Several studies, including a recent study from our group, have indicated that patients with Wegener’s granulomatosis are at increased risk of cancer of the urinary bladder.^1–,³ Studies of patients with malignant diseases treated with cyclophosphamide have indicated an association between cyclophosphamide and the risk of bladder cancer^4,5 based on less than 20 bladder cancers. Our present knowledge of bladder cancer risk in relation to cyclophosphamide use in Wegener’s granulomatosis rests upon fewer than a dozen cancer cases detected in two limited series of selected patients treated with cyclophosphamide (n = 145 and n = 158, respectively).^1,2 Likewise, reports on other rheumatological conditions are limited to a handful of observed cases of bladder cancer.^6–,⁸ Because cyclophosphamide has markedly improved survival in Wegener’s granulomatosis, and remains the mainstay induction treatment, not only for generalised Wegener’s granulomatosis but also for a series of manifestations of more common rheumatological diseases, the prevalence of subjects with a history of cyclophosphamide exposure is likely to increase substantially. It has therefore become increasingly important to assess accurately, and to attribute, the risks associated with cyclophosphamide use.

In this study we aimed at improving the understanding of bladder cancer in Wegener’s granulomatosis and, in particular, its association with cyclophosphamide. Firstly, in a case-control study nested within our previously identified population based cohort of 1065 patients with Wegener’s granulomatosis,³ we assessed the relative risk (odds ratio (OR)) of bladder cancer after exposure to cyclophosphamide. Secondly, we estimated the absolute risk (cumulative incidence) of bladder cancer after diagnosis of Wegener’s granulomatosis in the entire cohort of 1065 patients. Thirdly, we estimated the prevalence of a previous diagnosis of bladder cancer in the cohort already at the time of diagnosis of Wegener’s granulomatosis relative to that expected in the corresponding general population.

SUBJECTS AND METHODS

In Sweden, inpatient care is public, population based, and referrals are based on geography rather than financial capacity. The underlying cohort of patients with Wegener’s granulomatosis was identified in the population based and nationwide Swedish Inpatient Register that includes subject data on all inpatient care in Sweden, county wide since 1964, nationwide since 1987.⁹ In this register we identified all patients discharged with Wegener’s granulomatosis (International Classification of Diseases, version 8 = 446.2 1968–1986), version 9 = 446E 1987–1996) between 1969 and 1994—in total, 1065 subjects. Through linkage of the cohort to the Swedish Cancer Register (which has a completeness of 98% resulting from mandatory reporting of all diagnosed cancers by clinicians and pathologists),¹⁰ we identified a total of 23 subjects in the cohort who at some time between 1958 and 1995 had been diagnosed with a bladder cancer. Each bladder cancer case was then matched with three controls from the same cohort. The controls were matched for sex and age at diagnosis of Wegener’s granulomatosis, and the controls had to be alive on the date at which bladder cancer was diagnosed in the cases. All medical records of cases and controls were reviewed, and data including date of symptoms of Wegener’s granulomatosis, accumulated cyclophosphamide dose, duration of cyclophosphamide treatment, other treatments and, whenever possible, information on smoking habits, was abstracted. All cases and controls were evaluated to assess if they met the American College of Rheumatology (ACR) criteria for the diagnosis of Wegener’s granulomatosis, and patients for whom the diagnosis could not be confirmed were excluded. Likewise, patients for whom the bladder cancer diagnosis could not be confirmed by the medical files and pathology reports were excluded.

Of the 23 registered bladder cancer cases within the cohort, 14 had developed bladder cancer after the first discharge listing Wegener’s granulomatosis. Three of these cases had to be excluded as they either did not meet the ACR criteria for Wegener’s granulomatosis (one had giant cell arteritis and one pulmonary fibrosis) or because the medical file could not be retrieved (one case), leaving 11 confirmed incident bladder cancer cases in subjects with a confirmed diagnosis of Wegener’s granulomatosis. One of these cases had a history of chronic cystitis. Of the 33 controls selected for the 11 incident bladder cancer cases, the diagnosis of Wegener’s granulomatosis could be confirmed in 25: complete medical files could not be found in four controls, and another four controls turned out to have other vasculitic conditions (unspecified vasculitic disease, rheumatic polymyalgia, alveolitis, and polyarteritis nodosa, respectively). The nested case-control study thus consisted of 11 cases with Wegener’s granulomatosis and bladder cancer (table 1⇓), and 25 controls with Wegener’s granulomatosis but no bladder cancer. The median age at diagnosis of Wegener’s granulomatosis diagnosis among cases and controls was 67 and 68 years, respectively. Eight of 11 (73%) cases had kidney disease compared with 15/25 (60%) controls. Eight of the 11 cases (73%) had generalised Wegener’s granulomatosis (defined as kidney or lung disease, or both) and three had limited disease (ear, nose, and throat involvement only, or otherwise limited disease not affecting the lung/kidney). Seventeen of the 25 (68%) controls had generalised disease and eight had limited disease. All patients had received varying doses of steroids. Other treatments included azathioprine, plasmapheresis, cyclosporin A, chlorambucil, and intravenous immunoglobulins. One of the controls had received irradiation therapy only. Information on smoking habits was present in the medical files of eight cases and 18 controls.

In the remaining nine (23−14) subjects with a diagnosis of bladder cancer, the bladder cancer diagnosis had been made before the diagnosis of Wegener’s granulomatosis. One of these nine cases had to be excluded, as the bladder cancer diagnosis could not be confirmed by the pathology report, leaving eight confirmed prevalent cases of bladder cancer at the time of the first discharge listing Wegener’s granulomatosis.

RESULTS

Cyclophosphamide and risk of bladder cancer after Wegener’s granulomatosis

Ten of the eleven cases (91%) were exposed to cyclophosphamide (the eleventh case had been treated with chlorambucil and azathioprine). Twenty of the 25 (80%) controls were exposed to cyclophosphamide. None of the cases but three of the controls had received intravenous cyclophosphamide (together with mesna), but only in addition to oral cyclophosphamide. No other controls, and none of the cases, had received mesna. The median cumulative dose of cyclophosphamide among cases was 113 g, compared with 25 g among the controls (fig 1⇓, Wilcoxon p for difference  =  0.01). The median duration of treatment among the cases was 86 months (7 years and 2 months) compared with 13 months among the controls.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

 Distribution of the cumulative dose of cyclophosphamide among the 11 cases and their 25 controls in the case-control study nested in a population based cohort of 1065 patients with Wegener’s granulomatosis. (Wilcoxon p for difference  =  0.01).

Each 10 g increment in cumulative dose of cyclophosphamide was associated with a doubled risk of bladder cancer (OR = 2.0, 95% CI 0.8 to 4.9; table 2⇓). Similarly, cumulative doses above (versus below) the median among controls (25 g) were associated with a fivefold increase in risk of bladder cancer (OR = 5.2, 95% CI 0.8 to 36). There was also a tendency towards an increased risk of bladder cancer with increasing duration of treatment, with a 10% increase in risk for each month receiving cyclophosphamide (OR = 1.1, 95% CI 1.0 to 1.3). Likewise, exposure to cyclophosphamide for longer than 13 months (median among the controls) was associated with a near eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). Adjustment for smoking had a modest effect on the above risk estimates, and smoking itself did not emerge as a strong risk factor in the models (data not shown).

View this table:

• View inline
• View popup

Table 2

 Adjusted* odds ratios (OR, including 95% confidence interval (CI)) for bladder cancer associated with cyclophosphamide use in Swedish patients with Wegener’s granulomatosis

Cumulative risk of bladder cancer after Wegener’s granulomatosis

Starting at 0% at the time of the first discharge with Wegener’s granulomatosis, the cumulative risk of bladder cancer was 2% (95% CI 0.1 to 3.9) after 10 years of follow up, but increased to 10% (95% CI 2.7 to 17) after 16 years since the first discharge (fig 2⇓). The time from diagnosis of Wegener’s granulomatosis to diagnosis of bladder cancer varied between 4 and 15 years, and the latency from stopping cyclophosphamide treatment to diagnosis of bladder cancer varied between 0 and 14 years, with a median latency time of 2 years and 7 months.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

 Cumulative incidence of bladder cancer by time since first discharge for Wegener’s granulomatosis.

DISCUSSION

The results of our study suggest that cyclophosphamide in dosages fully comparable to those often encountered in clinical practice is associated with a dose-response increase in the relative risk of bladder cancer among patients with Wegener’s granulomatosis. The cumulative risk of bladder cancer in these patients is alarmingly high. These bladder cancers appear without connection to haemorrhagic cystitis, and the two conditions may not arise from the same mechanisms. In contrast, Wegener’s granulomatosis and bladder cancer may have some aetiological factors in common.

Cyclophosphamide is a commonly used drug in the treatment of malignant diseases—for example, as part of the CHOP regimen used for malignant lymphomas. In the management of inflammatory rheumatic diseases cyclophosphamide has proved to be highly effective and remains the standard treatment of serious extra-articular manifestations of rheumatoid arthritis, lung, central nervous system, and kidney manifestations of lupus, and for vasculitides such as Wegener’s granulomatosis. Because of the implementation of cyclophosphamide as first line induction treatment¹³ in the above conditions, the prevalence of subjects ever exposed to cyclophosphamide in doses similar to those of the present study is increasing.

Despite indications of malignant side effects in the urinary bladder,^4,6 surprisingly few studies have assessed the risk of bladder cancer after exposure to cyclophosphamide (table 3⇓). Indeed, our risk assessment today rests upon a few observed cases in non-population based studies. In the hitherto largest study, 145 patients with Wegener’s granulomatosis identified at a tertiary referral centre were followed up . The seven cases of bladder cancer observed corresponded to a 31-fold relative risk and a cumulative risk of 5% at 10 years and 10% at 15 years.¹ In our cohort, the relative risk of bladder cancer was fivefold,³ and the cumulative risk was 2% after 10 years, but increased to 10% after 16 years, which should be compared with a lifetime risk of bladder cancer below 2% in Sweden.¹⁴ Our results further indicate a dose-response relationship between cyclophosphamide and bladder cancer risk, with particularly high relative risks for treatments lasting longer than 1 year or cumulative doses above 25 g. Although recent reports¹⁵ indicate that the duration of cyclophosphamide treatment may be reduced, cumulative doses above 25 g (for example, as two 3 month cycles of oral cyclophosphamide) will remain a common finding.

Only one of our cases had undergone cystoscopy (which revealed a chronic cystitis) earlier in the disease course, 11 years before the diagnosis of bladder cancer. The other cases were examined because of haematuria (macro- or microscopic) only immediately before the cancer diagnosis. Haemorrhagic cystitis (microscopic) is known to have occurred in 18 of the 25 controls. This observation, which is in keeping with those of Talar-William and Pedersen-Bjergaard,^1,5 suggests that haemorrhagic cystitis does not precede cyclophosphamide associated bladder cancer, and that the mechanisms leading to haemorrhagic cystitis and bladder cancer may not be the same. The cytotoxic properties of the cyclophosphamide metabolite acrolein cause haemorrhagic cystitis and can be protected against by mesna.¹⁶ The carcinogenic effects, however, are more likely to be mediated through molecular changes caused by the alkylating properties of cyclophosphamide, such as mutations in the p53 tumour suppressor gene.^17–,¹⁹ If so, haemorrhagic cystitis would not be a good marker of the increased risk of bladder cancer, nor would mesna be cancer preventive. Instead, other measures would be required to reduce the cancer risk associated with cyclophosphamide.

Although our results are not formally significant, they point to the possibility of an increased risk of bladder cancer even before the diagnosis of Wegener’s granulomatosis, in turn suggesting shared aetiologies or risk factors for bladder cancer and Wegener’s granulomatosis. The possible relationship between a cancer diagnosis and Wegener’s granulomatosis has also been demonstrated in a study by Tatsis et al,²⁰ who found an increased risk for renal cell carcinoma in patients who later, or simultaneously, developed Wegener’s granulomatosis. In our previous study of cancer risk in a large population based cohort of Wegener’s granulomatosis³ we found that the risk for renal cell carcinoma was almost doubled, but we did not study the time relation between the diseases.

Smoking is a strong risk factor for bladder cancer and could be one such shared aetiological factor, although we are unaware of studies linking Wegener’s granulomatosis to smoking. In our nested case-control study, smoking did not emerge as a strong risk factor, nor did it materially confound the association with cyclophosphamide; but the information on smoking was scarce, and these results should be interpreted with caution.

The strength of our nested case-control study lies in the population based and nationwide setting of the source cohort, which is the hitherto largest identified cohort of patients with Wegener’s granulomatosis, the follow up of which extended up to 26 years. All subjects included in the analyses of this study had their diagnoses of Wegener’s granulomatosis and bladder cancer confirmed by a manual review of their medical records. The diagnosis of Wegener’s granulomatosis has also previously been validated³ against the ACR criteria, and we found a validity of about 88% in the diagnosis, therefore we do not think other vasculitic diseases have influenced these data. Further, the identification of bladder cancers was independent of the exposure and the diagnosis of Wegener’s granulomatosis, and most likely to be complete. Our study also observed the largest number of bladder cancers in an assessment of bladder cancer risk after cyclophosphamide exposure (table 3⇑). However, the power of the study was limited and several risk estimates did not reach beyond borderline significance. The fact that all patients had at some stage been admitted to hospital owing to Wegener’s granulomatosis is unlikely to affect the validity of our results, especially because the overwhelming majority of patients with Wegener’s granulomatosis in Sweden are diagnosed or treated as inpatients. Accordingly, we also found that all patients had been diagnosed with Wegener’s granulomatosis within a year of first admission to hospital, most of them during this admission. The possibility of surveillance bias cannot be excluded, as a patient with Wegener’s granulomatosis has regular medical examinations over many years. However, in this study, only one of the bladder cancer cases had had a chronic cystitis verified by cystoscopy long before the bladder cancer diagnosis. Among the diagnosed bladder cancers, 5/14 were invasive already at diagnosis, and six of the patients with bladder cancer died with bladder cancer noted on the death certificate, suggesting that early detection was not the case.

In conclusion, patients with Wegener’s granulomatosis are at a markedly increased risk of bladder cancer, with absolute risks as high as 10% some years after diagnosis. Our study indicates that this increased risk may partly be attributed to cyclophosphamide, but also that other factors even before the diagnosis of Wegener’s granulomatosis may be of importance. The results also indicate that measures to prevent haemorrhagic cystitis may not necessarily decrease the risk of bladder cancer. To avoid an accumulating number of cyclophosphamide related bladder cancers, sustained clinical attention should be directed towards patients with a history of cyclophosphamide exposure and the presence of other, possibly avoidable, risk factors for bladder cancers in these patients.