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.
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.
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.
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 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
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
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.
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
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
- 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.