Prolonged risk of specific malignancies following cyclophosphamide therapy among patients with granulomatosis with polyangiitis

Rheumatology (Oxford). 2015 Aug;54(8):1345-50. doi: 10.1093/rheumatology/keu372. Epub 2014 Sep 17.


Objective: The long-term cancer risk for patients treated for granulomatosis with polyangiitis (GPA) is not well characterized. We assessed the risk of early and late-occurring cancers among 293 patients diagnosed with GPA from 1973 to 1999 and followed throughout 2010.

Methods: Cancer incidence in the cohort was determined by linkage with the Danish Cancer Registry and compared with that in the general population by calculation of standardized incidence ratios (SIRs).

Results: The median duration of follow-up was 9.7 years (range 0-36). Seventy-three cancers occurred, of which 30 were non-melanoma skin cancers (NMSCs) and 11 were bladder carcinomas. A high occurrence of NMSC was observed from the second year of follow-up onwards, with a SIR of 7.0 (95% CI 2.3, 16) for cases diagnosed ≥20 years after GPA. The incidence of bladder cancer increased after 5-9, 10-14 and 15-19 years of follow-up, with SIR estimates for these latency periods of 5.3 (95% CI 1.1, 15), 14.4 (95% CI 5.3, 31) and 10.5 (95% CI 1.2, 38), respectively. The incidence of myeloid leukaemia was significantly increased during years 5-9 [SIR 23.9 (95% CI 2.7, 86)]. Increased incidence of NMSC, bladder cancer and myeloid leukaemia was observed among patients exposed to cumulative CYC doses >36 g, while the only malignancy type observed in excess among those treated with lower CYC doses was NMSC. The cancer risk among CYC-naive patients was not significantly increased.

Conclusion: GPA patients experience a greater than expected number of specific malignancies following conventional therapies. Our analyses demonstrate a substantially increased risk of very late-occurring NMSC and bladder cancer in this patient group.

Keywords: bladder cancer; granulomatosis with polyangiitis; leukaemia; long-term follow-up; malignancy; non-melanoma skin cancer.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antirheumatic Agents / adverse effects
  • Antirheumatic Agents / therapeutic use
  • Cohort Studies
  • Cyclophosphamide / adverse effects*
  • Cyclophosphamide / therapeutic use*
  • Denmark
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Granulomatosis with Polyangiitis / drug therapy*
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Registries
  • Retrospective Studies
  • Risk Factors
  • Skin Neoplasms / epidemiology*
  • Treatment Outcome
  • Urinary Bladder Neoplasms / epidemiology*
  • Young Adult


  • Antirheumatic Agents
  • Cyclophosphamide