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Originally published as JCO Early Release 10.1200/JCO.2007.14.9021 on April 14 2008 © 2008 American Society of Clinical Oncology. Ten-Year Follow-Up of Radiation Therapy Oncology Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer
From the Department of Radiation Oncology, Fox Chase Cancer Center; Department of Biostatistics, Radiation Therapy Oncology Group, Philadelphia; Northeast Radiation Oncology Center, Scranton, PA; Department of Radiation Oncology, McGill University, Montréal, Québec; Department of Radiation Oncology, University of Western Ontario, London, Ontario, Canada; Department of Pathology, Indiana University, Indianapolis, IN; Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; Department of Radiation Oncology, Radiological Associates of Sacramento, Sacramento, CA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI; and the Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA Corresponding author: Eric M. Horwitz, MD, Fox Chase Cancer Center, Department of Radiation Oncology, 333 Cottman Ave, Philadelphia, PA 19111-2497; e-mail: eric.horwitz{at}fccc.edu
Purpose To determine whether adding 2 years of androgen-deprivation therapy (ADT) improved outcome for patients electively treated with ADT before and during radiation therapy (RT). Patients and Methods Prostate cancer patients with T2c-T4 prostate cancer with no extra pelvic lymph node involvement and prostate-specific antigen (PSA) less than 150 ng/mL were included. All patients received 4 months of goserelin and flutamide before and during RT. They were randomized to no further ADT (short-term ADT [STAD] + RT) or 24 months of goserelin (long-term ADT [LTAD] + RT). A total of 1,554 patients were entered. RT was 45 Gy to the pelvic nodes and 65 to 70 Gy to the prostate. Median follow-up of all survival patients is 11.31 and 11.27 years for the two arms.
Results At 10 years, the LTAD + RT group showed significant improvement over the STAD + RT group for all end points except overall survival: disease-free survival (13.2% v 22.5%; P < .0001), disease-specific survival (83.9% v 88.7%; P = .0042), local progression (22.2% v 12.3%; P < .0001), distant metastasis (22.8% v 14.8%; P < .0001), biochemical failure (68.1% v 51.9%; P Conclusion LTAD as delivered in this study for the treatment of locally advanced prostate cancer is superior to STAD for all end points except survival. A survival advantage for LTAD + RT in the treatment of locally advanced tumors with a Gleason score of 8 to 10 suggests that this should be the standard of treatment for these high-risk patients.
The role of androgen-deprivation therapy (ADT) used in conjunction with external-beam radiation therapy (RT) to treat locally advanced prostate cancer has been investigated since the 1960s.1 Early studies demonstrated a benefit in clinical outcome when ADT was used, but many questions remained unanswered, including the duration and timing of treatment. Substantial toxicity was also identified when hormones were used. Beginning in the 1980s, the Radiation Therapy Oncology Group (RTOG) developed trials based on information from these early studies, which incorporated new hormonal agents with less cardiovascular toxicity. RTOG 85-31 randomly assigned patients with locally advanced prostate cancer between RT and goserelin indefinitely versus RT alone. A statistically significant improvement in 10-year biochemical no evidence of disease (bNED) control, distant metastasis survival (DMS), local control (LC), and overall survival (OS) was observed for patients treated with long-term ADT (LTAD).2 The role of short-term ADT (STAD) was examined in RTOG 86-10. Patients were randomly assigned between ADT before and during RT or RT alone. Significant improvement in LC was seen for patients treated with STAD.3 The difference between the two significant study arms from RTOG 85-31 and 86-10 was definitively tested in the largest phase III randomized prospective trial of prostate cancer patients in North America. The first analysis of RTOG 92-02, demonstrated statistically significant improvements in outcome in the long-term hormone arm for disease-free survival (DFS), cause-specific survival (CSS), biochemical failure (BF), distant metastasis (DM), and local failure (LF).4 This study updates the results of RTOG 92-02 and reports the clinical and biochemical results as well as toxicity at 10 years.
Patient Population Patients eligible for inclusion on RTOG 92-02 included those men with histologically confirmed adenocarcinoma of the prostate (T2c-T4N0-X). A pretreatment PSA less than 150 ng/mL was mandatory. The 1992 American Joint Committee on Cancer Staging Manual was used for clinical staging.5 There could be no documented, DM and the participants' Karnofsky performance status had to be at least 70%. No prior ADT, RT, or chemotherapy was allowed. Institutional review board approval was obtained at each participating center before patient enrollment and data was transferred to a single statistical center per Health Insurance Portability and Accountability Act (HIPAA) guidelines. Informed consent was obtained from each participant before enrollment, random assignment, and treatment. The details of pretreatment patient evaluations have been summarized in the previous report.4 After RT was completed, follow-up with prostate-specific antigen (PSA) was every 3 to 6 months during the first 5 years, and then yearly.
RT
ADT
Study Design and End Points Study end points included DFS, OS, local progression (LP), DM, BF, and disease-specific survival (DSS). LP was defined as clinical evidence of local recurrence (by any method) or persistent disease. DM was defined as the clinical evidence of distant disease (by any method). Patients without an event for either LP or DM end point were censored at the date of last follow-up or death. BF was defined as the earliest of the following: three consecutive rises after a post-treatment PSA nadir (the 1997 American Society for Therapeutic Radiology and Oncology [ASTRO] definition7), receiving additional ADT or PSA greater than 4 ng/mL. Patients were censored at the date of last PSA. DFS was defined as the first occurrence of LP, DF, BF, or death. DSS was defined as a death resulting from to prostate cancer, treatment toxicity or unknown causes with DM. All event times were measured from the date of random assignment. Acute RT toxicities were defined as those occurring within 90 days from the start of RT. Any toxicity continuing or developing after 90 days was considered a late RT toxicity. Results from a hypothesis-generating postrandomization subset analysis of patients with a Gleason score of 8 to 10 was performed in the first report and, on the basis of results from similar randomized prospective studies, was included in this update.
Statistical Methods
Table 1 shows pretreatment characteristics for 1,521 eligible patients. There was no statistically significant difference between treatment arms with respect to the stratification factors and other characteristics. As reported by the institutions, RT was completed as assigned in 96% of the cases in the STAD + RT arm and 95% of the cases in the LTAD + RT arm. Four percent and 3% of the reviewed cases were judged unacceptable major variations in the STAD + RT and LTAD + RT arm, respectively. The median follow-up for all living patients in this study is 11.3 years for both arms.
Toxicity Toxicity from treatment was scored using the previously reported RTOG criteria.12 Acute and late RT and hormone toxicities are listed in Table 2. Nine percent and 1% of the cases have reported grade 3 and grade 4 acute toxicity, respectively, caused by RT in the STAD + RT arm. Seven percent and 1% of the cases have reported grade 3 and grade 4 acute toxicity, respectively, caused by RT in the LTAD + RT arm. Hormone grade 3 and grade 4 toxicities are 4% and less than 1%, respectively, at any time in both arms. One patient in the LTAD + RT arm died as a result of chemical hepatitis during the hormone treatment. As seen in Table 2, LTAD increased late toxicity. Grade 3 and grade 4 late toxicity caused by RT have been reported in 6% and 1% of the cases in the STAD + RT arm and 7% and 3% of the cases in the LTAD + RT arm, respectively. One patient died as a result of proctitis and one as a result of sigmoid perforation in the STAD + RT arm, and one patient died as a result of colostomy obstruction in the LTAD + RT arm. Three patients experienced grade 3 cardiac toxicities, one in the STAD + RT group (congestive heart failure [CHF]) and two in the LTAD + RT arm (one with CHF and one with ischemia). There was no statistically significant difference in cardiac toxicity between the two groups, and there were no grade 4 or 5 cardiac events, although this may be an underestimation.
Treatment Outcomes Table 3 shows the 10-year treatment outcomes for the entire study population. The estimated DFS (the primary end point) at 10 years was 13.2% and 22.5% for the STAD + RT arm and LTAD + RT arm, respectively (P < .0001). The 10-year OS rates are 51.6% and 53.9% for the STAD + RT and LTAD + RT arms, respectively (P = .359). The LTAD + RT arm statistically significantly improved patients' 10-year DFS (P < .0001) and DSS (P = .004), and reduced LP (P < .0001), DM (P < .0001) and BF (P < .0001) compared with the STAD + RT arm. These differences remain when adjusted for PSA and T stage (Table 4). The LTAD + RT arm significantly improved patients' DFS (P < .0001), DSS (P = .002), LP (P < .0001), DM (< 0.0001), and BF (P < .0001) at 10 years compared with the STAD + RT arm (Fig 1).
Treatment Outcomes of the Subgroup With a Gleason Score of 8 to 10 For patients with a Gleason score of 8 to 10, there are statistically significant improvements in DFS (P < .0001), OS (P = 0061), and DSS (P = .0072), and reductions in LP (P = .0338), DM (P = .0019), and BF (P < .0001) for the patients in the LTAD + RT arm compared with the STAD + RT arm (Table 5; Fig 2).
In this study, we report the long-term clinical, biochemical, and toxicity results from RTOG 92-02. At 10 years, statistically significant differences in DFS, DSS, LP, DM, and BF were observed within the entire population, with patients randomly assigned to the LTAD + RT arm demonstrating superior outcome. The primary end point testing for an absolute 10% improvement in DFS, from 40% to 50%, was positive at 5 and 10 years. This trial was not designed to detect a survival difference, yet a difference in cause-specific mortality was seen. The subset of patients with a Gleason score of 8 to 10 treated with LTAD + RT had statistically significant improvements in OS, DFS, and DSS, and statistically significant reductions in LP, DM, and BF. Toxicity remained low, although patients who received LTAD had increased rates of GI toxicity. The RTOG began investigating the role of ADT combined with RT in the treatment of locally advanced prostate cancer in the 1980s. The long-term results of RTOG 85-31, which randomly assigned 977 patients to receive between 65 and 70 Gy external beam RT and goserelin started during the last week of RT (arm 1) and continuing indefinitely versus RT alone (arm 2) were reported by Pilepich et al2 and demonstrated significant differences between the two treatment arms at 10 years for bNED control, DMF, LF, and OS (P < .0001) after long follow-up. RTOG 86-10 opened after RTOG 85-31 began accruing patients. Prostate cancer patients with T2b-4N0-1M0 and tumors larger than 25 cm2 were randomly assigned between goserelin and flutamide 2 months before and during RT (arm 1, 226 patients) and RT alone (arm 2, 232 patients). At 8 years, a significant difference in LC was seen between the two arms (P = .004) as well as an improvement in PFS for arm I (P = .0019). With longer follow-up, a difference in the rate of DM was observed between the two groups (P = .04). All patients in RTOG 85-31 and 86-10, as well as those in the current study were treated with conventional RT doses (65 to 70 Gy).3 Both of these studies showed statistically significant improvements in outcome for patients treated with RT and ADT compared with patients treated with RT alone; however, the ideal duration and timing of hormones remained unknown. One of the primary goals of RTOG 92-02 was to determine the duration of the ADT. The initial report with 5-year data demonstrated the superiority of LTAD, and one of the strengths of the present analysis is that these results remain valid at 10 years. RTOG 92-02 showed improved results with LTAD for all end points with additional follow-up, except OS. Were these benefits observed elsewhere? Bolla et al13 reported results from European Organisation for Research and Treatment of Cancer (EORTC) 22863, where 415 men were randomized between RT alone (70 Gy), and RT with goserelin starting the first day of treatment and continuing for 3 years. The differences in clinical outcome persist between the two arms is similar to the results observed in the present study. LC, PSA DFS, and OS were 98%, 50%, and 70%, respectively for the combined modality arm compared with 84%, 20%, and 40%, respectively for the RT alone arm. These differences were all statistically significant (P < .0001). Patients in the control arm in the EORTC 22863 study received no adjuvant ADT, whereas the patients in the control arm of RTOG 92-02 received 4 months of neoadjuvant and adjuvant ADT. The difference in the trial design may be one explanation for the failure of RTOG 92-02 to demonstrate an OS benefit for the entire trial cohort. Another reason may include the age of the patients in this study and the issue of competing medical comorbidities. It is encouraging and significant that the difference in CSS persisted with longer follow-up in this study. The subset analysis performed on patients with a Gleason score of 8 to 10 demonstrated statistically significant improvements in OS and CSS. Bolla et al14 reported the early results from the successor trial to EORTC 22863 in 2007. EORTC 22961 was designed to test whether similar prostate cancer patients would benefit from STAD therapy instead of 3 years of LTAD therapy. An interim analysis demonstrated decreased PFS in the STAD therapy arm (68.9% v 81.8% at 5 years). Biochemical PFS was also improved with LTAD (78.3% v 58.9%). Preliminary results of this trial support the conclusion observed in the 10-year results of RTOG 92-02, although the survival advantage in the EORTC study may be explained by the inclusion of patients with more advanced disease (+N2). As the benefits of ADT have become known, so has the potential toxicity of this treatment.15,16 Patients treated with LTAD had overall increased late toxicity. This has been observed in the Fox Chase experience reported by Feigenberg et al. The authors reported the results for 1,204 patients were treated for prostate cancer with three-dimensional conformal RT (3DCRT). STAD therapy was administered to 140 patients, 119 patients received LTAD therapy and 945 patients received no ADT. Independent predictors of grade 2 or higher GI morbidity in the multivariable analysis were the use of AD (P = .0079), higher total radiation dose (P < .0001), the lack of a rectal shield (P = .0003), and older age (P = .0009). The 5-year actuarial risk of grade 2 or higher GI morbidity was 17% for no AD versus 18% for STAD and 26% for LTAD (P = .017).17 Recent studies have documented the potential long-term cardiovascular risks associated with ADT.16 In RTOG 92-02, only three grade 3 cardiovascular events were documented, one in the STAD + RT arm and two in the LTAD + RT arm. Although answering many questions, the results in this study leave several questions unanswered. These long-term results from RTOG 92-02 strongly support the recommendation that LTAD therapy used in conjunction with RT for locally advanced nonmetastatic prostate cancer is superior to STAD + RT. However, an OS advantage was not observed for the entire study group. Is it possible the excess toxicity for the LTAD arm negated a positive effect on CSS? Was the study underpowered to detect a survival difference? The arms were evenly balanced, and the accrual goals were exceeded. We do not believe that excess toxicity is a probable reason. One potential explanation for the lack of an OS advantage is that the follow-up interval is not yet long enough for the patients with lower Gleason scores. Patients with a Gleason score of 7 and lower represented more than 70% of the patient population, and so despite the locally advanced nature of the patient sample, the number of patients with a Gleason score of 8 to 10 at highest risk for DS mortality is relatively small. RTOG 92-02 has enough follow-up to observe a survival advantage in the high-grade patients because their life expectancy would be less, but there may not be enough follow-up time to see a difference in the low-grade patients.
The significance of RT dose in this setting is also unclear. Other randomized, prospective studies have demonstrated the importance of dose, but this has not been formally tested with STAD or LTAD therapy in North America. The University of Texas M.D. Anderson Cancer Center trial reported by Pollack et al18 is the most mature randomized prospective prostate cancer dose escalation trial. In this study, 301 men were randomly assigned to between 70 Gy and 78 Gy. With 60 months of median follow-up, patients with an initial pretreatment PSA greater than 10 ng/mL experienced the greatest benefit, whereas the additional 8 Gy had no effect on the more favorable patients (pretreatment PSA The long-term results for RTOG 92-02 presented in this report demonstrated an OS benefit for prostate cancer patients with a Gleason score of 8 to 10 treated with prolonged LTAD + RT. LTAD + RT should be regarded as the standard treatment for patients with prostate cancer patients with a Gleason score of 8 to 10. Subsequent RTOG trials have adopted this regimen of LTAD + RT as the control arm in randomized clinical trials evaluating new therapies for patients with high-risk prostate cancer. Two successor trials introduced cytotoxic chemotherapy after the RT has been completed, with the strategy of intensifying systemic therapy. RTOG 99-02 utilized a three-drug regimen of paclitaxel, etoposide, and estramustine, in addition to LTAD + RT.20 RTOG 05-21 utilizes a similar schema, but with docetaxel-based chemotherapy. Updated RT techniques, such as intensity-modulated radiation therapy, and doses are utilized in contemporary trials. The fact that the experimental arm of RTOG 92-02 is still being utilized as the basis of the control arm in ongoing clinical trials for high-risk, poorly differentiated prostate cancer provides additional testimony to the significance of the results of this trial. The long-term results of RTOG 92-02 demonstrate that 24 months of ADT after total androgen suppression and RT is superior to total androgen suppression and RT alone in all end points except survival for patients with locally advanced nonmetastatic prostate cancer. In a hypothesis-generating postrandomization analysis, an overall survival benefit was observed in patients with tumors having a Gleason score of 8 to 10. No change in significant results from 5-year to 10-year follow-up was observed, proving the durability of these results.
The author(s) indicated no potential conflicts of interest.
Conception and design: Eric M. Horwitz, Gerald E. Hanks, William U. Shipley Administrative support: Kyounghwa Bae, David J. Grignon, Howard M. Sandler Provision of study materials or patients: Gerald E. Hanks, Arthur Porter, Varagur Venkatesan, Colleen A. Lawton, Seth A. Rosenthal, Howard M. Sandler, William U. Shipley Collection and assembly of data: Eric M. Horwitz, Kyounghwa Bae, Gerald E. Hanks, David J. Grignon, Harmar D. Brereton, Varagur Venkatesan, Seth A. Rosenthal, Howard M. Sandler, William U. Shipley Data analysis and interpretation: Eric M. Horwitz, Kyounghwa Bae, Gerald E. Hanks, Arthur Porter, David J. Grignon, Harmar D. Brereton, Varagur Venkatesan, Colleen A. Lawton, Seth A. Rosenthal, Howard M. Sandler, William U. Shipley Manuscript writing: Eric M. Horwitz, Kyounghwa Bae, Gerald E. Hanks, Seth A. Rosenthal, Howard M. Sandler Final approval of manuscript: Eric M. Horwitz, Kyounghwa Bae, Gerald E. Hanks, Arthur Porter, David J. Grignon, Harmar D. Brereton, Varagur Venkatesan, Colleen A. Lawton, Seth A. Rosenthal, Howard M. Sandler, William U. Shipley
We thank all of the patients, physicians, and support staff whose care and effort made the successful completion of this study possible.
published online ahead of print at www.jco.org on April 14, 2008 Supported by Grants No. RTOG U10 CA21661, CCOP U10 CA37422, and STAT U10 CA32115 from the National Cancer Institute. Presented at the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, November 5-9, 2006, Philadelphia, PA. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Zagars GK, Johnson DE, von Eschenbach AC, et al: Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: Long-term results of a prospective randomized study. Red Journal 14:1085-1091, 1988 2. Pilepich MV, Winter K, Lawton CA, et al: Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma: Long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 61:1285-1290, 2005[CrossRef][Medline] 3. 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] 4. 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 92-02. J Clin Oncol 21:3972-3978, 2003 5. American Joint Committee on Cancer: Prostate, in Beahrs OH, Henson DE, Hutter RVP, et al (eds): Manual for the Staging of Cancer (ed 4). Philadelphia, PA, JB Lippincott, 1992, pp 181-186 6. Zelen M: The randomization and stratification of patients to clinical trials. J Chronic Dis 27:365-375, 1974[CrossRef][Medline] 7. American Society for Therapeutic Radiology and Oncology Consensus Panel: Consensus statement: Guidelines for PSA following radiation therapy. Red Journal 37:1035-1041, 1997 8. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 9. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley & Sons, 1980 10. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719-748, 1959[Medline] 11. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988[CrossRef] 12. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995[CrossRef][Medline] 13. 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 randomised trial. Lancet 360:103-106, 2002[CrossRef][Medline] 14. Bolla M, van Tienhoven G, De Reijke TM, et al: Concomitant and adjuvant androgen deprivation (ADT) with external beam irradiation (RT) for locally advanced prostate cancer: 6 months versus 3 years ADT—Results of the randomized EORTC phase III trial 22961. J Clin Oncol 25:238s, 2007 (suppl; abstr 5014) 15. Rosenthal SA, Linstadt DE, Leibenhaut MH, et al: Flutamide-associated liver toxicity during treatment with total androgen suppression and radiation therapy for prostate cancer. Radiology 199:451-455, 1996 16. 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 17. Feigenberg SJ, Hanlon AL, Horwitz EM, et al: Long-term androgen deprivation increases grade 2 and higher late morbidity in prostate cancer patients treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 62:397-405, 2005[Medline] 18. Pollack A, Zagars GK, Antolak JA, et al: Prostate biopsy status and PSA nadir level as early surrogates for treatment failure: Analysis of a prostate cancer randomized radiation dose escalation trial. Int J Radiat Oncol Biol Phys 54:677-685, 2002[CrossRef][Medline] 19. Zietman AL, DeSilvio ML, Slater JD, et al: Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA 294:1233-1239, 2005 20. Sandler H, DeSilvio M, Pienta K, et al: Preliminary analysis of RTOG 92-02: Increased toxicity observed with the use of adjuvant chemotherapy. Int J Radiat Oncol Biol Phys 63:123, 2005[Medline] Submitted October 19, 2007; accepted February 4, 2008.
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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
.0001), and overall survival (51.6% v 53.9%, P = .36). One subgroup analyzed consisted of all cancers with a Gleason score of 8 to 10 cancers. An overall survival difference was observed (31.9% v 45.1%; P = .0061), as well as in all other end points herein. 
4 MV) to 44 to 46 Gy. This was followed by a conedown to the prostate for a total dose of 65 to 70 Gy for T2c tumors and 67.5 to 70 Gy for T3 to T4 tumors. The prescribed dose was recorded at the center of the prostate target volume. 
