- Email: [email protected]
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-7212; No. of Pages 2 EUROPEAN UROLOGY XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
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 Kishan et al [1] performed a retrospective analysis comparing patients with biopsy Gleason score 9–10 who were treated with either radical prostatectomy (RP), external-beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT). From their analysis they conclude that treatment with EBRT + BT substantially outperforms EBRT (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.12–0.72) and RP (HR 0.23, 95% CI 0.09–0.60) in controlling systemic progression. Although interesting, this conclusion should be interpreted with caution, as we suspect important bias in their retrospective observational study. A first major concern is the drastic differences in other-cause mortality rates between treatment groups. On the basis of the PCa-specific mortality and overall survival rates at 10-yr follow-up (Table 3 in [1]), we deduced that other-cause mortality differed significantly between patients undergoing EBRT + BT (28.9%), EBRT (15.2%), and RP (6.4%). These differences are a reflection of a patient selection bias and we hypothesize that patients who had a higher comorbidity profile were selected for EBRT + BT or EBRT rather than RP. This could have a led to a perceived lower risk of death from PCa because of a higher risk of death from other (competing) causes in the EBRT + BT group. The authors used a Fine and Gray regression model to correct for this. However, although this method incorporates competing risks, it is not able to correct for such a significant bias. The survival benefit seen in the EBRT + BT group could therefore be related to a patient selection bias. Therefore, a more appropriate methodology would be based on a causespecific hazard analysis for the development of distant metastases corrected for patient comorbidities. Although the authors state that a uniform comorbidity index was not available, this does not justify the appropriateness of alternative analyses.
Furthermore, we must be cautious in interpreting distant progression as an endpoint when comparing different treatment modalities. This is especially true when comparing radiotherapy with surgical treatment because of the use of adjuvant androgen deprivation therapy (ADT; 86.2% for EBRT, 93.3% for EBRT + BT, and 10.6% for RP). Studer et al [2] showed that in patients not undergoing active treatment, immediate versus deferred ADT resulted in a delay in progression but did not change PCa-specific mortality. Furthermore, D’Amico et al [3] also showed that in patients receiving >6 mo of ADT, testosterone recovery took longer than 2 yr in 50% of cases. Thus, besides the effect of ADT on postponing the occurrence of metastases, the persistent testosterone suppression after adjuvant ADT might have influenced prostate-specific antigen levels and therefore clinical decision-making, such as when to perform imaging. As a result, metastases might be detected later in patients treated with adjuvant ADT. Owing to the short median follow-up of 4.6 yr, this could have introduced an important bias in the detection of metastases, which could explain the authors’ observations. Because of these limitations, no conclusions can be drawn regarding the efficacy of different treatment modalities in patients with a biopsy Gleason score of 9– 10. Only a direct head-to-head comparison would be able to answer this question. Conflicts of interest: The authors have nothing to disclose. Acknowledgments: Thomas Van den Broeck is supported by a PhD Fellowship from the Research Foundation of Flanders.
References [1] Kishan AU, Shaikh T, Wang P-C, 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] Studer UE, Whelan P, Wimpissinger F, et al. Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: final results of EORTC randomized trial 30891 with 12 years of follow-up. Eur Urol 2014;66:829–38. [3] D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Interval to testosterone recovery after hormonal therapy for
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2016.06.046. http://dx.doi.org/10.1016/j.eururo.2017.01.018 0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Van den Broeck T, et al. 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), http://dx.doi.org/10.1016/j.eururo.2017.01.018
EURURO-7212; No. of Pages 2 e2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
prostate cancer and risk of death. Int J Radiat Oncol Biol Phys
b
Department of Urology, University Hospitals Leuven, Leuven, Belgium c
2009;75:10–5.
Department of Urology, Mayo Clinic, Rochester, MN, USA
Thomas Van den Broecka,b
*Corresponding author. Department of Urology, University Hospitals
R. Jeffrey Karnesc Steven Joniaub,*
Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel. +32 16 346930; Fax: +32 16 330735. E-mail address: [email protected] (S. Joniau).
a
Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
January 6, 2017
Please cite this article in press as: Van den Broeck T, et al. 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), http://dx.doi.org/10.1016/j.eururo.2017.01.018
available at www.sciencedirect.com journal homepage: www.europeanurology.com
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 Kishan et al [1] performed a retrospective analysis comparing patients with biopsy Gleason score 9–10 who were treated with either radical prostatectomy (RP), external-beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT). From their analysis they conclude that treatment with EBRT + BT substantially outperforms EBRT (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.12–0.72) and RP (HR 0.23, 95% CI 0.09–0.60) in controlling systemic progression. Although interesting, this conclusion should be interpreted with caution, as we suspect important bias in their retrospective observational study. A first major concern is the drastic differences in other-cause mortality rates between treatment groups. On the basis of the PCa-specific mortality and overall survival rates at 10-yr follow-up (Table 3 in [1]), we deduced that other-cause mortality differed significantly between patients undergoing EBRT + BT (28.9%), EBRT (15.2%), and RP (6.4%). These differences are a reflection of a patient selection bias and we hypothesize that patients who had a higher comorbidity profile were selected for EBRT + BT or EBRT rather than RP. This could have a led to a perceived lower risk of death from PCa because of a higher risk of death from other (competing) causes in the EBRT + BT group. The authors used a Fine and Gray regression model to correct for this. However, although this method incorporates competing risks, it is not able to correct for such a significant bias. The survival benefit seen in the EBRT + BT group could therefore be related to a patient selection bias. Therefore, a more appropriate methodology would be based on a causespecific hazard analysis for the development of distant metastases corrected for patient comorbidities. Although the authors state that a uniform comorbidity index was not available, this does not justify the appropriateness of alternative analyses.
Furthermore, we must be cautious in interpreting distant progression as an endpoint when comparing different treatment modalities. This is especially true when comparing radiotherapy with surgical treatment because of the use of adjuvant androgen deprivation therapy (ADT; 86.2% for EBRT, 93.3% for EBRT + BT, and 10.6% for RP). Studer et al [2] showed that in patients not undergoing active treatment, immediate versus deferred ADT resulted in a delay in progression but did not change PCa-specific mortality. Furthermore, D’Amico et al [3] also showed that in patients receiving >6 mo of ADT, testosterone recovery took longer than 2 yr in 50% of cases. Thus, besides the effect of ADT on postponing the occurrence of metastases, the persistent testosterone suppression after adjuvant ADT might have influenced prostate-specific antigen levels and therefore clinical decision-making, such as when to perform imaging. As a result, metastases might be detected later in patients treated with adjuvant ADT. Owing to the short median follow-up of 4.6 yr, this could have introduced an important bias in the detection of metastases, which could explain the authors’ observations. Because of these limitations, no conclusions can be drawn regarding the efficacy of different treatment modalities in patients with a biopsy Gleason score of 9– 10. Only a direct head-to-head comparison would be able to answer this question. Conflicts of interest: The authors have nothing to disclose. Acknowledgments: Thomas Van den Broeck is supported by a PhD Fellowship from the Research Foundation of Flanders.
References [1] Kishan AU, Shaikh T, Wang P-C, 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] Studer UE, Whelan P, Wimpissinger F, et al. Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: final results of EORTC randomized trial 30891 with 12 years of follow-up. Eur Urol 2014;66:829–38. [3] D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Interval to testosterone recovery after hormonal therapy for
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2016.06.046. http://dx.doi.org/10.1016/j.eururo.2017.01.018 0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Van den Broeck T, et al. 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), http://dx.doi.org/10.1016/j.eururo.2017.01.018
EURURO-7212; No. of Pages 2 e2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
prostate cancer and risk of death. Int J Radiat Oncol Biol Phys
b
Department of Urology, University Hospitals Leuven, Leuven, Belgium c
2009;75:10–5.
Department of Urology, Mayo Clinic, Rochester, MN, USA
Thomas Van den Broecka,b
*Corresponding author. Department of Urology, University Hospitals
R. Jeffrey Karnesc Steven Joniaub,*
Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel. +32 16 346930; Fax: +32 16 330735. E-mail address: [email protected] (S. Joniau).
a
Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
January 6, 2017
Please cite this article in press as: Van den Broeck T, et al. 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), http://dx.doi.org/10.1016/j.eururo.2017.01.018