- Email: [email protected]
Impact of Statin Use on Oncologic Outcomes of Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy
EUROPEAN UROLOGY 63 (2013) 1134–1136
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Letters to the Editor NOT referring to a recent journal article Impact of Statin Use on Oncologic Outcomes of Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy Statins, among the most commonly prescribed drugs worldwide, are cholesterol-lowering agents used to manage and prevent cardiovascular diseases. Evidence suggests a dichotomous effect of statins with both cancer-inhibiting and -promoting effects. To date, the impact of statin use on oncologic outcomes in patients with urothelial carcinoma has been investigated only for the lower tract (ie, bladder) [1,2]. The aim of this study was to assess the impact of statin use on disease recurrence and cancer-specific mortality in patients with upper tract urothelial carcinoma (UTUC). For this purpose, we performed an institutional review board–approved retrospective analysis of 2490 patients with UTUC treated with radical nephroureterectomy (RNU) at 11 international institutions between 1987 and 2007 (for details, see the study by Xylinas et al. [3]). None of the patients received neoadjuvant chemotherapy or perioperative radiotherapy. Statin use at the time of diagnosis was recorded for each patient. Disease recurrence was defined as tumor relapse in the operative field, regional lymph nodes, and/or distant metastasis. Cause of death was determined by treating physician, by chart review, or by death certificate alone [4]. Associations of statin use with categorical variables were assessed using the chi-square test. Differences in continuous variables were analyzed using the Mann-Whitney U test. Univariable Cox regression models addressed the association of statin use with disease recurrence and cancer-specific mortality. All tests were two-sided with a significance level set at 0.05 (SPSS v.20.0; IBM Corp, Armonk, NY, USA). Overall, 1020 patients (41%) used statins and 1470 (59%) did not. Statin-user and non-statin-user groups were similar with regard to clinical features (age at RNU, American Society of Anesthesiologists score, gender, smoking status, tumor location and focality, and pathologic features [stage, grade, presence of lymphovascular invasion, and lymph node involvement]). However, statin users were more likely to have had laparoscopic RNU (21% vs 16%, p = 0.001). With a median follow-up of 45 mo (interquartile
range: 20–81), 663 patients (26.6%) experienced disease recurrence and 545 (21.9%) died of UTUC. Respective actuarial recurrence-free survival estimates at 2, 5, and 10 yr after RNU were 73 1%, 69 1%, and 64 2% for nonstatin users and 73 2%, 68 2%, and 64 2% for statin users (hazard ratio [HR]: 1.11; confidence interval [CI], 0.92–1.33; p = 0.27). Respective actuarial cancer-specific survival estimates at 2, 5, and 10 yr after RNU were 79 1%, 71 1%, and 64 2% for non-statin users and 82 1%, 74 2%, and 67 2% for statin users (HR: 0.96; CI, 0.78–1.18; p = 0.68). In multivariable analyses that adjusted for standard clinicopathologic factors, we did not find an association of statin use with either disease recurrence (HR: 1.06; CI, 0.91–1.24; p = 0.46) or cancer-specific mortality (HR: 0.86; CI, 0.72–1.03; p = 0.10). However, statin use was preventive of overall mortality (HR: 0.83; CI, 0.72–0.95; p = 0.01). In this large cohort of patients with UTUC who underwent RNU, we found that statin use was not associated with disease recurrence or cancer-specific mortality. Recently, an observational study showed that cancer patients who use statins before diagnosis have reduced cancer-related mortality compared with those who had never taken statins (15% decrease in relative risk) [5]. This effect was similar for different statin types, doses, and general tumor characteristics. However, this study did not address UTUC patients specifically, and its conclusions are limited by confounding factors. Statin users might be more health-conscious or more likely to be targeted for other health interventions such as smoking cessation [6]. Concerning the lower tract, it has been proposed that the immunosuppressive effects of statins may reduce the efficacy of bacillus Calmette-Gue´rin (BCG). Only one clinical study to date has supported this relationship [7], suggesting that discontinuation of statins during BCG therapy may improve outcomes. Three subsequent studies failed to validate that statin therapy affects patient responses to BCG [2,8,9]. To date, the current data do not suggest an influence of statin therapy on UTUC prognosis. Moreover, patients should not terminate statin regimens while undergoing treatment for UTUC because this may increase the risk of adverse cardiovascular events. Conflicts of interest: The authors have nothing to disclose.
0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1135
EUROPEAN UROLOGY 63 (2013) 1134–1136
Evanguelos Xylinasa,c Luis A. Klutha,d
References [1] Kamat SA, Gandhi SK, Davidson M. Comparative effectiveness of
Joseph J. Crivellia Malte Riekena,e
rosuvastatin versus other statin therapies in patients at increased risk of failure to achieve low-density lipoprotein goals. Curr Med Res
Vitaly Margulisf Christian Seitzg Shahrokh F. Shariata,b,g,*
Opin 2007;23:1121–30. [2] Berglund RK, Savage CJ, Vora KC, Kurta JM, Cronin AM. An analysis of the effect of statin use on the efficacy of bacillus Calmette-Guerin a
treatment for transitional cell carcinoma of the bladder. J Urol 2008;180:1297–300, discussion 1300. b
[3] Xylinas E, Rink M, Cha EK, et al. Impact of distal ureter management on oncologic outcomes following radical nephroureterectomy
Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA
Division of Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA c
for upper tract urothelial carcinoma. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2012.04.052. d
[4] Rink M, Fajkovic H, Cha EK, et al. Death certificates are valid for the determination of cause of death in patients with upper and lower
Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany e
tract urothelial carcinoma. Eur Urol 2012;61:854–5. [5] Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med 2012;367:1792–802. [6] Rink M, Xylinas E, Margulis V, et al. Impact of smoking on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Eur Urol 2013;63:1082–90. [7] Hoffmann P, Roumegue`re T, Schulman C, van Velthoven R. Use of statins and outcome of BCG treatment for bladder cancer. N Engl J Med 2006;355:2705–7. [8] Kamat AM, Wu X. Statins and the effect of BCG on bladder cancer. N Engl J Med 2007;356:1276. [9] Skolarus TA, Lee EW, Virgo KS, et al. Intravesical bacille CalmetteGue´rin therapy for non-muscle-invasive bladder cancer: effects of concurrent statin therapy. J Am Coll Surg 2009;209:248–53.
How Well Does the PCA3–incorporated Chun Nomogram Perform in Predicting Prostate Biopsy Outcome Among South African Men?
The incidence of prostate cancer among South African men is just as significant as it is worldwide [1,2]. Although the role of the prostate cancer antigen 3 (PCA3) assay in predicting biopsy outcome has proven beneficial in a South African context [3], the assessment of its role incorporated into a prostate cancer risk calculator has not yet been explored on the continent of Africa. We aimed to assess the performance of the PCA3-incorporated Chun nomogram [4] and to compare its performance with other contemporary risk calculators. We prospectively evaluated 107 consecutive South African men that were already scheduled for a 13-core transrectal ultrasound prostate biopsy at two referral centres in the South African capital city, Pretoria. The urine PCA3 assay was always performed prior to biopsy and was evaluated using the Progensa assay (Gen-Probe, San Diego, CA, USA). Performance of the following four calculators was compared: Chun nomogram [4] Prostate Cancer Prevention Trial (PCPT) risk calculator [5] Updated (PCA3 incorporated) PCPT risk calculator [5]
f
Department of Urology, Cochin Hospital, APHP, Paris Descartes University, Paris, France
Department of Urology, University Hospital Basel, Basel, Switzerland
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA g
Department of Urology, Medical University of Vienna, Vienna, Austria (SFS)
*Corresponding author. Department of Urology and Division of Medical Oncology, Weill Cornell Medical College, 525 East 68th St., Starr 900, New York, NY 10065, USA. Tel. +1 212 746 5562. E-mail address: [email protected] (S.F. Shariat). March 8, 2013 Published online ahead of print on March 19, 2013 http://dx.doi.org/10.1016/j.eururo.2013.03.027
European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator [6] Histologic evidence of cancer in the prostate biopsy specimen was set as the primary end point. The discriminating ability of each risk calculator was assessed and compared using the concordance index (c-index). The mean patient age was 67 yr. A positive cancer outcome was present in 46 of 107 men, with only 19 of 107 scheduled for a repeat biopsy. Ultimately, 97 patients were assessed because 10 patients were excluded from the comparison data set due to inconclusive PCA3 assay scores (2 of 10) and patient age <55 yr (8 of 10). The four calculators had the following c-indexes: Chun nomogram, 0.93 (95% confidence interval [CI], 0.88–0.97); PCPT, 0.80 (95% CI, 0.72–0.89); updated PCPT, 0.77 (95% CI, 0.68–0.86); ERSPC, 0.91 (95% CI, 0.85–0.97) (Fig. 1). The Chun nomogram outperformed the other calculators assessed. Because the initial development of the Chun nomogram involved multiple centres in Europe and included both Canada and the United States [4], our findings may further support the universality of this PCA3-incorporated risk calculator. The PCPT risk calculators do not have a specific option within the racial category for the local black African man, so the option other was used for this racial group. This may have underestimated the risk for a certain racial subset in
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Letters to the Editor NOT referring to a recent journal article Impact of Statin Use on Oncologic Outcomes of Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy Statins, among the most commonly prescribed drugs worldwide, are cholesterol-lowering agents used to manage and prevent cardiovascular diseases. Evidence suggests a dichotomous effect of statins with both cancer-inhibiting and -promoting effects. To date, the impact of statin use on oncologic outcomes in patients with urothelial carcinoma has been investigated only for the lower tract (ie, bladder) [1,2]. The aim of this study was to assess the impact of statin use on disease recurrence and cancer-specific mortality in patients with upper tract urothelial carcinoma (UTUC). For this purpose, we performed an institutional review board–approved retrospective analysis of 2490 patients with UTUC treated with radical nephroureterectomy (RNU) at 11 international institutions between 1987 and 2007 (for details, see the study by Xylinas et al. [3]). None of the patients received neoadjuvant chemotherapy or perioperative radiotherapy. Statin use at the time of diagnosis was recorded for each patient. Disease recurrence was defined as tumor relapse in the operative field, regional lymph nodes, and/or distant metastasis. Cause of death was determined by treating physician, by chart review, or by death certificate alone [4]. Associations of statin use with categorical variables were assessed using the chi-square test. Differences in continuous variables were analyzed using the Mann-Whitney U test. Univariable Cox regression models addressed the association of statin use with disease recurrence and cancer-specific mortality. All tests were two-sided with a significance level set at 0.05 (SPSS v.20.0; IBM Corp, Armonk, NY, USA). Overall, 1020 patients (41%) used statins and 1470 (59%) did not. Statin-user and non-statin-user groups were similar with regard to clinical features (age at RNU, American Society of Anesthesiologists score, gender, smoking status, tumor location and focality, and pathologic features [stage, grade, presence of lymphovascular invasion, and lymph node involvement]). However, statin users were more likely to have had laparoscopic RNU (21% vs 16%, p = 0.001). With a median follow-up of 45 mo (interquartile
range: 20–81), 663 patients (26.6%) experienced disease recurrence and 545 (21.9%) died of UTUC. Respective actuarial recurrence-free survival estimates at 2, 5, and 10 yr after RNU were 73 1%, 69 1%, and 64 2% for nonstatin users and 73 2%, 68 2%, and 64 2% for statin users (hazard ratio [HR]: 1.11; confidence interval [CI], 0.92–1.33; p = 0.27). Respective actuarial cancer-specific survival estimates at 2, 5, and 10 yr after RNU were 79 1%, 71 1%, and 64 2% for non-statin users and 82 1%, 74 2%, and 67 2% for statin users (HR: 0.96; CI, 0.78–1.18; p = 0.68). In multivariable analyses that adjusted for standard clinicopathologic factors, we did not find an association of statin use with either disease recurrence (HR: 1.06; CI, 0.91–1.24; p = 0.46) or cancer-specific mortality (HR: 0.86; CI, 0.72–1.03; p = 0.10). However, statin use was preventive of overall mortality (HR: 0.83; CI, 0.72–0.95; p = 0.01). In this large cohort of patients with UTUC who underwent RNU, we found that statin use was not associated with disease recurrence or cancer-specific mortality. Recently, an observational study showed that cancer patients who use statins before diagnosis have reduced cancer-related mortality compared with those who had never taken statins (15% decrease in relative risk) [5]. This effect was similar for different statin types, doses, and general tumor characteristics. However, this study did not address UTUC patients specifically, and its conclusions are limited by confounding factors. Statin users might be more health-conscious or more likely to be targeted for other health interventions such as smoking cessation [6]. Concerning the lower tract, it has been proposed that the immunosuppressive effects of statins may reduce the efficacy of bacillus Calmette-Gue´rin (BCG). Only one clinical study to date has supported this relationship [7], suggesting that discontinuation of statins during BCG therapy may improve outcomes. Three subsequent studies failed to validate that statin therapy affects patient responses to BCG [2,8,9]. To date, the current data do not suggest an influence of statin therapy on UTUC prognosis. Moreover, patients should not terminate statin regimens while undergoing treatment for UTUC because this may increase the risk of adverse cardiovascular events. Conflicts of interest: The authors have nothing to disclose.
0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1135
EUROPEAN UROLOGY 63 (2013) 1134–1136
Evanguelos Xylinasa,c Luis A. Klutha,d
References [1] Kamat SA, Gandhi SK, Davidson M. Comparative effectiveness of
Joseph J. Crivellia Malte Riekena,e
rosuvastatin versus other statin therapies in patients at increased risk of failure to achieve low-density lipoprotein goals. Curr Med Res
Vitaly Margulisf Christian Seitzg Shahrokh F. Shariata,b,g,*
Opin 2007;23:1121–30. [2] Berglund RK, Savage CJ, Vora KC, Kurta JM, Cronin AM. An analysis of the effect of statin use on the efficacy of bacillus Calmette-Guerin a
treatment for transitional cell carcinoma of the bladder. J Urol 2008;180:1297–300, discussion 1300. b
[3] Xylinas E, Rink M, Cha EK, et al. Impact of distal ureter management on oncologic outcomes following radical nephroureterectomy
Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA
Division of Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA c
for upper tract urothelial carcinoma. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2012.04.052. d
[4] Rink M, Fajkovic H, Cha EK, et al. Death certificates are valid for the determination of cause of death in patients with upper and lower
Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany e
tract urothelial carcinoma. Eur Urol 2012;61:854–5. [5] Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med 2012;367:1792–802. [6] Rink M, Xylinas E, Margulis V, et al. Impact of smoking on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Eur Urol 2013;63:1082–90. [7] Hoffmann P, Roumegue`re T, Schulman C, van Velthoven R. Use of statins and outcome of BCG treatment for bladder cancer. N Engl J Med 2006;355:2705–7. [8] Kamat AM, Wu X. Statins and the effect of BCG on bladder cancer. N Engl J Med 2007;356:1276. [9] Skolarus TA, Lee EW, Virgo KS, et al. Intravesical bacille CalmetteGue´rin therapy for non-muscle-invasive bladder cancer: effects of concurrent statin therapy. J Am Coll Surg 2009;209:248–53.
How Well Does the PCA3–incorporated Chun Nomogram Perform in Predicting Prostate Biopsy Outcome Among South African Men?
The incidence of prostate cancer among South African men is just as significant as it is worldwide [1,2]. Although the role of the prostate cancer antigen 3 (PCA3) assay in predicting biopsy outcome has proven beneficial in a South African context [3], the assessment of its role incorporated into a prostate cancer risk calculator has not yet been explored on the continent of Africa. We aimed to assess the performance of the PCA3-incorporated Chun nomogram [4] and to compare its performance with other contemporary risk calculators. We prospectively evaluated 107 consecutive South African men that were already scheduled for a 13-core transrectal ultrasound prostate biopsy at two referral centres in the South African capital city, Pretoria. The urine PCA3 assay was always performed prior to biopsy and was evaluated using the Progensa assay (Gen-Probe, San Diego, CA, USA). Performance of the following four calculators was compared: Chun nomogram [4] Prostate Cancer Prevention Trial (PCPT) risk calculator [5] Updated (PCA3 incorporated) PCPT risk calculator [5]
f
Department of Urology, Cochin Hospital, APHP, Paris Descartes University, Paris, France
Department of Urology, University Hospital Basel, Basel, Switzerland
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA g
Department of Urology, Medical University of Vienna, Vienna, Austria (SFS)
*Corresponding author. Department of Urology and Division of Medical Oncology, Weill Cornell Medical College, 525 East 68th St., Starr 900, New York, NY 10065, USA. Tel. +1 212 746 5562. E-mail address: [email protected] (S.F. Shariat). March 8, 2013 Published online ahead of print on March 19, 2013 http://dx.doi.org/10.1016/j.eururo.2013.03.027
European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator [6] Histologic evidence of cancer in the prostate biopsy specimen was set as the primary end point. The discriminating ability of each risk calculator was assessed and compared using the concordance index (c-index). The mean patient age was 67 yr. A positive cancer outcome was present in 46 of 107 men, with only 19 of 107 scheduled for a repeat biopsy. Ultimately, 97 patients were assessed because 10 patients were excluded from the comparison data set due to inconclusive PCA3 assay scores (2 of 10) and patient age <55 yr (8 of 10). The four calculators had the following c-indexes: Chun nomogram, 0.93 (95% confidence interval [CI], 0.88–0.97); PCPT, 0.80 (95% CI, 0.72–0.89); updated PCPT, 0.77 (95% CI, 0.68–0.86); ERSPC, 0.91 (95% CI, 0.85–0.97) (Fig. 1). The Chun nomogram outperformed the other calculators assessed. Because the initial development of the Chun nomogram involved multiple centres in Europe and included both Canada and the United States [4], our findings may further support the universality of this PCA3-incorporated risk calculator. The PCPT risk calculators do not have a specific option within the racial category for the local black African man, so the option other was used for this racial group. This may have underestimated the risk for a certain racial subset in