Saturday, May 26, 2012

Cancer Related Fatigue in Breast Cancer Patients: Exercise As A Therapy to Decrease the Deregulation of Cellular Energetics

Cancer-related fatigue (CRF) is one of the most prominent and under-discussed symptoms of cancer. 48% of cancer patients experience CRF and 58% to 94% of patients with breast cancer experience CRF while they are undergoing treatment (1). The National Comprehensive Cancer Network defines CRF as “a distressing persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” (2). Due to the persistent sense of tiredness unrelated to activity, patients often describe feeling paralyzed by CRF, as it interferes significantly with their quality of life. What I found fascinating was symptoms of CRF could be present after the cancer has been treated up until death, meaning something about the cancer, treatment, or both, caused a long-lasting, if not permanent change in the patient on a molecular level (1). It is also worth noting that breast cancer patients who received chemotherapy and radiation versus radiation alone were more likely to be fatigued years after treatment, showing the type of therapy most definitely influences the duration and severity of CRF (1).

In a way, CRF mirrors cancer. Although a common term, its causes are not well known and it does not stem from a single or direct source. Our current understanding of CRF suggests that it is brought on via a multitude of factors, just as cancer is. The web-like interactions between the numerous factors that cause CRF make it extremely complex and difficult to define. In recent years, health professionals have been trying to more strictly define CRF as well as create a universal scale and develop clearer guidelines that will illustrate its severity in a patient. This will also allow data to be compared with better accuracy in hopes to improve success with treatment and overall knowledge of CRF. I created a chart showing what are thought to be the top contributors to CRF and how they influence one another. Although the interactions are more complex than what I have shown, the diagram encompasses the general idea.

This article discusses several hypotheses and treatment options/potential treatments for CRF in breast cancer patients but I wanted to focus on one particular hypothesis, which supports the idea that exercises can help combat the debilitating symptoms of CRF. This hypothesis ties into one of the newer hallmarks of cancer that we have not discussed in much detail, ‘Deregulating Cellular Energetics’. It states, “CRF…may reflect disordered mitochondrial biogenesis, which upsets the balance between aerobic and anaerobic metabolism” (1). Tumor cells, unlike normal cells, have the ability to proliferate under hypoxic conditions – they rely on anaerobic glycolysis versus oxidative phosphorylation, the preferred pathway for muscle tissues (3).

Anaerobic Respiration: Oxygen is not required
C6H12O6 + (2) C3H6O3 (lactic acid) + (2) ATP
Aerobic Respiration: Oxygen is required
C6H12O6 + O+ CO2 + H2O + (38) ATP
Without oxygen, cancer cells are able to enter this glycolytic pathway, which produces lactic acid and a very minimal amount of ATP (1/19th the amount), depriving the normal muscle tissues of adequate levels of ATP, hence the lack of energy patients experience with CRF (4). This is a huge advantage for cancer cells because as the cells proliferate, the tumor environment becomes more hypoxic and thus the cells must be able to adapt to the conditions in order to thrive.;324/5930/1029/F2

How are they able to do this?
One of the ways cancer cells are able to survive under hypoxic conditions is due to the activation of the hypoxia-inducible factor gene (HIF). HIF is a heterodimer that is activated under hypoxic conditions. HIF induces a multitude of genes that lead to the modification of many cellular functions, allowing cancer cells to proliferate under conditions where normal cells would die (3). 

The Role of Mitochondria in CRF Under This Theory
This cellular energetics-based hypothesis infers that muscle tissues are deprived of ATP as a result of the tumors use of anaerobic metabolism; it is essentially based on the idea that there is an imbalance of aerobic and anaerobic metabolism that is created in the presence of breast cancer (1).

Muscles are full of mitochondria, which is where the Krebs cycle takes place. In glycolysis, pyruvate enters the mitochondria and undergoes oxidation, resulting in ATP as a product. ATP is energy that allows for protein synthesis to take place. Therefore a lack of ATP leads to in the “diminution of muscle biosynthesis” and impacts cardiac performance (1).

The Benefits of Exercise for Breast Cancer Patients with CRF
According to this hypothesis, the problem is that cardiac performance is negatively impacted due to the lack of muscle biosynthesis. This stems from the mitochondria being unable to produce as much ATP for protein synthesis. The idea behind exercising aiding in CRF treatment is that “resistance training or aerobic exercise stimulates mitochondrial biogenesis” and will thus lead to increased production of ATP and proteins (1).

Exercise is known specifically to help regulate sleep, mood, and cortisol levels (a hormone released in higher levels during periods of stress that also aids in fat, protein and carbohydrate metabolism). These are all critical targets in patients experiencing CRF. Just improving ones sleep can alleviate psychological disturbances, mood, and some comorbid conditions. Furthermore, exercising helps combat obesity, which increases the likelihood of breast cancer recurrence (1).

Other Treatments
Since CRF causes a whole host of symptoms, there are many ways it is treated. The book, Putting Evidence Into Practice, contains an entire chapter on fatigue and the effect of certain treatments. These treatments range from massage, relaxation, healing touch, behavioral techniques, exercise, to pharmacological treatments (5).

Problems Arising from CRF Treatment
As mentioned several times previously, there is no direct cause of CRF and many factors influence its severity and onset. Therefore, each patient must be considered on an individual basis. I imagine the future of CRF treatment being similar to personalized medicine and targeted drug therapy. What I see needing to be to be taken into account in treatment is:

Type of cancer
Stage of cancer
Date of diagnosis
Recurrence of cancer (1st or 2nd time having it etc.)
Type and duration of treatment
Past medical history
Current conditions (medical or psychological)
Current medications
General lifestyle (profession, levels of activity, diet, weight, etc.)
Family history   

Thinking about this reminded me of Kate Loranger’s lecture on her profession as a genetic counselor. CRF seems like a significant enough condition to where a specialized profession specifically dedicated to treating patients suffering from it would be extremely beneficial. Just like a genetic counselor, they would spend a long time getting to know the patient in detail and from there would decide the best course of treatment and monitor them along the way. Right now, doctors are the ones treating patients with CRF however it seems as though the condition calls for much more personalized attention. Perhaps it could be a profession available to those who have gone through medical school and would then require an additional amount of training. These specialists would not only be skilled in medicine and diagnosis, but also in psychological treatments like a genetic counselor. From my knowledge of CRF, the psychological part is an incredibly important area to target. There should be open communication with not only patients but also their family, friends, and caregivers so they all can contribute to improving the comfort and quality of life for the patient.

1.) I liked this article because it helped me gain a better perspective about what it’s like on an everyday basis to have cancer. We learn a lot about cancer on the molecular level and can often see the physical symptoms of cancer like hair loss, but if it has not had a direct impact on your life, it is difficult to imagine what it’s like to be the patient. I know I often think of symptoms of cancer as a direct result of chemotherapy and radiation like nausea, hair loss, and exhaustion but I never really realized the stress and fatigue patients constantly experience even after they have been treated.

2.) After reading this, I was surprised by the percentage of people who suffer from CRF without treatment success. Modern day medicine is so advanced it seems we can treat almost anything. Many of the symptoms of CRF also mimic those of chronic fatigue or depression, which we can typically treat with success, so it is interesting that so many people still suffer from it.