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Re: Clinical significance of the positive surgical margin based upon location, grade and stage
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Letters to the Editor / Urologic Oncology: Seminars and Original Investigations 29 (2011) 115–117
[5] Van der Kwast TH, Bolla M, Van Poppel H, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25: 4178 – 86. [6] Thompson IM, Tangen CM, Klein EA. Is there a standard of care for pathologic stage T3 prostate cancer? J Clin Oncol 2009;27:2898 –9. [7] Trabulsi EJ, Valicenti RK, Hanlon AL, et al. A multi-institutional matched-control analysis of adjuvant and salvage postoperative radiation therapy for pT3-4N0 prostate cancer. Urology 2008;72:1298 –302; discussion 1302– 4. [8] Abramowitz MC, Pollack A. Post-prostatectomy radiation therapy for prostate cancer. Semin Radiat Oncol 2008;18:15–22.
Re: Clinical significance of the positive surgical margin based upon location, grade and stage To the Editor: We appreciate the insightful discussion by Azmi and O’Neill. However, some of their contentions are a matter of opinion and interpretation of the available evidence. These authors have correctly identified the 3 randomized trials analyzing the outcomes of adjuvant radiotherapy (RT) after radical prostatectomy and emphasized the survival benefit identified in the SWOG trial for those with pT3 prostate cancer or positive surgical margins [1]. One major issue with the SWOG study was the analysis of positive margins and extracapsular extension as a combined group. Clearly, this is a heterogeneous group so that conclusions regarding survival outcome with respect to positive margin status are limited. Nonetheless, we agree that a positive surgical margin is a predictive factor for better adjuvant RT outcome based on EORTC data [2]. With regard to the site of margin positivity Azmi and O’Neill have identified, a few important citations that contest our opinion that site of positive surgical margin can be a selective indicator of need for adjuvant RT. Indeed, van der Kwast and colleagues showed that even apical margin positivity derives benefit from adjuvant RT [2]. However, we still feel for the reasons stated in our review (trauma, electrocautery artifacts) that apical and anterior margins are less worrisome than other areas due to the difficult interpretation of these areas by pathologists. In the EORTC study by van der Kwast and colleagues, all specimens were read by one of the most experienced uropathologists with intimate knowledge of the shortcomings of anterior/apical margins and thus the results may not be generalized to all pathology practices. The issue of salvage RT is controversial. We do not state that this is a “safe default,” but rather an option that balances the possibility of never requiring RT with low level evidence of efficacy when used for failures of observation post-radical prostatectomy. Adjuvant RT for all patients with a positive margin as advocated by Azmi and O’Neill is overtreatment since biochemical relapse is prevented at 5 years in only 299 of 1,000 patients [2]. The adverse effects of adjuvant RT, while low, are not unde-
tectable in the 3 adjuvant trial and should still be a consideration when recommending adjuvant RT. Another important consideration is the fact that 11% of men in the EORTC and 34% of men in the SWOG trials they cite as evidence in favor of adjuvant RT had a postoperative PSA ⬎ 0.2 ng/ml prior to randomization such that any treatment in this subgroup would in fact be considered salvage and not adjuvant. In addition, a large proportion of patients from the non-adjuvant arms in both trials did not receive salvage radiation for biochemical recurrence and thus these trials do not definitively assess whether adjuvant RT is superior to salvage. D’Amico at el. have recently shown that in patients with a positive margin or pT3 disease, a Gleason score of ⱕ7 and a PSA doubling time ⱖ10 months, there was no difference in all-cause mortality between those who had adjuvant versus salvage radiotherapy [3]. The issue of when to start salvage RT is not resolved and, in our opinion, the majority of evidence suggests to start when the PSA is in the range of 0.4 –1.0 ng/ml. This is well reviewed in the European Association of Urology guidelines 2010 (www.uroweb.org?id⫽218&gid⫽3). Starting at 0.1– 0.2 ng/ml is not unreasonable, though some may argue that benign tissue could be causing a low lingering PSA, in which case waiting for an increase to a higher PSA would be more suggestive of cancer recurrence. Overall, management of positive margins after radical prostatectomy requires an individualized approach and the recommendations in our review are a rough guideline. We outlined those patients we feel require an immediate radiation oncology referral. In spite of the discussion by Azmi and O’Neill, we do not agree that all lower risk patients (pT2 or pT3a with a focal margin positive and undetectable postoperative PSA) require a multidisciplinary review. This should be left to the urologist’s discretion. The best upcoming evidence to discern whether adjuvant RT outperforms salvage RT will be available with the Radiation and Androgen Deprivation in Combination After Local Surgery (RADICALS) randomized control trial comparing these 2 management strategies [4]. Until these results are reported, there can be no certainty regarding superiority of adjuvant or salvage RT for positive margins or extracapsular extension in prostate cancer. Greg Trottier Neil E. Fleshner Princess Margaret Hospital University of Toronto Toronto, Ontario, Canada
References [1] Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of
Letters to the Editor / Urologic Oncology: Seminars and Original Investigations 29 (2011) 115–117 metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009;181:956 – 62. [2] Van der Kwast TH, Bolla M, Van Poppel H, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25: 4178 – 86.
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[3] D’Amico AV, Chen MH, Sun L, et al. Adjuvant vs. salvage radiation therapy for prostate cancer and the risk of death. BJU Int 2010 Jun 14 [Epub ahead of print]. [4] Parker C, Clarke N, Logue J, et al. RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery). Clin Oncol (R Coll Radiol) 2007;19:167–71.
Letters to the Editor / Urologic Oncology: Seminars and Original Investigations 29 (2011) 115–117
[5] Van der Kwast TH, Bolla M, Van Poppel H, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25: 4178 – 86. [6] Thompson IM, Tangen CM, Klein EA. Is there a standard of care for pathologic stage T3 prostate cancer? J Clin Oncol 2009;27:2898 –9. [7] Trabulsi EJ, Valicenti RK, Hanlon AL, et al. A multi-institutional matched-control analysis of adjuvant and salvage postoperative radiation therapy for pT3-4N0 prostate cancer. Urology 2008;72:1298 –302; discussion 1302– 4. [8] Abramowitz MC, Pollack A. Post-prostatectomy radiation therapy for prostate cancer. Semin Radiat Oncol 2008;18:15–22.
Re: Clinical significance of the positive surgical margin based upon location, grade and stage To the Editor: We appreciate the insightful discussion by Azmi and O’Neill. However, some of their contentions are a matter of opinion and interpretation of the available evidence. These authors have correctly identified the 3 randomized trials analyzing the outcomes of adjuvant radiotherapy (RT) after radical prostatectomy and emphasized the survival benefit identified in the SWOG trial for those with pT3 prostate cancer or positive surgical margins [1]. One major issue with the SWOG study was the analysis of positive margins and extracapsular extension as a combined group. Clearly, this is a heterogeneous group so that conclusions regarding survival outcome with respect to positive margin status are limited. Nonetheless, we agree that a positive surgical margin is a predictive factor for better adjuvant RT outcome based on EORTC data [2]. With regard to the site of margin positivity Azmi and O’Neill have identified, a few important citations that contest our opinion that site of positive surgical margin can be a selective indicator of need for adjuvant RT. Indeed, van der Kwast and colleagues showed that even apical margin positivity derives benefit from adjuvant RT [2]. However, we still feel for the reasons stated in our review (trauma, electrocautery artifacts) that apical and anterior margins are less worrisome than other areas due to the difficult interpretation of these areas by pathologists. In the EORTC study by van der Kwast and colleagues, all specimens were read by one of the most experienced uropathologists with intimate knowledge of the shortcomings of anterior/apical margins and thus the results may not be generalized to all pathology practices. The issue of salvage RT is controversial. We do not state that this is a “safe default,” but rather an option that balances the possibility of never requiring RT with low level evidence of efficacy when used for failures of observation post-radical prostatectomy. Adjuvant RT for all patients with a positive margin as advocated by Azmi and O’Neill is overtreatment since biochemical relapse is prevented at 5 years in only 299 of 1,000 patients [2]. The adverse effects of adjuvant RT, while low, are not unde-
tectable in the 3 adjuvant trial and should still be a consideration when recommending adjuvant RT. Another important consideration is the fact that 11% of men in the EORTC and 34% of men in the SWOG trials they cite as evidence in favor of adjuvant RT had a postoperative PSA ⬎ 0.2 ng/ml prior to randomization such that any treatment in this subgroup would in fact be considered salvage and not adjuvant. In addition, a large proportion of patients from the non-adjuvant arms in both trials did not receive salvage radiation for biochemical recurrence and thus these trials do not definitively assess whether adjuvant RT is superior to salvage. D’Amico at el. have recently shown that in patients with a positive margin or pT3 disease, a Gleason score of ⱕ7 and a PSA doubling time ⱖ10 months, there was no difference in all-cause mortality between those who had adjuvant versus salvage radiotherapy [3]. The issue of when to start salvage RT is not resolved and, in our opinion, the majority of evidence suggests to start when the PSA is in the range of 0.4 –1.0 ng/ml. This is well reviewed in the European Association of Urology guidelines 2010 (www.uroweb.org?id⫽218&gid⫽3). Starting at 0.1– 0.2 ng/ml is not unreasonable, though some may argue that benign tissue could be causing a low lingering PSA, in which case waiting for an increase to a higher PSA would be more suggestive of cancer recurrence. Overall, management of positive margins after radical prostatectomy requires an individualized approach and the recommendations in our review are a rough guideline. We outlined those patients we feel require an immediate radiation oncology referral. In spite of the discussion by Azmi and O’Neill, we do not agree that all lower risk patients (pT2 or pT3a with a focal margin positive and undetectable postoperative PSA) require a multidisciplinary review. This should be left to the urologist’s discretion. The best upcoming evidence to discern whether adjuvant RT outperforms salvage RT will be available with the Radiation and Androgen Deprivation in Combination After Local Surgery (RADICALS) randomized control trial comparing these 2 management strategies [4]. Until these results are reported, there can be no certainty regarding superiority of adjuvant or salvage RT for positive margins or extracapsular extension in prostate cancer. Greg Trottier Neil E. Fleshner Princess Margaret Hospital University of Toronto Toronto, Ontario, Canada
References [1] Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of
Letters to the Editor / Urologic Oncology: Seminars and Original Investigations 29 (2011) 115–117 metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009;181:956 – 62. [2] Van der Kwast TH, Bolla M, Van Poppel H, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25: 4178 – 86.
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[3] D’Amico AV, Chen MH, Sun L, et al. Adjuvant vs. salvage radiation therapy for prostate cancer and the risk of death. BJU Int 2010 Jun 14 [Epub ahead of print]. [4] Parker C, Clarke N, Logue J, et al. RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery). Clin Oncol (R Coll Radiol) 2007;19:167–71.