- Email: [email protected]
RE: NEOADJUVANT HORMONE THERAPY BEFORE SALVAGE RADIOTHERAPY FOR AN INCREASING POST-RADICAL PROSTATECTOMY SERUM PROSTATE SPECIFIC ANTIGEN LEVEL
LETTERS TO THE EDITOR survival. In the meantime, we and others have found that margin status impacts time to PSA failure, and time to PSA failure is a major predictor of cancer specific survival.6 Thus, we believe that as more investigators examine this issue, it is only a matter of time until the data linking surgical margin status and cancer specific survival exist. In conclusion, our findings suggest that in general, a positive surgical margin affects PSA outcome and should be avoided. However, for patients with high volume disease outcome may not be as dependent on surgical margin status as in low volume disease. Clearly, more studies from other centers with varying patient populations are needed to examine this issue. 1. Kausik, S. J., Blute, M. L., Sebo, T. J., Leibovich, B. C., Bergstralh, E. J., Slezak, J. et al: Prognostic significance of positive surgical margins in patients with extraprostatic carcinoma after radical prostatectomy. Cancer, 95: 1215, 2002 2. Blute, M. L., Bergstralh, E. J., Iocca, A., Scherer, B. and Zincke, H.: Use of Gleason score, prostate specific antigen, seminal vesicle, and margin status to predict biochemical failure after radical prostatectomy. J Urol, 165: 119, 2001 3. Swindle, P., Ohori, M., Kattan, M., Wheeler, T., Slawin, K., Maru, N. et al: Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens—18 year experience. J Urol, suppl., 169: 180, abstract 694, 2003 4. Epstein, J. I., Pizov, G. and Walsh, P. C.: Correlation of pathological findings with progression after radical prostatectomy. Cancer, 71: 3582, 1993 5. D’Amico, A. V., Whittington, R., Malkowitz, S. B., Schultz, D., Schnall, M., Tomaszewski, J. E. et al: A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol, 154: 131, 1995 6. Pound, C. R., Partin, A. W., Eisenberger, M. A., Chan, D. W., Pearson, J. D. and Walsh, P. C.: Natural history of progression after PSA elevation following radical prostatectomy. JAMA, 281: 1591, 1999 DOI: 10.1097/01.ju.0000108381.08334.ac
RE: NEOADJUVANT HORMONE THERAPY BEFORE SALVAGE RADIOTHERAPY FOR AN INCREASING POSTRADICAL PROSTATECTOMY SERUM PROSTATE SPECIFIC ANTIGEN LEVEL R. Tiguert, J. Rigaud, L. Lacombe, J. Laverdie`re and Y. Fradet J Urol, 170: 447– 450, 2003 To the Editor. I read with great interest the report by Tiguert et al on their substantial experience with salvage radiation in patients with biochemical failure following radical prostatectomy. All of their cases matched the temporal criteria of biochemical failure, suggesting future local clinical recurrence, and the majority of cases also satisfied the pathological criteria, facts extremely relevant for correct case selection for salvage radiation.1 However, none of the facts presented in this article sustain the conclusion presented by the authors, that “Neoadjuvant ADT [androgen deprivation therapy] before salvage external beam radiation is effective in eradicating disease in select patients.” The only retrospective study dealing with this subject and cited by the authors when comparing their data with those in the literature was reported by Eulau et al and had a control arm of patients.2 In that study the authors used a supersensitive prostate specific antigen assay when establishing the cutoff value for biochemical failure (0.07 ng/ml). Patients received an average of 6 months of hormone therapy before radiation, and only patients who received hormones for more than a year before radiation were excluded from the study. Consequently, the biochemical relapse rates in patients receiving hormone therapy in these 2 studies are not comparable. The American Society for Therapeutic Radiology and Oncology (ASTRO) panel concluded that there is no statistically significant clinical evidence that proves the role of hormone therapy in the context of post-radical prostatectomy radiation.3 To my knowledge there are no subsequent reports in the urological literature that prove otherwise in a statistically accepted manner. By translational and deductive thinking we can, of course, only assume that the combination of hormones and radiation is more effective than radi-
809
ation alone following radical prostatectomy, as it is in primary definitive treatment for carcinoma of the prostate.4 Respectfully, Endre Z. Neulander Department of Urology Ben Gurion University Beer Sheba, Israel P.O. Box 151, 84101
Reply by Authors. As academic urologists, we are gratified to find that other urologists are reading our work and find it interesting enough to require comment. The letter by Neulander warrants rebuttal, as we believe that he has misinterpreted our data. Neulander proposes that our study data do not support our conclusion that neoadjuvant ADT is beneficial before salvage external beam radiation therapy (EBRT) for patients with biochemical failure following radical prostatectomy for prostate cancer. We disagree. The results of our study are strikingly similar to those of the neoadjuvant ADT group in the retrospective study by Eulau et al.2 In that study 2 months of neoadjuvant followed by 4 months of adjuvant ADT showed a clear benefit when added to salvage EBRT. We acknowledge that our study had a slightly different definition of biochemical relapse than the study by Eulau et al, a fact that reflects the current ambiguity in the urological literature rather than a profound difference in our study populations.5, 6 Regardless of the precise cutoff used, the take home message seems to remain the same—patients with biochemical failure following radical prostatectomy have roughly a 50% 5-year biochemical disease-free survival when treated with salvage EBRT preceded by 3 months of neoadjuvant ADT. These results contrast with those of patients treated with salvage EBRT alone, whose 5-year biochemical disease-free survival rates vary from 10% to 45%.7, 8 Our data also support that initiating treatment before prostate specific antigen reaches 1 ng/ml may result in a higher response rate. Hence, neoadjuvant ADT seems to provide a benefit in select patients treated with salvage EBRT. It is important to mention that 86% of the patients in our study received substandard doses of radiation (less than 64 Gy). As ASTRO currently recommends a minimum of 64 Gy for salvage EBRT, one might speculate that our results will improve as we increase the radiation dose to the prostate bed. Neulander is correct in indicating that an ASTRO consensus panel did not find evidence to support neoadjuvant ADT before salvage EBRT.3 This conference was convened on September 6, 1997, and its report was published in 1999. As such, the panel did not have the opportunity to evaluate the data of Eulau et al and our data before setting out its consensus statement, and was cautious in making recommendations regarding the role of ADT in association with salvage EBRT. We agree that our data do not provide the level of evidence that would be achieved by the results of a randomized trial. However, adding a single 3-month injection of luteinizing hormone releasing hormone agonist before salvage EBRT is not a major inconvenience in view of the potential benefit. 1. Neulander, E. Z. and Soloway, M. S.: Failure after radical prostatectomy. Urology, 61: 30, 2003 2. Eulau, S. M., Tate, D. J., Stamey, T. A., Bagshaw, M. A. and Hancock, S. L.: Effect of combined transient androgen deprivation and irradiation following radical prostatectomy for prostatic cancer. Int J Radiat Oncol Biol Phys, 41: 735, 1998 3. Cox, J. D., Gallagher, M. J., Hammond, E. H., Kaplan, R. S. and Schellhammer, P. F.: Consensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostatespecific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol, 17: 1155, 1999 4. Bolla, M., Collette, L., Blank, L., Warde, P., Dubois, J. B., Mirimanoff, R. O. et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet, 360: 103, 2002 5. Amling, C. L., Bergstralh, E. J., Blute, M. L., Slezak, J. M. and Zincke, H.: Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol, 165: 1146, 2001 6. Freedland, S. J., Sutter, M. E., Dorey, F. and Aronson, W. J.:
RE: NEOADJUVANT HORMONE THERAPY BEFORE SALVAGE RADIOTHERAPY FOR AN INCREASING POSTRADICAL PROSTATECTOMY SERUM PROSTATE SPECIFIC ANTIGEN LEVEL R. Tiguert, J. Rigaud, L. Lacombe, J. Laverdie`re and Y. Fradet J Urol, 170: 447– 450, 2003 To the Editor. I read with great interest the report by Tiguert et al on their substantial experience with salvage radiation in patients with biochemical failure following radical prostatectomy. All of their cases matched the temporal criteria of biochemical failure, suggesting future local clinical recurrence, and the majority of cases also satisfied the pathological criteria, facts extremely relevant for correct case selection for salvage radiation.1 However, none of the facts presented in this article sustain the conclusion presented by the authors, that “Neoadjuvant ADT [androgen deprivation therapy] before salvage external beam radiation is effective in eradicating disease in select patients.” The only retrospective study dealing with this subject and cited by the authors when comparing their data with those in the literature was reported by Eulau et al and had a control arm of patients.2 In that study the authors used a supersensitive prostate specific antigen assay when establishing the cutoff value for biochemical failure (0.07 ng/ml). Patients received an average of 6 months of hormone therapy before radiation, and only patients who received hormones for more than a year before radiation were excluded from the study. Consequently, the biochemical relapse rates in patients receiving hormone therapy in these 2 studies are not comparable. The American Society for Therapeutic Radiology and Oncology (ASTRO) panel concluded that there is no statistically significant clinical evidence that proves the role of hormone therapy in the context of post-radical prostatectomy radiation.3 To my knowledge there are no subsequent reports in the urological literature that prove otherwise in a statistically accepted manner. By translational and deductive thinking we can, of course, only assume that the combination of hormones and radiation is more effective than radi-
809
ation alone following radical prostatectomy, as it is in primary definitive treatment for carcinoma of the prostate.4 Respectfully, Endre Z. Neulander Department of Urology Ben Gurion University Beer Sheba, Israel P.O. Box 151, 84101
Reply by Authors. As academic urologists, we are gratified to find that other urologists are reading our work and find it interesting enough to require comment. The letter by Neulander warrants rebuttal, as we believe that he has misinterpreted our data. Neulander proposes that our study data do not support our conclusion that neoadjuvant ADT is beneficial before salvage external beam radiation therapy (EBRT) for patients with biochemical failure following radical prostatectomy for prostate cancer. We disagree. The results of our study are strikingly similar to those of the neoadjuvant ADT group in the retrospective study by Eulau et al.2 In that study 2 months of neoadjuvant followed by 4 months of adjuvant ADT showed a clear benefit when added to salvage EBRT. We acknowledge that our study had a slightly different definition of biochemical relapse than the study by Eulau et al, a fact that reflects the current ambiguity in the urological literature rather than a profound difference in our study populations.5, 6 Regardless of the precise cutoff used, the take home message seems to remain the same—patients with biochemical failure following radical prostatectomy have roughly a 50% 5-year biochemical disease-free survival when treated with salvage EBRT preceded by 3 months of neoadjuvant ADT. These results contrast with those of patients treated with salvage EBRT alone, whose 5-year biochemical disease-free survival rates vary from 10% to 45%.7, 8 Our data also support that initiating treatment before prostate specific antigen reaches 1 ng/ml may result in a higher response rate. Hence, neoadjuvant ADT seems to provide a benefit in select patients treated with salvage EBRT. It is important to mention that 86% of the patients in our study received substandard doses of radiation (less than 64 Gy). As ASTRO currently recommends a minimum of 64 Gy for salvage EBRT, one might speculate that our results will improve as we increase the radiation dose to the prostate bed. Neulander is correct in indicating that an ASTRO consensus panel did not find evidence to support neoadjuvant ADT before salvage EBRT.3 This conference was convened on September 6, 1997, and its report was published in 1999. As such, the panel did not have the opportunity to evaluate the data of Eulau et al and our data before setting out its consensus statement, and was cautious in making recommendations regarding the role of ADT in association with salvage EBRT. We agree that our data do not provide the level of evidence that would be achieved by the results of a randomized trial. However, adding a single 3-month injection of luteinizing hormone releasing hormone agonist before salvage EBRT is not a major inconvenience in view of the potential benefit. 1. Neulander, E. Z. and Soloway, M. S.: Failure after radical prostatectomy. Urology, 61: 30, 2003 2. Eulau, S. M., Tate, D. J., Stamey, T. A., Bagshaw, M. A. and Hancock, S. L.: Effect of combined transient androgen deprivation and irradiation following radical prostatectomy for prostatic cancer. Int J Radiat Oncol Biol Phys, 41: 735, 1998 3. Cox, J. D., Gallagher, M. J., Hammond, E. H., Kaplan, R. S. and Schellhammer, P. F.: Consensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostatespecific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol, 17: 1155, 1999 4. Bolla, M., Collette, L., Blank, L., Warde, P., Dubois, J. B., Mirimanoff, R. O. et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet, 360: 103, 2002 5. Amling, C. L., Bergstralh, E. J., Blute, M. L., Slezak, J. M. and Zincke, H.: Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol, 165: 1146, 2001 6. Freedland, S. J., Sutter, M. E., Dorey, F. and Aronson, W. J.: