Cancer cachexia and cannabinoids [Archive] - Oregon Green Free Forums

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November 21st, 2008, 09:10 AM

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Cancer Anorexia-Cachexia SyndromeCurrent Issues in Research and Managementhttp://www.cancer.org/common/images/shim.gifCA Cancer J Clin 2002;52:72-91
Akio Inui, MD, PhD
Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a six-month period.
The two major options for pharmacological therapy have been either progestational agents, such as megestrol acetate, or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide—all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release.
Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life. (CA Cancer J Clin 2002;52:72-91.)
Introduction
Anorexia, involuntary weight loss, tissue wasting, poor performance, and ultimately death characterize cancer cachexia—a condition of advanced protein calorie malnutrition.1-9 Referred to as “the cancer anorexia-cachexia syndrome,” anorexia, or loss of compensatory increase in feeding, is a major contributor to the development of cachexia.
The word “cachexia” is derived from the Greek words “kakos” meaning “bad” and “hexis” meaning “condition.”1 About half of all cancer patients suffer from this syndrome.2
In general, while patients with hematological malignancies and breast cancer seldom have substantial weight loss, most other solid tumors are associated with a higher frequency of cachexia. At the moment of diagnosis, 80 percent of patients with upper gastrointestinal cancers and 60 percent of patients with lung cancer have already experienced substantial weight loss.2
Cachexia is more common in children and elderly patients and becomes more pronounced as the disease progresses. The prevalence of cachexia increases from 50 percent to more than 80 percent before death and in more than 20 percent of patients, cachexia is the main cause of death.2 Cachexia occurs secondarily as a result of a functional inability to ingest or use nutrients. This can be related to mechanical interference in the gastrointestinal tract, such as obstruction or malabsorption, surgical interventions, or treatment-related toxicity. And in patients receiving chemotherapy or radiation therapy, nausea, vomiting, taste changes, stomatitis, and diarrhea can all contribute to weight loss.8
Patients with cancer often experience psychological distress as a result of uncertainties about the disease, its diagnosis, treatment, and anticipated final outcome. This psychological state, which often coexists with depression, is bound to affect food intake.
Thus, cancer anorexia-cachexia syndrome is seen as a multidimensional (mal)adaptation encompassing a variety of alterations that range from physiological to behavioral and is correlated with poor outcomes and compromised quality of life.
Detection of Cachexia
A patient’s nutritional state is usually evaluated with a combination of clinical assessment and anthropometric tests, such as body weight, skin fold thickness, and mid-arm circumference.10,11 But most clinicians rely on body weight as the major measure of nutritional status, using usual adult weights as a reference.
Although the range of body weight is wide, the range of individual weight fluctuations over time is known to be much narrower. It was shown that the 95% confidence intervals for change in body weight in healthy adults were approximately ±2% in one month, ±3.5% in three months, and ±5% within a six-month period of follow-up.5,12 Therefore, any weight change occurring at a higher rate can be considered abnormal. Cachexia should be suspected if an involuntary weight loss of greater than 5 percent of premorbid weight is observed within a six-month period, especially when combined with muscle wasting. Often a weight loss of 10 percent or more, which indicates severe depletion, is used as a starting criterion for the anorexia-cachexia syndrome in obese patients. It was shown by body compartment analysis that patients with cachexia lose roughly equal amounts of fat and fat-free mass.5,13 Losses of fat-free mass are centered in skeletal muscle and reflect decreases in both cellular mass and intracellular potassium concentration.5,13
Cancer patients with a known involuntary 5% weight loss have a shorter median survival rate than patients with stable weight.14 Patients with weight loss also respond poorly to chemotherapy and experience increased toxicity.12 It should be emphasized that cachexia can be an early manifestation of tumor-host interaction (i.e., pulmonary and upper aerodigestive cancers).
A number of laboratory tests to assist in evaluation of nutritional status are available, such as the measurement of short half-life proteins (transferrin and transthyretin) and analysis of urinary metabolites (creatinine), but many of these are of limited value among cancer patients because of the chronic nature of malnutrition.10,11
Serum albumin is one of the most common parameters used because of its low cost and accuracy, in the absence of liver and kidney diseases. Fat and muscle differ in their water composition and therefore, their electrical impedance.10,11 Bio-electrical impedance analysis measures impedance between surface electrodes on the extremities in order to estimate total body lean mass. Although not routinely used, this method can provide data that is helpful in evaluating investigational treatments and, in the future, may become more important in clinical practice than simple measurement of weight, which cannot discriminate lean tissues and fat mass.
Pathogenetic Mechanisms of Cachexia
Anorexia
Energy intake has been shown to be substantially reduced among weight-losing cancer patients.15,16 Cancer patients may frequently suffer from physical obstruction of the gastrointestinal tract, pain, depression, constipation, malabsorption, debility or the side effects of treatment such as opiates, radiotherapy, or chemotherapy—any of which may decrease food intake.6 Cancer-associated hypercalcemia is a fairly common medical emergency and leads to nausea, vomiting, and appetite loss.
However, there remains a large number of patients with cancer in whom there is no obvious clinical cause of reduced food intake.
Disruption of Leptin Regulation
Weight loss is a potent stimulus to food intake in healthy humans and animals (Figure 1 (http://www.cancer.org/docroot/PUB/content/PUB_3_8_1x_Figure_1_Cancer_Anorexia-Cachexia_Syndrome.asp)). The persistence of anorexia in cancer patients therefore implies a failure of this adaptive feeding response, which is so robust in normal subjects.17-20
Leptin, a hormone secreted by adipose tissue, is now known to be an integral component of the homeostatic loop of body weight regulation.21-28 Leptin plays an important role in triggering the adaptive response to starvation since weight loss causes leptin levels to fall in proportion to the loss of body fat.
Low leptin levels in the brain increase the activity of the hypothalamic orexigenic signals that stimulate feeding and suppress energy expenditure, and decrease the activity of anorexigenic signals that suppress appetite and increase energy expenditure.17-20 Most of the orexigenic signals are known to be up-regulated through fasting in experimental animals. This suggests these signals play an important role in facilitating the recovery of lost weight.
Cancer-induced anorexia may result from circulating factors produced by the tumor or by the host in response to the tumor (Figure 1 (http://www.cancer.org/docroot/PUB/content/PUB_3_8_1x_Figure_1_Cancer_Anorexia-Cachexia_Syndrome.asp)). Several cytokines have been proposed as mediators of the cachectic process, among which are tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-g (IFN-g).1,4,29-37 High serum levels of TNF-a, IL-1, and IL-6 have been found in some (but not all) cancer patients, and the levels of these cytokines seem to correlate with the progression of the tumors.38-40
Chronic administration of these cytokines, either alone or in combination, is capable of reducing food intake and reproducing the distinct features of the cancer anorexia-cachexia syndrome.1,4,38-41 These cytokines may produce long-term inhibition of feeding by stimulating the expression and release of leptin and/or by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, leading to the prevention of the normal compensatory mechanisms in the face of both decreased food intake and body weight (Figure 1 (http://www.cancer.org/docroot/PUB/content/PUB_3_8_1x_Figure_1_Cancer_Anorexia-Cachexia_Syndrome.asp)).4,16,32 Therefore, the weight loss seen in cancer patients differs considerably from that seen in simple starvation (Table 1 (http://www.cancer.org/docroot/PUB/content/PUB_3_8_1x_Table_1_Cancer_Anorexia-Cachexia_Syndrome.asp)).
Disruption of Neuropeptide Y Regulation
Another mechanism is related to neuropeptide Y (NPY)—a 36-amino acid peptide that is abundantly distributed in the brain, including the hypothalamus, and is situated downstream from leptin in this pathway.25,27 NPY is the most potent feeding-stimulatory peptide and consists of an interconnected orexigenic network that includes galanin, opioid peptides, melanin-concentrating hormone (MCH), orexin, and agouti-related peptide (AGRP) (Figure 1 (http://www.cancer.org/docroot/PUB/content/PUB_3_8_1x_Figure_1_Cancer_Anorexia-Cachexia_Syndrome.asp)). NPY may stimulate feeding on its own and also via stimulation of the release of the other orexigenic peptides.
Previous studies demonstrated that NPY feeding systems are dysfunctional in anorectic tumor-bearing rats. NPY injected intrahypo-thalamically stimulated feeding less potently in rats bearing methylcholanthrene-induced sarcoma than in controls. This was observed prior to the onset of anorexia and became more severe as the rats developed anorexia.42 The level or release of NPY in the hypothalamus is also reduced in tumor-bearing rats, whereas it is increased in fasting animals and in nutritional controls that have their food restricted to match their body weight to the carcass weight of tumor-bearing rats.43,44 IL-1b administered directly into cerebral ventricles antagonizes NPY-induced feeding in rats at a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid such as those observed in anorectic tumor-bearing rats.45-47 IL-1b decreases hypothalamic NPY mRNA levels that are specific to and not associated with a generalized reduction in the brain levels.46
The hypothalamic NPY system is thus one of the key neural pathways disrupted in anorexia induced by IL-1b and other cytokines. However, no change or even increase in NPY mRNA levels were reported in the hypothalamus of tumor-bearing rats,48,49 suggesting the involvement of other orexigenic and/or anorexigenic signals in anorexia and body weight loss.
Aberrant Melanocortin Signaling
It was recently reported that aberrant ...

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