Radiation Therapy After Radical Prostatectomy: Why Patience Is a Virtue! The Case for Salvage Radiation Therapy

W E N ON I T C SE POINT-COUNTERPOINT Radiation Therapy After Radical Prostatectomy: Why Patience Is a Virtue! The Case for Salvage Radiation Therapy Kevin M. Slawin, MD Scott Department of Urology and The Baylor Prostate Center, Baylor College of Medicine, Houston, TX Without reliable clinical or pathologic predictors of local recurrence, selection of patients for adjuvant radiotherapy based on any combination of clinical or pathological parameters is bound to lead to the unnecessary treatment of significant numbers of patients whose disease might not have ultimately recurred or who might have been destined to have recurrence with extrapelvic metastatic disease, for which pelvic radiation would be ineffective. Furthermore, new ultrasensitive prostate-specific antigen (PSA) assays can identify patients actually failing surgery with a detectable and rising PSA earlier than ever, when disease volume is low and still amenable to salvage radiation therapy, and can allow the calculation of the PSA doubling time, which is gaining widespread acceptance as a proven predictor of response to salvage radiation therapy in this setting. Therefore, the rationale for preemptive adjuvant radiation therapy after radical prostatectomy is weaker than ever. [Rev Urol. 2002;4(2):90–94] © 2002 MedReviews, LLC Key words: Prostate cancer • Radiotherapy • Prostate-specific antigen • Prostatic fossa biopsy espite the general consensus regarding clinical and pathological parameters that are associated with a higher risk of eventual recurrence of prostate cancer, few studies have clearly identified parameters that can reliably predict an isolated local recurrence and thus identify those patients most likely to benefit from adjuvant radiotherapy. Especially difficult is clearly establishing the presence of local recurrence in patients with the low-volume disease that is typically seen initially in patients with a newly detectable prostate-specific antigen (PSA) rising in the absence of any other clinical or radiographic evidence of recurrence. D 90 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY The Case for Salvage Radiation Therapy Table 1 Response to Salvage Radiotherapy by Dose or PSA Level Author Number Median Radiotherapy Dose (Gy) Valicenti6 21 64.8 Post–Radiotherapy Assessment Point 2.7 years Biochemical Recurrence-Free Survival (bRFS) 79% RT > 64.8 Gy 57% RT < 64.8 Gy Crane 41 7 60.0 5 years 48% PSA < 2.7 ng/mL 0% PSA > 2.7 ng/mL Leventis 1 50 66.0 3 years 62% PSA < 2.1ng/mL 5 years 62% PSA < 2.1 ng/mL 26% PSA > 2.1 ng/mL 10% PSA > 2.1 ng/mL Garg 78 8 66.0 3 years 78% PSA < 2.0 ng/mL 31% PSA > 2.0 ng/mL Catton 59 9 60.0 5 years 30% PSA < 2.0 ng/mL 5% PSA > 2.0 ng/mL Schild5 46 3 years 76% PSA < 1.1 ng/mL 26% PSA > 1.1 ng/mL Nudell 68 10 66.4 3 years 60% PSA < 1.0 ng/mL 25% PSA > 1.0 ng/mL Zelefsky 11 42 64.8 2 years 74% PSA < 1.0 ng/mL 17% PSA > 1.0 ng/mL Wilder12 14 64.9 2 years 67% PSA < 1.0 ng/mL 20% PSA > 1.0 ng/mL Although a complete response to salvage radiotherapy in this setting may be the best indicator of an isolated local recurrence, response to radiotherapy does not appear to be examination were the only predictive parameters of a positive prostatic fossa biopsy in 95 patients with recurrence after radical prostatectomy.1 However, in multivariate analyses con- Biopsy of the prostatic fossa was not an independent predictor of response to salvage radiotherapy. associated with other conventional definitions of locally recurrent disease, eg, a positive prostatic fossa biopsy. For example, Leventis and colleagues showed that prebiopsy PSA level, postrecurrence PSADT (PSA doubling time), and a positive digital rectal trolling for all clinical and pathological parameters, including the prostatic fossa biopsy result, the often-cited positive surgical margin, and pathologic extracapsular extension, only PSADT and PSA level predicted response to salvage radiotherapy in these patients. Similarly, Koppie and colleagues showed that biopsy of the prostatic fossa was not an independent predictor of response to salvage radiotherapy.2 Others have also failed to confirm any prognostic significance for pathologic features of the radical prostatectomy specimen in the prediction of response to salvage radiotherapy.3 Without reliable clinical or pathologic predictors of local recurrence, selection of patients for adjuvant radiotherapy based on any combination of clinical or pathological parameters is bound to lead to the unnecessary treatment of significant numbers of patients whose disease VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 91 The Case for Salvage Radiation Therapy continued Table 2 Univariate and Multivariate Cox Proportional Hazards Regression Analysis for the Prediction of Salvage Radiotherapy Outcome Univariate Variable Hazards Ratio P Multivariate 95% CI Hazards Ratio P 95% CI Extraprostatic extension 1.46 .452 0.54-3.92 0.53 .478 0.10-3.02 Seminal vesicle involvement 1.08 .877 0.42-2.75 1.71 .419 0.47-6.25 Surgical margins status 0.56 .169 0.24-1.28 0.89 .877 0.20-3.90 RRP Gleason score 1.01 .964 0.64-1.60 0.76 .396 0.41-1.43 Prostatic fossa biopsy status 0.53 .167 0.22-1.30 0.30 .077 0.08-1.14 DRE of prostatic fossa 1.20 .663 0.53-2.75 2.07 .233 0.63-6.80 Time to PSA elevation* 0.90 .530 0.64-1.26 0.71 .300 0.37-1.36 Preradiation PSA* 2.16 .004 1.28-3.64 3.22 .025 1.16-8.93 PSA doubling time* 0.35 .001 0.19-0.65 0.30 .020 0.11-0.83 *Continuous variables have been logarithmically transformed. From Leventis AK, Shariat S, Kattan MW, et al. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol. 2001;19:1036. Reproduced with permission of the publisher, Lippincott Williams & Wilkins. RRP, radical retropubic prostatectomy; DRE, digital rectal examination. might not have ultimately recurred or who might have been destined to have recurrence with extrapelvic metastatic disease, for which pelvic radiation would be ineffective. Depending on the selection criteria for the administration of adjuvant radiotherapy, as many as 30%–70% of patients may be unnecessarily exposed to the potential complications and cost of this therapy.4 Yet the morbidity and cost of some overtreatment would perhaps be acceptable if waiting for patients to demonstrate recurrence by a detectable and rising PSA led to a lower response rate to radiotherapy applied in the salvage setting as patients potentially missed a possible “therapeutic window" for local disease control. However, no apparent difference in outcome between adjuvant and salvage radiotherapy has been convincingly demonstrated. For example, Schild reported that two thirds of patients with a rising PSA level after radical retropubic prostatectomy 92 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY could be salvaged by radiation alone, as long as patients were treated with an adequate dose of radiation before the PSA rose above 1.1 ng/mL.5 Similar higher rates of success have been reported by other investigators as long as patients were treated with an adequate dose prior to the PSA rising above a cutpoint of around 1 ng/mL (Table 1).6-12 There is clear consensus that preradiation PSA levels predict the response to salvage radiotherapy, lower. In addition to PSA, the PSADT calculated once recurrence is established, typically by a detectable and rising PSA, is also gaining acceptance as a predictor of the progression of prostate cancer to metastasis and death,13 as well as a host of other clinically significant endpoints, including response to salvage radiotherapy.1 For example, we recently reported that the outcome of salvage radiotherapy can be independently predicted by postrecurrence serum PSADT as Preradiation PSA levels predict the response to salvage radiotherapy. with low rates of response seen when the treatment is given after the PSA has risen above some threshold value. Though this threshold value has not been properly derived, and numerous investigators have proposed various cutpoints, it appears that this value will be no higher than 1.0 ng/mL and most likely will be significantly well as by preradiation serum PSA level (Table 2).1 Although these two parameters were also predictive of prostatic fossa biopsy results, biopsy confirmation of local recurrence did not seem to provide significant additional prognostic information with regard to outcome of salvage radiotherapy when the PSA and the The Case for Salvage Radiation Therapy PSADT were known. Postrecurrence serum PSADT can be readily determined when the PSA level is still well below 1.0 ng/mL, making the value of this parameter available to the clinician at the very earliest signs of prostate cancer recurrence. We are currently developing a nomogram for the prediction of response to salvage radiotherapy that includes the predictive parameters, preradiotherapy PSA, and PSADT to help clinicians better counsel recurring patients who are evaluating their therapeutic options. The Southwestern Oncology Group (SWOG 8794), the European Organization for Research and Treatment of Cancer (EORTC 22911), and the German Cancer Society (ARO 96-02) have all either initiated or completed randomized phase III trials to assess the role of adjuvant radiotherapy after radical prostatectomy. However, because most patients in these studies have been followed with conventional PSA assays, which have a lower limit of detection of 0.1 to 0.2 ng/mL, these studies no longer represent current best clinical practice. With the development of third-generation PSA assays that can reliably report serum PSA levels as low as 0.009, the reliable identification of prostate cancer recurrence earlier than ever before possible, at a very low volume of recurrent disease, is blurring the distinction between adjuvant and salvage radiotherapy and may make interpretation of these trials difficult.14 In our most current practice, a PSA level at 0.03 ng/mL and rising on two repeat determinations at least 6 weeks apart using the IMMULITE thirdgeneration PSA assay (Diagnostics Products Corporation, Los Angeles, CA) defines PSA recurrence postprostatectomy. In many instances, especially in patients with local recurrence who would be expected to have a long PSADT, this definition of recurrence often precedes by many months and even years our prior definition of a PSA at 0.1 or above and rising. Thus the difference between adjuvant and salvage radiotherapy continues to blur as we identify and treat patients with very low volumes of recurrent prostate cancer. Waiting for disease recurrence by these newer criteria, with the subsequent ability to calculate a reliable PSADT even while the PSA remains below 0.1 ng/mL, may allow us to preserve what is best about adjuvant and salvage therapy: 1) the treatment of patients with very low-volume residual disease (which is the hallmark benefit of adjuvant radiotherapy); and 2) the selection of patients with established recurrence (who are more likely to have local disease recurrence as evidenced by lower PSA and slower PSADT). This provides the advantage of limiting treatment to those patients most likely to benefit from it. Consideration of the value of a combination of these strategies may convince a greater proportion of urologists, who today seldom recommend either option to their patients, of the benefits of radiotherapy after radical prostatectomy. Ultimately, trials that randomize patients to adjuvant radiotherapy or to a watchful waiting strategy, with the subsequent treatment of established recurrence using these lower PSA levels, will be required to compare these two strategies fairly. References 1. 2. 3. 4. Leventis AK, Shariat SF, Kattan MW, et al. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol. 2001;19:1030–1039. Koppie TM, Grossfeld GD, Nudell DM, et al. Is anastomotic biopsy necessary before radiotherapy after radical prostatectomy? J Urol. 2001;166:111–115. Do T, Parker RG, Do C, et al. Salvage radiotherapy for biochemical and clinical failures following radical prostatectomy. Cancer J Sci Am. 1998;4:324–330. Forman JD, Duclos M, Shamsa F, Pontes EJ. Main Points • Response to radiotherapy does not appear to be associated with other conventional definitions of locally recurrent prostate cancer, eg, a positive prostatic fossa biopsy. • Some 30%–70% of patients may be unnecessarily exposed to the potential complications and cost of adjuvant radiotherapy when applied based on pathologic parameters of the radical prostatectomy specimen, eg, extracapsular extension or seminal vesicle invasion. • No apparent difference in outcome between adjuvant and salvage radiotherapy has been convincingly demonstrated. • There is clear consensus that preradiation prostate-specific antigen (PSA) levels predict the response to salvage radiotherapy, with low rates of response seen when the treatment is given after the PSA has risen above a threshold value that may be no higher than 1.0 ng/mL and perhaps significantly lower. • PSA doubling time, calculated once recurrence is established, is also gaining acceptance as a predictor of the progression of prostate cancer to metastasis and death and of the response to salvage radiation therapy after radical prostatectomy. • With third-generation PSA assays that can reliably report serum PSA levels as low as 0.009, the reliable identification of prostate cancer recurrence at a very low volume of recurrent disease is blurring the distinction between adjuvant and salvage radiotherapy. VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 93 The Case for Salvage Radiation Therapy continued 5. 6. 7. 94 Predicting the need for adjuvant systemic therapy in patients receiving postprostatectomy irradiation. Urology. 1996;47:382–386. Schild SE. Radiation therapy (RT) after prostatectomy: the case for salvage therapy as opposed to adjuvant therapy. Int J Cancer. 2001;96:94–98. Valicenti RK, Gomella LG, Ismail M, et al. Effect of higher radiation dose on biochemical control after radical prostatectomy for PT3N0 prostate cancer. Int J Radiat Oncol Biol Phys. 1998;42:501–506. Crane CH, Rich TA, Read PW, et al. Preirradiation PSA predicts biochemical disease-free survival in patients treated with postprostatectomy external beam irradiation. Int J Radiat Oncol Biol VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 8. 9. 10. 11. Phys. 1997;39:681–686. Garg MK, Tekyi-Mensah S, Bolton S, et al. Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy. Urology. 1998;51:998–1002. Catton C, Gospodarowicz M, Warde P, et al. Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother Oncol. 2001;59:51–60. Nudell DM, Grossfeld GD, Weinberg VK, et al. Radiotherapy after radical prostatectomy: treatment outcomes and failure patterns. Urology. 1999;54:1049–1057. Zelefsky MJ, Aschkenasy E, Kelsen S, Leibel SA. Tolerance and early outcome results of post- 12. 13. 14. prostatectomy three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 1997;39:327–333. Wilder RB, Hsiang JY, Ji M, et al. Preliminary results of three-dimensional conformal radiotherapy as salvage treatment for a rising prostate-specific antigen level postprostatectomy. Am J Clin Oncol. 2000;23:176–180. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591–1597. Parker C, Warde P, Catton C. Salvage radiotherapy for PSA failure after radical prostatectomy. Radiother Oncol. 2001;61:107–116.