Etoposide in Wegener's granulomatosis

S. J. Morton, P. C. Lanyon and R. J. Powell

Clinical Immunology Unit, University Hospital, Queens Medical Centre, Nottingham NG7 2UH, UK

SIR, Further to the letter of Papo et al. [1], we would like to report on five more patients with Wegener's granulomatosis (WG) who have been treated with etoposide. The indications were as follows: (1) induction of remission in severe cyclophosphamide- and steroid-resistant disease (patients 1 and 2); (2) induction of remission in patients with severe disease who were intolerant of cyclophosphamide (patients 3, 4 and 5).

Patient 1 is a 28-yr-old lady who presented to our unit with a severe flare of scleritis and sinusitis whilst taking azathioprine. WG had been diagnosed 8 yr earlier, with an average prednisolone dose during this time of 15 mg. Treatment with pulse i.v. cyclophosphamide and i.v. and oral steroids (10–40 mg prednisolone daily) was commenced, but 5 months of cyclophosphamide (cumulative dose 13.25 g) failed to induce a remission and she remained symptomatic, with a magnetic resonance imaging (MRI) scan confirming ongoing inflammatory disease. Etoposide was commenced as a cyclical regime of 150 mg o.d. for 5 days every 28 days (750 mg/month). Initial improvement was followed 3 months later by a relapse and cyclical etoposide was replaced with continuous therapy of 50 mg daily (1.5 g/month); symptoms resolved within 2 weeks. After a further 3 months, the etoposide dose was reduced to 50 mg on alternating days because of neutropenia. In the subsequent 9 months there have been no flares of disease despite reduction of prednisolone to 5 mg daily. This clinical improvement has been matched by a reduction in cANCA titre from 1:80 to 1:20 and a fall in erythrocyte sedimentation rate (ESR) from 40 to 11.

Patient 2 is a 52-yr-old lady with WG who developed an orbital pseudotumour which failed to respond to a 16-month course of i.v. cyclophosphamide (cumulative dose 29 g) or to a 1-month trial of cyclosporin. Etoposide was commenced at 50 mg daily and within 7 days there had been some improvement in eye redness and conjunctival chemosis. The dose was subsequently increased to 100 mg daily (3 g/month), but after 1 month neutropenia and an urticarial rash necessitated dose reduction. A maintenance dose of 50 mg on alternate days has prevented clinical relapse for 14 months, and there has been a fall in ESR from 77 to 34. No increase in tumour size has been detected on computed tomography (CT) and ophthalmological assessment has demonstrated a reduction in proptosis and improvement in eye movements.

Patient 3 is a 57-yr-old man who developed diplopia secondary to a mass in the left frontal sinus whilst receiving daily oral cyclophosphamide for symptoms of arthralgia, haemoptysis, chronic sinusitis and paraesthesia. A trial of i.v. cyclophosphamide was unsuccessful due to uncontrollable drug-induced vomiting; therefore, daily oral cyclophosphamide was continued for 7 months until the diplopia had resolved and at this stage his cANCA became negative. The diplopia returned 3 months later, and responded well to cyclosporin but ensuing renal toxicity necessitated withdrawal. Within 4 months a further relapse occurred with symptoms of mononeuritis multiplex, arthralgia, diplopia and haemoptysis. Cyclical etoposide was started (see above) and within 1 month all symptoms, including the diplopia, had improved. He received five treatment cycles and 4 months after stopping etoposide remains asymptomatic with a negative cANCA.

Patient 4 is a 48-yr-old lady who developed WG characterized by erosive nasal disease in 1992. She was initially treated with i.v. cyclophosphamide but an allergic reaction at 3 months necessitated withdrawal. Subsequent treatments, including ifosfamide, chlorambucil, methotrexate, i.v. immunoglobulin, thalidomide and cyclosporin failed to produce lasting remission. Cyclical etoposide was commenced with improvement in nasal symptoms within 1 month, and treatment was continued for 10 cycles. One year after stopping etoposide, a relapse characterized by arthritis, nasal blockage, diarrhoea and fatigue necessitated the re-introduction of the drug; ear, nose and throat (ENT) assessment after seven cycles confirmed remission and treatment was again stopped. In the subsequent 6 months there has been no sign of relapse.

Patient 5 is a 29-yr-old lady who presented with a history of progressive subglottic stenosis whilst receiving weekly i.m. methotrexate. Prior to this she had received 18 months of i.v. cyclophosphamide. This treatment was reinstituted, but was discontinued due to uncontrollable drug-induced vomiting. Etoposide was commenced, initially at 50 mg daily, increasing to 100 mg daily after 4 weeks. Neutropenia occurred 6 weeks later complicated by urinary and respiratory tract infections and etoposide was temporarily withdrawn. It was reinstituted as a cyclical regime but progressive enlargement of her subglottic inflammatory mass occurred and after four cycles the etoposide was stopped.

Although we accept that only limited conclusions can be drawn from individual case reports, the therapeutic options for patients with WG who either have disease that is resistant to cyclophosphamide, or are intolerant of this agent, are very limited. In patients 1 and 2, we found etoposide to be more effective than cyclophosphamide in treating sinus and orbital disease, respectively. In patients 3 and 4, who were intolerant of cyclophosphamide, etoposide was an effective and well tolerated alternative. In the fifth patient, progression of disease occurred whilst on etoposide.

Etoposide was generally very well tolerated as either a cyclical regime (150 mg daily for 5 days every 28 days) or as continuous daily therapy (50 mg daily). The continuous regime enables the administration of a 2-fold greater monthly dose than the cyclical regime (750 mg cf. 1.5 g), but neutropenia necessitating dose reduction occurred in the two patients treated with doses of 100 mg daily.

In summary, our observations and those of Papo et al. [1] suggest that etoposide may be a useful alternative in patients with WG who are either resistant to, or intolerant of, cyclophosphamide. This hypothesis merits further study.

Accepted 17 January 2000

References

  1. Papo T, Le Thi Huong D, Wiederkehr JL, Woehl-Kremer B, Bletry O, Wechsler B et al. Etoposide in Wegener's granulomatosis. Rheumatology1999;38:473–5.[Free Full Text]

 

Reply

T. Papo and J.-C. Piette

47–83 Boulevard de l'Hôpital, 75651 Paris, Cedex 13, France

We were very interested by Morton et al.'s letter that provides extended data on treatment with etoposide in five more Wegener's granulomatosis (WG) patients. Clearly, disease activity diminished under therapy in four patients. On the basis of cumulative retrospective results, etoposide may indeed appear as a possible alternative to cyclophosphamide. A few points may be raised to balance such a view: (a) whereas WG relapse occurred after 23.5 ± 11 months in our patients, follow-up was only 9–13 months in three patients of Morton et al.; (b) etoposide treatment may be complicated with secondary leukaemia and should be avoided in young patients; and (c) promising alternative immunosuppressive treatments are currently under study in WG, including mycophenolate mofetil and etanercept.

Accepted 17 January 2000





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