J Clin Oncol 26: by American Society of Clinical Oncology INTRODUCTION

Transcription

1 VOLUME 26 NUMBER 4 FEBRUARY 1 28 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Short-Term Neoadjuvant Androgen Deprivation Therapy and External-Beam Radiotherapy for Locally Advanced Prostate Cancer: Long-Term Results of RTOG 861 Mack Roach III, Kyounghwa Bae, Joycelyn Speight, Harvey B. Wolkov, Phillip Rubin, R. Jeffrey Lee, Colleen Lawton, Richard Valicenti, David Grignon, and Miljenko V. Pilepich From the Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco; Radiation Oncology Center, Sutter Cancer Center, Sacramento; Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA; University of Rochester, Medical Center, Rochester, NY; Latter-Day Saints Hospital Radiation Center, Salt Lake City, UT; Medical College of Wisconsin Department of Radiation Oncology, Milwaukee, WI; Radiation Therapy Oncology Group Department of Statistics; and Department of Radiation Oncology, Thomas Jefferson University Hospital, Bodine Cancer Center, Philadelphia, PA; and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN. Submitted August 14, 27; accepted October 26, 27; published online ahead of print at on January 2, 28. Supported by Grants No. Radiation Therapy Oncology Group U1 CA21661, CCOP U1 CA37422, and Stat U1 CA32115 from the National Cancer Institute. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Mack Roach III, MD, University of California San Francisco, 16 Divisadero St, Suite H131, San Francisco, CA ; mroach@radonc.ucsf.edu. 28 by American Society of Clinical Oncology X/8/ /$2. DOI: 1.12/JCO A B S T R A C T Purpose Radiation Therapy Oncology Group (RTOG) 861 was the first phase III randomized trial to evaluate neoadjuvant androgen deprivation therapy (ADT) in combination with external-beam radiotherapy (EBRT) in men with locally advanced prostate cancer. This report summarizes long-term followup results. Materials and Methods Between 1987 and 1991, 456 assessable patients (median age, 7 years) were enrolled. Eligible patients had bulky (5 5 cm) tumors (T2-4) with or without pelvic lymph node involvement according to the 1988 American Joint Committee on Cancer TNM staging system. Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks and flutamide mg tid for 2 months before and concurrent with EBRT, or they received EBRT alone. Study end points included overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), diseasefree survival (DFS), and biochemical failure (BF). Results Ten-year OS estimates (43% v 34%) and median survival times (8.7 v 7.3 years) favored ADT and EBRT, respectively; however, these differences did not reach statistical significance (P.12). There was a statistically significant improvement in 1-year DSM (23% v 36%; P.1), DM (35% v 47%; P.6), DFS (11% v 3%; P.1), and BF (65% v 8%; P.1) with the addition of ADT, but no differences were observed in the risk of fatal cardiac events. Conclusion The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events. J Clin Oncol 26: by American Society of Clinical Oncology INTRODUCTION All major, prospective, randomized trials that have been completed to date suggest that long-term ( 2 years) adjuvant androgen deprivation therapy (ADT) improves survival in patients with locally advanced, high-risk prostate cancer that is managed with external-beam radiotherapy (EBRT). 1,4 These patients typically had high clinical T stages (T2c-3); high Gleason scores (7 to 1); high prostate-specific antigen (PSA) values ( 2 ng/ml); and, in some cases, positive lymph nodes. Unfortunately, long-term ADT is associated with increased morbidity, such as an increased risk of osteoporosis, depression, development of a metabolic syndrome associated with diabetes, an unfavorable lipid profile, and increased abdominal obesity. 5,6 The value of short-term ADT in patients with intermediate-risk disease has also been established; however, the role of short-term ADT in patients with high-risk disease is more controversial. 3,7,8 Radiation Therapy Oncology Group (RTOG) 861 was the first major, phase III randomized trial to test the hypothesis that short-term neoadjuvant ADT combined with EBRT would improve treatment outcomes compared with EBRT alone. 9 With relatively short follow-up, the addition of ADT was associated with an improvement in local control, a reduction in distant metastases, and cause-specific mortality. Herein, we update the long-term results of RTOG 861 and confirm the important clinical 585

2 Roach et al benefits of adding short-term ADT to EBRT in patients with high-risk, locally advanced disease. PATIENTS AND METHODS This trial included 456 assessable patients and was conducted from April 15, 1987, to June 1, The analysis was performed on eligible and assessable patients as of July 17, 26. Eligible patients were those with bulky (defined as 5 5 cm) tumors (T2-4) according to the 1988 American Joint Committee on Cancer TNM staging system. Patients were eligible with or without pelvic lymph node involvement and were randomly assigned to receive combined ADT consisting of goserelin 3.6 mg every 4 weeks and flutamide mg tid for 2 months before EBRT (neoadjuvant) and concurrent with EBRT or to receive EBRT alone. Study End Points Overall survival. Failure is defined as death as a result of any cause. Survival time is measured from the date of random assignment to the date of death or last follow-up. Disease-specific mortality. Failure is defined as death as a result of prostate cancer or treatment-related complications. The time to disease-specific mortality is measured from the date of random assignment to the date of treatment-related death or to the date of the most recent follow-up. Distant metastasis. Failure is defined as disease beyond the pelvis by any method of evaluation. The time to distant metastasis is measured from the date of random assignment to the occurrence of an event or to the date of the most recent follow-up if no event occurred. Biochemical failure. Failure is defined as a PSA level greater than 2 ng/ml at 1 year from the date of random assignment. The time to biochemical failure is measured from the date of random assignment to the event date or to the date of the most recent follow-up if no event occurred. 1 Local progression. Failure is defined as an increase of more than % in tumor size (cross-sectional area), a recurrence of a palpable tumor after initial clearance, a biopsy specimen that reveals adenocarcinoma of the prostate at 2 years after study entry, or a tumor that never cleared. The time to local progression is measured from the date of random assignment to the occurrence of an event or to the date of the most recent follow-up if no event occurred. Disease-free survival. Failure is defined as death as a result of any cause, local progression, regional metastasis, biochemical failure, salvage hormone therapy, or distant metastasis. The time to disease-free survival is measured from the date of random assignment to the earliest event or to the date of most recent follow-up if no event occurred. Fatal cardiac events. Failure is defined as death recorded in the medical records as myocardial infarction (MI) with or without secondary codes, coronary, probable MI, congestive heart failure (CHF), cardiac arrest, heart attack, acute MI, cardiac, arteriosclerotic cardiovascular disease, and cardiopulmonary arrest. Statistical Methods The Kaplan-Meier method was used to estimate the rates of overall survival (OS) and disease-free survival (DFS). 11 The log-rank test was used to test the significance between the two treatment arms for these two end points. 12,13 The cumulative incidence approach was used to estimate the rates for diseasespecific mortality (DSM), local progression (LP), distant metastasis (DM), Assessed for eligibility (N = 471) Enrollment Excluded (n = 15) Not meeting inclusion criteria (n = 12) Other reasons: no follow-up data (n = 3) Randomly assigned (n = 456) Goserelin acetate (3.6 mg) monthly 4, starting 2 months prior to radiation and flutamide ( mg) po TID + radiation therapy (n = 224) Received allocated intervention (n = 221) Did not receive allocated intervention (n = 3): patients refused hormonal therapy Allocation Allocated to: radiotherapy alone (44-46 Gy, Gy/day to regional lymphatics followed by 2- Gy, Gy/day to a total of 65-7 Gy to the prostate), (n = 232) Received allocated intervention (n = 232) Did not receive allocated intervention (n = ) Fig 1. Consort diagram. po, orally; TID, three times per day; RT, radiotherapy. Lost to follow-up (n = 2) No RT toxicity data: (n = 4) Follow-Up Lost to follow-up (n = 1) No RT toxicity data: (n = 4) Analyzed (n = 224) Excluded from analysis (n = 11): No tumor size data (n = 2) Tumor < cm 2 (n = 4) Common iliac nodes positive (n = 1) Institution submitted no follow-up data (n = 2) Metastasis at time of registration (n = 1) Lung primary at registration (n = 1) Analysis Analyzed (n = 232) Excluded from analysis (n = 4): Prior RT (n = 1) No follow-up information (n = 1) Benign prostate (n = 1) Tumor < cm 2 (n = 1) 586 JOURNAL OF CLINICAL ONCOLOGY

3 Short-Term Neoadjuvant ADT and EBRT for High-Risk Prostate Cancer biochemical failure (BF), and fatal cardiac events and to consider competing risks. Competing risks for disease-specific mortality were death not as a result of prostate cancer and death not as a result of treatment complications. The competing risk for LP, DM, BF, and fatal cardiac events was death without failure events. Gray s test 14 was used to test the significance between the two treatment arms for these four end points and to consider competing risks. A two-sided test was used at a significance level of.5 for testing. The Cox proportional hazards model was used to assess the effects of covariates on OS and DFS. Fine and Gray s regression model 15 was used for the other outcomes (LP, DM, CSM, and BF) to assess the effects of covariates on each outcome in the presence of competing risks. RESULTS Alive (%) Total Dead MST ADT and EBRT EBRT alone The trial was powered to detect an absolute 15% improvement in OS, from % to 65%, at 5 years. A total of 471 patients were accrued during the trial period. Table 1 lists pretreatment characteristics for the 456 eligible patients. Pretreatment PSA values were available for 131 patients (29%), and the median PSA value for these patients was 26.3 ng/ml. There was a good balance between treatment arms with respect to the stratification factors and other characteristics. OS, DSM, and time to distant metastases curves are shown in Figures 2, 3, and 4, respectively. The median follow-up times for all living patients in this trial were 11.9 and 13.2 years for the ADT-EBRT arm and the EBRT-alone arm, respectively. Treatment comparisons with respect to these end points are listed in Tables 2 and 3 as 1-year Characteristic Table 1. Pretreatment Characteristics ADT and EBRT (n 224) Treatment EBRT Alone (n 232) No. % No. % Age,years Median 7 71 Range PSA No Median Range Karnofsky PS Institutional Gleason Missing Central Gleason Missing 9 17 Group stage B C Abbreviations: ADT, androgen deprivation therapy; EBRT, external-beam radiotherapy; PSA, prostate-specific antigen; PS, performance status. ADT and EBRT EBRT alone Fig 2. Overall survival. Failure is defined as death resulting from any cause. Survival time is measured from the date of random assignment to the date of death or last follow-up. ADT, androgen deprivation therapy; MST, median survival time; EBRT, external-beam radiotherapy. estimates that used a 95% CI. The estimated 1-year OS (primary end point) rates were 42.6% (95% CI, 35.9 to 49.3) and 33.8% (95% CI, 27.5 to 4.1) for the ADT-EBRT arm and the EBRT-alone arm, respectively (P.12). The estimated 1-year DSM rates were 23.3% (95% CI, 17.6 to 29.1) and 35.6% (95% CI, 29.2 to 42.) for the ADT-EBRT arm and the EBRT-alone arm, respectively (P.1). The estimated DM failure rates at 1 years were 34.9% (95% CI, 28.5 to 41.3) and 46.9% (95% CI, 4.3 to 53.5) for the ADT-EBRT arm and the EBRTalone arm, respectively (P.6). The estimated BF rates at 1 years were 65.1% (95% CI, 58.6 to 71.6) and 8.% (95% CI, 74.7 to 85.4) for the ADT-EBRT arm and the EBRT-alone arm, respectively Failed (%) Total Fail ADT and EBRT EBRT alone ADT and EBRT EBRT alone Fig 3. Disease-specific mortality. Failure is defined as death resulting from prostate cancer. Time to a disease-specific mortality is measured from the date of random assignment to the date of death or to the date of the most recent follow-up. ADT, androgen deprivation therapy; EBRT, external-beam radiotherapy

4 Roach et al Failed (%) Total Fail ADT and EBRT EBRT alone ADT and EBRT EBRT alone Fig 4. Time to distant metastasis. Failure is defined as disease beyond the pelvis by any method of evaluation. Time to distant metastasis is measured from the date of random assignment to the occurrence of an event or to the date of the most recent follow-up if no event occurred. ADT, androgen deprivation therapy; EBRT, external-beam radiotherapy. (P.1). The estimated DFS rates at 1 years were 11.2% (95% CI, 7. to 15.6) and 3.4% (95% CI, 1. to 5.8) for the ADT-EBRT arm and the EBRT-alone arm, respectively (P.1). There was no significant difference in 1-year local progression rate between the two arms (P.18). Multivariate analysis revealed that age and stage were correlated with OS, whereas the use of ADT was the only predictor of DSM, DM, BF, and DFS (P.1, P.1, P.1, and P.1, respectively; Table 3). Toxicities, Cardiac Events, and Compliance Nearly 4% of the patients in each arm have reported grade 3 EBRT toxicity. Acute grade 3 toxicities were reported in 2% and 4% of the patients in the ADT-EBRT arm and the EBRT-alone arm, respectively. Grade 4 late toxicities were reported in 1% and 3% of patients in these arms, respectively, whereas grade 3 late toxicities were reported in 8% of the patients in both arms. All radiotherapy treatment plans were reviewed by the study chair; 96% of the patient cases in the ADT-EBRT arm and 97% of the patient cases in the EBRT-alone arm were judged as having been administered per protocol or with acceptable variation. Ninety-nine percent of the patient cases were reviewed for ADT delivery. A study chair review showed that 95% of the patient cases in the ADT-EBRT arm were judged as having been administered per protocol or with acceptable variation. The frequency of fatal cardiac events is listed in Table 4. At 1 years, fatal cardiac events were reported to have occurred in 12.5% (95% CI, 8. to 17.) of patients treated with ADT and EBRT compared with 9.1% (95% CI, 5.3 to 13.) in patients treated with EBRT alone (P.32). Figure 5 demonstrates that there was no evidence that fatal cardiac events occurred earlier or more frequently in patients who received ADT. In summary, the ADT-EBRT arm had a statistically significantly improvement in 1-year DSM (P.1), DM (P.6), DFS (P.1), and BF (P.1) compared with the EBRTalone arm. Perhaps the most dramatic clinically meaningful end point was the impact of ADT on the risk of distant failure. For example, by 5 years post-therapy, approximately 4% of men treated with EBRT alone had developed bone metastases. Conversely, it took 13 years for 4% of men treated with ADT and EBRT to be diagnosed with bone metastases. The addition of just 4 months of neoadjuvant ADT before EBRT was associated with a 26% relative improvement in the 1-year, disease-specific survival rate and with an increase of 1.4 years in the median survival time. The failure to demonstrate a statistically significant impact on OS is most likely because of the sample size and competing causes of death in this elderly population of patients. DISCUSSION These updated findings of RTOG 861 suggest that patients with high-risk, locally advanced disease who decline or who, for medical reasons, are not considered candidates for long-term ADT should be offered short-term neoadjuvant and concurrent ADT in combination with EBRT. The biologic rationale for using ADT with EBRT includes a reduction in the tumor volume and enhanced biologic effects. 16,17 Experimental data suggest that it is best to administer ADT until the tumor activity is maximally suppressed before the delivery of EBRT. Outcome Table 2. Univariate Cox Proportional Hazards Models Univariate Analysis Comparison Hazard Ratio* 95% CI Overall survival ADT and EBRT v EBRT alone RL to Disease-specific mortality ADT and EBRT v EBRT alone RL to Distant metastases ADT and EBRT v EBRT alone RL to Biochemical failure ADT and EBRT v RT alone RL to Local progression ADT and EBRT v EBRT alone RL to Fatal cardiac events ADT and EBRT v EBRT alone RL to Disease-free survival ADT and EBRT v EBRT alone RL to Abbreviations: ADT, androgen deprivation therapy; EBRT, external-beam radiotherapy; RL, reference list. *Hazard ratio quantifies how much more or less risk patients at some level have than those at the reference level. A confidence interval that includes 1 that indicates no difference exists between the subgroups. P from 2 test using the Cox proportional hazards model. P from 2 test using Fine and Gray s model. P 588 JOURNAL OF CLINICAL ONCOLOGY

5 Short-Term Neoadjuvant ADT and EBRT for High-Risk Prostate Cancer Outcome Table 3. Multivariate Analysis* Multivariate Analysis Comparison Hazard Ratio* 95% CI Overall survival ADT and EBRT v EBRT alone RL to Disease-specific mortality ADT and EBRT v EBRT alone RL to Distant metastases ADT and EBRT v EBRT alone RL to Biochemical failure ADT and EBRT v EBRT alone RL to Local progression ADT and EBRT v EBRT alone RL to Disease-free survival ADT and EBRT v EBRT alone RL to Abbreviations: ADT, androgen deprivation therapy; EBRT, external-beam radiotherapy; RL, reference list. *Adjusted for age ( 7 years v 7 years), Karnofsky performance status (9- v 6-8), central Gleason (3-6 v 7-1), stage (B2 v C), and central differentiation (well v moderate v poor). P from 2 test using the Cox proportional hazards model. P from 2 test using Fine and Gray s model. P These long-term results of RTOG 861 demonstrate that, as in the animal model, there is a potent interaction between EBRT and ADT that can delay the time to development of metastatic disease by up to 8 years compared with EBRT alone. The patients treated on RTOG 861 had bulkier disease and higher PSA levels than those treated on RTOG 922, and RTOG 861 included some patients who were known to have positive lymph nodes. 3 Because the follow-up to RTOG 922 is shorter and the patients have more favorable forms of disease, a comparison of these studies is problematic. It is likely, however, that at least some subsets of the patients may have lived longer had they been treated with long-term ADT. Of note, prospective trials that incorporated neoadjuvant ADT before radical prostatectomy demonstrated a reduction in the incidence of extracapsular extension and positive surgical margins but failed to demonstrate an improvement in BF or OS These findings and those of other trials highlight the unique nature of the interactions between short-term neoadjuvant ADT and EBRT. 21 The clinical significance of these findings is profound. Shortterm ADT is relatively inexpensive, well tolerated, and readily available. The delayed the time for 4% of patients to develop metastasis by approximately 293 days (8 years) with the addition of just 4 months of neoadjuvant ADT with EBRT is remarkable. In contrast, zoledronic acid received Food and Drug Administration approval for delaying skeletal-related events by a mere 41 days. 22 It is likely that a substantial number of men may have avoided the need for this agent if the time to metastasis was delayed by the earlier use of ADT in combination with EBRT. Similarly, docetaxel was approved for treatment of metastatic hormone-refractory disease on the basis of a 2-month improvement in survival with prostate cancer. 23 In contrast, approximately one third of patients treated with EBRT alone had died as a result of prostate cancer by 9 years, but it took an additional 9 years for one third of patients to die as a result of prostate cancer when ADT was added to EBRT. The biologic mechanism by which 4 months of ADT could have such a profound effect remains unknown. It could be that 4 months of ADT results in long-term or permanent castration in such an elderly population of men (median age, 7 years). Pickles et al 24 studied this question in a cohort of men with a similar median age who received ADT for 3 to 34 months (median, 9 months). They noted that nearly 8% of patients who received monthly injections of luteinizing hormone-releasing hormone had recovered testicular function within 12 months. Failed (%) Total Fail ADT and EBRT EBRT alone Outcome Table 4. Fatal Cardiac Events ADT and EBRT Treatment EBRT Alone No. % No. % Total No. of patients Alive Death related to cardiovascular event Death not related to cardiovascular event Abbreviations: ADT, androgen deprivation therapy; EBRT, externalbeam radiotherapy. ADT and EBRT EBRT alone Fig 5. Time to fatal cardiac events. Failure is defined as death resulting from myocardial infarction (MI) with or without secondary codes, from coronary cause, from probable MI, from congestive heart failure, from cardiac arrest, from heart attack, from acute MI, from cardiac cause, from arteriosclerotic cardiovascular disease, and from cardiopulmonary arrest. Time to fatal cardiac events is measured from the date of random assignment to the occurrence of an event or to the date of the most recent follow-up if no event occurred. ADT, androgen deprivation therapy; EBRT, external-beam radiotherapy

6 Roach et al Recent studies have raised questions about the safety of ADT. 6, Although most of the data relevant to risk factors associated with fatal cardiac events grows out of the literature that addresses long-term use of ADT, at least one recent report raises concerns about ADT administered for as few as 3 months. 6, Methodological problems with this report raise serious questions about the validity of this analysis; furthermore, this updated analysis of RTOG 861 does not support their conclusions (Fig 4). 26 The true incidence of the onset of important metabolic changes that might occur in association with ADT (eg, diabetes, hyperlipidemia, depression) was not an end point of this study and as such cannot be estimated accurately. 5,6 However, the cause of death is a reasonably accurate end point as made on the basis of death certificates from patients with prostate cancer. 27 Thus, cause of death was also included in this analysis. It is possible that there is actually a small but real increase in the risk of fatal MIs associated with the use of short-term ADT that did not reach statistical significance because of the sample size in this study. It is reassuring to note that the absolute 1-year OS was 9% higher (P.12) among the men treated with ADT despite a 3% higher absolute rate of fatal MIs in these men. This data must be interpreted with caution, however, because the benefits of ADT might be reduced if ADT is used in patients with a lower or higher risk of death as a result of prostate cancer. Although several recent, phase III trials have demonstrated that higher radiation doses reduce the risk of BF, none have demonstrated differences as significant as those shown in this trial More importantly, none of these trials have demonstrated an improvement in clinically meaningful end points, such as DSM, or in the time to distant failure. Thus, the preponderance of data supports the use of ADT in combination with EBRT in patients with intermediate- and high-risk prostate cancer. 1-4,7,8 How much higher doses of EBRT will improve outcomes ultimately and the optimal timing and duration of ADT remain to be elucidated. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Mack Roach III, Astra-Zeneca (C) Stock Ownership: None Honoraria: Mack Roach III, TAP; Richard Valicenti, Astra-Zeneca Research Funding: None Expert Testimony: Mack Roach III, Astra-Zeneca (C) Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Miljenko V. Pilepich Collection and assembly of data: Kyounghwa Bae Data analysis and interpretation: Mack Roach III, Kyounghwa Bae, David Grignon Manuscript writing: Mack Roach III, Kyounghwa Bae, Joycelyn Speight, Harvey B. Wolkov, Phillip Rubin, R. Jeffrey Lee, Colleen Lawton, Richard Valicenti, David Grignon, Miljenko V. Pilepich Final approval of manuscript: Mack Roach III, Kyounghwa Bae REFERENCES 1. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group Protocol J Clin Oncol 15: , 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 36:13-16, Hanks GE, Pajak TF, Porter A, et al: Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 922. J Clin Oncol 21: , Granfors T, Modig H, Damber JE, et al: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: A prospective randomized study. J Urol 159:23-234, Shahinian VB, Kuo YF, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352: , Braga-Basaria M, Dobs AS, Muller DC, et al: Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 24: , 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: , Denham JW, Steigler A, Lamb DS, et al: Short-term androgen deprivation and 13 radiotherapy for locally advanced prostate cancer: Results from the Trans-Tasman Radiation Oncology Group 96.1 randomized controlled trial. Lancet Oncol 6:841-8, Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 861 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys : , Roach M III, Hanks G, Thames H, Jr., et al: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 65: , Kaplan EL, Meier P: Nonparameteric estimation from incomplete observations. Journal American Statistical Association 53: , Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep :163-17, Kim K, Tsiatis AA: Study duration for clinical trials with survival response and early stopping rule. Biometrics 46:81-92, Gray R: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16: , Fine J GR: A proportional hazards model for the subdistribution of a competing risk. J Am Statist Assoc 94:496-9, Zelefsky MJ, Harrison A: Neoadjuvant androgen ablation prior to radiotherapy for prostate cancer: Reducing the potential morbidity of therapy. Urology 49:38-45, Zietman AL: The case for neoadjuvant androgen suppression before radiation therapy. Mol Urol 4:23-28, 2; discussion Van Poppel H, Ridder DD, Elgamal AA, et al: Neoadjuvant hormonal therapy before radical prostatectomy decreases the number of positive surgical margins in stage T2 prostate cancer: Interim results of a prospective randomized trial. J Urol 154: , Meng MV, Grossfeld GD, Carroll PR, et al: Neoadjuvant strategies for prostate cancer prior to radical prostatectomy. Semin Urol Oncol 2:1-18, 22 (3 suppl 1) 2. Gleave ME, Goldenberg SL, Chin JL, et al: Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: Biochemical and pathological effects. J Urol 166:-6, 21; discussion Roach M, Valicenti R, Asbell SO, Lawton C, Thomas CR, Shipley W.U.: Whole Pelvic, Mini- Pelvic or Prostate Only External Beam Radiotherapy Field following Neoadjuvant and Concurrent Hormonal Therapy: In Patients Treated on RTOG Int J Rad Bio Phys 66: , Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94: , JOURNAL OF CLINICAL ONCOLOGY

7 Short-Term Neoadjuvant ADT and EBRT for High-Risk Prostate Cancer 23. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351: , Pickles T, Agranovich A, Berthelet E, et al: Testosterone recovery following prolonged adjuvant androgen ablation for prostate carcinoma. Cancer 94: , 22. D Amico AV, Denham JW, Crook J, et al: Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol :242-24, Roach M III: Regarding the influence of adjuvant suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarction: How real is the risk? J Clin Oncol : , Penson DF, Albertsen PC, Nelson PS, et al: Determining cause of death in prostate cancer: Are death certificates valid? J Natl Cancer Inst 93: , Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: Results of the M.D. Anderson phase III randomized trial Int J Radiat Oncol Biol Phys 53: , Zietman AL, DeSilvio M, Slater JD, Rossi CJ, Yonemoto LT, Slater JM, Berkey B, Adams JA, Shipley WU: A randomized trial comparing conventional dose (7.2gye) and high-dose (79.2gye) conformal radiation in early stage adenocarcinoma of the prostate: Results of an interim analysis of PROG 99, in Cox (ed): Proceedings of American Society for Therapeutic Radiology and Oncology. Atlanta, GA, Elsevier, 24, pp S Peeters ST, Heemsbergen WD, Koper PC, et al: Dose-response in radiotherapy for localized prostate cancer: Results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 24: ,