Two clinical trials having essentially the same design have demonstrated an increase in survival and a reduction in recurrence rate in the subset of patients with resected Dukes' C colon cancer treated with a regimen of ERGAMISOL^®, (levamisole hydrochloride) plus fluorouracil.^1,2 After surgery, patients were randomized to no further therapy, ERGAMISOL^® alone, or ERGAMISOL^® plus fluorouracil.

In one clinical trial in which 408 Dukes' B and C colorectal cancer patients were studied, 262 Dukes' C patients were evaluated for a minimum follow-up of five years.¹ A subset analysis of these Dukes' C patients showed the estimated reduction in death rate was 27% for ERGAMISOL^® plus fluorouracil (p = 0.11) and 28% for ERGAMISOL^® alone (p = 0.11).³ The estimated reduction in recurrence rate was 36% for ERGAMISOL^® plus fluorouracil (p = 0.025) and 28% for ERGAMISOL^® alone (p = 0.11).³ In another clinical trial designed to confirm the above results, 929 Dukes' C colon cancer patients were evaluated for a minimum follow-up of 2 years.² The estimated reduction in death rate was 33% for ERGAMISOL^® plus fluorouracil (p = 0.006). The estimated reduction in recurrence rate was 41% for ERGAMISOL^® plus fluorouracil, (p < 0.0001). The ERGAMISOL^® alone group did not show advantage over no treatment on improving recurrence or survival rates. There are presently insufficient data to evaluate the effect of the combination of ERGAMISOL^® plus fluorouracil in Dukes' B patients. There are also insufficient data to evaluate the effect of ERGAMISOL^® plus fluorouracil in patients with rectal cancer because only 12 patients with rectal cancer were treated with the combination in the first study and none in the second study.

The mechanism of action of ERGAMISOL^® in combination with fluorouracil is unknown. The effects of levamisole on the immune system are complex. The drug appears to restore depressed immune function rather than to stimulate response to above-normal levels. Levamisole can stimulate formation of antibodies to various antigens, enhance T-cell responses by stimulating T-cell activation and proliferation, potentiate monocyte and macrophage functions including phagocytosis and chemotaxis, and increase neutrophil mobility, adherence, and chemotaxis. Other drugs have similar short-term effects and the clinical relevance is unclear.

Besides its immunomodulatory function, levamisole has other mammalian pharmacologic activities, including inhibition of alkaline phosphatase, and cholinergic activity.

The pharmacokinetics of ERGAMISOL^® have not been studied in the dosage regimen recommended with fluorouracil. After administration of a single oral dose of 50 mg of a research formulation of ERGAMISOL^®, it appears that levamisole is rapidly absorbed from the gastrointestinal tract. Mean peak plasma concentrations of 0.13 mcg/ml are attained within 1.5 to 2 hours. The plasma elimination half-life of levamisole is between 3-4 hours. Following a 150-mg radio-labeled dose, levamisole is extensively metabolized by the liver in humans and the metabolites excreted mainly by the kidneys (70% over 3 days). The elimination half-life of metabolite excretion is 16 hours. Approximately 5% is excreted in the feces. Less than 5% is excreted unchanged in the urine and less than 0.2% in the feces. Approximately 12% is recovered in the urine as the glucuronide of p-hydroxy-levamisole. The clinical significance of these data are unknown since a 150-mg dose may not be proportional to a 50-mg dose. In the presence of cirrhosis in twelve patients with alcoholic cirrhosis and hepatitis, the C_max of ERGAMISOL^® was not clearly increased, but the AUC was 1 to 20-fold increased compared to normal volunteers.

Bookmark this page: