Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide

OBJECTIVE: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis. METHODS: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969-95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated. RESULTS: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis. CONCLUSION: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.     

Pulse cyclophosphamide therapy in Wegener's granulomatosis: a pilot study.

Five patients with Wegener's granulomatosis (WG) have been treated with 6- to 8-monthly pulses of intravenous cyclophosphamide (CP) and glucocorticoids in an open pilot study. One patient achieved complete remission sustained during 30 months of follow-up; one patient had features of active disease after 28 months of remission; two patients after an initial remission had an exacerbation of the disease and received continuous oral administration of CP, and one patient required continuous oral CP to control the symptoms. These results suggest that this regimen may not achieve a high degree of sustained remission in patients with WG.     

Failure of cyclophosphamide to prevent cerebritis in Wegener's granulomatosis

Two patients with diffuse cerebritis due to Wegener's granulomatosis are described. The cerebritis developed despite prolonged treatment with cyclophosphamide. This may be the first report of such an occurrence. Both patients had excellent functional recovery with intravenous corticosteroids.     

Wegener's granulomatosis: long-term follow-up of patients treated with pulse cyclophosphamide

Treatment with daily oral cyclophosphamide (CY) has improved survival in Wegener's granulomatosis (WG), but is associated with severe and potentially lethal adverse effects. Less toxic treatment regimens, such as pulse CY, have been used, but the effect has been questioned. We have treated 11 patients with WG with pulse CY (15 mg/kg initially every second week, gradually increasing the pulse interval). After 4.5 yr follow-up and a total of 501 pulses of CY, one patient died and eight patients (73%) were in complete remission. Remission was induced in 91% of the patients after a median period of 3.5 months and relapses were seen in 60%. With the same treatment protocol, a new complete remission was induced in 75% of those relapsing. Except for one patient who died, no patient developed end-stage renal failure. Haemorrhagic cystitis was not observed and no malignancies recorded. Severe infections were seen in 36%, but none caused by Pneumocystis carinii. Nausea was the most frequent side-effect, seen in 64% of the patients. We conclude that treatment with pulse CY every second week is safe and effective in inducing remission and treating relapses in WG. The relapse rate seems to be higher than with low-dose oral CY, but the cumulative dose of CY is less.      

Wegener's granulomatosis. Long-term followup of patients treated with cyclophosphamide.

Ten patients with Wegener's granulomatosis were treated with cyclophosphamide and followed for periods up to 7 years. In all cases cyclophosphamide induced complete remissions. The mean duration of remission (to date) was 38 months. Six patients have been in remission for a mean of 46 months after cyclophosphamide was discontinued; 2 have been disease-free for 7 years. Of the 10 patients treated, only 1 relapsed and she responded to a second course of cyclophosphamide. These results indicate that cyclophosphamide is the drug of choice in Wegener's granulomatosis. The long-term effectiveness of this drug suggests that it may induce permanent remissions in certain patients with Wegener's granulomatosis.     

Wegener's granulomatosis in New Zealand: evidence for a latitude-dependent incidence gradient

Background: The aim of the study was to determine whether there was evidence for a geographic gradient in the incidence of Wegener’s granulomatosis (WG) and WG‐like disease in New Zealand (NZ). Methods: The National Minimum Dataset of the Ministry of Health, NZ was searched for individual patient discharges coded by the International Classification of Diseases 10th Revision, Australian Modification as either M301 (polyarteritis with lung involvement, including Churg Strauss and allergic granulomatous angiitis) or M313 (WG, necrotizing respiratory granulomatosis) for the period 1 January 1999 to 31 December 2003. Data were standardized using the 2001 NZ census. Results: One hundred and ninety‐five patients (95 men) were given a first‐time discharge code of either M301 (40 patients) or M313 (155 patients). No gender bias was seen. The rate among Europeans was twice that of NZ Maoris or Asians. The rate of disease peaked in the age band 70–79 years and during winter months. A significant positive north–south geographic gradient was present for M313. No difference in the rate of readmission or time to relapse between geographic regions was found for M313. Conclusion: A north–south gradient in the rate of patient discharges given a diagnostic code of M313 (WG, necrotizing respiratory granulomatosis) was present in NZ. This finding supports the hypothesis that there is a latitude‐dependent risk factor(s) for WG possibly common to both global hemispheres.     

Diffuse histiocytic lymphoma in a patient treated with cyclophosphamide for Wegener's granulomatosis

Diffuse histiocytic lymphoma developed in a 48-year-old man with Wegener's granulomatosis after nine years of therapy with cyclophosphamide. He died despite aggressive surgical and medical therapy for the lymphoma. This may be the first report of diffuse histiocytic lymphoma following treatment of Wegener's granulomatosis with cyclophosphamide. Recommendations for the approach towards extended therapy of smoldering Wegener's granulomatosis are discussed.     

Hodgkin's lymphoma in a patient treated for Wegener's granulomatosis with cyclophosphamide and azathioprine

Only 5 neoplasms have been reported associated with the use of cytotoxic drugs in the treatment of Wegener's granulomatosis. Described here for the first time, to our knowledge, is a patient with Wegener's granulomatosis treated with cyclophosphamide and azathioprine who later developed Hodgkin's lymphoma.     

Advances in the therapy of Wegener's granulomatosis

PURPOSE OF REVIEW: In the past, recommendations for the treatment of Wegener's granulomatosis were primarily based on findings reported from open-label clinical trials. Results from several randomized controlled trials in patients with Wegener's granulomatosis and other antineutrophil cytoplasm antibody-associated vasculitides have recently been reported that have a great impact on patient care. RECENT FINDINGS: In view of the considerable toxicity of cyclophosphamide, strategies to limit exposure to it have recently been evaluated. The replacement of cyclophosphamide by azathioprine after the successful induction of remission has been demonstrated not to increase the rate of relapse compared with continued cyclophosphamide. In patients with early antineutrophil cytoplasm antibody-associated vasculitides without critical organ manifestations low-dose methotrexate can replace cyclophosphamide for induction treatment with similar remission rates. As the early discontinuation of immunosuppressive treatment is associated with unacceptably high relapse rates, however, treatment for the maintenance of remission is mandatory. Besides azathioprine, leflunomide and methotrexate were efficacious in preventing relapses in Wegener's granulomatosis. Data on anti-cytokine therapy in Wegener's granulomatosis are controversial, possibly related to differences in study design. Open-label clinical studies suggest a beneficial effect of infliximab in addition to standard therapy in refractory Wegener's granulomatosis. In contrast, a recent randomized controlled trial showed that etanercept in addition to standard therapy, with the subsequent tapering of standard medications, is not effective for the maintenance of remission. SUMMARY: Despite recent progress, the prevention of relapses and treatment of refractory cases remain the greatest challenges in the treatment of Wegener's granulomatosis.     

Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's)

Objective

Standard treatment for severe granulomatosis with polyangiitis (Wegener's) (GPA) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX).

Methods

Patients in the Wegener's Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women ages <50 years, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti‐Müllerian hormone (AMH) and follicle‐stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as an AMH level of <1.0 ng/ml.

Results

Of 42 women in this analysis (mean age 35 years), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6 of 8 who received CYC during the trial developed diminished ovarian reserve, compared to 0 of 4 who did not receive CYC (P < 0.05). Changes in AMH correlated inversely with cumulative CYC dose (P < 0.01), with a 0.74 ng/ml decline in AMH level for each 10 gm of CYC.

Conclusion

Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age.