Five-year outcomes after iodine-125 seed brachytherapy for low-risk prostate cancer at three cancer centres in the UK

Five-year outcomes after iodine-125 seed brachytherapy for low-risk prostate cancer at three cancer centres in the UK Peter D. Dickinson*, Jahangeer Malik, Paula Mandall*, Ric Swindell*, David Bottomley, Peter Hoskin, John P. Logue* and James P. Wylie* *Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, Department of Clinical Oncology, Edinburgh Cancer Centre, Edinburgh, Department of Clinical Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, Department of Clinical Oncology, Mount Vernon Hospital, Northwood, UK P.D. and J.M. are joint first authors Objective To report the outcomes of >1000 men with low-risk prostate cancer treated with low-dose-rate (LDR) brachytherapy at three large UK cancer centres. Patients and Methods A total of 1038 patients with low-risk prostate cancer (prostate-specific antigen [PSA] 10 ng/ml, Gleason score 6, T2b disease) were treated with LDR iodine 125 (I-125) brachytherapy between 2002 and 2007. Patients were treated at three UK centres. PSA and clinical follow-up was performed at each centre. Biochemical recurrence-free survival was reported for the cohort. Results The median (range) PSA follow-up for the whole group was 5 years (4 months to 9 years). A total of 79 patients had biochemical failure, defined by a rise in PSA level: 16 patients fulfilled the ASTRO definition of biochemical failure, 25 patients fulfilled the Phoenix definition and 38 patients fulfilled both definitions. The 5-year biochemical relapse-free survival (brfs) rate was 94.1% by the ASTRO definition and 94.2% by the Phoenix definition. The absence of neoadjuvant hormone therapy was predictive of inferior biochemical control as defined by the Phoenix definition (P = 0.033). Conclusions Our prospective multicentre series showed excellent brfs with LDR I-125 brachytherapy for patients with low-risk prostate cancer. Further work is necessary to define the role of neoadjuvant androgen deprivation therapy in combination with brachytherapy. Keywords prostate, brachytherapy, low-risk, outcomes Introduction Low-dose-rate (LDR) iodine-125 (I-125) brachytherapy is an established treatment option for low-risk prostate adenocarcinoma. There are no reported randomized controlled trials comparing LDR brachytherapy with surgical prostatectomy or external beam radiotherapy, but many single-centre series have reported excellent biochemical control rates at 5 and 10 years after implantation [1 9]. Low-risk prostate cancer has previously been defined in the D Amico classification as patients presenting with a PSA level 10 ng/ml, Gleason score 6 and T2b disease [5]. The present paper reports the outcomes of a cohort of >1000 men with low-risk prostate cancer treated with I-125 brachytherapy. The rates of biochemical failure according to both the ASTRO [10] and Phoenix [11] definitions are reported to allow easier comparison with other series in the literature. Patients and Methods Patient Characteristics A total of 1069 men with biopsy-proven low-risk prostate adenocarcinoma, were identified from our multi-institutional database. Data were entered into the database in a prospective fashion. The definition of low risk in the present study was PSA 10 ng/ml, Gleason score 6 and T2b disease. The patients were treated between 2002 and 2007 at three large UK BJU Int 2014; 113: 748 753 wileyonlinelibrary.com BJU International 2013 BJU International doi:10.1111/bju.12358 Published by John Wiley & Sons Ltd. www.bjui.org

I-125 brachytherapy for low-risk prostate cancer: 5-year outcomes brachytherapy centres: the Christie, Leeds and Mount-Vernon centres. All patients were clinically staged according to DRE and all patients had a TRUS-guided biopsy. Staging MRI and bone scans were not performed routinely and were used at the clinician s discretion. All patients provided informed consent before treatment. All pathology and imaging was reviewed by experienced pathologists and radiologists in multidisciplinary team meetings. Patients were excluded from the study if they hadreceivedexternalbeamradiotherapyinadditionto brachytherapy or if fewer than two post-treatment PSA levels were recorded. Treatment Technique Neoadjuvant androgen deprivation therapy (ADT) was given in selected patients to reduce the prostate volume before implantation and was at the treating clinician s discretion. All patients were treated with I-125 seed implants. The majority of patients were treated using the two-step Seattle technique [12]. The seed strengths used ranged from 0.30 to 0.39mCi. The dose prescription in all cases was 145 Gy as a minimum peripheral dose to the clinical target volume (Task Group-43 dosimetry [13]). The clinical target volume was defined by the prostate capsule with a 2 5 mm margin. Post-implantation dosimetry was performed in some patients using CT imaging 4 6 weeks after implantation. It was not standard practice within two of these experienced brachytherapy centres to perform post-implantation dosimetry on all patients during the study period. Before, and where possible after implantation, dose to 90% of the prostate volume in Grays (D90) and volume of prostate receiving 100, 150 and 200% of the prescribed dose (V100, V150 and V200, respectively) dosimetry values were recorded. Follow-Up and Biochemical Failure Patients were followed up at 3 6-month intervals, depending on the treating centre, and PSA level was recorded at each visit. Biochemical failure was defined using both the ASTRO consensus and Phoenix definitions. A PSA bounce was defined as any rise in PSA level above the nadir which subsequently fell back to the pre-bounce level, or lower, without any intervention. Patients who met the definition for a PSA bounce were excluded from the biochemical failure analysis unless they developed a subsequent PSA rise fulfilling the ASTRO/Phoenix definitions. Analysis Time to biochemical failure and duration of follow-up were calculated from the date of implantation. The Kaplan Meier method [14] was used to calculate the 5-year biochemical relapse- free survival (brfs) and the log-rank test was used to compare the survival curves. Univariate and multivariate logistic regression analyses were performed to look for factors predictive of inferior biochemical control. The following factors were assessed in the univariate analysis: patient age; presenting PSA; Gleason score; T-stage; prostate volume; use of neoadjuvant hormones; presenting IPSS score; D90; V100; V150; V200; seed strength; number of needles; and number of seeds implanted. Statistical analysis was performed using SPSS version 18.0 (Chicago, IL, USA). Patients who had a PSA relapse were treated at their clinician s discretion by observation, hormone therapy and systemic chemotherapy. No patients had local salvage treatment. Results A total of 1069 patients were treated with LDR brachytherapy between 2002 and 2007. All patients had a recorded initial pre-implantation PSA. Of the 1069 patients, 29 were excluded from further analysis as fewer than two post-implant PSA levels were available. Two patients were excluded as they received external beam radiotherapy in addition to brachytherapy. Data from 1038 patients were used for the final analysis. The median (range) patient age was 62 (40 77) years, and all patients had Gleason 6 disease. The median (range) presenting PSA was 6 (0.1 10) ng/ml and the median (range) prostate volume was 36 (13 61) ml at time of implantation. The median (interquartile range) presenting IPSS was 5 (4 15). The clinical stage of the tumours is shown in Table 1. In all, 231 patients (22%) had neoadjuvant ADT to reduce the prostate volume before implantation. The median (range) number of needles implanted was 28 (18 41) and the median number of seeds implanted was 84 (50 121). Post-implantation dosimetry was performed in 479 (46%) patients. Pre- and post-implantation dosimetry information is shown in Table 2. Post-implantation dosimetry was performed at a median (range) of 40 (22 140) days after the procedure. The median (range) follow-up was 5 years (4 months to 9 years). At the time of analysis 100 patients had experienced a PSA bounce. A total of 79 patients had a biochemical (PSA) failure; 16 patients as defined by the ASTRO criteria and 25 patients as defined by the Phoenix criteria, and 38 patients fulfilled the criteria for both definitions. The 5-year brfs was 94.1% according to the ASTRO criteria and 94.2% according to the Phoenix criteria (Fig. 1). Table 1 Clinical stage of tumours at presentation. n (%) Clinical stage T1c 766 (74) T2a 226 (22) T2 (not specified) 46 (4) BJU International 2013 BJU International 749

Dickinson et al. Table 2 Pre- and post-implantation dosimetry data. Variable Pre-implantation Post-implantation D90, Gy No. of patients (%) 1021 (98.4) 479 (46.1) Median (range) 186.0 (120.7 204) 124.9 (48.4-201.0) IQR 180.8-186.0 109.5-124.9 V100 No. of patients (%) 1010 (97.3) 479 (46.1) Median 100 (10 100) 82.4 (44.5 99.4) IQR 98.2-100 75.3 82.4 V150 No. of patients (%) 1020 (98.4) 479 (46.1) Median (range) 61.8 (27.1 82.5) 45.6 (16.0 83.6) IQR 54.0 61.8 38.3 45.6 V200 No. of patients (%) 1000 (96.3) 479 (46.1) Median (range) 20.7 (10.7 37.3) 19.1 (4.7 50.5) IQR 18.1 20.7 15.0 19.1 IQR, interquartile range. Fig. 1 Biochemical recurrence-free survival according to (A) ASTRO definition of biochemical failure and (B) the Phoenix definition. A Astro failure - all patients with low-risk disease (n = 1038) 100 80 Biochemical failure-free, % 60 40 20 On univariate analysis, no factors were found to predict inferior biochemical control for an ASTRO-defined failure. On multivariate analysis, the absence of neoadjuvant hormone therapy was predictive of inferior biochemical control as defined by the Phoenix definition: the 5-year brfs rates for those receiving and those not receiving neoadjuvant hormones were 96.8 and 93.4%, respectively (P = 0.033). brfs rates, depending on the use of neoadjuvant ADT, are shown in Fig. 2. Discussion Low-dose-rate prostate brachytherapy is a well-established treatment option for low-risk prostate cancer. The results from this multicentre collaboration show a 5-year brfs that is similar to those in other reported international series [1 9] and add to the growing body of evidence that LDR brachytherapy is an effective and durable treatment option for men with low-risk prostate cancer. No trials have compared brachytherapy directly with external beam radiotherapy or surgery. In low-risk prostate cancer, surgery has been shown to achieve a brfs rate of >80% at 5 years [15 17]. Similar brfs rates have been seen in patients treated with external beam radiotherapy [18 20]. Active surveillance is an alternative option for selected men with low-risk prostate cancer and can potentially spare men with indolent disease the side effects associated with radical treatment [21]. The addition of ADT to external beam radiotherapy is now established in the treatment of intermediate- and high-risk localized prostate cancer because of the demonstrated improvement in overall survival [22 24], but the added benefit in patients with low-risk disease has not been proven. The role of ADT in patients treated with brachytherapy has not yet been defined. In the present study, the use of neoadjuvant hormones was associated with a clinically small but B Biochemical failure-free, % 0 0 1 2 3 4 5 6 7 8 9 Time, years 1038 1012 934 857 730 502 292 136 49 0 100 80 60 40 20 Phoenix failure - all patients with low-risk disease 0 0 1 2 3 4 5 6 7 8 9 Time, years 1038 1022 951 874 750 516 301 137 49 0 statistically significant improvement in Phoenix-defined brfs: a 3.4% improvement at 5 years. The previously reported benefits of neoadjuvant ADT before brachytherapy are conflicting and there is little information on the low-risk group. Some studies have shown no benefit from ADT in combination with brachytherapy [25 27], whilst a study by Merrick et al. [28] found that ADT had no effect on survival, but improved bpfs in patients with high-risk disease. 750 BJU International 2013 BJU International

I-125 brachytherapy for low-risk prostate cancer: 5-year outcomes Fig. 2 Phoenix-defined brfs depending on use of neoadjuvant androgen deprivation therapy. Biochemical failure-free, % 100 80 60 40 20 Phoenix failure by Hormones Given No Yes P = 0.033 0 0 1 2 3 4 5 6 7 8 9 Time, years N 798 787 738 674 576 383 218 90 35 0 Y 231 227 207 195 169 130 82 47 14 0 Similarly Lee et al. [29] found an increase in freedom from biochemical failure in the intermediate- and high-risk groups with ADT. By contrast, Beyer et al. [30] found that overall survival was worse in men receiving neoadjuvant ADT before brachytherapy. In our cohort of patients with low-risk disease there was a trend towards improved brfs in the neoadjuvant hormone group using the ASTRO definition but this did not reach significance. This may be explained by the fact that there were fewer ASTRO-defined failures during the study period. The Phoenix criteria have been shown to be more sensitive and specific in defining biochemical failure in patients treated with either external beam radiotherapy or brachytherapy [31,32]. In summary, the small absolute benefit in brfs, the lack of significance seen in the ASTRO definition and lack of supporting data from other studies raises significant doubts about the validity of this finding. Prospective randomized trials are therefore needed to better clarify the role of neoadjuvant ADT before brachytherapy. The American Brachytherapy Guidelines recommend that post-implantation dosimetry is performed within 60 days of the implantation [33]. Post-implantation dosimetry studies have found that a higher post-implantation D90 is associated with improved brfs [9,34]. The median post-implantation dosimetry D90 of 124.9 Gy observed in the present series would be considered low, and was lower than the median pre-implantation D90 of 186 Gy. We believe that this discrepancy is attributable to interobserver variation across the three sites in outlining the prostate post-implantation. Significant interobserver variability in contouring the prostate post-implantation has previously been reported [35,36] and will affect the accuracy of the calculated D90. The interval between implantation and contouring the prostate also affects post-implantation dosimetry [37,38] and this interval was not standardized between our three centres. It is noteworthy that routine post-implantation dosimetry has now been reinstated for all patients receiving brachytherapy at the three centres. Routine toxicity data were not collated in our database, but previous studies have reported on the favourable toxicity profile of LDR seed brachytherapy. In a study of 712 patients, the 5-year rate of Radiation Therapy Oncology Group grade 3 urinary toxicity was 6.3%. The factors which predicted late grade 2 toxicity were pre-treatment IPSS, maximum post-implantation IPSS, presence of acute toxicity and higher prostate V150 [39]. There is a reduction in late urinary toxicity rates as treatment centres become more experienced in seed brachytherapy [40]. Reported brachytherapy-induced erectile dysfunction rates vary greatly, but are 50% [41]. The rates of late rectal toxicity are low after seed brachytherapy; grade 3 late rectal toxicity affected only 1% of patients in a study of 367 patients [6]. In conclusion, the present prospective series has shown excellent brfs with LDR I-125 brachytherapy for patients with low-risk prostate cancer. LDR brachytherapy should be considered for this group of patients. Further work is necessary to define the role of neoadjuvant ADT in combination with brachytherapy. Conflict of Interest None declared. References 1 Sylvester JE, Grimm PD, Wong J, Galbreath RW, Merrick G, Blasko JC. Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following I 125 prostate brachytherapy in clinically localized prostate cancer: Seattle experience. Int J Radiat Oncol Biol Phys 2011; 81: 376 81 2 Crook J, Borg J, Evans A et al. 10-year experience with I-125 prostate brachytherapy at the Princess Margaret Hospital: results for 1,100 patients. Int J Radiat Oncol Biol Phys 2011; 80: 1323 9 3 Grimm PD, Blasko JC, Sylvester JE, Meier RM, Cavanagh W. 10-year biochemical (prostate-specific antigen) control of prostate cancer with I 125 brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51: 31 40 4 Potters L, Morgenstern C, Calugaru E et al. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J Urol 2005; 173: 1562 6 5 D Amico AV, Whittington R, Malkowicz SB et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 969 74 6 Zelefsky MJ, Yamada Y, Cohen G et al. Five year outcome of intra-operative conformal permanent I125 interstitial implantation for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2007; 67: 65 70 BJU International 2013 BJU International 751

Dickinson et al. 7 Henry AM, Al-Qaisieh B, Gould K et al. Outcomes following iodine-125 monotherapy for localized prostate cancer: the results of Leeds 10-year single-center brachytherapy experience. Int J Radiat Oncol Biol Phys 2010; 76: 50 6 8 Hinnen KA, Batterman JJ, van Roermund JGH et al. Long term biochemical and survival outcome of 921 patients treated with I-125 permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2010; 76: 1433 8 9 Zelefsky MJ, Kuban DA, Levy LB et al. Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. Int J Radiat Oncol Biol Phys 2007; 67: 327 33 10 ASTRO, Consensus Statement. Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997; 37: 1035 41 11 Roach M 3rd, Hanks G, Thames H Jr et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Pheonix Consensus Conference. Int J Radiat Oncol Biol Phys 2006; 65: 965 74 12 Grimm PD, Blasko JC, Ragde H. Ultrasound-guided transperineal implantation of Iodine-125 and Paladium-103 for the treatment of early-stage prostate cancer: technical concepts in planning, operative technique, and evaluation. In Schellhammer PF ed., New Techniques in Prostate Surgery, Philadelphia: WB Saunders Co, 1994; 113 26 13 Bice WS Jr, Prestidge BR, Prete JJ, Dubois DF. Clinical impact of implementing the recommendations of AAPM Task Group 43 on permanent prostate brachytherapy using I 125. American Association of Physicists in Medicine. IntJRaditOncolBiolPhys1998; 40: 1237 41 14 Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457 81 15 Boorjian SA, Karnes RJ, Rangel LJ, Bergstralh EJ, Blute ML. Mayo Clinic validation of the D amico risk group classification for predicting survival following radical prostatectomy. J Urol 2008; 179: 1354 60; discussion 1360 1 16 Hruza M, Bermejo JL, Flinspach B et al. Long-term oncological outcomes after laparoscopic radical prostatectomy. BJU Int 2013; 111: 271 80 17 Touijer K, Secin FP, Cronin AM et al. Oncologic outcome after laparoscopic radical prostatectomy: 10 years of experience. Eur Urol 2009; 55: 1014 9 18 Zelefsky MJ, Yamada Y, Fuks Z et al. Long-term results of conformal radiotherapy for prostate cancer: impact of dose escalation on biochemical tumor control and distant metastases-free survival outcomes. Int J Radiat Oncol Biol Phys 2008; 71: 1028 33 19 Shipley WU, Thames HD, Sandler HM et al. Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. JAMA 1999; 281: 1598 604 20 Dearnaley DP, Sydes MR, Graham JD et al.; RT01 collaborators. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007; 8: 475 87 21 National Comprehensive Cancer Network (NCCN) guidelines. Available at: http://www.nccn.org. Accessed on February 2013 22 D Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs. radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004; 292: 821 7 23 Bolla M, Collette L, Blank L et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002; 360: 103 6 24 Pilepich MV, Winter K, Lawton CA et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma: long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005; 61: 1285 90 25 Ash D, Al-Qaisieh B, Bottomley D, Carey B, Joseph J. The impact of hormone therapy on post-implant dosimetry and outcome following Iodine-125 implant monotherapy for localised prostate cancer. Radiother Oncol 2005; 75: 303 6 26 D Amico AV, Moran BJ, Braccioforte MH et al. Risk of death from prostate cancer after brachytherapy alone or with radiation, androgen suppression therapy, or both in men with high-risk disease. J Clin Oncol 2009; 27: 3923 8. Erratum in: J Clin Oncol. 2011 Apr 1; 29 (10): 1394 27 Potters L, Torre T, Ashley R, Liebel S. Examining the role of neoadjuvant hormone androgen deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2000; 18: 1187 92 28 Merrick GS, Butler WM, Wallner KE, Galbreath RW, Allen ZA, Adamovich E. Androgen-deprivation therapy does not impact cause-specific or overall survival after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2006; 65: 669 77 29 Lee LN, Stock RG, Stone NN. Role of hormonal therapy in the management of intermediate- to high-risk prostate cancer treated with permanent radioactive seed implantation. Int J Radiat Oncol Biol Phys 2002; 52: 444 52 30 Beyer DC, McKeough T, Thomas T. Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005; 61: 1299 305 31 Kuban DA, Levy LB, Potters L et al. Comparison of biochemical failure definitions for permanent prostate brachytherapy. IntJ Radiat Oncol Biol Phy 2006; 65: 1487 93 32 Fitch DL, McGrath S, Martinez AA, Vicini FA, Kestin LL. Unification of a common biochemical failure definition for prostate cancer treated with brachytherapy or external beam radiotherapy with or without androgen deprivation. Int J Radiat Oncol Biol Phys 2006; 66: 1430 9 33 Davis BJ, Horwitz EM, Lee WR et al.; American Brachytherapy Society. American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy 2012; 11: 6 19 34 Miles EF, Nelson JW, Alkaissi AK et al. Equivalent uniform dose, D(90), and V(100) correlation with biochemical control after low-dose-rate prostate brachytherapy for clinically low-risk prostate cancer. Brachytherapy 2008; 7: 206 11 35 Crook J, Milosevic M, Catton P et al. Interobserver variation in postimplant computed tomography contouring affects quality assessment of prostate brachytherapy. Brachytherapy 2002; 1: 66 73 36 Dubois DF, Prestidge BR, Hotchkiss LA, Prete JJ, Bice WS Jr. Intraobserver and interobserver variability of MR imaging- and CT-derived prostate volumes after transperineal interstitial permanent prostate brachytherapy. Radiology 1998; 207: 785e789 37 Dogan N, Mohideen N, Glasgow GP, Keys K, Flanigan RC. Effect of prostatic edema on CT-based postimplant dosimetry. IntJRadiatOncol Biol Phys 2002; 53: 483 9 38 Waterman FM, Dicker AP. Impact of postimplant edema on V(100) and D(90) in prostate brachytherapy: can implant quality be predicted on day 0? Int J Radiat Oncol Biol Phys 2002; 53: 610 21 39 Keyes M, Miller S, Moravan V et al. Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy: long-term outcome in 712 consecutive patients. Int J Radiat Oncol Biol Phys 2009; 73: 1023 32 40 Keyes M, Schellenberg D, Moravan V et al. Decline in urinary retention incidence in 805 patients after prostate brachytherapy: the effect of learning curve? Int J Radiat Oncol Biol Phys 2006; 64: 825 34 752 BJU International 2013 BJU International

I-125 brachytherapy for low-risk prostate cancer: 5-year outcomes 41 Merrick GS, Butler WM, Wallner KE et al. Erectile function after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005; 6: 437 47 Correspondence: James Wylie, Department of Clinical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. e-mail: james.wylie@christie.nhs.uk Abbreviations: LDR, low-dose rate; I-125, iodine 125; brfs, biochemical relapse-free survival; ADT, androgen deprivation therapy; D90, dose to 90% of target volume; V100, percentage of target volume receiving at least 100% of prescribed dose; V150, percentage of target volume receiving at least 150% of prescribe dose; V200, percentage of target volume receiving at least 200% of prescribed dose. BJU International 2013 BJU International 753