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1. Prostate cancer-specific survival following salvage radiotherapy vs. observation in men with biochemical recurrence after radical prostatectomy
682
D.W. Lin / Urologic Oncology: Seminars and Original Investigations 26 (2008) 680 – 691
Reference [1] Onik G, Barzell W. Transperineal 3D mapping biopsy of the prostate: An essential tool in selecting patients for focal prostate cancer therapy. Urol Oncol 2008;26:506 –10.
1. Prostate cancer-specific survival following salvage radiotherapy vs. observation in men with biochemical recurrence after radical prostatectomy. Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC, Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD. JAMA 2008;299(23):2760 –9 Context: Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival and, if so, the subgroup of men most likely to benefit. Objectives: To quantify the relative improvement in prostate cancer-specific survival of salvage radiotherapy vs. no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial. Design, Setting, and Patients: Retrospective analysis of a cohort of 635 U.S. men undergoing prostatectomy from 1982–2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n ⫽ 397), salvage radiotherapy alone (n ⫽ 160), or salvage radiotherapy combined with hormonal therapy (n ⫽ 78). Main Outcome Measure: Prostate cancer-specific survival defined from time of recurrence until death from disease. Results: With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19 – 0.54]; P ⬍ 0.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer-specific survival (HR, 0.34 [95% CI, 0.17– 0.69]; P ⫽ 0.003). The increase in prostate cancer-specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer-specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival. Conclusions: Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.
2. Adjuvant radiotherapy for patients with locally advanced prostate cancer—A new standard? Ganswindt U, Stenzl A, Bamberg M, Belka C, Department of Radiation Oncology, Ludwig-Maximilians-University München, München, Germany. Eur Urol 2008;54(3):528 – 42. Epub 2008 Jun 23 Context: After radical prostatectomy (RPE), pathologically advanced disease is detected in 38% to 52% of patients. Retrospective data on the role of postoperative radiotherapy (RT) are controversial. Objectives: To clarify in how far an adjuvant radiation treatment (ART) in cases of locally advanced disease affects outcome, three randomized trials have been started. The available data are critically reviewed. Evidence Acquisition: Relevant publications were detected by searching the Medical Literature Analysis and Retrieval System Online (MEDLINE) and the Public/Publisher MEDLINE (PUBMED; National Library of Medicine journal articles database) databases using the medical subject headings “prostatic neoplasms,” “radiotherapy,” and “adjuvant.” A major emphasis was placed on the results of the randomized trials. Evidence Synthesis: The European Organization for Research and Treatment of Cancer (EORTC) trial number 22911, Southwest Oncology Group (SWOG) trial number 8794, and German Intergroup trial ARO 96-02/AUO AP 09/95 randomized patients to receive ART with 60 Gray (Gy) and 60 – 64 Gy (SWOG trial), respectively. The majority of patients had undetectable PSA levels postoperatively. The data concordantly show that ART improves biochemical progression-free survival rates (EORTC trial, progression-free survival rate after 5 years: 74.0% with ART vs, 52.6% without ART; SWOG trial, after 5 years: approximately 73% vs. approximately 44%, respectively; and ARO 96-02/AUO AP 09/95 trial, after 5 years: 72% vs. 54%, respectively). The EORTC trial shows improved local control of cancer progression (P ⬍ 0.0001) for treated patients. The SWOG trial demonstrates an improved freedom from hormonal treatment (5 years: 21% with ART vs. 10% without ART). A statistically significant benefit with regard to metastasis-free survival and overall survival was not seen. Genitourinary and gastrointestinal toxicity was moderate, with late side-effects (ⱖgrade 3) between 3% (in the ARO 96-02 trial) and ⬍5% (in the EORTC trial). Conclusion: Biochemical progression-free survival and local control are significantly improved by postoperative RT with 60 Gy. Patients should be offered adjuvant treatment when they are at high risk for local relapse (especially with positive surgical margins).
D.W. Lin / Urologic Oncology: Seminars and Original Investigations 26 (2008) 680 – 691
683
Commentary These two reports present different approaches for the treatment of prostate cancer following radical prostatectomy, in particular high-risk prostate cancer. The major presumptions of adjuvant radiotherapy are that residual local disease following surgery causes future clinically relevant harm and that earlier local adjuvant treatment can alter this natural history. The major randomized studies have clearly shown benefits in biochemical failure [1,2], although it is noteworthy to mention that a substantial proportion of men never reached undetectable PSA after radical prostatectomy (balanced in both arms), which biased the PSA results against the observation arm. Additionally, the KM curves for the primary endpoint of metastasis-free survival seemingly never plateau in either arm, suggesting that there does not exist a subset of men who are clearly cured by adjuvant radiotherapy. Finally, the EORTC has published a subset analysis that positive surgical margins were the most significant risk factor for recurrence, and that margin-negative patients may not benefit from adjuvant radiation [3]. Trock and colleagues report on their single institution experience with salvage radiotherapy for biochemical recurrence following prostatectomy, and appropriately provide exhaustive details and subanalyses to justify their nonrandomized, retrospective data. These authors provide the first large report to link salvage radiotherapy with disease-specific survival. Their data also confirm previous studies reporting that even in men with aggressive features (e.g., fast PSA doubling times, high-grade disease), salvage radiotherapy is a viable therapeutic option [4]. It is noteworthy to point out that the disease-specific survival curves here do show clear plateaus in the treatment arm, suggesting durable benefits in a subset of patients. The common threads in both approaches are that earlier treatment may provide improved disease-specific outcomes, and that there exists a substantial amount of disease in the pelvis that potentially can be treated with early/adjuvant vs. late/salvage radiotherapy. The question still remains whether careful follow-up of men after radical prostatectomy with early initiation of salvage radiation is equal to immediate adjuvant therapy, thus sparing the 40% to 50% of men who would never have suffered recurrence. The question is currently being addressed in the appropriately named trial: Radiation and Androgen Deprivation in Combination After Local Surgery (RADICALS), an ambitious Medical Research Council clinical trial that aims to randomize men to adjuvant vs. salvage radiotherapy with or without androgen deprivation with disease-specific survival as the primary endpoint (see http://www.clinicaltrials.gov/ct2/show/NCT00541047). This trial will be no easy endeavor with the goal enrollment estimated at over 4,000 patients with accrual based primarily in the United Kingdom and Canada, but these results will provide vital, practice-changing information for the management of our patients following radical prostatectomy. doi:10.1016/j.urolonc.2008.10.003 Daniel W. Lin, M.D.
References [1] Bolla M, van Poppel H, Collette L, et al. European Organization for Research and Treatment of Cancer. Postoperative radiotherapy after radical prostatectomy: A randomized controlled trial (EORTC trial 22911). Lancet 2005;366:572– 8. [2] Thompson IM Jr., Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: A randomized clinical trial. JAMA 2006;296:2329 –35. [3] Van der Kwast TH, Bolla M, Van Poppel H, et al. EORTC 22911. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25:4178 – 86. [4] Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035– 41.
Mid-term results demonstrate salvage high-intensity focused ultrasound (HIFU) as an effective and acceptably morbid salvage treatment option for locally radiorecurrent prostate cancer. Murat FJ, Poissonnier L, Rabilloud M, Belot A, Bouvier R, Rouviere O, Chapelon JY, Gelet A, Urology Department, Val d’Ouest Hospital, Ecully, France; Urology and Transplantation Department, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France. Eur Urol 2008;May 9 [Epub ahead of print] Background: Local occurrence of prostate cancer (PCa) after external beam radiation (EBRT) may benefit from definitive local therapy. Objective: To evaluate the safety and efficacy of salvage high-intensity focal ultrasound (HIFU) in local PCa recurrence after EBRT and to determine prognostic factors for optimal patient selection. Design, Setting, and Participants: Between 1995 and 2006, patients with a local PCa recurrence after EBRT were retrospectively included. Intervention: All patients received salvage HIFU with the Ablatherm device. Measurements: Prognostic factors (pre-EBRT risk group, androgen-deprivation [AD] use, pre-HIFU prostate-specific antigen [PSA], Gleason score and positive biopsy percentage) were studied in univariate and multivariate analyses. Progression was defined as positive biopsy and/or last PSA ⬎ nadir⫹2 ng/ml and/or adjuvant therapy introduction. All complications were recorded. Results and Limitations: Some 194 HIFU sessions for 167 patients were performed. Local cancer control was achieved with negative biopsy results in 122 (73%) patients. The median PSA nadir was 0.19 ng/ml. The mean follow-up period was 18.1 months (range: 3–121 mo). Seventy-four patients required no hormone therapy. The actuarial 5-year overall survival rate was 84%. The actuarial 3-yearr progression-free survival rate was significantly lower in 3 circumstances: (1) worsening of the pre-EBRT stage with 53%, 42%, and 25%
D.W. Lin / Urologic Oncology: Seminars and Original Investigations 26 (2008) 680 – 691
Reference [1] Onik G, Barzell W. Transperineal 3D mapping biopsy of the prostate: An essential tool in selecting patients for focal prostate cancer therapy. Urol Oncol 2008;26:506 –10.
1. Prostate cancer-specific survival following salvage radiotherapy vs. observation in men with biochemical recurrence after radical prostatectomy. Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC, Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD. JAMA 2008;299(23):2760 –9 Context: Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival and, if so, the subgroup of men most likely to benefit. Objectives: To quantify the relative improvement in prostate cancer-specific survival of salvage radiotherapy vs. no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial. Design, Setting, and Patients: Retrospective analysis of a cohort of 635 U.S. men undergoing prostatectomy from 1982–2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n ⫽ 397), salvage radiotherapy alone (n ⫽ 160), or salvage radiotherapy combined with hormonal therapy (n ⫽ 78). Main Outcome Measure: Prostate cancer-specific survival defined from time of recurrence until death from disease. Results: With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19 – 0.54]; P ⬍ 0.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer-specific survival (HR, 0.34 [95% CI, 0.17– 0.69]; P ⫽ 0.003). The increase in prostate cancer-specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer-specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival. Conclusions: Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.
2. Adjuvant radiotherapy for patients with locally advanced prostate cancer—A new standard? Ganswindt U, Stenzl A, Bamberg M, Belka C, Department of Radiation Oncology, Ludwig-Maximilians-University München, München, Germany. Eur Urol 2008;54(3):528 – 42. Epub 2008 Jun 23 Context: After radical prostatectomy (RPE), pathologically advanced disease is detected in 38% to 52% of patients. Retrospective data on the role of postoperative radiotherapy (RT) are controversial. Objectives: To clarify in how far an adjuvant radiation treatment (ART) in cases of locally advanced disease affects outcome, three randomized trials have been started. The available data are critically reviewed. Evidence Acquisition: Relevant publications were detected by searching the Medical Literature Analysis and Retrieval System Online (MEDLINE) and the Public/Publisher MEDLINE (PUBMED; National Library of Medicine journal articles database) databases using the medical subject headings “prostatic neoplasms,” “radiotherapy,” and “adjuvant.” A major emphasis was placed on the results of the randomized trials. Evidence Synthesis: The European Organization for Research and Treatment of Cancer (EORTC) trial number 22911, Southwest Oncology Group (SWOG) trial number 8794, and German Intergroup trial ARO 96-02/AUO AP 09/95 randomized patients to receive ART with 60 Gray (Gy) and 60 – 64 Gy (SWOG trial), respectively. The majority of patients had undetectable PSA levels postoperatively. The data concordantly show that ART improves biochemical progression-free survival rates (EORTC trial, progression-free survival rate after 5 years: 74.0% with ART vs, 52.6% without ART; SWOG trial, after 5 years: approximately 73% vs. approximately 44%, respectively; and ARO 96-02/AUO AP 09/95 trial, after 5 years: 72% vs. 54%, respectively). The EORTC trial shows improved local control of cancer progression (P ⬍ 0.0001) for treated patients. The SWOG trial demonstrates an improved freedom from hormonal treatment (5 years: 21% with ART vs. 10% without ART). A statistically significant benefit with regard to metastasis-free survival and overall survival was not seen. Genitourinary and gastrointestinal toxicity was moderate, with late side-effects (ⱖgrade 3) between 3% (in the ARO 96-02 trial) and ⬍5% (in the EORTC trial). Conclusion: Biochemical progression-free survival and local control are significantly improved by postoperative RT with 60 Gy. Patients should be offered adjuvant treatment when they are at high risk for local relapse (especially with positive surgical margins).
D.W. Lin / Urologic Oncology: Seminars and Original Investigations 26 (2008) 680 – 691
683
Commentary These two reports present different approaches for the treatment of prostate cancer following radical prostatectomy, in particular high-risk prostate cancer. The major presumptions of adjuvant radiotherapy are that residual local disease following surgery causes future clinically relevant harm and that earlier local adjuvant treatment can alter this natural history. The major randomized studies have clearly shown benefits in biochemical failure [1,2], although it is noteworthy to mention that a substantial proportion of men never reached undetectable PSA after radical prostatectomy (balanced in both arms), which biased the PSA results against the observation arm. Additionally, the KM curves for the primary endpoint of metastasis-free survival seemingly never plateau in either arm, suggesting that there does not exist a subset of men who are clearly cured by adjuvant radiotherapy. Finally, the EORTC has published a subset analysis that positive surgical margins were the most significant risk factor for recurrence, and that margin-negative patients may not benefit from adjuvant radiation [3]. Trock and colleagues report on their single institution experience with salvage radiotherapy for biochemical recurrence following prostatectomy, and appropriately provide exhaustive details and subanalyses to justify their nonrandomized, retrospective data. These authors provide the first large report to link salvage radiotherapy with disease-specific survival. Their data also confirm previous studies reporting that even in men with aggressive features (e.g., fast PSA doubling times, high-grade disease), salvage radiotherapy is a viable therapeutic option [4]. It is noteworthy to point out that the disease-specific survival curves here do show clear plateaus in the treatment arm, suggesting durable benefits in a subset of patients. The common threads in both approaches are that earlier treatment may provide improved disease-specific outcomes, and that there exists a substantial amount of disease in the pelvis that potentially can be treated with early/adjuvant vs. late/salvage radiotherapy. The question still remains whether careful follow-up of men after radical prostatectomy with early initiation of salvage radiation is equal to immediate adjuvant therapy, thus sparing the 40% to 50% of men who would never have suffered recurrence. The question is currently being addressed in the appropriately named trial: Radiation and Androgen Deprivation in Combination After Local Surgery (RADICALS), an ambitious Medical Research Council clinical trial that aims to randomize men to adjuvant vs. salvage radiotherapy with or without androgen deprivation with disease-specific survival as the primary endpoint (see http://www.clinicaltrials.gov/ct2/show/NCT00541047). This trial will be no easy endeavor with the goal enrollment estimated at over 4,000 patients with accrual based primarily in the United Kingdom and Canada, but these results will provide vital, practice-changing information for the management of our patients following radical prostatectomy. doi:10.1016/j.urolonc.2008.10.003 Daniel W. Lin, M.D.
References [1] Bolla M, van Poppel H, Collette L, et al. European Organization for Research and Treatment of Cancer. Postoperative radiotherapy after radical prostatectomy: A randomized controlled trial (EORTC trial 22911). Lancet 2005;366:572– 8. [2] Thompson IM Jr., Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: A randomized clinical trial. JAMA 2006;296:2329 –35. [3] Van der Kwast TH, Bolla M, Van Poppel H, et al. EORTC 22911. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25:4178 – 86. [4] Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035– 41.
Mid-term results demonstrate salvage high-intensity focused ultrasound (HIFU) as an effective and acceptably morbid salvage treatment option for locally radiorecurrent prostate cancer. Murat FJ, Poissonnier L, Rabilloud M, Belot A, Bouvier R, Rouviere O, Chapelon JY, Gelet A, Urology Department, Val d’Ouest Hospital, Ecully, France; Urology and Transplantation Department, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France. Eur Urol 2008;May 9 [Epub ahead of print] Background: Local occurrence of prostate cancer (PCa) after external beam radiation (EBRT) may benefit from definitive local therapy. Objective: To evaluate the safety and efficacy of salvage high-intensity focal ultrasound (HIFU) in local PCa recurrence after EBRT and to determine prognostic factors for optimal patient selection. Design, Setting, and Participants: Between 1995 and 2006, patients with a local PCa recurrence after EBRT were retrospectively included. Intervention: All patients received salvage HIFU with the Ablatherm device. Measurements: Prognostic factors (pre-EBRT risk group, androgen-deprivation [AD] use, pre-HIFU prostate-specific antigen [PSA], Gleason score and positive biopsy percentage) were studied in univariate and multivariate analyses. Progression was defined as positive biopsy and/or last PSA ⬎ nadir⫹2 ng/ml and/or adjuvant therapy introduction. All complications were recorded. Results and Limitations: Some 194 HIFU sessions for 167 patients were performed. Local cancer control was achieved with negative biopsy results in 122 (73%) patients. The median PSA nadir was 0.19 ng/ml. The mean follow-up period was 18.1 months (range: 3–121 mo). Seventy-four patients required no hormone therapy. The actuarial 5-year overall survival rate was 84%. The actuarial 3-yearr progression-free survival rate was significantly lower in 3 circumstances: (1) worsening of the pre-EBRT stage with 53%, 42%, and 25%