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pT3 Prostate Cancer: The Case for Salvage (as Opposed to Adjuvant) Radiation Therapy
european urology supplements 6 (2007) 521–524
available at www.sciencedirect.com journal homepage: www.europeanurology.com
pT3 Prostate Cancer: The Case for Salvage (as Opposed to Adjuvant) Radiation Therapy Laurent Boccon-Gibod Department of Urology, CHU BICHAT, Paris, France
Article info
Abstract
Keywords: Adjuvant Prostate cancer Radiation therapy Treatment
Objectives: It is unclear as yet whether or not adjuvant treatment for radical prostatectomy achieves better oncologic results than early salvage treatment. Methods: Three recently published randomized clinical trials have shown that adjuvant radiation therapy (ART) for pT3 prostate cancer with or without positive surgical margins (PSMs) and seminal vesicle invasion (SVI) is associated with a 25–30% improvement in biochemical and clinical relapse-free survival; however, this was not translated into a significant improvement in metastatic-free and overall survival. Results: Recent studies have shown that salvage radiation therapy (SRT) given at very low levels of prostate-specific antigen (0.5–1 ng/ml) is probably as efficient as adjuvant radiation therapy given to everyone in terms of biochemical-free survival. Conclusions: A plea is made for a more selective and individualized use of radiation therapy in prostate cancer patients with pT3 disease.
Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
# 2007 Published by Elsevier B.V. on behalf of European Association of Urology. E-mail address: [email protected].
1.
Introduction
The adequate timing of radiation therapy for patients with prostate cancer with stage pT3 positive surgical margins (PSMs) at radical prostatectomy (RP) has been a long-lasting debate between the proponents of adjuvant radiation therapy (ART) in which the treatment is given on the basis of pathologic findings, and those of salvage radiation therapy (SRT), in which the treatment is given at biochemical or clinical relapse. The arguments in favor of one or the other attitude were of limited strength because they relied on nonrandomized, retrospective studies based on heterogenous patient populations.
The scene dramatically changed in 2005 when three adequately powered, randomized clinical trials [1–3] demonstrated without any ambiguity that in the presence of extracapsular extension (ECE) with or without PSMs or seminal vesical invasion (SVI) ART was significantly better than observation with delayed treatment as far as biochemical (74% vs. 52.6%, 61% vs. 38%, and 81% vs. 50%) and clinical (85% vs. 75.5%, 84% vs. 69%, 81% vs. 60%) progression-free survival were concerned; consequently, ART is about to be considered as the standard of care for prostate cancer patients with pT3/SVI/PSMs. How then can one be presumptuous enough to argue a case apparently closed on the basis of evidence-based medicine and to make a plea for
1569-9056/$ – see front matter # 2007 Published by Elsevier B.V. on behalf of European Association of Urology.
doi:10.1016/j.eursup.2007.01.026
522
european urology supplements 6 (2007) 521–524
with SVI and negative surgical margins may experience a 40% 5-yr biochemical relapse-free survival [6,7].
SRT? Indeed, a closer look at the three different papers points to issues that tend to weaken their case: The patient population is heterogenous in the European Organization for Research and Treatment of Cancer (EORTC) [1] as well as in the Southwest Oncology Group (SWOG) [2] trials not only regarding the pathologic stage (in the EORTC study 16% were pT2 with PSMs and 26% had ECE without PSMs or SVI), but, more importantly, in the prostate-specific antigen (PSA) level at entry, 12% and 35% had a detectable PSA after radical prostatectomy (RP) so that, by definition, the treatment should be considered more as a salvage therapy for residual disease that as adjuvant treatment. The type and timing of the treatment in the observation arms of the three trials were not defined nor documented so that none of these trials was able to compare ART to SRT given at the first sign of relapse characterized by a detectable serum PSA level. Finally, an important finding of the SWOG trial was that ART, although undoubtedly beneficial in terms of biochemical and clinical relapse-free survival, had no significant impact on metastasisfree survival and overall survival. Therefore, one may argue for a more selective use of radiation therapy for patients with pT3 prostate cancer based on (1) the natural history of the disease, (2) the real documented benefits of ART, (3) the efficacy of SRT as documented in the literature, and (4) the complications associated with the use of radiation therapy after RP and their impact on quality of life.
Therefore, in a significant proportion, probably around 50%, of patients, ART is undoubtedly overtreatment, exposing these men to potentially significant side effects.
3. What is the real benefit of adjuvant radiation therapy: does it prolong metastatic-free and overall survival? Systematic adjuvant treatment is accepted in other tumor models such a cytotoxic chemotherapy in breast cancer because it offers a significant even if small benefit in overall survival. This is not yet the case for ART after RP. Undoubtedly, ART does prolong biochemical and clinical control and this may translate into a gain in metastatic-free and overall survival, but this has not yet be shown to be the case, demonstrating once again that PSA failure per se is not a solid surrogate end point. Indeed, the SWOG trial [2] has not been able to demonstrate that improvement in biochemical and clinical control and even delay in introduction of hormone therapy did translate into a benefit in overall and metastaticfree survival. Furthermore, the natural history of PSA relapse may be long and protracted when it is associated with good prognostic features, such as a long PSA doubling time, so that many patients suffering from PSA relapse indeed may well die with rather than from their recurrent prostate cancer [8].
4. 2. The natural history of pT3 prostate cancer: does everyone need adjuvant therapy? Several recent studies have shown that not every patient with T3 prostate cancer is doomed to fail by PSA. In the observation arms of the three randomized clinical trials, 56%, 38%, and 60% of the patients were free of PSA relapse at 5 yr. Two recently published series have shown that (1) patients with ECE and negative surgical margins have a 75% biochemical-free relapse rate at 10 yr [4] and (2) patients with positive margins still enjoy a 75% biochemical relapse-free survival at 10 yr irrespective of the character of the margins, whether focal or extensive [4,5] and even patients
Is SRT really inferior to ART?
The driving force behind ART has undoubtedly been the poor results achieved in historical series using SRT for significant relapsing PSA levels or documented clinical failures [8–11]. In these cases, occult metastatic disease stemming from poor control of local residual/recurrent tumor was probably present explaining a relapse-free rate as low as 35% and giving strength to the argument of immediate treatment to treat residual disease at it lowest possible volume. However, recent prospective, albeit nonrandomized, studies have shown that when radiation therapy is started when the PSA is <1 ng/ml, there is no difference in outcome between salvage and radiation therapy, so that patients with pT3 < B, Gleason < 8, and PSA before radiation therapy <1 ng/ml have a 50% biochemical-free relapse rate
european urology supplements 6 (2007) 521–524
at 10 yr after SRT [12,13]. Because it is now possible to monitor patients using ultrasensitive PSA assays, biochemical failure can be detected much earlier than previously and consequently the treatment can be implemented at the first sign of PSA relapse.
5. Is ART devoid of side effects and impact on quality of life? Although, the EORTC and SWOG studies demonstrated a low rate of grade 3 toxicity and apparently no difference in quality of life in both groups [1,2] with a grade 3 toxicity as low as 4.2%, it is worth mentioning that in the SWOG trial [2], rectal proctitis and bleeding occurred in 3.2% of the patients and that the rates of urethral stricture and total urinary incontinence were, respectively, 17% and 6.5%, inducing obviously a significant impact on quality of life considering the difficulties related to the treatment of these conditions after radiation therapy.
6. The plea for an individualized use of radiation therapy in patients with pT3 prostate cancer Considering that ART has not been shown (yet) to prolong metastatic-free or overall survival, and that it may induce rare but significant side effects, one may argue for a more selective approach based on PSA monitoring using ultrasensitive assays done in the same laboratory by the same method, so as to treat only those patients who demonstrate a PSA relapse and to treat them early at a time when radiation therapy has been demonstrated to be extremely efficient, that is, before the PSA reaches 1 ng/ml and probably 0.5 ng/ml. In this setting, patients with good prognostic factors (pT3 < B, Gleason < 8, PSA < 1 ng/ml before radiation therapy) have a 15-yr 50% relapse-free survival. Patients not meeting these criteria have a much less favorable outcome and should definitely be entered into a randomized clinical trial studying the efficacy of other forms of systemic therapy.
7.
Conclusion
To conclude: one may assume [7] the following: The probability of an 8-yr PSA relapse-free survival is 70% with immediate ART after RP.
523
40% of the patients with pT3 prostate cancer will be relapse free at 8 yr. Of the remaining 60% who will fail by PSA, 50% will be rendered disease free with SRT. In this setting, the proportion of patients who would remain disease free at 8 yr is 40% + (60% 0.5) = 70%; therefore, there is probably no huge difference between the two strategies, that is, one of ART for everyone and one of tailored individualized SRT at PSA relapse. However, this important question can be answered only by a prospective, randomized clinical trial.
References [1] Bolla M, Van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomized controlled trial (EORTC trial 22911). Lancet 2005;366: 572–8. [2] Thompson IM, Tanger CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer, a randomized clinical trial. JAMA 2006;296:2329–35. [3] Wiegel T, Bohke D, Willich N. Phase III results of adjuvant radiotherapy versus ‘‘wait and see’’ in patients with pT3 prostate cancer following radical prostatectomy (ARO 9202/AUO AP 0995). J Clin Oncol 2005;23:165 (abstract no. 3815). [4] Swindle P, Eastham JA, Ohori M, et al. Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 2005;174:903–7. [5] Vis AN, Schroder FH, Van Der Kwast T. The actual value of the surgical margin status ad a predictor of disease progression in men with early prostate cancer. Eur Urol 2006;50:258–65. [6] Materson TA, Pettus JA, Middelton RG, Stephenson RA. Isolated seminal vesicle invasion imparts better outcomes after radical retropubic prostatectomy for clinically localized prostate cancer: prognostic stratification of pT3B disease by nodal and margin status. Urology 2005; 152–5. [7] Eggener SE, Roehl KA, Smith ND, et al. Contemporary survival results and the role of radiation therapy in patients with node negative seminal vesicle invasion following radical prostatectomy. J Urol 2005;173:1150–5. [8] Choo R, Kawakami J, Siemens R, et al. Two different perspectives in the management of pT3 and/or margin-positive prostate cancer after radical prostatectomy. BJU Int 2006;98:773–6. [9] Stephenson A, Shariat SF, Zelewsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004;291:1325–32. [10] Vargas C, Kestin LL, Weed DW, et al. Improved biochemical outcome with adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features. Int J Rad Oncol Bio Phys 2005;61: 714–24.
524
european urology supplements 6 (2007) 521–524
[11] Teh BS, Bastasch MD, Mai WY, et al. Long term benefits of elective radiotherapy after prostatectomy for patients with positive surgical margins. J Urol 2006;175:2097–102. [12] Hagan M, Zlotecki R, Medina C, et al. Comparison of adjuvant versus salvage radiotherapy policies for postprostatectomy radiotherapy. Int J Rad Oncol Biol Phys 2004;59:329–40.
[13] Buskirk SJ, Pisansky TM, Schild SE, et al. Salvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: evaluation of prognostic factors and creation of a prognostic scoring system. J Urol 2006;176:985–90.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
pT3 Prostate Cancer: The Case for Salvage (as Opposed to Adjuvant) Radiation Therapy Laurent Boccon-Gibod Department of Urology, CHU BICHAT, Paris, France
Article info
Abstract
Keywords: Adjuvant Prostate cancer Radiation therapy Treatment
Objectives: It is unclear as yet whether or not adjuvant treatment for radical prostatectomy achieves better oncologic results than early salvage treatment. Methods: Three recently published randomized clinical trials have shown that adjuvant radiation therapy (ART) for pT3 prostate cancer with or without positive surgical margins (PSMs) and seminal vesicle invasion (SVI) is associated with a 25–30% improvement in biochemical and clinical relapse-free survival; however, this was not translated into a significant improvement in metastatic-free and overall survival. Results: Recent studies have shown that salvage radiation therapy (SRT) given at very low levels of prostate-specific antigen (0.5–1 ng/ml) is probably as efficient as adjuvant radiation therapy given to everyone in terms of biochemical-free survival. Conclusions: A plea is made for a more selective and individualized use of radiation therapy in prostate cancer patients with pT3 disease.
Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
# 2007 Published by Elsevier B.V. on behalf of European Association of Urology. E-mail address: [email protected].
1.
Introduction
The adequate timing of radiation therapy for patients with prostate cancer with stage pT3 positive surgical margins (PSMs) at radical prostatectomy (RP) has been a long-lasting debate between the proponents of adjuvant radiation therapy (ART) in which the treatment is given on the basis of pathologic findings, and those of salvage radiation therapy (SRT), in which the treatment is given at biochemical or clinical relapse. The arguments in favor of one or the other attitude were of limited strength because they relied on nonrandomized, retrospective studies based on heterogenous patient populations.
The scene dramatically changed in 2005 when three adequately powered, randomized clinical trials [1–3] demonstrated without any ambiguity that in the presence of extracapsular extension (ECE) with or without PSMs or seminal vesical invasion (SVI) ART was significantly better than observation with delayed treatment as far as biochemical (74% vs. 52.6%, 61% vs. 38%, and 81% vs. 50%) and clinical (85% vs. 75.5%, 84% vs. 69%, 81% vs. 60%) progression-free survival were concerned; consequently, ART is about to be considered as the standard of care for prostate cancer patients with pT3/SVI/PSMs. How then can one be presumptuous enough to argue a case apparently closed on the basis of evidence-based medicine and to make a plea for
1569-9056/$ – see front matter # 2007 Published by Elsevier B.V. on behalf of European Association of Urology.
doi:10.1016/j.eursup.2007.01.026
522
european urology supplements 6 (2007) 521–524
with SVI and negative surgical margins may experience a 40% 5-yr biochemical relapse-free survival [6,7].
SRT? Indeed, a closer look at the three different papers points to issues that tend to weaken their case: The patient population is heterogenous in the European Organization for Research and Treatment of Cancer (EORTC) [1] as well as in the Southwest Oncology Group (SWOG) [2] trials not only regarding the pathologic stage (in the EORTC study 16% were pT2 with PSMs and 26% had ECE without PSMs or SVI), but, more importantly, in the prostate-specific antigen (PSA) level at entry, 12% and 35% had a detectable PSA after radical prostatectomy (RP) so that, by definition, the treatment should be considered more as a salvage therapy for residual disease that as adjuvant treatment. The type and timing of the treatment in the observation arms of the three trials were not defined nor documented so that none of these trials was able to compare ART to SRT given at the first sign of relapse characterized by a detectable serum PSA level. Finally, an important finding of the SWOG trial was that ART, although undoubtedly beneficial in terms of biochemical and clinical relapse-free survival, had no significant impact on metastasisfree survival and overall survival. Therefore, one may argue for a more selective use of radiation therapy for patients with pT3 prostate cancer based on (1) the natural history of the disease, (2) the real documented benefits of ART, (3) the efficacy of SRT as documented in the literature, and (4) the complications associated with the use of radiation therapy after RP and their impact on quality of life.
Therefore, in a significant proportion, probably around 50%, of patients, ART is undoubtedly overtreatment, exposing these men to potentially significant side effects.
3. What is the real benefit of adjuvant radiation therapy: does it prolong metastatic-free and overall survival? Systematic adjuvant treatment is accepted in other tumor models such a cytotoxic chemotherapy in breast cancer because it offers a significant even if small benefit in overall survival. This is not yet the case for ART after RP. Undoubtedly, ART does prolong biochemical and clinical control and this may translate into a gain in metastatic-free and overall survival, but this has not yet be shown to be the case, demonstrating once again that PSA failure per se is not a solid surrogate end point. Indeed, the SWOG trial [2] has not been able to demonstrate that improvement in biochemical and clinical control and even delay in introduction of hormone therapy did translate into a benefit in overall and metastaticfree survival. Furthermore, the natural history of PSA relapse may be long and protracted when it is associated with good prognostic features, such as a long PSA doubling time, so that many patients suffering from PSA relapse indeed may well die with rather than from their recurrent prostate cancer [8].
4. 2. The natural history of pT3 prostate cancer: does everyone need adjuvant therapy? Several recent studies have shown that not every patient with T3 prostate cancer is doomed to fail by PSA. In the observation arms of the three randomized clinical trials, 56%, 38%, and 60% of the patients were free of PSA relapse at 5 yr. Two recently published series have shown that (1) patients with ECE and negative surgical margins have a 75% biochemical-free relapse rate at 10 yr [4] and (2) patients with positive margins still enjoy a 75% biochemical relapse-free survival at 10 yr irrespective of the character of the margins, whether focal or extensive [4,5] and even patients
Is SRT really inferior to ART?
The driving force behind ART has undoubtedly been the poor results achieved in historical series using SRT for significant relapsing PSA levels or documented clinical failures [8–11]. In these cases, occult metastatic disease stemming from poor control of local residual/recurrent tumor was probably present explaining a relapse-free rate as low as 35% and giving strength to the argument of immediate treatment to treat residual disease at it lowest possible volume. However, recent prospective, albeit nonrandomized, studies have shown that when radiation therapy is started when the PSA is <1 ng/ml, there is no difference in outcome between salvage and radiation therapy, so that patients with pT3 < B, Gleason < 8, and PSA before radiation therapy <1 ng/ml have a 50% biochemical-free relapse rate
european urology supplements 6 (2007) 521–524
at 10 yr after SRT [12,13]. Because it is now possible to monitor patients using ultrasensitive PSA assays, biochemical failure can be detected much earlier than previously and consequently the treatment can be implemented at the first sign of PSA relapse.
5. Is ART devoid of side effects and impact on quality of life? Although, the EORTC and SWOG studies demonstrated a low rate of grade 3 toxicity and apparently no difference in quality of life in both groups [1,2] with a grade 3 toxicity as low as 4.2%, it is worth mentioning that in the SWOG trial [2], rectal proctitis and bleeding occurred in 3.2% of the patients and that the rates of urethral stricture and total urinary incontinence were, respectively, 17% and 6.5%, inducing obviously a significant impact on quality of life considering the difficulties related to the treatment of these conditions after radiation therapy.
6. The plea for an individualized use of radiation therapy in patients with pT3 prostate cancer Considering that ART has not been shown (yet) to prolong metastatic-free or overall survival, and that it may induce rare but significant side effects, one may argue for a more selective approach based on PSA monitoring using ultrasensitive assays done in the same laboratory by the same method, so as to treat only those patients who demonstrate a PSA relapse and to treat them early at a time when radiation therapy has been demonstrated to be extremely efficient, that is, before the PSA reaches 1 ng/ml and probably 0.5 ng/ml. In this setting, patients with good prognostic factors (pT3 < B, Gleason < 8, PSA < 1 ng/ml before radiation therapy) have a 15-yr 50% relapse-free survival. Patients not meeting these criteria have a much less favorable outcome and should definitely be entered into a randomized clinical trial studying the efficacy of other forms of systemic therapy.
7.
Conclusion
To conclude: one may assume [7] the following: The probability of an 8-yr PSA relapse-free survival is 70% with immediate ART after RP.
523
40% of the patients with pT3 prostate cancer will be relapse free at 8 yr. Of the remaining 60% who will fail by PSA, 50% will be rendered disease free with SRT. In this setting, the proportion of patients who would remain disease free at 8 yr is 40% + (60% 0.5) = 70%; therefore, there is probably no huge difference between the two strategies, that is, one of ART for everyone and one of tailored individualized SRT at PSA relapse. However, this important question can be answered only by a prospective, randomized clinical trial.
References [1] Bolla M, Van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomized controlled trial (EORTC trial 22911). Lancet 2005;366: 572–8. [2] Thompson IM, Tanger CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer, a randomized clinical trial. JAMA 2006;296:2329–35. [3] Wiegel T, Bohke D, Willich N. Phase III results of adjuvant radiotherapy versus ‘‘wait and see’’ in patients with pT3 prostate cancer following radical prostatectomy (ARO 9202/AUO AP 0995). J Clin Oncol 2005;23:165 (abstract no. 3815). [4] Swindle P, Eastham JA, Ohori M, et al. Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 2005;174:903–7. [5] Vis AN, Schroder FH, Van Der Kwast T. The actual value of the surgical margin status ad a predictor of disease progression in men with early prostate cancer. Eur Urol 2006;50:258–65. [6] Materson TA, Pettus JA, Middelton RG, Stephenson RA. Isolated seminal vesicle invasion imparts better outcomes after radical retropubic prostatectomy for clinically localized prostate cancer: prognostic stratification of pT3B disease by nodal and margin status. Urology 2005; 152–5. [7] Eggener SE, Roehl KA, Smith ND, et al. Contemporary survival results and the role of radiation therapy in patients with node negative seminal vesicle invasion following radical prostatectomy. J Urol 2005;173:1150–5. [8] Choo R, Kawakami J, Siemens R, et al. Two different perspectives in the management of pT3 and/or margin-positive prostate cancer after radical prostatectomy. BJU Int 2006;98:773–6. [9] Stephenson A, Shariat SF, Zelewsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004;291:1325–32. [10] Vargas C, Kestin LL, Weed DW, et al. Improved biochemical outcome with adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features. Int J Rad Oncol Bio Phys 2005;61: 714–24.
524
european urology supplements 6 (2007) 521–524
[11] Teh BS, Bastasch MD, Mai WY, et al. Long term benefits of elective radiotherapy after prostatectomy for patients with positive surgical margins. J Urol 2006;175:2097–102. [12] Hagan M, Zlotecki R, Medina C, et al. Comparison of adjuvant versus salvage radiotherapy policies for postprostatectomy radiotherapy. Int J Rad Oncol Biol Phys 2004;59:329–40.
[13] Buskirk SJ, Pisansky TM, Schild SE, et al. Salvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: evaluation of prognostic factors and creation of a prognostic scoring system. J Urol 2006;176:985–90.