Levamisole

Brucellosis

Adding levamisole to conventional antibiotic therapy may improve anergy against Brucella , bacteria that can survive in phagocytic cells. This hypothesis has been investigated in patients with chronic brucellosis in Turkey [ ]. A 6-week course of levamisole in addition to conventional antibiotic therapy in chronic brucellosis was not superior to conventional antibiotic treatment alone with respect to lymphocyte subgroup ratios and phagocytic function. Adverse reactions were not reported.

Aphthous stomatitis

Levamisole has been used in the treatment of recurrent aphthous stomatitis [ ] and its value reviewed [ ]. In four of seven placebo-controlled studies there was a reduction in the frequency and duration of aphthous ulcers during levamisole treatment. Efficacy did not differ whether levamisole was given routinely or started at the first sign of ulcers. In most patients levamisole was well tolerated. Of 128 patients who took levamisole, two withdrew as result of adverse effects (nausea and flu-like symptoms). The most frequent adverse effects were dysgeusia (21%) and nausea (16%). The other adverse effects occurred in less than 10% of the patients and included dysosmia, headaches, diarrhea, flu-like symptoms, and rash, but not all may have been due to levamisole. Levamisole rarely results in objective clinical improvement, and the associated adverse effects discourage its use.

Cancers

In 63 patients with stage III and stage IV squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, and larynx, with no distant metastases, randomized to either adjuvant oral chemotherapy with futraful + uracil + levamisole (n = 29) or no treatment (n = 34), oral chemotherapy showed a trend of better control of distant tumor recurrence [ ]. However, there was no statistically significant improvement in overall long-term survival. Of the 29 patients who received adjuvant oral chemotherapy, 17 finished the 1-year course without withdrawing. In nine patients treatment with futraful + uracil + levamisole was withdrawn because of local, regional, or distant metastases. Three patients withdrew after 4 months because of vomiting and mucositis. One developed a mild gastric upset and completed the course. There were no major hematological or nephrotoxic adverse effects.

Levamisole is used as an immunomodulating drug in colorectal cancer, usually in combination with 5-fluorouracil. The IGCS-COL multicenter randomized phase III study partly addressed the role of levamisole in the modulation of 5-fluorouracil as adjuvant systemic chemotherapy in patients with colorectal cancer [ ]. There was no evidence of improvement of disease-free survival or overall survival advantage by adding levamisole; nor did the addition of levamisole produce any statistically significant effect on the adverse effects profile of 5-fluorouracil.

In another study in 598 patients with stage III colon cancer the addition of levamisole to adjuvant fluorouracil significantly worsened the prognosis [ ].

Candidiasis

In two patients with thymoma associated with myasthenia gravis, who both had recurrent oral candidiasis after thymectomy, radiotherapy, and chemotherapy levamisole was added as adjunctive therapy in combination with oral nystatin [ ]. Oral candidiasis responded favorably and substantial relief was obtained, with a concurrent increase in T cells and CD4/CD8 ratio, suggesting restoration of T cell immunity. Adverse reactions were not mentioned.

Glomerulonephritis

In an extensive review of the treatment of minimal lesion glomerulonephritis the use of levamisole was briefly mentioned [ ]. The author concluded that levamisole has a beneficial effect in this disorder, although no new studies have appeared in recent years and well-controlled studies are scarce. Levamisole appears to be well tolerated in this condition. The adverse effects were neutropenia, rash, and raised liver aminotransferases.

Many children with steroid-dependent nephritis have significant sequelae despite steroid-sparing therapies. Levamisole may reduce short-term relapse frequency with minimal adverse reactions. However, there is little information about its long-term effects. In 10 consecutive children with steroid-dependent nephritis treated with levamisole, both the relapse frequency and annual steroid burden fell compared with the period before levamisole treatment [ ]. These effects lasted for 12 months after withdrawal of levamisole. None of the patients had any serious sequelae attributable to levamisole. Hematological measurements fell slightly but remained well within the reference ranges. Aminotransferases and renal function tests were unchanged. Serum albumin concentrations improved significantly. There were no rashes or signs or symptoms of vasculitis.

Nephrotic syndrome

In 11 children with nephrotic syndrome, of whom five were glucocorticoid-sensitive, six glucocorticoid-resistant, and all resistant to other immunosuppressive drugs, levamisole 2.5 mg/kg was given every 48 hours for up to 18 months [ ]. Two patients were also given ciclosporin. All the patients in the steroid-sensitive group but none in the steroid-resistant group reacted favorably to levamisole, with disappearance of protein from the urine. There were serious adverse reactions in two patients: one developed a transient leukopenia 2 months after the start of treatment and another developed a severe exacerbation of pre-existing psoriasis, although that may have been due to the withdrawal of cyclophosphamide.

Levamisole 2 mg/kg on alternate days was given to 25 glucocorticoid-dependent children with frequent relapses of idiopathic nephrotic syndrome [ ]. The steroid was tapered, and continued for 3–14 months. During treatment with levamisole the relapse frequency was reduced by 40%. Two patients developed mild transient leukopenia, which disappeared 2 weeks after withdrawal. One had a slight rash that disappeared while treatment was continued and one complained of epigastric pain, which led to drug withdrawal.

In a detailed review of the management of nephrotic syndrome in childhood, levamisole was advocated as a weak but effective glucocorticoid-sparing agent [ ]. In a prospective study in 20 children (aged 3–15 years; 16 boys, 4 girls) with steroid-dependent minimal-change nephrotic syndrome, there were no significant adverse effects during adjunctive therapy with levamisole, which led to successful withdrawal of glucocorticoids after 2 months in 11 children [ ].

It has been stressed that levamisole is generally well tolerated by children with steroid-dependent nephrotic syndrome [ , ]. Adverse effects are uncommon but include neutropenia, vasculitis, liver toxicity, and convulsions; they are reversible after withdrawal of levamisole. In 40 children with idiopathic steroid-dependent minimal-change nephrotic syndrome levamisole 2.5 mg/kg on alternate days was compared with intravenous cyclophosphamide 500 mg/m ² /month for 6 months [ ]. Prednisolone was gradually tapered. After withdrawal of treatment, five children in the levamisole and cyclophosphamide groups stayed in remission at 6 months, four versus two respectively at 1 year, three versus one at 2 years, and one in each group at 3 and 4 years of follow-up. Adverse effects were mild, and none of the patients withdrew because of adverse reactions. In the 20 patients who took levamisole, infections occurred in 13 but only when glucocorticoids were used in conjunction. Nine patients had respiratory infections (acute bronchitis), two had scalp infections, and one had a urinary tract infection. One developed sialadenitis. One had personality changes characterized by aggression and nervousness after the start of glucocorticoid therapy. None developed neutropenia but there was a lower leukocyte count during levamisole treatment.

Pediculosis capitis

In 28 patients with pediculosis capitis (aged 7–12 years) levamisole was given in a dose of 3.5 mg/kg for 10 days; there were no adverse reactions [ ].

Rheumatoid arthritis

The possible benefits of levamisole in rheumatoid arthritis are generally outweighed by its adverse effects [ ].

Colorectal cancer

The efficacy of levamisole has been studied in several studies of patients with colorectal carcinoma [ ]. In a phase III trial 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation have been compared in patients with residual, non-measurable, intra-abdominal metastases after resection of colorectal carcinoma [ ]. The adverse reactions were as expected, and there were no differences between any of the treatments. The main adverse reactions were hematological and gastrointestinal. However, analysis of life-threatening adverse reactions showed some slight differences: there were fewer than expected in the 5-fluorouracil alone group, and more than expected in the 5-fluorouracil plus hepatic irradiation group. There was no treatment advantage for any of the combinations over 5-fluorouracil alone.

Levamisole combined with 5-fluorouracil in the adjuvant treatment of resected colon cancer has been studied in a prospective, randomized trial in which 891 patients were randomized to receive either intensive fluorouracil + leucovorin combined with levamisole, or a standard regimen of fluorouracil + levamisole [ ]. The patients were then again randomized to receive either 6 or 12 months of treatment. Standard fluorouracil + levamisole was not as effective as fluorouracil + levamisole + leucovorin, and treatment for 12 months was not superior to treatment for 6 months. Unfortunately, there was no treatment arm with fluorouracil + leucovorin only, which is widely considered to be the treatment of choice. Serious grade 3–4 adverse reactions were more frequent in the three-drug treatment groups, and consisted of diarrhea (13 versus 3 patients in the 6-month groups, 17 versus 7 in the 12-month groups) and stomatitis (10 versus 3 in the 6-month groups, 11 versus 6 in the 12-month groups). Leukopenia occurred more frequently in the standard treatment groups (10 versus 18, one of whom died, in the 6-month groups, and 13 patients, one of whom died, versus 14, one of whom died). There were four treatment-associated deaths.

In another study combined intravenous and intraperitoneal fluorouracil + leucovorin was compared with standard treatment with fluorouracil + levamisole in 241 patients with resected stage 3 or high-risk stage 2 colon cancers [ ]. In the combined treatment group there was an increased disease-free interval, an estimated 43% reduction in death rate, and a reduction in local tumor recurrence. Adverse reactions were relatively uncommon and were generally judged to be mild to moderate; they were slightly more common in those treated with fluorouracil + levamisole, and consisted of nausea and vomiting (18% versus 14%), diarrhea (16% versus 10%), mucositis (17% versus 12%), granulocytopenia (29% versus 23%), and thrombocytopenia (5% versus 3%). Four cases of unspecified nervous system toxicity were noted in those given fluorouracil plus levamisole. There was abdominal pain during or shortly after intraperitoneal drug administration in 19% of patients. Overall 53% of the patients given fluorouracil plus levamisole and 56% of those given fluorouracil plus leucovorin had mild to moderate adverse effects. Severe reactions, requiring a 20% dosage reduction of fluorouracil, were more common in the fluorouracil plus levamisole arm (13% versus 3%). There were no deaths. Unfortunately, in this study no patients were treated with fluorouracil + leucovorin intravenously only.

It is likely that most of these reported adverse reactions, although perhaps enhanced by levamisole, except for the nervous system toxicity noted in a few individuals, were caused by fluorouracil. This has been further emphasized by a dose-finding study to determine the maximum tolerated dose of levamisole in the treatment of colon cancer in 38 patients with advanced non-resectable colon cancer, treated with fluorouracil 450 mg/m ² by rapid intravenous infusion for 5 days [ ]. Levamisole was given orally three times daily for 5 days every 5 weeks until disease progression. The main dose-limiting toxic effects were nausea and vomiting and an unpleasant metallic taste. The dose used was about five times the total amount of levamisole given in the standard fluorouracil plus levamisole regimen. Levamisole enhanced the gastrointestinal toxicity of fluorouracil, with anorexia, nausea, vomiting, and occasional diarrhea, but did not enhance the bone-marrow suppression associated with fluorouracil. Increasing the dose of levamisole to 150 mg/m ² tds for 5 days resulted in significant nervous system toxicity, with confusion, vertigo, and severe vomiting. None of the patients treated with this dosage were able to complete the course.

Fluorouracil plus leucovorin has been compared with fluorouracil + levamisole and combined fluorouracil + leucovorin + levamisole in 2151 patients with Dukes B and C colon cancers [ ]. The regimens were as follows:

• fluorouracil + leucovorin: six 8-week cycles of leucovorin 500 mg/m ² as a 2-hour infusion repeated weekly for six doses and fluorouracil 500 mg/m ² , given as an intravenous bolus 1 hour after the start of the leucovorin infusion, also weekly for six doses; the cycle was repeated after a rest period of 2 weeks;

• fluorouracil + levamisole: fluorouracil 350 mg/m ² as an intravenous bolus daily for five consecutive days, then once weekly starting on day 29 and levamisole orally tds for 3 days and repeated every 14 days;

• fluorouracil + leucovorin + levamisole: the same fluorouracil + leucovorin treatment as described above, with the addition of levamisole in the dose used in the fluorouracil + levamisole group.

There were small increases in the disease-free interval and overall survival in favor of fluorouracil + leucovorin, although of borderline statistical significance. Information on toxicity was obtained in 98% of the patients. Eighteen died while on chemotherapy, four in the fluorouracil plus leucovorin group, three in the fluorouracil plus levamisole group, and 11 in the fluorouracil plus leucovorin and levamisole group. Grade 3–4 toxicity was reported equally in the three groups: fluorouracil + leucovorin 35%, fluorouracil + leucovorin and levamisole 36%, and fluorouracil + levamisole 28%. They consisted mainly of adverse reactions attributed to fluorouracil, such as diarrhea, vomiting, and stomatitis. Hematological toxicity was minimal (less than 2% in grades 3–4) and not significantly different across the groups. Neurotoxicity was rare. Ataxia was the most frequent neurological disorder, in 2% of the patients who received fluorouracil plus levamisole and in 1% of the patients in the other two groups combined.

QUASAR was a study of the effects of a higher dose of leucovorin or the addition of levamisole to 5-fluorouracil and leucovorin on survival in 4927 patients with colorectal cancer with no evidence of residual disease after resection [ ]. High-dose leucovorin was not associated with a survival or recurrence benefit compared with low-dose leucovorin. The addition of levamisole had no apparent survival benefit compared with placebo, with slightly more deaths in patients assigned to levamisole than placebo. Tumor recurrences were also higher in those who took levamisole. Dermatological adverse reactions were significantly more frequent in those who took levamisole compared with placebo.

In 680 patients with curatively resected stage III colon cancer, adjuvant treatment with 5-fluorouracil + leucovorin was significantly more effective than 5-fluorouracil + levamisole in reducing tumor relapse and improving survival [ ]. There were fewer adverse reactions in those given 5-fluorouracil + levamisole compared with 5-fluorouracil + leucovorin (820 versus 1190); the difference was mainly due to gastrointestinal toxicity. Only a few patients developed grade 3 or grade 4 adverse reactions. There were no treatment-related deaths in either group.

The Gastrointestinal Intergroup has studied postoperative adjuvant chemotherapy and radiation therapy in 1659 patients with T3/4 and lymph-node-positive rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure [ ]. There was no advantage to regimens containing leucovorin or levamisole over bolus 5-fluorouracil alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates were still high, especially in T3 and T4 lymph node positive patients, even with full adjuvant chemoradiation therapy.

In a multicenter, phase 3, randomized comparison of fluorouracil + levamisole (n = 92) versus fluorouracil alone (n = 93) in 185 patients with stage III colon cancer the relative contribution of levamisole (50 mg tds for 3 consecutive days, repeated every 2 weeks for 1 year) was established [ ]. After a median follow-up time of 48 months, 80 patients had recurrent disease (40 in each arm) and there were no advantages in terms of disease-free survival and overall survival for fluorouracil + levamisole. However, leukopenia (18% versus 4.3%) and hepatic toxicity (16% versus 4.4%) were more frequent in patients receiving fluorouracil + levamisole compared with fluorouracil alone, whereas other adverse reactions were equally distributed among both treatment arms. Some patients had neurological symptoms, consisting of mood-altering effects and disabling cerebellar ataxia, attributed to treatment with levamisole. They abated when therapy was withdrawn.

In a randomized trial in 218 patients with stage II–III resectable rectal cancer, adjuvant postoperative radiotherapy has been compared with sequential radiotherapy and chemotherapy with fluorouracil + levamisole [ ]. Adherence to chemotherapy in patients undergoing sequential radiotherapy and chemotherapy was poor; 32% of the patients had to stop chemotherapy owing to severe toxicity, mostly gastrointestinal. The authors concluded that fluorouracil + levamisole is not effective in patients with resected rectal cancer.