, Volume 1, Issue 4, pp 317-337

Levamisole/Fluorouracil

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Summary

Synopsis

The combination of the antimetabolite fluorouracil plus the immunomodulator levamisole is used as adjuvant therapy following surgical tumour removal in patients with Dukes’ stage C colon cancer.

Flourouracil given alone in this setting results in only a modest improvement in survival rate, and levamisole monotherapy is clinically ineffective. Well controlled studies, however, demonstrate that combined levamisole/fluorouracil reduces the recurrence rate by between 31 and 41% and the total mortality rate by between 13 and 33% compared with surgery alone in patients with Dukes’ stage C colon cancer after median follow-up of 3 or 7.75 years. The median time to recurrence and median survival time are also extended significantly by levamisole/fluorouracil compared with fluorouracil alone or no adjuvant treatment.

Thus, levamisole/fluorouracil has been recommended as the standard adjuvant therapy for patients with Dukes’ C colon cancer, against which new investigative regimens should be compared. Methods for optimising the impressive results already achieved with this combination, and using this as a basis for further progress should be the thrust of future trials.

Pharmacological Properties

The antimetabolite fluorouracil inhibits DNA and RNA synthesis in tumour cells via a series of active metabolites, the most active of which is fluorodeoxyuridine monophosphate.

Levamisole displays a range of immunomodulatory activity centred on cell—mediated (i.e. T cell-directed) mechanisms. Mitogen—induced and autologous T cell proliferation is enhanced by levamisole in animals and humans with immunosuppression induced by cancer, surgery and/or fluorouracil administration, and T cell sensitivity to interleukin 2 is augmented. Allograft response and tumour immunity, which may be associated with increased survival in patients with colorectal cancer, are also maintained during levamisole administration. Levamisole 2.5 mg/kg or 150mg daily restored E-rosette forming capacity in cancer patients, and increased macrophage and neutrophil function, including mobility, chemotaxis and phagocytosis, in vitro and in vivo.

Human colorectal cancer cell line growth and viability were inhibited in vitro by levamisole, and an additive and synergistic activity was demonstrated with fluorouracil, but only at plasma concentrations (1000 µmol/L) not achieved clinically. In rats with colonic tumours, levamisole has had a variable effect on tumour and metastasis development, and survival.

It thus appears that the mechanism of action of levamisole in the adjuvant setting with fluorouracil may be related to its ability to restore depressed cell—mediated immune responses rather than a direct antitumour effect, although tentative in vitro evidence exists for additive cytotoxicity and modulation of the activity of fluorouracil.

Pharmacokinetic Properties

Intravenous injection of fluorouracil 300 to 600 mg/m2 usually results in plasma concentrations of between 400 and 600 µmol/L in patients with colorectal cancer. Its volume of distribution is 8 to 54L, with rapid distribution (⩽ 5 minutes) into the liver, kidneys and urinary bladder. It also appears to be preferentially taken up by tumour versus healthy colonic tissue, and formation of the active metabolites of fluorouracil may be greater in tumour tissue. Inactivation occurs through metabolism, predominantly in the liver with some renal contribution. Excretion is mainly urinary; a mean of 95% of a total dose is recovered in urine within 24 hours. The mean elimination half-life is 5 to 20 minutes following intravenous administration, and total body clearance is 30 to 120 L/h. Hepatic and pulmonary clearance each form up to 50% of the total, and renal 6 to 24%.

Peak plasma concentrations of approximately 3 µmol/L are achieved 1 to 2 hours after a single oral dose of levamisole 150mg in healthy volunteers, with an absorption half-life of 22 to 33 minutes. Absorption appears to be more rapid in women, but bioavailability (about 60 to 70%) is similar in healthy volunteers and in colorectal cancer patients without hepatic involvement. Levamisole is extensively distributed out of the plasma, with an apparent volume of distribution of 86 to 266L. Within 72 hours of an oral dose, 70% of the total is recovered in the urine; predominantly as metabolites. About 4% of an oral levamisole dose is detected in the faeces within 72 hours. The elimination half-life of levamisole is 4 to 5 hours. Total plasma clearance (mainly via hepatic extraction) was 17.5 to 20 L/h in 46 healthy volunteers and cancer patients.

Therapeutic Use

Adjuvant therapy (i.e. treatment following curative-intent surgical tumour removal) is recommended for all patients with Dukes’ stage C colon cancer or stage B2–3 rectal cancer. However, 5-year survival has been only increased by 2.3 to 5.7% (not significant) with fluorouracil-containing regimens in clinical studies. Similarly, levamisole alone did not significantly reduce the rate of recurrence or extend survival compared with placebo administration.

Early studies failed to reveal a lower recurrence rate or extended survival in patients with Dukes’ B or C colorectal cancer receiving levamisole/fluorouracil in combination compared with those receiving fluorouracil alone for 1 year postoperatively. However, patient groups were small (between 16 and 26 patients), no distinction was made between colon and rectal cancer, and follow-up was short. A subsequent randomised study demonstrated a reduction in recurrence rate and a significant increase in 5-year survival rate in 131 patients (42% of whom had rectal cancer; 69% with Dukes’ A or B disease) receiving fluorouracil plus levamisole for the first 3 postoperative days followed by fluorouracil alone, compared with just fluorouracil alone for 6 months or no treatment.

Two further large, well-designed trials in patients with more advanced Dukes’ C colon cancer revealed that levamisole/fluorouracil for 1 year beginning within 5 weeks of surgery reduced the rate of recurrence by 31 and 41% and the mortality rate by 13 and 33% after a median follow-up of 7.75 and 3 years, respectively, compared with surgery alone. Survival rates after 3.5 years were 71% in levamisole/fluorouracil recipients, and 55% in both levamisole-treated and untreated patients, and after 5 years were 61%, 59% and 42%, respectively, in Dukes’ C patients. The median time to recurrence was extended up to 2-fold, to between 4.3 and 4.5 years, with the combination. The advantage of the combined adjuvant regimen was still apparent when confounding prognostic variables including tumour stage, location and degree of invasion were allowed for.

A distinct benefit of levamisole/fluorouracil in patients with Dukes’ B disease is not proven, with similar 5- and 3.5-year survival rates (77 to 84%) in patients receiving the combination, levamisole alone or no adjuvant therapy. A longer follow-up may be required to reveal a significant treatment effect, if any, in these patients.

Tolerability

Nausea (56%), diarrhoea (47%), stomatitis (28%), dermatitis (22%), alopecia (22%) and vomiting (17%) are the most frequent symptomatic unwanted effects of combined levamisole/fluorouracil and are largely attributable to fluorouracil. Leucopenia, usually mild (WBC 2 to 4 × 109/L) is present in up to 38% of patients and may lead to infection in 2%. Dizziness, depression, irritability, ataxia and hyperbilirubinaemia occur in 2 to 4% of treated patients.

Dosage and Administration

In patients with Dukes’ C colon cancer, levamisole 50mg orally every 8 hours for 3 days on alternate weeks plus fluorouracil 450 mg/m2/day by rapid intravenous injection for 5 days and then, 28 days later, once each week for 1 year is currently recommended as adjuvant therapy. Levamisole should be started 7 to 30 days after surgery and fluorouracil after 21 to 34 days. Treatment must be modified if intolerable stomatitis, diarrhoea, leucopenia (WBC < 3.5 × 109/L) or thrombocytopenia (< 100 × 109/L) occur. Other schedules are being investigated.

Various sections of the manuscript reviewed by: G. Bianchi Porro, Gastrointestinal Unit, Ospedale ‘L. Sacco’, Milan, Italy; R.M. Hansen, Division of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; A.K. House, Department of Surgery, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia; U. Metzger, Chirurgische Klinik, Stadtspital Triemli, Zürich, Switzerland; E. Mini, Dipartimento di Farmacologia Preclinica e Clinica ‘Mario Aiazzi Mancini’, Università degli Studi di Firenze, Firenze, Italy; C.G. Moertel, Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA; L. Saltz, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; R. Windle, Glenfield General Hospital, Leicester, England.