- Email: [email protected]
Reply to Thomas Van den Broeck, R. Jeffrey Karnes, and Steven Joniau's Letter to the Editor re: Amar U. Kishan, Talha Shaikh, Pin-Chieh Wang, et al. Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis. Eur Urol 2017;71:766–73
EURURO-7211; No. of Pages 2 EUROPEAN UROLOGY XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Letter to the Editor Reply to Thomas Van den Broeck, R. Jeffrey Karnes, and Steven Joniau’s Letter to the Editor re: Amar U. Kishan, Talha Shaikh, Pin-Chieh Wang, et al. Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis. Eur Urol 2016. In press. http://dx.doi.org/10.1016/j.eururo.2016.06.046 We thank Dr. Van den Broeck and colleagues for their interest in our article [1]. They correctly state that there were differences in other-cause mortality between the three treatment cohorts (radical prostatectomy [RP], external-beam radiotherapy [EBRT], and EBRT plus brachytherapy [BT]). However, we disagree that a cause-specific hazard model would have been more appropriate than the Fine and Gray competing-risks model we used. Both strategies are considered reasonable means of accounting for competing risks [2], and the Fine and Gray model is widely used in urologic oncology (as evidenced by multiple publications, including recent reports in European Urology [3]). Furthermore, it is well known that patients in surgical cohorts are younger and healthier, on average, than those in radiotherapy cohorts; for example, the median age of surgical patients in our series was 62 yr, compared to 70 yr in both radiotherapy cohorts (p < 0.0001). It is highly likely that other-cause mortality would be much higher in a population of older patients, and a cause-specific hazard model (which removes patients who experience othercause mortality from the at-risk population) would have introduced a significant bias against both radiotherapybased cohorts. Moreover, in addition to competing-risks analysis via the Fine and Gray model, we also performed Cox regression analysis that was not adjusted for competing risks, and did not find differences in prostate cancer– specific mortality. Van den Broeck et al also note that androgen deprivation therapy (ADT) use in the EBRT and EBRT + BT cohorts introduced a bias in terms of the endpoint of distant metastasis–free survival (DMFS), as ADT may simply delay rather than prevent metastases. They are correct that ADT probably delays metastases, but this cannot explain the findings of our study. The median follow-up duration for
EBRT patients was 4.2 yr, and they received ADT for a median duration of 24 mo. The median follow-up for EBRT + BT patients, however, was 6.5 yr, compared to 4.9 yr for RP patients, and the median ADT duration in the EBRT + BT cohort was only 8 mo. Even if ADT provided a near 2-yr lead time against metastasis development, this would not explain the significant differences in DMFS seen at 5- and 10-yr follow-up between the EBRT + BT and the RP cohorts. Moreover, simply attributing the DMFS effect to ADT delay of metastases would leave unresolved the large DMFS difference between the EBRT + BT and EBRT cohorts; in fact, this difference is particularly notable because of the significantly shorter ADT duration in the EBRT + BT cohort. Finally, we agree that a head-to-head comparison of RP, EBRT, and EBRT + BT for Gleason score 9–10 disease would be the optimal means of comparing treatment efficacy. However, while laudable, we posit that achieving this goal is improbable given not only the significant provider biases regarding treatment allocation but also the relative rarity of Gleason score 9–10 disease. Indeed, this series constitutes the largest such cohort with individual patient-level outcome data that has been published. We are actively working to expand our analysis to include additional institutions and increase the statistical power of our study [3,4]. Conflicts of interest: The authors have nothing to disclose.
References [1] Kishan AU, Shaikh T, Wang PC, et al. Clinical outcomes for patients with Gleason score 9-10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: a multi-institutional comparative analysis. Eur Urol. In press. http://dx.doi.org/10.1016/ j.eururo.2016.06.046. [2] Lau B, Cole SR, Gange SJ. Competing risk regression models for epidemiologic data. Am J Epidemiol 2009;170:244–56. [3] Lee BH, Kibel AS, Ciezki JP, et al. Are biochemical recurrence outcomes similar after radical prostatectomy and radiation therapy? Analysis of prostate cancer-specific mortality by nomogram-predicted risks of biochemical recurrence Eur Urol 2015;67:204–9. [4] Kishan AU, Shaikh T, Stock RG, et al. Radiotherapy versus radical prostatectomy for Gleason score 9-10 prostate adenocarcinoma: a multi-institutional comparative analysis of 1001 patients treated in the modern eraPresented at Genitourinary Cancers Symposium; Orlando, FL. Abstract 7; February 15–18, 2017.
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2017.01.018, http://dx.doi.org/10.1016/j.eururo.2016.06.046. http://dx.doi.org/10.1016/j.eururo.2017.01.017 0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Kishan AU, et al. Reply to Thomas Van den Broeck, R. Jeffrey Karnes, and Steven Joniau’s Letter to the Editor re: Amar U. Kishan, Talha Shaikh, Pin-Chieh Wang, et al. Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or. . .. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.01.017
EURURO-7211; No. of Pages 2 e2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
Amar U. Kishan*
*Corresponding author at: Department of Radiation Oncology,
Michael L. Steinberg
University of California, Los Angeles, Suite B265, 200 Medical Plaza,
Patrick A. Kupelian
Los Angeles, CA 90095, USA. Tel.: +1 310 8259771; fax: +1 310 8257194.
Christopher R. King
E-mail address: [email protected] (A.U. Kishan).
Department of Radiation Oncology, University of California, Los Angeles, CA, USA
January 6, 2017
Please cite this article in press as: Kishan AU, et al. Reply to Thomas Van den Broeck, R. Jeffrey Karnes, and Steven Joniau’s Letter to the Editor re: Amar U. Kishan, Talha Shaikh, Pin-Chieh Wang, et al. Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or. . .. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.01.017
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Letter to the Editor Reply to Thomas Van den Broeck, R. Jeffrey Karnes, and Steven Joniau’s Letter to the Editor re: Amar U. Kishan, Talha Shaikh, Pin-Chieh Wang, et al. Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis. Eur Urol 2016. In press. http://dx.doi.org/10.1016/j.eururo.2016.06.046 We thank Dr. Van den Broeck and colleagues for their interest in our article [1]. They correctly state that there were differences in other-cause mortality between the three treatment cohorts (radical prostatectomy [RP], external-beam radiotherapy [EBRT], and EBRT plus brachytherapy [BT]). However, we disagree that a cause-specific hazard model would have been more appropriate than the Fine and Gray competing-risks model we used. Both strategies are considered reasonable means of accounting for competing risks [2], and the Fine and Gray model is widely used in urologic oncology (as evidenced by multiple publications, including recent reports in European Urology [3]). Furthermore, it is well known that patients in surgical cohorts are younger and healthier, on average, than those in radiotherapy cohorts; for example, the median age of surgical patients in our series was 62 yr, compared to 70 yr in both radiotherapy cohorts (p < 0.0001). It is highly likely that other-cause mortality would be much higher in a population of older patients, and a cause-specific hazard model (which removes patients who experience othercause mortality from the at-risk population) would have introduced a significant bias against both radiotherapybased cohorts. Moreover, in addition to competing-risks analysis via the Fine and Gray model, we also performed Cox regression analysis that was not adjusted for competing risks, and did not find differences in prostate cancer– specific mortality. Van den Broeck et al also note that androgen deprivation therapy (ADT) use in the EBRT and EBRT + BT cohorts introduced a bias in terms of the endpoint of distant metastasis–free survival (DMFS), as ADT may simply delay rather than prevent metastases. They are correct that ADT probably delays metastases, but this cannot explain the findings of our study. The median follow-up duration for
EBRT patients was 4.2 yr, and they received ADT for a median duration of 24 mo. The median follow-up for EBRT + BT patients, however, was 6.5 yr, compared to 4.9 yr for RP patients, and the median ADT duration in the EBRT + BT cohort was only 8 mo. Even if ADT provided a near 2-yr lead time against metastasis development, this would not explain the significant differences in DMFS seen at 5- and 10-yr follow-up between the EBRT + BT and the RP cohorts. Moreover, simply attributing the DMFS effect to ADT delay of metastases would leave unresolved the large DMFS difference between the EBRT + BT and EBRT cohorts; in fact, this difference is particularly notable because of the significantly shorter ADT duration in the EBRT + BT cohort. Finally, we agree that a head-to-head comparison of RP, EBRT, and EBRT + BT for Gleason score 9–10 disease would be the optimal means of comparing treatment efficacy. However, while laudable, we posit that achieving this goal is improbable given not only the significant provider biases regarding treatment allocation but also the relative rarity of Gleason score 9–10 disease. Indeed, this series constitutes the largest such cohort with individual patient-level outcome data that has been published. We are actively working to expand our analysis to include additional institutions and increase the statistical power of our study [3,4]. Conflicts of interest: The authors have nothing to disclose.
References [1] Kishan AU, Shaikh T, Wang PC, et al. Clinical outcomes for patients with Gleason score 9-10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: a multi-institutional comparative analysis. Eur Urol. In press. http://dx.doi.org/10.1016/ j.eururo.2016.06.046. [2] Lau B, Cole SR, Gange SJ. Competing risk regression models for epidemiologic data. Am J Epidemiol 2009;170:244–56. [3] Lee BH, Kibel AS, Ciezki JP, et al. Are biochemical recurrence outcomes similar after radical prostatectomy and radiation therapy? Analysis of prostate cancer-specific mortality by nomogram-predicted risks of biochemical recurrence Eur Urol 2015;67:204–9. [4] Kishan AU, Shaikh T, Stock RG, et al. Radiotherapy versus radical prostatectomy for Gleason score 9-10 prostate adenocarcinoma: a multi-institutional comparative analysis of 1001 patients treated in the modern eraPresented at Genitourinary Cancers Symposium; Orlando, FL. Abstract 7; February 15–18, 2017.
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2017.01.018, http://dx.doi.org/10.1016/j.eururo.2016.06.046. http://dx.doi.org/10.1016/j.eururo.2017.01.017 0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Kishan AU, et al. Reply to Thomas Van den Broeck, R. Jeffrey Karnes, and Steven Joniau’s Letter to the Editor re: Amar U. Kishan, Talha Shaikh, Pin-Chieh Wang, et al. Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or. . .. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.01.017
EURURO-7211; No. of Pages 2 e2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
Amar U. Kishan*
*Corresponding author at: Department of Radiation Oncology,
Michael L. Steinberg
University of California, Los Angeles, Suite B265, 200 Medical Plaza,
Patrick A. Kupelian
Los Angeles, CA 90095, USA. Tel.: +1 310 8259771; fax: +1 310 8257194.
Christopher R. King
E-mail address: [email protected] (A.U. Kishan).
Department of Radiation Oncology, University of California, Los Angeles, CA, USA
January 6, 2017
Please cite this article in press as: Kishan AU, et al. Reply to Thomas Van den Broeck, R. Jeffrey Karnes, and Steven Joniau’s Letter to the Editor re: Amar U. Kishan, Talha Shaikh, Pin-Chieh Wang, et al. Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or. . .. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.01.017