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Salvage radiotherapy for men with isolated rising PSA or locally palpable recurrence after radical prostatectomy: Do outcomes differ?
ADULT UROLOGY
SALVAGE RADIOTHERAPY FOR MEN WITH ISOLATED RISING PSA OR LOCALLY PALPABLE RECURRENCE AFTER RADICAL PROSTATECTOMY: DO OUTCOMES DIFFER? O. KENNETH MACDONALD, STEVEN E. SCHILD, SUJAY A. VORA, PAUL E. ANDREWS, ROBERT G. FERRIGNI, DONALD E. NOVICKI, SCOTT K. SWANSON, AND WILLIAM W. WONG
ABSTRACT Objectives. To compare, in a retrospective analysis, the outcome of salvage external beam radiotherapy (EBRT) for isolated prostate-specific antigen (PSA) elevation or palpable local recurrence after radical prostatectomy (RP). Methods. We evaluated 102 men who underwent EBRT from 1993 to 1999, 60 for a rising PSA level alone and 42 for palpable local disease after RP. Biochemical disease-free survival and overall survival were calculated. Prognostic factors were evaluated to determine associations with biochemical disease-free survival. Results. The 5-year rate of biochemical disease-free survival, local control, freedom from distant metastasis, and overall survival for all 102 patients was 38%, 94%, 87%, and 88%, respectively. All palpable disease resolved completely after salvage EBRT. The greatest 5-year rate of biochemical control (69%) was obtained in patients with a pre-EBRT PSA level of 0.5 ng/mL or less. The 5-year overall survival rate was significantly better for those who underwent salvage EBRT for a rising PSA level than for those with palpable recurrence (96% versus 78%, P ⫽ 0.02). A low pre-EBRT PSA level and a less than 2-year interval from RP to EBRT were independent predictors of biochemical failure. Five patients (5%) experienced chronic grade 3 or 4 RT-related toxicity. Conclusions. Salvage EBRT provides excellent local control of recurrent disease after RP. Salvage EBRT before the development of palpable local disease may confer a survival benefit and decrease the risk of metastasis, and durable biochemical control was achieved best in those whose pre-EBRT PSA level was 0.5 ng/mL or less. Early referral and careful patient selection is vital for salvage EBRT to be of optimal benefit. UROLOGY 64: 760–764, 2004. © 2004 Elsevier Inc.
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adical prostatectomy (RP) as a primary treatment for clinically localized prostate cancer has increased in its application during the past decade.1 Despite the generally favorable results obtained with RP, some men will develop a detectable serum prostate-specific antigen (PSA) level. An elevated serum PSA level after RP is generally the earliest indication of recurrence, and an estimated 27% to 53% of men will develop detectable PSA levels within 10 years after RP.2 Although controversial, the treatment options for patients with a detectable PSA level after RP include observation, androgen deprivation therapy, and salFrom the Department of Radiation Oncology and Section of Urology, Mayo Clinic Scottsdale, Scottsdale, Arizona Reprint requests: Steven Schild, M.D., Department of Radiation Oncology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259 Submitted: March 1, 2004, accepted (with revisions): May 14, 2004 © 2004 ELSEVIER INC. 760
ALL RIGHTS RESERVED
vage external beam radiotherapy (EBRT) to the prostate bed. A survey of 1000 urologists indicated that 54% of respondents recommended observation for men with a detectable PSA level 1 year after RP and 13% recommended EBRT.3 In men with documented local recurrence, however, 81% of respondents recommended EBRT. Little evidence exists to confirm the benefit or detriment of these reported treatment patterns. Most published reports regarding salvage EBRT for biochemical or local recurrence after RP have not discussed these two clinical situations as separate entities. As a result, current studies have not provided sufficient information to address adequately the question of for whom salvage EBRT would be most efficacious. Therefore, we retrospectively evaluated the outcomes, analyzed the prognostic variables, and compared the results of salvage EBRT in men with rising PSA levels alone versus those with clinically apparent local prostate cancer recurrence after RP. 0090-4295/04/$30.00 doi:10.1016/j.urology.2004.05.016
TABLE I. Patient characteristics and crude outcomes data Characteristic Total (n) Median age (yr) Gleason score ⱖ8 (n) ⫹ Seminal vesicle invasion ⫹ Surgical margin involvement Median pre-EBRT PSA (ng/mL) Total median radiation dose (Gy) Median time to referral (yr) Median PSADT (mo) Follow-up (yr) Median Range Local failure (n) Distant failure (n) Biochemical failure (n) Total deaths (n) Deaths from prostate cancer (n)
Rising PSA Palpable 60 65.5 15 (25) 12 (20) 12 (20) 0.69 64 1.4 7.5
42 70.5 8 (19) 6 (14) 10 (23) 1.75 68.4 4.3 12
4.2 2 mo to 9 yr 2 (3) 4 (7) 30 (50) 3 (5) 2 (3)
4.3 2 mo to 8.7 yr 2 (5) 7 (17) 26 (62) 9 (21) 6 (14)
FIGURE 1. Overall survival after salvage EBRT for rising PSA level versus palpable local recurrence (P ⫽ 0.02).
KEY: PSA ⫽ prostate-specific antigen; EBRT ⫽ external beam radiotherapy; PSADT ⫽ PSA doubling time. Data in parentheses are percentages.
MATERIAL AND METHODS A total of 102 men who presented for salvage EBRT after RP with a detectable PSA level from 1993 to 1999 were included. Of these men, 42 patients had a detectable PSA level with a palpable local recurrence by digital rectal examination; 36 of these patients had biopsy-proven evidence of recurrent disease. The remaining 60 men had a rising PSA level alone. The median time to referral from RP to EBRT was 2 years (range 0.18 to 10). This study was performed with the appropriate institutional review board approval. All men had undergone RP with pelvic lymphadenectomy between 1984 and 1996. All patients were free of pelvic nodal metastasis at surgery. At referral, all men underwent an evaluation for metastatic disease, including bone scan and computed tomography of the abdomen and pelvis. No patient underwent androgen deprivation therapy before or during EBRT. The patient characteristics are presented in Table I. The median follow-up for the entire cohort was 4.2 years (range 2 months to 9 years). The PSA doubling time (PSADT) was calculated for 88 (86%) of the 102 patients using the log-linear regression method.2,4 EBRT was delivered to the prostatic bed with 10-MV photons using a four-field technique and custom blocks. The delivery of EBRT was confined to the prostatic bed based on localization using urethral, bladder, and rectal contrast at simulation. The total dose ranged from 41 to 70 Gy (median 66), with daily doses of 1.8 to 2.0 Gy. No intensity-modulated RT or three-dimensional conformal RT was used. Late toxicity was evaluated using the Radiation Therapy Oncology Group toxicity criteria. Freedom from PSA failure after salvage EBRT (biochemical disease-free survival [bDFS]) was defined as maintaining a serum PSA level of 0.3 ng/mL or less.5,6 Additional criteria of biochemical failure included a post-EBRT PSA level that was greater than the pre-EBRT PSA level, initiation of androgen deprivation therapy after EBRT, or clinical or radiographic evidence of local or metastatic disease. The time of failure was dated to the point at which a criterion for failure was met; no back dating was used. Local failure was defined as clinical UROLOGY 64 (4), 2004
FIGURE 2. Freedom from distant metastasis (DM) and bDFS after salvage EBRT for rising PSA level versus palpable local recurrence (P ⫽ 0.05 and P ⫽ 0.1, respectively).
persistence or recurrence of a palpable lesion in the prostatic bed on digital rectal examination or follow-up computed tomography scan. Distant failure was defined as symptomatic or radiographic evidence of metastasis. We evaluated the primary endpoints of bDFS, local failure, distant failure, cause-specific survival, and overall survival. The rates of survival and freedom from failure were calculated using the Kaplan-Meier method.7 Univariate analysis of the prognostic variables was performed using the log-rank test.8 Multivariate analysis was performed using the Cox proportional hazards model.9 Statistical significance was declared for P ⬍0.05.
RESULTS The 5-year rate of bDFS, local control, freedom from distant metastases, and overall survival for all 102 men was 38%, 94%, 87%, and 88%, respectively. The 5-year rate of overall survival for the isolated PSA failure group was significantly better than for the palpable failure group (96% versus 78%, respectively; P ⫽ 0.02; Fig. 1). Similarly, the 5-year rate of cause-specific survival significantly favored those with a rising PSA level alone (98% 761
versus 84%; P ⫽ 0.02). A benefit in the control of distant failure at 5 years for the isolated PSA failure group approached statistical significance (P ⫽ 0.05; Fig. 2). The rate of local control at 5 years was similar for the two groups (P ⫽ 0.68). The initial biochemical response to salvage EBRT for all patients was favorable; 74 patients (73%) achieved an undetectable PSA level within the first year after EBRT and 22 (22%) had a decrease from the pre-EBRT level. The complete response (achieving an undetectable PSA level) rate after salvage EBRT was similar between the two groups— 78% and 64% for men in the isolated PSA and palpable recurrence group, respectively. Of the 102 men, 56 (55%) experienced biochemical failure at or before the last follow-up. The rate of bDFS at 5 years for the palpable and isolated PSA group was 27% and 45%, respectively (P ⫽ 0.1; Fig. 2). Similar rates of bDFS were obtained using an alternative definition— undetectable PSA at less than 0.1 ng/mL—as the criterion for freedom from biochemical recurrence. All those with palpable disease at salvage had resolution of the palpable disease within 1 year after EBRT. The PSA level before salvage EBRT was associated with the rate of bDFS. Men whose PSA level was less than 1.0 ng/mL at salvage experienced a 5-year bDFS rate of 51% versus 18% in those with a PSA level of 1.0 ng/mL or greater (P ⫽ 0.009). The entire cohort was divided into quartiles according to the pre-EBRT PSA level, revealing a 5-year bDFS rate of 69%, 28%, 33%, and 14% for a pre-EBRT PSA level of 0.5 ng/mL or less, 0.6 to 1.0 ng/mL, 1.1 to 2.4 ng/mL, and 2.5 ng/mL or greater, respectively (P ⫽ 0.02). A subset of men with a pre-EBRT PSA level of less than 1.0 ng/mL and a total EBRT dose of 66 Gy or greater (median EBRT dose) experienced a statistically significant benefit in bDFS at 5 years compared with the others (51% versus 22%, P ⫽ 0.02). The median pre-EBRT PSADT for the entire cohort was calculated to be 8 months (range 2 months to 22 years). Patients with a PSADT longer than 8 months had a 5-year bDFS rate of 48% compared with 28% for those whose doubling time was less than 8 months (P ⫽ 0.16). When evaluated separately, men with palpable recurrence (median PSADT 12 months) whose doubling time was longer than 1 year experienced a statistically significant benefit in biochemical control after salvage EBRT (5-year rate of 51% versus 0%; P ⫽ 0.02). No statistically significant effect of PSADT on bDFS was found in the rising PSA group (P ⫽ 0.34). The possible prognostic factors analyzed included pathologic stage (T2 versus T3–T4), pre-RP PSA level, pre-EBRT PSA by quartile, Gleason score (6, 7, or 8 or more), surgical margin status, seminal vesicle involvement, interval from RP to 762
salvage EBRT, PSADT, and EBRT dose (less than 66 and 66 Gy or greater). Univariate analysis showed Gleason score, interval from RP to salvage EBRT, and pre-EBRT PSA level were significantly associated with bDFS. Multivariate analysis revealed that pre-EBRT PSA by quartile (relative risk 1.46, 95% confidence interval 1.13 to 1.9, P ⫽ 0.004) and a shorter than 2-year interval from RP to salvage EBRT (relative risk 2.15, 95% confidence interval 1.20 to 3.93, P ⫽ 0.01) independently predicted for biochemical failure after EBRT. A Gleason score of 8 or more displayed a trend toward independent prognostic significance (P ⫽ 0.06). No factor significantly predicted for overall survival. Among all patients, 46 late RT-related toxicities occurred. Seventeen patients experienced late Grade 1 or 2 bladder toxicity, and three reported Grade 3 or 4 toxicity. Twenty patients reported late Grade 1 or 2 gastrointestinal toxicity, and two reported grade 3 toxicity. Twenty-one men reported incontinence at the referral for salvage EBRT— three had resolution of incontinence after EBRT and four developed new incontinence 8, 17, 17, and 64 months after EBRT. COMMENT In contrast to most reports concerning salvage EBRT after RP, we separately evaluated and compared EBRT among men for a rising PSA level alone10 –19 or for palpable recurrent disease.4,11,13,20 –23 Our report appears to be the first to suggest a statistically significant difference in survival between these two groups. Within the available published data, we found one report that addressed the issue of survival and salvage EBRT. The report, by Choo et al.,13 showed no statistically significant difference in the 4-year rates of overall survival for 98 men who were treated with salvage EBRT for a persistently elevated PSA level, delayed PSA elevation, or clinically apparent local recurrence after RP. In contrast, we found a statistically significant difference in overall survival favoring men with delayed PSA elevation after RP. Retrospective analyses have inherent limitations. Several reasons are possible for the survival advantage in our series. First, the survival difference may have represented a true treatment effect specific to the clinical scenario at recurrence (ie, PSA rise alone versus palpable recurrence). The observed survival difference may have been no more than a lead-time bias. Also, a survival bias might have been present owing to the disparity in the median age between the two groups—the men in the palpable failure group were a median 5 years older than their counterparts in the rising PSA group. However, a survival bias owUROLOGY 64 (4), 2004
ing to an age difference was unlikely because the cause-specific survival between the two groups remained significantly different despite the age difference. Other factors that were not evaluated in the study could not be excluded as confounding variables. We acknowledge that this single-institutional series was not sufficient evidence to confirm a definitive survival benefit. The combined response rate to EBRT of 95% among the entire group suggests that most of our patients who underwent salvage EBRT had a component of locally recurrent disease. This shows that a large number of men with a rising PSA level may benefit from localized salvage EBRT. In this series, all men with palpable disease experienced complete resolution, substantiating the available data that demonstrates a benefit of salvage EBRT in local tumor control for overt recurrence.13,14,24,25 Those with clinically evident locally recurrent disease were statistically significantly more likely to develop distant disease despite salvage EBRT. These results indicate that not treating PSA failure before the development of palpable local disease may unnecessarily increase the risk of developing distant metastases after RP. Thus, we would argue against the referral patterns reported by Ornstein et al.3 and would advocate early referral for localized therapy in men with a rising PSA level. The pre-RT PSA level is the most commonly reported variable found to predict for biochemical control after salvage EBRT.4,6,10,14,16,18,20 In our series, a lower pre-EBRT PSA level (0.5 ng/mL or less) independently predicted for a favorable biochemical outcome. The statistically significant benefit in the rate of bDFS for men with a pre-EBRT PSA level of 0.5 ng/mL or less was more than twice that of any other pre-EBRT PSA group. Analysis of salvage EBRT in isolated PSA failure at our institution showed that men with a PSA level less than 0.69 ng/mL, who received a sufficient EBRT dose, experienced a 5-year bDFS rate of 77%.26 Furthermore, a recent report from Memorial Sloan-Kettering Cancer Center identified a pre-RT PSA level of more than 0.6 ng/mL to be a statistically significant predictor for PSA relapse after salvage RT.16 Cumulatively, these reports serve to support a shift in the current referral pattern to earlier treatment with salvage EBRT, at a lower PSA level to increase the likelihood of controlling biochemical disease. Our experience revealed that salvage EBRT is reasonably tolerated. Our reported rate of chronic RT-related complications is comparable to that in current studies.6,10,12–14,16 –18 Furthermore, newonset incontinence related to EBRT was not a common complication and generally occurred 8 to 17 months after salvage. A single patient developed incontinence 64 months after salvage, but it was UROLOGY 64 (4), 2004
unclear whether EBRT was solely to blame that far removed from the therapy. Although the men in our series were not treated with androgen deprivation therapy, the beneficial effect of hormonal manipulation with EBRT as primary therapy for locally advanced prostate cancer has been reported.27 The Radiation Therapy Oncology Group recently closed a randomized prospective study (96-01) that compared EBRT with or without bicalutamide in men with a rising PSA level after RP. The results should prove helpful in determining whether men with recurrent disease after RP would benefit from a combined modality approach. The difference in distant failure and survival among the two groups of men in our series suggests the need for careful patient selection for optimal benefit to be achieved from salvage EBRT alone. Men who present with a greater pre-EBRT PSA level (more than 0.5 ng/mL) or a less than 2-year interval from RP to salvage EBRT are less likely to benefit from salvage EBRT alone. Early referral (before the onset of clinically apparent disease and/or pre-EBRT PSA level of 0.5 ng/mL or less) appeared to enhance the potential for biochemical salvage and decrease the risk of developing metastatic disease, and might confer a survival advantage for patients with failure after RP. REFERENCES 1. Stephenson RA, and Stanford JL: Population-based prostate cancer trends in the United States: patterns of change in the era of prostate-specific antigen. World J Urol 15: 331– 335, 1997. 2. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281: 1591–1597, 1999. 3. Ornstein DK, Colberg JW, Virgo KS, et al: Evaluation and management of men whose radical prostatectomies failed: results of an international survey. Urology 52: 1047–1054, 1998. 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 19: 1030 –1039, 2001. 5. Lange PH, Lightner DJ, Medini E, et al: The effect of radiation therapy after radical prostatectomy in patients with elevated prostate specific antigen levels. J Urol 144: 927–933, 1990. 6. Schild SE, Buskirk SJ, Wong WW, et al: The use of radiotherapy for patients with isolated elevation of serum prostate specific antigen following radical prostatectomy. J Urol 156: 1725–1729, 1996. 7. Kaplan EL, and Meier P: Nonparametric estimation from incomplete observations. Am Stat Assoc J 53: 457– 481, 1958. 8. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35: 1–39, 1977. 9. Cox DR: Regression models and life tables. J R Stat Soc B 34: 187–220, 1972. 10. Anscher MS, Clough R, and Dodge R: Radiotherapy for a rising prostate-specific antigen after radical prostatectomy: the first 10 years. Int J Radiat Oncol Biol Phys 48: 369 –375, 2000. 763
11. Cadeddu JA, Partin AW, DeWeese TL, et al: Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 159: 173–178, 1998. 12. Chawla AK, Thakral HK, Zietman AL, et al: Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology 59: 726 –731, 2002. 13. Choo R, Hruby G, Hong J, et al: (IN)-efficacy of salvage radiotherapy for rising PSA or clinically isolated local recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 53: 269 –276, 2002. 14. Do T, Parker RG, Do C, et al: Salvage radiotherapy for biochemical and clinical failures following radical prostatectomy. Cancer J Sci Am 4: 324 –330, 1998. 15. Garg MK, Tekyi-Mensah S, Bolton S, et al: Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy. Urology 51: 998 –1002, 1998. 16. Katz MS, Zelefsky MJ, Venkatraman ES, et al: Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J Clin Oncol 21: 483– 489, 2003. 17. Pisansky TM, Kozelsky TF, Myers RP, et al: Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer. J Urol 163: 845– 850, 2000. 18. Song DY, Thompson TL, Ramakrishnan V, et al: Salvage radiotherapy for rising or persistent PSA after radical prostatectomy. Urology 60: 281–287, 2002. 19. Taylor N, Kelly JF, Kuban DA, et al: Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 56: 755–763, 2003.
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20. Catton C, Gospodarowicz M, Warde P, et al: Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother Oncol 59: 51– 60, 2001. 21. Koppie TM, Grossfeld GD, Nudell DM, et al: Is anastomotic biopsy necessary before radiotherapy after radical prostatectomy? J Urol 166: 111–115, 2001. 22. Rogers R, Grossfeld GD, Roach M III, et al: Radiation therapy for the management of biopsy proved local recurrence after radical prostatectomy. J Urol 160: 1748 –1753, 1998. 23. vander Kooy MJ, Pisansky TM, Cha SS, et al: Irradiation for locally recurrent carcinoma of the prostate following radical prostatectomy. Urology 49: 65–70, 1997. 24. 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 Phys 39: 681– 686, 1997. 25. Forman JD, and Velasco J: Therapeutic radiation in patients with a rising post-prostatectomy PSA level. Oncology (Huntingt) 12: 33–39, 1998. 26. MacDonald OK, Schild SE, Vora SA, et al: Radiotherapy for men with isolated increase in serum prostate specific antigen after radical prostatectomy. J Urol 170: 1833– 1837, 2003. 27. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360: 103– 106, 2002.
UROLOGY 64 (4), 2004
SALVAGE RADIOTHERAPY FOR MEN WITH ISOLATED RISING PSA OR LOCALLY PALPABLE RECURRENCE AFTER RADICAL PROSTATECTOMY: DO OUTCOMES DIFFER? O. KENNETH MACDONALD, STEVEN E. SCHILD, SUJAY A. VORA, PAUL E. ANDREWS, ROBERT G. FERRIGNI, DONALD E. NOVICKI, SCOTT K. SWANSON, AND WILLIAM W. WONG
ABSTRACT Objectives. To compare, in a retrospective analysis, the outcome of salvage external beam radiotherapy (EBRT) for isolated prostate-specific antigen (PSA) elevation or palpable local recurrence after radical prostatectomy (RP). Methods. We evaluated 102 men who underwent EBRT from 1993 to 1999, 60 for a rising PSA level alone and 42 for palpable local disease after RP. Biochemical disease-free survival and overall survival were calculated. Prognostic factors were evaluated to determine associations with biochemical disease-free survival. Results. The 5-year rate of biochemical disease-free survival, local control, freedom from distant metastasis, and overall survival for all 102 patients was 38%, 94%, 87%, and 88%, respectively. All palpable disease resolved completely after salvage EBRT. The greatest 5-year rate of biochemical control (69%) was obtained in patients with a pre-EBRT PSA level of 0.5 ng/mL or less. The 5-year overall survival rate was significantly better for those who underwent salvage EBRT for a rising PSA level than for those with palpable recurrence (96% versus 78%, P ⫽ 0.02). A low pre-EBRT PSA level and a less than 2-year interval from RP to EBRT were independent predictors of biochemical failure. Five patients (5%) experienced chronic grade 3 or 4 RT-related toxicity. Conclusions. Salvage EBRT provides excellent local control of recurrent disease after RP. Salvage EBRT before the development of palpable local disease may confer a survival benefit and decrease the risk of metastasis, and durable biochemical control was achieved best in those whose pre-EBRT PSA level was 0.5 ng/mL or less. Early referral and careful patient selection is vital for salvage EBRT to be of optimal benefit. UROLOGY 64: 760–764, 2004. © 2004 Elsevier Inc.
R
adical prostatectomy (RP) as a primary treatment for clinically localized prostate cancer has increased in its application during the past decade.1 Despite the generally favorable results obtained with RP, some men will develop a detectable serum prostate-specific antigen (PSA) level. An elevated serum PSA level after RP is generally the earliest indication of recurrence, and an estimated 27% to 53% of men will develop detectable PSA levels within 10 years after RP.2 Although controversial, the treatment options for patients with a detectable PSA level after RP include observation, androgen deprivation therapy, and salFrom the Department of Radiation Oncology and Section of Urology, Mayo Clinic Scottsdale, Scottsdale, Arizona Reprint requests: Steven Schild, M.D., Department of Radiation Oncology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259 Submitted: March 1, 2004, accepted (with revisions): May 14, 2004 © 2004 ELSEVIER INC. 760
ALL RIGHTS RESERVED
vage external beam radiotherapy (EBRT) to the prostate bed. A survey of 1000 urologists indicated that 54% of respondents recommended observation for men with a detectable PSA level 1 year after RP and 13% recommended EBRT.3 In men with documented local recurrence, however, 81% of respondents recommended EBRT. Little evidence exists to confirm the benefit or detriment of these reported treatment patterns. Most published reports regarding salvage EBRT for biochemical or local recurrence after RP have not discussed these two clinical situations as separate entities. As a result, current studies have not provided sufficient information to address adequately the question of for whom salvage EBRT would be most efficacious. Therefore, we retrospectively evaluated the outcomes, analyzed the prognostic variables, and compared the results of salvage EBRT in men with rising PSA levels alone versus those with clinically apparent local prostate cancer recurrence after RP. 0090-4295/04/$30.00 doi:10.1016/j.urology.2004.05.016
TABLE I. Patient characteristics and crude outcomes data Characteristic Total (n) Median age (yr) Gleason score ⱖ8 (n) ⫹ Seminal vesicle invasion ⫹ Surgical margin involvement Median pre-EBRT PSA (ng/mL) Total median radiation dose (Gy) Median time to referral (yr) Median PSADT (mo) Follow-up (yr) Median Range Local failure (n) Distant failure (n) Biochemical failure (n) Total deaths (n) Deaths from prostate cancer (n)
Rising PSA Palpable 60 65.5 15 (25) 12 (20) 12 (20) 0.69 64 1.4 7.5
42 70.5 8 (19) 6 (14) 10 (23) 1.75 68.4 4.3 12
4.2 2 mo to 9 yr 2 (3) 4 (7) 30 (50) 3 (5) 2 (3)
4.3 2 mo to 8.7 yr 2 (5) 7 (17) 26 (62) 9 (21) 6 (14)
FIGURE 1. Overall survival after salvage EBRT for rising PSA level versus palpable local recurrence (P ⫽ 0.02).
KEY: PSA ⫽ prostate-specific antigen; EBRT ⫽ external beam radiotherapy; PSADT ⫽ PSA doubling time. Data in parentheses are percentages.
MATERIAL AND METHODS A total of 102 men who presented for salvage EBRT after RP with a detectable PSA level from 1993 to 1999 were included. Of these men, 42 patients had a detectable PSA level with a palpable local recurrence by digital rectal examination; 36 of these patients had biopsy-proven evidence of recurrent disease. The remaining 60 men had a rising PSA level alone. The median time to referral from RP to EBRT was 2 years (range 0.18 to 10). This study was performed with the appropriate institutional review board approval. All men had undergone RP with pelvic lymphadenectomy between 1984 and 1996. All patients were free of pelvic nodal metastasis at surgery. At referral, all men underwent an evaluation for metastatic disease, including bone scan and computed tomography of the abdomen and pelvis. No patient underwent androgen deprivation therapy before or during EBRT. The patient characteristics are presented in Table I. The median follow-up for the entire cohort was 4.2 years (range 2 months to 9 years). The PSA doubling time (PSADT) was calculated for 88 (86%) of the 102 patients using the log-linear regression method.2,4 EBRT was delivered to the prostatic bed with 10-MV photons using a four-field technique and custom blocks. The delivery of EBRT was confined to the prostatic bed based on localization using urethral, bladder, and rectal contrast at simulation. The total dose ranged from 41 to 70 Gy (median 66), with daily doses of 1.8 to 2.0 Gy. No intensity-modulated RT or three-dimensional conformal RT was used. Late toxicity was evaluated using the Radiation Therapy Oncology Group toxicity criteria. Freedom from PSA failure after salvage EBRT (biochemical disease-free survival [bDFS]) was defined as maintaining a serum PSA level of 0.3 ng/mL or less.5,6 Additional criteria of biochemical failure included a post-EBRT PSA level that was greater than the pre-EBRT PSA level, initiation of androgen deprivation therapy after EBRT, or clinical or radiographic evidence of local or metastatic disease. The time of failure was dated to the point at which a criterion for failure was met; no back dating was used. Local failure was defined as clinical UROLOGY 64 (4), 2004
FIGURE 2. Freedom from distant metastasis (DM) and bDFS after salvage EBRT for rising PSA level versus palpable local recurrence (P ⫽ 0.05 and P ⫽ 0.1, respectively).
persistence or recurrence of a palpable lesion in the prostatic bed on digital rectal examination or follow-up computed tomography scan. Distant failure was defined as symptomatic or radiographic evidence of metastasis. We evaluated the primary endpoints of bDFS, local failure, distant failure, cause-specific survival, and overall survival. The rates of survival and freedom from failure were calculated using the Kaplan-Meier method.7 Univariate analysis of the prognostic variables was performed using the log-rank test.8 Multivariate analysis was performed using the Cox proportional hazards model.9 Statistical significance was declared for P ⬍0.05.
RESULTS The 5-year rate of bDFS, local control, freedom from distant metastases, and overall survival for all 102 men was 38%, 94%, 87%, and 88%, respectively. The 5-year rate of overall survival for the isolated PSA failure group was significantly better than for the palpable failure group (96% versus 78%, respectively; P ⫽ 0.02; Fig. 1). Similarly, the 5-year rate of cause-specific survival significantly favored those with a rising PSA level alone (98% 761
versus 84%; P ⫽ 0.02). A benefit in the control of distant failure at 5 years for the isolated PSA failure group approached statistical significance (P ⫽ 0.05; Fig. 2). The rate of local control at 5 years was similar for the two groups (P ⫽ 0.68). The initial biochemical response to salvage EBRT for all patients was favorable; 74 patients (73%) achieved an undetectable PSA level within the first year after EBRT and 22 (22%) had a decrease from the pre-EBRT level. The complete response (achieving an undetectable PSA level) rate after salvage EBRT was similar between the two groups— 78% and 64% for men in the isolated PSA and palpable recurrence group, respectively. Of the 102 men, 56 (55%) experienced biochemical failure at or before the last follow-up. The rate of bDFS at 5 years for the palpable and isolated PSA group was 27% and 45%, respectively (P ⫽ 0.1; Fig. 2). Similar rates of bDFS were obtained using an alternative definition— undetectable PSA at less than 0.1 ng/mL—as the criterion for freedom from biochemical recurrence. All those with palpable disease at salvage had resolution of the palpable disease within 1 year after EBRT. The PSA level before salvage EBRT was associated with the rate of bDFS. Men whose PSA level was less than 1.0 ng/mL at salvage experienced a 5-year bDFS rate of 51% versus 18% in those with a PSA level of 1.0 ng/mL or greater (P ⫽ 0.009). The entire cohort was divided into quartiles according to the pre-EBRT PSA level, revealing a 5-year bDFS rate of 69%, 28%, 33%, and 14% for a pre-EBRT PSA level of 0.5 ng/mL or less, 0.6 to 1.0 ng/mL, 1.1 to 2.4 ng/mL, and 2.5 ng/mL or greater, respectively (P ⫽ 0.02). A subset of men with a pre-EBRT PSA level of less than 1.0 ng/mL and a total EBRT dose of 66 Gy or greater (median EBRT dose) experienced a statistically significant benefit in bDFS at 5 years compared with the others (51% versus 22%, P ⫽ 0.02). The median pre-EBRT PSADT for the entire cohort was calculated to be 8 months (range 2 months to 22 years). Patients with a PSADT longer than 8 months had a 5-year bDFS rate of 48% compared with 28% for those whose doubling time was less than 8 months (P ⫽ 0.16). When evaluated separately, men with palpable recurrence (median PSADT 12 months) whose doubling time was longer than 1 year experienced a statistically significant benefit in biochemical control after salvage EBRT (5-year rate of 51% versus 0%; P ⫽ 0.02). No statistically significant effect of PSADT on bDFS was found in the rising PSA group (P ⫽ 0.34). The possible prognostic factors analyzed included pathologic stage (T2 versus T3–T4), pre-RP PSA level, pre-EBRT PSA by quartile, Gleason score (6, 7, or 8 or more), surgical margin status, seminal vesicle involvement, interval from RP to 762
salvage EBRT, PSADT, and EBRT dose (less than 66 and 66 Gy or greater). Univariate analysis showed Gleason score, interval from RP to salvage EBRT, and pre-EBRT PSA level were significantly associated with bDFS. Multivariate analysis revealed that pre-EBRT PSA by quartile (relative risk 1.46, 95% confidence interval 1.13 to 1.9, P ⫽ 0.004) and a shorter than 2-year interval from RP to salvage EBRT (relative risk 2.15, 95% confidence interval 1.20 to 3.93, P ⫽ 0.01) independently predicted for biochemical failure after EBRT. A Gleason score of 8 or more displayed a trend toward independent prognostic significance (P ⫽ 0.06). No factor significantly predicted for overall survival. Among all patients, 46 late RT-related toxicities occurred. Seventeen patients experienced late Grade 1 or 2 bladder toxicity, and three reported Grade 3 or 4 toxicity. Twenty patients reported late Grade 1 or 2 gastrointestinal toxicity, and two reported grade 3 toxicity. Twenty-one men reported incontinence at the referral for salvage EBRT— three had resolution of incontinence after EBRT and four developed new incontinence 8, 17, 17, and 64 months after EBRT. COMMENT In contrast to most reports concerning salvage EBRT after RP, we separately evaluated and compared EBRT among men for a rising PSA level alone10 –19 or for palpable recurrent disease.4,11,13,20 –23 Our report appears to be the first to suggest a statistically significant difference in survival between these two groups. Within the available published data, we found one report that addressed the issue of survival and salvage EBRT. The report, by Choo et al.,13 showed no statistically significant difference in the 4-year rates of overall survival for 98 men who were treated with salvage EBRT for a persistently elevated PSA level, delayed PSA elevation, or clinically apparent local recurrence after RP. In contrast, we found a statistically significant difference in overall survival favoring men with delayed PSA elevation after RP. Retrospective analyses have inherent limitations. Several reasons are possible for the survival advantage in our series. First, the survival difference may have represented a true treatment effect specific to the clinical scenario at recurrence (ie, PSA rise alone versus palpable recurrence). The observed survival difference may have been no more than a lead-time bias. Also, a survival bias might have been present owing to the disparity in the median age between the two groups—the men in the palpable failure group were a median 5 years older than their counterparts in the rising PSA group. However, a survival bias owUROLOGY 64 (4), 2004
ing to an age difference was unlikely because the cause-specific survival between the two groups remained significantly different despite the age difference. Other factors that were not evaluated in the study could not be excluded as confounding variables. We acknowledge that this single-institutional series was not sufficient evidence to confirm a definitive survival benefit. The combined response rate to EBRT of 95% among the entire group suggests that most of our patients who underwent salvage EBRT had a component of locally recurrent disease. This shows that a large number of men with a rising PSA level may benefit from localized salvage EBRT. In this series, all men with palpable disease experienced complete resolution, substantiating the available data that demonstrates a benefit of salvage EBRT in local tumor control for overt recurrence.13,14,24,25 Those with clinically evident locally recurrent disease were statistically significantly more likely to develop distant disease despite salvage EBRT. These results indicate that not treating PSA failure before the development of palpable local disease may unnecessarily increase the risk of developing distant metastases after RP. Thus, we would argue against the referral patterns reported by Ornstein et al.3 and would advocate early referral for localized therapy in men with a rising PSA level. The pre-RT PSA level is the most commonly reported variable found to predict for biochemical control after salvage EBRT.4,6,10,14,16,18,20 In our series, a lower pre-EBRT PSA level (0.5 ng/mL or less) independently predicted for a favorable biochemical outcome. The statistically significant benefit in the rate of bDFS for men with a pre-EBRT PSA level of 0.5 ng/mL or less was more than twice that of any other pre-EBRT PSA group. Analysis of salvage EBRT in isolated PSA failure at our institution showed that men with a PSA level less than 0.69 ng/mL, who received a sufficient EBRT dose, experienced a 5-year bDFS rate of 77%.26 Furthermore, a recent report from Memorial Sloan-Kettering Cancer Center identified a pre-RT PSA level of more than 0.6 ng/mL to be a statistically significant predictor for PSA relapse after salvage RT.16 Cumulatively, these reports serve to support a shift in the current referral pattern to earlier treatment with salvage EBRT, at a lower PSA level to increase the likelihood of controlling biochemical disease. Our experience revealed that salvage EBRT is reasonably tolerated. Our reported rate of chronic RT-related complications is comparable to that in current studies.6,10,12–14,16 –18 Furthermore, newonset incontinence related to EBRT was not a common complication and generally occurred 8 to 17 months after salvage. A single patient developed incontinence 64 months after salvage, but it was UROLOGY 64 (4), 2004
unclear whether EBRT was solely to blame that far removed from the therapy. Although the men in our series were not treated with androgen deprivation therapy, the beneficial effect of hormonal manipulation with EBRT as primary therapy for locally advanced prostate cancer has been reported.27 The Radiation Therapy Oncology Group recently closed a randomized prospective study (96-01) that compared EBRT with or without bicalutamide in men with a rising PSA level after RP. The results should prove helpful in determining whether men with recurrent disease after RP would benefit from a combined modality approach. The difference in distant failure and survival among the two groups of men in our series suggests the need for careful patient selection for optimal benefit to be achieved from salvage EBRT alone. Men who present with a greater pre-EBRT PSA level (more than 0.5 ng/mL) or a less than 2-year interval from RP to salvage EBRT are less likely to benefit from salvage EBRT alone. Early referral (before the onset of clinically apparent disease and/or pre-EBRT PSA level of 0.5 ng/mL or less) appeared to enhance the potential for biochemical salvage and decrease the risk of developing metastatic disease, and might confer a survival advantage for patients with failure after RP. REFERENCES 1. Stephenson RA, and Stanford JL: Population-based prostate cancer trends in the United States: patterns of change in the era of prostate-specific antigen. World J Urol 15: 331– 335, 1997. 2. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281: 1591–1597, 1999. 3. Ornstein DK, Colberg JW, Virgo KS, et al: Evaluation and management of men whose radical prostatectomies failed: results of an international survey. Urology 52: 1047–1054, 1998. 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 19: 1030 –1039, 2001. 5. Lange PH, Lightner DJ, Medini E, et al: The effect of radiation therapy after radical prostatectomy in patients with elevated prostate specific antigen levels. J Urol 144: 927–933, 1990. 6. Schild SE, Buskirk SJ, Wong WW, et al: The use of radiotherapy for patients with isolated elevation of serum prostate specific antigen following radical prostatectomy. J Urol 156: 1725–1729, 1996. 7. Kaplan EL, and Meier P: Nonparametric estimation from incomplete observations. Am Stat Assoc J 53: 457– 481, 1958. 8. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35: 1–39, 1977. 9. Cox DR: Regression models and life tables. J R Stat Soc B 34: 187–220, 1972. 10. Anscher MS, Clough R, and Dodge R: Radiotherapy for a rising prostate-specific antigen after radical prostatectomy: the first 10 years. Int J Radiat Oncol Biol Phys 48: 369 –375, 2000. 763
11. Cadeddu JA, Partin AW, DeWeese TL, et al: Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 159: 173–178, 1998. 12. Chawla AK, Thakral HK, Zietman AL, et al: Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology 59: 726 –731, 2002. 13. Choo R, Hruby G, Hong J, et al: (IN)-efficacy of salvage radiotherapy for rising PSA or clinically isolated local recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 53: 269 –276, 2002. 14. Do T, Parker RG, Do C, et al: Salvage radiotherapy for biochemical and clinical failures following radical prostatectomy. Cancer J Sci Am 4: 324 –330, 1998. 15. Garg MK, Tekyi-Mensah S, Bolton S, et al: Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy. Urology 51: 998 –1002, 1998. 16. Katz MS, Zelefsky MJ, Venkatraman ES, et al: Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J Clin Oncol 21: 483– 489, 2003. 17. Pisansky TM, Kozelsky TF, Myers RP, et al: Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer. J Urol 163: 845– 850, 2000. 18. Song DY, Thompson TL, Ramakrishnan V, et al: Salvage radiotherapy for rising or persistent PSA after radical prostatectomy. Urology 60: 281–287, 2002. 19. Taylor N, Kelly JF, Kuban DA, et al: Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 56: 755–763, 2003.
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20. Catton C, Gospodarowicz M, Warde P, et al: Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother Oncol 59: 51– 60, 2001. 21. Koppie TM, Grossfeld GD, Nudell DM, et al: Is anastomotic biopsy necessary before radiotherapy after radical prostatectomy? J Urol 166: 111–115, 2001. 22. Rogers R, Grossfeld GD, Roach M III, et al: Radiation therapy for the management of biopsy proved local recurrence after radical prostatectomy. J Urol 160: 1748 –1753, 1998. 23. vander Kooy MJ, Pisansky TM, Cha SS, et al: Irradiation for locally recurrent carcinoma of the prostate following radical prostatectomy. Urology 49: 65–70, 1997. 24. 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 Phys 39: 681– 686, 1997. 25. Forman JD, and Velasco J: Therapeutic radiation in patients with a rising post-prostatectomy PSA level. Oncology (Huntingt) 12: 33–39, 1998. 26. MacDonald OK, Schild SE, Vora SA, et al: Radiotherapy for men with isolated increase in serum prostate specific antigen after radical prostatectomy. J Urol 170: 1833– 1837, 2003. 27. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360: 103– 106, 2002.
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