doi: /s (03) CLINICAL INVESTIGATION

Transcription

1 doi: /s (03) Int. J. Radiation Oncology Biol. Phys., Vol. 58, No. 4, pp , 2004 Copyright 2004 Elsevier Inc. Printed in the USA. All rights reserved /04/$ see front matter CLINICAL INVESTIGATION Prostate LONG-TERM OUTCOME BY RISK FACTORS USING CONFORMAL HIGH- DOSE-RATE BRACHYTHERAPY (HDR-BT) BOOST WITH OR WITHOUT NEOADJUVANT ANDROGEN SUPPRESSION FOR LOCALIZED PROSTATE CANCER RAZVAN M. GALALAE, M.D.,* ALVARO MARTINEZ, M.D., TIM MATE, M.D., CHRISTINA MITCHELL, R.N., GREGORY EDMUNDSON, M.S., NILS NUERNBERG, M.D.,* STEPHEN EULAU, M.D., GARY GUSTAFSON, M.D., MICHAEL GRIBBLE, M.S., AND GYOERGY KOVÁCS, M.D.* *Clinics for Radiation Therapy and Urology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Radiation Oncology and Urology Departments, William Beaumont Hospital, Royal Oak, MI; Clinic for Radiation Therapy, Seattle Prostate Institute, Seattle, WA Purpose: The aim of this study is to analyze, during the prostate-specific antigen (PSA) era, the long-term outcome of patients treated with conformal high-dose-rate (HDR) brachytherapy boost to the prostate with or without androgen deprivation therapy (ADT) when patients are stratified by risk factors for failure. Methods and Materials: Between 1986 and 2000, 611 patients were treated for clinically localized prostate cancer in three prospective trials of external beam radiation therapy (EBRT) and dose-escalating HDR brachytherapy (BT) boost. There were 104 patients treated at Seattle, 198 at Kiel University, and 309 at William Beaumont Hospital. Of the 611 patients, 177 received a short course of neoadjuvant/concurrent ADT. The patients were divided into three risk groups. Group I, comprised of 46 patients, had stage <T2a, Gleason score (GS) < 6, and initial PSA (ipsa) < 10 ng/ml. Group II comprised 188 patients with stage >T2b, GS > 7, and ipsa > 10, with any one factor higher. Group III included 359 patients with any two risk factors higher. The American Society for Therapeutic Radiology and Oncology definition for biochemical failure was used. Results: The mean follow-up was 5 years (range, ). For the 611 patients, the 5-year and 10-year biochemical control (BC) rates were 77% and 73%, disease-free survival (DFS) was 67% and 49%, and cause-specific survival (CSS) was 96% and 92%, respectively. BC at 5 years for Group I patients was 96%, for Group II 88%, and for Group III patients 69%. CSS at 5 years was 100% in Group I, 99% in Group II, and 95% in Group III patients. In univariate and multiple regression analyses for BC, risk group, stage, ipsa, and GS were significant in predicting failure. However, age, follow-up interval, and ADT did not. Conclusions: EBRT with HDR-BT produced excellent long-term outcomes in terms of BC, DFS, and CSS in patients with prostate cancer even for those at highest risk. Conformal HDR-BT is both a precise dose delivery system and an effective treatment for both favorable and unfavorable prostate cancer. The addition of a short course of neoadjuvant/concurrent ADT failed to improve outcome. The results were similar at all three institutions, giving credence to the reproducibility of the brachytherapy treatment Elsevier Inc. Conformal HDR brachytherapy, Prostate cancer, Pelvic irradiation, Androgen deprivation, Risk factors. INTRODUCTION Cancer of the prostate (CaP) is one of the most common malignancies in men (1). Standard definitive therapies for CaP, currently, are surgery (radical prostatectomy) or radiation therapy (external beam or brachytherapy). The development of three-dimensional conformal beam techniques has reduced the therapy-related morbidity and improved the efficacy of external beam radiation therapy (EBRT) (2). Brachytherapy (BT) for CaP has evolved into two forms: Reprint requests to: Razvan M. Galalae, M.D., Clinic for Radiation Therapy (Radiooncology), University Hospital, Christian- Albrechts-University of Kiel, Arnold-Heller-Str. 9, Kiel, Germany. Tel: ( 49) ; Fax: ( 49) ; galalae@onco.uni-kiel.de BT with permanent seed (e.g., I 125 or Pd 106 ) implants, and temporary interstitial conformal high-dose-rate brachytherapy (HDR-BT) with a stepping source (e.g., Ir 192 ). For both BT options long-term data have been published in the literature (3 8). Many authors have shown that radiation dose is an important predictor of biochemical no evidence of disease (bned) control rate and that a radiation dose response for patients with clinically localized prostate carcinoma exists Presented at the ASTRO 44th Annual Meeting, October 2002, New Orleans, LA. Oral presentation, Session G, GU.II, No. 57. Received Jan 13, 2003, and in revised form Aug 4, Accepted for publication Aug 5,

2 Long-term outcome using HDR brachytherapy for localized prostate cancer R. M. GALALAE et al (3, 9, 10). A different strategy, the use of adjuvant androgen deprivation therapy (ADT) in addition to standard radiation therapy doses and fields, resulted in a significant improvement in terms of local control, freedom from distant metastasis, and biochemical free survival. However, this advantage was proven for the use of hormonal manipulation following standard EBRT as part of their initial management only, in patients with locally advanced (clinical or pathologic T3; clinical or pathologic node-positive) prostate cancer vs. hormones initiated at relapse (11). Whether this potential advantage is still present with modern local doseescalated techniques is not known. Despite the data in the various studies supporting adjuvant ADT for men with localized CaP, the topic remains controversial. The present study also aims to address the effect of a short course of neoadjuvant/concurrent ADT on the long-term outcome of patients treated with pelvic EBRT and conformal HDR brachytherapy boost to the prostate when patients are stratified by risk factors. METHODS AND MATERIALS The current study includes pooled data of three prospective single-institution trials. Between 1986 and 2000, 611 patients were treated for clinically staged, localized prostate cancer according to the American Joint Committee on Cancer/International Union Against Cancer (12) classification. All patients treated had a histologically proven prostate cancer and a complete clinical staging with chest X-ray, bone scan, and pelvic computed tomography (CT) or magnetic resonance imaging (MRI) scan before treatment. The patients characteristics are detailed in Table 1. Between institutions, differences were noted in the distribution of patient characteristics. There was a trend for more favorable patients treated in Seattle, more unfavorable patients at Kiel University, and in between at William Beaumont Hospital. Of the 611 patients, there were 104 patients treated at Seattle Prostate Institute (Phase II initiated in 1989), 198 at Kiel University (Phase II study initiated in 1986), and 309 at William Beaumont Hospital (Phase II dose escalating trial initiated in 1991). The treatment strategies and techniques were quite similar. The pelvic EBRT was CT-based planned and applied using a beam from a MV linear accelerator. The clinical target volume (CTV) of the EBRT included the prostate, the seminal vesicles, and the pelvic lymph nodes and was not significantly different between the institutions. The total EBRT dose ranged from 45.6 to 50 Gy in 1.8 to 2 Gy daily fractions, 5 times per week. Characteristic Table 1. Patients characteristics All n 611 (%) Pretreatment PSA (9%) (41%) (26%) (20%) Not known 27 (4%) Age (25%) (62%) (13%) Stage UICC 1992 T1a T1c 102 (17%) T2a T2b 276 (45%) T2c 121 (20%) T3a T3c 112 (18%) Gleason score (76%) (24%) Abbreviations: PSA prostate-specific antigen; UICC International Union Against Cancer. HDR brachytherapy techniques The conformal interstitial HDR-BT was planned on the base of a complete prostate volumetric study by transrectal ultrasound, which was also used to visualize the normal prostate and the organs at risk (e.g., urethra, rectum, and bladder) during the implantation procedure. To shorten the overall treatment time (8 weeks down to 5 6 weeks), 2 to 4 fractions of conformal HDR brachytherapy were performed during the course of EBRT treatment. Initially on the trial, three implants were performed at William Beaumont Hospital (Weeks 1, 2, and 3), while in Seattle four fractions were applied. In Kiel (Weeks 3 and 5) the conformal BT was given in 2 fractions only. In October 1995, the BT fraction frequency at William Beaumont Hospital was reduced to 2 (Weeks 1 and 3). An iridium-192 stepping source from an afterloader with an initial activity of 370 GBq was used in all institutions. The treatment planning was performed according to the International Commission on Radiation Units and Measurements (ICRU) Report 58 (13). At the Seattle Prostate Institute, increasing boost doses from 3 to 4 Gy were applied. At Kiel University, the CTV for brachytherapy was differentiated in two levels. The CTV 1 was defined in the peripheral zone of McNeal (14), whereas the CTV 2 included the entire prostate. The planning target volume (PTV) encompassed the corresponding CTV with a small margin (1 3 mm) especially in high-risk tumors to address extracapsular disease. The minimum target dose (MTD) at the periphery of the PTV 1 according to the ICRU Report 58 was defined as reference dose and was equal to 15 Gy per fraction. The MTD corresponding to PTV 2 was 8 to 9 Gy per fraction. Two HDR fractions were performed. At William Beaumont Hospital, the HDR BT boost doses were escalated prospectively from 5.5 up to 11.5 Gy. Total combined biologically effective doses ranged from 79.6 Gy to 123 Gy if a value of 1.5 is assumed for / ratio, or up to 82.9 if 10 is assumed for /. However, many recent publications provided supporting evidence that alpha/ beta values for prostate tumor control are low (15, 16). Details of the techniques have been published (3 5, 17, 18).

3 1050 I. J. Radiation Oncology Biology Physics Volume 58, Number 4, 2004 Androgen deprivation therapy (ADT) There were 177 patients who received a short-term course of neoadjuvant/concurrent ADT as part of their initial management: 75 patients at Kiel University, and 102 at William Beaumont Hospital. A total of 434 patients were hormonenaïve and treated by radiotherapy only: 104 patients at Seattle Prostate Institute, 123 patients at Kiel University, and 207 at William Beaumont Hospital. The ADT therapy was performed specially in cases with an enlarged prostate volume for downsizing. It was initiated as neoadjuvant treatment, before the start of radiotherapy, and was terminated shortly before, during, or shortly after the radiotherapy. The median duration of ADT was 4 months. There were no significant institutional differences in the management of the ADT. Definition of risk factor groups Of the 611 patients, there were 593 eligible for the risk factor selection analysis. The pretreatment prostate-specific antigen (PSA) of 27 patients was not known. Nine of these patients had a Gleason score 8 and were included in the risk group 3 as defined below. Eighteen of the 27 patients were dropped from the analysis. The 593 remaining patients were divided into three risk groups. Group I comprised 46 patients who had stage T2a, Gleason score 6, and PSA 10. Group II comprised 188 patients with stage T2b, Gleason score 7, and PSA 10, with any one factor defined higher, and Group III comprised 359 patients with any two risk factors higher. Statistical analysis Times to events were measured from the start of radiotherapy to death, to failure, or to the most recent follow-up examination for evaluation of overall survival (OS), causespecific survival (CSS), and disease-free survival (DFS), whereas for biochemical control (BC) it was the date of the last post-treatment PSA testing. The American Society for Therapeutic Radiology and Oncology definition was used to define biochemical control. Digital examination and/or transrectal ultrasound was utilized to assess local control. The estimation of actuarial survival rates defined above was performed using Kaplan-Meier product limit methodology (19). Univariate analyses using the log rank test compared Kaplan-Meier rates. Cox regression models (20) were used to examine the effect of clinical and treatment variables in order to determine independent prognostic factors. Fig. 1. Actuarial analysis of long-term outcomes of conformal HDR brachytherapy boost. revealed no statistical difference at 5 and 10 years between institutions (p 0.276). In addition, in the three series the biochemical failures appear to plateau after 5 years. The actuarial analysis of biochemical control stratified by ADT for all 611 patients showed no statistically significant benefit (p 0.159) for the ADT group vs. no ADT group (Fig. 3). The actuarial 5-year survival analysis and local recurrence rates by risk factor groups are detailed in Table 2. A remarkably high biochemical control was observed even for the high-risk patient Group III. A small but gradual decrease in outcome was seen as risk factors increased. Also a higher local recurrence rate of 10% was seen in the high-risk group when compared with 0% for the low-risk group (mean RESULTS The mean follow-up time for the entire cohort of 611 patients was 5 years: for Group I 6.2 years (range, ), for Group II 4.4 years (range, ), and for Group III 5.3 years (range, ). For the 611 patients, the 5-year and 10-year BC rates were 77% and 73%, for OS they were 85% and 65%, and for CSS they were 96% and 92%, respectively (Fig. 1). The actuarial analysis of biochemical control stratified by institution depicted in Fig. 2 Fig. 2. Actuarial analysis of biochemical control stratified by institution.

4 Long-term outcome using HDR brachytherapy for localized prostate cancer R. M. GALALAE et al Fig. 3. Actuarial analysis of biochemical control of all patients stratified by ADT. Table 2. Actuarial analysis at 5 years by risk factors groups Endpoint All (n 593) Group I (n 46) Group II (n 188) Group III (n 359) OS 85% 88% 86% 85% CSS 96% 100% 99% 95% BC 77% 96% 88% 69% DFS 67% 83% 75% 61% LR 7.4% 0% 3.5% 10% Abbreviations: BC biochemical control; CSS cause-specific survival; DFS disease-free survival; LR local recurrence; OS overall survival. follow-up of 6.2 years). The survival analyses stratified by ADT are shown in Table 3. No evidence of any type of survival advantage was demonstrated by the addition of a short course of neoadjuvant/concurrent ADT. The biochemical control at 5 years for Group I patients was 96%, for Group II 88% (87% with no ADT and 91% with ADT), and for Group III patients 69% (69% with no ADT and 68% with ADT). Figure 4 shows the biochemical control curves stratified by risk group. It revealed worsening of BC in Group III with a significant p value of The cancer death cause-specific survival at 5 years is depicted in Fig. 5 Fig. 4. Actuarial analysis of biochemical control stratified by risk groups. and was 100% in Group I, 99% in Group II (100% with no ADT and 97% with ADT), and 95% in Group III patients (97% with no ADT and 90% with ADT). A more detailed survival analysis at 5 years comparing Groups II and III and stratified by ADT is presented in Table 3. The differences were not statistically significant with the exception of CSS in Group III, where the no ADT group showed a better survival when compared with the ADT group (p 0.002). To analyze in more detail the worse subgroup within Groups II and III, Fig. 6a depicts the actuarial analysis for patients with only one of the following poor factors: stage T2b, PSA 20, and Gleason score 8. This group comprises 265 patients, of whom 117 (44.2%) have a follow-up longer than 5 years. No benefit can be seen for those patients receiving ADT. Figure 6b depicts patients with any combination of two of the three above-mentioned poor factors. More than 50% of the 123 patients were followed for greater than 5 years. Once again, no benefit can be observed from a short course of neoadjuvant/concurrent ADT. In addition, univariate analyses for biochemical control at Table 3. Survival analysis at 5 years of risk factors groups stratified by ADT Group II Group III Endpoint No ADT (n 137) ADT (n 51) p values No ADT (n 240) ADT (n 119) p values OS 86% 90% % 80% CSS 100% 97% % 90% BC 87% 91% % 68% DFS 73% 85% % 61% Abbreviations: ADT androgen deprivation therapy. Other abbreviations as in Table 2.

5 1052 I. J. Radiation Oncology Biology Physics Volume 58, Number 4, 2004 Table 4. Univariate and multivariate analysis for biochemical control at 5 years Variable Univariate p values Multivariate p values Risk group Stage Pretreatment PSA Gleason group 7 vs Age Hormones Follow-up interval Cox proportional hazards regression. Fig. 5. Actuarial analysis of cause-specific survival stratified by risk groups. 5 years (chi-square/logistical regression) and multivariate analyses (Cox proportional hazards regression) for the entire cohort were performed. Risk group, stage, pretreatment PSA, and Gleason score were significant in predicting failure. However, age (p 0.332), follow-up interval (p 0.244), and the use of hormones (p 0.123) did not. These data are detailed in Table 4. DISCUSSION Radical prostatectomy is one standard local therapy modality for CaP. Radical prostatectomy may lead to cure as long as the cancer is confined to the prostate and all malignant cells are removed. Neoadjuvant hormone therapy (NHT) is one option being used to increase the likelihood of cure after radical prostatectomy. Fair and Betancourt (21) reported the results of radical prostatectomy at Memorial Sloan-Kettering Cancer Center in 520 patients with clinically localized CaP who received preoperative NHT for 3 to 11 (or more) months. The results in the NHT patients were compared with those in 1413 men having surgery without NHT at the same institution during the same time period. The overall DFS rate was defined according to serum PSA concentration 0.2 ng/ml, and it was 75% at 5 years and 50% at 10 years. NHT did not improve DFS. The presence of positive surgical margins was a negative prognostic factor (p 0.001). Men who received NHT had a statistically lower positive margin rate (p 0.001). However, NHT did not increase the likelihood of a durable DFS (p 0.175). The duration of NHT did not affect DFS (p for 3 vs. 3 months). The authors concluded that there appeared to be no subset of men undergoing radical prostatectomy in which the routine administration of NHT is beneficial. A Fig. 6. (a) Actuarial analysis of BC for patients with only one of the following factors: Stage T2b, PSA 20, or Gleason score 8(n 265). (b) Actuarial analysis of BC for patients with any two of the following factors: Stage T2b, PSA 20, or Gleason score 8(n 123).

6 Long-term outcome using HDR brachytherapy for localized prostate cancer R. M. GALALAE et al Table 5. Literature comparison by risk factors groups Author All Biochemical control at 5 years Group I Group II Group III Zelefsky et al. (25) % 65% 35% Current study % 87% 69% decrease in the number of positive surgical margins was found also by other authors in clinically staged T1 and T2 prostate cancer patients receiving NHT before surgery (22), with a further decrease in those receiving treatment over longer periods of time (3 vs. 8 months; the positive margin rates were 17% and 5%, p 0.01) (23). In ct3 prostate cancer patients equivocal results have been obtained (22). However, none of the studies reported a positive impact of neoadjuvant hormonal ablative treatment before radical prostatectomy on survival. The positive effect on surgical margins by NHT did not translate into improved survival outcomes. Radiotherapy is another potentially curative treatment modality for localized CaP. Many studies have clearly shown that total radiotherapy dose is a strong predictor of outcome, using three-dimensional conformal radiotherapy (3D-CRT) (24, 25), intensity-modulated radiotherapy (26, 27), or conformal brachytherapy (3). Zelefsky et al. (25) reported a significantly improved PSA relapse-free survival in patients with intermediate and unfavorable prognosis receiving 75.6 Gy (p 0.05). The 5-year actuarial biochemical control rate for patients with favorable prognostic indicators (stage T1 2, pretreatment PSA 10.0 ng/ml, and Gleason score 6) was 85%, compared with 65% for those with intermediate prognosis (one of the prognostic indicators with a higher value) and 35% for the group with unfavorable prognosis (two or more indicators with higher values) (p 0.001). However, no dose response was observed for patients with pretreatment PSA 10 ng/ml (24). Compared with the outcome after 3D-CRT, our results in terms of biochemical control in 434 hormone-naïve patients were excellent (for Risk Group I patients it was 96%, for Group II 87%, and for Group III patients 69%). This literature comparison is detailed in Table 5. Adjuvant ADT has been used to increase the likelihood of cure as adjunct to radiotherapy also. Three large prospective Phase III trials addressed the potential advantage of adjuvant ADT in addition to standard radiotherapy in year The Radiation Therapy Oncology Group (RTOG) trial tested from 1987 to 1991 the hypothesis whether androgen ablation before and during conventional radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival. The study randomized 226 patients to receive a short course of androgen ablation administered before and during radiotherapy, or 230 patients to receive radiation therapy alone. RTOG trial evaluated the potential benefit of long-term adjuvant androgen suppression following standard radiation therapy for unfavorable-prognosis carcinoma of the prostate in 945 men from 1987 to In both trials, the radiotherapy total dose was 65 to 70 Gy. In 2001, Horwitz et al. reported the updated pooled results of the RTOG and trials (28). Based on this analysis, adjuvant long-term hormones compared with short-term hormones and by today s standards, suboptimal radiotherapy resulted in statistically significant improvements in biochemical control, distant metastases failure, and cause-specific failure rates for patients with locally advanced nonmetastatic prostate cancer. However, a benefit in overall survival could not be detected at 8 years with rates of 50%, 51%, and 44%, respectively (p 0.2). Both studies have also clearly shown that conventional definitive radiotherapy alone cannot be considered an effective curative modality in men with locally advanced CaP. The 8-year biochemical control rate was only 14%. This could be improved by short-term hormones to 27% and by long-term hormones to 52% (p ). The comparison with our excellent results of 69% biochemical control in Group III patients with unfavorable prognosis highlights the low probability of conventional radiotherapy to cure locally advanced prostate cancer and the necessity to use modern techniques with capabilities for dose escalation. The third prospective trial addressing this specific question, the European Organization for Research and Treatment of Cancer trial 22863, included from 1987 to patients with locally advanced prostate cancer. They were randomly assigned to receive conventional radiotherapy alone or radiotherapy plus immediate treatment with goserelin a luteinizing hormone releasing hormone analog for 3 years (29). Long-term adjuvant treatment with goserelin improved local control (p 0.001) and overall survival (p 0.001). Taking into account all three randomized Phase III trials, the results suggest that androgen suppression before and during standard conventional radiation according to (technique and doses) improves disease-free survival; and administration of long-term hormones during and after conventional radiation improves overall survival. Whether this is true for adjuvant ADT as an adjunct to dose-escalated radiotherapy using modern state-of-the-art irradiation techniques is not known. The RTOG study determined the effect on toxicity by the addition of induction hormonal therapy (HT) to 3D-CRT in 547 men treated at dose level I (68.4 Gy), level II (73.8 Gy), or level III (79.2 Gy) (30). Induction HT did not have an independent effect on the risk of side effects after 3D-CRT. However, induction HT combined with 3D-CRT significantly increased the risk of acute genitourinary effects compared with 3D-CRT alone in men with poor baseline urinary function. Longterm effects of induction HT on survival from this study are not published yet. Further randomized Phase III trials specifically addressing this question have not been published. Velasco et al. reported the data of 105 patients with locally advanced prostate cancer who had received radiotherapy in two dose-escalation studies (31). The total dose ranged from

7 1054 I. J. Radiation Oncology Biology Physics Volume 58, Number 4, to 87 Gy in 2 Gy per fraction. Sixty-seven of those patients received additionally neoadjuvant hormonal therapy. The median duration of the treatment was 4 months. However, the patients were not randomized. The post-radiation PSA nadir was shown to be a predictor of outcome. After radiation, the actuarial 3-year bned rate for patients achieving a PSA nadir value less than 1 ng/ml was 63% vs. 22% for those with a nadir of 1 ng/ml or greater (p 0.001). Neoadjuvant hormonal therapy allowed patients to achieve the nadir after radiation more quickly (p ) and to a lower value (p ). However, there was no impact on the bned results. The 3-year actuarial bned rate for patients receiving neoadjuvant hormonal therapy was not different from those who did not receive hormonal therapy (p 0.3). Their preliminary findings support our results of failing to detect an effect of short-term neoadjuvant/concurrent ADT with dose-escalated radiotherapy on survival. Our results are the first published addressing this question and reporting long-term outcome. However, we recognize the limitations of our study, which did not randomize ADT and no ADT treatment. Whether long-term hormonal exposure provides a survival benefit to patients when both precise and very high biologic doses are delivered, such as is the case with HDR prostate brachytherapy, is not known. There are no data published addressing this question at the present time. So far, there is no evidence of survival benefit of neoadjuvant/concurrent ADT as adjunct to dose-escalated radiotherapy. Timing and sequence of neoadjuvant androgen suppression and radiation might be important, with radiation being most effective if given at the point of maximal tumor regression (32). However, many murine adenocarcinomas respond to androgen deprivation by a reduction in the proliferation rate and arrest in cell cycle phase G(0), and in vitro data suggest that this arrest may interfere with radiation-induced cell killing (32). Furthermore, the effect on cell killing after EBRT (2 Gy per fraction) is different than for hypofractionated HDR brachytherapy, giving HDR a clear advantage (16). Clinical trials seem to support a positive interaction of androgen deprivation with conventional EBRT only. However, from today s perspective it has been also long established that conventional/standard EBRT characterized by old techniques and suboptimal doses represents an insufficient therapy and should be replaced by modern techniques and strategies with the ability to deliver much higher doses of radiation. It cannot be assumed that the same advantage of adjuvant androgen deprivation will hold with dose-escalated radiotherapy, e.g., by HDR brachytherapy or high-dose 3D-CRT. In the meantime, patients must be informed of the advantages and disadvantages of adjuvant hormonal treatment to allow them to make informed treatment decisions. CONCLUSION Pelvic EBRT with conformal HDR boost produced excellent long-term outcomes in terms of BC, DFS, and CSS in patients with prostate cancer, even for patients in Group III with a biochemical control rate of 69%, which represents the best result ever published for this unfavorable-prognosis group of patients. Conformal HDR prostate brachytherapy is a precise dose delivery system and a very effective treatment for both favorable and unfavorable prostate cancer. The results were similar at all three institutions, giving credence to the reproducibility of the brachytherapy treatment. The presented data suggest that when the prostate is treated to a significantly higher BED, compared with conventional EBRT, the addition of a short course 6 months of neoadjuvant/concurrent ADT appears to be unnecessary. REFERENCES 1. Jemal A, Thomas A, Murray T, et al. Cancer statistics, CA Cancer J Clin 2002;52: Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: Early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53: Martinez AA, Gustafson G, Gonzalez J, et al. Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer. Int J Radiat Oncol Biol Phys 2002;53: Galalae R, Kovács G, Schultze J, et al. Long-term outcome following high dose rate brachytherapy and external-beam radiotherapy in men with advanced local prostate cancer: Does elective irradiation of the pelvic lymphatics compromise the feasibility of local dose escalation? Int J Radiat Oncol Biol Phys 2002;52: Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading 192Iridium prostate brachytherapy: Feasibility report. Int J Radiat Oncol Biol Phys 1998;41: Grado GL, Larson TR, Balch CS, et al. Actuarial diseasefree survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance. Int J Radiat Oncol Biol Phys 1998;42: Blasko JC, Mate T, Sylvester JE, Grimm PD, Cavanagh W. Brachytherapy for carcinoma of the prostate: Techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 2002;12: Blasko JC, Grimm PD, Sylvester JE, Cavanagh W. The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma. Radiother Oncol 2000;57: Hanks GE, Hanlon AL, Pinover WH, et al. Survival advantage for prostate cancer patients treated with high-dose three-dimensional conformal radiotherapy. Cancer J Sci Am 1999;5: Horwitz EM, Hanlon AL, Pinover WH, et al. Defining the optimal radiation dose with three-dimensional conformal radiation therapy for patients with nonmetastatic prostate carcinoma by using recursive partitioning techniques. Cancer 2001;92: Lawton CA, Winter K, Murray K, et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable progno-

8 Long-term outcome using HDR brachytherapy for localized prostate cancer R. M. GALALAE et al sis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;49: Union International Contre le Cancer (UICC). Illustrated guide to TNM/pTNM classification of malignant tumors. 3rd ed., 2nd rev. Spiessl B, Bears OH, Hermanek P, et al., editors. New York: Springer; Chassagne D, Dutreix A, Ash D, et al. ICRU Report No 58: Dose and volume specification for reporting interstitial therapy. Washington, DC: International Commission on Radiation Units and Measurements; McNeal JE. Zonal anatomy of the prostate. Prostate 1981;2: Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50: Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52: Stromberg J, Martinez A, Gonzalez J, et al. Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: Treatment description and preliminary results of a dose escalating clinical trial. Int J Radiat Oncol Biol Phys 1995;33: Bertermann H, Brix F. Ultrasonically guided interstitial high dose brachytherapy with iridium 192: Technique and preliminary results in locally confined prostate cancer. In: Martinez A, Orton C, Mould RF, editors. Brachytherapy HDR and LDR. Columbia, MD: Nucletron Corp.; p Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: Cox DR. Regression models and life table. J Royal Stat Soc 1971;34: Fair WR, Betancourt JE. Update on Memorial Sloan-Kettering Cancer Center studies of neoadjuvant hormonal therapy for prostate cancer. Mol Urol 2000;4: Schulman CC, Debruyne FM, Forster G, et al. 4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in T2-3N0M0 prostate cancer. European Study Group on Neoadjuvant Treatment of Prostate Cancer. Europ Urol 2000; 38: Klotz L, Gleave M, Goldenberg SL. Neoadjuvant hormone therapy: The Canadian trials. Mol Urol 2000;4: Hanks GE, Hanlon AL, Schultheiss TE, et al. Dose escalation with 3-D conformal treatment: Five-year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 1998;41: Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41: Martinez AA, Yan D, Lockman D, et al. Improvement in dose escalation using the process of adaptive radiotherapy combined with three-dimensional conformal or intensity-modulated beams for prostate cancer. Int J Radiat Oncol Biol Phys 2001;50: Kupelian PA, Reddy CA, Carlson TP, et al. Preliminary observations on biochemical relapse-free survival rates after short-course intensity-modulated radiotherapy (70 Gy at 2.5 Gy/fraction) for localized prostate cancer. Int J Radiat Oncol Biol Phys 2002;53: Horwitz EM, Winter K, Hanks GE, et al. Subset analysis of RTOG and indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys 2001;49: Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337: Valicenti RK, Winter K, Cox JD, et al. The effect on toxicity of induction hormonal therapy in prostate cancer patients receiving dose escalated 3D conformal radiation therapy on RTOG Int J Radiat Oncol Biol Phys 2002;54(Suppl. 2): Velasco J, Tekyi-Mensah S, Bolton S, et al. Postneoadjuvant hormone PSA levels and prognosis in locally advanced prostate cancer. Urology 1999;54: Zietman AL. The case for neoadjuvant androgen suppression before radiation therapy. Mol Urol 2000;4: