cancer cachexia occurs most frequently in malignancy and is associated with more than 20% of cancer deaths .
patients with upper gastrointestinal cancer are especially likely to suffer from substantial weight loss , and patients with pancreatic cancer have the highest frequency of developing a cachectic syndrome .
thus the research groups and physicians dealing with pancreatic cancer are very interested in finding an effective treatment for cachectic patients .
but there is still little known about this clinical issue , and our knowledge grows slowly .
much more research and many more clinical trials are needed to increase our understanding of the syndrome and to develop therapeutic strategies for one of the major symptoms of cancer .
the word " cachexia " comes from the greek words " kakos " and " hexis " , meaning " bad conditions " .
cachexia is a complex metabolic status with progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle .
cachexia should be suspected if involuntary weight loss of greater than five percent of premorbid weight occurs within a six - month period .
cachexia represents the clinical consequence of a chronic , systemic inflammatory response , with high hepatic synthesis of acute - phase proteins resulting in depletion of essential amino acids .
in contrast , in starvation only fat metabolism is increased while the organism tries to conserve lean body mass .
in addition to metabolic changes , cachexia is often associated with anorexia . in cancer patients there
can be mechanical interference such as obstructions , as well as treatment - related toxicity . in patients receiving chemotherapy or radiation , subsequent nausea , vomiting and diarrhea can contribute to weight loss .
but the lack of nutrients alone can not explain the metabolic changes seen in cachexia . in clinical trials , nutritional supplementation and dietary counseling failed to increase body weight .
several appetite - stimulating drugs have been tested in an attempt to increase the food intake of cachexia patients , but most of them had little or no effect on body weight .
only limited treatment options exist for patients with clinical cancer cachexia . in one trial , corticosteroids improved the sensation of well - being and led to increased food intake , but this effect lasted only a few weeks .
body composition analysis showed that the weight gain resulted only from increased body fat and fluid , with no change in lean body mass .
additionally , therapy with progestogens led to a decline in the response rate to chemotherapy and an increase in the frequency of thrombembolic events .
demonstrated that neuropeptid y ( npy ) , the most potent feeding - stimulatory peptide in this cycle , is deregulated in the hypothalamic orexigenic network , leading to decreased energy intake but high metabolic demand for nutrients .
high levels of leptin , a hormone secreted by adipocytes , block the release of npy . in cachexia
the leptin feedback loop seems to become out of control , altering the neuropeptidergic control cycles .
the second theory is based on the idea that tumor - derived factors maintain the cachectic syndrome .
postulated a factor that was extracted from the urine of cachectic patients and which induces protein degradation in skeletal muscle by upregulation of the ubiquitin - proteasome pathway .
this proteolysis - inducing factor ( pif ) is closely related to weight loss in cachexia , and in a recent study it was shown that pif is produced in human colon cancer .
a second factor extracted from the urine of cachectic patients  lipid mobilizing factor ( lmf )  is closely related to weight loss and induces lipolysis in murine adipocytes .
lmf produces a significant increase in the ucps in brown adipose tissue , skeletal muscle and liver .
mitochondrial uncoupling proteins ( ucps ) 1 , 2 , and 3 are involved in the control of energy metabolism through thermogenesis in brown adipose tissue and possibly in skeletal muscle tissue in humans . in many animal models ,
overexpression of ucps ( especially ucp 2 ) in white adipocytes and in muscle and liver tissue was associated with cachexia .
however , it is still uncertain how they interact and whether they come into play at the beginning or at the end stage of the disease . despite the controversial discussion of cachexia - inducing mechanisms uncertainty over what causes cachexia
, it is quite clear that proinflammatory cytokines are linked to all pathways that induce cachexia .
as mentioned , cachexia is associated with a chronic systemic inflammatory response and the elevation of acute phase proteins .
high serum levels of il-1 , il-6 and inf gamma are present in many cancer patients , and the levels of these cytokines seem to correlate with tumor progression .
these cytokines stimulate the expression of leptin and/or mimic the hypothalamic effect of negative feedback from leptin by disarranging the signaling pathway of npy , resulting in long - term inhibition of food intake .
il-1 antagonizes npy  induced feeding in rats and disrupts the orexigenic pathway of npy .
on the other hand , central corticotropin - releasing factor ( crf ) , which is upregulated by il-1 , seems to influence satiety , and is a potent anorexigenic signal .
tumor necrosis factor alpha ( tnf- ) also increases the mrna levels of ucp2 and 3 . in combination with inf tnf- activates the transcription factor nfb that leads to reduction of myo d , a transcription factor essential for repairing damaged muscle tissue .
although il-6 is one of the key cytokines involved in the development of cachexia , the definite mechanisms have not yet been clarified .
improvements in appetite and weight gain through decreased cytokine expression after the application of corticosteroids or special antagonists like il-6 antibodies were seen over short periods , but further investigations of the cytokine system are necessary to elucidate the interaction between host and tumor - derived cytokines and to determine their effect on biochemical mechanisms .
many trials have been performed in the search for a treatment for cachexia , but most therapies have not fulfilled expectations . currently , eicosapaentanoic acid is being tested in cachectic patients .
eicosapaentanoic acid seems to interfere with the signaling pathway of pif , and first results are promising .
although in recent years our understanding of cachexia has increased , we are still in the fledgling stages . the scientists and clinicians dedicated to finding an effective treatment for cachectic patients have their work cut out for them .
mem and pk drafted the paper . hf provided comments and suggestions for its finalization .
 in recent years many efforts of researchers and clinicians were made to improve our knowledge of cachexia syndrome . 
 not only cancer , but also many chronic or end - stage diseases such as aids , chronic obstructive pulmonary disease ( copd ) , rheumatoid arthritis , tuberculosis and crohn 's disease are associated with cachexia , a condition of abnormally low weight , weakness , and general bodily decline which deteriorates quality of life and reduces the prognosis of the patients who suffer from it . in the present editorial 
 we will focus cachexia related on cancer and provide some insight into this prognosis - limiting syndrome . 