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Originally published as JCO Early Release 10.1200/JCO.2007.13.9881 on January 2 2008 © 2008 American Society of Clinical Oncology. Short-Term Neoadjuvant Androgen Deprivation Therapy and External-Beam Radiotherapy for Locally Advanced Prostate Cancer: Long-Term Results of RTOG 8610
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 Corresponding author: Mack Roach III, MD, University of California San Francisco, 1600 Divisadero St, Suite H1031, San Francisco, CA 94143-1708; e-mail: mroach{at}radonc.ucsf.edu
Purpose Radiation Therapy Oncology Group (RTOG) 8610 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 follow-up results. Materials and Methods Between 1987 and 1991, 456 assessable patients (median age, 70 years) were enrolled. Eligible patients had bulky (5 x 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 250 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), disease-free 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 10-year DSM (23% v 36%; P = .01), DM (35% v 47%; P = .006), DFS (11% v 3%; P < .0001), and BF (65% v 80%; P < .0001) 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.
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 10); high prostate-specific antigen (PSA) values (> 20 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) 8610 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 8610 and confirm the important clinical benefits of adding short-term ADT to EBRT in patients with high-risk, locally advanced disease.
This trial included 456 assessable patients and was conducted from April 15, 1987, to June 1, 1991. The analysis was performed on eligible and assessable patients as of July 17, 2006. Eligible patients were those with bulky (defined as 5 x 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 250 mg tid for 2 months before EBRT (neoadjuvant) and concurrent with EBRT or to receive EBRT alone.
Study End Points 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
Local progression.
Failure is defined as an increase of more than 50% 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 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 disease-specific mortality (DSM), local progression (LP), distant metastasis (DM), 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 test14 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 .05 for testing. The Cox proportional hazards model was used to assess the effects of covariates on OS and DFS. Fine and Gray's regression model15 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.
The trial was powered to detect an absolute 15% improvement in OS, from 50% 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 10-year estimates that used a 95% CI. The estimated 10-year OS (primary end point) rates were 42.6% (95% CI, 35.9 to 49.3) and 33.8% (95% CI, 27.5 to 40.1) for the ADT-EBRT arm and the EBRT-alone arm, respectively (P = .12). The estimated 10-year DSM rates were 23.3% (95% CI, 17.6 to 29.1) and 35.6% (95% CI, 29.2 to 42.0) for the ADT-EBRT arm and the EBRT-alone arm, respectively (P = .01). The estimated DM failure rates at 10 years were 34.9% (95% CI, 28.5 to 41.3) and 46.9% (95% CI, 40.3 to 53.5) for the ADT-EBRT arm and the EBRT-alone arm, respectively (P = .006). The estimated BF rates at 10 years were 65.1% (95% CI, 58.6 to 71.6) and 80.0% (95% CI, 74.7 to 85.4) for the ADT-EBRT arm and the EBRT-alone arm, respectively (P < .0001). The estimated DFS rates at 10 years were 11.2% (95% CI, 7.0 to 15.6) and 3.4% (95% CI, 1.0 to 5.8) for the ADT-EBRT arm and the EBRT-alone arm, respectively (P < .0001). There was no significant difference in 10-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 = .01, P = .01, P < .0001, and P < .0001, 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 10 years, fatal cardiac events were reported to have occurred in 12.5% (95% CI, 8.0 to 17.0) of patients treated with ADT and EBRT compared with 9.1% (95% CI, 5.3 to 13.0) 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 10-year DSM (P = .01), DM (P = .006), DFS (P < .0001), and BF (P < .0001) compared with the EBRT-alone 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 40% of men treated with EBRT alone had developed bone metastases. Conversely, it took 13 years for 40% 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 10-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.
These updated findings of RTOG 8610 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. These long-term results of RTOG 8610 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 8610 had bulkier disease and higher PSA levels than those treated on RTOG 9202, and RTOG 8610 included some patients who were known to have positive lymph nodes.3 Because the follow-up to RTOG 9202 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.18-20 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. Short-term ADT is relatively inexpensive, well tolerated, and readily available. The delayed the time for 40% of patients to develop metastasis by approximately 2903 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, 70 years). Pickles et al24 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 80% of patients who received monthly injections of luteinizing hormone-releasing hormone had recovered testicular function within 12 months. Recent studies have raised questions about the safety of ADT.6,25 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.6,25 Methodological problems with this report raise serious questions about the validity of this analysis; furthermore, this updated analysis of RTOG 8610 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 10-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 trial28-30. 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.
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
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
published online ahead of print at www.jco.org on January 2, 2008. Supported by Grants No. Radiation Therapy Oncology Group U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 from the National Cancer Institute. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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 8531. J Clin Oncol 15:1013-1021, 1997 2. 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] 3. 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 9202. J Clin Oncol 21:3972-3978, 2003 4. 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 159:2030-2034, 1998[CrossRef][Medline] 5. Shahinian VB, Kuo YF, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164, 2005 6. 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 24:3979-3983, 2006 7. 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 292:821-827, 2004 8. 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 96.01 randomized controlled trial. Lancet Oncol 6:841-850, 2005[CrossRef][Medline] 9. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 8610 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] 10. 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 65:965-974, 2006[CrossRef][Medline] 11. Kaplan EL, Meier P: Nonparameteric estimation from incomplete observations. Journal American Statistical Association 53:457-481, 1958[CrossRef] 12. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 13. Kim K, Tsiatis AA: Study duration for clinical trials with survival response and early stopping rule. Biometrics 46:81-92, 1990[CrossRef][Medline] 14. Gray R: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988[CrossRef] 15. Fine J GR: A proportional hazards model for the subdistribution of a competing risk. J Am Statist Assoc 94:496-509, 1999[CrossRef] 16. Zelefsky MJ, Harrison A: Neoadjuvant androgen ablation prior to radiotherapy for prostate cancer: Reducing the potential morbidity of therapy. Urology 49:38-45, 1997[CrossRef][Medline] 17. Zietman AL: The case for neoadjuvant androgen suppression before radiation therapy. Mol Urol 4:203-208, 2000; discussion 215[Medline] 18. 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 154:429-434, 1995[CrossRef][Medline] 19. Meng MV, Grossfeld GD, Carroll PR, et al: Neoadjuvant strategies for prostate cancer prior to radical prostatectomy. Semin Urol Oncol 20:10-18, 2002 (3 suppl 1)[Medline] 20. 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 166:500-506, 2001; discussion 506-507[CrossRef][Medline] 21. 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 9413. Int J Rad Bio Phys 66:647-653, 2006 22. 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 94:1458-1468, 2002 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 351:1513-1520, 2004 24. Pickles T, Agranovich A, Berthelet E, et al: Testosterone recovery following prolonged adjuvant androgen ablation for prostate carcinoma. Cancer 94:362-367, 2002[Medline] 25. 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 25:2420-2425, 2007 26. 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 25:5325-5326, 2007 27. Penson DF, Albertsen PC, Nelson PS, et al: Determining cause of death in prostate cancer: Are death certificates valid? J Natl Cancer Inst 93:1822-1823, 2001 28. 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 53:1097-1105, 2002[CrossRef][Medline] 29. Zietman AL, DeSilvio M, Slater JD, Rossi CJ, Yonemoto LT, Slater JM, Berkey B, Adams JA, Shipley WU: A randomized trial comparing conventional dose (70.2gye) and high-dose (79.2gye) conformal radiation in early stage adenocarcinoma of the prostate: Results of an interim analysis of PROG 9509, in Cox (ed): Proceedings of American Society for Therapeutic Radiology and Oncology. Atlanta, GA, Elsevier, 2004, pp S131-132 30. 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 24:1990-1996, 2006 Submitted August 14, 2007; accepted October 26, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
