Tumor cachexia

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Classification according to ICD-10
C80 Malignant neoplasm cachexia.
Annotation:
ICD-10 online (WHO version 2019)

Cancer cachexia , rare cancerous cachexia called, is the name given to an as a result of cancer occurring in patients metabolic disorder leading to wasting ( cachexia ) and emaciation leads to those affected. Tumor cachexia is a common complication of cancer, especially malignant tumors of the digestive tract , which has an unfavorable effect on the course of the disease , quality of life and prognosis and can itself be directly life-threatening. Tumor cachexia is a major factor in the high death rate in cancer.

The molecular and biochemical causes that lead to tumor cachexia are highly complex and not yet fully understood. Metabolic products of the tumor and messenger substances that - as a result of cancer - are formed by the body of the person affected play an important role in the development of this syndrome . There are also psychological factors and side effects of cancer therapy measures that can lead to a loss of appetite in the patient. In contrast to the weight loss in the case of malnutrition , tumor cachexia not only reduces fat reserves, but also the skeletal muscles.

There is currently no effective curative treatment . So far , all therapeutic approaches have been palliative , that is, merely alleviate the disease.

Classification and definition

The development of cancer to the fatal stage

Most authors prefer the term syndrome for tumor cachexia . This designation is more appropriate to the complex situation than the classification as an independent disease. The Anglo-Saxon specialist literature usually speaks of cancer cachexia syndrome (CCS) or cancer anorexia-cachexia syndrome (CACS). Cachexia is a suitcase word from the Greek κακὸς = kakos = "bad" and ἕξiς = hexis = "condition".

Cachexia is generally described as a multifactorial syndrome that affects any area of ​​the body and is most easily identified in its advanced form from the massive loss of subcutaneous fat and skeletal muscle . There is currently no binding or standardized definition for either cachexia or tumor cachexia, which, given the high prevalence and severity of this syndrome, has repeatedly been admonished as inadequate. The same applies to a classification . One of the reasons for this is the lack of reliable biomarkers with which the tumor cachexia could be diagnosed and classified using measured values. Due to the lack of classification, there are currently no treatment regimens adapted to the degree of the syndrome.

To date, very different definitions of tumor cachexia have been used for clinical studies , based on the percentage loss of body mass or falling below a certain value in the body mass index , for example . The lack of a binding definition makes it much more difficult to compare clinical studies.

Depending on the definition chosen, there are different percentages of cancer patients who also suffer from tumor cachexia. For example, a group of 8541 cancer patients with solid tumors was analyzed according to four different criteria. According to the ICD-9 diagnosis of cachexia as a criterion, 2.4 percent of these patients would have tumor cachexia. With an expanded ICD-9 classification with cachexia, anorexia, abnormal weight loss, or problems with nutrition, it would have been 5.5 percent. If the prescription of drugs such as megestrol , oxandrolone , somatotropin or dronabinol , which indicate a medication for tumor cachexia, is used as a criterion, 6.4 percent of the patients fell under this criterion. If a loss of body mass of more than 5 percent were the definition of tumor cachexia, 14.7 percent of these cancer patients would have met this criterion.

The lack of a definition of cachexia has a negative impact on the diagnosis and treatment of affected patients. This also makes the development and approval of potential active ingredients more difficult. On December 13th and 14th, 2006, a new definition of cachexia was proposed at the Cachexia Consensus Conference in Washington, DC . According to them, cachexia is “a complex metabolic syndrome which is caused by a chronic illness and is characterized by the loss of muscle mass, with or without loss of body fat. Anorexia (loss of appetite), inflammation , insulin resistance and an increased breakdown of muscle proteins are common side effects of cachexia. Cachexia, which is associated with increased morbidity , must be distinguished from: malnutrition , age-related loss of muscle mass, primary depression , malassimilation (reduced use of nutrients) and hyperthyroidism (overactive thyroid) ”.

A current recommendation defines cachexia when the

  • Loss of body mass over 5 percent within twelve months or less, and if so
  • at least three of the five following criteria are met at the same time:

However, this proposed definition has not yet been used in either epidemiological or clinical studies.

Epidemiology and relevance to health policy

Type of cancer Weight Loss Incidence
Pancreatic tumor 83%
Stomach cancer 83%
Esophageal cancer 79%
Head and neck cancer 72%
Colorectal cancer 55 to 60%
Bronchial carcinoma 50 to 66%
Prostate cancer 56%
Breast cancer 10 to 35%
All cancers together average 63%

About 50 percent of all cancer patients are affected by tumor cachexia in the course of their illness. The likelihood of tumor cachexia is very much dependent on the type of cancer. After sepsis (blood poisoning), tumor cachexia is the most common cause of cancer death. Depending on the author, the proportion of tumor cachexia among the causes of death from cancer is 20 to 50 percent. The range of fluctuation in the prevalence data (disease frequency) is causally due to the previously mentioned lack of definition of tumor cachexia.

The type of cancer plays a major role in the likelihood of developing tumor cachexia. For example, around 80 percent of patients with pancreatic tumors and 30 to 50 percent of patients with cancer in the gastrointestinal tract die of tumor cachexia. In pancreatic tumors, the incidence of tumor cachexia is highest at 80 percent at the time the carcinoma is diagnosed. Tumor cachexia occurs in the course of the disease in up to 85 percent of all patients with gastrointestinal (gastrointestinal) cancer. With solid tumors, the probability of tumor cachexia is significantly higher than with cancers of the hematopoietic system ( leukemia , myelodysplastic syndromes and other hematological neoplasias). Breast cancer is an exception among solid tumors . The likelihood of tumor cachexia is significantly lower here. The development of tumor cachexia is very individual, even with the same type of tumor, depending on the patient. Tumor cachexia can be observed in affected patients in all stages of cancer, but is particularly common in the terminal stage of the disease.

Tumor cachexia affects children and the elderly significantly more frequently.

In absolute terms, tumor cachexia is one of the most common causes of death. In Germany, roughly 50,000 people die each year from tumor cachexia. Exact data are not available due to the lack of definition of tumor cachexia and the usual death certificate practice .

Clinical picture

Distribution of body mass in cachectic patients with bronchial carcinoma (right), compared to a healthy control group (left)

Tumor cachexia is essentially characterized by a weight loss in the patient, often associated with anorexia (loss of appetite), symptoms of inflammation , insulin resistance and the breakdown of skeletal muscles . In many cases, anorexia is a symptom of tumor cachexia, but tumor cachexia can develop without anorexia. The occurrence of anorexia accelerates the progression of tumor cachexia.

While weight loss in healthy individuals is compensated for by an increased appetite and the associated higher food intake, this is not the case with cachectic patients. Tumor cachexia leads to general weakness, decreased strength and immobility in the affected patients, as well as fatigue, listlessness and depression , which in turn leads to an impairment of the quality of life . The quality of life, as assessed by those affected, is significantly impaired by tumor cachexia. Some concomitant symptoms of tumor cachexia lead to the further progression of this syndrome through a self-reinforcing process . The breakdown of muscle proteins is associated with increased energy consumption, which in turn leads to disease progression. Loss of appetite and nausea lead to decreased food intake and also increase the catabolic state. Protein breakdown is essentially limited to the skeletal muscles. The internal organs , on the other hand, are hardly affected by protein breakdown. Here, too, the picture of tumor cachexia differs from that of malnutrition, in which - after the fat reserves have been used up - both skeletal and visceral proteins are broken down. The mass of the liver in cachectic patients can even increase significantly due to increased metabolic activities and the production of acute phase proteins .

diagnosis

A reliably diagnosed cancer is the first prerequisite for the diagnosis of tumor cachexia. The diagnosis of tumor cachexia itself is very difficult in most cases. Weight loss in a cancer patient does not have to be cachexia. A number of psychological factors also play a role, such as obstructions or stenoses in the gastrointestinal tract, which can be a result of tumor growth. Inflammation of the oral mucous membranes ( stomatitis ), dry mouth or fungal infections ( mycoses ) of the oral cavity ( oral thrush ) are possible side effects of cancer that have a negative effect on food intake. Diagnostic and above all therapeutic measures, in particular chemotherapy and radiation therapy , can lead to weight loss due to a decrease in appetite. Even if these influencing factors can be ruled out, a clear diagnosis is often difficult. The most important criteria for making a diagnosis at present are the patient's medical history and physical examination. The body weight before the onset of cancer serves as a reference . Also anthropometric studies can be used for diagnosis of cancer cachexia. In addition to the already mentioned elementary determination of body weight, these are, for example, measuring the circumference of the upper arm or the thickness of a skin fold. With the bioelectrical impedance analysis (BIA) the fat-free mass of the patient can be determined. However, this method is not available in many clinics and has not yet been established as a diagnostic standard for tumor cachexia.

Some laboratory parameters can be used to support the diagnosis. However, the informative value is often very limited due to physiological changes - caused by the underlying malignant disease and any therapeutic measures. The level of human albumin in the serum can be used as the laboratory parameter to support the diagnosis , which is usually lower in the case of tumor cachexia, but can be falsified in the case of liver and kidney dysfunction - for example caused by cancer. The concentration of C-reactive protein (CRP) in the serum can be increased as a result of an acute phase reaction (APR) which is frequently observed in tumor cachexia . Typical markers for an acute phase reaction are transferrin , transthyretin and ceruloplasmin . On the other hand, an acute phase reaction can also occur without cachexia in cancer, so that these markers are not a reliable measure for the diagnosis of “cachexia”. Increased levels of glycerol and catecholamines are often detectable in the blood of the patients . The increased glycerine content is due to the increased breakdown of body fats. Anemia is often an accompanying symptom of tumor cachexia .

At the time of diagnosis of cancer, about 80 percent of patients with tumors of the upper gastrointestinal tract and 60 percent of patients with lung cancer have lost significant weight (over 10 percent in six months). In many cases, the weight loss observed by the patient is the first symptom of the cancer, which - as part of the medical examination - is diagnosed as the cause of the weight loss.

At the time of the diagnosis of “cancer”, up to 50 percent of cancer patients already complain of anorexia in the form of loss of appetite and premature satiety.

Pathogenesis

The new model for the pathogenesis of tumor cachexia

Tumor cachexia arises from a complex interplay of metabolic products of the tumor and messenger substances that are formed in the body of the person affected as a result of the cancer, which has not yet been fully elucidated . These compounds cause a catabolic metabolism , an increased mobilization of fats from the adipose tissue, an increased breakdown and a reduced build-up of proteins in the skeletal muscles as well as an increased energy consumption of the body cells (hypermetabolism).

Tumor cachexia is a chronic inflammatory condition - similar to infection or inflammation or tissue damage. Various pro-inflammatory (pro-inflammatory) cytokines, prostaglandins and factors produced by the tumor itself are overexpressed . These substances intervene directly in the peripheral and central control loops of food intake and metabolism and are also able to trigger muscle atrophy. In addition, there are other factors such as decreased food intake, poor digestion ( maldigestion ) or absorption ( malabsorption ), among other things as a result of the patient's depressed mood . Disorders in taste or the hunger center can also contribute to tumor cachexia. Recurrent bleeding, for example in ulcerating or polypoid gastrointestinal carcinomas , can also lead to an increased loss of proteins in the body.

Cytokines

From a certain critical size of a tumor, tumor necrosis sets in . This means that in the center of the tumor - due to an insufficient supply of blood - tumor cells die. When these tumor cells disintegrate, the tumor necrosis factor TNF-α (formerly known as cachectin in relation to cachexia ) and a number of other cytokines are released . These substances cause functional disorders in hepatocytes (liver cells) in particular and lead to a negative nitrogen balance. The metabolism is switched to catabolism . The cytokines TNF-α, interleukin-1, interleukin-6 and interferon-γ have been identified in various experiments as mediators for the loss of muscle mass in tumor cachexia. In fact, these compounds are in principle capable of causing cachexia. In animal models, for example, the state of cachexia can be established experimentally through the injection of TNF-α. TNF-α causes both a breakdown of body fat and the skeletal muscles. TNF-α directly influences the ubiquitin-proteasome system , the most important intracellular protein degradation mechanism. The formation of reactive oxygen species (ROS) leads to an increased expression of the transcription factor NF-κB . TNF-α lowers protein synthesis through reduced phosphorylation of the eukaryotic translation initiation factor-4E eIF4E , which can thereby bind more strongly to EIF4EBP1 (eukaryotic translation initiation factor 4E binding protein-1) and reduces the active eukaryotic initiation factor 4F ( eIF4F ) . For a long time it was therefore assumed that the cytokines mentioned - and above all TNF-α - are the main cause of tumor cachexia.

In studies of patients with advanced and end-stage cancer, however, it was found that there was no correlation between the concentration of these cytokines and weight loss and anorexia in those affected. Also in cancer patients - in comparison to healthy people - no higher serum concentrations of TNF-α could be detected. In contrast, the plasma levels of these cytokines are significantly increased in patients with cachexia caused by AIDS or septicemia . The fact that cytokines can inhibit the enzyme lipoprotein lipase also speaks in favor of cytokines as a trigger of tumor cachexia . As a result of the inhibition, the adipocytes can not build up any triglycerides (fats) from the lipoproteins in the plasma and consequently cannot store them. Interestingly, however, the total activity of lipoprotein lipase and also the concentration of the corresponding mRNA in adipose tissue in cancer patients are unchanged compared to healthy individuals, while that of hormone-sensitive lipase (HSL) is about twice as high. The inhibition of TNF-α production - as a possible therapeutic approach - does not lead to any improvement in the state of health. Based on these data, it is currently assumed that TNF-α, interleukin-1, interleukin-6 and interferon-γ are in principle capable of causing cachexia - as in AIDS or sepsis, for example - but in the case the pathogenesis of tumor cachexia are obviously not the main factor.

Metabolic products of the tumor

Schematic representation of the interactions between tumor and healthy body tissue in tumor cachexia

Tumors produce catabolic messenger substances. Of the messenger substances identified so far, the proteolysis-inducing factor (PIF) and the lipid-mobilizing factor (LMF) are the most important factors in the pathogenesis of tumor cachexia. These factors cause complex, not yet fully understood, neurohormonal and metabolic changes that can lead to catabolic metabolism and nutritional deficiencies.

Lipid mobilizing factor

In the mid-1990s, a peptide was isolated for the first time from the urine of patients with tumor cachexia , which cannot be detected in cancer patients without weight loss and which is able to induce lipolysis in animal models . The peptide, known as the lipid-mobilizing factor , acts directly on the adipocytes and stimulates lipolysis there via a cAMP- dependent process that is mechanistically similar to that of lipolytic hormones. LMF is a 43  kDa heavy homolog binding zinc to the plasma protein α-2-Glycoprotein ( AZGP1 , also called ZAG). If LMF is injected into mice, the treated animals lose body fat without changing the animals' food intake. ZAG is overexpressed by the univacuolar adipocytes of the white adipose tissue in cachectic mice. Based on the data, it is currently assumed that LMF makes a significant contribution to tumor cachexia in the breakdown of body fat.

Proteolysis-inducing factor

In the mid-1990s, a sulfated glycoprotein with a molar mass of 24 kDa was isolated in mice with MAC16 adenocarcinoma , which leads to tumor cachexia by inducing catabolism in the skeletal muscles. This peptide , later called proteolysis-inducing factor (PIF), was also found in the urine of patients with tumor cachexia. In contrast, it could not be detected in cancer patients without weight loss or in patients with weight loss not initiated by cancer. These results have been confirmed in a number of other tests and studies. The detection of PIF is indicative of weight loss in tumor cachexia. NF-κB mediates the protein synthesis induced by PIF in the skeletal muscles through an increased phosphorylation of eIF2 on its α-subunit. Blocking the PIF receptor or the signal cascade in the skeletal muscles is seen as a potential starting point for future drugs for the treatment of tumor cachexia.

In animal experiments, in addition to the breakdown of the skeletal muscles, an increased production of prostaglandin E2 was demonstrated. In vitro, PIF binds with a very high affinity in the nanomolar range to the sarcolemma of skeletal muscle cells in mice, pigs and humans and to murine myoblasts . PIF is a potential marker for diagnosing tumor cachexia. The role of PIF in human tumor cachexia is not rated equally by all working groups and is the subject of controversial discussions. In some studies, results were obtained that contradict the previous data. Also, no correlation could be found between the presence / absence of PIF and a patient's prognosis.

anorexia

→ see also main article anorexia

For a long time, it was assumed that malnutrition and weight loss in many cancer patients are the sole consequences of anorexia. Obstructions (constrictions, occlusions) in the gastrointestinal tract, pain , side effects of cancer therapy, nausea or changes in gustatory perception (sense of taste) caused by the tumor can cause loss of appetite. Since anorexia can occur in cancer patients even in the absence or treatment of these symptoms , it is believed that changes caused by the tumor cause the loss of appetite. The body mass index (BMI) of cancer patients correlates with the concentration of leptin in the same way as that of healthy comparators . This means that if the BMI value in the serum is high, high leptin concentrations are measured. Leptin is an important messenger substance produced by adipocytes that inhibits the feeling of hunger . Certain cytokines can affect the production of leptin in adipocytes. In advanced cancer patients, the serum concentration of the cytokine interleukin-6 (IL-6) is significantly increased, which leads to a decrease in the blood leptin level in those affected. The survival rate in patients with high IL-6 concentrations, and the resulting particularly low leptin levels, is significantly reduced. In addition to the altered leptin production, the activity of the enzyme fatty acid synthase (FAS) and the melanocyte-stimulating hormone (MSH) obviously play an important role in anorexia.

If the loss of appetite in cancer is treated with medication, for example with substances that stimulate the appetite , or through artificial nutrition ( enteral or parenteral ), there is no improvement in metabolism towards anabolism (building up body mass) and away from catabolism (breaking down body mass ) reached. Measurable increases in weight, which are achieved through the administration of appetite-stimulating substances, are limited to the increase in fatty tissue and the storage of water in the interstitium of the treated cachectic patients. Muscle mass is hardly built up.

In contrast to anorexia, in which the lean body mass (lean mass) is largely retained, in tumor cachexia the skeletal muscles are also broken down. Up to 80 percent of the fatty tissue and skeletal muscles can be lost. For example, in patients with lung cancer who have lost 30 percent of their original body mass due to the disease, the weight loss results from a reduction in adipose tissue by 85 percent and that of skeletal muscle protein by 75 percent.

Anorexia is an additional symptom - very often accompanying tumor cachexia - that is the result of a disturbed appetite signaling pathway and is not responsible for the massive loss of muscle protein in cancer. In the Anglo-Saxon language area, the term Cancer Anorexia-Cachexia Syndrome (CACS) has established itself in place of the term Cancer Cachexia .

Direct influences of the tumor

The old model for the pathogenesis of tumor cachexia

According to the outdated development model of tumor cachexia, it was assumed that the increased energy requirement of the tumor is essentially responsible for this syndrome. This thesis was generally accepted until the 1980s and is still widespread among the population today - but no longer tenable in this form. Larger tumors can cause the affected patient to need more nutrients. However, this increased nutrient requirement is not the cause of tumor cachexia.

Tumor cachexia can occur regardless of the size and extent of the tumor and regardless of metastasis. The risk of developing tumor cachexia is much more dependent on the type of cancer than, for example, on the size of the tumor, the tumor location and the degree of metastasis. Cachexia can be observed in certain tumor types as early as 5 cm³ tumor volume, while large tumors do not trigger cachexia in other carcinomas. This is an indication that cachectic tumors have an altered gene expression that allows the tumor cells to produce lipolytic (fat-degrading) and proteolytic (protein-degrading) proteins that enable cachexia.

In a number of different studies was examined whether the resting energy expenditure ( resting energy expenditure , REE) is increased from cachectic cancer patients. The data are partly contradicting or without a significant cause-effect relationship . In some cases, the studies show an increased energy requirement, partly the exact opposite or an unchanged energy requirement, so that there are currently no reliable findings on this.

Larger tumors can have an additional energy requirement of up to 300  kcal per day. Tumors consume large amounts of glucose , which, due to the anaerobic conditions in the tumor, is broken down into lactate . The lactate is converted back into glucose in the liver in the so-called Cori cycle . This process is very energy-intensive. In healthy people, the proportion of glucose converted via the Cori cycle is around 20 percent, in cachectic patients around 50 percent. This then corresponds to a share of 60 percent of the total lactate production. Although this additional energy requirement is not the cause of tumor cachexia, it is an important aspect of the patient's diet.

Therapy and future therapeutic approaches

There is currently no drug approved by the FDA or the European Commission for the treatment of tumor cachexia. Some dietary supplements , as well as finished medicinal products that are approved for other indications ( off-label use ) , are sometimes used for treatment. Their use is purely palliative . An immediate curative treatment of tumor cachexia is currently not known. A cure is only possible if the cancer underlying the tumor cachexia is eliminated (indirect treatment). This would be the most effective therapy for tumor cachexia. Since tumor cachexia often only occurs in a late stage of cancer, the chances of a cure for the cancer and thus the tumor cachexia are usually very low. In many cases it is no longer possible to cure the underlying disease “cancer” through therapeutic measures. The affected patients are resistant to therapy - "out of therapy ". The main therapeutic goal of tumor cachexia is to significantly improve the quality of life of the affected patient. In addition, the overall survival time should be increased and the body strengthened for tumor therapeutic measures (surgery, chemotherapy , radiation therapy ).

The currently established measures for the treatment of tumor cachexia are inadequate in their effectiveness, so that the success of treatment is very modest. The reasons for this lie on the one hand in the incomplete knowledge about the pathogenesis of tumor cachexia and on the other hand in the multitude of influencing factors on the pathogenesis itself. Due to the latter aspect, it is currently assumed that a single therapy alone - also in the future - will not be the universal one Solution will be. Rather, there is a need to combine several types of treatment. Some oncologists see future cancer therapies combined with therapy for anorexia and tumor cachexia right at the beginning of the diagnosis of "cancer". This promises synergistic effects, which are reflected on the one hand in a better response rate in tumor therapy and on the other hand in a significantly improved quality of life.

Increase in food intake and appetite stimulant

The most obvious therapeutic measure is to increase the patient's food intake. Even if the patient's loss of appetite can be overcome and the nutritional needs are more than met - if necessary through artificial nutrition with a high physiological calorific value - these measures alone do not lead to an increase in lean and anhydrous body mass. The catabolic protein breakdown in the skeletal muscles cannot be stopped or even reversed. The administration of substances that only stimulate the appetite can therefore not prevent the catabolic degradation.

Ghrelin

→ see main article Ghrelin
The ribbon model of preproghrelin

Ghrelin (engl. G rowth H ormone Rel ease In ducing ) is from 28 amino acids existing appetizing peptide hormone . It is formed from the precursor protein preproghrelin - which consists of 117 amino acids - through post-translational modification in the gastric mucosa . It is the only currently identified hormone that circulates in the human body and stimulates appetite. Ghrelin stimulates the release of neuropeptide Y (NPY), which among other things affects hunger and the motility of the gastrointestinal tract.

In preclinical experiments with model organisms , promising results have been obtained in the treatment of cachectic mice with ghrelin. The stimulation of the appetite and an increased food intake could be demonstrated; likewise the building of muscle mass. The positive effects against digestive disorders and vomiting when chemotherapy was carried out at the same time were also surprising .

Ghrelin can be administered subcutaneously or intravenously . It is generally well tolerated. Undesirable side effects are largely unknown. Ghrelin does not stimulate tumor growth. In the animal model and in the first tests on humans, however, ghrelin resistance was found after repeated administration, which could be compensated by higher doses. The mechanism of resistance development is similar to that of insulin resistance. The dangers of diabetes mellitus when taking ghrelin for long periods of time are also discussed.

Ghrelin is still in clinical trials. Proof of effectiveness in humans with the indication tumor cachexia (successful phase III) is still pending. Only then can drug approval and market launch take place.

Megestrol

The structural formula of Megestrol

Megestrol is a sex hormone from the progesterone group . The substance has been shown to have an orexigenic (appetite-stimulating) effect. In 1993, Megestrol was approved by the FDA for the treatment of anorexia, cachexia, or unexplained weight loss in AIDS patients. There is no approval for cancer patients with tumor cachexia. This medicinal product is well tolerated and has few side effects. The mechanism of action for appetite stimulation is still unclear. Megestrol has been shown to increase appetite in patients with tumor cachexia. Weight gain can also be demonstrated. A significant increase in quality of life could not be proven in the studies carried out so far. The survival time could also not be increased compared to patients who received a placebo .

Megestrol is effective in the presence of anorexia without cachexia. In contrast, the weight gain in cachectic patients is essentially due to the increase in adipose tissue and the storage of water in the interstitium. However, the desired effect of increasing skeletal muscle mass does not materialize.

Cannabinoids

The cannabinoids contained in hemp have an appetite-stimulating effect, but have not been able to provide any proof of effectiveness in the treatment of tumor cachexia in controlled studies.

Endocannabinoids have an appetite-stimulating effect in humans. Plant cannabinoids , for example from hemp ( Cannabis sativa ), have been known to have the same effect since ancient times. The appetite-stimulating effect has been proven for Δ9- tetrahydrocannabinol (THC), the main active ingredient of Cannabis sativa , and the partly synthetically produced THC dronabinol . The substance is approved in the United States as a drug for the treatment of anorexia and cachexia in AIDS and as an antiemetic in cancer.

In a large-scale, multicentre, randomized, placebo-controlled, double-blind phase III study with 289 patients over a period of six weeks, however, no difference was found between the THC arm and the placebo arm with regard to appetite, nausea, mood and quality of life. Other comparative studies come to similar results.

Other appetite stimulants or serotonin antagonists have also shown in clinical studies that they cannot stop the progressive weight loss in tumor cachexia.

Inhibition of acute phase proteins or their messenger substances

Acute phase proteins (APP) are mainly produced in the liver and released into the bloodstream in acute or chronic inflammatory reactions. The production of the acute phase proteins is mainly stimulated by the messenger substances tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). C-reactive protein as well as various transport and complement proteins are produced as acute phase proteins . The APPs affect the central nervous system , among other things, and influence appetite, eating habits and metabolism there. Which APP works how and where exactly is not yet fully known and is the subject of current research. The production of APPs is significantly increased especially in tumors in the organs of the pancreas , lungs , esophagus and kidneys . A therapeutic approach to the treatment of tumor cachexia consists in the inhibition of the acute phase proteins or the messenger substances that stimulate the production of APPs in the liver.

Nonsteroidal anti-inflammatory drugs

Compounds with anti-inflammatory effects, such as the nonsteroidal anti-inflammatory drugs (NSAID) ibuprofen or indomethacin , inhibit the acute phase proteins non-specifically. The protein metabolism was positively influenced both in the animal model and in patients with a pancreatic tumor or colorectal cancer . With indomethacin, survival time was significantly increased. In addition to these unspecific approaches to inhibiting acute phase proteins, research is also being carried out into the specific inhibition of individual APPs - or of messenger substances that stimulate the production of the APPs. An example of this is the inhibition of interleukin-6. However, previous attempts have been unsuccessful.

Steroidal anti-inflammatory drugs

Steroidal anti-inflammatory drugs such as the glucocorticoid prednisolone have also shown positive results in clinical studies. Glucocorticoids are often given to treat tumor cachexia. The usually undesirable side effect of weight gain with glucocorticoids is desirable in this application. Prednisolone and dexamethasone significantly increase the appetite of patients and thus improve their quality of life. In addition, cytokines are inhibited via the anti-inflammatory effect. The effect of the glucocorticoids is short-lived and the condition of the skeletal muscles is not improved by the administration of glucocorticoids. In some studies, the overall survival time is significantly increased compared to the placebo administration. The undesirable side effects of glucocorticoids, such as nausea, pain, water retention , weakness and insulin resistance or even osteoporosis and immunosuppression, are so significant that the therapeutic benefit is very questionable and controversial. Glucocorticoids are not well established in the treatment of tumor cachexia.

TNF-α inhibitors (thalidomide)

The structural formula of thalidomide, better known under the brand name Contergan

The approaches to inhibit TNF-α are more promising. Thalidomide - much better known under the brand name Contergan - is a selective antagonist of TNF-α and TGF-β . Positive results were obtained in the animal model as well as in the first clinical studies. For example, the administration of thalidomide resulted in an increase in lean and anhydrous body mass in eight out of ten patients with unresectable esophageal cancer . The breakdown of skeletal muscles was also significantly delayed in patients with pancreatic cancer. However, the survival time of the thalidomide-treated patients - compared to the placebo group - could not be increased, although tumor cachexia is the direct cause of death in a large number of patients with pancreatic cancer. Thalidomide and other inhibitors are being tested in a number of controlled clinical studies for the treatment of tumor cachexia and have yet to prove their therapeutic effectiveness.

Inhibition of proteasome activity

The breakdown of the proteins of the skeletal muscles takes place - regardless of the triggering messenger substance - via the ubiquitin-proteasome system. A therapeutic starting point is therefore to reduce the activity of the proteasome. Several proteasome inhibitors are in clinical trials. The first proteasome inhibitor to be approved in the US and the EU, bortezomib , is effective against multiple myeloma .

3-hydroxy-3-methylbutyric acid

The structural formula of 3-hydroxy-3-methylbutyric acid

3-Hydroxy-3-methylbutyric acid (HMB), usually referred to as β-hydroxy-β-methylbutyric acid or β-hydroxy-β-methylbutyrate, is a metabolic product of the essential amino acid leucine . About 5 percent of the ingested leucine is metabolized to HMB. HMB is offered as a dietary supplement and shows, among other things, anabolic, anti-catabolic and lipolytic effects in the human body . HMB is therefore taken by many bodybuilders and strength or endurance athletes to legally increase muscle mass or performance. In well-trained athletes, however, neither aerobic nor anaerobic performance can be measured through taking HMB.

In the animal model of cachectic mice, it was possible to show that the breakdown of protein is reduced and the build-up of muscle mass is stimulated. If HMB is administered to the test animals together with PIF, which upregulates the ubiquitin proteasome system, the effect of PIF can be completely compensated for by HMB. HMB apparently has a regulating effect on the expression of NF-κB, which is less strongly produced by the cells. The mechanism for building protein mass is via the mTOR receptor, the phosphorylation of which is apparently stimulated by HMB.

A number of clinical studies with healthy volunteers, trained and untrained, have been conducted with HMB. The results are partly contradictory. However, there are conclusive indications that the administration of HMB for tumor cachexia could be an effective future form of therapy. In a study with cachectic patients, an increase in lean body mass was demonstrated by the administration of HMB in combination with the amino acids arginine and glutamine . In a phase III, double-blind, randomized, placebo-controlled study of 472 patients, lean body mass increased in patients who received HMB with arginine and glutamine. However, only 37 percent of all patients completed the study, as a result of which the primary and secondary endpoints could not be achieved and therefore no proof of the effectiveness of HMB for the treatment of tumor cachexia is provided. Further, large-scale studies are necessary to provide evidence of effectiveness.

Bortezomib

→ see main article bortezomib
The structural formula of bortezomib

Bortezomib is a proteasome inhibitor approved for the treatment of multiple myeloma . In clinical studies that aimed to delay or prevent the proteolytic muscle breakdown occurring in tumor cachexia, the compound did not show sufficient effectiveness.

Eicosapentaenoic acid

→ see main article eicosapentaenoic acid
The structural formula of eicosapentaenoic acid

Eicosapentaenoic acid , usually abbreviated as EPA ( Eicosapentaenoic acid ), is a polyunsaturated fatty acid from the class of omega-3 fatty acids . It is one of the main components of certain fish oils, especially fatty fish . EPA has anti-inflammatory properties and is the only dietary supplement that is able to influence the proteasome through various mechanisms . The activity of the proteasome, which breaks up proteins into fragments inside the body's cells, is reduced by EPA. According to the model of action, it should be possible to reduce the breakdown of muscle proteins. In the first studies on patients with pancreatic cancer , cachectic weight loss could be reduced. The EPA was well tolerated by the patients without significant side effects. This success could not be repeated in three subsequent, large-scale, placebo-controlled, randomized double-blind studies . In the “mouse” animal model, no influence of EPA on protein synthesis could be determined.

Other therapy concepts

insulin

→ see main article insulin

The hormone insulin is a potent regulator of protein turnover in the body. The administration of insulin can stimulate the uptake of carbohydrates in cachectic patients. In a clinical study, the patients with various tumor diseases gained body weight, but mainly due to an increased percentage of body fat. The lean body mass remained unchanged. The administration of insulin did not affect tumor growth and the survival time was slightly increased compared to the control group.

Hydrazine sulfate

Hydrazine sulfate was one of the first active ingredients to be used specifically against tumor cachexia. The compound is an inhibitor of gluconeogenesis , i.e. the formation of glucose in the body from non-carbohydrates. Hydrazinium sulfate deactivates the enzyme phosphoenolpyruvate carboxykinase . In the first clinical studies in the treatment of cancer patients at a late stage of the disease, improved glucose tolerance, reduced glucose metabolism, increased uptake of nutrients and a stabilization or even increase in body weight could be determined. The undesirable side effects were minor. The intention at the time to administer hydrazinium sulfate was to start from the hypothesis that uncontrolled glucogenesis was closely related to tumor cachexia.

In later studies it was found that the administration of hydrazine sulfate for the treatment of tumor cachexia is ineffective, making this therapeutic approach obsolete .

Gene therapy

Follistatin and myostatin are two natural proteins that control muscle growth. While follistatin stimulates muscle growth, myostatin does the exact opposite. Both compounds form a control loop that controls muscle growth in mammals . The administration or cellular overexpression of follistatin, or the inhibition of myostatin or the switching off of the gene coding for myostatin , are potential therapeutic approaches for tumor cachexia. With these approaches it may be possible to counteract the reduction in muscle mass caused by tumor cachexia. The first successes were achieved in animal models. This therapeutic approach is still in the preclinical phase and - even with proof of effectiveness - is still many years away from approval as a medicinal product.

forecast

The severity of tumor cachexia correlates inversely with the mean survival time of a cancer patient. This means that the more pronounced the tumor cachexia, the shorter the survival time of the person affected. Basically, tumor cachexia is associated with a poor prognosis for the patient. Weight loss with cancer is an independent prognostic factor. Tumor cachexia increases the likelihood of postoperative complications and also has a negative impact on the success of chemotherapy. Patients with breast cancer without tumor cachexia respond on average 2.5 times better to chemotherapy than patients with tumor cachexia. Even a relatively small loss of body mass of less than five percent, for example, can significantly worsen the prognosis.

There is only a chance of a cure if the cancer underlying the tumor cachexia is cured.

literature

Reference books

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Review article

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Web links

Individual evidence

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