
<b>This section discusses weight loss.</b>
Weight loss in cancer is essentially one of two types:

1.  <b>A General Weight Loss...  where if you increase the calories absorbed, the weight stops being lost.</b>  This weight loss is discussed in the first part of this section, further below.

2.  And a <b>Tumor-Induced Weight Loss [Cancer Cachexia Syndrome]</b>, where the metabolism of the patient's body has gone haywire, and calories are shunted to useless inflammatory pathways. <b> No matter how much the patient eats, he still loses weight.</b>  Many things have been tried to stop this, as it kills the patients.  What does seem to work is either Ibuprofen 400mg three times a day,  or omega-3 fish oils, 2 grams a day for at least four weeks.   The second part of this section discusses this.  
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<b>Advances in the Management of Tumor-Induced Weight Loss 
Continuing Medical Education Article on Medscape.com
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<b>GENERAL WEIGHT LOSS IN CANCER PATIENTS</b>
Cancer patients with weight loss live approximately half as long as those without, and those with greater weight loss appear to live a shorter time than those with less or no weight loss.  80% of advanced cancer patients have marked weight loss [cachexia].  Weight loss becomes more pronounced as the disease progresses, and the prevalence of cachexia increases to more than 80% before death. In more than 20% of patients with cancer, cachexia is the primary cause of death.
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<b>Mechanism of General Weight Loss in Cancer Patients</b>
The intake of calories, providing energy to the patient with cancer, has been shown to be substantially reduced among patients who are losing weight. 

<b>Weight loss in the cancer patient may occur because of:</b>

<b>Mechanical problems in the gastrointestinal tract</b> 
	obstruction
	malabsorption
	constipation
	surgical interventions

<b>Side effects of opiates, chemotherapy, radiation therapy:</b>
	nausea
	vomiting
	taste changes
	stomatitis
	constipation
	diarrhea

<b>Electrolyte imbalances from the cancer or from treatment can cause:</b>
	nausea 
	vomiting
	decreased appetite

<b>Depression and/or anxiety can affect a patient's appetite and ability to eat.</b>

<b>These factors should be controlled as part of the general care of the cancer patient. </b> Estimates are that more than half of the patients who are receiving cancer treatment are underweight, have decreased appetite, and decreased oral intake. In a large number of patients with cancer, no obvious clinical cause of reduced food intake can be identified.  
<b>Patients who are malnourished need a complete nutritional evaluation</b> [determination of nutritional needs as well as assessment of metabolic stress. This evaluation includes the protein, caloric, electrolyte, mineral, and fluid requirements of the patient, most often completed by a dietitian.]  

<b>Lab Tests</b>
Serum albumin is one of the most common tests used due to its low cost, and provides a measure of body protein stores. It has been used as a predictor of survival for cancer patients, but is also low in liver and kidney disease, and in other conditions.  It also responds slowly to treatment.
Transferrin, also sometimes used, can be affected by infection, active tumorigenesis, inflammation, and hepatic or renal diseases.   There is no single measurement or test that solely reflects nutritional status, which must be determined by multiple factors, not just lab tests.

<b>Management of General Weight Loss</b>
Decreased appetite and the subsequent weight loss worry the cancer patient and the patient's family. Patients often report that their family's emphasis on eating is stressful to them, and a family's efforts to increase the patient's intake of food does nothing to change their level of food intake. Clinicians need to attempt to address this symptom in a systematic manner to address both the physiologic and psychological issues. 
Providing nutritional support has been shown to increase the patient's weight, measurements, and albumin levels.
For more information &&url
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<b>TUMOR-INDUCED WEIGHT LOSS or the CANCER CACHECTIC SYNDROME</b>

Despite the efforts above, and increasing food intake adequately, SOME patients will continue to lose weight.   The major difference between Tumor-Induced Weight Loss [TIWL] and other forms of weight loss is that TIWL will not respond to feeding or overfeeding.  This seems to be due to metabolic changes in cachexia, produced by the tumor or by the host in response to the tumor.

Anorexia and cachexia accompany advancing cancer to a greater extent than any other symptom.  Anorexia is loss of appetite.  The term cachexia is derived from the Greek words kakos, meaning "bad," and hexis, meaning "condition." There is no clear definition of cachexia, but a reasonable approximation would be the unintentional loss of more than 5% to 10% of pre-illness stable weight with no obviously reversible cause in the presence of a systemic illness.  

Cachexia, however, is not just weight loss from starvation, but weight loss from a complex set of metabolic changes in the cancer patient's body. Cachexia is not exclusive to cancer but is also seen in a variety of inflammatory conditions such as AIDS, rheumatoid arthritis, and cardiac failure, and this gives us the first clues toward its etiology [cause]. 

In TIWL/cachexia, resting energy expenditures are elevated, and abnormal intermediary metabolism, breaking down of proteins, and breaking down of fat occur independently of caloric intake.  This means that weight loss will continue despite adequate or more than adequate caloric intake.  The tumor, or the body's reaction to the tumor, changes how the body uses its nutrients and caloric intake.  A facilitative interaction between catecholamines, prostaglandins, and inflammatory cytokines is responsible for cachexia. Successful treatment requires reduction of energy expenditures, reversal of anorexia, and correction of abnormal intermediary metabolism, lipolysis, and proteolysis.
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TIWL is important to the outcome of the patient's disease. Cancer patients with weight loss live approximately half as long as those without, and those with greater weight loss appear to live a shorter time than those with less or no weight loss.  Those cancer patients with TIWL have also been reported to have a reduced performance status and quality of life.  Patients with an apparently identical primary cancer and disease stage can vary considerably in terms of the development of cachexia, suggesting variations in tumor phenotype and host response as important determinants.
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Weight loss becomes more pronounced as the disease progresses, and the prevalence of cachexia increases to more than 80% before death. In more than 20% of patients with cancer, cachexia is the primary cause of death.

For More Information &&url 
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<b> For possible mechanisms of action for TIWL, see &&url
Our understanding of the role of inflammatory mediators in cachexia has opened up a new opportunity for intervention to manipulate the inflammatory response and to influence the progress of cachexia.</b>


<b>Treatment of TIWL
Nutritional Approaches</b>
Curing the cancer is the most effective way to treat cancer cachexia.  Unfortunately, this may be difficult to achieve among adults with advanced solid tumors.   The obvious option -- to increase nutritional intake by enteral or parenteral means-- did not work.

Two randomized trials with more than 100 patients each, and over a 3-month period, demonstrated a significant increase in nutritional intake in the intervention group --without any improvement in weight, anthropometric measures, chemotherapy response rate, survival, or quality of life.

In the 1980's a number of clinical trials of parenteral nutrition showed no benefit in terms of nutritional measures, AND an increase in infective complications. As a consequence, the American College of Physicians to publish a position paper in 1989 that concluded that, in cancer patients, "parenteral nutritional support was associated with net harm, and no conditions could be defined in which such treatment appeared to be of benefit."

The trials of parenteral nutrition with cancer patients since 1989 have shown a significant improvement in energy intake,  no improvement in nutritional measures or functional outcome - and increased complications [especially infections], as well as a trend toward a shorter duration of survival.  

The disappointing results of increasing nutritional intake led to the suggestion of a block to weight gain in this group of cancer patients due to the metabolic changes described in the footnote below.

<b>Pharmacologic Approaches
Steroids </b>
such as prednisolone, dexamethasone, and I.V. methyprednisolone help short term with appetite improvement, but do not stop ongoing weight loss, and have marked adverse side effects.  They may have a palliative role, but cannot stop the cachexia.

<b>Progestational agents</b> 
like megestrol and medroxyprogesterone have created weight gain, but the increased weight tends to be fat and water, not lean body mass.  These agents have a number of side effects at well.  Recently, a study found decreased response to chemotherapy and a trend to poorer survival with these.  The appetite-stimulating properties of these agents might be useful in combination with other agents, or in very advanced disease. 

<b>Other agents</b>
like anabolic steroids and cannabis have not been tested against placebo.  There is no obvious benefit when they were tested against megestrol.  

Serotonin is thought to have a role in appetite control, but a trial of the antiserotonergic cyproheptadine  showed no obvious benefits with cachectic cancer patients.   A controlled trial of pentoxifylline [inhibits the production of TNF-alpha] failed to demonstrate any benefit in terms of appetite or nutritional measures in cachectic cancer patients when compared with placebo.  <b>Melatonin</b> appeared to produce a significant slowing of this weight loss compared with controls, and continues to be studied. Some other agents including growth hormone, insulin and related proteins, thalidomide, and beta-2-adrenoceptor agonists are being tested; these are either appetite stimulants or agents directed at some part of the cachectic process, and have a relative lack of success.

An agent that has influence on the wider inflammatory metabolic state driven by the host of mediators described below might be more effective.   Studies done using more general anti-inflammatory agents like NSAIDs and omega-3 fish oils to downregulate the cachectic state are very promising.   

<b>NSAIDs
Indomethacin 50 mg twice daily or placebo produced a stabilization of Karnofsky performance status and a near doubling of survival in the indomethacin group.
Ibuprofen 400 mg 3 times daily has been shown to reduce levels of acute-phase proteins, IL-6, and cortisol and to normalize whole-body protein kinetics to some extent in cachectic colorectal cancer patients. 
Ibuprofen will also reduce levels of acute-phase proteins and resting energy expenditure in those with pancreatic cancer.

The trial combination of an appetite-stimulator progestogent with the anti-inflammatory properties of an NSAID [using megestrol and ibuprofen together] suggest that this combination may stabilize quality of life and weight in cachectic patients.</b>
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<b>Fish oil and eicosapentaenoic acid (EPA)</b>
Fish oil and EPA (the major omega-3 fatty acid component of fish oil) affect potential mediators of cachexia, including cytokine production, PIF, and the APPR.  Clinical studies of fish oil (providing 2.2 g EPA per day) and pure EPA (6 g per day) in small groups of weight-losing pancreatic cancer patients have suggested that these agents will stabilize weight. There was no change in the percentage of total body water over the time of the study.   Side effects were minimal.  A mixed group of 60 cancer patients in a trial of a fish oil preparation providing about 3 g EPA per day suggested a prolonged survival in patients receiving fish oil. 

<b>"A combination of fish oil to downregulate the cachectic process and additional nutrients to provide substrate for potential anabolism has also been investigated. The fish oil-enriched nutritional supplement providing 2 g EPA and 600 kcal daily was given to 20 patients with advanced pancreatic cancer losing weight at a median rate of 2.9 kg per month. After 3 and 7 weeks, patients had significant weight gain of 1 kg and 2.5 kg. Body composition analysis suggested a significant gain in lean body mass. Negative nitrogen balance was reversed. The Karnofsky performance score, reflecting the functional ability of patients, also improved significantly. Appetite was significantly improved, with an increase in nutritional intake of around 400 kcal per day.  This regimen also produced a stabilization of the APPR and downregulation of a number of inflammatory mediators."</b>

<b>"A controlled trial of 200 cachectic patients received either the experimental supplement enriched with fish oil or an identical supplement without fish oil. Patients were initially losing weight at a rate of 3.3 kg per month. Patients in both groups became weight stable. A number of patients had difficulty ingesting the suggested quantity of supplement, but a subgroup of those in the experimental group who managed the target of around 2 g of EPA and 600 kcal per day achieved a significant increase in weight and lean body mass. Overall, the change in patients' plasma EPA directly correlated with change in lean body mass.  A subgroup of these patients underwent detailed analysis of resting and total energy expenditure in an attempt to ascertain whether the supplement resulted in any change in physical activity as an objective measure of the functional aspects of quality of life. There was no change in physical activity in the control group, but there was a significant increase in the experimental group, suggesting the functional ability of the patients receiving the fish oil-enriched supplement was improved.  While this work is promising, much remains to be done to confirm the role of fish oil-based preparations in TIWL."</b>
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<b>There are no clear diagnostic criteria for TIWL. Obvious causes of weight loss should be excluded. In patients who describe cachectic symptoms, treatment should be started early. "Cancer cachexia is a complex, multifactorial syndrome that results from a reduction in food intake, a variety of metabolic abnormalities or  a combination of the two. Multiple mediator pathways including pro-inflammatory cytokines, neuroendocrine hormones and tumour-specific factors are involved. Therapy requires an approach that addresses both reduced food intake and metabolic change. Combination treatments such as nutritional support plus metabolic/inflammation modulation promise improved functional capacity and quality of life."</b>
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<b>"Possible Mechanisms of TIWL"
From &&url

includeThe Acute-Phase Protein Response (APPR)</b>
The balance of liver export proteins is altered in many cancer patients such that while albumin synthesis remains unchanged, fibrinogen synthesis rates are significantly increased.  These changes occur on a background of a decrease in the circulating concentration of albumin (a negative acute-phase protein) and an increase in the concentration of fibrinogen (a positive acute-phase protein).  These changes reflect aspects of the APPR, a reprioritization of liver protein synthesis often seen in trauma, inflammation, and infection.  

An APPR is seen in a significant proportion of patients with a variety of cancers.  The presence of an APPR has been related to increased TIWL in pancreatic and lung cancer.  An APPR is also strongly associated with a reduced quality of life in gastrointestinal cancer patients  and a shortened survival in renal, pancreatic, and colorectal cancer. 

<b>During an inflammatory response, there are altered demands for amino acids. The cachectic cancer patient may have an insufficient nutritional intake to provide the required amino acids, and, consequently, there may be relatively increased breakdown of skeletal muscle to supply sufficient amino acids. This breakdown may be further exaggerated, as there is an imbalance between the amino acid composition of skeletal muscle and acute-phase proteins.  It has recently been shown that in cancer patients, feeding stimulates the synthesis not only of the negative acute-phase protein albumin (as seen in normal individuals) but also the positive acute-phase protein fibrinogen.  This may provide a mechanism whereby a proportion of supplied nutrients are diverted away from anabolism toward fueling the inflammatory response in TIWL.</b>

<b>Mediators of TIWL
Neurotransmitters</b>
Several neurotransmitter systems within the hypothalamus have been implicated in the anorexia associated with TIWL. 

<b>Proinflammatory Cytokines</b>
Several proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin (IL)-1-beta, IL-6, and interferon gamma, have been implicated in cachexia. 
However, individual cytokines do not work alone but in a complex network of multiple cytokines in combination with other factors.

<b>Prostaglandins</b>
Release of prostaglandins is a major step in the signaling pathway leading to muscle protein breakdown in normal tissues.  It also appears that prostaglandins may mediate the actions of most proinflammatory cytokines.   Specific inhibitors of prostaglandin synthesis prevent the experimental cachectic effects of TNF-alpha and IL-1.  It is likely that prostaglandins have a role to play as part of the network of mediators of cachexia.

<b>Neuroendocrine Hormones</b>
Infusion of hormones such as cortisol, glucagon, and adrenaline in humans will produce features of cachexia such as protein loss, an APPR, increased energy expenditure, and glucose intolerance.   In humans with cancer, elevated levels of cortisol and glucagon have been observed. 

<b>Tumor-Derived Catabolic Factors</b>
 PIF has been found to be expressed in tumor cells from patients with significant weight loss but not in those who are reasonably weight stable. 

A mouse tumor-derived lipid mobilizing factor has also been described, and this has also been identified in the urine of TIWL patients.  