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Journal of Clinical Oncology, Vol 24, No 12 (April 20), 2006: pp. 1868-1876 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.7423 Immediate or Deferred Androgen Deprivation for Patients With Prostate Cancer Not Suitable for Local Treatment With Curative Intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891
From the Department of Urology, University Hospital of Bern; Department of Urology, University Hospital of Zurich, Switzerland; Department of Urology, St James' Hospital, Leeds; Department of Urology, Pinderfields Hospital, Wakefield, United Kingdom; Department of Urology, Rudolfstiftung, Vienna; Department of Urology, Krankenhaus Barmherzige Schwestern, Linz, Austria; Department of Urology, Academisch Medisch Centrum, Amsterdam, the Netherlands; Department of Urology, Hospital Nuestra Senora Del Pino, Las Palmas, Spain; Department of Urology, Damiaan Ziekenhuis, Oostende; European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium; and the European Organisation for Research and Treatment of Cancer Genitourinary Group Address reprint requests to Urs E. Studer, Department of Urology, University Hospital of Bern, 3010 Bern, Switzerland; e-mail: urs.studer{at}insel.ch
PURPOSE: This study (EORTC 30891) attempted to demonstrate equivalent overall survival in patients with localized prostate cancer not suitable for local curative treatment treated with immediate or deferred androgen ablation. PATIENTS AND METHODS: We randomly assigned 985 patients with newly diagnosed prostate cancer T0-4 N0-2 M0 to receive androgen deprivation either immediately (n = 493) or on symptomatic disease progression or occurrence of serious complications (n = 492). RESULTS: Baseline characteristics were well balanced in the two groups. Median age was 73 years (range, 52 to 81). At a median follow-up of 7.8 years, 541 of 985 patients had died, mostly of prostate cancer (n = 193) or cardiovascular disease (n = 185). The overall survival hazard ratio was 1.25 (95% CI, 1.05 to 1.48; noninferiority P > .1) favoring immediate treatment, seemingly due to fewer deaths of nonprostatic cancer causes (P = .06). The time from randomization to progression of hormone refractory disease did not differ significantly, nor did prostate-cancer specific survival. The median time to the start of deferred treatment after study entry was 7 years. In this group 126 patients (25.6%) died without ever needing treatment (44% of the deaths in this arm). CONCLUSION: Immediate androgen deprivation resulted in a modest but statistically significant increase in overall survival but no significant difference in prostate cancer mortality or symptom-free survival. This must be weighed on an individual basis against the adverse effects of life-long androgen deprivation, which may be avoided in a substantial number of patients with a deferred treatment policy.
Since introduction of the serum prostate-specific antigen (PSA) test, the number of newly diagnosed patients with prostate cancer have increased dramatically and exceeds by several fold the number of patients who would die from this disease if left untreated. This not only implies a difficult decision making process for younger men with localized disease who could be treated with curative intent, but also for those patients in whom such treatment is not indicated either because of too far advanced disease, comorbidities, or age. For the latter, androgen deprivation remains the most potent treatment option. This study addressed the question of whether deferred treatment started when the disease becomes symptomatic would result in the same survival rate as treatment started immediately after diagnosis.
Eligible patients had recently (< 105 days) histologically or cytologically confirmed prostate cancer stage T0-4,1 N0-2 assessed by pelvic computed tomography (CT), with a negative bone scan and chest x-ray for metastases (M0) and no previous local or systemic treatment. All patients either refused local definitive treatment or were judged not suitable for it either because of decreased life expectancy, advanced local tumor stage, and/or severe comorbidities. Patients older than 80 years of age, with other malignancies (except adequately treated basal cell carcinoma of the skin), with pain or ureteric obstruction caused by the prostate cancer, or proven iuxtaregional metastatic lymph nodes were ineligible. All patients gave oral consent. In all countries the protocol was approved according to national regulations in use at that time. Dynamic treatment allocation stratified patients according to treating institution, WHO performance status, disease stage, and treatment modality. Treatment consisted of either subcapsular orchiectomy or 2-monthly subcutaneous injections of the luteinizing hormone-releasing hormone analog buserelin 6.3 mg (Suprefact Hoechst, Frankfurt, Germany) combined with an initial 2-week treatment with 50 mg cyproterone acetate tid2,3 Patients were randomly assigned to immediate androgen deprivation or to deferred treatment starting only at the time of symptomatic progression defined as one of the following: new symptomatic metastases or metastases whose location threatened to produce serious complications, such as pathologic fractures or paralysis; increase in pain score due to the prostate cancer by more than or equal to two categories (pain was scored as: 0 = no pain; 1 = non-narcotic analgesia required occasionally; 2 = non-narcotic analgesia required regularly; 3 = narcotic analgesia required occasionally; 4 = narcotic analgesia required regularly); deterioration in WHO performance status by two levels due to prostate cancer; and evidence of ureteric obstruction caused either by the primary tumor or metastases. In the absence of symptoms, deferred treatment was not to be initiated on a rise in serum PSA or alkaline phosphatase, or asymptomatic new hot spots in the bone scan or soft tissue metastases. Rectal palpation, PSA, and alkaline phosphatase measurement were observed at 6-monthly intervals for 2 years and then yearly until death. Chest x-ray, liver ultrasound, pelvic CT, bone scan, and bone x-ray were performed in case of suspected progression. Additional treatment of patients with symptomatic progression of hormone refractory disease after immediate or deferred androgen deprivation was left to the discretion of the treating physician. The primary end point was overall survival from the time of random assignment until death of any cause or date of most recent follow-up. Secondary end points were prostate-cancer and nonprostate-cancer mortality, time from study entry to first symptomatic progression and to first objective progression (documented metastases), time from study entry to symptomatic progression or to objective progression of hormone refractory disease after immediate or deferred androgen deprivation. Symptoms were defined as above. For progression, death without progression was considered a competing risk. Other end points were complications and incidence of bladder outlet obstruction requiring transurethral resection of the prostate (TURP).
Cause of death was determined primarily by the local investigator and reviewed by the study coordinator (U.E.S.). Two independent reviewers not involved in the study evaluated all causes of death based on case records (including PSA data), but they were blinded to the study coordinator's review. There was strong agreement on attributing the cause of death both between the local investigator and the study coordinator and between the study coordinator and the independent reviewers with kappa (
The primary trial objective was to demonstrate equivalent overall survival between the two study arms. The initial design assumed a 5-year survival rate of 55% with immediate treatment. This assumption appeared overly pessimistic and in June 1997, an independent data monitoring committee recommended increasing the sample size to 900 patients to provide 80% power (450 events) to rule out a
Intention-to-treat was the primary analysis. Sensitivity analyses of survival were performed by repeating the analysis in per protocol subsets defined as all eligible patients treated as they were randomly assigned (N = 944); all patients from institutions that entered 10 or more patients (N = 854 patients); all patients with
A total of 1,002 patients entered the study between February 1990 and January 1999. Two centers (17 patients) were excluded for nonavailability of source documentation, leaving 985 patients for analysis (492 on immediate and 493 on deferred treatment). There were 12 and 13 ineligible patients, respectively, in each arm (2.5% of the 985 patients), mostly due to study entry more than 105 days after diagnosis (Fig 1). These patients remained in the analysis. There were no significant differences in the baseline characteristics of patients in the two arms (Table 1). The median follow-up was 7.8 years and 541 deaths (54.9%) were recorded.
Of the 492 patients assigned to immediate androgen deprivation, 475 (96.5%) were treated immediately. Seventeen patients refused treatment and in five of these, treatment was initiated on disease progression. The median time from study entry to treatment initiation for the 493 patients in the deferred treatment arm was 7 years (Fig 2). Eight patients were treated immediately and 245 patients (50.5%) received treatment after a median time of 3.2 years during follow-up. The reason for starting deferred treatment was protocol conform in 136 of 245 patients (ie, symptomatic progression, 55.5%; Table 2). The majority of the patients (73.4%) had no or minimal pain attributable to the prostate cancer and a good or minimally decreased performance status (74.3%). At present, deferred treatment has not been started in 240 (48.7%) patients. Of these, 125 patients died from unrelated causes without evidence of progressive prostate cancer, 80 patients were alive and had not yet required treatment, 15 patients were lost to follow-up, and nine patients refused to continue protocol follow-up. Another eight patients had progressed or died, but refused treatment and three patients were ineligible. Orchiectomy was performed more frequently in the immediate treatment group than in the deferred treatment group (52.1% v 36.8%; P < .0001).
Few patients experienced pain during follow-up. However, pain occurred significantly more often in patients on the deferred treatment arm (P = .0002; Fig 3), mostly just before starting deferred treatment. In both groups, if pain was reported, it was predominantly mild to moderate (Table 3). In the deferred treatment group significantly more patients required a TURP for obstruction (113 v 55 patients; P < .0001; Table 3). In the immediate treatment group, hot flushes, gynecomastia, headache, and skin complaints were significantly more frequent (P < .0001).
At the time of analysis 257 of 492 patients (52.2%) on the immediate and 284 of 493 patients (57.6%) on the deferred treatment arm had died. In both arms the leading causes of death were prostate cancer (35.7%) and cardiovascular diseases (34.2%; Table 4).
The intent-to-treat analysis failed to prove noninferiority for overall survival, with a median of 6.5 years (95% CI, 5.9 to 7.2) on deferred treatment compared with 7.4 years (95%CI, 6.6 to 8.5) on immediate treatment (noninferiority P = .4341), corresponding to a mortality hazard ratio of 1.25 (95% CI, 1.05 to 1.48) that indicates with 95% confidence a + 5% to + 48% increase of the risk of death on the deferred arm (Fig 4A and Table 5). The sensitivity analyses showed similar results, but the difference was slightly less pronounced, HR =1.19 (95% CI, 1.00 to 1.43) in the subset of patients entered by institutions that accrued 10 or more patients (Fig 4B). The survival benefit on immediate treatment also remained significant (HR = 1.29; 95% CI, 1.09 to 1.53) when adjusting for baseline risk factors (age, performance status, voiding symptoms, T-stage, tumor grade, PSA  20 ng/mL, TURP, and associated chronic disease).
The comparison of the cumulative incidence of prostate cancer death, based on only 193 events and thus with limited statistical power, showed no significant difference between the treatment arms (Fig 5A and Table 5, P = .4361): at 5 and 10 years, the difference was + 4.2% (95% CI, + 0.2% to + 8.2%) and + 1.2% (95% CI, –5.9% to + 8.3%), respectively. The sensitivity analyses also showed no significant difference, as did the analysis adjusted for baseline prostate cancer specific prognostic factors (T-stage, grade of tumor, serum PSA > 20 ng/mL, TURP for obstruction, and voiding symptoms).
The analysis of 348 nonprostate cancer deaths showed a borderline significant difference in favor of immediate androgen deprivation (Fig 5B and Table 5, P = .0622). The cumulative incidence of nonprostate cancer related mortality on the deferred arm was in excess of 2.8% at 5 years (95% CI, –2.7 to + 8.3%) and of 9.9% at 10 years (95% CI, 1.6 to 18.2%). The sensitivity analyses showed even more pronounced differences as did the analysis adjusted for the nonprostate cancer specific prognostic factors (age, performance status, and associated chronic disease; P = .0210). In the deferred arm, the absolute number of deaths from prostate cancer and nonprostate cancer tended to be highest between 2 and 5 years after random assignment (Fig 6). However, the numbers were too small to draw a definite conclusion.
The time from random assignment to the first symptomatic progression was significantly longer for patients on the immediate treatment arm (Fig 7A and Table 5) as was the time to the first objective progression (P < .0001; Fig 7B). The time from study entry to first evidence of symptomatic (Fig 8A) or, respectively, objective (Fig 8B) progression of hormone refractory disease after immediate or deferred hormonal treatment was similar (Table 5).
The Veterans Affairs Research Service Cooperative Urological Research Group performed the first controlled trial on immediate versus deferred orchiectomy in patients with advanced prostate cancer and found no difference in survival at 9 years.4,5 In addition, there was no difference in cancer specific mortality in patients with stage III and IV disease. However, too few patients were enrolled to conclude equivalence. The British Medical Research Council subsequently conducted a trial in more than 900 M0/M1 prostate cancer patients. Early results suggested a survival benefit in favor of immediate hormonal treatment for M0 patients that, however, disappeared after longer follow-up.6,7 Recently, a prospective randomized Swiss trial was reported involving 197 patients: 67% with T3-T4 tumors, 20% with lymph node metastases, and 22% with distant metastases at randomization.8 Results showed a trend toward improved prostate cancer specific survival with immediate therapy (P = .09), but the trial was underpowered to conclude equivalence. This study is the first to have a sufficient number of patients to allow equivalence testing between immediate and deferred hormonal treatment. Furthermore, employing the most accurate staging modalities available, it allowed for exclusion of patients with detectable metastatic disease. Several prospective randomized trials comparing external beam radiation therapy combined with concurrent androgen deprivation to radiation therapy alone and androgen deprivation at relapse9-11 showed significantly better survival for patients with concurrent androgen deprivation. Several aspects, however, suggest that the benefit of the combined treatment is most likely due to an improved local control (androgen deprived prostate cancer cells responding better to radiation) rather than to an additive systemic effect on survival.12,13 This was recently supported by D'Amico et al who showed a similar significant improvement of overall survival for patients with concurrent radio-hormonotherapy, although androgens were deprived for only 6 months.14 A statistically significant overall survival advantage for immediate adjuvant hormonal treatment has been documented in the Eastern Cooperative Oncology Group study of 98 prostate cancer patients who had positive lymph nodes removed at the time of radical prostatectomy.15 Similar to our study, the differences in survival are found predominantly in patients who died within 3 to 5 years after random assignment. Unfortunately, the number of patients was small and they did not report either the number of lymph nodes removed or their location. Nevertheless, these data suggest that hormonal therapy might be most effective when only minimal systemic disease is present. On the other hand, Iversen et al demonstrated that the antiandrogen bicalutamide (150 mg per day) significantly decreased the overall survival probability if given at an early stage of the disease or if used as an adjuvant after local treatment with curative intent.16 Whether this is due to toxic adverse effects of this particular antiandrogen or also pertains to other forms of very early endocrine treatment remains to be seen. A major finding of this trial is a statistically significant difference in overall survival favoring immediate androgen deprivation. It remains to be seen whether this difference will persist or even increase with longer follow-up. Indeed, it could be speculated that the actual survivors with a less aggressive prostate cancer might respond better to immediate androgen deprivation. Nevertheless, in the MRC trial the difference disappeared with longer follow-up. The reasons why the significant survival benefit with immediate androgen deprivation was apparently due to fewer nonprostate cancer deaths and not to prostate cancer-related deaths, can only be speculated on. Until now, only 20% of all patients have died of progressive prostate cancer. In patients who are unsuitable for local treatment with curative intent, age and comorbidity play an important role; competing causes of death may mask a possible beneficial treatment effect on prostate cancer. Deferred treatment was started earlier than foreseen by the protocol in 20% of all patients, mostly due to the psychological pressure of a rising PSA or the appearance of new scintigraphic hot spots, thus potentially reducing any possible difference between the two arms. The closer the timing of immediate and deferred treatment, the less likely it becomes that a significant difference in prostate cancer related survival can be demonstrated. Despite the extensive review performed in this trial and the high agreement among reviewers of the causes of death, misclassification cannot be totally excluded as a reason for the apparent absence of a difference in prostate cancer death rates. However, the absence of a difference in the times from study entry to subjective or objective progression from hormone refractory disease after immediate or deferred androgen deprivation speaks against a selection bias in evaluating prostate cancer related mortality. Lack of statistical power is another possible explanation. Finally, it cannot be excluded that androgen ablation itself might have an impact on longevity by resulting in a generally less stressful lifestyle. It may be a shortcoming of this trial that, despite the exclusion of patients with documented metastatic disease, patients with different prostate cancer risk profiles (including well/poorly differentiated and differences in tumor volume) were included. Although immediate treatment at the time of diagnosis appeared to be a well-defined point of time, it varies widely within the individual course of disease. Therefore, it is unlikely that the time when the disease is diagnosed is always the appropriate time to start androgen deprivation. For some patients, it may be too late to achieve a substantial beneficial effect, while many others do not require treatment at all. Indeed, at 7 years, only 49.7% of the patients on the deferred arm had started treatment (even though the majority of them had rather advanced palpable local disease) and another 25% died of other causes before ever requiring treatment. These results suggest that the deferred treatment policy could spare a substantial number of patients the known adverse effects of androgen deprivation (including negative impact on mood and cognitive function, impotence, osteoporosis, gynecomastia, headache, skin complaints). While it must be kept in mind that the number of patients requiring a TURP because of bladder outlet obstruction was significantly higher in the deferred treatment arm, this alone would not justify immediate androgen deprivation for all patients. Also the number of patients experiencing moderate to severe pain, ureteric obstruction, or risk of pathologic fracture caused by the disease at some time during follow-up was higher in the deferred treatment arm. This is inherent to the design of the trial, which allowed the start of androgen deprivation for patients on the deferred treatment arm only on the occurrence of such symptoms or signs. Because patients were followed regularly, progressive disease was detected in time, and the risk of irreversible complications could be kept low. Of importance is that the time to first symptoms from hormone refractory disease after androgen deprivation was comparable for both treatment groups. Additional research is underway to try to define subgroups of patients with prostate cancer that will benefit from early or, once established by ongoing trials, intermittent androgen deprivation and those patients in which this may be unnecessary over-treatment with substantial side effects that could at least be delayed for a long time. Furthermore, small but significant differences in overall survival must be carefully weighted against the possible negative impact on quality of life of lifelong androgen deprivation.17 In conclusion, this study demonstrated that immediate androgen deprivation results in a significant, albeit small improvement in overall survival, but no significant difference in prostate cancer mortality or overall symptom free survival. Additional research is needed to identify possible subgroups of patients at low risk of prostate cancer progression for whom the deferred approach would be a valid treatment option.
The following investigators contributed patients to EORTC trial 30891: P. Whelan, St. James, Leeds, United Kingdom (133); W. Albrecht, Rudolfstiftung, Vienna, Austria (114); J. Casselman, St. Josef, Oostende, Belgium (68); U.E. Studer, University Hospital, Bern, Switzerland (66); Th.M. de Reijke, K.H. Kurth, AMC, Amsterdam, the Netherlands (58); D. Hauri, University Hospital, Zurich, Switzerland (45); W. Loidl, Krankenhaus, Linz, Austria (44); S. Isorna, Hosp. NS del pino, Las Palmas, Spain (42); M. Robinson, S.K. Sundaram, General Infirmary, Pontefract, United Kingdom (42); J Kliment, Comenius University, Martin, Czech Republik (35); P.P.M Karthaus, Onze Lieve Vrouw Gasthuis, Amsterdam, the Netherlands (22); P. van Cangh, Université Catholique de Louvain, Brussels, Belgium (20); R. Casella, Kantonsspital Basel, Switzerland (19); J. Hetherington, Princess Royal Hospital, Hull, United Kingdom (19); G. Studler, Donauspital, Vienna, Austria (19); P. Kil, Sint Elizabethziekenhuis, Tilburg, the Netherlands (18); L. Denis, Middleheim Hospital, Antwerpen, Belgium (17); J. Mattelaer, CAZK Groenhjnge, Kortrijk, Belgium (16); K.E.J. Lantsoght, Lierse Ziekenhuis, Lier, Belgium (16); A. Verbaeys, Universitair Ziekenhuis, Gent, Belgium (16); C.L. Cutajar, Saint Luke's Hospital, Malta (15); L. Domes, Nemocnice Kromeriz, Czech Republik (10); M. Brausi, Ospedale B. Ramazzini, Carpi, Italy (9); F. Calais da Silva, Hospital Do Desterro, Amadora, Portugal (9); F.H. Schröder, Erasmus Medical Center, Rotterdam, the Netherlands (8); D. Jacqmin, Hospices civils de Strasbourg, France (8); L. Boccon-Gibod, Hôpital Bichat Claude Bernard, Paris, France (7); G.A. Dijkman, Amphia Ziekenhuis, Breda, the Netherlands (7); O. Koriakine, Medical Radiological Research Center, Obninsk, Russia (7); W. Höltl, Kaiser Franz Josef Spital, Vienna, Austria (6); A. Borkowski, Warsaw School of Medicine, Warsaw, Poland (6); F. Keuppens, Akademisch Ziekenhuis Vrije University Brussels, Belgium (6); L. Hoekx, Universitair Ziekenhuis Antwerpen, Belgium (6); B. Malavaud, Centre Hospitalier Universitaire de Purpan, Toulouse, France (5); F. Recker, Kantonsspital Aarau, Switzerland (5); D. Mack, Landeskliniken Salzburg, Austria (5); C.G.G. Boeken-Krüger, Zuiderziekenhuis Rotterdam, the Netherlands (5); J.M. Marechal, Hopital Edouard Herriot, Lyon, France (4); A. Akdas, Marmara University Hospital, Istanbul, Turkey (3); F. Debruyne, University Medical Center Nijmegen, the Netherlands (3); C. Sternberg, San Camillo and Forlanini Hospitals, Roma, Italy (3); K. Pummer, Karl-Franzens Universitaet, Graz, Austria (3); G. Keizer, Twee Steeden Ziekenhuis, Leiden, the Netherlands (2); D. Newling, Allgemeine Ziekenhuis Vrije University Amsterdam, the Netherlands (2); G.O.N. Oosterhof, Academisch Ziekenhuis Maastricht, the Netherlands (2); R. Morant, Center for tumor detection and prevention, St. Gallen, Switzerland (2); S.D. Fossa, Radiumhospital, Oslo, Norway (2); D. Hanbury, Lister Hospital, Stevenage, United Kingdom (2); R. van Velthoven, Institut Jules Bordet, Brussels, Belgium (1); H. Bittard, Centre hospitalier regional de Besançon, Besançon, France (1); J. Jager, Radiotherapeutisch Instituut Limburg, Heerlen, the Netherlands (1); H. van Poppel, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium (1).
The authors indicated no potential conflicts of interest.
We are grateful to the independent data monitoring and cause of death review committee members (Philip Smith, Leeds, and Mel Robinson, Pontefract, United Kingdom; Peter Ekman, Stockholm, Sweden; Simon Horenblas, and Ottilia Dalesio, Amsterdam, the Netherlands; Stefan Suciu, Brussels, Beligium) and the participating investigators (see online appendix).
Supported by Grants No. 5U10-CA11488-19 through 5U10 CA11488-35 from the National Cancer Institute, Bethesda, MD. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute. Buserelin was in part supplied free by the Hoechst Company (now Sanofi-Aventis). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Harmer MH: TNM Classifications. Geneva, Switzerland, UICC (Union International Contra Cancer), 1978 2. Klign JG, de Voogt HJ, Schroeder FH, et al: Combined treatment with buserelin and cyproterone in metastatic prostatic carcinoma. Lancet 2:493, 1985[Medline] 3. Thompson IM, Zeidman EJ, Rodriguez FR: Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol 144:1479-1480, 1990[Medline] 4. Arduino LJ, Bailar JC, Becker LE, et al: Carcinoma in the prostate: Treatment comparisons. J Urol 98:516-522, 1967[Medline] 5. Byar DP: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 32:1126-1130, 1973[CrossRef][Medline] 6. The Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: Initial results of the medical research council trial. Br J Urol 79:235-246, 1997[CrossRef][Medline] 7. Kirk D. Immediate vs. deferred hormone treatment for prostate cancer: How safe is androgen deprivation? Br J Urol 86(suppl 3):S220, 2000 8. Studer UE, Hauri D, Hanselmann S, et al: Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: Results of the randomized trial SAKK 08/88. J Clin Oncol 22:4109-4118, 2004 9. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavourable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol 15:1013-1021, 1997 10. 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 337:295-300, 1997 11. 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 360:103-106, 2002[CrossRef][Medline] 12. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243-1252, 2001[CrossRef][Medline] 13. Laverdiere J, Gomez JL, Cusan L, et al: Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys 37:245-246, 1997[Medline] 14. D'Amico AV, Manola J, Loffredo M, et al: 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial. JAMA 292:864-866, 2004 15. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341:1781-1788, 1999 16. Iversen P, Johansson JE, Lodding P, et al: Bicalutamide (150mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median follow up from the Scandinavian Prostate Cancer Group Study Number 6. J Urol 172:1871-1876, 2004[CrossRef][Medline] 17. Salminen EK, Portin RI, Koskinen A, et al: Associations between serum testosterone fall and cognitive function on prostate cancer patients. Clin Cancer Res 10:7575-7582, 2004 Submitted October 28, 2005; accepted February 14, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) values of 0.89 and 0.82 (95% CI, 0.76 to 0.87), respectively. For the few cases with initial discrepancies agreement was obtained at a consensus meeting. 
