscle wasting, a resistance program increased muscle strength by 60% and lean body mass by 5% was found (16,21). In another study, it was found that using high-intensity resistance training in patients during chemotherapy that there was an average increase in muscle strength of 41.3%, as well as, a 1% increase in body weight (16). With cancer cachexia wasting muscle at 5% or more in 12 months, this form of treatment can help delay the onset of cachexia or even refractory by slowing down the process because of the increase in muscle strength percentage (4). Resistance training showed in a study by Strasser, Steindorf, and Wiskemann that there were significant improvements in muscle mass and muscle strength in both upper and lower limbs (27). The 14.6kg increase in lower limb muscle and a 6.9 kg in the upper limbs in a period of 12 weeks to one year (27). These large gains produced in the study can have the potential to increase the individual’s life expectancy (27). In the same study, it was predicted that if an individual with cancer cachexia performed resistance training two times a week there is potential to have an increase in muscle mass by 1-2kg per 6 months (27). Increases of that magnitude can help prevent disease muscle wasting as well as age-associated muscle wasting losses. If this type of treatment could prevent patients suffering from pre-cachexia from progressing into cachexia or cachexia into refractory, the chances of survival would increase in the individual.

The musculoskeletal part of a human is so vital to daily living that it will have the potential to slow the progression of cachexia. “An improved musculoskeletal fitness is linked to bettered health status and greater quality of life (29). As described before, quality of life is important in the recovery process. Exercise has been found to improve a person’s mental health which is needed in all deterring health conditions Resistance training generates force in the muscle, before any other improvement the first is increasing the size of the muscle (29). This hypertrophy is due to the increased protein synthesis in actin and myosin, which is reduced during cancer cachexia (29). This increase in protein synthesis in the muscles is the element that increases muscle mass and muscle strength (29). When trying to produce improvement in muscle mass or muscle strength, whether in a healthy individual or someone suffering from cachexia, it is necessary to keep increasing the exercise prescription (29). Modifications are different for each individual as they begin to become more familiar with the training or when they start to see plateaus in the improvements (27). “Resistance training is well established non-pharmacological anabolic strategy promoting skeletal muscle hypertrophy and improving muscle function” (23).

Aerobic training

Aerobic training has been found to increase multiple different aspects that are, produced through cancer cachexia. Cancer cachexia pathogenesis has the following linked; anorexia, metabolic issues, inflammation, and enhanced muscle proteolysis (7). Aerobic exercise provides improvements in quality of life, exercise capacity, flexibility, body composition, fatigue, muscle endurance, pain, nausea, diarrhea, sense of control, depression, self-esteem, and life satisfaction were all found in cancer patients during or following aerobic training cancer treatments (29). With these improvements, it is likely that providing aerobic treatment during or after cancer treatments provide positive effects on the individual in quality of life and physical functioning (29).

This form of training stimulates oxidative metabolism (5). Oxidative metabolism is directly correlated with the prevention of hyperlipidemia, a condition where there are high levels of fat deposits in the blood, this can restrict blood flow through the vessels, increasing the risk of heart attack or strokes (5,11). It can also improve insulin resistance; aerobic training can help decrease the amount of insulin that is found in the blood and decrease the chance of developing type 2 diabetes (1). The inflammatory response is also reduced when aerobic training is implemented (5). “Regular exercise appears to significantly lower circulate C-reactive protein and inflammatory cytokines concentrations” (26). C-reactive protein is a protein made by the liver and is sent to the bloodstream as a response to inflammation, high levels of C-reactive proteins mean there is a serious infection in the body (12). It also lowers the concentrations of plasma that has interleukin, and tumor necrosis factor-alpha (26). In the study by Laura Stewart et al., there was found to be a 58% reduction in the C-Reactive protein due to aerobic exercise (26). When healthy active individuals are compared to inactive individuals, the active individuals show a response of a lower concentration in the blood with C-reactive proteins (26). In a study done in animal models, it was found that chronic endurance exercise prevents/ reduces the symptoms of cancers, so it was proposed that endurance exercises can be a low-cost, and safe option for patients with inflammations (20).

Aerobic exercise is “associated with the prevention of a large spectrum of disorders” (1). This exercise regime causes many adaptions to happen in the body; inducing protein turnover, mitochondrial biogenesis, and anti-oxidant capacity (1). While cancer cachexia is an imbalance of protein synthesis and degradation, protein turnover can help balance out these two battling forces, helping to stabilize the wasting process (15). Helping to stabilize this process can also lead to more mitochondria being stored and made in the body (1). With this, you can also expect an increase in mitochondrial biogenesis because the more muscle, the better the ability of the muscle to make and store these mitochondria (1). Mitochondrial biogenesis is the process in which there is an increase in the number of mitochondria being made in the body, which in hand also helps the muscle uptake more glucose, helping the insulin sensitivity that cancer cachexia presents (1). Aerobic exercise training “also included an increase in aerobic consumption of substrates and prevention of glucose and glutamine metabolism impairment in immune cells” helping to increase insulin sensitivity(1). There are many benefits that aerobic exercise is associated with, including, increased survival, decreased tumor growth, prevention of body mass losses, and a decrease in skeletal muscle degradation (1).

Ubiquitin-proteasome and autophagy are also increased through aerobic exercise training (1). Both of these processes maintain the cellular mechanisms and recycle damaged organelles that happen because of cancer (1). Autophagy will improve muscle energy balance because it rids the body of damaged and aged mitochondria (6). Aerobic training has benefits such as autophagy, positive metabolic changes, and oxidative metabolism processes making it easy to see that this form of exercise needs to be implemented in someone who is suffering from these types of muscle wasting diseases. It is a low-cost, low-risk form of rehabilitation that could help prevent, delay and possibly reverse the disorder at hand.

Conclusion:

Your body is made up of over 600 different muscles and contributes up to 50% of a person’s total body weight (19). Cachexia starts to diminish these muscles and induce muscular wasting and a loss of overall body strength, along with the normal decline in muscle because of aging (27). A decrease in protein synthesis and an increase in protein degradation in combination produce the loss of skeletal muscle mass (7,15). This can account for twenty to thirty percent of cancer deaths (1,5,16). This high prevalence of deaths makes prevention a key factor in slowing down this process. Prevention won’t only affect the survival rate but can also help the tolerance to anti-cancer treatment, and quality of life (5,6,30). Exercise, in any form, whether aerobic or endurance seems to promote good outcomes for someone who is suffering from cancer cachexia. It has been shown to increase lean body mass, and functionality, increase strength, increase anti-inflammatory cytokines, decrease the pro-inflammatory cytokines, increase protein turnover, and increase oxidative metabolism, and insulin sensitivity (8). It can also help prevent and slow down these negative determents that cancer cachexia can put onto the body (5,6,30).

Exercise is a low-cost and low-risk form of treatment that when used and prescribed correctly can cause great outcomes (3, 20). To make the best impact on the individual, a multidimensional approach needs to be done, exercise, nutrition, and pharmacology (2,6). Physical exercise produces many great outcomes but these potential benefits can be abrogated if the patient does not have a good nutrient basis (5). The nutritional state needs to be looked at in the patients because if not enough nutrients in the body this could further the wasting process in the individual (5). Pharmacological can be added, such as steroids, and at the appropriate time, nutritional supplementation can promote large gains in muscle mass in cachexic patients (21).

It was very emphasized that cachexia needs to try to be prevented instead of trying to be reversed (6). This makes early recognition of cachexia a very important factor in survival, it can also help reduce its effect (6). When cachexia is diagnosed earlier in the progression, treatments can be used to slow down the process (30). Another early factor is the introduction of physical activity (3). It is important in health maintenance and cancer prevention, but now, research shows that it can be a vital part of cancer treatment (3). The exercise showed reductions and improvements in many cancer patients’ progression from cachexia. Reduce fatigue, improve strength, improvements in muscle mass, increase function capacity, increase quality of life, and many other cachexia-prone impairments (8,9,14,16,18,21,27,28,29,31). This makes it important to start implementing physical activity to help prevent or delay cachexia effects (6). Even if exercise was not a part of the patient’s life beforehand, exercise has still shown benefits during and after treatment, it helps improve quality of life and reduces fatigue brought on by cancer (6).

Exercise dosing is a very important individualized component. While exercise helps decrease the amount of fatigue, every patient needs to be evaluated differently than the last and differently than the next (5,6). Cancer and cancer-related cachexia affect each individual differently, as well as, each patient will have a different exercise capacity (5,6,9). A large part of a patient’s recovery will be dependent on the exercise program and their ability to perform the exercises at the given workload and intensity (5,6,9).” Exercise training needs to be compatible with the exercise capacity of the cancer patients” (5,6). Aerobic and resistance exercises both have shown numerous advantages when implemented in the recovery of cachexic patients. Aerobic and resistance exercises have also been “accepted extremely well and enjoyed when the programs are tailored specifically to the individual patient” (8).

Exercise alone or in conjunction with the other methods has a lack of negative effects and an abundance of positive benefits. With all this information on the positive effects of exercise, it has proven as a low-risk therapy that can improve activities of daily living and improve quality of life (3). Being proactive needs to have a greater emphasis placed on it, this will have the goal to maintain or delay the process of losing physical function (17). It has been proven to be a safe complementary treatment (22). Physical exercise needs to be recommended for everyone because of the role it has in preventing these negative effects of cancer (3). Physical exercise has been successful in increasing muscle mass, and muscle strength, reducing fatigue, enhancing the quality of life, and has had no negative effects reported, making this treatment option safe and beneficial to a person suffering from cancer cachexia (3,8,9,14,16,18,21,27,28,29,31).

Future Research:

There are multiple different research aspects that could provide beneficial information on delaying cachexia effects. While multiple studies showed the effects of exercise on patients after treatments, a study that showed the effects of muscle mass and strength on these patients during active treatment could show some positive results. While chemotherapy and radiation can have deleterious effects on muscle mass, and strength, it also shows fatigue (6). A study by Dimeo showed that exercise when tailored to the individual can increase energy in the patient, as well as physical and mental benefits, increased functional capacity, improved QOL, and decreased depression and anxiety (9,14) it is also known that resistance exercise can increase muscle mass and strength. A new study could be beneficial to see the kinds of results that could come from trying physical activity during active treatments to see if the results from the exercise can delay the negative effects or even help sustain the amount of muscle mass and strength that an individual has before the start of the disease. If the positive effect of exercise can equal or increase the body mass and strength of pre-disease then pushing for patients to include physical activity during treatment would be a new modality that could be added. So when these are used coincidently the exercise may be able to help reduce the number of negative effects put on the body.

Another spin-off to the above future research would be to see if patients who were physically active before their diagnosis helped to lessen the cachexia effects or slowed the down the progression. Having a larger percentage of muscle mass can contribute to a longer time frame of how severe the negative effects arise in the patients. This could provide more time to further slow down the progression, as well as, have a longer time frame to cure cancer. Being able to cure cancer before the severe effects show up could potentially raise the survival rate.

If being previously active was not in the patient’s lifestyle. Researching how the effects differ if exercise is added in at different stages. Timing can be key in many situations, including the diagnosis of cancer. While someone in the refractory stage has a very low survival rate, would introducing exercise provide enough time to make any difference in the patient’s final outcome, whether it be cachexia or cancer-related?

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