Functional Outcomes and Complications Following Radiation Therapy for Prostate Cancer: A Critical Analysis of the Literature

Transcription

1 EUROPEAN UROLOGY 61 (2012) available at journal homepage: Review Prostate Cancer Functional Outcomes and Complications Following Radiation Therapy for Prostate Cancer: A Critical Analysis of the Literature Lars Budäus a, *, Michel Bolla b, Alberto Bossi c, Cesare Cozzarini d, Juanita Crook e, Anders Widmark f, Thomas Wiegel g a Martini-Clinic Prostate Cancer Centre, University Hospital Hamburg-Eppendorf, Hamburg, Germany; b Department of Oncology-Radiotherapy, Centre Hospitalier Universitaire, Grenoble, France; c Departments of Radiation Oncology, Institut Gustave-Roussy, Villejuif, France; d Department of Radiotherapy, Scientific Institute Hospital San Raffaele, Milan, Italy; e Department of Radiation Oncology, British Columbia Cancer Agency Centre for the Southern Interior, Kelowna, British Columbia, Canada; f Department of Radiation Sciences, Oncology, Umea University Hospital, Umea, Sweden; g Department of Radio Oncology, University Hospital Ulm, Ulm, Germany Article info Article history: Accepted September 27, 2011 Published online ahead of print on October 6, 2011 Keywords: Prostate cancer Functional outcome Radiation therapy Intensity modulated radiotherapy Tomotherapy Abstract Context: Prostate cancer (PCa) patients have many options within the realms of surgery or radiation therapy (RT). Technical advancements in RT planning and delivery have yielded different approaches, such as external beam, brachytherapy, and newer approaches such as image-guided tomotherapy or volumetric-modulated arc therapy. The selection of the optimal RT treatment for the individual is still a point of discussion, and the debate centres on two important outcomes namely, cancer control and reduction of side-effects. Objective: To critically review and summarise the available literature on functional outcomes and rectal sequelae following RT for PCa treatment. Evidence acquisition: A review of the literature published between 1999 and 2010 was performed using Medline and Scopus search. Relevant reports were identified using the terms prostate cancer, radiotherapy, functional outcomes, external beam radiation, brachytherapy, IMRT, quality of life, and tomotherapy and were critically reviewed and summarised. Evidence synthesis: Related to nonuniform definition of their assessed functional end points and uneven standards of reporting, only a minority of series retrieved could be selected for analyses. Moreover, patterns of patient selection for different types of RT, inherent differences in the RT modalities, and the presence or absence of hormonal treatment also limit the ability to synthesise results from different publications or perform meta-analyses across the different treatment types. Nonetheless, several studies agree that recent technical improvements in the field of RT planning and delivery enable the administration of higher doses with equal or less toxicity. Regardless of the type of RT, the most frequently considered functional end points in the published analyses are gastrointestinal (GI) complications and rectal bleeding. Established risk factors for acute or late toxicities after RT include advanced age, larger rectal volume, a history of prior abdominal surgery, the concomitant use of androgen deprivation, preexisting diabetes mellitus, haemorrhoids, and inflammatory bowel disease (IBD). Similarly, mild acute irritative urinary symptoms are reported in several studies, whereas total urinary incontinence and other severe urinary symptoms are rare. Pretreatment genitourinary complaints, prior transurethral resection of the prostate (TURP), and the presence of acute genitourinary toxicity are suggested as contributing to long-term urinary morbidity. Erectile dysfunction (ED) is not an immediate side-effect of RT, and the occurrence of spontaneous erections before treatment is the best predictor * Corresponding author. Martini-Clinic Prostate Cancer Centre, University Hospital Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany. Tel ; Fax: address: Lars.Budaeus@gmail.com (L. Budäus) /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 61 (2012) for preserving erections sufficient for intercourse. In addition, the use of magnetic resonance imaging (MRI) permits a reduction in the dose delivered to vascular structures critical for erectile function. Conclusions: In the future, further improvement in RT planning and delivery will decrease side-effects and permit administration of higher doses. Related to the anatomy of the prostate, these higher doses may favour rectal sparing while not readily sparing the urethra and bladder neck. As a consequence, there may be a future shift from doselimiting long-term rectal morbidity towards long-term urinary morbidity. In the absence of prospective randomised trials comparing different types of surgical and RT-based treatments in PCa, the introduction of validated tools for reporting functional and clinical outcomes is crucial for evaluating and identifying each individual s best treatment choice. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. 1. Introduction The number of radiotherapeutic treatment modalities for prostate cancer (PCa) has increased in recent years and now includes different types of external-beam radiation therapy (EBRT) or brachytherapy, with or without androgen deprivation, as well as several newer approaches [1]. Many factors, including clinical characteristics (age, comorbidities, tumour stage and grade) and other factors like institutional standards, patient preference, and the availability of radiation therapy (RT) resources, influence the choice of the treatment [2 4]. During the past decade, a reduction in side-effects was achieved by improvement of RT planning and the introduction of several technical advances for RT delivery and application. For example, the use of dose volume histograms (DVHs) during RT planning for organs at risk has helped to establish dose constraints to limit both acute and late rectal toxicity [5 12]. Moreover, a tool for prediction of rectal bleeding based on individual gene profiling combined with DVHs has been developed [13]. New techniques for RT [(Fig._1)TD$FIG] delivery allow dose escalation with better cancer control rates and fewer or similar side-effects [14 17]. For example, intensity-modulated radiation therapy (IMRT) better conforms to the shape of the prostate, and sculpting of the dose to the prostatic target minimises harmful irradiation of the rectum (level of evidence [LoE]: 1b) [18 24] (Fig. 1). Similarly, other new technologies like real-time tracking of the target while RT is delivered (eg, image-guided tomotherapy or volumetric-modulated arc therapy) also allow more precise RT delivery [25,26]. Despite these improvements, acute and late rectal sequelae are still the main dose-limiting toxicities, and rectal bleeding is often used as an end point because of its objectivity [13,27,28]. Unfortunately, a direct comparison of different publications reporting on functional outcomes after the same RT modality is difficult because of incompatible or ambiguous end points and incomplete reporting of results [29]. Similarly, a comparison between functional outcomes like erectile function and urinary function of patients treated with different RT modalities is also limited by differences in patients clinical baseline characteristics. Fig. 1 Comparison between three-dimensional conformal radiation therapy (RT) and tomotherapy plan for radiation of the prostate bed. Similar to intensity-modulated radiation therapy, rapid arc, and volumetric-modulated arc therapy, tomotherapy allows conformal spare RT delivery to critical structures, such as the rectum.

3 114 EUROPEAN UROLOGY 61 (2012) Despite these potential limitations, we have attempted to systematically describe the functional outcomes and complications after different types of primary RT for PCa as well as after adjuvant or deferred RT following radical prostatectomy (RP). Moreover, we discuss the problems when reporting on functional data and give an outline on the future developments of RT monitoring and delivery. We hope to provide a comprehensive literature reference guide on functional outcomes after different types of RT for urologists and radiation oncologists. 2. Evidence acquisition A Medline search was conducted in March 2010 and updated in September 2010 to identify original articles, review articles, and editorials addressing the outcomes after external beam, brachytherapy, tomotherapy, and newer approaches of RT for PCa treatment by combining the following terms: prostate cancer, radiotherapy, external beam radiation, IMRT, conformal RT, brachytherapy, quality of life, functional outcomes, tomotherapy, and arc therapy. Manuscripts were restricted to the English language. Overall, 442 records were identified through database searching. Cross-referencing identified 112 additional records. The search results were restricted to those studies using validated questionnaires for assessment of baseline characteristics and outcomes. Moreover, because erectile dysfunction (ED) is not an immediate side-effect of RT, only articles with follow-up >24 mo after treatment were included, as referenced in Table 1. Based on these criteria, 132 articles were included in the review. LoE was assigned according to the Centre for Evidence-Based Medicine rating scheme [30]. Manuscripts published between 1999 and February 2010 as well as randomised trials were selected primarily, but welldesigned control studies (eg, nonrandomised comparative studies and quality of life [QoL] studies) were also included. The articles with the highest LoE were identified with the consensus of all of the collaborative authors and were critically reviewed. Finally, important QoL contributions to this field, which report on functional outcomes and QoL changes, were also included. 3. Evidence synthesis 3.1. Rectal sequelae following radiation therapy Randomised trials have demonstrated that higher doses of RT improve local tumour control (LoE 1a); however, dose escalation is ultimately limited by the occurrence of sideeffects [16,17,31]. Gastrointestinal (GI) complications are the most frequently considered end points in the published analyses, with rectal bleeding accounting for the majority of late GI toxicity. Onset is usually within the first 2 yr after treatment [32]. Because of its objectivity, rectal bleeding is sometimes the sole end point reported [27,28], but the Radiation Therapy Oncology Group (RTOG) toxicity scale is also frequently used (Tables 2 and 3) [13]. Based on a lack of Table 1 Characteristics of selected studies addressing gastrointestinal and genitourinary toxicity after different types of radiation therapy ADT LoE Late genitourinary toxicity, grade, % Late GI toxicity, grade, % Acute genitourinary toxicity, grade, % Acute GI toxicity, grade, % Assessment Median follow up, mo Treatment modality No. of study patients 1b I43 II 18 vs 20 III 1 vs 2 IV 0 I36vs43 II 8 vs 17 III 1 I35vs40 II 42 vs 49 III 1 RTOG scale 60 I 25 vs 31 II 41 vs 57 III 0 vs 1 IV Zietmann [16]: 393 3DCRT 70.2 vs 79.2 Gy 1b More symptoms in patients receiving ADT vs vs 7 4 IV vs vs vs 0.3 IV 0 vs vs vs RTOG/EORTC adopted Peeters [31,33]: 669 3DCRT Gy 2 41vs47 3 6vs4 4 2a Yes (increased incidence of long-term adverse events) I II 8 11 III 2 4 I II III 6 10 I II 38 vs 39 III RTOG scale 6 I II 30 vs 33 III MRC RT01 [125,126]: 843 3DCRT Gy 1b 1 21vs vs vs 7 4 RTOG/EORTC vs vs vs 10 4 Kuban [17]: 301 Initial conventional rather than 3DCRT 70 vs 78 Gy 6 mo 1b I52vs46 II 35 vs 25 III 6 vs 11 CTCAE 2.0 I 51 vs 40 II 18 vs 7 III 1 vs 0 3DCRT (n = 652) Gy IMRT (n = 139) Gy Matzinger [24] (EORTC 22991): 791

4 Table 1 (Continued ) No. of study patients Treatment modality Assessment Median follow up, mo Acute GI toxicity, grade, % Acute genitourinary toxicity, grade, % Late GI toxicity, grade, % Late genitourinary toxicity, grade, % ADT LoE Zapatero [127]: 426 3DCRT (4 to 6) Gy Zelefsky [44]: 561 IMRT 81 Gy NCI-CTC for adverse events Vora [46]: 145 Kupelian [45]: 770 Gomez-Iturriaga Pina [105]: 96 Ishiyama [128]: 100 IMRT 70 77Gy IMRT Hypofractionated 70Gy 125 I LDR brachytherapy Gy 192 Ir HDR brachytherapy 31.5 Gy EBRT 30 Gy Gelblum [48]: Pd LDR brachytherapy 120 Gy 120 J LDR brachytherapy 144 Gy Gelblum [48]: Pd LDR brachytherapy 120 Gy 120 J LDR brachytherapy 144 Gy + EBRT 43 Gy Lee [129]: 130 EBRT I 108 Gy Zelefsky [47]: 248 RTOG/EORTC I II 1.6 III 0.1 IV RTOG scale 60 I 34 II 49 III 1 RTOG/EORTC CTCAE 30 I 37.2 II 9.6 III I23 II 46 III I 1.1 II 1.1 RTOG scale 36 I 58 II 6 III 6 ADT: 235 None: 71 (No impact on toxicity) I27 II 23 III I 38.3 II 11.7 III 3.2 RTOG scale 48 I 8.9 II 6.5 III 0.4 RTOG scale 48 I 10.5 II 7.1 III 0.7 RTOG scale 49 I II III 4 IV 125 I LDR brachytherapy RTOG scale 60 I 33 II 9 III 0.4 I II 3 III 9 IV I20 II 23 III I 6.4 II 1.1 III I 68 II 4 III 12 2a 2c 2c 2c 2c ADT 3a 3a I II III 3 IV 1 I40 II 55 III 3 2c 2c 2c GI = gastrointestinal; ADT = androgen-deprivation therapy; LoE = level of evidence; 3DCRT = three-dimensional conformal radiation therapy; RTOG = Radiation Therapy Oncology Group; EORTC = European Organization for Research and Treatment of Cancer; IMRT = intensity-modulated radiation therapy; CTCAE = Common Terminology Criteria for Adverse Events; NCI-CTC = National Cancer Institute Common Toxicity Criteria; LDR = low dose rate; HDR = high dose rate. EUROPEAN UROLOGY 61 (2012)

5 116 EUROPEAN UROLOGY 61 (2012) Table 2 Acute gastrointestinal and genitourinary complications according to the Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer morbidity scale (adaptations with regard to the original RTOG scale in italics) according to Huang et al. [39] Grade 1 Grade 2 Grade 3 Grade 4 GI GU Increased frequency or change in quality of bowel habits not requiring medication Rectal discomfort not requiring analgesics Frequency of urination or nocturia twice pretreatment habit Dysuria or urgency not requiring medication Diarrhoea requiring parasympatholytic drugs Mucous discharge not necessitating sanitary pads Rectal or abdominal pain requiring analgesics Frequency of urination is less frequent than every hour (day: times; nocturia 5 8 times) Dysuria, urgency, bladder spasm requiring local anaesthetic Diarrhoea requiring parenteral support Severe mucous or blood discharge necessitating sanitary pads Abdominal distension (flat plate radiograph demonstrates distended bowel loops) Frequency of urination is more frequent than every hour (day: >16 times; nocturia: >8 times) Dysuria, bladder spasm, urgency requiring frequent regular narcotic Gross haematuria complaints requiring permanent or suprapubic catheter Obstruction, fistula, or perforation GI bleeding requiring transfusion; Abdominal pain or tenesmus requiring tube decompression or bowel diversion Haematuria requiring transfusion Obstruction not resulting from clots Ulceration Necrosis GI = gastrointestinal; GU = genitourinary. Table 3 Late gastrointestinal and genitourinary complications according to the Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer (EORTC) morbidity scale (adaptations with regard to the original RTOG/EORTC scale in italics) according to Huang et al. [39] GI * GU Grade 1 Grade 2 Grade 3 Grade 4 Mild diarrhoea Mild cramping Bowel movements 2 5 per day Slight rectal discharge or bleeding Frequency during day h Nocturia 2 3/night Slight dysuria or microscopic haematuria requiring no medication Slight epithelial atrophy, minor telangiectasia Bladder capacity >300 ml Moderate diarrhoea Intermittent, severe cramping Bowel movements (5 per day) Moderate excessive, rectal discharge Intermittent, frequent bleeding (3 single laser treatments or transfusion) Frequency during day: 1 2 h Nocturia 4 6/night Moderate dysuria or intermittent (mild, moderate) haematuria requiring medication y Moderate telangiectasia Bladder capacity: ml Watery diarrhoea Obstruction requiring surgery Bleeding requiring surgery or 2 laser treatments or transfusions Frequency during day: 2h Nocturia 6/night Severe dysuria Frequent (severe) haematuria Severe telangiectasia Bladder capacity: ml Benign urethral strictures requiring TURP, dilation, or suprapubic or permanent catheter Necrosis Perforation Fistula Abdominal pain or tenesmus requiring tube decompression or bowel diversion Necrosis Severe haemorrhagic cystitis Bladder capacity >100 ml * The difference between grade 1 and grade 2 GI pain, mucosal loss, or bleeding is most easily made when grade 2 is defined as morbidity requiring specific medication: grade 1 = stool softener, diet modification, occasional (<2/wk) non-narcotic drug, occasional antidiarrhoeal agent (2/wk), occasional use of incontinence pads (1 2 d/wk); grade 2 = regular (>2/wk) use of (non)narcotic drugs for pain, regular (2/wk) antidiarrhoeals, steroid suppositories, one laser. y With the exception of antibiotics. GI = gastrointestinal; GU = genitourinary; TURP = transurethral resection of the prostate. specificity and objectivity, quantifiable modifications to the criteria have been proposed [33]. Established risk factors for acute and late toxicities after RT for PCa include advanced age; larger rectal volume; a history of prior abdominal surgery; the concomitant use of androgen deprivation; and preexisting diabetes mellitus, haemorrhoids, or inflammatory bowel disease (IBD; LoE 3a) [8,34 41]. In addition, a diagnosis of acute rectal toxicity is now recognised to be associated with an increased risk of developing late rectal complications [19,42,43]. In the future, prediction of late rectal toxicity may be improved by incorporating DVHs that more accurately reflect the volume of rectal wall receiving a specific dose. Refined knowledge of the location of dose maximums, combined with separate scoring and modelling of the different aspects of rectal toxicity (bleeding, stool frequency, and faecal incontinence), may clarify specific anatomic regions of dose sensitivity [27]. Moreover, identification of relevant risk factors for each end point and incorporation of these factors into the dose volume based models may improve the predictive power for long-term sequelae (Tables 2 and 3) Studies reporting on rectal sequelae following radiation therapy Three-dimensional conformal radiation therapy. Kuban et al. assessed the impact of 70 Gy versus 78 Gy doses on GI toxicity in 301 patients treated with three-dimensional conformal RT (3DCRT). After a median follow-up of 8.7 yr, GI toxicity greater than Radiation Therapy Oncology Group (RTOG) grade 2 occurred twice as often in high-dose patients (28% vs 15%; p = 0.013; LoE 1b). DVH analysis showed that the complication rate could be significantly

6 EUROPEAN UROLOGY 61 (2012) decreased by reducing the volume of treated rectum. The rate of GI toxicity greater than RTOG grade 2 was only 14%, provided that no >26% of the rectum received >70 Gy as compared to 46% when larger volumes received more than this dose [17]. The impact of 68 Gy versus 78 Gy on acute and late GI was examined by Peeters et al. in 669 randomised patients. Toxicity was assessed using an adaptation of the RTOG scoring system [33]. Late GI toxicity greater than grade 2 was recorded in 23 27% of patients after a median followup of 31 mo. Higher rates of late rectal bleeding and late nocturia were reported for those patients treated with the higher dose ( p = and p = 0.05; LoE 1b) [33]. The influence of the type of RT on acute toxicity in patients undergoing 70, 74, or 78 Gy, delivered by 3DCRT or IMRT, in the European Organisation for Research and Treatment of Cancer (EORTC) trial were examined by Matzinger et al. [24]. The authors demonstrated that doses up to 78 Gy were well tolerated, and the risk of acute Common Terminology Criteria for Adverse Events (CTCAE) 2.0 grade 2 GI toxicity is influenced by the type of RT. Less GI toxicity was detected in patients who underwent IMRT, in those treated to a smaller volume, or to a dose <78 Gy, because all of these aspects resulted in less irradiation of the rectum (LoE 1b) [24] Intensity-modulated radiation therapy. Long-term results of 561 patients who were treated with up to 81 Gy IMRT between 1996 and 2001 at the Memorial Sloan-Kettering Cancer Centre were reported by Zelefsky et al. [44]. The authors reported a 1.6% rate of rectal bleeding and a 0.1% rate of National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 rectal toxicity after 8 yr of follow-up when using a fraction size of 1.8 Gy (LoE 2c). In their analyses, side-effects were clearly dependent on fractionation schedules, and the same dose constraints cannot be used in a hypofractionated regimen. Kupelian et al. reported on 770 patients who were treated with 70 Gy in 28 fractions (daily dose: 2.5 Gy) and reported much higher toxicity with acute grade >2 toxicity in 18% and late RTOG grade >2 toxicity in 9% of patients after a median follow-up of 45 mo (LoE 2c) [45]. Vora et al. detected no difference in rates of late toxicity in 145 patients treated with IMRT and Gy compared to a similar cohort of patients treated with 3DCRT, despite an increase in median dose from 68.4 Gy to 75.6 Gy. Moreover, no RTOG grade 4 or 5 toxicity was reported, with acute RTOG grade >2 toxicity in 49% (only 1% grade 3) and late RTOG grade >2 toxicity in 23% of patients (LoE 2c) [46]. The percentage of the rectal volume receiving >70 Gy was limited to 30% I ; 103 Pd low-dose-rate brachytherapy. Zelefsky et al. reported on the incidence of late GI toxicity after 125 I lowdose-rate (LDR) brachytherapy in 248 patients treated between 1989 and The 5-yr incidence of late RTOG grade 2 rectal bleeding was 9%, and one patient (0.4%) developed a grade 4 rectal complication (LoE 2c) [47]. Gelblum et al. reported on LDR brachytherapy with and without EBRT, with a peak incidence of 9.5% grade RTOG 1 2 rectal complications at 8 mo after implantation. All resolved completely by 3.5 yr. Grade 3 toxicity was seen in only 0.5% (four patients), with two having been initiated by biopsies of the anterior rectal wall. Three patients healed completely with conservative management, and the fourth improved [48]. The addition of EBRT did not affect the incidence of rectal morbidity, nor did the selection of isotope, the addition of hormone therapy, or case order (LoE 3a) [48]. The dose volume relationship for rectal bleeding after permanent seed prostate brachytherapy was examined by Snyder et al. [49]. The authors demonstrated that if the volume of rectal wall receiving the prescribed dose (RV100) is maintained at <1.3 ml, the risk of RTOG grade >2 proctitis is <5%. The current recommendation of the American Brachytherapy Society is to maintain the RV100 <1 ml[49] Urinary symptoms following radiation therapy Patient selection affects the risk of developing genitourinary symptoms [50,51]. As is the case for GI toxicity, the methodology of symptom assessment influences the reported rates. Pretreatment genitourinary complaints, prior transurethral resection of the prostate (TURP) or of a bladder tumour, and the presence of acute genitourinary toxicity are suggested as contributing to urinary morbidity [50,51]. However, the prediction of urinary toxicity is less reliable than for rectal sequelae. Variation in bladder filling from day to day during treatment leads to difficulties in calculating the actual dose to the bladder [52]. For these reasons, only a limited number of predictive models of late urinary toxicity have been developed [52,53]. Occurrence of mild acute irritative urinary symptoms after different radiation modalities are reported in several studies (LoE 2c) [54]. Long-term treatment type specific changes in QoL domains were reported by Sanda et al. [55]. Within a large series, the effects of RT on urinary symptoms had resolved at 12 mo and improved over baseline at 24 mo. Compared to those patients who received EBRT, patients in the brachytherapy group reported significant detriments in urinary irritation or obstruction as compared with baseline (LoE 1b). Long-term total urinary incontinence and other severe urinary symptoms (indicating a complication of RTOG grade >2) are rare [16,54,56]. Ferrer et al. reported that Expanded Prostate Cancer Index Composite (EPIC) scores for urinary function after EBRT treatment dropped 1 mo after treatment and returned nearly to the baseline score after 6 and 24 mo [57]. A systematic review of 622 permanent brachytherapy patients with T1/T2 localised PCa confirmed that the main toxicity is urinary [58]. The predominant acute toxicity is related to radiation urethritis, with a peak increase of the International Prostate Symptom Score (IPSS) of 7 12 units above the baseline at 2 10 wk postimplant. This toxicity may persist for a number of months, but 75% return to normal within 1 yr, and the remainder tend to show a gradual improvement even up to year 3. Acute urinary

7 118 EUROPEAN UROLOGY 61 (2012) retention occurs in 7 25%, depending on technical factors and patient characteristics [56,59]. Urinary retention later than 1 yr is rare and reported in only 1.1% of patients [54,56,60 64]. Large prostate volume, previous TURP, worse comorbidities, and higher preimplant IPSS have been identified as risk factors for urinary toxicity (LoE 2c) [56,58,63,65 68]. Kollmeier et al. reported a substantial risk of incontinence if permanent brachytherapy is followed by transurethral resection for obstructive symptoms (LoE 3a) [69]. Conversely, Mabjeesh et al. reported only a negligible risk of incontinence after minimal channelling TURP performed in patients with prolonged postimplant retention and who had failed to respond to medical therapy (LoE 3b) [70]. The relationship among preoperative IPSS scores, peak flow rate (PFR), and the risk of catheterisation following 125 I brachytherapy was examined in 207 patients by Martens et al. [71]. Multivariate analysis revealed that preimplant PFR was most predictive of subsequent urinary retention, along with preimplant prostate volume. Men with a PFR <10 ml/s had an incidence of retention of 30% compared to 3% for those with a PFR >20 ml/s. Because the IPSS score was not independently predictive, the authors suggest that pretreatment IPSS scores combined with the urinary flow study provided a more objective evaluation of urinary function and allowed some men with higher subjective scores to be treated safely (LoE 3a). The impact of timing of the cyclooxygenase-2 inhibitor meloxicam for reducing retention rates after permanent brachytherapy was recently examined in a phase 3 trial [59]. The examined end points within this trial were prostate oedema at 1 mo, IPSS at 1 and 3 mo, and any need for catheterisation [59]. No reduction in the risk of postimplant urinary retention was recorded in those patients, who started meloxicam 1 wk prior versus concurrent with brachytherapy. Baseline prostate volume was confirmed as the primary predictor for postimplant retention (LoE 1b) [59]. Similarly, a double-blind placebocontrolled study in patients undergoing 125 I brachytherapy revealed that starting tamsulosin (0.8 mg/dl) before treatment did not significantly affect urinary retention rates but did have a positive effect on urinary morbidity during follow-up (LoE 1b) [72] Studies reporting on urinary toxicity associated with specific radiation therapy modalities Three-dimensional conformal radiation therapy. The impact of a three-dimensional (3D) conformal technique with margin reduction from 1 cm to 0.5 cm for the final 10 Gy in the 78 Gy arm on the occurrence of acute and late urinary complications after 68 Gy or 78 Gy in 669 patients was assessed by Peeters et al. [33]. No significant differences were seen for overall toxicity scores, although the incidence of late genitourinary toxicity was slightly higher in the 78 Gy arm. The 3-yr cumulative risks for RTOG/EORTC genitourinary toxicity greater than grade 2 were 28.5% and 30.2% for the 68 Gy arm and the 78 Gy arm, respectively ( p = 0.3). For genitourinary toxicity greater than grade 3, these risks were 5.1% and 6.9%, respectively (LoE 1b) [33] Intensity-modulated radiation therapy. Zelefsky et al. reported on the incidence of late urologic toxicity at 10 yr after 3DCRT (66 Gy) and IMRT (81 Gy) in 1571 patients treated between 1988 and Patients who experienced acute symptoms were at higher risk of experiencing late toxicities [19]. Moreover, the authors reported that higher doses were associated with a 20% incidence of genitourinary symptoms at 10 yr compared to 12% for lower doses ( p = 0.01) [19]. Another series by the same authors, which included only patients treated with 81 Gy IMRT, demonstrated a 9% risk of grade >2 and 3% risk of grade >3 genitourinary toxicity after a median follow-up of 7 yr (LoE 2c) [44] I ; 103 Pd low-dose-rate brachytherapy. Merrick et al. examined temporal trends in the changes of late lower urinary tract symptoms (LUTS) after permanent brachytherapy. The authors evaluated the severity of LUTS by using a 1-to-10 scale questionnaire and found that symptoms tended to peak by 1 mo in 50% of patients, with nearcomplete resolution by 4 yr in 546 patients (median follow up: 26 mo; LoE 3a) [62]. Similarly, Stone et al. assessed 325 patients and recorded an increase in the mean IPSS score at 6 mo of 5.6 points but no long-term morbidity, with scores being only 0.41 points above baseline at 4 and 5 yr (LoE 3a) [73] Erectile dysfunction following radiation therapy Despite ED being a relatively common complication following all treatments for PCa, the specific aetiology of ED after RT remains unclear [74 77]. In addition, the multifactorial nature of ED makes it difficult to quantify the incidence of treatment-related ED precisely (Table 4). Vascular damage to the nerves that supply the cavernosa smooth muscles has been attributed by some authors and refuted by others. The damage to small blood vessels within the penile tissue, possibly from radiation-accelerating arteriosclerosis, has been postulated from studies using penile Doppler ultrasonography (LoE 3b) [78,79]. Moreover, some authors reported on the impact of RT on anatomic structures like the penile bulb, crura, and internal pudendal arteries [80 84]. Gillan et al. used magnetic resonance (MR) angiography to visualise the internal pudendal arteries in men undergoing permanent brachytherapy [85]. The authors demonstrated that these arteries receive a low but calculable (mean maximum: 17 Gy) dose from permanent brachytherapy, indicating that dose to the internal pudendal arteries is probably not a factor in ED after prostate brachytherapy (LoE 3a) [85]. Similarly, McLaughlin et al. demonstrated that the use of MR imaging (MRI) for treatment planning [86] results in a significant reduction in the average dose delivered to critical vascular structures and permits better definition of the prostate apex, penile bulb, and adjacent structures [80,86 89]. Considering the frequency with which ED antedates a PCa diagnosis, assessment of erectile function prior to RT is important [77,90 92]. Unlike the situation after prostate surgery, ED is not an immediate side-effect of RT, and assessment of erectile function in the

8 Table 4 Characteristics of selected studies addressing erectile function after different types of radiation therapy No. of patients in study Treatment modality Assessment preintervention Mangar [102]: 51 3DCRT 64 or 74 Gy UCLA/EPIC adopted score: Potent, intermediate, or impotent Potency defined as Potent according to questionnaires Median follow-up, mo Assessment postintervention Erectile function,* % PDE5-I use N/A Yes 2a Van den Wielen [83]: 139 3DCRT 68 or 78 Gy Dutch Sexual Activity Score 24 Dutch Sexual Activity Score 64 14% Yes 1b MacDonald [95]: I; 144 Gy Physician Physician and 36 Physician and Physician: 52 Yes Yes if prostate 3a patient documented patient documented Patient: 34 volume >50 ml Stone [73]: I; 167 Gy MSEF 2 84 MSEF % 3b Bottomley [64]: I EPIC EPIC 42 N/A 3b Cesaretti [104]: I; 103 P IIEF-5 and IIEF-5 and MSEF 32 40% Yes 4 MSEF 2 68 Sanchez-Ortis [130]: I; 103 P UCLA-PCa 23 UCLA-PCa 49 N/A 70% 4 Merrick [131]: I; 103 P 2 = optimal IIEF IIEF % 2c 1 = Suboptimal 0 = inability to obtain erections Mabjeesh [106]: I IIEF-6 IIEF IIEF-6 80 Yes Yes 3a Merrick [132]: I; 103 P 2 = optimal IIEF-5 12 IIEF % No 2b 1 = Suboptimal 0 = inability to obtain erections Taira [133]: I; 103 P IIEF-6 IIEF IIEF Yes No 1c PDE5-I = phosphodiesterase type 5 inhibitor; ADT = androgen-deprivation therapy; LoE = level of evidence; 3DCRT = three-dimensional conformal radiation therapy; UCLA = University of California, Los Angeles; EPIC = Expanded Prostate Cancer Index Composite; N/A = not applicable; MSEF = Mount Sinai Erectile Function; IIEF = International Index of Erectile Function; UCLA-PCa = UCLA Prostate Cancer Index. ADT LoE EUROPEAN UROLOGY 61 (2012)

9 120 EUROPEAN UROLOGY 61 (2012) long term is confounded by age-related decline and worsening comorbidities [83,91]. Similar to patients undergoing RP, patient age, use of androgen-deprivation therapy (ADT), and baseline erectile function were identified as important predictors for posttreatment erectile function (LoE 2c) [77,93 95]. Specifically, Fransson et al. recently analysed the 15-yr follow-up of patient-reported sexual function and identified disease progression and the use of ADT as risk factors for worse sexual and erectile function [96]. These long-term results should be weighed against the apparent benefit of ADT in randomised trials demonstrating the superiority of 3 yr compared to 6 mo of ADT suppression in patients undergoing conventional-dose EBRT. However, if ADT is indicated, the addition of EBRT compared to ADT alone reduces 10-yr cancer-specific mortality (LoE 1a) [97,98]. Recently, Pinkawa et al. reported that the occurrence of spontaneous erections in the morning or night before treatment is the best predictor for preserving erections sufficient for intercourse (LoE 3b) [77]. Several analyses have revealed that diabetic patients are predisposed for ED and consequently have a higher incidence of ED following RT (LoE 3b) [77,95,99,100]. Because ED following RT is likely of vascular origin, phosphodiesterase type 5 inhibitors (PDE-5Is) can be effective in treatment and possibly also in prevention. Schiff et al. found that earlier use of PDE-5Is following brachytherapy was associated with better long-term erectile function. The widespread use and acceptance of PDE-5Is in the general population makes the nonpunitive inclusion of PDE-5 use in any assessment of erectile function essential [101] Studies reporting on erectile dysfunction Three-dimensional conformal radiation therapy. Mangar et al. examined the impact of different doses 64 or 74 Gy of 3DCRT after 3 6 mo and ADT in 51 men. The authors reported that 12 men (23.5%) remained potent, 22 men (43.1%) had reduced potency, and 17 men (33.3%) were impotent at 2 yr by using the University of California, Los Angeles, Prostate Cancer Index (UCLA-PCa Index) and the Functional Assessment of Cancer Therapy-Prostate questionnaire. Moreover, the authors found a dose volume effect on the penile bulb and ED, where a D90 >50 Gy is associated with a significant risk of ED (LoE 2a) [102]. Conversely, the differences in 139 patients potent prior to RT and treated with 68 or 78 Gy was assessed by Van den Wielen et al. [83]. After 2 yr and 3 yr, the incidence of new onset ED was 36% and 38%, respectively. No differences were recorded for the two different RT dose arms (LoE 1b) Permanent brachytherapy. Bottomley et al. reported on 402 patients fully potent prior to permanent brachytherapy. Overall, 58% of patients reported different grades of ED, and only 42% of patients were reported to be able to achieve erections sufficient for intercourse after a follow-up of 2 8 yr [64]. Lehrer et al. assessed LUTS flare and erectile function with the IPSS and Sexual Health Inventory for Men >2 yr after LDR brachytherapy. Flare of urinary tract symptoms was defined as a five-point increase in the IPSS from nadir 1 yr after brachytherapy. LUTS flare was significantly associated with an increased risk of ED [103]. Cesaretti et al. demonstrated the strongly age-dependent ability to maintain erectile function in 223 patients, of whom 131 reported optimal erectile function prior to brachytherapy [104]. Satisfactory erectile function was maintained in 64% of patients yr of age at the time of implant when defined as an International Index of Erectile Function (IIEF)-5 score >16 but in 92% of patients when the Mount Sinai Erectile Function (MSEF) physician-assigned scoring system was used. Overall, 40% of patients within the examined cohort were using PDE-5 s [104]. The same questionnaire was used by Stone et al. in 325 patients to evaluate the long-term outcomes after LDR brachytherapy. The authors recorded adequate erectile function at a median follow-up of 84 mo in 61.5% of patients who were potent prior to implant [73]. Similar results were reported by Gomez-Iturriaga Piña et al, who found the preservation of erectile function in 93.4% of patients at a median followup of 63 mo (minimum 30 mo) in patients 55 yr of age at the time of implant [105]. A temporary detrimental effect of permanent brachytherapy with or without the addition of hormone therapy on erectile function is reported by Mabjeesh et al. (LoE 3a) [106]. The mean erectile function score dropped within 3 mo but recovered at the end of the first year and was maintained until 2 yr after treatment, regardless of the addition of neoadjuvant hormone therapy. The authors concluded that the detrimental effect of permanent brachytherapy with or without the addition of hormone therapy on erectile function is reversible, and recovery is expected by 1 yr after treatment in most patients [106]. MacDonald et al. also found that age and pretreatment erectile function were significantly related to the development of post-treatment ED (LoE 3a) [95]. Interestingly, the percentage of patients with ED at 2 yr was 48% if physician documented compared to 66% if patient documented [95]. However, the effect of PDE-5 use on the definition of potency by physicians and patients was not specified. In contrast to other series, the authors found no evidence to support penile bulb dosimetry as an independent predictor for ED, but 68% of the population received 6 mo of hormonal therapy, which might mask an effect of dosimetry [95] Functional outcomes in patients with adjuvant and salvage radiation therapy after radical prostatectomy Three randomised clinical trials demonstrated that immediate adjuvant EBRT (ie, within 4 5 mo of surgery) with conventional doses is well tolerated in patients with extraprostatic extension and positive surgical margins after RP. Moreover, adjuvant EBRT is not only associated with a significant reduction in the risk of biochemical, local, and distant recurrence and but has also been shown to improve overall survival in a phase 3 randomised trial (LoE 1a) [107]. The EORTC trial randomly assigned 1005 patients to adjuvant EBRT with 60 Gy (n = 502) or observation (n = 503)

10 EUROPEAN UROLOGY 61 (2012) followed by salvage RT for biochemical failure (n = 113). Within this series, only 4.2% of patients developed grade 2 or 3 late effects [108]. Similarly, disease- and treatmentrelated morbidity were analysed in a subset of 217 patients of the Southwest Oncology Group trial, comparing observation to adjuvant EBRT following RP [109]. Assessment of genitourinary symptoms revealed that the addition of RT to surgery resulted in more frequent urination over the first 5 yr and an early compromise in bowel function in the first 2 yr. However, these differences diminished over time [109], and the RT group had higher global health-related QoL (HRQoL) at 5 yr, which is most likely related to the lower incidence of metastatic disease (LoE 2c) [109]. Finally, the ARO study randomly assigned 388 patients to immediate postoperative RT with 60 Gy (range: Gy) or observation and reported no RTOG grade 4 and only one RTOG grade 3 genitourinary toxicity after a median follow-up of 53 mo [110]. In addition, RTOG grade 2 genitourinary and GI events occurred in only 2% and 1.4% of patients, respectively [110]. The overall cumulative rate of grade >1 adverse effects for bladder and rectum was 21.9% in those patients who received RT compared to 3.7% for those in the wait-and-see group [110]. The occurrence of significantly fewer effects in this series compared to other trials may be related to the use of 3D treatment planning. Although these three randomised adjuvant RT trials encouraged salvage treatment for those patients who failed after observation, the timing and indications for initiation of salvage were not well defined [111]. Despite these limitations, achieving an undetectable prostate-specific antigen (PSA; <0.1 ng/ml) in the absence of hormonal treatment before salvage therapy emerged as an independent highly significant predictor for favourable long-term biochemical outcomes in 162 European patients treated with 66.6 Gy [112]. Stephenson et al. recently devised a nomogram based on a multi-institutional database that includes 12 different variables, such as presurgery PSA, Gleason score, seminal vesicle invasion, extracapsular extension, surgical margins, and lymph node status, for prediction of salvage RT failure [113]. Although side-effects after salvage RT tend to be underreported in retrospective analyses, severe late effects are uncommon and reported in only 3 6% of patients [114]. A randomised study comparing 100 patients receiving 60 Gy or observation did not detect any difference in toxicities after 24 mo of follow-up (93). The theoretical advantages of IMRT compared to 3DCRT in terms of dose fall-off and geometric conformity to irregularly shaped targets also applies if IMRT is used for salvage RT [111]. De Meerleer et al. reported that a higher dose using IMRT is feasible in the salvage setting, with acceptable acute and late toxicity [22]. The authors analysed 68 patients who were treated with IMRT up to 75 Gy and reported grade 3 late GI toxicity in two patients (2.9%) and grade 2 in nine patients (13.2%). Two patients (2.9%) developed grade 3 genitourinary toxicity and 21 developed grade 2 effects (30.8%; in-house scoring system) [22]. Based on their findings, the authors concluded that IMRT permits delivery of doses up to 75 Gy with low levels of acute and late toxicity [22] Health-related quality of life comparison During the past decade, several nonrandomised studies evaluated post-treatment QoL outcomes for RT and surgical treatment of PCa patients [17,55]. Sanda et al. reported on 1201 patients and 625 partners with T1 2 localised PCa who were treated with RP, brachytherapy, or EBRT. QoL was assessed using validated questionnaires. All patients noted a reduction in their sexual QoL, which was similar in all groups but caused significant distress in 44% of those patients who underwent RP, 22% of those patients who underwent EBRT, and 13% for the brachytherapy group (LoE 1b). Deterioration caused by urinary symptoms was 7%, 11%, and 18%, respectively, at 1 yr. Rectal side-effects at 1 yr, including pain, urgency, incontinence, and frequency, affected QoL in 9% of both the EBRT and brachytherapy groups. No bowel disturbance was reported in the RP group. Antiandrogen use resulted in significant distress for 19% of patients and partners, persisting for 2 yr [55]. In patients who underwent permanent brachytherapy, a decreased erectile function 3 mo after treatment, a recovery at the end of the first year, and no change up to 2 yr after brachytherapy regardless of the addition of neoadjuvant hormone therapy was reported by Mabjeesh et al. [106]. Madalinska et al. conducted a prospective longitudinal cohort study among 278 patients with early screendetected (59%) or clinically diagnosed (41%) PCa. Generic and disease-specific HRQoL measures (SF-36, UCLA-PCa Index (urinary and bowel modules), and items relating to sexual functioning were used for assessment of symptoms at baseline, after 6 mo, and 12 mo. Within this study, significantly higher ( p < 0.01) post-treatment incidences of urinary incontinence (39 49%) and ED (80 91%) were found after prostatectomy compared to RT (6 7% and 41 55%, respectively). Conversely, bowel problems (urgency) affected 30 35% of the RT group versus 6 7% of the prostatectomy group ( p < 0.01; LoE 2a) [115] New techniques, future trends, and quality control Recent technologic advances in radiation delivery and organ motion tracking have brought about significant improvements in the treatment of PCa patients [116]. For example, the use of volumetric-modulated arc therapy or intensitymodulated arc therapy allows a reduction in treatment time per fraction by using a rotational treatment with more degrees of freedom in gantry speed, dose rate, and collimator angle [117]. Another approach uses magnetic transponders implanted in the prostate for real-time tracking during treatment (LoE 3a) [118]. Similarly, the CyberKnife system uses a linear accelerator mounted on a robotic arm and incorporates modelling of respiratory motion and intermittent radiographic checks of implanted fiducials. In a series of 41 low-risk PCa patients treated with this system, late RTOG grade 2 genitourinary toxicity was seen in 24% of patients and grade 3 in 5% of patients,

11 122 EUROPEAN UROLOGY 61 (2012) whereas grade 2 late rectal toxicity was reported in 15% (LoE 3a) [119]. Using such systems could result in increased cure rates in the future by allowing more accurate radiation delivery using reduced treatment margins and resulting in less rectal toxicity. Similarly, Talcott et al. reported a post hoc cross-sectional survey of surviving participants in the Proton Radiation Oncology Group treated with combined photon and proton radiation. The estimated 10-yr biochemical progression rate for patients receiving a standard dose was 32% compared with 17% for patients receiving a high dose ( p < 0.001). In addition, the authors demonstrated that treatment with higher-dose radiation (79.2 Gy) compared to standard dose (70.2 Gy) was not associated with an increase in patient-reported PCa symptoms after a median of 9.5 yr (LoE 1b) [120]. Ideally, the introduction of such innovative irradiation techniques should be accompanied through quality assurance programmes such as those used in clinical trials [121]. These programmes, including dummy runs and individual case reviews, allow evaluation of the RT technique and compliance with protocol guidelines. Also, standardised toxicity assessment tools and validated HRQoL questionnaires may help to better monitor the outcomes of each individual physician. These assessments of individual outcomes are important, because similar to surgically treated patients, higher provider volume for RT patients is associated with lower rates of secondary therapies [122]. Moreover, the use of validated tools enables the physician to monitor progress in outcomes and complications related to the introduction of such new approaches. Accordingly, a group of experienced radiation oncologists recently proposed suggestions for better analysing and reducing the causes of severe normal tissue complications in RT patients [29]. In their analyses, the authors provide excellent resources on the literature and shortcomings of quantitative analyses of normal tissue effects in the clinics (QUANTEC) [29,123]. Specifically, the authors recommended that grading schemes based on symptoms of coherent clinical syndromes (rather than organ-specific collections of disparate symptoms) should be used for dose volume toxicity studies [29]. In addition, they outlined the need for a peer-reviewed central repository of dose volume constraint standards such as atlases, end point definitions, grading schemes, and toxicity data [29]. 4. Conclusions Similar to series reporting on morbidity after surgical treatment of PCa, three important limitations in assessing functional outcomes after RT became apparent. First were the uneven standards of reporting results without adequate assessment of baseline characteristics using validated questionnaires (patient-reported vs physician-reported vs nonvalidated tools). Second was the difficulty in defining meaningful uniform clinical end points across studies. For example, one systematic review found 112 definitions for incontinence and 79 definitions for erectile dysfunction related to RT for PCa [124]. Finally, aspects like uneven baseline characteristics of patients selected for different types of RT, type of RT delivery, and presence or absence of hormonal treatment also influence the reported outcomes [54,77,83,84,90]. When analysing the reasons for this variance, the same pitfalls exist as in comparisons of surgical and nonsurgical treatment modalities. Patients are selected preferentially according to age, comorbidities, clinical stage, and tumour characteristics for certain types of treatment. For example, LDR brachytherapy tends to be selected for men with favourable localised PCa but only if they are healthy enough to undergo anaesthesia. Otherwise, they would be directed towards external-beam treatment or surveillance. Even when treatment groups are uniformly selected or can be stratified to eliminate imbalances, the end points for various functional outcomes must be consistent. More widespread adoption of toxicity scales in recent years, such as those established by the RTOG, or specific patientreported questionnaires, such as the IPSS for LUTS or the IIEF-5 for erectile function, have helped considerably. Nonetheless, there remain major areas of poor communication. For example, is the IIEF reported with or without pharmacologic assistance? When introducing a treatment modification or a new modality, assessment of side-effects takes some advanced planning. Without application of identical assessment tools at baseline, one cannot possibly evaluate post-treatment toxicity and correctly attribute it as treatment related or a result of age or comorbidities. One area where guidance is still lacking is in the timing of toxicity assessments. Many late side-effects of RT evolve over time and often resolve with additional follow-up or appropriate intervention. Standardised evaluation time points would make comparisons between modalities much more meaningful. Similarly, the method of assessment (physician documented vs patient documented) also affects the results of different trials. Therefore, the QUANTEC group suggested recommendations for reporting and gathering data on treatment outcomes. Finally, the technical intricacies of dose prescription and quality assessment for men undergoing RT need to be described with as much detail as is feasible and practical. Although it used to be considered adequate to provide the total dose, the elapsed time for delivery and the number of fractions are also important factors. Despite these difficulties, the literature demonstrated technical improvements in the field of RT planning and delivery, enabling the administration of higher doses with equal or less toxicity. Assessment of treatment specific changes in QoL and side-effects will remain crucial. Therefore, we anticipate ongoing evolution of prostate RT in several fields. First, planning and delivery of RT will be improved by realtime tracking in combination with individualised therapy approaches. These approaches may use genetic studies for correlating dose and toxicity according to individual genetic variation and permit administration of higher doses. Related to the anatomy of the prostate, these higher doses may favour rectal sparing while not readily sparing the urethra and bladder neck. As a consequence, there may be a future shift

12 EUROPEAN UROLOGY 61 (2012) from dose-limiting long-term rectal morbidity towards a focus on long-term urinary morbidity, because the higher doses delivered with new techniques favour rectal sparing while not readily sparing the urethra and bladder neck. Second, the interest in pelvic lymph node irradiation with a more acceptable toxicity profile may be renewed related to novel RT technologies available. Third, research for defining reporting standards and end points for patients treated with RT and the widespread use of such instruments for assessment of functional and oncologic outcomes will gain further importance. Finally, we anticipate in the future the maintenance of a multidisciplinary approach among urologists, radiation oncologists, pathologists, and medical oncologists, which is supported by guidelines based on LoE for optimal RT treatment of PCa patients. Author contributions: Lars Budäus 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: Budäus, Bolla, Bossi, Cozzarini, Crook, Widmark, Wiegel. Acquisition of data: Budäus, Bolla, Bossi, Cozzarini, Crook, Widmark, Wiegel. Analysis and interpretation of data: Budäus, Bolla, Bossi, Cozzarini, Crook, Widmark, Wiegel. Drafting of the manuscript: Budäus, Bolla, Bossi, Cozzarini, Crook, Widmark, Wiegel. Critical revision of the manuscript for important intellectual content: Budäus, Bolla, Bossi, Cozzarini, Crook, Widmark, Wiegel. Statistical analysis: Budäus, Bolla, Bossi, Cozzarini, Crook, Widmark, Wiegel. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Bolla, Bossi, Cozzarini, Crook, Widmark, Wiegel. 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] Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2008;53: [2] Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010;28: [3] Kramer KM, Bennett CL, Pickard AS, et al. Patient preferences in prostate cancer: a clinician s guide to understanding health utilities. Clin Prostate Cancer 2005;4: [4] Jani AB, Johnstone PA, Liauw SL, Master VA, Rossi PJ. Prostate cancer modality time trend analyses from 1973 to 2004: a Surveillance, Epidemiology, and End Results registry analysis. Am J Clin Oncol 2010;33: [5] Vargas C, Martinez A, Kestin LL, et al. Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys 2005;62: [6] Chan LW, Xia P, Gottschalk AR, et al. Proposed rectal dose constraints for patients undergoing definitive whole pelvic radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;72: [7] Jackson A, Skwarchuk MW, Zelefsky MJ, et al. Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys 2001; 49: [8] Peeters ST, Lebesque JV, Heemsbergen WD, et al. Localized volume effects for late rectal and anal toxicity after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2006;64: [9] Fiorino C, Cozzarini C, Vavassori V, et al. Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions. Radiother Oncol 2002;64:1 12. [10] Fiorino C, Fellin G, Rancati T, et al. Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: preliminary results of a multicenter prospective study. Int J Radiat Oncol Biol Phys 2008;70: [11] Fiorino C, Alongi F, Perna L, et al. Dose-volume relationships for acutebowel toxicityin patients treated with pelvic nodal irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 2009;75: [12] Fellin G, Fiorino C, Rancati T, et al. Clinical and dosimetric predictors of late rectal toxicity after conformal radiation for localized prostate cancer: results of a large multicenter observational study. Radiother Oncol 2009;93: [13] Valdagni R, Rancati T, Ghilotti M, et al. To bleed or not to bleed. A prediction based on individual gene profiling combined with dose-volume histogram shapes in prostate cancer patients undergoing three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 2009;74: [14] Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with threedimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41: [15] Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53: [16] Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 2005;294: [17] Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70: [18] Teh BS, Mai WY, Uhl BM, et al. Intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of a rectal balloon for prostate immobilization: acute toxicity and dose-volume analysis. Int J Radiat Oncol Biol Phys 2001;49: [19] Zelefsky MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;70: [20] Al-Mamgani A, Heemsbergen WD, Peeters ST, Lebesque JV. Role of intensity-modulated radiotherapy in reducing toxicity in dose escalation for localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;73: [21] Cahlon O, Zelefsky MJ, Shippy A, et al. Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer: toxicity and biochemical outcomes. Int J Radiat Oncol Biol Phys 2008;71: [22] De Meerleer G, Fonteyne V, Meersschout S, et al. Salvage intensitymodulated radiotherapy for rising PSA after radical prostatectomy. Radiother Oncol 2008;89:

13 124 EUROPEAN UROLOGY 61 (2012) [23] Arcangeli S, Saracino B, Petrongari MG, et al. Analysis of toxicity in patients with high risk prostate cancer treated with intensitymodulated pelvic radiation therapy and simultaneous integrated dose escalation to prostate area. Radiother Oncol 2007;84: [24] Matzinger O, Duclos F, van den Bergh A, et al. Acute toxicity of curative radiotherapy for intermediate- and high-risk localised prostate cancer in the EORTC trial Eur J Cancer 2009; 45: [25] Cozzarini C, Fiorino C, Di Muzio N, et al. Significant reduction of acute toxicity following pelvic irradiation with helical tomotherapy in patients with localized prostate cancer. Radiother Oncol 2007;84: [26] Cozzarini C, Fiorino C, Di Muzio N, et al. Hypofractionated adjuvant radiotherapy with helical tomotherapy after radical prostatectomy: planning data and toxicity results of a phase I-II study. Radiother Oncol 2008;88: [27] Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation dose-volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys 2010;76(Suppl 3):S [28] Brenner DJ. Fractionation and late rectal toxicity. Int J Radiat Oncol Biol Phys 2004;60: [29] Jackson A, Marks LB, Bentzen SM, et al. The lessons of QUANTEC: recommendations for reporting and gathering data on dosevolume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys 2010;76(Suppl 3):S [30] Oxford Centre for Evidence-based Medicine Levels of Evidence. website: accessed: July 13, [31] Peeters ST, Heemsbergen WD, Koper PC, et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006;24: [32] Phan J, Swanson DA, Levy LB, Kudchadker RJ, Bruno TL, Frank SJ. Late rectal complications after prostate brachytherapy for localized prostate cancer: incidence and management. Cancer 2009;115: [33] Peeters ST, Heemsbergen WD, van Putten WL, et al. Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005;61: [34] Akimoto T, Muramatsu H, Takahashi M, et al. Rectal bleeding after hypofractionated radiotherapy for prostate cancer: correlation between clinicalanddosimetricparametersandthe incidence ofgrade 2 or worse rectal bleeding. Int J Radiat Oncol Biol Phys 2004; 60: [35] Herold DM, Hanlon AL, Hanks GE. Diabetes mellitus: a predictor for late radiation morbidity. Int J Radiat Oncol Biol Phys 1999;43: [36] Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 2000; 47: [37] Vavassori V, Fiorino C, Rancati T, et al. Predictors for rectal and intestinal acute toxicities during prostate cancer high-dose 3D- CRT: results of a prospective multicenter study. Int J Radiat Oncol Biol Phys 2007;67: [38] Cheung R, Tucker SL, Ye JS, et al. Characterization of rectal normal tissue complication probability after high-dose external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2004;58: [39] Huang EH, Pollack A, Levy L, et al. Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2002;54: [40] Cozzarini C, Fiorino C, Ceresoli GL, et al. Significant correlation between rectal DVH and late bleeding in patients treated after radical prostatectomy with conformal or conventional radiotherapy ( Gy). Int J Radiat Oncol Biol Phys 2003;55: [41] Fiorino C, Sanguineti G, Cozzarini C, et al. Rectal dose-volume constraints in high-dose radiotherapy of localized prostate cancer. Int J Radiat Oncol Biol Phys 2003;57: [42] Denham JW, O Brien PC, Dunstan RH, et al. Is there more than one late radiation proctitis syndrome? Radiother Oncol 1999;51: [43] Heemsbergen WD, Peeters ST, Koper PC, Hoogeman MS, Lebesque JV. Acute and late gastrointestinal toxicity after radiotherapy in prostate cancer patients: consequential late damage. Int J Radiat Oncol Biol Phys 2006;66:3 10. [44] Zelefsky MJ, Chan H, Hunt M, Yamada Y, Shippy AM, Amols H. Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol 2006;176: [45] Kupelian PA, Willoughby TR, Reddy CA, Klein EA, Mahadevan A. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2007;68: [46] Vora SA, Wong WW, Schild SE, Ezzell GA, Halyard MY. Analysis of biochemical control and prognostic factors in patients treated with either low-dose three-dimensional conformal radiation therapy or high-dose intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2007;68: [47] Zelefsky MJ, Hollister T, Raben A, Matthews S, Wallner KE. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;47: [48] Gelblum DY, Potters L. Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2000;48: [49] Snyder KM, Stock RG, Hong SM, Lo YC, Stone NN. Defining the risk of developing grade 2 proctitis following 125I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2001;50: [50] Fiorino C, Valdagni R, Rancati T, Sanguineti G. Dose-volume effects for normal tissues in external radiotherapy: pelvis. Radiother Oncol 2009;93: [51] Bittner N, Merrick GS, Wallner KE, Lief JH, Butler WM, Galbreath RW. The impact of acute urinary morbidity on late urinary function after permanent prostate brachytherapy. Brachytherapy 2007;6: [52] Cheung MR, Tucker SL, Dong L, et al. Investigation of bladder dose and volume factors influencing late urinary toxicity after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2007;67: [53] Harsolia A, Vargas C, Yan D, et al. Predictors for chronic urinary toxicity after the treatment of prostate cancer with adaptive threedimensional conformal radiotherapy: dose-volume analysis of a phase II dose-escalation study. Int J Radiat Oncol Biol Phys 2007; 69: [54] Williams SG, Zietman AL. Does radical treatment have a role in the management of low-risk prostate cancer? The place for brachytherapy and external beam radiotherapy. World J Urol 2008;26: [55] Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358: [56] Williams SG, Millar JL, Duchesne GM, Dally MJ, Royce PL, Snow RM. Factors predicting for urinary morbidity following 125iodine transperineal prostate brachytherapy. Radiother Oncol 2004;73:33 8. [57] Ferrer M, Suarez JF, Guedea F, et al. Health-related quality of life 2 years after treatment with radical prostatectomy, prostate brachytherapy, or external beam radiotherapy in patients with

14 EUROPEAN UROLOGY 61 (2012) clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;72: [58] Crook J, Lukka H, Klotz L, Bestic N, Johnston M. Genitourinary Cancer Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative. Systematic overview of the evidence for brachytherapy in clinically localized prostate cancer. CMAJ 2001;164: [59] Crook J, Patil N, Wallace K, et al. A phase III randomized trial of the timing of meloxicam with iodine-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 2010;77: [60] Crook J, McLean M, Catton C, Yeung I, Tsihlias J, Pintilie M. Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation. Int J Radiat Oncol Biol Phys 2002;52: [61] Ash D, Bottomley D, Al-Qaisieh B, Carey B, Gould K, Henry A. A prospective analysis of long-term quality of life after permanent I-125 brachytherapy for localised prostate cancer. Radiother Oncol 2007;84: [62] Merrick GS, Butler WM, Wallner KE, et al. Dysuria after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003;55: [63] Gutman S, Merrick GS, Butler WM, et al. Severity categories of the International Prostate Symptom Score before, and urinary morbidity after, permanent prostate brachytherapy. BJU Int 2006;97:62 8. [64] Bottomley D, Ash D, Al-Qaisieh B, et al. Side effects of permanent I125 prostate seed implants in 667 patients treated in Leeds. Radiother Oncol 2007;82:46 9. [65] Kumar V, Toussi H, Marr C, Hough C, Javle P. The benefits of radical prostatectomy beyond cancer control in symptomatic men with prostate cancer. BJU Int 2004;93: [66] Gelblum DY, Potters L, Ashley R, Waldbaum R, Wang XH, Leibel S. Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys 1999;45: [67] Ohashi T, Yorozu A, Toya K, Saito S, Momma T. Serial changes of international prostate symptom score following I-125 prostate brachytherapy. Int J Clin Oncol 2006;11: [68] Terk MD, Stock RG, Stone NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998;160: [69] Kollmeier MA, Stock RG, Cesaretti J, Stone NN. Urinary morbidity and incontinence following transurethral resection of the prostate after brachytherapy. J Urol 2005;173: [70] Mabjeesh NJ, Chen J, Stenger A, Matzkin H. Preimplant predictive factors of urinary retention after iodine 125 prostate brachytherapy. Urology 2007;70: [71] Martens C, Pond G, Webster D, McLean M, Gillan C, Crook J. Relationship of the International Prostate Symptom score with urinary flow studies, and catheterization rates following 125I prostate brachytherapy. Brachytherapy 2006;5:9 13. [72] Elshaikh MA, Ulchaker JC, Reddy CA, et al. Prophylactic tamsulosin (Flomax) in patients undergoing prostate 125I brachytherapy for prostate carcinoma: final report of a double-blind placebocontrolled randomized study. Int J Radiat Oncol Biol Phys 2005; 62: [73] Stone NN, Stock RG. Long-term urinary, sexual, and rectal morbidity in patients treated with iodine-125 prostate brachytherapy followed up for a minimum of 5 years. Urology 2007;69: [74] Akbal C, Tinay I, Simsek F, Turkeri LN. Erectile dysfunction following radiotherapy and brachytherapy for prostate cancer: pathophysiology, prevention and treatment. Int Urol Nephrol 2008;40: [75] Brown MW, Brooks JP, Albert PS, Poggi MM. An analysis of erectile function after intensity modulated radiation therapy for localized prostate carcinoma. Prostate Cancer Prostatic Dis 2007;10: [76] Peters CA, Stock RG, Cesaretti JA, et al. TGFB1 single nucleotide polymorphisms are associated with adverse quality of life in prostate cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 2008;70: [77] Pinkawa M, Gagel B, Piroth MD, et al. Erectile dysfunction after external beam radiotherapy for prostate cancer. Eur Urol 2009;55: [78] Goldstein I, Feldman MI, Deckers PJ, Babayan RK, Krane RJ. Radiation-associated impotence. A clinical study of its mechanism. JAMA 1984;251: [79] Mittal B. A study of penile circulation before and after radiation in patients with prostate cancer and its effect on impotence. Int J Radiat Oncol Biol Phys 1985;11: [80] Perna L, Fiorino C, Cozzarini C, et al. Sparing the penile bulb in the radical irradiation of clinically localised prostate carcinoma: a comparison between MRI andct prostatic apex definition in3dcrt, Linac-IMRT and helical tomotherapy. Radiother Oncol 2009;93: [81] Roach M, 3rd, Nam J, Gagliardi G, El Naqa I, Deasy JO, Marks LB. Radiation dose-volume effects and the penile bulb. Int J Radiat Oncol Biol Phys 2010;76(Suppl 3):S [82] van der Wielen GJ, Mulhall JP, Incrocci L. Erectile dysfunction after radiotherapy for prostate cancer and radiation dose to the penile structures: a critical review. Radiother Oncol 2007;84: [83] van der Wielen GJ, van Putten WL, Incrocci L. Sexual function after three-dimensional conformal radiotherapy for prostate cancer: results from a dose-escalation trial. Int J Radiat Oncol Biol Phys 2007;68: [84] Mendenhall WM, Henderson RH, Indelicato DJ, Keole SR, Mendenhall NP. Erectile dysfunction after radiotherapy for prostate cancer. Am J Clin Oncol 2009;32: [85] Gillan C, Kirilova A, Landon A, Yeung I, Pond G, Crook J. Radiation dose to the internal pudendal arteries from permanent-seed prostate brachytherapy as determined by time-of-flight MR angiography. Int J Radiat Oncol Biol Phys 2006;65: [86] McLaughlin PW, Narayana V, Meirovitz A, et al. Vessel-sparing prostate radiotherapy: dose limitation to critical erectile vascular structures (internal pudendal artery and corpus cavernosum) defined by MRI. Int J Radiat Oncol Biol Phys 2005;61: [87] Sethi A, Mohideen N, Leybovich L, Mulhall J. Role of IMRT in reducing penile doses in dose escalation for prostate cancer. Int J Radiat Oncol Biol Phys 2003;55: [88] Kao J, Turian J, Meyers A, et al. Sparing of the penile bulb and proximal penile structures with intensity-modulated radiation therapy for prostate cancer. Br J Radiol 2004;77: [89] Buyyounouski MK, Horwitz EM, Price RA, Hanlon AL, Uzzo RG, Pollack A. Intensity-modulated radiotherapy with MRI simulation to reduce doses received by erectile tissue during prostate cancer treatment. Int J Radiat Oncol Biol Phys 2004;58: [90] Turner SL, Adams K, Bull CA, Berry MP. Sexual dysfunction after radical radiation therapy for prostate cancer: a prospective evaluation. Urology 1999;54: [91] Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol 2000;163: [92] Salomon G, Isbarn H, Budaeus L, et al. Importance of baseline potency rate assessment of men diagnosed with clinically localized prostate cancer prior to radical prostatectomy. J Sex Med 2009; 6: [93] Zagar TM, Stock RG, Cesaretti JA, Stone NN. Assessment of postbrachytherapy sexual function: a comparison of the IIEF-5 and the MSEFS. Brachytherapy 2007;6:26 33.

15 126 EUROPEAN UROLOGY 61 (2012) [94] Burnett AL, Aus G, Canby-Hagino ED, et al. Erectile function outcome reporting after clinically localized prostate cancer treatment. J Urol 2007;178: [95] Macdonald AG, Keyes M, Kruk A, Duncan G, Moravan V, Morris WJ. Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: is dose to the penile bulb important? Int J Radiat Oncol Biol Phys 2005;63: [96] Fransson P, Widmark A. Does one have a sexual life 15 years after external beam radiotherapy for prostate cancer? Prospective patient-reported outcome of sexual function comparison with age-matched controls. Urol Oncol 2011;29: [97] Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360: [98] Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2009; 373: [99] Incrocci L. Sexual function after external-beam radiotherapy for prostate cancer: what do we know? Crit Rev Oncol Hematol 2006; 57: [100] Incrocci L, Hop WC, Slob AK. Efficacy of sildenafil in an open-label study as a continuation of a double-blind study in the treatment of erectile dysfunction after radiotherapy for prostate cancer. Urology 2003;62: [101] Schiff JD, Bar-Chama N, Cesaretti J, Stock R. Early use of a phosphodiesterase inhibitor after brachytherapy restores and preserves erectile function. BJU Int 2006;98: [102] Mangar SA, Sydes MR, Tucker HL, et al. Evaluating the relationship between erectile dysfunction and dose received by the penile bulb: using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN ). Radiother Oncol 2006;80: [103] Lehrer S, Cesaretti J, Stone NN, Stock RG. Urinary symptom flare after brachytherapy for prostate cancer is associated with erectile dysfunction and more urinary symptoms before implantation. BJU Int 2006;98: [104] Cesaretti JA, Kao J, Stone NN, Stock RG. Effect of low dose-rate prostate brachytherapy on the sexual health of men with optimal sexual function before treatment: analysis at > or = 7 years of follow-up. BJU Int 2007;100: [105] Gomez-Iturriaga Pina A, Crook J, Borg J, Lockwood G, Fleshner N. Median 5 year follow-up of 125iodine brachytherapy as monotherapy in men aged < or = 55 years with favorable prostate cancer. Urology 2010;75: [106] Mabjeesh N, Chen J, Beri A, Stenger A, Matzkin H. Sexual function after permanent 125I-brachytherapy for prostate cancer. Int J Impot Res 2005;17: [107] Thompson IM, Tangen CM, Klein EA. Is there a standard of care for pathologic stage T3 prostate cancer? J Clin Oncol 2009;27: [108] Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005;366: [109] Moinpour CM, Hayden KA, Unger JM, et al. Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J Clin Oncol 2008;26: [110] Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pt3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol 2009;27: [111] Bottke D, de Reijke TM, Bartkowiak D, Wiegel T. Salvage radiotherapy in patients with persisting/rising PSA after radical prostatectomy for prostate cancer. Eur J Cancer 2009;45(Suppl 1): [112] Wiegel T, Lohm G, Bottke D, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome results of a retrospective study. Int J Radiat Oncol Biol Phys 2009; 73: [113] Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25: [114] Do T, Parker RG, Do C, Tran L, Do L, Dolkar D. Salvage radiotherapy for biochemical and clinical failures following radical prostatectomy. Cancer J Sci Am 1998;4: [115] Madalinska JB, Essink-Bot ML, de Koning HJ, Kirkels WJ, van der Maas PJ, Schroder FH. Health-related quality-of-life effects of radical prostatectomy and primary radiotherapy for screendetected or clinically diagnosed localized prostate cancer. J Clin Oncol 2001;19: [116] Rajendran RR, Plastaras JP, Mick R, McMichael Kohler D, Kassaee A, Vapiwala N. Daily isocenter correction with electromagneticbased localization improves target coverage and rectal sparing during prostate radiotherapy. Int J Radiat Oncol Biol Phys 2010; 76: [117] Wolff D, Stieler F, Hermann B, et al. Clinical implementation of volumetric intensity-modulated arc therapy (VMAT) with ERGO++. Strahlenther Onkol 2010;186: [118] Bittner N, Butler WM, Reed JL, et al. Electromagnetic tracking of intrafraction prostate displacement in patients externally immobilized in the prone position. Int J Radiat Oncol Biol Phys 2010; 77: [119] King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti Jr JC. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int J Radiat Oncol Biol Phys 2009;73: [120] Talcott JA, Rossi C, Shipley WU, et al. Patient-reported long-term outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer. JAMA 2010;303: [121] Matzinger O, Poortmans P, Giraud JY, et al. Quality assurance in the EORTC ROG trial in localized prostate cancer: dummy run and individual case review. Radiother Oncol 2009;90: [122] Jeldres C, Suardi N, Saad F, et al. High provider volume is associated with lower rate of secondary therapies after definitive radiotherapy for localized prostate cancer. Eur Urol 2008;54: [123] Marks LB, Ten Haken RK, Martel MK. Guest editor s introduction to QUANTEC: a users guide. Int J Radiat Oncol Biol Phys 2010; 76(Suppl 3):S1 2. [124] Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med 2008;148: [125] Dearnaley DP, Sydes MR, Langley RE, Graham JD, Huddart RA, Syndikus I, et al. The early toxicity of escalated versus standard dose conformal radiotherapy with neo-adjuvant androgen suppression for patients with localised prostate cancer: results from the MRC RT01 trial (ISRCTN ). Radiother Oncol 2007;83: [126] Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 2009;74:

16 EUROPEAN UROLOGY 61 (2012) [127] Zapatero A, Valcarcel F, Calvo FA, Algas R, Bejar A, Maldonado J, et al. Risk-adapted androgen deprivation and escalated threedimensional conformal radiotherapy for prostate cancer: Does radiation dose influence outcome of patients treated with adjuvant androgen deprivation? A GICOR study. J Clin Oncol 2005; 23: [128] Ishiyama H, Kitano M, Satoh T, Kotani S, Uemae M, Matsumoto K, et al. Genitourinary toxicity after high-dose-rate (HDR) brachytherapy combined with Hypofractionated External beam radiotherapy for localized prostate cancer: an analysis to determine the correlation between dose-volume histogram parameters in HDR brachytherapy and severity of toxicity. Int J Radiat Oncol Biol Phys 2009;75:23 8. [129] Lee WR, Bae K, Lawton C, Gillin M, Morton G, Firat S, et al. Late toxicity and biochemical recurrence after external-beam radiotherapy combined with permanent-source prostate brachytherapy: analysis of Radiation Therapy Oncology Group study Cancer 2007;109: [130] Sanchez-Ortiz RF, Broderick GA, Rovner ES, Wein AJ, Whittington R, Malkowicz SB. Erectile function and quality of life after interstitial radiation therapy for prostate cancer. Int J Impot Res 2000;12(Suppl 3):S [131] Merrick GS, Butler WM, Galbreath RW, Stipetich RL, Abel LJ, Lief JH. Erectile function after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;52: [132] Merrick GS, Wallner K, Butler WM, Lief JH, Sutlief S. Short-term sexual function after prostate brachytherapy. Int J Cancer 2001;96: [133] Taira AV, Merrick GS, Galbreath RW, Butler WM, Wallner KE, Kurko BS, et al. Erectile function durability following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2009;75: