Adjuvant High-Dose Intensity-Modulated Radiotherapy after Radical Prostatectomy for Prostate Cancer: Clinical Results in 104 Patients

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1 available at journal homepage: Prostate Cancer Adjuvant High-Dose Intensity-Modulated Radiotherapy after Radical Prostatectomy for Prostate Cancer: Clinical Results in 104 Patients Piet Ost a, *, Valérie Fonteyne a, Geert Villeirs b, Nicolaas Lumen c, Willem Oosterlinck c, Gert De Meerleer a a Department of Radiotherapy, Ghent University Hospital, Ghent, Belgium b Department of Radiology, Ghent University Hospital, Ghent, Belgium c Department of Urology, Ghent University Hospital, Ghent, Belgium Article info Article history: Accepted May 19, 2009 Published online ahead of print on May 29, 2009 Keywords: Adjuvant IMRT Prostate cancer Prostatectomy Radiotherapy Abstract Background: Approximately 25% of patients treated with adjuvant radiotherapy (RT) will develop a biochemical failure within 5 yr after RT when doses of Gray (Gy) are used. Objective: To report on the safety and biochemical outcome of adjuvant intensitymodulated RT (IMRT) with doses >70 Gy. Design, setting, and participants: Between 1999 and 2008, 104 patients underwent radical prostatectomy (RP) followed by adjuvant IMRT with or without androgen deprivation (AD) with a median follow-up of 36 mo. Indications for adjuvant IMRT were capsule perforation, seminal vesicle invasion (SVI) and/or positive surgical margins at prostatectomy specimen. All patients were irradiated at a single tertiary academic centre. AD was initiated on the basis of SVI, a preprostatectomy prostate-specific antigen level >20 ng/ml, Gleason score 4+3(n = 36), or personal preference of the referring urologist (n = 32). Intervention: A median dose of 74 Gy was prescribed to the planning target volume using IMRT in all patients. AD consisted out of a luteinising hormone-releasing hormone analogue for 6 mo. Measurements: We report on acute and late toxicity, biochemical relapse free survival (brfs), and clinical progression. The Kaplan-Meier method was used to estimate brfs. Univariate analysis was used to examine the influence of patient- and treatment-related factors on brfs. Results and limitations: With respect to acute toxicity, no patients developed grade 3 gastrointestinal (GI) toxicity, and eight patients developed grade 3 genitourinary (GU) toxicity(8%). With respecttolatetoxicity, no patientsdevelopedgrade3 GItoxicity, andfour patients(4%) developedgrade 3 GU toxicity. A urethralstricture was observedinsixpatients (6%). The 3- and 5-yr actuarial brfs was 93%. On univariate analysis, brfs rates were worse when SVI ( p < 0.02), Gleason score 4+3 (p < 0.02), or negative surgical margins ( p < 0.02) were present. AD did not influence brfs. Six patients had a clinical relapse. Conclusions: Adjuvant high-dose IMRT after prostatectomy is safe and brfs is excellent. # 2009 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 Ghent, Belgium. Tel ; Fax: address: piet.ost@ugent.be (P. Ost) /$ see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 Introduction Table 1 Patient and tumour characteristics Radical prostatectomy (RP) offers excellent control rates in patients with organ-confined prostate cancer (PCa) [1]. Approximately 38 52% of the patients who undergo RP, however, have high-risk disease [2,3], that is, pathologic extension beyond the prostate, seminal vesicle invasion (SVI), or positive surgical margins (PSM), that reduces disease-control rates [4 6]. Three randomised trials have shown that immediate postoperative radiotherapy (RT) improves biochemical/clinical progression-free survival (PFS) in these high-risk patients [7 9]. An overall survival (OS) benefit in favour of immediate postoperative RT was recently demonstrated for the first time by Thompson et al [10]. Nevertheless, approximately 25% of patients will develop biochemical failure within 5 yr after RT when doses of Gray (Gy) are used [7,8]. For primary irradiation of the prostate, ample level 1 evidence exists in support of doses 78 Gy [11,12]. For immediate postoperative RT, however, no such data are available. One retrospective, nonrandomised trial did show improved biochemical control rates with doses >65 Gy compared with lower doses [13]. King and Kapp estimated that a proportional gain in biochemical relapse free survival (brfs) of about 3% can be expected per incremental Gy [14]. Intensity-modulated RT (IMRT) allows for this further dose escalation, and its safety has been proven as a salvage treatment in the postoperative setting [15]. This paper reports on the clinical outcome and safety of immediate postprostatectomy IMRT with doses >70 Gy. 2. Materials and methods Between 1999 and 2008, 104 patients underwent RP followed by immediate adjuvant IMRT with or without 6 mo of androgen deprivation (AD). Indications for adjuvant IMRT were based on Bolla s criteria for European Organisation for Research and Treatment of Cancer (EORTC) study and included capsule perforation, SVI, and/or PSM [7]. Patient and tumour characteristics are described in Table 1. All patients had at least 6 mo of follow-up. Mean and median follow-up was 36 mo (range: 6 108). Median age at the start of adjuvant IMRT was 64 yr (range: 51 77). A modified extended lymph node dissection (LND) was carried out when the Roach formula was 15% (two-thirds prostate-specific antigen (PSA) + [Gleason-6] 10) [16]. Thirty percent of our patients did not reach these criteria. When positive lymph nodes were detected, the patients were excluded from this study and were treated in another protocol. Consequently, none of the patients in this study received pelvic RT. AD (luteinising hormone-releasing hormone [LHRH] analogue for 6 mo) was initiated on the basis of SVI, preprostatectomy PSA >20 ng/ml, Gleason score 4 +3 (n = 36), or personal preference of the referring urologist (n = 32). Eighty-nine patients had a PSA < 0.2 ng/ml before the start of RT. In eight patients, PSA was measured too early after surgery to have an undetectable value in view of a PSA half-life of 3.2 d [17]. In seven patients, postoperative PSA was not documented. All patients were treated with IMRT (step-and-shoot technique) using 18-MV photons of an Elekta linear accelerator (Crawley, United Kingdom) equipped with a multileaf collimator. Mean time between surgery and initiation of RT was 2 mo (range: 1 7; standard deviation: 1.2 mo). Details about pretreatment imaging (computed tomography [CT] and magnetic resonance imaging [MRI] scans), delineation of Characteristics * No. of patients (%) Tumour stage pt2 19 (18%) pt3a 51 (49%) pt3b 27 (26%) pt4 7 (7%) Nodal stage pn0 73 (70%) pnx (all cn0) 31 (30%) Gleason score 2 7 (3 + 4) 70 (67%) 7 (4 + 3) 9 34 (33%) Median PSA (ng/ml) before surgery (range) 12.0 ( ) PSA before adjuvant IMRT (ng/ml) < (86%) >0.2 8 (7%) Unknown 7 (7%) PSM Yes 79 (76%) No 25 (24%) CP Yes 72 (69%) No 32 (31%) SVI Yes 27 (26%) No 77 (74%) PSM only 19 (18%) CP only 12 (12%) SVI only 4 (4%) PSM and CP 51 (49%) PSM and SVI 15 (14%) CP and SVI 14 (13%) PSM and CP and SVI 6 (6%) PNI Yes 78 (75%) No 11 (11%) Unknown 15 (14%) Median time in mo between surgery and adjuvant IMRT (range) 2 (1 7) Adjuvant hormone therapy Yes 68 (65%) No 36 (35%) CP = capsule perforation; IMRT = intensity-modulated radiotherapy; p = pathologic; PNI = perineural invasion; PSA = prostate-specific antigen; PSM = positive surgical margins; SVI = seminal vesicle invasion. * Except for median PSA before surgery and median time between surgery and adjuvant IMRT, all data express the patient number with the percentages between brackets. relevant structures, treatment beams, beam segmentation, leaf position optimisation, and plan optimisation are described elsewhere [18 20]. The clinical target volume (CTV) consisted of the bed of the prostate and seminal vesicles. To create the planning target volume (PTV), an isotropic three-dimensional expansion of the CTV of 7 mm was performed. Treatment was delivered in 36 fractions, with a maximal dose to the rectum, the urethral anastomosis, and the bladder of 72, 76, and 80 Gy, respectively. A median dose of 74 Gy was prescribed to the PTV. A typical IMRT dose distribution is presented in Fig. 1a and b. Patients were evaluated weekly during treatment and at 1 and 3 mo after RT. Thereafter, follow-up consisted of visits every 3 mo during the first year and every 6 mo thereafter. PSA was measured at the end of

3 671 Fig. 1 Inverse computed tomography images presenting (a) transverse and (b) sagittal dose distributions, both at the level of the pubic symphysis. NU = neourethra (status postprostatectomy); PTV = planning target volume; R = rectum. treatment and at every follow-up visit. A digital rectal examination (DRE) was routinely performed before the start of adjuvant IMRT and after adjuvant IMRT at every subsequent visit. Imaging was performed if biochemically or clinically indicated. Acute toxicity was defined as an increase of radiation-induced toxicity during or within 3 mo of the end of RT. Late toxicity was defined as an increase of radiation-induced toxicity starting 6 mo after RT or as any acute toxicity that lasting >3 mo. For each symptom, the maximum toxicity score was registered. To register acute and late genitourinary (GU) toxicity, an in-house developed toxicity score based on the Radiation Therapy Oncology Group (RTOG) criteria [21], the Common Toxicity Criteria for Adverse Events (CTCAE v.3.0) [22] and the Subjective, Objective, Management, Analytic (SOMA) Late Effects Normal Tissue Task Force (LENT) [23] toxicity scoring system was used [19]. In total, six different GU symptoms were recorded: frequency, nocturia, incontinence, urgency, haematuria, and dysuria. To register acute and late rectal or gastrointestinal (GI) toxicity, a scoring system was used consisting of eight different symptoms including the five symptoms from the RTOG toxicity scoring system supplemented with rectal urgency, anal pain, and incontinence [24]. Biochemical progression was defined as an increase >0.2 ng/ml above the lowest postoperative value measured [7]. Clinical progression was defined as the occurrence of a local relapse, lymph node metastasis, or haematogenous metastasis. When a DRE was suggestive of local relapse, the prostatectomy bed was evaluated with MRI. Bone scans and fluorine-18 2-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) CT scans were carried out to look for bone metastases and lymph node metastases, respectively, if clinically relevant. We calculated brfs from the last day of adjuvant IMRT 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 product limit method was used to estimate brfs. Univariate (logrank) and multivariate (Cox proportional hazards regression model) analysis were used to examine the predictive value of patient-related (eg, preoperative PSA, postoperative PSA, perineural invasion [PNI], Gleason score, margin status, SVI, and capsule perforation) and treatment-related (ie, AD) factors for relapse after adjuvant IMRT. A p value of 0.05 was considered significant. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA) version Results 3.1. Acute toxicity Table 2 provides a detailed overview of acute GI and GU toxicity. No patients developed grade 3 GI toxicity. Twenty-

4 672 Table 2 Acute and late gastrointestinal and genitourinary toxicity Symptom Grade Acute toxicity * Patients (%) Late toxicity * Patients (%) Abdominal cramps Grade 1 5 (5) 2 (2) Grade 2 4 (4) 2 (2) Diarrhoea Grade 1 17 (16) 8 (8) Grade 2 9 (9) 1 (1) Frequency Grade 1 18 (17) 20 (19) Grade 2 8 (8) 2 (2) Mucus loss Grade 1 15 (14) 14 (13) Red blood loss Grade 1 4 (4) 7 (7) Grade 2 1 (1) 2 (2) Urgency Grade 1 12 (12) 10 (10) Grade 2 3 (3) 1 (1) Continence Grade 1 7 (7) 0 (0) Grade 2 1 (1) 2 (2) Anal pain Grade 1 13 (13) 4 (4) Grade 2 4 (4) 1 (1) Nocturia Grade 1 27 (26) 17 (16) Grade 2 10 (10) 3 (3) Grade 3 3 (3) 0 (0) Pollakisuria Grade 1 27 (26) 4 (4) Grade 2 9 (9) 6 (6) Grade 3 5 (5) 0 (0) Haematuria Grade 1 2 (2) 6 (6) Grade 2 3 (3) 8 (8) Grade 3 0 (0) 2 (2) Dysuria Grade 1 17 (16) 7 (7) Grade 2 4 (4) 0 (0) Urgency Grade 1 28 (27) 19 (18) Grade 2 5 (5) 4 (4) Incontinence Grade 1 12 (12) 12 (12) Grade 2 3 (3) 6 (6) Grade 3 1 (1) 2 (2) CTCAE = Common Toxicity Criteria for Adverse Events; GI = gastrointestinal; GU = genitourinary; RTOG = Radiation Therapy Oncology Group; SOMA- LENT = Subjective, Objective, Management, Analytic Late Effects Normal Tissue Task Force. * Acute and late toxicity grading in detail for every symptom scored. To register GU toxicity, an in-house developed toxicity score based on RTOG, CTCAE v3.0, and SOMA-LENT toxicity scoring systems was used. To register rectal/gastrointestinal toxicity, a scoring system was used consisting of eight different symptoms including the five symptoms from the RTOG toxicity scoring system supplemented with rectal urgency, anal pain, and incontinence. nocturia (n = 10) and pollakisuria (n = 9). Complete recovery within 3 mo was observed in 20 patients (74%) Late toxicity Table 2 provides a detailed overview of late GI and GU toxicity. No patients developed grade 3 GI toxicity. Seven patients (7%) experienced grade 2 GI toxicity. Complete recovery was seen in four (57%) patients within 3 mo. Four patients (4%) developed grade 3 late GU toxicity. Two patients had grade 3 haematuria. Two patients experienced worsening of preexisting prostatectomyinduced incontinence (grade 1 and 2, respectively) to grade 3 incontinence. Grade 2 GU toxicity was observed in 23 patients (22%), with recuperation in 75% of the cases. A urethral stricture was observed in six patients (6%). One patient required intermittent bladder catheterisation; one patient required urethroplasty for his stricture. This patient had already undergone urethral surgery for a urethral stricture before prostatectomy. Endoscopic urethrotomy was required in four patients. Two of them suffered from severe posturethrotomy incontinence and were treated with a urethral sphincter prosthesis (n = 1)or a permanent urinary derivation (n = 1) Disease-control rates After a median follow-up of 3 yr following adjuvant IMRT with or without AD, three patients died (one of ureteral carcinoma and two of PCa). No local recurrences were documented, resulting in a 100% local control rate. The 3- and 5-yr actuarial brfs for the whole group was 93% (Fig. 2). The pathologic risk factor stratification for all patients is shown in Table 3. The following factors resulted in a significantly worse 3-yr brfs: SVI (97% vs 81%, p < 0.02), Gleason score (96% vs 84%, p < 0.02), and negative surgical margin (NSM) status (97% vs 82%, p < 0.02). Preoperative PSA, postoperative PSA, PNI, capsular perforation, and AD (3-yr brfs: 96% with AD vs 85% three patients developed grade 2 GI toxicity (22%). Grade 2 diarrhoea (n = 9) and increased frequency (n = 8) were most commonly observed. Eighty-seven percent of patients recovered within 3 mo after occurrence of grade 2 toxicity. Eight patients developed grade 3 GU toxicity (8%), six of whom recovered within 3 mo. Two patients experienced worsening of preexisting nocturia (grade 2) to grade 3 nocturia. One patient developed both grade 3 pollakisuria and nocturia resulting from a urethral stricture. Other grade 3 toxicities observed in patients without preexisting complaints were pollakisuria (n = 4) and incontinence (n = 1). Grade 2 GU toxicity was seen in 27 patients (26%). Most frequently observed grade 2 toxicities were Fig. 2 Kaplan-Meier curve representing biochemical relapse free survival.

5 673 Table 3 Patient risk factor stratification * Margin pt stage Capsular perforation without AD, p = 0.27) did not influence brfs. On multivariate analysis, none of the factors was significant. Seven patients (7%) had a biochemical relapse, which occurred at a mean and median delay of 24 mo and 18 mo, respectively (range: 0 84 mo). Six of them had a clinical relapse. In four patients, the biochemical relapse preceded the clinical relapse with a mean delay of 9 mo, while in two patients, biochemical and clinical relapse occurred at the same time. Two patients presented with an isolated lymph node relapse, two patients developed bone metastases, and two patients developed both lymph node and bone metastases. The remaining patient had no clinical relapse at last follow-up. 4. Discussion No Grand total Recently, three randomised trials have provided level 1 evidence in favour of immediate postoperative RT after RP in patients at high risk for biochemical/clinical PFS [7 9]. With doses varying from 60 Gy to 64 Gy, brfs significantly improved, with 5-yr actuarial results of 72 74% compared to 35 54% without RT [7 9]. Very recently, a significant improvement in OS was observed in favour of adjuvant RT (median OS of 15.2 yr vs 13.3 yr) [10]. A dose response relationship has been documented when RT is applied as the primary treatment for PCa [11,12]. In the immediate postoperative setting, the tumour burden is microscopic; therefore, it is commonly presumed that lower radiation doses are sufficient for disease control. Moreover, clinicians are reluctant to deliver higher doses in view of a possible excess in toxicity. From radiobiologic models, however, a 3% gain in brfs per incremental Gy can be expected [14]. To the best of our knowledge, this paper is the first to report on the clinical results of immediate adjuvant postoperative RT doses (with or without AD) >70 Gy and with the use of IMRT. Our early 3- and 5-yr brfs rates of 93% support the hypothesis of King and Kapp [14], as they Yes Negative 3a b Negative total Positive 2a b c a b Positive Total Grand Total * Patient risk factor stratification according to margin status, pathologic stage (pt stage), and capsular perforation. compare favourably with the approximately 73% from the above-mentioned randomised trials [7 9]. The 20% gain in brfs obtained with a 10-Gy dose escalation results in an estimated gain of 2% per Gy, which is very close to the King and Kapp data [14]. The individual risk factors of our patient population are comparable to those in the large randomised trials [7 9]. With univariate analysis, SVI, Gleason score 4 + 3, and NSM status had a significantly worse brfs. On multivariate analysis, none of these factors remained significant. Two other, and probably stronger, arguments in favour of dose escalation in the adjuvant setting can be derived from the data of the randomised trials [7,8]. First, treatment failure after RP is predominantly local instead of metastatic. In the observational arm of the EORTC trial, the clinical local failure rate was four times higher than the systemic failure rate [7]. This finding was confirmed by the Southwest Oncology Group (SWOG) trial, which showed that the local failure rate was 1.3 times higher than the systemic failure rate [25]. Second,RTwasableto reduce local treatment failure approximately by a factor of three(swog:22%vs8%;eortc:15%vs5%)butdidnot eradicate local failure completely. So far, we have not observed any local failures, but our follow-up period is shorter. The SWOG trial clearly demonstrated the importance of local control. The reduction in local failure with RT was associated with a 25% reduction in metastasis-free survival at 10 yr [25]. Further improvement in local control, obtained by higher radiation doses, is thus likely to improve metastasis-free survival. Adjuvant treatments need to be balanced against their side-effects. Doses of about 60 Gy delivered by conventional technology are rarely associated with severe long-term side-effects (<5% grade 3 GI and GU toxicity) [7,9]. Higher doses, however, are accompanied by a significant increase in side-effects when conventional technology is used [26]. With the advent of IMRT, it became feasible to irradiate the prostate bed to a higher dose while sparing critical organs at risk, resulting in less toxicity. For a median follow-up of 36 mo, which is sufficient to report on late toxicity [24,27],we observed late grade 3 complications in a minority of patients (4%, all GU toxicity), although a median dose of 74 Gy was delivered. This result is comparable to the data of the EORTC trial [7]. Late grade 2 GI toxicity was rare and was lower than or comparable to series using lower doses and conventional technologies [28]. Both observations confirm the low toxicity rates of our former work [15]. With IMRT, concave, horseshoe-shaped dose distributions can be obtained, sparing the rectal wall to a higher extent than conventional or conformal radiation [18,20]. This technology allows us to reduce the rectal volume treated to an intermediate dose (50 65 Gy), which is the main contributor for late rectal toxicity [24]. Late grade 2 GU toxicity was observed in 23% of patients but was transient in 75% of them. This transient character of urinary toxicity confirms the assumption that urinary toxicity is related more to inflammation of the urethra than to the mucosal toxicity of the bladder [29].

6 674 Anastomotic or urethral stricture is a debilitating complication in the postoperative and/or postprostatectomy radiation setting. No RTOG/EORTC guidelines are available to adequately grade strictures [21], but the randomised trials do report strictures using these guidelines [7,8]. The SWOG trial reported, but did not grade a significant difference in stricture rates (18% in the RT arm vs 10% in the wait-and-see arm) [8]. At the American Society for Therapeutic Radiology and Oncology meeting in 2002, Bolla et al reported only 1.5% grade 3 strictures in the RT arm at 3-yr follow-up [27]. It is not specified which grading system was used. The final EORTC report does not report strictures [7]. The CTCAE v3.0 classify urethral obstructions in more detail [22]. Endoscopic interventions (eg, urethrotomy) are somewhat surprisingly categorised as grade 2, where one would expect them to be grade 3. When we apply this criteria to our population, five out of six strictures become a grade 2, resulting in only 1% grade 3 incidence of urethral stricture. The role of AD in the postprostatectomy setting remains unclear. We did not find a significant impact of AD on brfs, probably because of the low number of events. To detect a significant difference between a 5-yr brfs of 96% with AD and 85% without AD as in our study (with a two-sided a of 0.05 and an 80% power), the sample size would require 264 patients (171 treated with AD and 93 without). Hopefully, trials like Radiotherapy and Androgen Deprivation in Combination after Local Surgery (RADICALS) [30] and the EORTC trial , which will start accrual soon, will clarify the role of AD in the postprostatectomy setting. This study is susceptible to the shortcomings of every retrospective analysis. We acknowledge the fact that the median follow-up of 36 mo is too short to draw final conclusions on biochemical control. In contrast, our results still compare favourably with the early results of the randomised, controlled trials using conventional RT doses [7,9]. This report may serve as a foundation to justify the initiation of randomised controlled trials to explore the full advantage of dose escalation in this setting, as it has been done in the setting for primary prostate irradiation. 5. Conclusions Adjuvant high-dose IMRT after prostatectomy is safe. The brfs at 3 yr is excellent. 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, Fonteyne, De Meerleer. Acquisition of data: Ost, Fonteyne, Villeirs, Lumen, Oosterlinck. Analysis and interpretation of data: Ost, Fonteyne. Drafting of the manuscript: Ost, De Meerleer. Critical revision of the manuscript for important intellectual content: Ost, Fonteyne, Villeirs, Lumen, Oosterlinck, De Meerleer. Statistical analysis: Ost. Obtaining funding: None. Administrative, technical, or material support: Ost, De Meerleer. 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: This work has been sponsored by a scientific grant of the Stichting Emmanuel van der Schueren, scientific partner of the Vlaamse Liga tegen Kanker. References [1] Zincke H, Bergstralh EJ, Blute ML, et al. Radical prostatectomy for clinically localized prostate cancer: long-term results of 1,143 patients from a single institution. 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Int J Radiat Oncol Biol Phys 2004;60: [20] De Meerleer GO, Vakaet LA, De Gersem WR, et al. Radiotherapy of prostate cancer with or without intensity modulated beams: a planning comparison. Int J Radiat Oncol Biol Phys 2000;47: [21] Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31: [22] Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13: [23] LENT SOMA tables. Radiother Oncol 1995;35: [24] Fonteyne V, De Neve W, Villeirs G, De Wagter C, De Meerleer G. Late radiotherapy-induced lower intestinal toxicity (RILIT) of intensitymodulated radiotherapy for prostate cancer: the need for adapting toxicity scales and the appearance of the sigmoid colon as coresponsible organ for lower intestinal toxicity. Radiother Oncol 2007;84: [25] Swanson GP, Hussey MA, Tangen CM, et al. Predominant treatment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG J Clin Oncol 2007;25: [26] Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 1999;353: [27] Bolla M, Van Poppel H, Van Cangh P, et al. Acute and late toxicity of post-operative external irradiation in pt3n0 prostate cancer patients treated within EORTC trial Int J Radiat Oncol Biol Phys 2002;54:62 3. [28] 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: [29] Zelefsky MJ, Aschkenasy E, Kelsen S, Leibel SA. Tolerance and early outcome results of postprostatectomy three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 1997;39: [30] Parker C, Clarke N, Logue J, et al. RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery). Clin Oncol (R Coll Radiol) 2007;19: Editorial Comment on: Adjuvant High-Dose Intensity-Modulated Radiotherapy after Radical Prostatectomy for Prostate Cancer: Clinical Results in 104 Patients Luigi F. Da Pozzo Department of Urology, Ospedali Riuniti di Bergamo, Largo Barozzi, 1, Bergamo, Italy ldapozzo@ospedaliriuniti.bergamo.it Three large randomised studies (references 7 9 in the original article) have demonstrated in the recent past that biochemical progression-free survival and local control following radical prostatectomy for locally advanced prostate cancer are significantly improved by adjuvant radiotherapy (ART) delivered at Gy. An overall survival benefit in favour of ART has also been recently demonstrated for the first time (reference 10 in the original article). A recent report in literature has suggested that even node positive patients at radical prostatectomy might benefit from ART [1]. Although these results allow one to conclude that ART for high risk of recurrence prostate cancer can be considered a clinical standard, several issues related to this treatment modality need to be further investigated. Among these, dose escalation is one of hottest topics. Can brilliant results reported by the above mentioned studies be further improved by increasing total dose delivered to the prostatic bed without significantly increasing acute and late complications and ultimately without negatively impacting on quality of life? This nice retrospective analysis [2] seems to demonstrate that adjuvant high-dose intensity-modulated radiotherapy (IMRT) allows for irradiation of the prostate bed to >70 Gy, still resulting in a safe and well tolerated procedure with excellent biochemical relapse-free survival compared to doses ranging from 60 Gy to 64 Gy. A retrospective analysis performed on 334, high-risk, node negative patients recently indicated a clinical benefit deriving from ART doses 70Gyonlyinthecaseofundetectablepostoperative PSA [3]. Three major limitations of this study need to be clearly outlined. 1. This is a retrospective and nonrandomized study that was conducted in a relative small cohort of patients. None of the predictors significantly associated with biochemical recurrence at univariate analysis remained significant at multivariate analysis thus reflecting a statistically underpowered study. 2. The study also suffers from lack of a control group, that in the authors intention is represented by the results reported in previous larger multicentric and randomized clinical series. This limitation has been acknowledged

8 676 by the authors who argue that the study should be considered as hypothesis generating and a foundation to perform a randomised controlled trial concerning this issue 3. Finally, a median follow-up of three years with or without androgen deprivation is too short to allow any definitive conclusion regarding disease control rate. A 3- and 5-yr actuarial biochemical recurrence free survival of 93% is a promising result but cannot be considered definitive. The same short follow-up should also be taken into account when late GU complications are considered with particular regard to gross haematuria, frequency, incontinence and urgency that should be considered in a longer time frame before definitive results can be drawn. In conclusion although in my personal opinion dose escalation is the future of adjuvant radiotherapy, for the above reported reasons, this study should be considered a nice introduction to a complicate issue, but does not give any evidence to claim superiority of a high dose treatment over the standard at Gy. The authors enthusiastic synthesis in the take-home message should thus be reconsidered in order to avoid a misleading piece of information. References [1] Da Pozzo LF, Cozzarini C, Briganti A, et al. Long-term follow-up of patients with prostate cancer and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of adjuvant radiotherapy. Eur Urol 2009;55: [2] 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: [3] Cozzarini C, Montorsi F, Fiorino C: Need for high radiation doses (70 Gy) in early postoperative irradiation after radical prostatectomy: a single-institution analysis of 334 high-risk, node negative, patients. Int J Radiat Oncol Biol Phys. In press. DOI: /j.eururo DOI of original article: /j.eururo Editorial Comment on: Adjuvant High-Dose Intensity-Modulated Radiotherapy after Radical Prostatectomy for Prostate Cancer: Clinical Results in 104 Patients Ofer Yossepowitch Department of Urology, Rabin Medical Center, Petah-Tikva, Israel oferyoss@netvision.net.il For men with localized prostate cancer who choose to undergo radical prostatectomy, complete surgical extirpation of the tumor is paramount to successful oncologic outcome. In some of these patients, however, additional local therapy is required to control the disease. Radiation therapy delivered in an adjuvant setting to those with poor pathologic features has been shown, unequivocally, to improve biochemical-relapse rates as well as to reduce the risk of metastatic disease and to prolong survival [1]. With the recognition that a higher radiation dose can enhance the clinical response in the primary setting [2], the authors of this paper rightfully endeavored to explore the impact of high-dose (>70 Gy) intensity-modulated radiotherapy (IMRT) after radical prostatectomy in men at high risk of recurrence [3]. Compared with the standard radiation dose (60 64 Gy), this promising IMRT technique demonstrated better prostate-specific antigen control with acceptable toxicity. Efforts to improve the efficacy of radiation therapy in both the primary and adjuvant settings ought to be commended, but several concerns must be recognized with regard to the present article. First, as with any suggested treatment modification, adequate comparative data remain the only acceptable means to ascertain clear advantage of a novel strategy over a traditional technique. Acknowledging the lack of a control group in their paper, the authors plea for a randomized trial exploring the role of dose escalation in the adjuvant setting is evident. Second, radiation therapy appears to affect biochemical-relapse rates favorably and to cause specific survival not only in men with locally advanced tumors but also in those with node-positive disease [4]. Forgoing node dissections in 30% of the study participants and excluding men with nodal metastases from getting radiation therapy might not reflect the optimal contemporary treatment strategy for high-risk cancers. Finally, given the protracted natural history of prostate cancer, the importance of maintaining adequate quality of life for these patients cannot be overstated. Potency preservation is undoubtedly imperative to most men and remains unaccounted for in this analysis. Recognizing that a higher radiation dose might be associated with a greater risk of erectile dysfunction [5], the true merits of highdose IMRT remain elusive for men who, in fact, might have been cured by their surgery. References [1] Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009;181:

9 [2] Zelefsky MJ, Yamada Y, Kollmeier MA, Shippy AM, Nedelka MA. 677 pelvic lymphadenectomy and radical prostatectomy: the positive Long-term outcome following three-dimensional conformal/ impact of adjuvant radiotherapy. Eur Urol 2009;55: intensity-modulated external-beam radiotherapy for clinical [5] van der Wielen GJ, Mulhall JP, Incrocci L. Erectile dysfunction after stage T3 prostate cancer. Eur Urol 2008;53: [3] Ost P, Fonteyne V, Villeirs G, Lumen N, Oosterlinck W, De Meerleer radiotherapy for prostate cancer and radiation dose to the penile structures: a critical review. Radiother Oncol 2007;84: G. Adjuvant high-dose intensity-modulated radiotherapy after radical prostatectomy for prostate cancer: clinical results in 104 patients. Eur Urol 2009;56: [4] Da Pozzo LF, Cozzarini C, Briganti A, et al. Long-term follow-up of patients with prostate cancer and nodal metastases treated by DOI: /j.eururo DOI of original article: /j.eururo