EUROPEAN UROLOGY 60 (2011)

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1 EUROPEAN UROLOGY 60 (2011) available at journal homepage: Prostate Cancer High-Dose Salvage Intensity-Modulated Radiotherapy With or Without Androgen Deprivation After Radical Prostatectomy for Rising or Persisting Prostate-Specific Antigen: 5-Year Results Piet Ost a, *, Nicolaas Lumen b, An-Sofie Goessaert b, Valérie Fonteyne a, Bart De Troyer b, Filip Jacobs a, Gert De Meerleer a a Department of Radiotherapy, Ghent University Hospital, Belgium b Department of Urology, Ghent University Hospital, Belgium Article info Article history: Accepted April 7, 2011 Published online ahead of print on April 16, 2011 Keywords: Salvage Postoperative IMRT Prostate cancer Radiotherapy Abstract Background: Long-term results with salvage radiotherapy (SRT) for a biochemical recurrence after radical prostatectomy (RP) are poor. It has been suggested that radiotherapy doses >70 Gy might result in improved outcome. Objective: To report on the late toxicity profile and outcome of patients treated with high-dose salvage intensity-modulated radiotherapy (HD-SIMRT) with or without androgen deprivation (AD). Design, setting, and participants: Between 1999 and 2008, 136 patients were referred for HD-SIMRT with or without AD. The median follow-up was 5 yr. Indications for HD-SIMRT were persisting prostate-specific antigen (PSA) or a rising PSA following RP. All patients were irradiated at a single, tertiary, academic centre. AD was initiated on the basis of seminal vesicle invasion, preprostatectomy PSA >20 ng/ml, Gleason score 4 + 3(n = 43), or personal preference of the referring urologist (n = 54). Intervention: A median 76-Gy dose was prescribed to the RP bed using intensitymodulated radiotherapy (IMRT) in all patients. AD consisted of a luteinising hormone-releasing hormone analogue for 6 mo. Measurements: Univariate and multivariate analyses were used to examine the influence of patient- and treatment-related factors on late toxicity, biochemical relapse-free survival (brfs), and clinical relapse-free survival (crfs). Results and limitations: The 5-yr actuarial brfs and crfs were 56% and 86%, respectively. On multivariate analysis, the presence of perineural invasion at RP (hazard ratio [HR]: 6.19, p = 0.001) and an increasing pre-srt PSA (PSA 0.5 ng/ml: HR: 1; PSA ng/ml: HR: 1.60, p = 0.30; and PSA >1 ng/ml: HR: 2.70, p = 0.02) were independent factors for a decreased brfs. The addition of AD improved brfs (HR: 0.33, p = 0.005). On multivariate analysis, none of the variables was a predictor of crfs. The 5-yr risk of grade 2 3 toxicity was 22% and 8% for genitourinary and gastrointestinal symptoms, respectively. Conclusions: IMRT allows for safe dose escalation to 76 Gy with good brfs. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Radiotherapy, Ghent University Hospital, De Pintelaan 185, B-9000, Gent, Belgium. Tel ; Fax: address: piet.ost@ugent.be (P. Ost) /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 60 (2011) Introduction Salvage radiotherapy (SRT) is the only therapeutic option offering a potential cure for patients with a prostate-specific antigen (PSA) relapse following radical prostatectomy (RP), with an improved prostate cancer-specific [1] and all-cause survival [2]. However, long-term biochemical relapse-free survival (brfs) is poor, with <50% of patients remaining without evidence of disease after 5 yr when treated with conventional doses [3,4]. This might be one of the reasons why the dominant pattern of care for a PSA relapse is still a noncurative approach (ie, androgen deprivation [AD]), with only 40% of the patients receiving SRT, according to a Surveillance Epidemiology and End Results analysis [5]. New strategies improving biochemical results are therefore highly welcomed. According to the radiobiologic model of King and Kapp, brfs might be improved with increasing radiation doses [6]. This has been confirmed for doses 70 Gy by a limited number of retrospective series [7 12]. It has been suggested that the dose-response relationship of SRT and definitive, primary, prostate radiotherapy is similar [6]. If so, the delivered dose should exceed 70 Gy in the salvage setting. The present study reports on late toxicity and biochemical/clinical results of high-dose (76 Gy) salvage intensity-modulated radiotherapy (HD-SIMRT) with or without AD. 2. Materials and methods Between 1999 and December 2008, 136 patients were referred to our department for HD-SIMRT with or without AD (Table 1). HD-SIMRT was indicated in case of persisting PSA (n = 56) or a rising PSA (n = 80) following RP. Median time between surgery and initiation of radiotherapy was 21 mo (range: <1 180 mo). A lymph node dissection was carried out at time of RP when the Roach formula (2/3 PSA + [(Gleason score 6) 10]) was 15% [13]. Between 1999 and 2006, the lymph node dissection included removal of the obturator chains. Since 2006, the lymph node dissection has been expanded to a modified extended dissection with removal of the lymph nodes along the internal and external iliac vessels. Forty percent of our patients did not reach these criteria at RP and were considered as clinically node negative on magnetic resonance imaging (MRI) or computed tomography. AD (luteinising hormone-releasing hormone [LHRH] analogue for 6 mo) was initiated on the basis of seminal vesicle invasion, preprostatectomy PSA >20 ng/ml, Gleason score >7 (n =43), or personal preference of the referring urologist (n =54) during and after the course of radiotherapy. If an external urologist started the AD, this was stopped after 6 mo by mutual consent in all cases but two. These two patients received an LHRH analogue for 12 and 36 mo, respectively. All patients were treated with intensity-modulated radiotherapy (IMRT) using 18-MV photons of an Elekta linear accelerator (Elekta AB, Crawley, UK) equipped with a multileaf collimator. The clinical target volume (CTV) consisted of the postoperative prostate and seminal vesicle bed. None of the patients in this study received pelvic radiotherapy. To create the planning target volume (PTV), an isotropic, 3-dimensional, 7-mm expansion of the CTV was performed. Treatment was delivered in 37 fractions with a median 76-Gy dose to the PTV (range: Gy). Further radiotherapy details can be found in our previous report [14]. Patients were evaluated weekly during treatment and at 1 and 3 mo after radiotherapy. Thereafter, follow-up consisted of quarterly visits during the first year and twice yearly visits thereafter. PSA was measured at the end of treatment and at every follow-up visit. A digital rectal examination (DRE) was routinely performed before start of HD-SIMRT and after HD-SIMRT at every subsequent visit. Imaging was performed if biochemically or clinically indicated. Biochemical progression after HD-SIMRT was defined as a single PSA value >0.20 ng/ml after a postradiotherapy nadir or a continued rise in the serum PSA despite HD-SIMRT [4]. Clinical progression was defined as the occurrence of a local relapse, lymph node metastasis, haematogenous metastasis, or a combination of both. When a DRE was suggestive of local relapse, the prostatectomy bed was evaluated with T2-weighed MRI using an endorectal coil. The brfs was calculated from the last day of HD-SIMRT to the date of first biochemical progression. For the end point biochemical progression, deaths without progression were censored at time of death. The Kaplan-Meier method was used to estimate brfs and clinical relapse-free survival (crfs). Univariate (log-rank) and multivariate (Cox regression) analyses were used to examine the predictive value of patient- and tumour-related (eg, preoperative PSA, preradiotherapy PSA, PSA doubling time, perineural invasion, Gleason score, margin status, seminal vesicle invasion, and capsule perforation) and treatment-related (ie, AD) factors for relapse after HD-SIMRT. The preradiotherapy PSA level was considered a categorical variable in the Cox regression model because of the nonlinear relationship with the biochemical control; all other continuous variables were entered continuous in the Cox model (Table 1). A p value <0.05 was considered significant. All patients completed a pre-hd-simrt questionnaire, scoring genitourinary (GU) and gastrointestinal (GI) symptoms. Late toxicity was defined as an increase of radiation-induced toxicity starting >3mo after radiotherapy, or as any acute toxicity lasting >3 mo.guandgi symptoms present before HD-SIMRT and not worsening after treatment were not considered as radiotherapy-induced symptoms. For each symptom, the maximal score was registered. To register late GU, an inhouse-developed toxicity score based on the Radiation Therapy Oncology Group (RTOG), the Common Toxicity Criteria for Adverse Events (CTCAE v.3.0), and SOMA/LENT toxicity scoring systems was used [15]. To register late GI toxicity, a scoring system was used consisting of eight different symptoms: the five symptoms from the RTOG toxicity scoring system plus rectal urgency, anal pain, and incontinence [16]. An overview of the scoring system can be found in Table 2. Statistical analysis was performed with SPSS v.15.0 (IBM Corp, Somers, NY, USA). 3. Results 3.1. Disease control rates After a median follow-up of 5 yr (range: mo), 57 patients had a biochemical relapse resulting in a 5-yr actuarial brfs of 56% (Fig. 1). On univariate analysis, presence of perineural invasion (PNI) and PSA level before RT (Fig. 2) resulted in a significantly worse brfs (Table 3). On multivariate analysis, omission of AD, presence of PNI, and a higher pre-rt PSA resulted in a worse brfs (Table 4). A clinical relapse occurred in 18 patients (bone metastases in 11, lymph node metastases in 6, and liver metastases in 1), resulting in a 5-yr clinical relapse-free survival of 86%. Four out of six patients with lymph node metastases did not undergo a lymph node dissection at time of RP.

3 844 EUROPEAN UROLOGY 60 (2011) Table 1 Patient and tumour characteristics Characteristics All patients HD-IMRT HD-IMRT + AD p value Age, yr, median (range) 64 (43 81) 65 (43 80) 64 (44 81) 0.25 Radiotherapy dose, Gy, median (range) 76 (70 79) 76 (72 78) 75 (70 79) 0.19 Tumour stage, no. (%) pt2 58 (43) 20 (15) 38 (28) pt3a 48 (35) 13 (10) 35 (25) pt3b 25 (18) 3 (2) 22 (16) pt4 5 (4) 3 (2) 2 (1) Nodal stage pn0, no. (%) 80 (59) 24 (18) 60 (41) 0.97 No. nodes removed, median (range) 5 (1 32) 5 (1 18) 5 (1 132) 0.86 pnx (all cn0), no. (%) 56 (41) 17 (12) 39 (29) Gleason score, no. (%) <8 113 (83) 36 (26) 77 (57) (17) 3 (2) 20 (15) Preoperative PSA before surgery, ng/ml, median (range) 11 ( ) 9.4 (3.5 42) 10.9 ( ) 10 ng/ml, no. (%) 65 (48) 20 (15) 45 (33) 0.61 >10 ng/ml, no. (%) 71 (52) 19 (14) 52 (38) Postoperative PSA, ng/ml, median (range) 0.1 ( ) 0 (0 1) 0 ( ) <0.2 ng/ml, no. (%) 80 (59) 27 (20) 53 (39) ng/ml, no. (%) 56 (41) 12 (9) 44 (32) PSA before SRT, ng/ml, median (range) 0,8 ( ) 0.6 ( ) 0.9 ( ) <0.5 ng/ml, no. (%) 51 (38) 18 (13) 33 (24) ng/ml, no. (%) 30 (22) 10 (7) 20 (15) >1 ng/ml, no. (%) 55 (37) 11 (8) 44 (32) PSA doubling time, no. (%) 6 mo 52 (38) 15 (11) 37 (27) 0.67 >6 mo 52 (38) 17 (12) 35 (26) Positive margin, no. (%) Yes 65 (48) 20 (15) 45 (33) 0.40 No 66 (48) 16 (12) 50 (37) Unknown 5 (4) 5 (4) 0 Capsule perforation, no. (%) Yes 75 (55) 18 (13) 57 (42) 0.18 No 61 (45) 21 (15) 40 (30) Seminal vesicle invasion, no. (%) Yes 111 (82) 36 (27) 75 (55) 0.04 No 25 (18) 3 (2) 22 (16) Perineural invasion, no. (%) Yes 100 (74) 22 (16) 78 (58) 0.02 No 27 (20) 12 (9) 15 (11) Unknown 9 (6) 7 (5) 2 (1) Time between surgery and SRT, mo, median (range) 17 (0 180) 26 (1 132) 18 (0 180) Adjuvant AD, no. (%) Yes 97 (71) No 39 (29) HD-IMRT = high-dose intensity-modulated radiotherapy; AD = androgen deprivation; PSA = prostate-specific antigen; SRT = salvage radiotherapy. The other two patients had fewer than five nodes removed. A Gleason score of 8 10 was a significant predictor of a decreased crfs on univariate analysis (Table 2). On multivariate analysis, none of the variables was significant. In total, nine patients died, seven due to prostate cancer, one due to rectal cancer, and another due to a small-cell lung cancer. The 5-yr overall survival was 94%. On univariate analysis, only Gleason score 8 10 was associated with a poorer overall survival than Gleason score <8 (60% vs 92%, p < 0.05). On multivariate analysis, none of the variables was significant Late toxicity The 5-yr, actuarial grade 2 3 GU toxicity was 22% (Fig. 3). The absolute incidence of grade 3 GU toxicity was 3% (n = 4), from which two patients recovered. Recuperation from grade 2 GU toxicity was seen in 61% of the cases after a median time of 1 yr following the first appearance of the symptom (range: mo). A detailed overview of GU toxicity is given in Table 5. The 5-yr, actuarial grade 2 3, GI toxicity was 8% (Fig. 3). Only one patient suffered from late grade 3 GI toxicity (anal pain), and recovered after 2 yr. Recupera-

4 EUROPEAN UROLOGY 60 (2011) Table 2 Detailed overview of the late toxicity scoring system * Grade 1 Grade 2 Grade 3 Grade 4 Late GU Dysuria No therapy Oral treatment Narcotic analgesics Not defined (no narcotic analgesics) Haematuria Microscopic Gross Gross with cloths Requiring transfusion Incontinence No therapy Therapy or using two or fewer pads per day Pollakisuria Increase in frequency 2 normal Increase >2 normal but less than every hour Using more than two pads per day Once or more per hour Surgery Not defined Urgency No therapy Urgency requiring therapy Narcotic analgesics Not defined Nocturia Increase in frequency Increase >2 normal Once or more per hour Not defined 2 normal but less than every hour Late GI Diarrhoea Present, no therapy Peroral therapy IV therapy Surgery Abdominal Present, no therapy Peroral therapy IV therapy Surgery cramps Urgency Present, no therapy Peroral therapy IV therapy Mucus loss Present, no therapy Need hygienic pads Continuous, invasive therapy Surgery Red blood loss Present, no therapy <3 /wk Noninvasive therapy 3 /wk Invasive therapy (eg, laser coagulation) Frequency Present, no therapy Peroral therapy IV therapy Surgery Continence Present, no therapy Need hygienic pads Need hygienic pads Surgery (two or fewer per day) (more than two per day) Anal pain Present, no therapy Local anaesthetic Narcotic analgesica Surgery Transfusion, surgery * To register late GU toxicity, an in-house-developed toxicity score based on the Radiation Therapy Oncology Group scoring system, the Common Toxicity Criteria for Adverse Events (CTCAE v.3.0), and SOMA/LENT toxicity scoring systems was used. To register acute and late rectal/intestinal toxicity (GI), a scoring system was used consisting of eight different symptoms, five from the RTOG toxicity scoring system plus rectal urgency, anal pain, and incontinence. GU = genitourinary; GI = gastrointestinal; IV = intravenous; RTOG = Radiation Therapy Oncology Group. tion from grade 2 GI toxicity occurred in 82% of cases after a median time of 6 mo (range: 3 60 mo). A detailed overview of GI toxicity is given in Table Discussion No prospective data have been published regarding the most efficacious dose of SRT. The American Society for [()TD$FIG] Therapeutic Radiology and Oncology (ASTRO) Consensus Panel suggested the highest dose of radiation therapy that can be given without morbidity is justifiable [17]. However, in 1999 this dose was judged to be only 64 Gy or slightly higher [17]. This is supported by the European Association of Urology (EAU) guidelines, which advocate a dose of Gy in the salvage setting [18]. However, the 5-yr brfs with these doses is <50% [3,4]. Retrospective data [()TD$FIG] Fig. 1 Kaplan-Meier curve representing biochemical relapse-free survival. Fig. 2 Kaplan-Meier curve representing biochemical relapse-free survival stratified according to prostate-specific antigen (PSA) prior to salvage radiotherapy.

5 846 EUROPEAN UROLOGY 60 (2011) [()TD$FIG] Table 3 Five-year biochemical and clinical relapse-free survival (univariate analysis) 5-yr biochemical relapse-free survival 5-yr clinical relapse-free survival Factor Univariate p value * Univariate p value * All patients, % PSA before surgery, % <10 ng/ml >10 ng/ml Gleason score at RP, % < Margins, % Positive Negative Extracapsular extension, % 0.49 Present Absent Seminal vesicle invasion, % Present Absent Perineural invasion, % Present Absent Nodal status, % cn pn PSA before radiotherapy, % <0.5 ng/ml ng/ml >1.0 ng/ml PSA doubling time, % <6 mo >6 mo Adjuvant androgen deprivation, % Yes No Salvage sort, % Persisting PSA Rising PSA PSA = prostate-specific antigen; RP = radical prostatectomy; cn0 = clinical node negative; pn0 = pathological node negative. * p < 0.05 is considered significant suggest doses >64.8 Gy to be beneficial [7 12], with two recent retrospective series observing a 5-yr biochemical control of 58 61% using doses >66.6 Gy [8,9]. A radiobiologic model points out that dose escalation >70 Gy might further improve results. In the current report, we observed a 5-yr brfs of 56%. Although the dose was increased with an additional 6 Gy compared to the series of Bernard et al and King et al [8,9], the brfs was comparable. However, due to heterogeneity between patient populations in reported literature, a direct comparison might be biased. Nevertheless, the PSA value at the start of radiotherapy is one of the most important factors predicting the outcome of SRT [4]. In the current report, the median PSA before SRT was 0.8 ng/ml, compared to 0.5 ng/ml in the reports of Bernard et al and King et al [8,9]. When exploring published Fig. 3 Probability of grade 2 3 genitourinary and gastrointestinal late toxicity. subgroups of patients treated low pre-srt PSA levels, the 5- yr brfs of 73% in the current series (Fig. 2) compares favourably to the 65% reported by Bernard et al ( Gy with PSA <0.6 ng/ml) and the 6-yr brfs of 48% of Stephenson et al (64.8 Gy with PSA <0.5 ng/ml) [4,9]. Our data (Fig. 2) confirm the importance of starting SRT at biochemical relapse and before the PSA reaches 0.5 ng/ml, which is the current consensus of the EAU guidelines [18]. Table 4 Variables on multivariate analysis Biochemical relapse-free survival Multivariate (HR, 95% CI) p value * Perineural invasion 6.19 ( ) PSA before radiotherapy < (reference) NA ( ) 0.30 > ( ) 0.02 Adjuvant androgen deprivation 0.33 ( ) PSA doubling time 0.97 ( ) 0.35 Margins 1.49 ( ) 0.25 Extracapsular extensions 0.82 ( ) 0.63 Seminal vesicle invasion 2.26 ( ) 0.18 Gleason score 0.97 ( ) 0.67 Lymph node status (pn0/cn0) 0.75 ( ) 0.47 Radiotherapy dose 0.99 ( ) 0.34 Preoperative PSA 1.00 ( ) 0.80 HR = hazard ratio; CI = confidence interval; PSA = prostate-specific antigen; NA = not applicable; cn0 = clinical node negative; pn0 = pathological node negative. * p < 0.05 is considered significant.

6 EUROPEAN UROLOGY 60 (2011) Table 5 Late gastrointestinal and genitourinary toxicity Symptom Grade Late toxicity patients, No. (%) Abdominal cramps Grade 1 3 (2) Diarrhoea Grade 1 10 (7) Frequency Grade 1 20 (15) Grade 2 4 (3) Mucus loss Grade 1 18 (13) Grade 2 1 (<1) Red blood loss Grade 1 16 (12) Urgency Grade 1 17 (13) Continence Grade 1 13 (10) Anal pain Grade 1 4 (3) Grade 2 1 (<1) Grade 3 1 (<1) Nocturia Grade 1 25 (18) Grade 2 7 (5) Grade 3 1 (<1) Pollakisuria Grade 1 9 (7) Grade 2 4 (3) Grade 3 1 (<1) Haematuria Grade 1 3 (2) Grade 2 12 (9) Grade 3 2 (1) Dysuria Grade 1 8 (6) Urgency Grade 1 24 (18) Grade 2 3 (2) Incontinence Grade 1 23 (17) Grade 2 10 (7) Grade 3 2 (1) Consequently, waiting for a secure evidence of PSA failure (PSA 0.5 ng/ml) before initiation of salvage RT, as suggested by the ASTRO Consensus Panel more than a decade ago, cannot be recommended anymore [17]. On the other hand, patients with unfavourable pre-srt PSA levels should not be denied SRT, because a durable response is still possible. In the current series, the 5-yr brfs for patients referred at pre-srt PSA levels >1 ng/ml was 40%. This compares favourably to the 28% of lower-dose series (median dose: 64.8 Gy) [3,4], suggesting the benefit of dose escalation in this patient subgroup. This was also reported by Bernard et al [9], who observed no difference in the relationship between dose and biochemical failure with low versus high pre-srt levels. Although not significant, they suggested that higher pre-srt levels might require a higher SRT dose [9]. PNI was an independent predictor of biochemical recurrence associated with a hazard ratio of 6.19 (95% confidence interval [CI], ). Moreover, PNI almost reached statistical significance relative to clinical relapse on univariate analysis (Table 2). However, few studies have investigated the role of PNI in predicting outcome of SRT [19 22]. Our findings indicate that PNI is a factor worthy of further investigation and its presence or absence in the pathology specimen should be routinely reported. The improvement of brfs with the addition of AD to SRT has been observed in several retrospective series [23 25]. Our findings confirm the beneficial role of adjuvant AD to HD-SIMRT (HR: 0.33; 95%CI, ), improving the biochemical relapse rate. Several randomised trials are currently investigating the role of AD in this setting. The preliminary data of the RTOG trial look promising [26]. A reduced rate of biochemical and distant failures was observed with the addition of 2 yr of bicalutamide after SRT (64.8 Gy), with a benefit for all subgroups [26]. The benefit of dose escalation should be weighted against the possible increase in side effects. A dose 64 Gy delivered by conventional radiotherapy is rarely associated with severe long-term side effects (<5% grade 3 GI and GU toxicities) [27 29]. Three-dimensional conformal radiotherapy (3D-CRT) was a first improvement over conventional radiotherapy, allowing for dose escalation to biologic equivalent doses of 68 Gy without increase in toxicity [30]. However, a dose >68 Gy was associated with an increase in late grade 3 urinary toxicity (HR: 3.25) even when using 3D-CRT [30]. IMRT offers the advantage of further reducing the dose to the bladder and rectum by creating concave dose distributions along the prostate bed [14,31]. This is the first manuscript on late toxicity with HD- SIMRT. We observed a 5-yr risk of late grade 2 3 toxicity of 22% (76 Gy), which is comparable with the 23.7% reported by Cozzarini et al (3D-CRT with 68 Gy) [30] and the 22.6% observed by Pearse et al (conventional radiotherapy with Gy) [28]. Moreover, Cozzarini et al reported a 5-yr, 16% risk of late grade 3 GU toxicity (deducted from Fig. 3b) for doses >68 Gy [30], where we only observed 3% of grade 3 GU toxicity after 5-yr follow-up. This is in line with toxicity reported with doses of 64 Gy using conventional radiotherapy [27 29]. The 5-yr risk of late grade 2 3 GI toxicity was 8%, with only one event of grade 3 toxicity, which is again similar to low-dose conventional radiotherapy [27 29]. This study is susceptible to the shortcomings of every retrospective analysis. We solely report on the feasibility of high-dose radiotherapy in the postoperative setting, which is often feared because of a possible increase in side effects [32]. However, we lack a low-dose control group, which biases a direct comparison with other studies in literature. Moreover, differences in patient characteristics and surgical protocols might be a possible explanation for the observed differences between the mentioned retrospective studies. We welcome other centres to join in, comparing results. A longer follow-up is necessary to explore potential predictors for crfs and the role of AD in preventing distant metastases. The current study is underpowered to identify subgroups of patients who might not benefit from AD. Data on toxicity affecting erectile dysfunction and quality of life were not registered; therefore, our results should be considered hypothesis generating. It appears that results from a randomised trial addressing dose escalation would be meaningful [6].

7 848 EUROPEAN UROLOGY 60 (2011) Conclusions HD-SIMRT allows for safe dose escalation to 76 Gy in the post-rp salvage setting with good brfs and crfs. Author contributions: Piet Ost had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Ost, Lumen, Fonteyne, De Meerleer. Acquisition of data: Ost, Goessaert, De Troyer, Jacobs. Analysis and interpretation of data: Ost, De Meerleer. Drafting of the manuscript: Ost, Lumen, De Meerleer. Critical revision of the manuscript for important intellectual content: Ost, Fonteyne, De Meerleer, De Troyer, Lumen. Statistical analysis: Ost. Obtaining funding: None. Administrative, technical, or material support: Ost, Fonteyne, De Meerleer, Goessaert, Jacobs. Supervision: De Meerleer. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 2008;299: [2] Choueiri TK, Chen MH, D Amico AV, et al. Impact of postoperative prostate-specific antigen disease recurrence and the use of salvage therapy on the risk of death. Cancer 2010;116: [3] Buskirk SJ, Pisansky TM, Schild SE, et al. 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8 EUROPEAN UROLOGY 60 (2011) patients following radical prostatectomy (RP) with pt2-3, N0 disease and elevated PSA levels. Paper presented at: American Society of Clinical Oncology 2011 Genitourinary Cancers Symposium; February 17 19, 2011; Orlando, FL. [27] Feng M, Hanlon AL, Pisansky TM, et al. Predictive factors for late genitourinary and gastrointestinal toxicity in patients with prostate cancer treated with adjuvant or salvage radiotherapy. Int J Radiat Oncol Biol Phys 2007;68: [28] Pearse M, Choo R, Danjoux C, et al. Prospective assessment of gastrointestinal and genitourinary toxicity of salvage radiotherapy for patients with prostate-specific antigen relapse or local recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 2008;72: [29] Peterson JL, Buskirk SJ, Heckman MG, et al. Late toxicity after postprostatectomy salvage radiation therapy. Radiother Oncol 2009;93: [30] Cozzarini C, Fiorino C, Da Pozzo LF, et al. Clinical factors predicting late severe urinary toxicity after postoperative radiotherapy for prostate carcinoma: a single-institute analysis of 742 patients. Int J Radiat Oncol Biol Phys. In press. doi: /j.ijrobp [31] Ost P, Fonteyne V, Villeirs G, et al. Adjuvant high-dose intensitymodulated radiotherapy after radical prostatectomy for prostate cancer: clinical results in 104 patients. Eur Urol 2009;56: [32] Mendenhall WM, Henderson RH, Nichols RC, Keole SR, Mendenhall NP. Postprostatectomy radiotherapy for prostate cancer. Am J Clin Oncol 2009;32: