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Impact of pathological tumor stage for salvage radiotherapy after radical prostatectomy in patients with prostate-specific antigen < 1.0 ng/ml

Impact of pathological tumor stage for salvage radiotherapy after radical prostatectomy in... Background: To evaluate prognostic factors in salvage radiotherapy (RT) for patients with pre-RT prostate-specific antigen (PSA) < 1.0 ng/ml. Methods: Between January 2000 and December 2009, 102 patients underwent salvage RT for biochemical failure after radical prostatectomy (RP). Re-failure of PSA after salvage RT was defined as a serum PSA value of 0.2 ng/ml or more above the postradiotherapy nadir followed by another higher value, a continued rise in serum PSA despite salvage RT, or initiation of systemic therapy after completion of salvage RT. Biochemical relapse-free survival (bRFS) was estimated using the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards regression model. Results: The median follow-up period was 44 months (range, 11-103 months). Forty-three patients experienced PSA re-failure after salvage RT. The 4-year bRFS was 50.9% (95% confidence interval [95% CI]: 39.4-62.5%). In the log-rank test, pT3-4 (p < 0.001) and preoperative PSA (p = 0.037) were selected as significant factors. In multivariate analysis, only pT3-4 was a prognostic factor (hazard ratio: 3.512 [95% CI: 1.535-8.037], p = 0.001). The 4-year bRFS rates for pT1-2 and pT3-4 were 79.2% (95% CI: 66.0-92.3%) and 31.7% (95% CI: 17.0-46.4%), respectively. Conclusions: In patients who have received salvage RT after RP with PSA < 1.0 ng/ml, pT stage and preoperative PSA were prognostic factors of bRFS. In particular, pT3-4 had a high risk for biochemical recurrence after salvage RT. Keywords: Prostate cancer, Radiotherapy, Radical Prostatectomy, PSA, Pathological tumor stage Background that 5- and 10-year prostate cancer-specific survival rates Radical prostatectomy (RP) is one of the curative treat- were 88% and 62%, respectively, for patients with no sal- ments for prostate cancer. However, biochemical recur- vage treatment and 96% and 86%, respectively, for patients rence after radical prostatectomy occurs in approximately who received salvage RT alone [5]. Recent studies have 15% to 40% of patients within 5 years [1,2]. Approximately suggested that early RT is more effective than delayed RT. one third of patients with biochemical recurrence will Some studies have demonstrated that pre-RT PSA is a prognostic factor [4,6-14]. Based on results of those stu- have distant metastases, and the median actuarial period to development of metastases following prostate-specific dies, it seems that pre-RT PSA < 1.0 ng/ml as a cutoff antigen (PSA) elevation is 8 years [3]. Many studies have value is a factor predicting PSA re-failure after salvage RT demonstrated that salvage radiotherapy (RT) for biochem- [4,7,8,12], though according to a consensus panel report ical recurrence after RP is effective and enables long-term published by the American Society of Therapeutic Radiol- suppression of PSA elevation [4]. Trock et al. reported ogy and Oncology (ASTRO), early treatment (PSA < 1.5 ng/ml) is more successful than later treatment [15]. How- * Correspondence: reirei513@hotmail.com ever, even some patients with pre-RT PSA < 1.0 ng/ml Department of Radiation Oncology, Tohoku University School of Medicine, who have received salvage RT have biochemical Seiryou-machi 1-1, Aobaku, Sendai, Japan © 2011 Umezawa et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Umezawa et al. Radiation Oncology 2011, 6:150 Page 2 of 8 http://www.ro-journal.com/content/6/1/150 recurrence. The objective of this study was to evaluate continued rise in serum PSA despite salvage RT, or prognostic factors in salvage RT after RP for patients with initiation of systemic therapy after completion of salvage pre-RT PSA < 1.0 ng/ml. RT [17]. The time to PSA re-failure after salvage RT was calculated from the first day of RT. Measurement of Methods PSA after salvage RT was done at least once every 3 Patients months. Between January 2000 and December 2009, 102 patients received salvage RT for biochemical failure after RP in Statistical analysis Tohoku University Hospital and seven affiliated hospi- Biochemical relapse-free survival (bRFS) was estimated tals. Although the American Urological Association using the Kaplan-Meier method, and the log-rank test (AUA) defines biochemical recurrence following RP as was used to analyze differences between patient sub- initial serum PSA of ≥ 0.2 ng/ml with a second confir- groups categorized by prognostic variables. Multivariate matory level of > 0.2 ng/ml [16], the main criterion for analysis was performed using the Cox proportional salvage RT in this study was that PSA after RP was 0.1 hazards regression model. Hazard ratios are presented ng/ml or more or that PSA after RP was three consecu- for each prognostic factor. We evaluated pathologic tive increasing. Patients with massive local recurrence tumor (pT) stage, surgical margin, Gleason score (GS), that was detectable by CT or MRI or patients with preoperative PSA, pre-RT PSA (Pre-RT PSA of patients lymph node or distant metastasis were excluded from who received hormone therapy was evaluated as that this study. Patients who continued to receive hormone before hormone therapy.), PSADT, dose to the prostate therapy for PSA failure after RP but became resistant to bed, biological effective dose (BED) (calculated using a/ the hormone therapy were also excluded. b = 1.5 according to the LQ model) [18], time from RP to the start of RT and hormonal therapy as prognostic PSA doubling time factors. Multivariate analysis included factors with p < PSA doubling time (PSADT) was calculated using PSA 0.10 in univariate analysis. All tests were two-sided, and values above 0.1 ng/ml after RP until the start of salvage statistical significance was set at the level of p < 0.05. RT. PSADT was not calculated for patients who did not Statistical analysis was performed using the Statistical have PSA above 0.1 ng/ml. PSADT was estimated by Package for Social Sciences (SPSS) version 14.0 (SPSS, the natural log of 2 (0.693) divided by the slope of the Chicago, IL). linear regression line of PSA over time [3]. Toxicity Radiotherapy Complications due to salvage RT were evaluated accord- The prostate bed, the bladder neck, the urethral anasto- ing to the common terminology criteria for adverse mosis and the seminal vesicle bed (in the case of inva- events (CTCAE) ver.4.0. Late toxicity was defined as a sion to seminal vesicle) were defined as the clinical complication occurring more than three months after target volume (CTV) with references to preoperative salvage RT. computed tomography or magnetic resonance imaging. The planning target volume (PTV) included the CTV Ethics with a margin of approximately 1 cm in all directions. Written informed consent for treatment was obtained The leaf margin was 0.5 cm in all directions. Salvage RT from all patients, and this retrospective study was per- was delivered using photon beams of 10 MV or 15 MV formed according to the principles of the Declaration of mostly with the four-field technique, three-dimensional Helsinki (2008). conformal RT. The median RT dose was 64 Gy (range, 60-72 Gy). The numbers of patients receiving 60 Gy at Results 2 Gy daily, 62 Gy at 2 Gy daily, 64 Gy at 2 Gy daily, Patient and tumor characteristics are shown in Table 1. 64.8 Gy at 1.8 Gy daily, 70 Gy at 2 Gy daily and 72 Gy Median age at salvage RT was 67 years (range, 49-81 at 1.2 Gy per fraction twice daily (hyperfractionation) to years). Median pre-RT PSA was 0.240 (range, 0.011- the prostate bed were 18, 1, 67, 12, 3 and 1, respectively. 0.994 ng/ml). Median preoperative PSA was 8.8 ng/ml The RT dose was prescribed at the center of the PTV. (range, 1.6-120 ng/ml). Median PSADT was 6.83 None of the patients underwent whole pelvic irradiation. months (range, 0.58-41.9 months). Hormone therapy was given to 29 patients before and/ Follow-up or during salvage RT for a median period of 6 months Re-failure of PSA after salvage RT was defined as a (range, 1-18 months). Eleven of those patients continued serum PSA value of 0.2 ng/ml or more above the post- to receive hormone therapy for a median period of 12 radiotherapy nadir followed by another higher value, a months (range, 1-15 months) after salvage RT. Two Umezawa et al. Radiation Oncology 2011, 6:150 Page 3 of 8 http://www.ro-journal.com/content/6/1/150 Table 1 Patients’ characteristics cancer, though one patient died of esophageal cancer and one patient died of bile duct cancer. PSA decreased Characteristic No. Median (range) in 64 of the 73 patients who received salvage RT after Age at salvage RT (years) 67 (49-81) RP without hormone therapy. Forty-three patients had Pathologic tumor stage re-failure after salvage RT at the last observation date. T1 2 The 4-year bRFS rate was 50.9% (95% CI: 39.4-62.5%) T2 41 (Figure 1). Multiple lung metastases occurred in one T3 57 patient 17 months after salvage RT, and bone metastases T4 1 occurred in two patients 36 and 43 months after salvage Unknown 2 RT. Surgical margin Resultsofthe log-rank testspresented in Table2 Positive 48 show the 4-year bRFS for each prognostic factor before Negative 51 salvage RT. It was found that pT stage (p < 0.001) and Unknown 3 preoperative PSA (p = 0.037) were significant prognostic Gleason score factors. The 4-year bRFS for pT1-2 and pT3-4 were ≤631 79.2% (95% CI: 66.0-92.3%) and 31.7% (95% CI: 17.0- 46.4%), respectively (Figure 2). We also analyzed bRFS 8 ≥ 31 for extracapsular extension and seminal vesicle invasion. Unknown 5 The 4-year bRFS for positive and negative extracapsular Preoperative PSA (ng/ml) 8.8 (1.6-120) extension were 79.9% (95% CI: 65.4-94.5%) and 35.9% <10 58 (95% CI: 21.0-49.8%) (p = 0.003), respectively. The 4- ≥ 10 44 year bRFS for positive and negative seminal vesicle inva- Pre-RT PSA (ng/ml) 0.240 (0.011-0.994) sion were 56.9% (95% CI: 44.3-71.0%) and 19.0% (95% < 0.25 52 CI: 0-39.1%) (p = 0.004), respectively. The 4-year bRFS ≥ 0.25 50 for preoperative PSA < 10 ng/ml and ≥ 10 ng/ml were PSA doubling time (months) 6.83 (0.58-41.9) 62.0% (95% CI: 47.7-76.3%) and 39.3% (95% CI: 22.5- <7 43 56.0%), respectively (Figure 3). Although not significant, ≥743 PSADT (p = 0.059) and RT dose (p = 0.068) tended to Not available 16 be prognostic factors. The 4-year bRFS for PSADT < 7 RT dose (Gy) (BED, a/b = 1.5) 64 (149.3) (60-72 [129.6- 163.3]) months and ≥ 7 months were 34.6% (95% CI: 17.5- 60 at 2 daily (140.0) 18 51.8%) and 62.2% (95% CI: 46.7-77.7%), respectively 62 at 2 daily (144.7) 1 64 at 2 daily (149.3) 67 64.8 at 1.8 daily (142.6) 12 70 at 2 daily (163.3) 3 72 at 1.2 per fraction twice daily (HF) 1 (129.6) Time from RP to RT (months) 21 (5-99) <24 56 ≥ 24 46 Hormone therapy Done 29 Not done 73 Abbreviations: RT = radiotherapy, PSA = prostate-specific antigen, BED = biological effective dose, HF = hyperfractionation, RP = radical prostatectomy patients received hormone therapy for PSA failure and stopped the therapy because of decrease in PSA but re- started the therapy when PSA had increased again. No patient received adjuvant hormone therapy after RP. The median follow-up period from the start of salvage RT was 44 months (range, 11-103 months). The 4-year Figure 1 Biochemical relapse-free survival (bRFS) after salvage overall survival rate was 97.3% (95% confidence interval radiotherapy. [95% CI]: 93.6-100%). No patient died of prostate Umezawa et al. Radiation Oncology 2011, 6:150 Page 4 of 8 http://www.ro-journal.com/content/6/1/150 Table 2 Results of log-rank tests Factor 4-year bRFS (%) (95% CI) p value Pathologic tumor stage < 0.001 T1-2 79.2 (66.0-92.3) T3-4 31.7 (17.0-46.4) Surgical margin 0.652 Positive 48.6 (32.0-65.1) Negative 57.1 (42.7-71.4) Gleason score 0.189 ≤ 7 58.9 (44.5-73.3) ≥ 8 35.2 (14.7-51.5) Preoperative PSA (ng/ml) 0.037 < 10 62.0 (47.7-76.3) ≥ 10 39.3 (22.5-56.0) Pre-RT PSA (ng/ml) 0.620 < 0.25 54.5 (37.5-71.6) ≥ 0.25 45.9 (30.2-64.9) PSA doubling time (months) 0.059 Figure 2 Four-year biochemical relapse-free survival in patients with pT3-4 and that in patients with pT1-2. < 7 34.6 (17.5-51.8) ≥ 7 62.2 (46.7-77.7) RT dose (Gy) 0.068 hazard ratio (HR) with pT3-4 was 3.512 (95% CI: 1.535- < 64 36.8 (15.2-58.5) 8.037) (Table 3). After adjusting for pT, none of the ≥ 64 51.7 (37.6-65.9) other variables retained prognostic significance. BED (Gy) (a/b = 1.5) 0.213 Grade 2 late urinary tract complication was observed < 145 41.4 (23.5-59.3) in one patient who suffered from urinary occlusion. ≥ 145 54.3 (39.5-69.1) Grade 3 late rectal complication was observed in one Time from RP to RT (months) 0.310 patient who suffered from rectal bleeding. < 24 45.2 (29.1-61.4) ≥ 24 57.4 (40.9-73.9) Discussion Hormone therapy 0.627 Moreira et al. reported that the 1-, 3- and 5-year risks of Done 50.5 (20.2-72.9) receiving any salvage treatment after RP were 29%, 48% Not done 50.7 (37.6-63.7) Abbreviations: bRFS = biochemical relapse-free survival, RT = radiotherapy, PSA = prostate-specific antigen, BED = biological effective dose, RP = radical prostatectomy, CI = confidence interval (Figure 4). The 4-year bRFS for dose < 64 Gy and ≥ 64 Gy were 36.8% (95% CI: 15.2-58.5%) and 52.7% (95% CI: 39.5-69.1%), respectively (Figure 5). When we evaluated bRFS in 73 patients without hormone therapy, pT stage (p < 0.001) and preoperative PSA (p = 0.018) were also significant prognostic factors. In those patients, the 4- year bRFS for pT1-2 and pT3-4 were 78.5% (95% CI: 62.9-94.2%) and 29.6% (95% CI: 13.7-45.6%), respec- tively, and the 4-year bRFS for preoperative PSA < 10 ng/ml and ≥ 10 ng/ml were 64.0% (95% CI: 48.5-79.5%) and 33.9% (95% CI: 14.3-53.6%), respectively. In 79 patients who received 64 or 64.8 Gy to the pros- tate bed, the 4-year bRFS for pT1-2 and pT3-4 were 85.5% (95% CI: 73.6-97.3%) and 28.8% (95% CI: 7.87- 49.8%) (p < 0.001), respectively (Figure 6). Multivariate analysis was evaluated by pT stage, preo- Figure 3 Four-year biochemical relapse-free survival in patients with preoperative prostate-specific antigen (PSA) ≥ 10 ng/ml perative PSA, PSADT and RT dose. Only pT stage was and that in patients with preoperative PSA < 10 ng/ml. a significant prognostic factor (p = 0.003) and the Umezawa et al. Radiation Oncology 2011, 6:150 Page 5 of 8 http://www.ro-journal.com/content/6/1/150 Figure 6 Four-year biochemical relapse-free survival for pT3-4 and that for pT1-2 in patients who received 64 or 64.8 Gy to the prostate bed. Figure 4 Four-year biochemical relapse-free survival in patients with prostate specific-antigen doubling time (PSADT) ≥ 7 months and that in patients with PSADT < 7 months. previous studies might not be appropriate differences in race, conditions under which salvage RT was performed and criteria of re-failure after salvage RT, bRFS in the and 53%, respectively [19]. Salvage RT is one of the present study was similar to that in previous studies major treatments for biochemical recurrence after RP, (Table 4). However, significant prognostic factors for re- and many studies have shown that salvage RT is effec- failure of salvage RT in those studies were different. tive [4,6-14,20-27]. In our study, PSA decreased in 64 of Some of those studies showed that pre-RT PSA < 1.0 the 73 patients who received salvage RT after RP with- ng/mlwas aprognosticfactor [4,7,8,12]. In those stu- out hormone therapy, suggesting that this treatment was dies, median values of pre-RT PSA were higher (0.7-4.5 effective for biochemical failure after RP. Those patients ng/ml) than that in the present study (0.240 ng/ml). might have had at least a component local disease. PSA However, even some patients with pre-RT PSA < 1.0 did not decrease in the patient who had multiple lung ng/ml who have received salvage RT experience bio- metastases. Although comparison with results of chemical recurrence. Therefore, we retrospectively eval- uated prognostic factors in salvage RT for patients with pre-RT PSA < 1.0 ng/ml. Table 3 Multivariate analysis of parameters with bRFS Factors Hazards ratio (95% CI) p value Pathologic tumor stage 0.003 T1-2 Reference T3-4 3.512 (1.535-8.037) Preoperative PSA (ng/ml) 0.177 < 10 Reference ≥ 10 1.566 (0.816-3.006) PSADT (months) 0.272 < 7 Reference ≥ 7 0.686 (0.350-1.344) RT dose (Gy) 0.357 < 64 Reference ≥ 64 0.712 (0.345-1.469) Figure 5 Four-year biochemical relapse-free survival in patients Abbreviations: bRFS = biochemical relapse-free survival, PSA = prostate- with radiotherapy (RT) dose ≥ 64 Gy and that in patients with specific antigen, PSADT = prostate-specific antigen doubling time, RT = RT dose < 64 Gy. radiotherapy, RP = radical prostatectomy, CI = confidence interval Umezawa et al. Radiation Oncology 2011, 6:150 Page 6 of 8 http://www.ro-journal.com/content/6/1/150 Table 4 Past studies on salvage RT for biochemical recurrence after RP Study Patients (n) Median pre-RT PSA (ng/ml) prognostic factors after salvage RT bRDS(%) Hagan et al [7] 91 4.5 pre-RT PSA (< 1.0 ng/ml) 55 (5-year) Quero et al [8] 59 1.43 pre-RT PSA (< 1.0 ng/ml) 41.2 (5-year) Macdonald et al [9] 121 1.4 pre-RT PSA (< 0.2 ng/ml) NA Anscher et al [10] 89 1.4 pre-RT PSA (< 2.5 ng/ml), RT dose (> 65 Gy) 50 (4-year) Chawla et al [20] 54 1.3 Gleason score (≤ 6), time to detectable postoperative PSA 35 (5-year) Tsien et al [21] 57 1.2 Gleason score (< or = 7) 58 (5-year) Neuhof et al [4] 171 1.1 Gleason score (< 7), pre-RT PSA (< 1.0 ng/ml) 35.1 (5-year) Jacinto et al [22] 43 0.87 PSADT (> 4.0 months) 71 (3-year) Taylor et al [23] 66 0.8 delayed rise in PSA after RP 66 (5-year) Pazona et al [11] 307 0.8 pre-RT PSA (< 1.3 ng/ml), Seminal vesicle 40 (5-year) Stephenson et al [6] 501 0.72 Gleason score (≤ 7), pre-RT PSA (≤ 2.0 ng/ml), 45 (4-year) PSADT (> 10 months) Buskirk et al [12] 368 0.7 pT2-3a, Gleason score (≤ 7), Pre-RT PSA (< 1.0 ng/ml) 46 (5-year) Bernard et al [13] 364 0.6 RT dose (> 66.6 Gy, patients with pre-RT PSA < 0.6 ng/ml) 50 (5-year) Ward et al [24] 211 0.6 PSADT (> 12 months) 34 (10-year) King et al [25] 37 0.49 PSAV (≤ 1.0 ng/ml/year) NA Wiegel et al [26] 162 0.33 PSA undetectable after salvage RT (< 0.1 ng/ml) 54 (3.5-year) Tomita et al [27] 51 0.25 PSADT (> 3.0 months), Gleason Score, RT dose (≥ 60 Gy) 55.1 (3-year) Terai et al [14] 37 0.146 cT1-2, pT2, pre-RT PSA (> 0.15 ng/ml) 54 (5-year) Abbreviations: RT = radiotherapy, RP = radical prostatectomy, PSA = prostate-specific antigen, bRDS = biochemical relapse-free survival, PSADT = PSA doubling time, PSAV = PSA velocity, NA = not available In the present study, pre-RT PSA was not a significant be that there were 16 patients for whom PSADT data factor. Therefore, there might be no need for early sal- were not available and the number of cases for analysis vage RT in patients with pre-RT PSA < 1.0 ng/ml. How- was insufficient. If pre-RT PSA is < 1.0 ng/ml, we might ever, early or more intense salvage RT in cases of high be able to refer to PSADT for starting salvage RT. risk for recurrence (e.g., pT3-4 and preoperative PSA > Although PSADT is widely used to predict outcomes 10 ng/ml) even with PSA < 1.0 ng/ml might be neces- such as time to progression, underlying the impressive sary because the rate of biochemical recurrence after evidence of predictive value and prognostic value of salvage RT is relatively high even in patients with pre- PSADT are many basic questions about how it should RT PSA < 1.0 ng/ml. Further investigation of the prog- be calculated [29]. Although Arlen et al. demonstrated nostic factors of salvage RT other than pre-RT PSA in that PSA kinetics was all calculated from the point of patients with high risk for recurrence is needed. failure of 0.2 ng/ml [30], PSADT was calculated using PSA values above 0.1 ng/ml after RP in our study. Recently, PSADT has been utilized as a prognostic In our study, only pT3-4 was a significant factor pre- factor for prostatectomy. Pound et al. found that PSADT predicted the likelihood of subsequent develop- dicting PSA re-failure after salvage RT in multivariate ment of metastatic disease [3]. Freedland et al. found analysis. In a study by Wiegel et al., bRFS for pT3-4 was that prostate cancer-specific survival of patients with worsethanthatfor pT2(p= 0.047) [26]. Although PSADT < 9 months (especially < 3 months) was worse bRFS for pT3-4 was poor in patients with PSA < 1.0 ng/ than that of patients with PSADT > 15 months [28]. ml, there may be some room for improvement in RT Some past studies have demonstrated that PSADT was for patients with pT3-4. One method for improving also a prognostic factor of salvage RT [6,22,24,27]. Med- bRFS in patients with pT3-4 is postoperative RT. ian pre-RT PSA in some of those studies was 1.0 ng/ml According to the European Organization for Research or less. In a study by Trock et al. with median pre-RT and Treatment of Cancer (EORTC) 22911, adjuvant PSA < 1.0 ng/ml, salvage RT performed within 2 years external irradiation after radical prostatectomy improves after biochemical recurrence significantly improved biochemical progression-free survival and local control prostate cancer-specific survival among patients with in patients with positive margins [31]. In that study, the PSADT of less than 6 months (HR: 0.14) [5]. Although 5-year biochemical progression-free survival rates for not significant in our study, the 4-year bRFS rate of patients in the Irradiation group and the Wait and see patients with PSADT < 7 months was worse than that group with one or more pathological risk factors (cap- of patients with PSADT ≥ 7 months. The reason why sule perforation, positive surgical margins and invasion PSADT was not a significant factor in our study might of seminal vesicles) were 74.0% and 52.6%, respectively. Umezawa et al. Radiation Oncology 2011, 6:150 Page 7 of 8 http://www.ro-journal.com/content/6/1/150 In the Southwest Oncology Group (SWOG) 8794, adju- strongly affected by hormone therapy. Therefore, we vant radiotherapy for patients with pT3 after RP also evaluated bRFS in 73 patients without hormone resulted in significant reduction of the risk for PSA therapy. Although the number of samples became small, relapse (median PSA relapse-free survival: 10.3 years for the result was similar. Second, we analyzed bRFS in the radiotherapy vs. 3.1 years for observation) [32]. In their present study retrospectively, and there were two sepa- further study, metastasis-free survival was significantly rate definitions of the criterion for salvage RT. The cri- teria were slightly different between previous studies. greater with adjuvant radiotherapy (93 of 214 patients AUA defines biochemical recurrence following RP as on the radiotherapy arm vs 114 of 211 patients on the initial serum PSA of ≥ 0.2 ng/ml with a second confir- observation arm) and survival improved significantly with adjuvant radiotherapy (88 deaths in 214 patients on matory level of > 0.2 ng/ml [16]. We analyzed bRFS in the radiotherapy arm vs 110 deaths in 211 patients on 65 patients with pre-PSA of ≥ 0.2 ng/ml. The results the observation arm) [33]. In a study by Jereczek-Fossa showed that only pT was only a siginificant prognostic et al., failure-free survival of postoperative RT patients factor (p < 0.001). The bRFS after salvage RT might be was significantly longer than that of patients who had affected by pT3-4 after all, even if we consider those undergone salvage RT (4-year biochemical control rates: limitations. 81.7% and 60.5%, respectively) [34]. Postoperative RT was suggested to be more effective than salvage RT in Conclusion patients with pT3-4. The reason why bRFS for patients Salvage RT is an effective treatment for patients with with pT3-4 is poor may also be that these patients biochemical recurrence after RP. In patients with PSA < already have latent lymph node metastases. Spiotto et al. 1.0 ng/ml, pT stage and preoperative PSA were prog- reported that whole pelvic RT resulted in superior bRFS nostic factors of bRFS. In particular, pT3-4 had a high compared with prostate bed RT, especially in high-risk risk for biochemical recurrence after salvage RT, and patients with GS ≥ 8, preoperative PSA > 20 ng/ml, more intense treatment is recommended for such pT3, or pathologic lymph node involvement (5-year patients. bRFS: 47% vs 21%) [35]. Whole pelvic RT might also be an effective treatment. Authors’ contributions The ASTRO consensus guidelines suggest a minimum RU participated in data collection, performed the statistical analysis and of 64 Gy at conventional dose fractionation [15]. In our drafted the manuscript. HA and YO conceived of the study and helped to draft the manuscript. KJ participated in its design and coordination and study, bRFS of patients treated with a dose ≥ 64 Gy helped to draft the manuscript. HM, KT, KF, TS, TS, MK, KN, ES helped with tended to be better than that of patients treated with a collection of data. YT and SY helped to draft the manuscript. All authors dose < 64 Gy (51.7% [95% CI: 38.5-67.0%] vs. 36.8% read and approved the final manuscript. [95% CI: 15.2-58.5%], p = 0.068). At least 64 Gy may be Competing interests required for salvage RT after RP. King et al. found that The authors declare that they have no competing interests. salvage RT with 70 Gy was superior to that with 60 Gy Received: 4 August 2011 Accepted: 5 November 2011 (5-year bRFS: 58% vs. 25%) [36]. Bernard et al. found Published: 5 November 2011 that doses higher than 66.6 Gy resulted in decreased risk of biochemical failure after salvage RT [13]. King et References al. reported that the dose-response relationships of sal- 1. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC: Long-term biochemical disease-free and cancer-specific survival following anatomic radical vage RT and definitive external beam radiotherapy for retropubic prostatectomy: The 15-year Johns Hopkins experience. Urol localized prostate cancer were similar [37]. Only in Clin North Am 2001, 28:555-565. patients treated with 64 or 64.8 Gy, the 4-year bRFS for 2. Ward JF, Moul JW: Rising prostate-specific antigen after primary prostate cancer therapy. Nat Clin Pract Urol 2005, 2:174-182. patients with pT3-4 was much worse than that for 3. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC: patients with pT1-2 (85.5% [95% CI: 73.6-97.3%] and Natural history of progression after PSA elevation following radical 28.8% [95% CI: 7.87-49.8%], respectively, p < 0.001), prostatectomy. JAMA 1999, 281:1591-1597. 4. Neuhof D, Hentschel T, Bischof M, Sroka-Perez G, Hohenfellner M, Debus J: (Figure 6). This result suggested that 64 Gy in patients Long-term results and predictive factors of three-dimensional conformal with pT3-4 might be insufficient. The results of a study salvage radiotherapy for biochemical relapse after prostatectomy. Int J by Cozzarini et al. provided strong support for the use Radiat Oncol Biol Phys 2007, 67:1411-1417. 5. 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Int J Radiat Oncol Biol Phys 2009, 73:1009-1016. prostatectomy: 10-year outcome estimates. J Urol 2005, 174:1282-1286. 27. Tomita N, Kodaira T, Furutani K, Tachibana H, Hasegawa Y, Mizoguchi N, 12. Buskirk SJ, Pisansky TM, Schild SE, Macdonald OK, Wehle MJ, Kozelsky TF, Hayashi N: Early salvage radiotherapy for patients with PSA relapse after Collie AC, Ferrigni RG, Myers RP, Prussaki KA, Heckman MG, Crook JE, radical prostatectomy. J Cancer Res Clin Oncol 2009, 135:1561-1567. Parker AS, Igel TC: Salvage radiotherapy for isolated prostate specific 28. Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, antigen increase after radical prostatectomy: evaluation of prognostic Walsh PC, Partin AW: Risk of prostate cancer-specific mortality following factors and creation of a prognostic scoring system. J Urol 2006, biochemical recurrence after radical prostatectomy. JAMA 2005, 176:985-990. 294:433-439. 13. Bernard JR Jr, Buskirk SJ, Heckman MG, Diehl NN, Ko SJ, Macdonald OK, 29. Daskivich TJ, Regan MM, Oh WK: Prostate specific antigen doubling time Schild PE, Pisansky TM: Salvage radiotherapy for rising prostate-specific calculation: not as easy as 1, 2, 4. J Urol 2006, 176:1927-1937. antigen levels after radical prostatectomy for prostate cancer: dose- 30. Arlen PM, Bianco F, Dahut WL, D’Amico A, Figg WD, Freedland SJ, Gulley JL, response analysis. Int J Radiat Oncol Biol Phys 2009, 76:735-740. Kantoff PW, Kattan MW, Lee A, Regan MM, Sartor O: Prostate Specific 14. Terai A, Matsui Y, Yoshimura K, Arai Y, Dodo Y: Salvage radiotherapy for Antigen Working Group. Prostate Specific Antigen Working Group biochemical recurrence after radical prostatectomy. BJU Int 2005, guidelines on prostate specific antigen doubling time. J Urol 2008, 96:1009-1013. 179:2181-2186. 15. Cox JD, Gallagher MJ, Hammond EH, Kaplan RS, Schellhammer PF: 31. 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Thompson IM Jr, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, Dmochowski RR, Eton DT, Forman JD, Goldenberg SL, Hernandez J, Messing E, Forman J, Chin J, Swanson G, Canby-Hagino E, Crawford ED: Higano CS, Kraus SR, Moul JW, Tangen C, Thrasher JB, Thompson I: Adjuvant radiotherapy for pathologically advanced prostate cancer: a Variation in the definition of biochemical recurrence in patients treated randomized clinical trial. JAMA 2006, 296:2329-2335. for localized prostate cancer: the American Urological Association 33. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, Prostate Guidelines for Localized Prostate Cancer Update Panel report Messing E, Forman J, Chin J, Swanson G, Canby-Hagino E, Crawford ED: and recommendations for a standard in the reporting of surgical Adjuvant radiotherapy for pathological T3N0M0 prostate cancer outcomes. J Urol 2007, 177:540-545. significantly reduces risk of metastases and improves survival: long-term 17. Stephenson AJ, Scardino PT, Kattan MW, Pisansky TM, Slawin KM, Klein EA, follwup of a randomized clinical trial. J Urol 2009, 181:956-962. Anscher MS, Michalski JM, Sandler HM, Lin DW, Forman JD, Zelefsky MJ, 34. Jereczek-Fossa BA, Zerini D, Vavassori A, Fodor C, Santoro L, Minissale A, Kestin LL, Roehrborn CG, Catton CN, DeWeese TL, Liauw SL, Valicenti RK, Cambria R, Cattani F, Garibaldi C, Serafini F, Matei VD, de Cobelli O, Kuban DA, Pollack A: Predicting the outcome of salvage radiation Orecchia R: Sooner or later? Outcome analysis of 431 prostate cancer therapy for recurrent prostate cancer after radical prostatectomy. J Clin patients treated with postoperative or salvage radiotherapy. Int J Radiat Oncol 2007, 25:2035-2041. Oncol Biol Phys 2009, 74:115-125. 18. Brenner DJ, Hall EJ: Fractionation and protraction for radiotherapy of 35. Spiotto MT, Hancock SL, King CR: Radiotherapy after prostatectomy: prostate carcinoma? 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Urology 2002, 59:726-731. 38. Cozzarini C, Montorsi F, Fiorino C, Alongi F, Bolognesi A, Da Pozzo LF, 21. Tsien C, Griffith KA, Sandler HM, McLaughlin P, Sanda MG, Montie J, Guazzoni G, Freschi M, Roscigno M, Scattoni V, Rigatti P, Di Muzio N: Need Reddy S, Hayman JA: Long-term results of three-dimensional conformal for high radiation dose (> or = 70 Gy) in early postoperative irradiation adjuvant and salvage radiotherapy after radical prostatectomy. Urology after radical prostatectomy: a single-institution analysis of 334 high-risk, 2003, 62:93-98. node-negative patients. Int J Radiat Oncol Biol Phys 2009, 74:966-974. 22. Jacinto AA, Fede AB, Fagundes LA, Salvajoli JV, Castilho MS, Viani GA, doi:10.1186/1748-717X-6-150 Fogaroli RC, Novaes PE, Pellizon AC, Maia MA, Ferrigno R: Salvage Cite this article as: Umezawa et al.: Impact of pathological tumor stage radiotherapy for biochemical relapse after complete PSA response for salvage radiotherapy after radical prostatectomy in patients with following radical prostatectomy: outcome and prognostic factors for prostate-specific antigen < 1.0 ng/ml. Radiation Oncology 2011 6:150. patients who have never received hormonal therapy. Radiat Oncol 2007, 2:8. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Impact of pathological tumor stage for salvage radiotherapy after radical prostatectomy in patients with prostate-specific antigen < 1.0 ng/ml

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Springer Journals
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Copyright © 2011 by Umezawa et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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22053922
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Abstract

Background: To evaluate prognostic factors in salvage radiotherapy (RT) for patients with pre-RT prostate-specific antigen (PSA) < 1.0 ng/ml. Methods: Between January 2000 and December 2009, 102 patients underwent salvage RT for biochemical failure after radical prostatectomy (RP). Re-failure of PSA after salvage RT was defined as a serum PSA value of 0.2 ng/ml or more above the postradiotherapy nadir followed by another higher value, a continued rise in serum PSA despite salvage RT, or initiation of systemic therapy after completion of salvage RT. Biochemical relapse-free survival (bRFS) was estimated using the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards regression model. Results: The median follow-up period was 44 months (range, 11-103 months). Forty-three patients experienced PSA re-failure after salvage RT. The 4-year bRFS was 50.9% (95% confidence interval [95% CI]: 39.4-62.5%). In the log-rank test, pT3-4 (p < 0.001) and preoperative PSA (p = 0.037) were selected as significant factors. In multivariate analysis, only pT3-4 was a prognostic factor (hazard ratio: 3.512 [95% CI: 1.535-8.037], p = 0.001). The 4-year bRFS rates for pT1-2 and pT3-4 were 79.2% (95% CI: 66.0-92.3%) and 31.7% (95% CI: 17.0-46.4%), respectively. Conclusions: In patients who have received salvage RT after RP with PSA < 1.0 ng/ml, pT stage and preoperative PSA were prognostic factors of bRFS. In particular, pT3-4 had a high risk for biochemical recurrence after salvage RT. Keywords: Prostate cancer, Radiotherapy, Radical Prostatectomy, PSA, Pathological tumor stage Background that 5- and 10-year prostate cancer-specific survival rates Radical prostatectomy (RP) is one of the curative treat- were 88% and 62%, respectively, for patients with no sal- ments for prostate cancer. However, biochemical recur- vage treatment and 96% and 86%, respectively, for patients rence after radical prostatectomy occurs in approximately who received salvage RT alone [5]. Recent studies have 15% to 40% of patients within 5 years [1,2]. Approximately suggested that early RT is more effective than delayed RT. one third of patients with biochemical recurrence will Some studies have demonstrated that pre-RT PSA is a prognostic factor [4,6-14]. Based on results of those stu- have distant metastases, and the median actuarial period to development of metastases following prostate-specific dies, it seems that pre-RT PSA < 1.0 ng/ml as a cutoff antigen (PSA) elevation is 8 years [3]. Many studies have value is a factor predicting PSA re-failure after salvage RT demonstrated that salvage radiotherapy (RT) for biochem- [4,7,8,12], though according to a consensus panel report ical recurrence after RP is effective and enables long-term published by the American Society of Therapeutic Radiol- suppression of PSA elevation [4]. Trock et al. reported ogy and Oncology (ASTRO), early treatment (PSA < 1.5 ng/ml) is more successful than later treatment [15]. How- * Correspondence: reirei513@hotmail.com ever, even some patients with pre-RT PSA < 1.0 ng/ml Department of Radiation Oncology, Tohoku University School of Medicine, who have received salvage RT have biochemical Seiryou-machi 1-1, Aobaku, Sendai, Japan © 2011 Umezawa et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Umezawa et al. Radiation Oncology 2011, 6:150 Page 2 of 8 http://www.ro-journal.com/content/6/1/150 recurrence. The objective of this study was to evaluate continued rise in serum PSA despite salvage RT, or prognostic factors in salvage RT after RP for patients with initiation of systemic therapy after completion of salvage pre-RT PSA < 1.0 ng/ml. RT [17]. The time to PSA re-failure after salvage RT was calculated from the first day of RT. Measurement of Methods PSA after salvage RT was done at least once every 3 Patients months. Between January 2000 and December 2009, 102 patients received salvage RT for biochemical failure after RP in Statistical analysis Tohoku University Hospital and seven affiliated hospi- Biochemical relapse-free survival (bRFS) was estimated tals. Although the American Urological Association using the Kaplan-Meier method, and the log-rank test (AUA) defines biochemical recurrence following RP as was used to analyze differences between patient sub- initial serum PSA of ≥ 0.2 ng/ml with a second confir- groups categorized by prognostic variables. Multivariate matory level of > 0.2 ng/ml [16], the main criterion for analysis was performed using the Cox proportional salvage RT in this study was that PSA after RP was 0.1 hazards regression model. Hazard ratios are presented ng/ml or more or that PSA after RP was three consecu- for each prognostic factor. We evaluated pathologic tive increasing. Patients with massive local recurrence tumor (pT) stage, surgical margin, Gleason score (GS), that was detectable by CT or MRI or patients with preoperative PSA, pre-RT PSA (Pre-RT PSA of patients lymph node or distant metastasis were excluded from who received hormone therapy was evaluated as that this study. Patients who continued to receive hormone before hormone therapy.), PSADT, dose to the prostate therapy for PSA failure after RP but became resistant to bed, biological effective dose (BED) (calculated using a/ the hormone therapy were also excluded. b = 1.5 according to the LQ model) [18], time from RP to the start of RT and hormonal therapy as prognostic PSA doubling time factors. Multivariate analysis included factors with p < PSA doubling time (PSADT) was calculated using PSA 0.10 in univariate analysis. All tests were two-sided, and values above 0.1 ng/ml after RP until the start of salvage statistical significance was set at the level of p < 0.05. RT. PSADT was not calculated for patients who did not Statistical analysis was performed using the Statistical have PSA above 0.1 ng/ml. PSADT was estimated by Package for Social Sciences (SPSS) version 14.0 (SPSS, the natural log of 2 (0.693) divided by the slope of the Chicago, IL). linear regression line of PSA over time [3]. Toxicity Radiotherapy Complications due to salvage RT were evaluated accord- The prostate bed, the bladder neck, the urethral anasto- ing to the common terminology criteria for adverse mosis and the seminal vesicle bed (in the case of inva- events (CTCAE) ver.4.0. Late toxicity was defined as a sion to seminal vesicle) were defined as the clinical complication occurring more than three months after target volume (CTV) with references to preoperative salvage RT. computed tomography or magnetic resonance imaging. The planning target volume (PTV) included the CTV Ethics with a margin of approximately 1 cm in all directions. Written informed consent for treatment was obtained The leaf margin was 0.5 cm in all directions. Salvage RT from all patients, and this retrospective study was per- was delivered using photon beams of 10 MV or 15 MV formed according to the principles of the Declaration of mostly with the four-field technique, three-dimensional Helsinki (2008). conformal RT. The median RT dose was 64 Gy (range, 60-72 Gy). The numbers of patients receiving 60 Gy at Results 2 Gy daily, 62 Gy at 2 Gy daily, 64 Gy at 2 Gy daily, Patient and tumor characteristics are shown in Table 1. 64.8 Gy at 1.8 Gy daily, 70 Gy at 2 Gy daily and 72 Gy Median age at salvage RT was 67 years (range, 49-81 at 1.2 Gy per fraction twice daily (hyperfractionation) to years). Median pre-RT PSA was 0.240 (range, 0.011- the prostate bed were 18, 1, 67, 12, 3 and 1, respectively. 0.994 ng/ml). Median preoperative PSA was 8.8 ng/ml The RT dose was prescribed at the center of the PTV. (range, 1.6-120 ng/ml). Median PSADT was 6.83 None of the patients underwent whole pelvic irradiation. months (range, 0.58-41.9 months). Hormone therapy was given to 29 patients before and/ Follow-up or during salvage RT for a median period of 6 months Re-failure of PSA after salvage RT was defined as a (range, 1-18 months). Eleven of those patients continued serum PSA value of 0.2 ng/ml or more above the post- to receive hormone therapy for a median period of 12 radiotherapy nadir followed by another higher value, a months (range, 1-15 months) after salvage RT. Two Umezawa et al. Radiation Oncology 2011, 6:150 Page 3 of 8 http://www.ro-journal.com/content/6/1/150 Table 1 Patients’ characteristics cancer, though one patient died of esophageal cancer and one patient died of bile duct cancer. PSA decreased Characteristic No. Median (range) in 64 of the 73 patients who received salvage RT after Age at salvage RT (years) 67 (49-81) RP without hormone therapy. Forty-three patients had Pathologic tumor stage re-failure after salvage RT at the last observation date. T1 2 The 4-year bRFS rate was 50.9% (95% CI: 39.4-62.5%) T2 41 (Figure 1). Multiple lung metastases occurred in one T3 57 patient 17 months after salvage RT, and bone metastases T4 1 occurred in two patients 36 and 43 months after salvage Unknown 2 RT. Surgical margin Resultsofthe log-rank testspresented in Table2 Positive 48 show the 4-year bRFS for each prognostic factor before Negative 51 salvage RT. It was found that pT stage (p < 0.001) and Unknown 3 preoperative PSA (p = 0.037) were significant prognostic Gleason score factors. The 4-year bRFS for pT1-2 and pT3-4 were ≤631 79.2% (95% CI: 66.0-92.3%) and 31.7% (95% CI: 17.0- 46.4%), respectively (Figure 2). We also analyzed bRFS 8 ≥ 31 for extracapsular extension and seminal vesicle invasion. Unknown 5 The 4-year bRFS for positive and negative extracapsular Preoperative PSA (ng/ml) 8.8 (1.6-120) extension were 79.9% (95% CI: 65.4-94.5%) and 35.9% <10 58 (95% CI: 21.0-49.8%) (p = 0.003), respectively. The 4- ≥ 10 44 year bRFS for positive and negative seminal vesicle inva- Pre-RT PSA (ng/ml) 0.240 (0.011-0.994) sion were 56.9% (95% CI: 44.3-71.0%) and 19.0% (95% < 0.25 52 CI: 0-39.1%) (p = 0.004), respectively. The 4-year bRFS ≥ 0.25 50 for preoperative PSA < 10 ng/ml and ≥ 10 ng/ml were PSA doubling time (months) 6.83 (0.58-41.9) 62.0% (95% CI: 47.7-76.3%) and 39.3% (95% CI: 22.5- <7 43 56.0%), respectively (Figure 3). Although not significant, ≥743 PSADT (p = 0.059) and RT dose (p = 0.068) tended to Not available 16 be prognostic factors. The 4-year bRFS for PSADT < 7 RT dose (Gy) (BED, a/b = 1.5) 64 (149.3) (60-72 [129.6- 163.3]) months and ≥ 7 months were 34.6% (95% CI: 17.5- 60 at 2 daily (140.0) 18 51.8%) and 62.2% (95% CI: 46.7-77.7%), respectively 62 at 2 daily (144.7) 1 64 at 2 daily (149.3) 67 64.8 at 1.8 daily (142.6) 12 70 at 2 daily (163.3) 3 72 at 1.2 per fraction twice daily (HF) 1 (129.6) Time from RP to RT (months) 21 (5-99) <24 56 ≥ 24 46 Hormone therapy Done 29 Not done 73 Abbreviations: RT = radiotherapy, PSA = prostate-specific antigen, BED = biological effective dose, HF = hyperfractionation, RP = radical prostatectomy patients received hormone therapy for PSA failure and stopped the therapy because of decrease in PSA but re- started the therapy when PSA had increased again. No patient received adjuvant hormone therapy after RP. The median follow-up period from the start of salvage RT was 44 months (range, 11-103 months). The 4-year Figure 1 Biochemical relapse-free survival (bRFS) after salvage overall survival rate was 97.3% (95% confidence interval radiotherapy. [95% CI]: 93.6-100%). No patient died of prostate Umezawa et al. Radiation Oncology 2011, 6:150 Page 4 of 8 http://www.ro-journal.com/content/6/1/150 Table 2 Results of log-rank tests Factor 4-year bRFS (%) (95% CI) p value Pathologic tumor stage < 0.001 T1-2 79.2 (66.0-92.3) T3-4 31.7 (17.0-46.4) Surgical margin 0.652 Positive 48.6 (32.0-65.1) Negative 57.1 (42.7-71.4) Gleason score 0.189 ≤ 7 58.9 (44.5-73.3) ≥ 8 35.2 (14.7-51.5) Preoperative PSA (ng/ml) 0.037 < 10 62.0 (47.7-76.3) ≥ 10 39.3 (22.5-56.0) Pre-RT PSA (ng/ml) 0.620 < 0.25 54.5 (37.5-71.6) ≥ 0.25 45.9 (30.2-64.9) PSA doubling time (months) 0.059 Figure 2 Four-year biochemical relapse-free survival in patients with pT3-4 and that in patients with pT1-2. < 7 34.6 (17.5-51.8) ≥ 7 62.2 (46.7-77.7) RT dose (Gy) 0.068 hazard ratio (HR) with pT3-4 was 3.512 (95% CI: 1.535- < 64 36.8 (15.2-58.5) 8.037) (Table 3). After adjusting for pT, none of the ≥ 64 51.7 (37.6-65.9) other variables retained prognostic significance. BED (Gy) (a/b = 1.5) 0.213 Grade 2 late urinary tract complication was observed < 145 41.4 (23.5-59.3) in one patient who suffered from urinary occlusion. ≥ 145 54.3 (39.5-69.1) Grade 3 late rectal complication was observed in one Time from RP to RT (months) 0.310 patient who suffered from rectal bleeding. < 24 45.2 (29.1-61.4) ≥ 24 57.4 (40.9-73.9) Discussion Hormone therapy 0.627 Moreira et al. reported that the 1-, 3- and 5-year risks of Done 50.5 (20.2-72.9) receiving any salvage treatment after RP were 29%, 48% Not done 50.7 (37.6-63.7) Abbreviations: bRFS = biochemical relapse-free survival, RT = radiotherapy, PSA = prostate-specific antigen, BED = biological effective dose, RP = radical prostatectomy, CI = confidence interval (Figure 4). The 4-year bRFS for dose < 64 Gy and ≥ 64 Gy were 36.8% (95% CI: 15.2-58.5%) and 52.7% (95% CI: 39.5-69.1%), respectively (Figure 5). When we evaluated bRFS in 73 patients without hormone therapy, pT stage (p < 0.001) and preoperative PSA (p = 0.018) were also significant prognostic factors. In those patients, the 4- year bRFS for pT1-2 and pT3-4 were 78.5% (95% CI: 62.9-94.2%) and 29.6% (95% CI: 13.7-45.6%), respec- tively, and the 4-year bRFS for preoperative PSA < 10 ng/ml and ≥ 10 ng/ml were 64.0% (95% CI: 48.5-79.5%) and 33.9% (95% CI: 14.3-53.6%), respectively. In 79 patients who received 64 or 64.8 Gy to the pros- tate bed, the 4-year bRFS for pT1-2 and pT3-4 were 85.5% (95% CI: 73.6-97.3%) and 28.8% (95% CI: 7.87- 49.8%) (p < 0.001), respectively (Figure 6). Multivariate analysis was evaluated by pT stage, preo- Figure 3 Four-year biochemical relapse-free survival in patients with preoperative prostate-specific antigen (PSA) ≥ 10 ng/ml perative PSA, PSADT and RT dose. Only pT stage was and that in patients with preoperative PSA < 10 ng/ml. a significant prognostic factor (p = 0.003) and the Umezawa et al. Radiation Oncology 2011, 6:150 Page 5 of 8 http://www.ro-journal.com/content/6/1/150 Figure 6 Four-year biochemical relapse-free survival for pT3-4 and that for pT1-2 in patients who received 64 or 64.8 Gy to the prostate bed. Figure 4 Four-year biochemical relapse-free survival in patients with prostate specific-antigen doubling time (PSADT) ≥ 7 months and that in patients with PSADT < 7 months. previous studies might not be appropriate differences in race, conditions under which salvage RT was performed and criteria of re-failure after salvage RT, bRFS in the and 53%, respectively [19]. Salvage RT is one of the present study was similar to that in previous studies major treatments for biochemical recurrence after RP, (Table 4). However, significant prognostic factors for re- and many studies have shown that salvage RT is effec- failure of salvage RT in those studies were different. tive [4,6-14,20-27]. In our study, PSA decreased in 64 of Some of those studies showed that pre-RT PSA < 1.0 the 73 patients who received salvage RT after RP with- ng/mlwas aprognosticfactor [4,7,8,12]. In those stu- out hormone therapy, suggesting that this treatment was dies, median values of pre-RT PSA were higher (0.7-4.5 effective for biochemical failure after RP. Those patients ng/ml) than that in the present study (0.240 ng/ml). might have had at least a component local disease. PSA However, even some patients with pre-RT PSA < 1.0 did not decrease in the patient who had multiple lung ng/ml who have received salvage RT experience bio- metastases. Although comparison with results of chemical recurrence. Therefore, we retrospectively eval- uated prognostic factors in salvage RT for patients with pre-RT PSA < 1.0 ng/ml. Table 3 Multivariate analysis of parameters with bRFS Factors Hazards ratio (95% CI) p value Pathologic tumor stage 0.003 T1-2 Reference T3-4 3.512 (1.535-8.037) Preoperative PSA (ng/ml) 0.177 < 10 Reference ≥ 10 1.566 (0.816-3.006) PSADT (months) 0.272 < 7 Reference ≥ 7 0.686 (0.350-1.344) RT dose (Gy) 0.357 < 64 Reference ≥ 64 0.712 (0.345-1.469) Figure 5 Four-year biochemical relapse-free survival in patients Abbreviations: bRFS = biochemical relapse-free survival, PSA = prostate- with radiotherapy (RT) dose ≥ 64 Gy and that in patients with specific antigen, PSADT = prostate-specific antigen doubling time, RT = RT dose < 64 Gy. radiotherapy, RP = radical prostatectomy, CI = confidence interval Umezawa et al. Radiation Oncology 2011, 6:150 Page 6 of 8 http://www.ro-journal.com/content/6/1/150 Table 4 Past studies on salvage RT for biochemical recurrence after RP Study Patients (n) Median pre-RT PSA (ng/ml) prognostic factors after salvage RT bRDS(%) Hagan et al [7] 91 4.5 pre-RT PSA (< 1.0 ng/ml) 55 (5-year) Quero et al [8] 59 1.43 pre-RT PSA (< 1.0 ng/ml) 41.2 (5-year) Macdonald et al [9] 121 1.4 pre-RT PSA (< 0.2 ng/ml) NA Anscher et al [10] 89 1.4 pre-RT PSA (< 2.5 ng/ml), RT dose (> 65 Gy) 50 (4-year) Chawla et al [20] 54 1.3 Gleason score (≤ 6), time to detectable postoperative PSA 35 (5-year) Tsien et al [21] 57 1.2 Gleason score (< or = 7) 58 (5-year) Neuhof et al [4] 171 1.1 Gleason score (< 7), pre-RT PSA (< 1.0 ng/ml) 35.1 (5-year) Jacinto et al [22] 43 0.87 PSADT (> 4.0 months) 71 (3-year) Taylor et al [23] 66 0.8 delayed rise in PSA after RP 66 (5-year) Pazona et al [11] 307 0.8 pre-RT PSA (< 1.3 ng/ml), Seminal vesicle 40 (5-year) Stephenson et al [6] 501 0.72 Gleason score (≤ 7), pre-RT PSA (≤ 2.0 ng/ml), 45 (4-year) PSADT (> 10 months) Buskirk et al [12] 368 0.7 pT2-3a, Gleason score (≤ 7), Pre-RT PSA (< 1.0 ng/ml) 46 (5-year) Bernard et al [13] 364 0.6 RT dose (> 66.6 Gy, patients with pre-RT PSA < 0.6 ng/ml) 50 (5-year) Ward et al [24] 211 0.6 PSADT (> 12 months) 34 (10-year) King et al [25] 37 0.49 PSAV (≤ 1.0 ng/ml/year) NA Wiegel et al [26] 162 0.33 PSA undetectable after salvage RT (< 0.1 ng/ml) 54 (3.5-year) Tomita et al [27] 51 0.25 PSADT (> 3.0 months), Gleason Score, RT dose (≥ 60 Gy) 55.1 (3-year) Terai et al [14] 37 0.146 cT1-2, pT2, pre-RT PSA (> 0.15 ng/ml) 54 (5-year) Abbreviations: RT = radiotherapy, RP = radical prostatectomy, PSA = prostate-specific antigen, bRDS = biochemical relapse-free survival, PSADT = PSA doubling time, PSAV = PSA velocity, NA = not available In the present study, pre-RT PSA was not a significant be that there were 16 patients for whom PSADT data factor. Therefore, there might be no need for early sal- were not available and the number of cases for analysis vage RT in patients with pre-RT PSA < 1.0 ng/ml. How- was insufficient. If pre-RT PSA is < 1.0 ng/ml, we might ever, early or more intense salvage RT in cases of high be able to refer to PSADT for starting salvage RT. risk for recurrence (e.g., pT3-4 and preoperative PSA > Although PSADT is widely used to predict outcomes 10 ng/ml) even with PSA < 1.0 ng/ml might be neces- such as time to progression, underlying the impressive sary because the rate of biochemical recurrence after evidence of predictive value and prognostic value of salvage RT is relatively high even in patients with pre- PSADT are many basic questions about how it should RT PSA < 1.0 ng/ml. Further investigation of the prog- be calculated [29]. Although Arlen et al. demonstrated nostic factors of salvage RT other than pre-RT PSA in that PSA kinetics was all calculated from the point of patients with high risk for recurrence is needed. failure of 0.2 ng/ml [30], PSADT was calculated using PSA values above 0.1 ng/ml after RP in our study. Recently, PSADT has been utilized as a prognostic In our study, only pT3-4 was a significant factor pre- factor for prostatectomy. Pound et al. found that PSADT predicted the likelihood of subsequent develop- dicting PSA re-failure after salvage RT in multivariate ment of metastatic disease [3]. Freedland et al. found analysis. In a study by Wiegel et al., bRFS for pT3-4 was that prostate cancer-specific survival of patients with worsethanthatfor pT2(p= 0.047) [26]. Although PSADT < 9 months (especially < 3 months) was worse bRFS for pT3-4 was poor in patients with PSA < 1.0 ng/ than that of patients with PSADT > 15 months [28]. ml, there may be some room for improvement in RT Some past studies have demonstrated that PSADT was for patients with pT3-4. One method for improving also a prognostic factor of salvage RT [6,22,24,27]. Med- bRFS in patients with pT3-4 is postoperative RT. ian pre-RT PSA in some of those studies was 1.0 ng/ml According to the European Organization for Research or less. In a study by Trock et al. with median pre-RT and Treatment of Cancer (EORTC) 22911, adjuvant PSA < 1.0 ng/ml, salvage RT performed within 2 years external irradiation after radical prostatectomy improves after biochemical recurrence significantly improved biochemical progression-free survival and local control prostate cancer-specific survival among patients with in patients with positive margins [31]. In that study, the PSADT of less than 6 months (HR: 0.14) [5]. Although 5-year biochemical progression-free survival rates for not significant in our study, the 4-year bRFS rate of patients in the Irradiation group and the Wait and see patients with PSADT < 7 months was worse than that group with one or more pathological risk factors (cap- of patients with PSADT ≥ 7 months. The reason why sule perforation, positive surgical margins and invasion PSADT was not a significant factor in our study might of seminal vesicles) were 74.0% and 52.6%, respectively. Umezawa et al. Radiation Oncology 2011, 6:150 Page 7 of 8 http://www.ro-journal.com/content/6/1/150 In the Southwest Oncology Group (SWOG) 8794, adju- strongly affected by hormone therapy. Therefore, we vant radiotherapy for patients with pT3 after RP also evaluated bRFS in 73 patients without hormone resulted in significant reduction of the risk for PSA therapy. Although the number of samples became small, relapse (median PSA relapse-free survival: 10.3 years for the result was similar. Second, we analyzed bRFS in the radiotherapy vs. 3.1 years for observation) [32]. In their present study retrospectively, and there were two sepa- further study, metastasis-free survival was significantly rate definitions of the criterion for salvage RT. The cri- teria were slightly different between previous studies. greater with adjuvant radiotherapy (93 of 214 patients AUA defines biochemical recurrence following RP as on the radiotherapy arm vs 114 of 211 patients on the initial serum PSA of ≥ 0.2 ng/ml with a second confir- observation arm) and survival improved significantly with adjuvant radiotherapy (88 deaths in 214 patients on matory level of > 0.2 ng/ml [16]. We analyzed bRFS in the radiotherapy arm vs 110 deaths in 211 patients on 65 patients with pre-PSA of ≥ 0.2 ng/ml. The results the observation arm) [33]. In a study by Jereczek-Fossa showed that only pT was only a siginificant prognostic et al., failure-free survival of postoperative RT patients factor (p < 0.001). The bRFS after salvage RT might be was significantly longer than that of patients who had affected by pT3-4 after all, even if we consider those undergone salvage RT (4-year biochemical control rates: limitations. 81.7% and 60.5%, respectively) [34]. Postoperative RT was suggested to be more effective than salvage RT in Conclusion patients with pT3-4. The reason why bRFS for patients Salvage RT is an effective treatment for patients with with pT3-4 is poor may also be that these patients biochemical recurrence after RP. In patients with PSA < already have latent lymph node metastases. Spiotto et al. 1.0 ng/ml, pT stage and preoperative PSA were prog- reported that whole pelvic RT resulted in superior bRFS nostic factors of bRFS. In particular, pT3-4 had a high compared with prostate bed RT, especially in high-risk risk for biochemical recurrence after salvage RT, and patients with GS ≥ 8, preoperative PSA > 20 ng/ml, more intense treatment is recommended for such pT3, or pathologic lymph node involvement (5-year patients. bRFS: 47% vs 21%) [35]. Whole pelvic RT might also be an effective treatment. Authors’ contributions The ASTRO consensus guidelines suggest a minimum RU participated in data collection, performed the statistical analysis and of 64 Gy at conventional dose fractionation [15]. In our drafted the manuscript. HA and YO conceived of the study and helped to draft the manuscript. KJ participated in its design and coordination and study, bRFS of patients treated with a dose ≥ 64 Gy helped to draft the manuscript. HM, KT, KF, TS, TS, MK, KN, ES helped with tended to be better than that of patients treated with a collection of data. YT and SY helped to draft the manuscript. All authors dose < 64 Gy (51.7% [95% CI: 38.5-67.0%] vs. 36.8% read and approved the final manuscript. [95% CI: 15.2-58.5%], p = 0.068). At least 64 Gy may be Competing interests required for salvage RT after RP. King et al. found that The authors declare that they have no competing interests. salvage RT with 70 Gy was superior to that with 60 Gy Received: 4 August 2011 Accepted: 5 November 2011 (5-year bRFS: 58% vs. 25%) [36]. Bernard et al. found Published: 5 November 2011 that doses higher than 66.6 Gy resulted in decreased risk of biochemical failure after salvage RT [13]. King et References al. reported that the dose-response relationships of sal- 1. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC: Long-term biochemical disease-free and cancer-specific survival following anatomic radical vage RT and definitive external beam radiotherapy for retropubic prostatectomy: The 15-year Johns Hopkins experience. Urol localized prostate cancer were similar [37]. 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Jacinto AA, Fede AB, Fagundes LA, Salvajoli JV, Castilho MS, Viani GA, doi:10.1186/1748-717X-6-150 Fogaroli RC, Novaes PE, Pellizon AC, Maia MA, Ferrigno R: Salvage Cite this article as: Umezawa et al.: Impact of pathological tumor stage radiotherapy for biochemical relapse after complete PSA response for salvage radiotherapy after radical prostatectomy in patients with following radical prostatectomy: outcome and prognostic factors for prostate-specific antigen < 1.0 ng/ml. Radiation Oncology 2011 6:150. patients who have never received hormonal therapy. Radiat Oncol 2007, 2:8.

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Published: Nov 5, 2011

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