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Salvage Radiotherapy After Prostatectomy: Two Sides of the Coin
EURURO-6731; No. of Pages 2 EUROPEAN UROLOGY XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Salvage Radiotherapy After Prostatectomy: Two Sides of the Coin Daniel E. Spratt * Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
Although well-selected men with high-risk prostate cancer (PCa) can achieve durable disease control after radical prostatectomy (RP) alone, a subset will suffer from biochemical and/or clinical recurrence. Based on the Memorial Sloan Kettering Cancer Center nomogram (https://www.mskcc. org/nomograms/prostate/pre-op), approximately 40–90% of men with high-risk PCa will experience progression within 5 yr after RP. Likewise, a recent multi-institutional analysis of 20 845 men who underwent RP demonstrated that Gleason score 8 and 9–10 tumors had 5-yr biochemical failure rates of 52% and 74%, respectively [1]. Various approaches have been undertaken to improve outcomes for high-risk PCa patients treated with RP. Notably, adjuvant radiotherapy (ART) has been demonstrated in three randomized trials to provide a 50% reduction in the risk of relapse compared with RP alone [2]. This has resulted in the American Urological Association (AUA), the American Society for Radiation Oncology (ASTRO), and the American Society of Clinical Oncology recommending discussion of ART with patients who have adverse pathologic findings (pT3a/T3b disease and positive surgical margins). Unfortunately, <10% of men receive ART [3], and given the high rate of progression after RP monotherapy for men with high-risk PCa, the majority will require subsequent salvage therapies. The most common salvage therapy used after RP is salvage radiotherapy (SRT). Given the lack of level 1 evidence for the benefits of SRT, the fundamental premise for recommending SRT is based on the hypothesis that the persistent prostate-specific antigen (PSA)– producing PCa cells are contained within the prostatic bed where SRT is targeted. This appears to be largely accurate, especially for men with favorable disease
characteristics, for which >70% may achieve long-term disease control after SRT. Unfortunately, for men with more aggressive tumor characteristics, the majority will progress after SRT alone, and based on data from RTOG 9601, approximately 70% of men will experience a PSA recurrence by 10 yr after SRT. With regard to optimizing tumor control, ‘‘early’’ SRT is often recommended based on the fact that the pre-SRT PSA remains one of the strongest predictors of success of SRT (a statement also endorsed by the AUA/ASTRO guidelines). However, there are two sides to the coin, and it is also important to weigh the side effects associated with SRT, especially early SRT. One of the main arguments for delaying the use of radiotherapy after RP is to potentially reduce toxicity and improve quality of life (QoL). In this month’s issue of European Urology, van Stam and colleagues presented important data on the impact of SRT and its timing on health-related QoL (HRQoL) [4]. They summarized several key points that are useful in clinical care: Patients who received SRT had greater immediate declines in select HRQoL domains compared with men who underwent RP alone. Notably, SRT patients reported significantly more diarrhea and bowel symptoms; however, over the first 2 yr, there was no lasting difference in bowel QoL between those who did or did not receive SRT. Patients who received SRT compared with men who had RP alone had no significant difference immediately after treatment or over time out to 2 yr after treatment in overall HRQoL. In addition, over time, there were no significant differences between groups with regard to sexual satisfaction.
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2016.03.010. * Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2016.03.022 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Spratt DE. Salvage Radiotherapy After Prostatectomy: Two Sides of the Coin. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.03.022
EURURO-6731; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
Nevertheless, patients who underwent early SRT <7 mo after RP had significantly greater declines in sexual satisfaction and urinary function compared with men who delayed SRT 7 mo after RP. These results should be contrasted with data from SWOG 8794, a randomized phase 3 trial comparing men who underwent RP versus RP plus adjuvant radiotherapy, which demonstrated that global QoL was worse in men receiving adjuvant radiotherapy throughout the first year after treatment [5]. By 2 yr after treatment, the two arms had nearly identical global QoL, and beyond 2 yr, global QoL was significantly higher in men who underwent ART and was suspected to be secondary to the marked reduction in recurrent disease afforded by ART. The follow-up interval in the study from van Stam et al was limited to 2 yr after treatment [4], and it will be of interest with longer followup to see if a similar divergence in overall QoL favoring SRT occurs as recurrences begin to accumulate. This also begs the question as how to best define early SRT going forward. Should it be based on time from RP (to allow functional improvement) or on the patient’s preSRT PSA (to optimize tumor control)? Multiple ongoing randomized trials are comparing the use of adjuvant radiotherapy with early SRT. The Radiotherapy-Adjuvant Versus Early Salvage (RAVES) trial (NCT00860652) defines the use of early SRT as no later than 4 mo following the first PSA measurement 0.2 ng/ml, whereas Radiation Therapy and Androgen Deprivation Therapy in Treating Patients Who Have Undergone Surgery for Prostate Cancer (RADICALS; NCT00541047) defines early SRT as treatment to be given at the time of PSA failure after RP. Long-term results from these trials will lend insight into the impact of delaying postoperative radiotherapy on both cure and QoL. Given the potential benefit by delaying SRT to allow further recovery, highlighted by van Stam et al, a potential method for delaying SRT after RP, and still allowing for early salvage therapy, is the addition of androgen deprivation therapy (ADT) prior to SRT. Recently, both RTOG 9601 and GETUG-16 reported on the combination of androgen ablation and SRT, both demonstrating a 50% reduction in
recurrence with combination therapy. With longer followup, RTOG 9601 also demonstrated that the addition of androgen ablation to SRT resulted in significant reduction in distant metastasis and an improvement in overall survival compared with SRT alone. Consequently, one is justified in initiating neoadjuvant ADT prior to SRT to halt PSA progression, to improve clinical outcome, and to allow for maximal functional recovery after RP. Data from RADICALS will also help further elucidate the impact of ADT and ADT duration on QoL. Last, patient selection is paramount in the use of postoperative radiotherapy, and significant progress continues to be made in optimizing prognostic and predictive models based on a composite of clinicopathologic features and genomic data to determine which men will benefit most from ART or SRT. Ultimately, a balance must be struck between maximizing cure and QoL, and both sides of the coin are important to discuss with our patients. Conflicts of interest: The author has nothing to disclose. Funding support: Dr. Spratt is funded by the US Department of Defense and the Prostate Cancer Foundation.
References [1] Epstein JI, Zelefsky MJ, Sjoberg DD, et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 2016;69:428–35. [2] Morgan SC, Waldron TS, Eapen L, et al. Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer: a systematic review and meta-analysis. Radiother Oncol 2008;88:1–9. [3] Sineshaw HM, Gray PJ, Efstathiou JA, et al. Declining use of radiotherapy for adverse features after radical prostatectomy: results from the National Cancer Data Base. Eur Urol 2015;68:768–74. [4] van Stam M-A, Aaronson NK, Pos FJ, et al. The effect of salvage radiotherapy and its timing on the health-related quality of life of prostate cancer patients. Eur Urol. In press, http://dx.doi.org/ 10.1016/j.eururo.2016.03.010. [5] Moinpour CM, Hayden KA, Unger JM, et al. Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J Clin Oncol 2008;26: 112–20.
Please cite this article in press as: Spratt DE. Salvage Radiotherapy After Prostatectomy: Two Sides of the Coin. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.03.022
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Salvage Radiotherapy After Prostatectomy: Two Sides of the Coin Daniel E. Spratt * Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
Although well-selected men with high-risk prostate cancer (PCa) can achieve durable disease control after radical prostatectomy (RP) alone, a subset will suffer from biochemical and/or clinical recurrence. Based on the Memorial Sloan Kettering Cancer Center nomogram (https://www.mskcc. org/nomograms/prostate/pre-op), approximately 40–90% of men with high-risk PCa will experience progression within 5 yr after RP. Likewise, a recent multi-institutional analysis of 20 845 men who underwent RP demonstrated that Gleason score 8 and 9–10 tumors had 5-yr biochemical failure rates of 52% and 74%, respectively [1]. Various approaches have been undertaken to improve outcomes for high-risk PCa patients treated with RP. Notably, adjuvant radiotherapy (ART) has been demonstrated in three randomized trials to provide a 50% reduction in the risk of relapse compared with RP alone [2]. This has resulted in the American Urological Association (AUA), the American Society for Radiation Oncology (ASTRO), and the American Society of Clinical Oncology recommending discussion of ART with patients who have adverse pathologic findings (pT3a/T3b disease and positive surgical margins). Unfortunately, <10% of men receive ART [3], and given the high rate of progression after RP monotherapy for men with high-risk PCa, the majority will require subsequent salvage therapies. The most common salvage therapy used after RP is salvage radiotherapy (SRT). Given the lack of level 1 evidence for the benefits of SRT, the fundamental premise for recommending SRT is based on the hypothesis that the persistent prostate-specific antigen (PSA)– producing PCa cells are contained within the prostatic bed where SRT is targeted. This appears to be largely accurate, especially for men with favorable disease
characteristics, for which >70% may achieve long-term disease control after SRT. Unfortunately, for men with more aggressive tumor characteristics, the majority will progress after SRT alone, and based on data from RTOG 9601, approximately 70% of men will experience a PSA recurrence by 10 yr after SRT. With regard to optimizing tumor control, ‘‘early’’ SRT is often recommended based on the fact that the pre-SRT PSA remains one of the strongest predictors of success of SRT (a statement also endorsed by the AUA/ASTRO guidelines). However, there are two sides to the coin, and it is also important to weigh the side effects associated with SRT, especially early SRT. One of the main arguments for delaying the use of radiotherapy after RP is to potentially reduce toxicity and improve quality of life (QoL). In this month’s issue of European Urology, van Stam and colleagues presented important data on the impact of SRT and its timing on health-related QoL (HRQoL) [4]. They summarized several key points that are useful in clinical care: Patients who received SRT had greater immediate declines in select HRQoL domains compared with men who underwent RP alone. Notably, SRT patients reported significantly more diarrhea and bowel symptoms; however, over the first 2 yr, there was no lasting difference in bowel QoL between those who did or did not receive SRT. Patients who received SRT compared with men who had RP alone had no significant difference immediately after treatment or over time out to 2 yr after treatment in overall HRQoL. In addition, over time, there were no significant differences between groups with regard to sexual satisfaction.
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2016.03.010. * Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2016.03.022 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Spratt DE. Salvage Radiotherapy After Prostatectomy: Two Sides of the Coin. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.03.022
EURURO-6731; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
Nevertheless, patients who underwent early SRT <7 mo after RP had significantly greater declines in sexual satisfaction and urinary function compared with men who delayed SRT 7 mo after RP. These results should be contrasted with data from SWOG 8794, a randomized phase 3 trial comparing men who underwent RP versus RP plus adjuvant radiotherapy, which demonstrated that global QoL was worse in men receiving adjuvant radiotherapy throughout the first year after treatment [5]. By 2 yr after treatment, the two arms had nearly identical global QoL, and beyond 2 yr, global QoL was significantly higher in men who underwent ART and was suspected to be secondary to the marked reduction in recurrent disease afforded by ART. The follow-up interval in the study from van Stam et al was limited to 2 yr after treatment [4], and it will be of interest with longer followup to see if a similar divergence in overall QoL favoring SRT occurs as recurrences begin to accumulate. This also begs the question as how to best define early SRT going forward. Should it be based on time from RP (to allow functional improvement) or on the patient’s preSRT PSA (to optimize tumor control)? Multiple ongoing randomized trials are comparing the use of adjuvant radiotherapy with early SRT. The Radiotherapy-Adjuvant Versus Early Salvage (RAVES) trial (NCT00860652) defines the use of early SRT as no later than 4 mo following the first PSA measurement 0.2 ng/ml, whereas Radiation Therapy and Androgen Deprivation Therapy in Treating Patients Who Have Undergone Surgery for Prostate Cancer (RADICALS; NCT00541047) defines early SRT as treatment to be given at the time of PSA failure after RP. Long-term results from these trials will lend insight into the impact of delaying postoperative radiotherapy on both cure and QoL. Given the potential benefit by delaying SRT to allow further recovery, highlighted by van Stam et al, a potential method for delaying SRT after RP, and still allowing for early salvage therapy, is the addition of androgen deprivation therapy (ADT) prior to SRT. Recently, both RTOG 9601 and GETUG-16 reported on the combination of androgen ablation and SRT, both demonstrating a 50% reduction in
recurrence with combination therapy. With longer followup, RTOG 9601 also demonstrated that the addition of androgen ablation to SRT resulted in significant reduction in distant metastasis and an improvement in overall survival compared with SRT alone. Consequently, one is justified in initiating neoadjuvant ADT prior to SRT to halt PSA progression, to improve clinical outcome, and to allow for maximal functional recovery after RP. Data from RADICALS will also help further elucidate the impact of ADT and ADT duration on QoL. Last, patient selection is paramount in the use of postoperative radiotherapy, and significant progress continues to be made in optimizing prognostic and predictive models based on a composite of clinicopathologic features and genomic data to determine which men will benefit most from ART or SRT. Ultimately, a balance must be struck between maximizing cure and QoL, and both sides of the coin are important to discuss with our patients. Conflicts of interest: The author has nothing to disclose. Funding support: Dr. Spratt is funded by the US Department of Defense and the Prostate Cancer Foundation.
References [1] Epstein JI, Zelefsky MJ, Sjoberg DD, et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 2016;69:428–35. [2] Morgan SC, Waldron TS, Eapen L, et al. Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer: a systematic review and meta-analysis. Radiother Oncol 2008;88:1–9. [3] Sineshaw HM, Gray PJ, Efstathiou JA, et al. Declining use of radiotherapy for adverse features after radical prostatectomy: results from the National Cancer Data Base. Eur Urol 2015;68:768–74. [4] van Stam M-A, Aaronson NK, Pos FJ, et al. The effect of salvage radiotherapy and its timing on the health-related quality of life of prostate cancer patients. Eur Urol. In press, http://dx.doi.org/ 10.1016/j.eururo.2016.03.010. [5] Moinpour CM, Hayden KA, Unger JM, et al. Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J Clin Oncol 2008;26: 112–20.
Please cite this article in press as: Spratt DE. Salvage Radiotherapy After Prostatectomy: Two Sides of the Coin. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.03.022