Elsevier

The Lancet

Volume 378, Issue 9788, 23–29 July 2011, Pages 338-346
The Lancet

Articles
Prednisone versus tamoxifen in patients with idiopathic retroperitoneal fibrosis: an open-label randomised controlled trial

https://doi.org/10.1016/S0140-6736(11)60934-3Get rights and content

Summary

Background

Glucocorticoids are the mainstay of treatment of idiopathic retroperitoneal fibrosis, but they often have substantial toxic effects. Several reports have suggested tamoxifen as an alternative to glucocorticoids. We compared the efficacy of prednisone with that of tamoxifen in maintainance of remission in patients with idiopathic retroperitoneal fibrosis.

Methods

In this open-label, randomised controlled trial, we enrolled patients aged 18–85 years with newly diagnosed idiopathic retroperitoneal fibrosis at the Parma Hospital, Parma, Italy, between Oct 1, 2000, and June 30, 2006. After induction therapy with 1 mg/kg daily of prednisone for 1 month, the patients who achieved remission were randomly assigned to receive tapering prednisone (initial dose 0·5 mg/kg daily) for 8 months or tamoxifen (fixed dose 0·5 mg/kg daily) for 8 months. The sequence of randomisation (1:1), blocked in groups of two and four (with block size randomly selected), was generated by the trial statistician with a computer programme. After the end of treatment, the patients were followed up for an additional 18 months. Neither patients nor those giving interventions or analysing the data were masked to group assignment. The two radiologists who assessed CT and MRI scans were masked. The primary endpoint was the relapse rate by the end of treatment (month 8), which was analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00440349.

Findings

After induction therapy, 36 of the 40 enrolled patients achieved remission and were randomly assigned to treatment (18 per group). One patient (6%) in the prednisone group and seven patients (39%) in the tamoxifen group relapsed by the end of treatment (difference −33% [95% CI −58 to −8, p=0·0408]. The difference in relapse rate between the groups was sustained after the additional 18-month follow-up: the 26-month estimated cumulative relapse probability was 17% with prednisone and 50% with tamoxifen (difference −33% [−62 to −3, p=0·0372]). Cushingoid changes and grade 2 hypercholesterolaemia were more common in the prednisone group than in the tamoxifen group (p=0·0116 and p=0·0408, respectively).

Interpretation

Prednisone is more effective in prevention of relapses than is tamoxifen in patients with idiopathic retroperitoneal fibrosis. Therefore, prednisone should be considered as first-line treatment for patients with newly diagnosed idiopathic retroperitoneal fibrosis.

Funding

Parma University Hospital.

Introduction

Idiopathic retroperitoneal fibrosis is a rare disease, characterised by the presence of a fibroinflammatory tissue that surrounds the abdominal aorta and the iliac arteries, and often entraps the ureters. The idiopathic form accounts for more than two-thirds of all cases of retroperitoneal fibrosis, with the remainder being secondary to different causes, such as drugs, tumours, infections, radiotherapy, and rare forms of histiocytosis such as the Erdheim-Chester disease.1, 2 Idiopathic retroperitoneal fibrosis is histologically characterised by abundant fibrosis and a mononuclear-cell inflammatory infiltrate mainly composed of lymphocytes, plasma cells, and macrophages.3, 4 Clinical manifestations include abdominal or back pain, systemic symptoms (eg, fatigue, weight loss), and, less frequently, constipation, testicular pain, and claudication. Ureteral obstruction occurs in about 60–80% of cases and often causes acute renal failure.5, 6, 7

The treatment of idiopathic retroperitoneal fibrosis is still empirical since no randomised trials have been done so far. Anecdotal cases of spontaneous resolution have been reported,8, 9, 10 and a few patients with asymptomatic disease not affecting adjacent structures might need only monitoring. With the exception of these rare cases, medical treatment is usually necessary in patients with active disease. Glucocorticoids are deemed the mainstay of therapy, but their optimum dose and duration are unknown. They induce rapid symptom remission, reduction in acute-phase reactant values, and often shrinkage of the disease, but they have substantial side-effects.11, 12 These properties make glucocorticoids ideal as induction treatment, provided that an effective maintenance regimen is available. Other immunosuppressive drugs (eg, mycophenolate mofetil, azathioprine)13, 14, 15, 16, 17 have been successfully used together with glucocorticoids, but the superiority of these combination therapies to glucocorticoids alone is still unproven.14

On the basis of the observed benefit in desmoid tumours, which are characterised by fibroblast proliferation, tamoxifen has been used for idiopathic retroperitoneal fibrosis in various case reports and case series.18, 19, 20, 21, 22 Because these cases had a favourable outcome and the drug tolerability was good, tamoxifen has become an attractive therapeutic option for this disease. We compared the efficacy of prednisone with that of tamoxifen in prevention of relapses in patients with newly diagnosed idiopathic retroperitoneal fibrosis who had received induction treatment with prednisone.

Section snippets

Patients

In this open-label, randomised controlled trial, we enrolled all patients meeting the eligibility criteria, diagnosed at or referred to the Department of Clinical Medicine and Nephrology of Parma Hospital, Parma, Italy, between Oct 1, 2000, and June 30, 2006. Key inclusion criteria were a new diagnosis of idiopathic retroperitoneal fibrosis and an age of 18–85 years; we also enrolled patients with perianeurysmal retroperitoneal fibrosis, since this form is also idiopathic.7, 23 Key exclusion

Results

Of the 40 patients enrolled (figure 1), one was excluded because the diagnosis was revised (this patient was the subject of a case report).31 Of the 39 patients who started induction prednisone therapy, three were excluded. The remaining 36 completed the month of induction prednisone therapy, at the end of which they all achieved symptom remission and normalisation of ESR and CRP values, and were thus randomly assigned to receive prednisone or tamoxifen.

Demographic, clinical, and laboratory

Discussion

This study, the first randomised trial in retroperitoneal fibrosis to our knowledge (panel), compared the efficacy of prednisone and tamoxifen in maintainance of remission in patients who had received induction prednisone therapy. Induction therapy was very effective in obtaining symptom remission and normalisation of acute-phase reactants. Subsequently, we noted that the proportion of patients who developed relapses while being on treatment was significantly higher in the tamoxifen group than

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