Cancer Cachexia

Cancer Cachexia

Anorexia-cachexia is a complex metabolic syndrome associated with underlying malignancy and is characterized by loss of appetite and ongoing loss of skeletal muscle mass, with or without loss of fat mass that can be partially, but not entirely, reversed by conventional nutritional support.

Synonym

  • Anorexia Cachexia Syndrome Associated with Malignancy

Epidemiology & Demographics

Incidence

Estimates of the prevalence of cancer cachexia vary widely due to variable diagnostic criteria used in prior studies. In one study of 405 patients, the incidence of cachexia ranged from 12% to 85% using different available definitions.

In another study, more than half of 644 cancer patients were reported as having cachexia using anorexia and weight loss exceeding 5% of premorbid weight. The highest incidence is reported in patients with lung and gastrointestinal cancers.

Genetics

In patients with elevated inflammatory markers, cachexia is associated with specific vitamin D receptor polymorphisms, thus representing a possible early clinical predictor phenomenon for the development of a more aggressive form. Polymorphisms resulting in an increase in levels of inflammatory cytokines, a decrease in lean or fat mass, and decreased survival in cancer are likely to be cachexia-prone variants.

However, to date, no specific single nucleotide polymorphisms (SNPs) have been found in association with cancer cachectic patients.

Etiology

In cancer patients, anorexia is common and results in decreased oral intake and malnourishment.

Cancer cachexia is characterized by an upregulation of muscle proteolysis and lipolysis due to an increased inflammatory response from cytokines including interleukins [IL-6 and IL-1], interferon-gamma [IFN-γ] and tumor necrosis factor-alpha [TNF- α].

These cytokines activate the ubiquitin-proteasome pathway via nuclear factor kappa B, resulting in a protein degradation pathway in the myocytes. At the same time, protein synthesis is downregulated by the human myogenic differentiation protein, MyoD.

Furthermore, the increased cytokine levels induce an overall hypermetabolic state and shift the balance toward catabolism.

Differential Diagnosis

  • •Starvation
  • •Malabsorption
  • •Hyperthyroidism
  • •Anorexia nervosa
  • •Depression

Workup

Patients can be categorized into three consecutive stages of cancer cachexia: Precachexia, cachexia, and refractory cachexia using available cachexia staging systems. Furthermore, there are five domains to assess including: Food intake, catabolic derangements, functional and psychosocial impact, and assessments of body composition including stores of adipose tissue and muscle mass. A diagnosis can be made in a patient with weight loss >5% in the absence of starvation, BMI <20 and 2% weight loss, or appendicular skeletal muscle index consistent with sarcopenia and >2% weight loss.

FIG. E1

Laboratory Tests

  • •Complete blood count, complete chemistry panel including albumin and prealbumin
  • •Inflammatory markers including ESR and C-reactive protein
  • •Endocrine assessment with TSH, cortisol, ACTH, testosterone

Imaging Studies

CT or MR imaging of the abdomen can be used to assess for sarcopenia by analyzing the body and muscle composition

Treatment

The mainstay of treatment is directed at aggressive nutritional and supportive therapy.

Functional causes of malabsorption or gastrointestinal obstruction should be evaluated at the start.

It has been proposed that the T.A.R.G.E.T. approach, encompassing different domains, namely Teaching, Awareness, Recognition, Genetics, Exercise/Early intervention and Treatment of cancer cachexia, should be utilized in all patients.

FIG. E2

Nonpharmacologic Therapy

  • •The general approach is to increase caloric intake by encouraging frequent (up to 5 to 6 times), small, and calorie-dense meals during the day along with supplemental liquid nutrition typically utilized alongside consultation with nutritionists.
  • •Physical activity may attenuate the effects of cachexia by modulating muscle metabolism, insulin sensitivity, and inflammation. In particular, exercise has been shown to have antiinflammatory properties, preserve muscle mass and function, enhance protein synthesis, decrease protein catabolism, and contribute to a better muscle performance.

Acute General Treatment

  • •Multimodal interventions should be scheduled in parallel with anticancer therapies and may consist of nutritional intervention and multitargeted pharmacologic therapies.
  • •Enteral nutrition should be started if undernutrition already exists or if food intake is markedly reduced for more than 1 to 2 wk. When enteral nutrition cannot be effectively used, parenteral nutrition may be considered instead as a supporting measure or as total nutritional requirement.
  • •The use of eicosapentaenoic acid (EPA)-enriched nutrition has been associated with improved anorexia outcomes in cancer patients, but a recent metanalysis found insufficient data to establish an overall benefit with EPA use in this setting.
  • •Appetite stimulants are the mainstay of pharmacologic intervention in cancer cachexia. Glucocorticoids have been extensively studied in patients with advanced cancer and are known to stimulate the appetite. Prednisone (at 20 to 40 mg/day) or dexamethasone (at 2 to 4 mg/day) are used commonly, but major side effects include insulin resistance, immune suppression, muscle myopathy, and adrenal insufficiency.
  • •Megestrol acetate, an appetite stimulant with progestational and antigonadotropic effects, has been shown to slightly improve appetite and increase weight but does not improve lean body mass or quality of life. Major complications include increased risk for thromboembolism, adrenal insufficiency, and hypogonadism in male patients.
  • •Dronabinol, a constituent of cannabis, has been studied for appetite stimulation in cancer patients, but results from large studies have revealed no major benefit.
  • •The psychiatric drugs mirtazapine and olanzapine both are potential therapies for cancer patients with anorexia-cachexia syndrome. Mirtazapine-treated patients gain weight and develop an improved appetite in some cases. Olanzapine treatment of cancer patients with cachexia who were receiving active chemotherapy showed a trend toward improved weight and may be useful for patients on chemotherapy who have difficult-to-control nausea and weight loss.
  • •Treatment with the NSAID celecoxib has resulted in weight gain, increased BMI, and improved quality of life. NSAIDs are frequently incorporated into combination drug therapy for cancer cachexia along with megestrol. A recent systematic review identified four studies that reported some evidence for the therapeutic benefits of NSAIDs in terms of weight gain, survival, quality of life, and inflammatory markers, but evidence was lacking for widespread use of NSAIDs in clinical practice.
  • •Anamorelin, a novel ghrelin-receptor agonist, has been evaluated in two large randomized trials in patients with advanced non–small cell lung cancer and cachexia. Although the trial failed to meet the primary endpoint, anamorelin significantly increased lean body mass, but not handgrip strength in these patients, and can be considered as an option.
  • •Based on promising results in a large phase II study, the concept of multimodal intervention is being tested in the large randomized MENAC (multimodal-exercise, nutrition and antiinflammatory medication for cachexia) trial in lung cancer, cholangiocarcinoma, and pancreatic cancer patients. Interventions include eicosapentaenoic acid (nutrition), ibuprofen (antiinflammatory medication), and a physical exercise program.

Chronic Treatment

  • •Nutritional supplements such as amino acids (l-glutamine, l-arginine, l-carnitine) have been evaluated with inconclusive results.
  • •Omega-3 fatty acids and docosahexaenoic acid (DHA), which are found in fish oil, have been also investigated with inconclusive results.
  • •Ongoing exercise and rehabilitation programs need to be offered to all patients.

Referral

  • •Nutritionists and cachexia clinics (if available).
  • •Palliative care specialists.

 Pearls & Considerations

  • •Cancer cachexia is an underrecognized problem present in up to half of all advanced cancer patients. Up to 1 in 5 cancer patients can die directly due to the effects of cancer cachexia.
  • •Multimodal intervention in early identified precachexia patients may prove to be beneficial.

Suggested Readings

  • Argiles J.M., et al.: Therapeutic strategies against cancer cachexia. Eur J Transl Myol 2019; 29 (1): pp. 4-13.
  • Dev R., et al.: The evolving approach to management of cancer cachexia. Oncology (Williston Park) 2017; 31 (1): pp. 23-32.
  • Dev R.: Measuring cachexia-diagnostic criteria. Ann Palliat Med 2019; 8 (1): pp. 24-32.
  • Fearon K., et al.: Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011; 12 (5): pp. 489-495.
  • Garcia JM.: Omega-3 fatty acids in patients with anorexia-cachexia syndrome associated with malignancy and its treatments. Am J Med 2017; 130: pp. 1151-1155.
  • Muscaritoli M., et al.: Cachexia: a preventable comorbidity of cancer. A T.A.R.G.E.T. approach. Crit Rev Oncol Hematol 2015; 94 (2): pp. 251-259.
  • Solheim T., et al.: Cancer cachexia: rationale for the MENAC (multimodal-exercise, nutrition and anti-inflammatory medication for cachexia) trial. BMJ Support Palliat Care 2018; 8 (3): pp. 258-265.
  • Wallengren O., et al.: Diagnostic criteria of cancer cachexia: relation to quality of life, exercise capacity and survival in unselected palliative care patients. Support Care Cancer 2013; 21 (6): pp. 1569-1577.
  • Zhou T., et al.: Development and validation of a clinically applicable score to classify cachexia stages in advanced cancer patients. J Cachexia Sarcopenia Muscle 2018; 9 (2): pp. 306-314.
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