Cachexia – What Do We Know?

Cachexia in cancer patients is characterized by progressive loss of appetite and muscle mass with few treatment options.

by Dr. C.H. Weaver M.D. updated 8/2019

Cancer anorexia and cachexia syndrome (CACS) is a complex syndrome characterized by a progressive loss of appetite and muscle mass that cannot be fully reversed by nutritional support alone and that leads to functional impairment. (1)

CACS can be present in 40–80% of cancer patients depending on the tumor type, it is linked to poor quality of life and is a strong predictor of survival. This syndrome can be due to the cancer itself or, paradoxically, to side effects of the chemo/radiation therapy used for its treatment. (2-4)

While the drug Megace and certain corticosteroids have demonstrated some benefit, they appear limited to stimulating appetite and increasing fat. In spite of the great progress made in increasing our understanding of CACS, developing a safe and effective treatment for this condition remains an elusive goal.

AR-42:

New research describes how an experimental drug may stop life-threatening cachexia associated with advanced cancers and restore muscle health. (5)

AR-42 s part of a class of drugs known as HDAC (histone deacetylase) inhibitors, which are designed to block proteins that play a key role in mediating skeletal muscle breakdown. In cancer, HDAC proteins also tend to drive the pathways in cancer cells that lead to aggressive cancers. AR-42 is unique among HDAC inhibitors because it appears to have beneficial effects on muscle health and function.

Preclinical studies suggest that orally administered AR-42 can significantly preserve body weight and prolong survival while simultaneously preventing the loss of muscle and fat tissue mass and preserving the health/strength of muscle.

Researchers evaluated AR-42 against two other HDAC inhibitors called vorinostat and romidepsin to determine each agent’s ability to prevent cachexia and AR-42 was the only agent shown to have a strong protective effect against tumor-associated muscle wasting. Researchers are evaluating AR-42 in human pancreatic cancer.

Celebrex®

Treatment of patients with cancer cachexia with Celebrex® (celecoxib) resulted in weight gain, increased body mass index, and better quality of life. (6)

Celebrex is a non-steroidal anti-inflammatory drug. Celebrex reduces the activity of cyclooxygenase 2 (COX-2)-a protein involved in the promotion of inflammation. Because inflammation appears to be a component in the development of cachexia, researchers from the University of North Carolina conducted a clinical study to evaluate Celebrex in the treatment of cachexia. This study included 11 patients with head and neck cancer or cancer of the gastrointestinal system. Patients were treated for 21 days prior to chemotherapy with either Celebrex or placebo (inactive substitute).

  • Patients treated with Celebrex experienced weight gain and an increase in BMI, but patients who received placebo experienced weight loss and a decline in BMI.
  • Patients treated with Celebrex reported better quality of life.

The researchers concluded that it appears as if Celebrex may help reduce or prevent cachexia among patients with cancer. Future trials further evaluating Celebrex for cancer-related cachexia are warranted.

Adenosine Triphosphate

Adenosine 5′-triphosphate (ATP) appears to improve energy intake and reduce muscle wasting associated with advanced non-small cell lung cancer (NSCLC) patients.

Two previous uncontrolled studies have suggested that ATP may inhibit weight loss. ATP is an organic compound produced within cells that provides energy for many metabolic reactions, particularly in muscles. Fifty-eight patients with advanced NSCLC were assigned to receive either ATP or no ATP (control group) at two to four week intervals. Every four weeks for 28 weeks, researchers collected data on fat mass, fat-free mass and arm muscle mass. At eight-week intervals, energy intake, body cell mass and resting energy expenditure were measured. (7)

Researchers found that fat-free mass showed no significant change in ATP-treated patients, whereas the control group exhibited a significant drop after the first 16 weeks of the trial. Arm muscle mass, as measured in the mid-upper arm, increased 1.1% in patients receiving ATP, but decreased 1.8% in the control group. The body cell mass and food intake of the control group also decreased significantly, with an overall decline of 0.6% of body cell mass per kilogram of body weight and a 568 kilo Joules/day reduction in energy intake from food. In contrast, the ATP group experienced no change in body cell mass and a non-significant increase in energy intake. The appetite of the ATP group remained stable but declined substantially in the control group. There was no difference in the resting energy expenditure between ATP and non-ATP patients.

This study’s data appears to suggest that ATP may prevent weight loss, of muscle in particular, in patients with advanced NSCLC, possibly because patients on ATP maintain their energy intake and appetite. Further research is necessary to confirm this data and resolve questions about dosing schedules and potential side effects. Individuals with advanced NSCLC may wish to speak with their physician regarding the risks and benefits of participating in a clinical trial further evaluating ATP or other novel therapeutic approaches for supportive care.

References:

  1. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, et al. Definition and classification of cancer cachexia: An international consensus. Lancet Oncol. 2011;12(5):489–495.
  1. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, Douglass HO, Jr, Engstrom PF, Ezdinli EZ, Horton J, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern cooperative oncology group. Am J Med. 1980;69(4):491–497.
  1. Reuben DB, Mor V, Hiris J. Clinical symptoms and length of survival in patients with terminal cancer. Arch Intern Med. 1988;148(7):1586–1591.
  1. Maltoni M, Nanni O, Pirovano M, Scarpi E, Indelli M, Martini C, Monti M, Arnoldi E, Piva L, Ravaioli A, Cruciani G, et al. Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian multicenter study group on palliative care. J Pain Symptom Manage. 1999;17(4):240–247.
  1. The Ohio State University Comprehensive Cancer Center – James. [Press Release]. Retrieved from http://cancer.osu.edu/news-and-media/news/investigational-drug-may-prevent-life-threatening-muscle-loss-in-advanced-cancers
  1. Lai V, George J, Richey L, et al. Results of a pilot study of the effects of celecoxib on cancer cachexia in patients with cancer of the head, neck and gastrointestinal tract. Head and Neck [early online publication]. July 5, 2007. DOI: 10.1002/hed.20662.
  1. Journal of Clinical Oncology, Vol 20, Issue 2, pp 371-378, 2002)
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