a Section of Infectious Diseases, Department of Medicine III, b Department of Surgery and c Department of Medicine I, University Hospital of Ulm, D-89070 Ulm, Germany
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Abstract |
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Introduction |
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The WHO (Informal Working Group on Echinococcosis) guidelines for the treatment of AE3 recommend that: (i) for patients with operable disease, surgical resection of the parasitic lesion is the treatment of choice, followed by chemotherapy for a limited time (minimum of 2 years); (ii) long-term chemotherapy is indicated in inoperable disease or after incomplete resection of lesions as well as after liver transplantation.
Without treatment, AE is fatal in >80% of cases4 and operative resection of lesions is frequently incomplete because of the tumour-like growth of the parasite with diffuse infiltration of non-resectable structures or insufficient safety margins. As a result of this infiltrative multilocular growth, therapeutic puncture and instillation of parasitocidal agents are not valid options in AE.
Two drugs are licensed for therapy of AE: mebendazole (Vermox forte; Janssen-Cilag GmbH, Neuss, Germany) and albendazole (Eskazole; SmithKline Beecham, Harlow, UK). These two drugs, both benzimidazoles, are administered orally. Mebendazole5 was first introduced as a veterinary anthelminthic against E. multilocularis in 1977 and soon proved to be effective in human AE as well.6 The recommended daily dosage is 4050 mg/kg/day taken with a fat-containing meal three times daily. Albendazole is taken together with a fat-containing meal twice daily (manufacturer's recommendation, 1015 mg/kg/day). The drug is licensed for cyclic treatment only (i.e. 28 days of treatment followed by 14 days of interruption); continuous treatment was discussed as a promising alternative only recently.79
The present comparative study between mebendazole and albendazole was started in 1992, when albendazole10 was first registered in Germany for the treatment of AE. Mebendazole and albendazole are presumed to have equally effective anthelminthic activities, but studies comparing their efficacies are scarce.1113 In the present open-labelled observational study, we compare the outcome of long-term benzimidazole treatment with cyclic and continuous regimens initiated after 1991 and we review the literature with regard to the clinical outcome of treatment with either drug.
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Materials and methods |
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Results |
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Between 1992 and 1998, of a total of 35 patients, seven patients were treated with mebendazole alone (four women and three men, median age 51 years) and 14 patients with albendazole alone (six women and eight men, median age 52 years), while the treatment regimen was changed in 14 cases (eight women and six men, median age 59 years) during the course of disease. First treatment with mebendazole was successful in 12/17 (71%) cases (95% CI: 5294%) and first treatment with albendazole was successful in 14/18 (78%) cases (95% CI: 4490%) (see Table I). The time between initiation of drug treatment and apparent progression varied between 4 and 36 months (median 11 months). Medication was changed in 14 cases either from mebendazole to albendazole (cyclic or continuous) or from cyclic albendazole to mebendazole or continuous albendazole. A change of treatment resulted from either suspected or confirmed progressive disease (n = 5) or intolerable side-effects (n = 4) (see Table II
), while five cases were changed from mebendazole to albendazole for financial reasons or because albendazole treatment involved taking fewer tablets (not included in Table II
). Four of five progressive cases were stabilized by changing the treatment regimen. In three of these four patients, the regimen had been changed from cyclic albendazole to continuous albendazole, while in the fourth it was changed from mebendazole to continuous albendazole. The regimen of the unsuccessful case had been changed from cyclic albendazole to mebendazole. The overall success of treatment was 97% (34/35).
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While side-effects were observed in seven patients, they were intolerable in only four cases and led to a change of treatment in three patients being treated with mebendazole (alopecia, drop in performance, psychic conspicuousness) and in one being treated with cyclic albendazole (elevation of serum transaminases). After treatment was changed, all these side-effects disappeared. Mild vertigo, loss of hair, itching and queasiness were also observed, but they were only minor and were thus tolerated by the affected patients.
Seven patients were treated with a continuous dosing of albendazole for >12 months each and for an average of 28 months (median 26 months, range 1350 months). All patients had a stable or regressive course of disease. One patient with extensive disease was started on continuous treatment with albendazole immediately after diagnosis. Two other patients were changed from mebendazole to continuous albendazole, one because of the easier mode of intake and the other because of persistently low serum concentrations of mebendazole. Four cases of progressive disease were successfully stabilized after changing medication to continuous albendazole. No significant side-effects were observed (only one case of minor, temporary, hair loss) with continuous dosing of albendazole.
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Discussion |
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The lack of early signs indicating progression or stability of disease make it difficult to evaluate the success of treatment in AE. The most reliable tools to date are imaging techniques: ultrasound is the standard screening method in AE. It is combined with computerized tomography every 1224 months and, in the hands of an experienced physician, allows adequate follow-up evaluation of this chronic disease. Laboratory tests and clinical findings are less valuable for the detection of progressive disease and may only give additional hints.
Table III summarizes the results of major studies on the clinical outcome of AE treated with mebendazole and albendazole. It is difficult to compare the different studies directly, as most studies differ significantly with regard to their study protocols and results. In Table III
we have therefore confined ourselves to differentiating between success of treatment and progression. Considering the unfavourable course of disease in untreated patients and the non-parasitocidal effect of benzimidazoles in most cases, non-progression is generally regarded as a success. Success of treatment thus includes stable disease and regression rather than regression alone.
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The present study is the first to evaluate the outcome of medical treatment for AE started after 1991, since albendazole was licensed for the treatment of AE in Germany in 1992. Follow-up in a specialized outpatient service and an intensified interdisciplinary cooperation were factors that improved the outcome of long-term treatment. In our specialized outpatient service, all ultrasound examinations are performed by the same experienced person and our radiologists are specially trained to evaluate imaging characteristics and follow-up in AE. These factors may have contributed to the high rate (97%) of successfully treated patients. Albendazole and mebendazole showed similar effectiveness against AE. It must be emphasized, however, that the two treatment groups differed with regard to their previous treatment and that there was more inoperable disease among patients in the mebendazole group (see Table I).
In 1994, Ammann et al.11 reported slightly lower overall success rates, with successful treatment in 84% and progressive disease in 16% of cases. As in the present study, the criterion for success was morphological non-progression as assessed by computerized tomography. Although these data are not directly comparable with ours (only three of 37 patients had been treated with albendazole and the success of treatment was not analysed separately for the two drugs), they further substantiate the tendency towards higher success rates during the last few years.
According to the literature,1,18 the most frequent adverse reactions associated with benzimidazole treatment are gastrointestinal disturbances, reversible alopecia, elevation of serum transaminases, proteinuria, neurological symptoms and neutropenia. In our study, adverse reactions were observed in seven patients. A change of treatment was necessary in four cases. In a study by Davis et al.,19 side-effects led to a change of treatment in five of 54 cases receiving mebendazole and in one of 20 cases receiving albendazole. Other authors have observed a tendency towards higher rates of adverse reactions associated with mebendazole treatment,20 but we observed only few side-effects. In general, both drugs were well tolerated and, in the few cases of severe side-effects, a change of treatment successfully stopped these adverse reactions.
One advantage of albendazole over mebendazole is its cost-effectiveness. Depending on the dosing regimen, albendazole is 40% cheaper than mebendazole.12 In Germany, costs per year for mebendazole range between 8200 and 16300 Euros (approximately US$7450 and 14800), depending on dosage, while albendazole costs between 4700 and 7000 Euros ( US$4300 and 6350) for cyclic and continuous dosing, respectively.
Patients are more likely to comply with the albendazole regimen as it involves taking fewer tablets (one tablet twice daily) than mebendazole (two to four tablets three times daily).
According to the manufacturer's recommendations, cyclic dosing is the regimen of choice for albendazole. One treatment cycle consists of 28 days of drug intake followed by 14 days without treatment (washout phase). This intermittent treatment is intended to reduce toxicity. However, the washout phase of albendazole treatment may reduce the control of parasite growth,9 and this may outweigh the need to avoid pharmacological adverse reactions. To date, cyclic dosing is the only licensed treatment regimen. Continuous dosing remains experimental and is reserved for severe and progressive cases. In the study described here, continuous dosing of albendazole in seven patients did not lead to increased toxicity or to higher rates of adverse reactions compared with cyclic dosing. After an average time of observation of 28 months, all of our patients treated with albendazole on a continuous regimen have stable or regressive disease and treatment is tolerated well without exception. It is of particular importance to note that four of our cases with progressive disease were stabilized by changing treatment to continuous albendazole. As only a small number of patients was studied, additional studies are needed to substantiate these promising results.
Several other studies have focused on the efficacy and adverse reactions of continuous long-term treatment with albendazole.79,21,22 All studies found the same low rate of side-effects as observed under intermittent regimens. As was to be expected, the response to treatment was highly successful. Liu9 noted progression in one of 20 patients with AE receiving continuous albendazole treatment. In the light of these favourable data, the manufacturer's recommendations of cyclic dosing might be revised. Continuous dosing should be strongly considered in AE patients with inoperable or progressive disease.
It has proven advantageous for AE patients to receive care from a family practitioner and to be followed regularly at longer intervals in a specialized outpatient department. This practice was presumably one reason for the high compliance and the high rate of success among our patients. It is essential for a successful long-term treatment of AE to build up the patients' motivation and to encourage compliance.
In summary, mebendazole and albendazole are both effective for the treatment of AE and both are well tolerated. A cost reduction of >40% and a simplified drug intake are advantages of albendazole. Although albendazole is not licensed for continuous dosing, this regimen is well tolerated and constitutes a promising alternative in cases of inoperable or progressive AE.
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Acknowledgments |
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Notes |
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References |
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Received 15 December 1999; returned 13 March 2000; revised 3 April 2000; accepted 27 April 2000