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Primary Anorexia-Cachexia Syndrome in cancer patients
Anorexia-Cachexia Syndrome, or ACS, affects up to 80% of patients with advanced cancer. Although definitions vary, ACS is often described as a weight loss of 5% of a patient’s pre-illness weight over a two-month to six-month period. ACS causes both physical and psychological distress and is often associated with other symptoms, including nausea, early satiety, fatigue and change in body image. In a 1980 retrospective study of over 3,000 ECOG trial participants by Dewys et al, pretreatment weight loss of 5% was associated with early mortality independent of staging, functional status or tumor histology. ACS can be categorized as primary or secondary. Primary ACS results from a hypermetabolic state caused directly by the cancer. Secondary ACS results from cancer-related barriers that reduce dietary intake, such as nausea/vomiting, mucositis, changes in taste/smell from chemotherapy, etc. This article will focus on primary ACS.
Pathophysiology
The pathophysiology of primary ACS is complex and continues to be studied. We now understand that primary ACS is a metabolic syndrome characterized by both increased metabolic rates and decreased muscle mass. Patients with primary ACS have increased production of acute-phase reactant proteins alongside increased proteolysis and decreased production of muscle proteins. Overall, patients develop an increased metabolic rate for their lean body mass. This differs from starvation, which is an overall hypometabolic state where lipolysis and ketone body production are predominant rather than proteolysis and increased glucose turnover.
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Primary ACS appears to be mediated by hormonal and cytokine-based interactions as well as factors originating from the cancer itself. These cytokines are primarily proinflammatory, particularly tumor necrosis factor, interleukins-1 and -6, and interferon-gamma. These cytokines in turn increase overall energy expenditure and influence the neurohormonal mechanisms that regulate appetite. The cancer-based factors include proteolysis-inducing factor and lipid-mobilizing factor. PIF has been found to directly act upon skeletal muscle and initiate its degradation.
Treatment of primary ACS
Although in the past increased nutritional support was the mainstay of treating primary ACS, multiple studies have shown that nutritional support does not increase lean body mass in these patients. Muscle protein degradation continues despite increased caloric intake. However, nutritional support does have a role in patients with secondary ACS, where the metabolic derangements of primary ACS are not present. For primary ACS, therapies have long been directed toward appetite stimulation; newer therapies targeting the proinflammatory cytokines and the hypermetabolic state are in development.
Progestins
Progestins have been one of the major treatments for primary ACS and have the most evidence demonstrating weight gain and improved appetite in cancer patients. Megestrol acetate increases weight, though primarily in fat, not lean body mass. Although studies have demonstrated symptomatic improvement of appetite, caloric intake, and general well-being at doses as low as 180 mg, ideal dosing for weight gain is in the range of 480 mg to 800 mg. The progestational agents proffer an increased risk of thrombosis so caution should be taken in patients with cancer with a prior history of thrombosis. Other possible side effects include peripheral edema, hypertension, hyperglycemia, breakthrough bleeding and suppression of the hypothalamic-pituitary-adrenal axis.
Corticosteroids
Corticosteroids have been shown to significantly improve appetite, caloric intake, energy/well-being, and functional status, but not weight. They are limited in use due to the consequences of long-term use (beyond four weeks), but can be beneficial in improving quality of life in patients with a limited prognosis. Common dosing for primary ACS has been the equivalent of prednisone 20 mg, but ideal dosing or choice of corticosteroids has not been established.
Cannabinoids
Dronabinol has been in use for AIDS-related cachexia and has demonstrated some appetite-stimulating effect, but not weight gain. It has not been shown to be as effective for patients with cancer with primary ACS, but does improve nausea and symptoms in secondary ACS.
Novel therapies and research
As more has become known about primary ACS, there have been more studies looking at anticytokine therapies, neurohormonal targets and anabolic agents in animal models with translation into clinical trials. Recent trials with oxandrolone and thalidomide have shown some improvement in lean body mass but further studies are needed.
Stephanie Harman, MD, is a Palliative Care Physician at Stanford University Medical Center and Director of its Inpatient Palliative Care service.
For more information:
- Hopkinson JB et al. Management of weight loss and anorexia. Annals of Oncol. 2008;19 (Suppl 7):289-293.
- Salacz M. Fast Facts and Concepts #100 Megestrol acetate for cancer anorexia/cachexia. October 2003. End-of-Life/Palliative Education Resource Center. www.eperc.mcw.edu.
- Strasser F, Bruera E. Update on anorexia and cachexia. Hematol Oncol Clin N Am. 2002;16:589-617.
- Talukdar R, Bruera E. Cachexia. In M. Abeloff J, Armitage J, Niederhuber M. Kastan, W. McKenna (Eds) Clinical Oncology, 3rd Ed. 2004;Philadelphia:Elsevier.