Cancer Cachexia

A multifactorial syndrome that encompasses a spectrum ranging from early weight loss to significant deterioration in body fat and lean muscle tissue resulting in death.

CACS - Cancer anorexia/cachexia syndrome - weight loss and loss of lean body mass.

50% of patients with cancer lose some body weight with one-third losin more than 5% of their original body weight and as many as 20% of cancer deaths resulting from cachexia.

Reduction in oral intake does not solely explain why cachexia occurs - may occur in patients that appear to take in sufficient calories.  Nutrition support does not successfully restore the loss of lean body mass with CACS.

Known factors contributing to development of CACS:

• Anorexia
• Early satiety
• Taste Changes
• Nausea
• Diarrhea/Constipation
• Fatigue
• Anemia

Cachexia Mediators:

Imbalance between pro-inflammatory and anti-inflammatory cytokines.

Pro-inflammatory (thought to be primary mediators assoc with development of CACS):

• Tumor necrosis factor (TNF)
• Interleukins 1 and 6 (IL-1, IL-6)
• Interferon Gamma (IFN-Y)

In animal studies, the infusion of pro-inflammatory cytokines found to produce anorexia, weight loss, proteolysis, lypolysis, and elevation sin cortisol and glucagon levels.  Also increase energy expenditure.

Hormones that affect appetite:

• Leptin - reduces appetite - down regulation of leptin production and expression of leptin receptors in the hypothalamus by tumor necrosis factor
• Grehlin - increases appetite - reductions in gstric production of ghrelin synthesis by various cytokines.

Proteolysis-inducing factor:  a glycoprotein isolated from the urine of weight-losing cancer patients but not from weight loss from other sources.

Malnutrition

Malnutrition characterized by a variety of clinical symptoms:

• Weight loss
• Poor wound healing
• Electrolyte and fluid imbalance
• Depressed immune function
• Increased morbidity and mortality

Not all patients with cancer become malnourished.  But all are at nutritional risk.

80% of patients present with weight loss before being diagnosed with cancer.

Malnutrition may result from:

• Disease process
• Use of antineoplastic therapy
• Both

Deterioration in nutrition status predicts outcome prior to start of therapy -  As little as 6% weight loss decreases response to treatment.

Malnutrition has detrimental effect on quality of life.

See also: Cancer Cachexia

Causes of Cancer

Exogenous Factors:

• Tobacco use
• Infectious Agents (bacteria, parasites, viruses)
• Medications
• Radiation
• Chemical Exposure (polychlorinated biphenyls, organic compounds used in plastics, paints, adhesives)
• Carcinogenic components founds in foods and beverages (aflatoxins, heterocyclic amines, polycyclic aromatics hydrocarbons, N-nitroso compounds)

Endogenous Factors:

• Inherited germ-line mutations
• Oxidative Stress
• Inflammation
• Hormones

Most experts believe that the majority of cancers are not inherited but rather arise from alterations in gene expression that promote changes in DNA over many years.

Nutrients that have been shown to influence cell-cycle progression and proliferation:

• Vitamin A - can result in cell-cycle arrist
• Retinoids can inhibit cellular proliferation of initiated cells by inducing apoptosis or inducing differentiation of abnormal cells back to normal
• Heme Iron - found to promote cellular proliferation of colonocytes

It is difficult to determine the precise etiology of specific cancers.  Many factors interact with one another as modifiers or precursors.

Energy intake and physical activity have been noted to alter pathophysiology.

• Energy restriction has been found to prevent cancer to a significant extent.  Supression of tumor development and increase in lifespan in animal studies.  Energy restriction results in reduced circulating levels of insulin-like growth factor (IGF-1) and insulin, both of which serve as growth factors for many cancer cells.  Other inflammatory markers also decline with energy restriction.
• Physical activity found to improve insulin sensitivity and reduce insulin levels.  Also decreases serum estrogen and androgen levels in both premenopausal and postmenopausal women (protection against hormone related cancers)

Lifestyle Factors

Cessation of tobacco use is the most critical modifiable risk factor in preventing cancer.
Body weight, diet and physical activity also play prominent roles in both primary and tertiary prevention of breast, colorectal, ovarian, endometrial, and prostate cancers.

Populations are increasingly sedentary.  Increasing physical activity may reduce risk for colorectal and breast cancers.  May also be beneficial for reducing risk of recurrence in survivors.

Cancer Development

Cancer is a cluster of more than 100 diseases that arise due to uncontrolled cellular growth.

The development of cancer occurs in three stages:  Initiation, Promotion, Progression'

Initiation
The development of precancerous cells.  The cell has been exposed to stress (such as oxidative stress) or to endogenous or exogenous carcinogens.  Precancerous cells form when the cell undergoes such exposure and fails to repair itself or die.  The cell forms DNA adducts - intermediates formed during phase I metabolism in the liver that may be carcinogenic and bind to DNA - which in turn distort the DNA, disrupting replication and/or translation.

Initiation alone is not enough for a cell to become cancerous.  However, the more precancerous cells that are initiated, the greater the risk for developing cancer.

Promotion
Stage 2 - the initiated cancer cell is further stimulated through cell signaling, which allows for cellular replication and growth leading to excess DNA damage that is beyond the capacity of the cell to repair the damage.
Also called cellular proliferation
Clusters of abnormal cells development, subsequently resulting in tumor formation,
Tumor types can be characterized by specific genetic lesions that develop during each step of the carcinogenesis pathway.
During the promotion stage, precancerous lesions can usually be detected (unlike during initiation)

Progression 
The cluster of abnormal cells may grow larger and/or translocate into other areas of the body (metastasize).

Cancer Related Fatigue

Cancer Related Fatigue

Definition:  a distressing persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer and/or cancer treatment that is not proportional to recent activity and interferes with usual functioning (NCCN 2015)

Fatigue is the most common side effect of cancer treatment.  It is also common in patients with advanced cancer who are not undergoing active cancer treatment.

Cancer treatment-related fatigue generally improves after therapy is completed, but some level may persist for months or years following treatment.

Cancer treatment–related fatigue is categorized as chronic fatigue because it is present over a long period of time, interferes with functioning, and is not completely relieved by sleep and rest.

Patients may describe fatigue as feeling:

• ·         Tired.
• ·         Weak.
• ·         Exhausted.
• ·         Lazy.
• ·         Weary.
• ·         Worn-out.
• ·         Heavy.
• ·         Slow.
• ·         Like they do not have any energy or any get-up-and-go.

Health professionals have included fatigue within concepts such as:

• ·         Asthenia.
• ·         Lassitude.
• ·         Malaise.
• ·         Prostration.
• ·         Exercise intolerance.
• ·         Lack of energy.
• ·         Weakness.

Most research is based on self-reports of fatigue, but could include objective measures such as muscle weakness, maximal oxygen uptake, cytokines and cortisol.

Fatigue has a negative impact on all areas of function, including the following:

• ·         Mood.
• ·         Physical function.
• ·         Work performance.
• ·         Social interaction.
• ·         Family care
• ·         Cognitive performance.
• ·         School work.
• ·         Community activities.
• ·         Sense of self.

Fatigue in cancer patients may be caused by the following:

1. ·         Cancer treatment with chemotherapy, radiation therapy, and some biologic therapies.    Nearly 90% of patients undergoing radiation therapy and 80% treated with chemotherapy experience cancer-related fatigue.  (Theory:  Caused by the build-up of toxic substances that are left in the body after cells are killed by cancer treatment.)
2. ·         Disease process – tumor requiring additional energy resources from the body
3. ·         Anemia (a lower than normal number of red blood cells).
4. ·         Neutropenia
5. ·         Hormone levels that are too low or too high.
6. ·         Trouble breathing or getting enough oxygen.
7. ·         Heart trouble.
8. ·         Infection.
9. ·         Pain.
10. ·         Stress - The emotional stress of cancer can cause physical problems, including fatigue.
11. ·         Anxiety/Depression - About 15% to 25% of patients who have cancer get depressed
12. ·         Loss of appetite or not getting enough calories and nutrients (The body needs extra energy to repair and heal body tissue damaged by treatment.  Additional calories are also needed because of a growing tumor, infection, fever, or shortness of breath.)
13. ·         Dehydration (loss of too much water from the body, such as from severe diarrhea or vomiting).
14. ·         Changes in how well the body uses food for energy.  A patient may eat the same amount as before having cancer, but the body may not be able to absorb and use all the nutrients from the food. This is caused by the cancer or its treatment.
15. ·         Loss of weight, muscle, and/or strength.
16. ·         Medicines that cause drowsiness.  Opioids, antidepressants, and antihistamines have this side effect. 
17. ·         Problems getting enough sleep.  Changes in the body's sleep-wake cycle.
18. ·         Being less active.
19. ·         During and after cancer treatment, patients may find they cannot pay attention for very long and have a hard time thinking, remembering, and understanding. This is called attention fatigue.
20. ·         Other co-existing medical conditions (diabetes, cardiopulmonary disease, renal failure, electrolyte imbalances, liver disease or thyroid disease)
21. ·         Alcohol or substance abuse

Patterns of fatigue:

·         People treated with cyclic chemotherapy regimens generally exhibit peak fatigue in the days following treatment, then report lower levels of fatigue until the next treatment.

·         Those undergoing external-beam radiation therapy report gradually increasing fatigue over the course of therapy of the largest treatment field. Fatigue usually increases until mid-way through the course of treatments and then stays about the same until treatment ends.

·         Biologic therapy often causes flu-like symptoms. These symptoms include being tired physically and mentally, fever, chills, muscle pain, headache, and not feeling well in general.

·         Few studies of people undergoing cancer treatment have addressed the issue of fatigue as a result of the emotional distress associated with undergoing a diagnostic evaluation for cancer and the effects of medical and surgical procedures used for that evaluation and for initial treatment. So they enter the cancer care system already experiencing fatigue even before treatment.

·         In men with prostate cancer, fatigue was increased by having the following symptoms before radiation therapy started:  Poor sleep, depression

·         In women with breast cancer, fatigue was increased by the following:  Working during XRT, having children at home, depression/anxiety, trouble sleeping, younger age, being underweight, having advanced cancer or other medical conditions.

Classification Criteria for Fatigue in Cancer Patients

Grade	1	2	3	4	5
Fatigue (asthenia, lethargy, malaise)	Mild fatigue over baseline	Moderate or causing difficulty in performing some ADLs	Severe fatigue interfering with ADLs	Disabling	NA
National Cancer Institute 2009

Recommendations for fatigue management:

Fatigue in cancer patients is often treated depending upon the symptoms and whether the cause of fatigue is known. When the cause of fatigue is not known, treatment is usually given to relieve symptoms and teach the patient ways to cope with fatigue.

The only definitive causal mechanism is chemotherapy-induced anemia – intervene here if possible.

The only level 1 intervention for CRF at this time is exercise.

Reduced sleep impacts fatigue in less well-functioning patients – less sleep, higher fatigue especially in those who were more ill.  Better sleep quality – less light in the environment, less noise

Treatment of anemia

Treating anemia (when known) may help decrease fatigue. Can include

• ·         Change in diet - Eating more foods rich in iron and vitamins may be combined with other treatments for anemia.
• ·         Transfusions of red blood cells
• ·         Medicine - Drugs that cause the bone marrow to make more red blood cells may be used to treat anemia-related fatigue in patients receiving chemotherapy. Epoetin alfa and darbepoetin alfa are two of these drugs. This type of drug may shorten survival time, increase the risk of serious heart problems, and cause some tumors to grow faster or recur. The Food and Drug Administration (FDA) has not approved these drugs solely for the treatment of fatigue.

Treatment of pain - If pain is making fatigue worse, the patient's pain medicine may be changed or the dose may be increased. If too much pain medicine is making fatigue worse, the patient's pain medicine may be changed or the dose may be decreased.

Treatment of depression –

·         Fatigue in patients who have depression may be treated with antidepressant drugs. 

·         Psychostimulant drugs may help some patients have more energy and a better mood, and help them think and concentrate. The use of psychostimulants for treating fatigue is still being studied - The FDA has not approved psychostimulants for the treatment of fatigue.  Psychostimulants have side effects, especially with long-term use. Patients who have heart problems or who take anticancer drugs that affect the heart may have serious side effects from psychostimulants. Some of the possible side effects include the following: trouble sleeping, headache, nausea, anxiety, mood changes, loss of appetite, nightmares, paranoia.

·         The doctor may prescribe low doses of a psychostimulant to be used for a short time in patients with advanced cancer who have severe fatigue. Talk to your doctor about the risks and benefits of these drugs.

The following drugs are being studied for fatigue related to cancer:

• ·         Bupropion is an antidepressant that is being studied to treat fatigue in patients with or without depression.
• ·         Dexamethasone is an anti-inflammatory drug being studied in patients with advanced cancer. In one clinical trial, patients who received dexamethasone reported less fatigue than the group that received a placebo. More trials are needed to study the link between inflammation and fatigue.
• 
  

The following dietary supplements are being studied for fatigue related to cancer:

• ·         L-carnitine is a supplement that helps the body make energy and lowers inflammation that may be linked to fatigue.
• ·         Ginseng is an herb used to treat fatigue which may be taken in capsules of ground ginseng root. In a clinical trial, cancer patients who were either in treatment or had finished treatment, received either ginseng or placebo. The group receiving ginseng had less fatigue than the placebo group.

Treatment of fatigue may include teaching the patient ways to increase energy and cope with fatigue in daily life.

Exercise  (including walking) may help people with cancer feel better and have more energy. The effect of exercise on fatigue in cancer patients is being studied. One study reported that breast cancer survivors who took part in enjoyable physical activity had less fatigue and pain and were better able to take part in daily activities.

In clinical trials, some patients reported the following benefits from exercise:  more physical energy, better appetite, more able to do normal activities of daily living, better quality of life, more satisfaction with life, greater sense of well-being, more able to meet the demands of cancer and cancer treatment.

Moderate activity for 3 to 5 hours a week may help cancer-related fatigue. You are more likely to follow an exercise plan if you choose a type of exercise that you enjoy. Patients may need to start with light activity for short periods of time and build up to more exercise little by little. Studies have shown that exercise can be safely done during and after cancer treatment.

Mind and body exercises such as qigong, tai chi, and yoga may help relieve fatigue. These exercises combine activities like movement, stretching, balance, and controlled breathing with spiritual activity such as meditation.

A schedule of activity and rest

Changes in daily routine make the body use more energy. A regular routine can improve sleep and help the patient have more energy to be active during the day. A program of regular times for activity and rest help to make the most of a patient's energy.

The following sleep habits may help decrease fatigue:

• ·         Lie in bed for sleep only.
• ·         Take naps for no longer than one hour.
• ·         Avoid noise (like television and radio) during sleep.

Cancer patients should not try to do too much. Health professionals have information about support services to help with daily activities and responsibilities.

Talk therapy

Therapists use talk therapy (counseling) to treat certain emotional or behavioral disorders. This kind of therapy helps patients change how they think and feel about certain things. Talk therapy may help decrease a cancer patient's fatigue by working on problems related to cancer that make fatigue worse, such as:

• ·         Stress from coping with cancer.
• ·         Fear that the cancer may come back.
• ·         Feeling hopeless about fatigue.
• ·         Not enough social support.
• ·         A pattern of sleep and activity that changes from day to day.
• ·         Self-care for fatigue
• Other considerations:
• ·         Teach energy conservation techniques (meal prep, eating smaller meals)
• ·         Distraction therapy (music, reading, journaling, social activities)
• ·         Support Groups

Study: University of Michigan School of Public Health
Could a diet rich in antioxidants improve fatigue?
Fatigue reduction diet improved fatigue and sleep in breast cancer patients.
Important nutrients: vitamin C, omega-3
  - from HEAL magazine, spring 2017

Resources and References:

ONS Foundation – Fatigue Initiative through Research and Education (FIRE)

Schwartz Cancer Fatigue Scale

ONS Get Up, Get Moving campaign

National Cancer Insitute:  https://www.cancer.gov/about-cancer/treatment/side-effects/fatigue/fatigue-hp-pdq

Nutrition Care Manual

Diet and Exercise for Cancer Survivors

Diet and Exercise for Cancer Survivors

Symptoms	Diet	Exercise
Depression	X	XX
Fatigue	X	XX
Adverse Body composition	X	XXX
Functional Decline	X	XXX
Co-Morbidity	XXX	XXX
Recurrent/Progressive Disease	XX	XX

ACS Nutrition and Physical Activity Guidelines for Survivors

·         Achieve and Maintain a Healthy Weight

o   Worldwide 35% overweight, 11% obese. Doubled since 1980

o   Especially important in Breast/Prostate Ca

o   65% population lives where obesity kills more than underweight

o   Obesity:

§  7 fold increased risk endometrium cancer

§  4.8 fold increased risk esophagus

§  Strong data on 11 other cancers (NEJM 2016)

§  Cancer mortality 15 cancers, including multiple myeloma in females (NEJM 2003)

o   Weight Gain after diagnosis:

§  Breast, 5kg increase increases mortality 30%

§  Prostate, recurrence risk 20% higher

BWEL study

American Society of Clinical Oncology – Position Statement on Obesity and Cancer

Avoid inactivity

Scale not as important as body composition

Sarcopenic Obesity:

                Gains in body fat without gains in muscle

                Recommended treatment is exercise, especially strength training

IARC – red meat is carcinogen, especially processed and cured

                No more than 18oz per week

                Each serving of red meat increases risk 10%

                Each serving processed meat increases risk 16%

                Substituting fish, nuts, legumes decreases risk of mortality 7-19%

Western diet double risk for breast and colon cancer

WHEL study

·         5 vegetables, 3 fruits, 30 grams fiber, 15-20% fat

·         No weight loss but may have had healthier diets at baseline

WINS Study

·         Low fat, especially for ER neg breast cancer. 

·         Women changed diet more and also lost weight, made big difference in survivorship

ETOH

·         H&N Cancer - Increases post treatment complications and reduces survival

·         Women who drink after breast cancer treatment increase risk of second cancer esp bowel

Supplements

·         H&N – supplements fueled second cancer, especially A + E

Important to wean high-dose supplements d/t rebound scurvy

Synergy with lifestyle choices – increases benefit versus just one change

Four Goals:

·         Lose Weight

·         Eat greater than five fruits and veggies

·         Activity

·         Quit Smoking

National Center for Complementary and Integrative Health

SURVIVORSHIP goals for breast cancer

·         D3 cognitive function

·         Bone density

·         Cardiovascular risks

·         Plant foods, exercise

·         Manage weight gain, DM, HTN, cholesterol

·         Omega 3 to reduce inflammation.  Use fish to replace arachidonic acid (meat)

o   Recommendations 2-3 grams/day?  Upper limit is 3

**Handwritten notes; ?? source

ALL – patients at risk for developing obesity during maintenance therapy and after treatment.  Rec increased activity.

Prostate cancer survivorship:

·         Lupron assoc with weight gain (~15# first year)

·         Enc daily exercise

·         Calcium, no more than 1500 mg combined diet and supps

·         ? checking vit D (esp if older, indoors, low intake