Use of Statins and Outcome of BCG Treatment for Bladder Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The intravesical administration of bacille Calmette–Guérin (BCG) vaccine for high-risk, non–muscle-invasive bladder cancer and carcinoma in situ is one of the most successful immunotherapies to date.1 Studies in animals have shown that the generation of effector cells, called BCG-activated killer cells, depends on type 1 helper T (Th1)–type cytokines.2 In humans, a high Th1-biased urinary cytokine profile after several weekly intravesical instillations of BCG correlates with a better clinical response.3
Statins have cholesterol-lowering properties and also immunomodulating actions. Several reports have indicated that statins can induce antiinflammatory type 2 helper T (Th2)–type cytokines (interleukin-4, interleukin-5, and interleukin-10) and inhibit the secretion of interleukin-2, interleukin-12, interferon gamma, and tumor necrosis factor through the inhibition of signal transducer and activator of transcription 4 (STAT4) and the transcription factor T-bet. The result is strong attenuation of the Th1-type immune response and promotion of the development of Th2 cells.4,5
We retrospectively analyzed the clinical outcomes for 84 patients who had received BCG immunotherapy for the treatment of non–muscle-invasive bladder cancer; 19 of the patients had taken statins during BCG immunotherapy, and 65 had not (Table 1). We determined the number of recurrences during the first year, the number of total recurrences, tumor progression, the time to cystectomy, and the time to the development of distant metastases. The two groups had similar medical histories, follow-up times, and pathological features.
Table 1. Baseline Characteristics of the Patients.
The median follow-up was 46 months. The number of recurrences during the first year or subsequent years did not differ significantly between the groups. However, in 53% of the patients who took statins, the tumor became more aggressive, whereas this change occurred in only 18% of the patients who did not take statins (P=0.004; odds ratio, 4.9; 95% confidence interval , 1.64 to 14.69). Similarly, 42% of the patients in the statin group had to undergo radical cystectomy, as compared with only 14% of the patients who did not take statins (P=0.01; odds ratio, 4.5; 95% CI, 1.43 to 14.30). Among the patients who underwent radical cystectomy, the number in whom metastases developed and the time to their development were similar in the two groups.
Our observations suggest that the discontinuation of statin therapy during BCG immunotherapy might improve the clinical outcome, since the use of statins was significantly associated with an increased risk of tumor progression and a subsequent need for radical cystectomy.
Paul Hoffmann, M.D.
Jules Bordet Institute
1000 Brussels, Belgium
pahoffma@ulb.ac.be
Thierry Roumeguère, M.D.
Claude Schulman, M.D., Ph.D.
Erasme Hospital
1070 Brussels, Belgium
Roland van Velthoven, M.D., Ph.D.
Jules Bordet Institute
1000 Brussels, Belgium
References
Lamm D, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163:1124-1129.
Bohle A, Brandau S. Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. J Urol 2003;170:964-969.
Watanabe E, Matsuyama H, Matsuda K, et al. Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guerin immunotherapy for carcinoma in situ of the bladder. Cancer Immunol Immunother 2003;52:481-486.
Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 2006;6:358-370.
Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399-1402.
Statins have cholesterol-lowering properties and also immunomodulating actions. Several reports have indicated that statins can induce antiinflammatory type 2 helper T (Th2)–type cytokines (interleukin-4, interleukin-5, and interleukin-10) and inhibit the secretion of interleukin-2, interleukin-12, interferon gamma, and tumor necrosis factor through the inhibition of signal transducer and activator of transcription 4 (STAT4) and the transcription factor T-bet. The result is strong attenuation of the Th1-type immune response and promotion of the development of Th2 cells.4,5
We retrospectively analyzed the clinical outcomes for 84 patients who had received BCG immunotherapy for the treatment of non–muscle-invasive bladder cancer; 19 of the patients had taken statins during BCG immunotherapy, and 65 had not (Table 1). We determined the number of recurrences during the first year, the number of total recurrences, tumor progression, the time to cystectomy, and the time to the development of distant metastases. The two groups had similar medical histories, follow-up times, and pathological features.
Table 1. Baseline Characteristics of the Patients.
The median follow-up was 46 months. The number of recurrences during the first year or subsequent years did not differ significantly between the groups. However, in 53% of the patients who took statins, the tumor became more aggressive, whereas this change occurred in only 18% of the patients who did not take statins (P=0.004; odds ratio, 4.9; 95% confidence interval , 1.64 to 14.69). Similarly, 42% of the patients in the statin group had to undergo radical cystectomy, as compared with only 14% of the patients who did not take statins (P=0.01; odds ratio, 4.5; 95% CI, 1.43 to 14.30). Among the patients who underwent radical cystectomy, the number in whom metastases developed and the time to their development were similar in the two groups.
Our observations suggest that the discontinuation of statin therapy during BCG immunotherapy might improve the clinical outcome, since the use of statins was significantly associated with an increased risk of tumor progression and a subsequent need for radical cystectomy.
Paul Hoffmann, M.D.
Jules Bordet Institute
1000 Brussels, Belgium
pahoffma@ulb.ac.be
Thierry Roumeguère, M.D.
Claude Schulman, M.D., Ph.D.
Erasme Hospital
1070 Brussels, Belgium
Roland van Velthoven, M.D., Ph.D.
Jules Bordet Institute
1000 Brussels, Belgium
References
Lamm D, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163:1124-1129.
Bohle A, Brandau S. Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. J Urol 2003;170:964-969.
Watanabe E, Matsuyama H, Matsuda K, et al. Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guerin immunotherapy for carcinoma in situ of the bladder. Cancer Immunol Immunother 2003;52:481-486.
Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 2006;6:358-370.
Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399-1402.