Bladder-cancer risk in Wegener's granulomatosis linked to cyclophosphamide dose

Janis Kelly

September 23, 2004

Sep 23, 2004

Uppsala, Sweden - The risk of bladder cancer rises steadily with increasing cumulative dose of cyclophosphamide in patients with Wegener's granulomatosis (WG), although some of this risk is attributable to factors present even before the development of WG, Dr Ann Knight (Uppsala University Hospital, Sweden) and colleagues report in the October 2004 issue of the Annals of the Rheumatic Diseases [ 1 ].

Knight tells rheuma wire that her group's most important findings were that WG patients have a very high risk of bladder cancer, that this risk increases with cumulative cyclophosphamide dose, and that there may be increased risk of bladder cancer in WG independent of cyclophosphamide use.

All patients ever exposed to cyclophosphamide are at risk, and it is important for the clinician to be aware of this.

"All patients ever exposed to cyclophosphamide are at risk, and it is important for the clinician to be aware of this," Knight says.

Long-term bladder-cancer risk 10% in WG patients

Knight and colleagues conducted a population-based, nationwide inpatient registry study that included 1065 patients with WG identified in the Swedish Inpatient Register. This search was linked with the Swedish Cancer Register to identify all 23 subjects in this cohort who developed bladder cancer. Within the cohort, a matched case-control study, including 11 bladder-cancer cases and 25 WG controls without cancer, was done to estimate the association between cyclophosphamide and bladder cancer.

This analysis revealed that WG patients who developed bladder cancer had much higher median cumulative doses of cyclophosphamide than did control WG patients who did not develop bladder cancer (113 g vs 25 g). Knight reports, "The risk of bladder cancer doubled for every 10-g increment in cyclophosphamide (OR=2.5, 95% CI 0.8-4.9)."

Risk increases with dose, duration of cyclophosphamide

Patients treated with cyclophosphamide for longer than 1 year had an 8-fold increased risk of bladder cancer compared with patients not treated with cyclophosphamide (OR 7.7, 95% CI 0.9-69). By 16 years after diagnosis of WG, the absolute risk for bladder cancer in the cyclophosphamide-treated cohort was 10%.

"This is important even though our study 'only' shows a 5-fold increase, compared with smaller studies in more select patient populations where the risks are described as even higher. Cumulative [cyclophosphamide] doses above 25 g definitely pose an increased risk," Knight says.

"As cyclophosphamide still is the 'gold standard' in treatment of generalized, serious WG and other systemic rheumatic diseases, one should not discard the treatment in severe disease. No other treatment has, so far, been as effective as cyclophosphamide in severe WG. However, it is important to keep the cumulative dose as low as possible, keeping track of the total amount given. Good hydration and treatment with mesna (2-mercaptoethane sulfonate sodium) should not be forgotten," Knight says.

In an editorial that accompanies this article [ 2 ], Dr Bernhard Hellmich (Universitatsklinikum Schleswig-Holstein, Lubeck, Germany) and colleagues write, "Owing to the increased risk of bladder cancer, a routine urological examination should be performed in patients after exposure to cyclophosphamide and especially in patients with concomitant micro- or macrohematuria. For the early diagnosis of bladder cancer, cystoscopy and urine cytology is still the preferred method."

Hellmich et al point out that although mesna significantly reduced the incidence of hemorrhagic cystitis compared with a control group treated with forced diuresis in bone-marrow-transplant patients treated with cyclophosphamide, its efficacy in protecting WG patients treated with cyclophosphamide is "still a matter of debate."

Hellmich concludes that the data of Knight et al "confirm our previous clinical observations, showing that development of tumors of the urinary tract is not necessarily caused by cyclophosphamide alone but appears to some extent to be related to the underlying autoimmune disease itself." Eight of the cases in Knight's cohort had bladder cancer diagnosed before WG developed.


  1. Knight A, Askling J, Granath F, et al.  Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide. Ann Rheum Dis 2004; 63:1307-1311. 

  2. Hellmich B, Kausch I, Doehn C, et al.  Urinary bladder cancer in Wegener's granulomatosis: is it more than cyclophosphamide? Ann Rheum Dis 2004; 632:1183-1185. 



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