- Email: [email protected]
In Reply to Morris and Tyldesley
242
Comments
References 1. Ciezki JP, Weller MD, Reddy CA, et al. A comparison between lowdose-rate brachytherapy with or without androgen deprivation , and radical prostatectomy with or without adjuvant or salvage radiation therapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;97:962-975. 2. Morris WJ, Tyldesley S, Rodda S, et al. Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;98:275-285. 3. Morris WJ, Tyldesley S, Pai H, et al. ASCENDE-RT*: A multicenter randomized trial of dose-escalated external beam radiation therapy (EBRTB) versus low-dose-rate brachytherapy (LDR-B) for men with unfavorable-risk localized prostate cancer. J Clin Oncol 2015;33(Suppl. 7). 4. Morris WJ, Tyldesley S, Rodda S, et al. LDR brachytherapy is superior to 78 of EBRT for unfavorable risk prostate cancer; the results of a randomized control trial. Radiother Oncol 2015;115:S239. 5. Morris WJ, Tyldesley S, Pai H, et al. Low-dose-rate brachytherapy is superior to dose-escalated EBRT for unfavorable risk prostate cancer: The results of the ASCENDE-RT* randomized control trial. Brachytherapy 2015;14(Suppl. 1):S12. 6. Morris WJ, Pickles T, Keyes M, et al. Pride or prejudice: Does Phoenix flatter radiation therapy? Brachytherapy 2014;13:299-303. 7. Rodda S, Tyldesley S, Keyes M, et al. Low-dose-rate brachytherapy is superior to dose-escalated EBRT for unfavorable risk prostate cancer: The results of the ASCENDE-RT* randomized control trial. Int J Radiat Oncol Biol Phys 2015;93(3 Suppl. ):E191-E192. 8. Lo AC, Morris WJ, Lapointe V, et al. Prostate-specific antigen at 4 to 5 years after low-dose-rate prostate brachytherapy is a strong predictor of disease-free survival. Int J Radiat Oncol Biol Phys 2014;88:87-93.
In Reply to Morris and Tyldesley To the Editor: We thank Drs Morris and Tyldesley for pointing out our error in reporting the results of the ASCENDE-RT trial (1, 2). When reading the abstract (3) we were mistaken in reading the “Results” section. Specifically, the results reporting begins with reference to biochemical failure scored via the Phoenix definition (4) and then proceeds to report specific percentages using a 0.2-ng/mL threshold definition. We made an error in assuming that the entire reporting of biochemical results was according to the definition mentioned in the initial sentences. The 10-year biochemical failure results Drs Morris and Tyldesley report in their letter according to the Phoenix definition are indeed superior to the 10-year biochemical failure rates in all of the modalities in our article. Our reason for making the comparison was not to deride the results of the authors’ ground-breaking trial but to point
Conflict of interest: J.P.C. serves as Senior Editor of the GU Section and C.A.R. serves as Statistical Editor of the International Journal of Radiation Oncology Biology Physics.
International Journal of Radiation Oncology Biology Physics
out the extreme difficulties in using biochemical failure as an endpoint for a clinical trial. The specific problems associated with biochemical failure as a robust endpoint have been discussed in the literature in great detail, and a complete exposition of these shortcomings is beyond the scope of this letter; however, in reporting the proceedings of the conference that helped promote the Phoenix definition, the attendees provide an excellent review of the issues (4). The confounding effects of a variety of factors, including androgen deprivation therapy, intensity of followup, and the specifics (timing) of applying a threshold definition are in play. Underscoring the last point regarding the application of a threshold definition to patients treated with radiation is our experience in trying to apply the authors’ threshold of 0.2 ng/mL to our patients. Upon realizing our error, we wanted to provide the literature with comparative biochemical failure data to reiterate the superiority of the authors’ biochemical failure results. We were confused as to when to apply the threshold. For instance, looking only at our first posttherapy prostate-specific antigen (PSA) value, 44.4% were biochemically free of recurrence. If one scores all PSA values after therapy, 41.8% were biochemically free of recurrence. To summarize our application of the 0.2 ng/mL threshold to our brachytherapy dataset: 168 patients (36.6%) have a PSA >0.2 ng/mL at first posttreatment PSA and never reach a PSA value 0.2 ng/mL 87 patients (19.0%) have a PSA >0.2 ng/mL at first posttreatment PSA and later have a PSA value 0.2 ng/mL 99 patients (21.6%) have PSA 0.2 ng/mL at first posttreatment PSA and later have a PSA value >0.2 ng/mL 105 patients (22.8%) have PSA 0.2 ng/mL at first posttreatment PSA and continue to have a PSA value 0.2 ng/mL The challenge is figuring out the timing of when the PSA rose above 0.2 ng/mL and the timing of when the PSAs >0.2 ng/mL fell below 0.2 ng/mL and had to be “unfailed” (if this is in fact done using the authors’ definition). Perhaps because of the use of androgen deprivation therapy for 12 months in the authors’ trial they did not encounter these problems and their patients’ PSA profile behaved more like a surgical cohort in which one expects a low/undetectable PSA soon after therapy, and any subsequent rise above a predefined threshold becomes a scorable event. We think that the difficulty we have in reproducing the reporting of biochemical failure using the authors’ definition in our patients emphasizes the importance of reporting research endpoints using standard definitions such as the Phoenix definition, and we thank Drs Morris and Tyldesley for providing these data in their letter. Because of the ambiguities discussed above, the importance of “hard” clinical endpoints is obvious. Multiple reports exist in the literature of superior biochemical outcomes
Volume 99 Number 1 2017
from local intensification efforts that do not translate into “hard” endpoints, such as clinical failure or mortality. One that is most germane to this discussion is a trial comparing external beam radiation plus 192Ir brachytherapy boost versus external beam radiation alone in high-risk prostate cancer (5). Those investigators noted a superiority of the combined-modality arm, with 8.2 years of median follow-up that did not translate into a survival advantage. Recognizing these problems, we elected to not only report biochemical outcomes but also show clinical failure and prostate cancerspecific mortality. We look forward to reading the update of ASCENDE-RT reporting similar “hard” endpoints. Jay P. Ciezki, MD Chandana A. Reddy, MS Department of Radiation Oncology Cleveland Clinic Cleveland, Ohio http://dx.doi.org/10.1016/j.ijrobp.2017.04.028
Comments
243
References 1. Morris WJ, Tyldesley S. The Biochemical Outcomes for the ASCENDE-RT Randomized Controlled Trial and Those Reported from the Cleveland Clinic: In Regard to Ciezki et al. Intl J Radiat Oncol Biol Phys 2017;99:240-242. 2. Ciezki JP, Weller MD, Reddy CA, et al. A comparison between lowdose-rate brachytherapy with or without androgen deprivation , and radical prostatectomy with or without adjuvant or salvage radiation therapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;97:962-975. 3. Rodda SL, Tyldesley S, Keyes M, et al. Low-dose-rate prostate brachytherapy is superior to dose-escalated EBRT for unfavorable risk prostate cancer: The results of the ASCENDE-RT randomized control trial. Int J Radiat Oncol Biol Phys 2015;93:E191-E192. 4. Roach M, Hanks G, Thames H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix consensus conference. Int J Radiat Oncol Biol Phys 2006;65:965-974. 5. Sathya JR, Davis IR, Julian JA, et al. Randomized trial comparing iridium implant plus external-beam radiation therapy with externalbeam radiation therapy alone in node-negative locally advanced cancer of the prostate. J Clin Oncol 2005;23:1192-1199.
Comments
References 1. Ciezki JP, Weller MD, Reddy CA, et al. A comparison between lowdose-rate brachytherapy with or without androgen deprivation , and radical prostatectomy with or without adjuvant or salvage radiation therapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;97:962-975. 2. Morris WJ, Tyldesley S, Rodda S, et al. Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;98:275-285. 3. Morris WJ, Tyldesley S, Pai H, et al. ASCENDE-RT*: A multicenter randomized trial of dose-escalated external beam radiation therapy (EBRTB) versus low-dose-rate brachytherapy (LDR-B) for men with unfavorable-risk localized prostate cancer. J Clin Oncol 2015;33(Suppl. 7). 4. Morris WJ, Tyldesley S, Rodda S, et al. LDR brachytherapy is superior to 78 of EBRT for unfavorable risk prostate cancer; the results of a randomized control trial. Radiother Oncol 2015;115:S239. 5. Morris WJ, Tyldesley S, Pai H, et al. Low-dose-rate brachytherapy is superior to dose-escalated EBRT for unfavorable risk prostate cancer: The results of the ASCENDE-RT* randomized control trial. Brachytherapy 2015;14(Suppl. 1):S12. 6. Morris WJ, Pickles T, Keyes M, et al. Pride or prejudice: Does Phoenix flatter radiation therapy? Brachytherapy 2014;13:299-303. 7. Rodda S, Tyldesley S, Keyes M, et al. Low-dose-rate brachytherapy is superior to dose-escalated EBRT for unfavorable risk prostate cancer: The results of the ASCENDE-RT* randomized control trial. Int J Radiat Oncol Biol Phys 2015;93(3 Suppl. ):E191-E192. 8. Lo AC, Morris WJ, Lapointe V, et al. Prostate-specific antigen at 4 to 5 years after low-dose-rate prostate brachytherapy is a strong predictor of disease-free survival. Int J Radiat Oncol Biol Phys 2014;88:87-93.
In Reply to Morris and Tyldesley To the Editor: We thank Drs Morris and Tyldesley for pointing out our error in reporting the results of the ASCENDE-RT trial (1, 2). When reading the abstract (3) we were mistaken in reading the “Results” section. Specifically, the results reporting begins with reference to biochemical failure scored via the Phoenix definition (4) and then proceeds to report specific percentages using a 0.2-ng/mL threshold definition. We made an error in assuming that the entire reporting of biochemical results was according to the definition mentioned in the initial sentences. The 10-year biochemical failure results Drs Morris and Tyldesley report in their letter according to the Phoenix definition are indeed superior to the 10-year biochemical failure rates in all of the modalities in our article. Our reason for making the comparison was not to deride the results of the authors’ ground-breaking trial but to point
Conflict of interest: J.P.C. serves as Senior Editor of the GU Section and C.A.R. serves as Statistical Editor of the International Journal of Radiation Oncology Biology Physics.
International Journal of Radiation Oncology Biology Physics
out the extreme difficulties in using biochemical failure as an endpoint for a clinical trial. The specific problems associated with biochemical failure as a robust endpoint have been discussed in the literature in great detail, and a complete exposition of these shortcomings is beyond the scope of this letter; however, in reporting the proceedings of the conference that helped promote the Phoenix definition, the attendees provide an excellent review of the issues (4). The confounding effects of a variety of factors, including androgen deprivation therapy, intensity of followup, and the specifics (timing) of applying a threshold definition are in play. Underscoring the last point regarding the application of a threshold definition to patients treated with radiation is our experience in trying to apply the authors’ threshold of 0.2 ng/mL to our patients. Upon realizing our error, we wanted to provide the literature with comparative biochemical failure data to reiterate the superiority of the authors’ biochemical failure results. We were confused as to when to apply the threshold. For instance, looking only at our first posttherapy prostate-specific antigen (PSA) value, 44.4% were biochemically free of recurrence. If one scores all PSA values after therapy, 41.8% were biochemically free of recurrence. To summarize our application of the 0.2 ng/mL threshold to our brachytherapy dataset: 168 patients (36.6%) have a PSA >0.2 ng/mL at first posttreatment PSA and never reach a PSA value 0.2 ng/mL 87 patients (19.0%) have a PSA >0.2 ng/mL at first posttreatment PSA and later have a PSA value 0.2 ng/mL 99 patients (21.6%) have PSA 0.2 ng/mL at first posttreatment PSA and later have a PSA value >0.2 ng/mL 105 patients (22.8%) have PSA 0.2 ng/mL at first posttreatment PSA and continue to have a PSA value 0.2 ng/mL The challenge is figuring out the timing of when the PSA rose above 0.2 ng/mL and the timing of when the PSAs >0.2 ng/mL fell below 0.2 ng/mL and had to be “unfailed” (if this is in fact done using the authors’ definition). Perhaps because of the use of androgen deprivation therapy for 12 months in the authors’ trial they did not encounter these problems and their patients’ PSA profile behaved more like a surgical cohort in which one expects a low/undetectable PSA soon after therapy, and any subsequent rise above a predefined threshold becomes a scorable event. We think that the difficulty we have in reproducing the reporting of biochemical failure using the authors’ definition in our patients emphasizes the importance of reporting research endpoints using standard definitions such as the Phoenix definition, and we thank Drs Morris and Tyldesley for providing these data in their letter. Because of the ambiguities discussed above, the importance of “hard” clinical endpoints is obvious. Multiple reports exist in the literature of superior biochemical outcomes
Volume 99 Number 1 2017
from local intensification efforts that do not translate into “hard” endpoints, such as clinical failure or mortality. One that is most germane to this discussion is a trial comparing external beam radiation plus 192Ir brachytherapy boost versus external beam radiation alone in high-risk prostate cancer (5). Those investigators noted a superiority of the combined-modality arm, with 8.2 years of median follow-up that did not translate into a survival advantage. Recognizing these problems, we elected to not only report biochemical outcomes but also show clinical failure and prostate cancerspecific mortality. We look forward to reading the update of ASCENDE-RT reporting similar “hard” endpoints. Jay P. Ciezki, MD Chandana A. Reddy, MS Department of Radiation Oncology Cleveland Clinic Cleveland, Ohio http://dx.doi.org/10.1016/j.ijrobp.2017.04.028
Comments
243
References 1. Morris WJ, Tyldesley S. The Biochemical Outcomes for the ASCENDE-RT Randomized Controlled Trial and Those Reported from the Cleveland Clinic: In Regard to Ciezki et al. Intl J Radiat Oncol Biol Phys 2017;99:240-242. 2. Ciezki JP, Weller MD, Reddy CA, et al. A comparison between lowdose-rate brachytherapy with or without androgen deprivation , and radical prostatectomy with or without adjuvant or salvage radiation therapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;97:962-975. 3. Rodda SL, Tyldesley S, Keyes M, et al. Low-dose-rate prostate brachytherapy is superior to dose-escalated EBRT for unfavorable risk prostate cancer: The results of the ASCENDE-RT randomized control trial. Int J Radiat Oncol Biol Phys 2015;93:E191-E192. 4. Roach M, Hanks G, Thames H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix consensus conference. Int J Radiat Oncol Biol Phys 2006;65:965-974. 5. Sathya JR, Davis IR, Julian JA, et al. Randomized trial comparing iridium implant plus external-beam radiation therapy with externalbeam radiation therapy alone in node-negative locally advanced cancer of the prostate. J Clin Oncol 2005;23:1192-1199.