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74 Gy) and permanent interstitial brachytherapy in 890 intermediate risk prostate cancer patients
Radiotherapy and Oncology 103 (2012) 223–227
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RT of intermediate risk prostate cancer
Comparison between external beam radiotherapy (70 Gy/74 Gy) and permanent interstitial brachytherapy in 890 intermediate risk prostate cancer patients Gregor Goldner a,⇑, Richard Pötter a, Jan J. Battermann b, Christian Kirisits a, Maximilian P. Schmid a, Samir Sljivic a, Marco van Vulpen b a
Department of Radiation Oncology, Medical University of Vienna, Austria; b Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands
a r t i c l e
i n f o
Article history: Received 1 November 2011 Received in revised form 29 December 2011 Accepted 23 January 2012 Available online 5 March 2012 Keywords: Prostate cancer External beam radiotherapy Permanent interstitial brachytherapy Biochemical control
a b s t r a c t Purpose: Aim of this analysis was to compare biochemical no evidence of disease (bNED) rates in intermediate-risk prostate-cancer patients treated at two centres of excellence using different approaches: permanent interstitial brachytherapy (BT) and external beam radiotherapy (EBRT). Materials and methods: A total of 890 intermediate-risk prostate-cancer patients, who were treated from 1998 to 2008, were identified in the two local databases. In Utrecht 601 patients received I-125 BT applying a dose of 144 Gy. In Vienna 289 patients were treated by EBRT, applying a local dose of 70 Gy in 105 patients and 74 Gy in 184 patients. bNED-rates (Phoenix-definition) were assessed. Results: Median follow-up was 48 months (1–150). 5-Year actuarial bNED-rates were 81% for BT-patients and 75% for EBRT-patients (67% for 70 Gy and 82% for 74 Gy), respectively. In univariate analysis no difference between BT and EBRT could be detected. In multivariate analysis including tumour-stage, GleasonScore, initial PSA, hormonal therapy and treatment-centre (BT vs. EBRT) only T-stage, GleasonScore and PSA were found to be significant. Additional analysis including radiation dose showed the same outcome. Conclusions: Intermediate-risk prostate cancer patients treated by permanent interstitial brachytherapy show biochemical tumour-control-rates which are comparable to EBRT of 74 Gy. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 103 (2012) 223–227
Patients presenting with low risk prostate cancer can be treated either by external beam radiotherapy or permanent interstitial brachytherapy. Both treatment options show excellent tumour control rates [1–12] and are therefore considered to be equivalent as stated in guidelines and recommendations [13–15]. These recommendations are based on non-randomized trials. Randomized trials evaluating the effectiveness of permanent interstitial brachytherapy compared to external beam radiotherapy or radical prostatectomy have not been published so far. However, the recommendation for permanent interstitial brachytherapy is limited to low-risk prostate cancer patients, whereas intermediate risk patients are not regarded to be candidates for seeds brachytherapy. Nevertheless, numerous studies evaluating the outcome after permanent interstitial brachytherapy included besides low-risk prostate cancer patients also a sufficient number of intermediate risk patients and were able to demonstrate tumour control rates comparable to the results after external beam radiotherapy in these patients [1–12,16]. ⇑ Corresponding author. Address: Department of Radiotherapy and Radiobiology, University Hospital of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail address: [email protected] (G. Goldner). 0167-8140/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2012.01.016
Aim of this analysis was therefore to evaluate the tumour control rates (biochemical no evidence of disease) within a large cohort of intermediate risk prostate cancer patients, who were treated by either permanent interstitial brachytherapy or external beam radiotherapy, in order to demonstrate the effectiveness of permanent interstitial brachytherapy in intermediate risk prostate cancer patients. Data were derived from the local data bases of two centres of excellence, from the University Medical Centre of Utrecht and the Medical University of Vienna. Material and methods Patient selection Patients with histological proven primary prostate cancer treated from 1998 to 2008 either at the Department of Radiation Oncology at the University Medical Centre of Utrecht, The Netherlands or at the Department of Radiotherapy at the Medical University of Vienna, Austria were part of this retrospective analysis. All patients were intermediate-risk patients according to the NCCN classification as well as described by Chism et al. showing T-stage T2b–T2c and/or GleasonScore 7 (=intermediate grade)
224
Intermediate risk prostate cancer: Seeds vs. EBRT
and/or maximal initial PSA > 10–20 ng/ml [17,18]. T-stage was described according to the 2002 American Joint Committee on Cancer system. Within this sequential cohort a total of 945 patients could be identified in the two local databases. Patients with insufficient information of follow-up – 55 patients (6%) – were excluded, resulting in a study population of 890 intermediate-risk patients.
In Vienna patients were seen during the first 3 years after radiotherapy every 3–6 months and at least once a year thereafter. Biochemical no evidence of disease (bNED) was defined according to the Phoenix definition, with absolute nadir +2 ng/ml rise [22] or in case of the start of hormonal therapy due to rising PSA.
Statistics
Permanent interstitial brachytherapy Patients treated in Utrecht received a transperineal implantation with I-125 seeds as monotherapy with an average seed activity of 0.45 mCi and a planned dose of 144 Gy according to the TG43 protocol of the American Association of Physicists in Medicine guidelines [19]. As previously described in more detail, different techniques have been introduced over the years [1–3,21]. Intraoperative real-time planning was introduced in December 2000 to further increase implant quality. For patients with gland sizes P50 cc, treatment for 6 months with hormonal therapy was begun to achieve prostate volume reduction before the planned brachytherapy procedure. External beam radiotherapy Patients treated in Vienna received three-dimensional conformal radiotherapy in supine position using a four-field-boxtechnique with individualised blocks and rectal balloon [7,8]. The gross tumour volume/clinical target volume (GTV/CTV) was defined based on a series of CT and MRI slices and included the prostate and the base of the seminal vesicles. The safety margin around the CTV was 10 mm in all directions applying a dose of 70 Gy and in case of 74 Gy a 5 mm posterior margin was used for the first 8 Gy followed by 66 Gy with a margin of 10 mm in all directions, again. Patients were treated up to a total dose of 70–74 Gy, 2 Gy per fraction 5 times a week. Dose was prescribed to the ICRU-reference point with at least 95% of the PTV receiving the prescribed dose [20]. Additional hormonal therapy was recommended for duration of at least 6 months. Biochemical no evidence of disease (bNED) and follow-up All measures of time were calculated from the last day of radiotherapy. In Utrecht follow-up was performed at intervals of 3 months for the first year and at an interval of 6 months thereafter.
All analyses were performed using SPSS 19.0. All statistical tests were two-sided and a p-level <0.05 was considered statistically significant. The Kaplan–Meier method was used to estimate bNED rates. Multivariate Cox regression models included the following variables: T-stage, iPSA, GleasonScore, hormonal therapy and dose. For all analyses GleasonScore (1 = ‘‘2–6’’ vs. 0 = ‘‘7’’), iPSA (1 = ‘‘<10’’ vs. 0 = ‘‘10–20’’) T-stage (1 = ‘‘T1’’ vs. 0 = ‘‘T2’’), hormonal therapy (1 = ‘‘no’’ vs. 0 = ‘‘yes’’) and dose (0 = ‘‘144 Gy’’ vs. 1 = ‘‘70 Gy’’, respectively 0 = ‘‘144 Gy’’ vs. 1 = ‘‘74 Gy’’) were treated as categorical variables, with the lowest category serving as reference category. Further regression analyses were conducted with a more specific definition of the participating centre (Utrecht and Vienna), duration of hormone therapy (0 months, 66 months, 7–12 months and >12 months) and T-stages (T1a + T1b, T1c, T2a, T2b, T2c). These variables did not show any major or significant results concerning the hazard ratios. Results A total of 890 intermediate risk group patients are included into this retrospective analysis. Patients’ characteristics according to treatment centre/treatment technique are presented in detail in Table 1. Median follow-up was 48 months (1–150 months) for all patients, 45 months (1–128 months) for the permanent interstitial brachytherapy patients and 54 months (2–150 months) for the EBRT patients, respectively. Permanent interstitial brachytherapy (=Utrecht patients) was performed in 601 patients. Median number of seeds implanted was 75 (33–127). Median maximal pre-treatment PSA was 11.7 ng/ml and 52% of these patients (n = 314) were presenting with a GleasonScore 2–6. Additional hormonal therapy received 142/601 patients (24%). External beam radiotherapy (=Vienna patients) was applied to 289 patients, of whom 105 patients (36%) were treated up to a local dose of 70 Gy and 184 patients (64%)
Table 1 Patients characteristics according to treatment centre = treatment technique; n = number of patients at risk and % = percentage (permanent interstitial brachytherapy = Utrecht/ external beam radiotherapy = Vienna); patients with GleasonScore unknown = intermediate grade. BT: 601 pts n T-stage
iPSA
GleasonScore
Risk factors
Hormonal Th Median duration Age Follow-up
T1 T2a T2b, T2c T2 610 ng/ml >10–20 ng/ml Median PSA 2–6 7 Unknown One Two Three Yes 66 months
Median >60 months
357 165 78 1 172 429 11.7 ng/ml 314 234 53 363 216 22 142 142 6 months 66.6 years 45 months 198
EBRT: 289 pts % 59 27 13 <1 29 71 52 39 9 60 36 4 24 100
33
All 890 pts
n
%
n
%
126 52 86 25 126 163 10.5 ng/ml 148 104 37 210 61 18 191 80 15,4 months 71.1 years 54 months 107
44 18 30 9 44 56
483 217 164 26 298 592 11.3 ng/ml 462 338 90 573 277 40 333 222 11,3 months 67.8 years 48 months 305
54 24 18 3 33 67
51 36 13 73 21 6 66 42
37
52 38 10 65 31 4 37 66
34
G. Goldner et al. / Radiotherapy and Oncology 103 (2012) 223–227
225
Fig. 1. Permanent interstitial brachytherapy-Utrecht: black; 5 years: 81%; external beam radiotherapy-70/74 Gy-Vienna: grey; 5 years: 75%; (BT vs. EBRT: p = 0.977) n = number of patients at risk.
Fig. 2. Permanent interstitial brachytherapy-Utrecht: black; 5 years: 81%; external beam radiotherapy-70 Gy-Vienna: dotted line; 5 years: 67%; external beam radiotherapy74 Gy-Vienna: grey; 5 years: 82%; BT vs. 74 Gy: p = 0.143/BT vs. 70 Gy: p = 0.156/70 Gy vs. 74 Gy: p = 0.017; n = number of patients at risk.
received a dose of 74 Gy. Median maximal pre-treatment PSA was 10.5 ng/ml and 51% of these patients (n = 148) were presenting with a GleasonScore 2–6. Additional hormonal therapy received 191/289 patients (66%) for a limited period of 6 months (Table 1). The 5-year actuarial bNED rate for patients receiving permanent interstitial brachytherapy was 81% using Phoenix definition and the corresponding rate for patients receiving EBRT was 75% showing no significant difference between the two treatment options in univariate analysis (Fig. 1). When bNED rates were stratified by dose applied (BT 144 Gy, EBRT 70 Gy and EBRT 74 Gy) the 5-year rate was 81%, 67% and 82%, respectively. A significant difference could be detected between the 70 Gy and the 74 Gy patients receiving EBRT (p = 0017), whereas no significant difference
compared to brachytherapy patients could be detected (Fig. 2). Comparing potential risk factors such as T-stage (T1 vs. T2) or GleasonScore (GleasonScore 66 vs. 7) or initial PSA (610 ng/ml vs. 10–20 ng/ml) within univariate analysis no significant difference regarding dose applied (EBRT 70 Gy vs. EBRT 74 Gy vs. permanent interstitial brachytherapy) was detected. Within multivariate analysis including Tumour-stage, initial PSA, GleasonScore, hormonal therapy and dose applied only Tumour stage, PSA and GleasonScore were found to be significant factors influencing bNED outcome whereas hormonal therapy and dose were not significant (Table 2). A significant difference in favour for the EBRT 74 Gy patients and permanent interstitial brachytherapy was found in patients presenting with one risk factor (p = 0,01 and p = 0,03),
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Intermediate risk prostate cancer: Seeds vs. EBRT
Table 2 Multivariate analysis (hazard ratio [HR] and confidence interval [CI]) of potential predictors of biochemical no evidence of disease (bNED). iPSA: initial prostate-specific antigen; HT: hormonal therapy; RC: reference category. Covariate
*
HR (95% CI)
p-Value
T-stage
T1 T2
0.668 (0.475–0.941) RC
0.021*
GleasonScore
2-6 7
0.508 (0.350–0.737) RC
<0.001*
iPSA (ng/ml)
<10 10–20
0.338 (0.218–0.524) RC
<0.001*
HT
No Yes
0.903 (0.610–1.335) RC
0.608
Dose
70 74 144
1.393 (0.865–2.242) 0.708 (0.412–1.218) RC
0.173 0.212
Significant.
whereas no significant difference (EBRT 70 Gy vs. EBRT 74 Gy vs. permanent interstitial brachytherapy) was found for patients presenting with two or more risk factors.
Discussion Numerous authors have used permanent interstitial brachytherapy to treat besides low-risk prostate cancer patients also patients presenting with intermediate- or even high-risk and intermediate-risk patients were reported to show comparable results to external beam radiotherapy patients [1–12,16,23]. However the use of permanent interstitial brachytherapy in intermediate-risk patients is still a matter of debate. The German ‘‘S3-Leitlinien’’, published in 2011, concluded that no recommendation for the use of permanent interstitial brachytherapy could be given until now [15]. This is in accordance to the European Society for Radiotherapy and Oncology and the American Brachytherapy Society recommending brachytherapy as monotherapy only in low-risk patients [14,24]. However, the French Society of Radiation Oncology and the French Urology Association opened permanent interstitial brachytherapy to selected intermediate-risk patients (favourable intermediate-risk) presenting with a Stage T1–T2a and GleasonScore <7 and PSA 10–15 ng/ml or presenting with a Stage T1–T2a and PSA <10 ng/ml and a GleasonScore 7 [25]. Cosset et al. were able to demonstrate a significant difference (p = 0.001) in 5-year relapse free survival comparing low-risk patients (97%) to these favourable intermediate-risk patients (94%). However, it is evident that intermediate-risk patients and even favourable ones are facing worse outcomes when compared to low-risk patients. Comparison within the same defined risk-group is therefore necessary. This analysis is, to our knowledge, the first to compare a standard of care external beam radiotherapy to permanent interstitial brachytherapy for intermediate patients in literature. Data derived from two different centres of excellence, from the University Medical Centre of Utrecht and the Medical University of Vienna resulting in a total of 890 intermediate-risk prostate cancer patients. Comparisons were limited to biochemical outcome due to the median follow-up of 48 months. Disease specific and overall survival needs more extensive follow-up. No significant difference in regard to biochemical no evidence of disease could be detected within this retrospective analysis. One limitation of our study might be the dose delivered by external beam radiotherapy (70 or 74 Gy) and one might argue that doses above 74 Gy would result in better treatment outcome. However the Dutch randomized dose-escalation trial comparing 68 Gy vs. 78 Gy resulted in a bNED-rate of 80% after 5 years in the high-dose
arm and the MRC-RT01 randomized trial comparing 64 Gy vs. 74 Gy detected a 5-year bNED-rate of 79% in the high-dose arm [26,10]. Both results are in accordance to the outcome of our patients receiving either permanent interstitial brachytherapy (5year rate 81%) or external beam radiotherapy with 74 Gy (5-year rate 82%). Kuban et al. reported a 5-year bNED-rate of 93% delivering external beam radiotherapy by conventional techniques followed by a conformal planned boost. This obviously resulted in larger treatment volumes and also included obturatorial lymphnodes treating patients with a mini-pelvic field followed by a local boost therapy [11]. By the use of more advanced local external beam radiotherapy techniques (IMRT) the Memorial Sloan-Kettering Centre achieved a 5-year bNED-rate of 90% delivering a local dose of 81 Gy [27]. The benefit of dose escalation in intermediate-risk prostate cancer patients is warrant. However the minimum dose required achieving proper outcome data remains unclear. In general practice – outside centres of excellence – intermediate-patients are treated by external beam radiotherapy applying a dose in the range of 74–76 Gy [28] according to the German ‘‘S3-Leitlinien’’ [15] recommending a dose of at least 74 Gy. Comparing teletherapy to brachytherapy the 5-year biochemical no evidence of disease rates are in the range of 67–93% by applying local external beam radiotherapy (64–81 Gy) and are in the range of 70–94% using permanent interstitial brachytherapy (Supplement Table 3). In contrast to Cosset et al. who included favourable intermediate risk patients only in our analysis all intermediate risk patients were part of the analysis. Intermediate risk patients with just one risk factor showed significant better bNED rates when treated with permanent interstitial brachytherapy or EBRT of 74 Gy compared to patients receiving EBRT of 70 Gy, whereas no difference between EBRT of 74 Gy and brachytherapy could be detected regardless of a number of risk factors. The proportion of patients presenting with two or three risk factors was higher in the brachytherapy group (40% vs. 27%). But, at least for the EBRT 74 Gy patients no difference in bNED outcome could be detected. Furthermore the proportion of patients receiving additional hormonal therapy was significantly lower than the brachytherapy-group (24%) and was limited to 6 months whereas patients receiving external beam radiotherapy (66% with hormonal therapy) got androgen deprivation for a median duration of 15 months. Nevertheless no difference in outcome could be detected. The higher the risk group and the more advanced the risk factors the higher is the probability of positive lymph nodes at the time of diagnosis. The well recognized Roach formula published in 1993 was set up in order to provide a quantitative tool in definitive radiotherapy to decide on the indication for additional pelvic lymph node radiotherapy [29]. Roach et al. demonstrated within a large randomized trial that primary prostate cancer patients showing an increased risk (P15%) of positive lymph nodes according to this formula benefit from definitive radiotherapy which includes the pelvic lymph nodes [30,31]. On the other hand a second randomized trial (GETUG-01) assessing the benefit of lymph node radiotherapy within definitive primary treatment not applying a lymph node risk parameter was not able to find a significant improvement regarding progression free survival [32]. As a consequence a debate has come up and is still going on, whether prophylactic pelvic radiotherapy in high risk prostate cancer patients (lymph node involvement P15% according to Roach formula) should become a clinical standard or not [31–35]. Furthermore within the guidelines no recommendation for pelvic lymph node irradiation in intermediate risk prostate cancer patients is given until now. Therefore local radiotherapy such as permanent interstitial brachytherapy might be sufficient when treating intermediate risk patients. Within this retrospective analysis we were able to demonstrate that patients receiving permanent interstitial brachytherapy show same tumour control rates
G. Goldner et al. / Radiotherapy and Oncology 103 (2012) 223–227
compared to 74 Gy applied within external beam radiotherapy. On the one hand it has to be investigated if 74 Gy EBRT is sufficiently high dose within these patients and on the other hand it also has to be verified if permanent interstitial brachytherapy is able to produce comparable results to escalated external beam radiotherapy schedules. These striking questions have to be investigated within randomized trials – however one should not exclude intermediate risk patients from permanent interstitial brachytherapy right from the beginning. Conclusion Intermediate-risk prostate cancer patients treated by permanent interstitial brachytherapy show biochemical tumour control rates which are comparable to external beam radiotherapy up to 74 Gy. Therefore these patients should be also considered for permanent interstitial brachytherapy when not receiving external beam radiotherapy at higher dose levels of about 78–80 Gy. Conflict of interest statement The authors declare that there are no conflicts of interest. Acknowledgement The authors want to thank Mag. Alexander Iro for his support regarding statistical analysis. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.radonc.2012.01.016. References [1] Battermann JJ. I-125 implantation for localized prostate cancer: the Utrecht University experience. Radiother Oncol 2000;57:269–72. [2] Battermann JJ, Boon TA, Moerland MA. Results of permanent prostate brachytherapy, 13 years of experience at a single institution. Radiother Oncol 2004;71:23–8. [3] Hinnen KA, Battermann 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. [4] Pieters BR, de Back DZ, Koning CC, Zwinderman AH. Comparison of three radiotherapy modalities on biochemical control and overall survival for the treatment of prostate cancer: a systematic review. Radiother Oncol 2009;93:168–73. [5] 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. [6] Sylvester JE, Blasko JC, Grimm PD, Meier R, Malmgren JA. Ten-year biochemical relapse-free survival after external beam radiation and brachytherapy for localized prostate cancer: the Seattle experience. Int J Radiat Oncol Biol Phys 2003;57:944–52. [7] Goldner G, Bombosch V, Geinitz H, et al. Moderate risk adapted dose escalation with three-dimensional conformal radiotherapy of localized prostate cancer from 70 to 74 Gy. Strahlenther Onkol 2009;185:94–100. [8] Goldner G, Dimopoulos J, Kirisits C, Pötter R. Moderate dose escalation in three-dimensional conformal localized prostate cancer radiotherapy singleinstitutional experience in 398 patients comparing 66 Gy versus 70 Gy versus 74 Gy. Strahlenther Onkol 2009;185:438–45. [9] 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 with78 Gy. J Clin Oncol 2006;24:1990–6. [10] Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose versus standarddose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8:475–87.
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[11] 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;70:67–74. [12] Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1–T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004;58:25–33. [13] Salembier C, Lavagnini P, Nickers P, et al. Tumour and target volumes in permanent prostate brachytherapy: a supplement to the ESTRO/EAU/EORTC recommendations on prostate brachytherapy. Radiother Oncol 2007;83:3–10. [14] Ash D, Flynn A, Battermann J, Lavagnini P, Blank L. ESTRO/EAU/EORTC recommendations on permanent seed implantation for localized prostate cancer. Radiother Oncol 2000;57:315–21. [15] Leitlinienprogramm Onkologie, S3-Leitlinie Prostatakarzinom, Version 2.0, 1. Aktualisierung 09.2011;. [16] Munro NP, Al-Qaisieh B, Bownes P, et al. Outcomes from Gleason 7, intermediate risk localized prostate cancer treated with iodine-125 monotherapy over 10 years. Radiother Oncol 2010;96:34–7. [17] National Comprehensive Cancer Network Website. . [18] Chism DB, Hanlon AL, Horwitz EM, Feigenberg SJ, Pollack A. A comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with 3D conformal radiotherapy. Int J Radiat Oncol Biol Phys 2004;59:380–5. [19] Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM radiation therapy committee task group no. 43. Med Phys 1995;22:209–34. [20] ICRU. Report 62: prescribing, recording and reporting photon beam therapy (supplement to ICRU report 50). Bethesda: International Commission on Radiation Units and Measurements; 1999. [21] Hinnen KA, Moerland MA, Battermann JJ, et al. Loose seeds versus stranded seeds in I-125 prostate brachytherapy: differences in clinical outcome. Radiother Oncol 2010;96:30–3. [22] Roach 3rd M, Hanks G, Thames Jr H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO phoenix consensus conference. Int J Radiat Oncol Biol Phys 2006;65:965–74. [23] Faria S, Pra AD, Cury F, et al. Treating intermediate-risk prostate cancer with hypofractionated external beam radiotherapy alone. Radiother Oncol 2011;101:486–9. [24] Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44:789–99. [25] Cosset JM, Flam T, Thiounn N, et al. Selecting patients for exclusive permanent implant prostate brachytherapy: the experience of the paris institut curie/ cochin hospital/necker hospital group on 809 patients. Int J Radiat Oncol Biol Phys 2008;71:1042–8. [26] Al-Mamgani A, Heemsbergen W, Levendag PC, Lebesque JV. Subgroup analysis of patients with localized prostate cancer treated within the Dutchrandomized dose escalation trial. Radiother Oncol 2010;96:13–8. [27] Alicikus ZA, Yamada Y, Zhang Z, et al. Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer. Cancer 2011;117:1429–37. [28] Goldner G, Sljivic S, Oismueller R, et al. Prostate cancer radiotherapy in Austria: overview on number of patients, intention to treat and treatment techniques based on the year 2007. Strahlenther Onkol 2011;187:279–83. [29] Roach 3rd M. Equations for predicting the pathologic stage of men with localized prostate cancer using the preoperative prostate specific antigen (PSA) and Gleason score. J Urol 1993;150:1923–4. [30] Roach 3rd M, DeSilvio M, Valicenti R, et al. Whole-pelvis, ‘‘mini-pelvis’’, or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial. Int J Radiat Oncol Biol Phys 2006;66:647–53. [31] Roach 3rd M, DeSilvio M, Lawton C, et al. Phase III trial comparing wholepelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003;21:1904–11. [32] Pommier P, Chabaud S, Lagrange JL, et al. Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01. J Clin Oncol 2007;25:5366–73. [33] Roach 3rd M. Predicting pathologic stage, nomograms, and clinical judgment: don’t miss the forest for the trees! Int J Radiat Oncol Biol Phys 2009;73:325–6. [34] Roach 3rd M. 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Contents lists available at SciVerse ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
RT of intermediate risk prostate cancer
Comparison between external beam radiotherapy (70 Gy/74 Gy) and permanent interstitial brachytherapy in 890 intermediate risk prostate cancer patients Gregor Goldner a,⇑, Richard Pötter a, Jan J. Battermann b, Christian Kirisits a, Maximilian P. Schmid a, Samir Sljivic a, Marco van Vulpen b a
Department of Radiation Oncology, Medical University of Vienna, Austria; b Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands
a r t i c l e
i n f o
Article history: Received 1 November 2011 Received in revised form 29 December 2011 Accepted 23 January 2012 Available online 5 March 2012 Keywords: Prostate cancer External beam radiotherapy Permanent interstitial brachytherapy Biochemical control
a b s t r a c t Purpose: Aim of this analysis was to compare biochemical no evidence of disease (bNED) rates in intermediate-risk prostate-cancer patients treated at two centres of excellence using different approaches: permanent interstitial brachytherapy (BT) and external beam radiotherapy (EBRT). Materials and methods: A total of 890 intermediate-risk prostate-cancer patients, who were treated from 1998 to 2008, were identified in the two local databases. In Utrecht 601 patients received I-125 BT applying a dose of 144 Gy. In Vienna 289 patients were treated by EBRT, applying a local dose of 70 Gy in 105 patients and 74 Gy in 184 patients. bNED-rates (Phoenix-definition) were assessed. Results: Median follow-up was 48 months (1–150). 5-Year actuarial bNED-rates were 81% for BT-patients and 75% for EBRT-patients (67% for 70 Gy and 82% for 74 Gy), respectively. In univariate analysis no difference between BT and EBRT could be detected. In multivariate analysis including tumour-stage, GleasonScore, initial PSA, hormonal therapy and treatment-centre (BT vs. EBRT) only T-stage, GleasonScore and PSA were found to be significant. Additional analysis including radiation dose showed the same outcome. Conclusions: Intermediate-risk prostate cancer patients treated by permanent interstitial brachytherapy show biochemical tumour-control-rates which are comparable to EBRT of 74 Gy. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 103 (2012) 223–227
Patients presenting with low risk prostate cancer can be treated either by external beam radiotherapy or permanent interstitial brachytherapy. Both treatment options show excellent tumour control rates [1–12] and are therefore considered to be equivalent as stated in guidelines and recommendations [13–15]. These recommendations are based on non-randomized trials. Randomized trials evaluating the effectiveness of permanent interstitial brachytherapy compared to external beam radiotherapy or radical prostatectomy have not been published so far. However, the recommendation for permanent interstitial brachytherapy is limited to low-risk prostate cancer patients, whereas intermediate risk patients are not regarded to be candidates for seeds brachytherapy. Nevertheless, numerous studies evaluating the outcome after permanent interstitial brachytherapy included besides low-risk prostate cancer patients also a sufficient number of intermediate risk patients and were able to demonstrate tumour control rates comparable to the results after external beam radiotherapy in these patients [1–12,16]. ⇑ Corresponding author. Address: Department of Radiotherapy and Radiobiology, University Hospital of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail address: [email protected] (G. Goldner). 0167-8140/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2012.01.016
Aim of this analysis was therefore to evaluate the tumour control rates (biochemical no evidence of disease) within a large cohort of intermediate risk prostate cancer patients, who were treated by either permanent interstitial brachytherapy or external beam radiotherapy, in order to demonstrate the effectiveness of permanent interstitial brachytherapy in intermediate risk prostate cancer patients. Data were derived from the local data bases of two centres of excellence, from the University Medical Centre of Utrecht and the Medical University of Vienna. Material and methods Patient selection Patients with histological proven primary prostate cancer treated from 1998 to 2008 either at the Department of Radiation Oncology at the University Medical Centre of Utrecht, The Netherlands or at the Department of Radiotherapy at the Medical University of Vienna, Austria were part of this retrospective analysis. All patients were intermediate-risk patients according to the NCCN classification as well as described by Chism et al. showing T-stage T2b–T2c and/or GleasonScore 7 (=intermediate grade)
224
Intermediate risk prostate cancer: Seeds vs. EBRT
and/or maximal initial PSA > 10–20 ng/ml [17,18]. T-stage was described according to the 2002 American Joint Committee on Cancer system. Within this sequential cohort a total of 945 patients could be identified in the two local databases. Patients with insufficient information of follow-up – 55 patients (6%) – were excluded, resulting in a study population of 890 intermediate-risk patients.
In Vienna patients were seen during the first 3 years after radiotherapy every 3–6 months and at least once a year thereafter. Biochemical no evidence of disease (bNED) was defined according to the Phoenix definition, with absolute nadir +2 ng/ml rise [22] or in case of the start of hormonal therapy due to rising PSA.
Statistics
Permanent interstitial brachytherapy Patients treated in Utrecht received a transperineal implantation with I-125 seeds as monotherapy with an average seed activity of 0.45 mCi and a planned dose of 144 Gy according to the TG43 protocol of the American Association of Physicists in Medicine guidelines [19]. As previously described in more detail, different techniques have been introduced over the years [1–3,21]. Intraoperative real-time planning was introduced in December 2000 to further increase implant quality. For patients with gland sizes P50 cc, treatment for 6 months with hormonal therapy was begun to achieve prostate volume reduction before the planned brachytherapy procedure. External beam radiotherapy Patients treated in Vienna received three-dimensional conformal radiotherapy in supine position using a four-field-boxtechnique with individualised blocks and rectal balloon [7,8]. The gross tumour volume/clinical target volume (GTV/CTV) was defined based on a series of CT and MRI slices and included the prostate and the base of the seminal vesicles. The safety margin around the CTV was 10 mm in all directions applying a dose of 70 Gy and in case of 74 Gy a 5 mm posterior margin was used for the first 8 Gy followed by 66 Gy with a margin of 10 mm in all directions, again. Patients were treated up to a total dose of 70–74 Gy, 2 Gy per fraction 5 times a week. Dose was prescribed to the ICRU-reference point with at least 95% of the PTV receiving the prescribed dose [20]. Additional hormonal therapy was recommended for duration of at least 6 months. Biochemical no evidence of disease (bNED) and follow-up All measures of time were calculated from the last day of radiotherapy. In Utrecht follow-up was performed at intervals of 3 months for the first year and at an interval of 6 months thereafter.
All analyses were performed using SPSS 19.0. All statistical tests were two-sided and a p-level <0.05 was considered statistically significant. The Kaplan–Meier method was used to estimate bNED rates. Multivariate Cox regression models included the following variables: T-stage, iPSA, GleasonScore, hormonal therapy and dose. For all analyses GleasonScore (1 = ‘‘2–6’’ vs. 0 = ‘‘7’’), iPSA (1 = ‘‘<10’’ vs. 0 = ‘‘10–20’’) T-stage (1 = ‘‘T1’’ vs. 0 = ‘‘T2’’), hormonal therapy (1 = ‘‘no’’ vs. 0 = ‘‘yes’’) and dose (0 = ‘‘144 Gy’’ vs. 1 = ‘‘70 Gy’’, respectively 0 = ‘‘144 Gy’’ vs. 1 = ‘‘74 Gy’’) were treated as categorical variables, with the lowest category serving as reference category. Further regression analyses were conducted with a more specific definition of the participating centre (Utrecht and Vienna), duration of hormone therapy (0 months, 66 months, 7–12 months and >12 months) and T-stages (T1a + T1b, T1c, T2a, T2b, T2c). These variables did not show any major or significant results concerning the hazard ratios. Results A total of 890 intermediate risk group patients are included into this retrospective analysis. Patients’ characteristics according to treatment centre/treatment technique are presented in detail in Table 1. Median follow-up was 48 months (1–150 months) for all patients, 45 months (1–128 months) for the permanent interstitial brachytherapy patients and 54 months (2–150 months) for the EBRT patients, respectively. Permanent interstitial brachytherapy (=Utrecht patients) was performed in 601 patients. Median number of seeds implanted was 75 (33–127). Median maximal pre-treatment PSA was 11.7 ng/ml and 52% of these patients (n = 314) were presenting with a GleasonScore 2–6. Additional hormonal therapy received 142/601 patients (24%). External beam radiotherapy (=Vienna patients) was applied to 289 patients, of whom 105 patients (36%) were treated up to a local dose of 70 Gy and 184 patients (64%)
Table 1 Patients characteristics according to treatment centre = treatment technique; n = number of patients at risk and % = percentage (permanent interstitial brachytherapy = Utrecht/ external beam radiotherapy = Vienna); patients with GleasonScore unknown = intermediate grade. BT: 601 pts n T-stage
iPSA
GleasonScore
Risk factors
Hormonal Th Median duration Age Follow-up
T1 T2a T2b, T2c T2 610 ng/ml >10–20 ng/ml Median PSA 2–6 7 Unknown One Two Three Yes 66 months
Median >60 months
357 165 78 1 172 429 11.7 ng/ml 314 234 53 363 216 22 142 142 6 months 66.6 years 45 months 198
EBRT: 289 pts % 59 27 13 <1 29 71 52 39 9 60 36 4 24 100
33
All 890 pts
n
%
n
%
126 52 86 25 126 163 10.5 ng/ml 148 104 37 210 61 18 191 80 15,4 months 71.1 years 54 months 107
44 18 30 9 44 56
483 217 164 26 298 592 11.3 ng/ml 462 338 90 573 277 40 333 222 11,3 months 67.8 years 48 months 305
54 24 18 3 33 67
51 36 13 73 21 6 66 42
37
52 38 10 65 31 4 37 66
34
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225
Fig. 1. Permanent interstitial brachytherapy-Utrecht: black; 5 years: 81%; external beam radiotherapy-70/74 Gy-Vienna: grey; 5 years: 75%; (BT vs. EBRT: p = 0.977) n = number of patients at risk.
Fig. 2. Permanent interstitial brachytherapy-Utrecht: black; 5 years: 81%; external beam radiotherapy-70 Gy-Vienna: dotted line; 5 years: 67%; external beam radiotherapy74 Gy-Vienna: grey; 5 years: 82%; BT vs. 74 Gy: p = 0.143/BT vs. 70 Gy: p = 0.156/70 Gy vs. 74 Gy: p = 0.017; n = number of patients at risk.
received a dose of 74 Gy. Median maximal pre-treatment PSA was 10.5 ng/ml and 51% of these patients (n = 148) were presenting with a GleasonScore 2–6. Additional hormonal therapy received 191/289 patients (66%) for a limited period of 6 months (Table 1). The 5-year actuarial bNED rate for patients receiving permanent interstitial brachytherapy was 81% using Phoenix definition and the corresponding rate for patients receiving EBRT was 75% showing no significant difference between the two treatment options in univariate analysis (Fig. 1). When bNED rates were stratified by dose applied (BT 144 Gy, EBRT 70 Gy and EBRT 74 Gy) the 5-year rate was 81%, 67% and 82%, respectively. A significant difference could be detected between the 70 Gy and the 74 Gy patients receiving EBRT (p = 0017), whereas no significant difference
compared to brachytherapy patients could be detected (Fig. 2). Comparing potential risk factors such as T-stage (T1 vs. T2) or GleasonScore (GleasonScore 66 vs. 7) or initial PSA (610 ng/ml vs. 10–20 ng/ml) within univariate analysis no significant difference regarding dose applied (EBRT 70 Gy vs. EBRT 74 Gy vs. permanent interstitial brachytherapy) was detected. Within multivariate analysis including Tumour-stage, initial PSA, GleasonScore, hormonal therapy and dose applied only Tumour stage, PSA and GleasonScore were found to be significant factors influencing bNED outcome whereas hormonal therapy and dose were not significant (Table 2). A significant difference in favour for the EBRT 74 Gy patients and permanent interstitial brachytherapy was found in patients presenting with one risk factor (p = 0,01 and p = 0,03),
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Intermediate risk prostate cancer: Seeds vs. EBRT
Table 2 Multivariate analysis (hazard ratio [HR] and confidence interval [CI]) of potential predictors of biochemical no evidence of disease (bNED). iPSA: initial prostate-specific antigen; HT: hormonal therapy; RC: reference category. Covariate
*
HR (95% CI)
p-Value
T-stage
T1 T2
0.668 (0.475–0.941) RC
0.021*
GleasonScore
2-6 7
0.508 (0.350–0.737) RC
<0.001*
iPSA (ng/ml)
<10 10–20
0.338 (0.218–0.524) RC
<0.001*
HT
No Yes
0.903 (0.610–1.335) RC
0.608
Dose
70 74 144
1.393 (0.865–2.242) 0.708 (0.412–1.218) RC
0.173 0.212
Significant.
whereas no significant difference (EBRT 70 Gy vs. EBRT 74 Gy vs. permanent interstitial brachytherapy) was found for patients presenting with two or more risk factors.
Discussion Numerous authors have used permanent interstitial brachytherapy to treat besides low-risk prostate cancer patients also patients presenting with intermediate- or even high-risk and intermediate-risk patients were reported to show comparable results to external beam radiotherapy patients [1–12,16,23]. However the use of permanent interstitial brachytherapy in intermediate-risk patients is still a matter of debate. The German ‘‘S3-Leitlinien’’, published in 2011, concluded that no recommendation for the use of permanent interstitial brachytherapy could be given until now [15]. This is in accordance to the European Society for Radiotherapy and Oncology and the American Brachytherapy Society recommending brachytherapy as monotherapy only in low-risk patients [14,24]. However, the French Society of Radiation Oncology and the French Urology Association opened permanent interstitial brachytherapy to selected intermediate-risk patients (favourable intermediate-risk) presenting with a Stage T1–T2a and GleasonScore <7 and PSA 10–15 ng/ml or presenting with a Stage T1–T2a and PSA <10 ng/ml and a GleasonScore 7 [25]. Cosset et al. were able to demonstrate a significant difference (p = 0.001) in 5-year relapse free survival comparing low-risk patients (97%) to these favourable intermediate-risk patients (94%). However, it is evident that intermediate-risk patients and even favourable ones are facing worse outcomes when compared to low-risk patients. Comparison within the same defined risk-group is therefore necessary. This analysis is, to our knowledge, the first to compare a standard of care external beam radiotherapy to permanent interstitial brachytherapy for intermediate patients in literature. Data derived from two different centres of excellence, from the University Medical Centre of Utrecht and the Medical University of Vienna resulting in a total of 890 intermediate-risk prostate cancer patients. Comparisons were limited to biochemical outcome due to the median follow-up of 48 months. Disease specific and overall survival needs more extensive follow-up. No significant difference in regard to biochemical no evidence of disease could be detected within this retrospective analysis. One limitation of our study might be the dose delivered by external beam radiotherapy (70 or 74 Gy) and one might argue that doses above 74 Gy would result in better treatment outcome. However the Dutch randomized dose-escalation trial comparing 68 Gy vs. 78 Gy resulted in a bNED-rate of 80% after 5 years in the high-dose
arm and the MRC-RT01 randomized trial comparing 64 Gy vs. 74 Gy detected a 5-year bNED-rate of 79% in the high-dose arm [26,10]. Both results are in accordance to the outcome of our patients receiving either permanent interstitial brachytherapy (5year rate 81%) or external beam radiotherapy with 74 Gy (5-year rate 82%). Kuban et al. reported a 5-year bNED-rate of 93% delivering external beam radiotherapy by conventional techniques followed by a conformal planned boost. This obviously resulted in larger treatment volumes and also included obturatorial lymphnodes treating patients with a mini-pelvic field followed by a local boost therapy [11]. By the use of more advanced local external beam radiotherapy techniques (IMRT) the Memorial Sloan-Kettering Centre achieved a 5-year bNED-rate of 90% delivering a local dose of 81 Gy [27]. The benefit of dose escalation in intermediate-risk prostate cancer patients is warrant. However the minimum dose required achieving proper outcome data remains unclear. In general practice – outside centres of excellence – intermediate-patients are treated by external beam radiotherapy applying a dose in the range of 74–76 Gy [28] according to the German ‘‘S3-Leitlinien’’ [15] recommending a dose of at least 74 Gy. Comparing teletherapy to brachytherapy the 5-year biochemical no evidence of disease rates are in the range of 67–93% by applying local external beam radiotherapy (64–81 Gy) and are in the range of 70–94% using permanent interstitial brachytherapy (Supplement Table 3). In contrast to Cosset et al. who included favourable intermediate risk patients only in our analysis all intermediate risk patients were part of the analysis. Intermediate risk patients with just one risk factor showed significant better bNED rates when treated with permanent interstitial brachytherapy or EBRT of 74 Gy compared to patients receiving EBRT of 70 Gy, whereas no difference between EBRT of 74 Gy and brachytherapy could be detected regardless of a number of risk factors. The proportion of patients presenting with two or three risk factors was higher in the brachytherapy group (40% vs. 27%). But, at least for the EBRT 74 Gy patients no difference in bNED outcome could be detected. Furthermore the proportion of patients receiving additional hormonal therapy was significantly lower than the brachytherapy-group (24%) and was limited to 6 months whereas patients receiving external beam radiotherapy (66% with hormonal therapy) got androgen deprivation for a median duration of 15 months. Nevertheless no difference in outcome could be detected. The higher the risk group and the more advanced the risk factors the higher is the probability of positive lymph nodes at the time of diagnosis. The well recognized Roach formula published in 1993 was set up in order to provide a quantitative tool in definitive radiotherapy to decide on the indication for additional pelvic lymph node radiotherapy [29]. Roach et al. demonstrated within a large randomized trial that primary prostate cancer patients showing an increased risk (P15%) of positive lymph nodes according to this formula benefit from definitive radiotherapy which includes the pelvic lymph nodes [30,31]. On the other hand a second randomized trial (GETUG-01) assessing the benefit of lymph node radiotherapy within definitive primary treatment not applying a lymph node risk parameter was not able to find a significant improvement regarding progression free survival [32]. As a consequence a debate has come up and is still going on, whether prophylactic pelvic radiotherapy in high risk prostate cancer patients (lymph node involvement P15% according to Roach formula) should become a clinical standard or not [31–35]. Furthermore within the guidelines no recommendation for pelvic lymph node irradiation in intermediate risk prostate cancer patients is given until now. Therefore local radiotherapy such as permanent interstitial brachytherapy might be sufficient when treating intermediate risk patients. Within this retrospective analysis we were able to demonstrate that patients receiving permanent interstitial brachytherapy show same tumour control rates
G. Goldner et al. / Radiotherapy and Oncology 103 (2012) 223–227
compared to 74 Gy applied within external beam radiotherapy. On the one hand it has to be investigated if 74 Gy EBRT is sufficiently high dose within these patients and on the other hand it also has to be verified if permanent interstitial brachytherapy is able to produce comparable results to escalated external beam radiotherapy schedules. These striking questions have to be investigated within randomized trials – however one should not exclude intermediate risk patients from permanent interstitial brachytherapy right from the beginning. Conclusion Intermediate-risk prostate cancer patients treated by permanent interstitial brachytherapy show biochemical tumour control rates which are comparable to external beam radiotherapy up to 74 Gy. Therefore these patients should be also considered for permanent interstitial brachytherapy when not receiving external beam radiotherapy at higher dose levels of about 78–80 Gy. Conflict of interest statement The authors declare that there are no conflicts of interest. Acknowledgement The authors want to thank Mag. Alexander Iro for his support regarding statistical analysis. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.radonc.2012.01.016. References [1] Battermann JJ. I-125 implantation for localized prostate cancer: the Utrecht University experience. Radiother Oncol 2000;57:269–72. [2] Battermann JJ, Boon TA, Moerland MA. Results of permanent prostate brachytherapy, 13 years of experience at a single institution. Radiother Oncol 2004;71:23–8. [3] Hinnen KA, Battermann 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. [4] Pieters BR, de Back DZ, Koning CC, Zwinderman AH. Comparison of three radiotherapy modalities on biochemical control and overall survival for the treatment of prostate cancer: a systematic review. Radiother Oncol 2009;93:168–73. [5] 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. [6] Sylvester JE, Blasko JC, Grimm PD, Meier R, Malmgren JA. Ten-year biochemical relapse-free survival after external beam radiation and brachytherapy for localized prostate cancer: the Seattle experience. Int J Radiat Oncol Biol Phys 2003;57:944–52. [7] Goldner G, Bombosch V, Geinitz H, et al. Moderate risk adapted dose escalation with three-dimensional conformal radiotherapy of localized prostate cancer from 70 to 74 Gy. Strahlenther Onkol 2009;185:94–100. [8] Goldner G, Dimopoulos J, Kirisits C, Pötter R. Moderate dose escalation in three-dimensional conformal localized prostate cancer radiotherapy singleinstitutional experience in 398 patients comparing 66 Gy versus 70 Gy versus 74 Gy. Strahlenther Onkol 2009;185:438–45. [9] 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 with78 Gy. J Clin Oncol 2006;24:1990–6. [10] Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose versus standarddose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8:475–87.
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