Although high doses of progestational agents can cause adrenal suppression because of their mild corticosteroid-type activity (a phenomenon not well understood by many clinicians), they do not appear to cause many of the side effects attributable to classic corticosteroids (such as peptic ulcer disease, myopathy, and opportunistic infections). In lieu of this adrenal suppression, however, stress doses of corticosteroids may be necessary in patients with trauma or infection or in surgical patients while on progestational agents. On the other hand, progestational agents increase the risk of thromboembolic phenomena–a side effect that is not seen with classic corticosteroids.
A dose-response study with megestrol(Drug information on megestrol) demonstrated a positive correlation between appetite stimulation and increased megestrol doses, as doses ranged from 160 to 800 mg/d. Nonetheless, given that appetite stimulation has been demonstrated with megestrol acetate doses as low as 240 mg/d, much lower doses are used by many physicians, based primarily upon cost considerations.
In the United States, a liquid formulation of megestrol is considerably less expensive than the tablet form, and, milligram for milligram, the liquid preparation is more bioavailable. It is reasonable to start with 400 mg/d of liquid megestrol, titrating this dose upward (maximum, 800 mg/d) or downward based upon clinical response or the emergence of side effects.
A randomized, prospective clinical trial comparing the utility of megestrol (800 mg/d) with dexamethasone(Drug information on dexamethasone) (0.75 mg qid) demonstrated similar effects of these medications on patients’ appetites but different toxicity profiles. Whereas megestrol was associated with a higher incidence of thromboembolic phenomena, dexamethasone was associated with more myopathy, cushingoid body changes, and peptic ulcers.
Various other drugs have been evaluated definitively for the treatment of cancer anorexia and cachexia and have demonstrated little or no benefit. These drugs include fluoxymesterone(Drug information on fluoxymesterone), pentoxifylline(Drug information on pentoxifylline), hydrazine sulfate, dronabinol, cyproheptadine(Drug information on cyproheptadine), eicosapentaenoic acid (EPA), and etanercept(Drug information on etanercept) (Enbrel). Of note, however, the antiserotonergic drug cyproheptadine does appear to be a relatively strong appetite stimulant in patients with the carcinoid syndrome, presumably because it directly counteracts the large amounts of serotonin secreted in these patients.
EPA has been tested extensively for cancer anorexia and cachexia. Although preliminary studies had claimed improvement in appetite, body composition, and survival with EPA, these favorable findings have not been borne out in subsequent phase III trials. Three phase III trials have shown that EPA does relatively little for cancer anorexia and cachexia when tested in the setting of either EPA versus placebo or EPA versus megestrol.
A number of other drugs have been evaluated in a pilot fashion for the treatment of cancer anorexia and cachexia. They include branched-chain amino acids, thalidomide(Drug information on thalidomide) (Thalomid), metoclopramide(Drug information on metoclopramide), oxandrolone(Drug information on oxandrolone) (Oxandrin), and adenosine(Drug information on adenosine) triphosphate. It is hoped that new information will be available in the near future to shed light on the possible therapeutic roles of these agents.
Even more recently, exciting data have arisen from a preliminary study of ghrelin, an endogenous ligand for the growth hormone secretagogue receptor. A study of 21 patients demonstrated the safety of this substance, allowing for the possibility of its further testing in the future.