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Journal of Clinical Oncology, Vol 24, No 25 (September 1), 2006: pp. 4190-4195 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.8239 Six-Month Androgen Suppression Plus Radiation Therapy Compared With Radiation Therapy Alone for Men With Prostate Cancer and a Rapidly Increasing Pretreatment Prostate-Specific Antigen Level
From the Departments of Radiation Oncology and Pathology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA; and the Department of Statistics, University of Connecticut, Storrs, CT Address reprint requests to Anthony V. D'Amico, MD, PhD, Brigham and Women's Hospital, Department of Radiation Oncology, 75 Francis St, L-2 Level, Boston, MA 02215; e-mail: adamico{at}lroc.harvard.edu
Purpose: We evaluated whether treatment with 6 months of androgen-suppression therapy (AST) and radiation therapy (RT) compared with RT was associated with the time to prostate-specific antigen (PSA) recurrence, prostate cancer–specific mortality (PCSM), and all-cause mortality (ACM) in men with a pretreatment PSA velocity more than 2 ng/mL/yr. Patients and Methods: The study cohort comprised 241 men with clinically localized or locally advanced prostate cancer treated with RT and AST or RT from 1989 to 2002. Cox regression and Gray's formulation were used to assess whether treatment was associated significantly with the time to PSA recurrence or ACM and PCSM, respectively, adjusting for known prognostic factors. Results: Despite the significantly longer median follow-up, younger age at diagnosis, higher proportion of Gleason score 7 to 10, and advanced T-category cancers, significantly lower estimates of PSA recurrence (P < .001), PCSM (P = .007), and ACM (P < .001) were observed in men who were treated using RT and AST compared with RT. Treatment with RT and AST compared with RT was associated with a longer time to PSA recurrence (adjusted hazard ratio [HR], 0.22; 95% CI, 0.14 to 0.35; P < .001), PCSM (HR, 0.23, 95% CI, 0.09 to 0.64; P = .005), and ACM (HR, 0.30; 95% CI, 0.16 to 0.58; P < .001). Conclusion: Treatment using 6 months of AST and RT compared with RT in men with a pretreatment PSA velocity greater than 2 ng/mL/yr was associated with a longer time to PSA recurrence, PCSM, and ACM.
The rate of increase of the serum prostate-specific antigen (PSA) level during the year before diagnosis (PSA velocity) has been shown by several investigators to be associated significantly with the time to PSA recurrence, prostate cancer–specific mortality (PCSM), and cancer and all-cause mortality (ACM) after radical prostatectomy (RP)1-3 or external-beam radiation therapy (RT).4 This result was also upheld when men were considered who presented with a PSA level of less than 10 ng/mL, clinical tumor (T) category T1c or T2a, and Gleason score of 6 or less for prostate cancer,4 suggesting that in these men occult prostate cancer may exist beyond the reach of locoregional therapies, despite classic low-risk tumor indices. Several randomized trials5-7 have documented a prolongation in the time to PSA recurrence, PCSM, and/or ACM when as little as 6 months or as much as 3 years of androgen-suppression therapy (AST) and RT compared with RT was used to treat men with higher risk prostate cancer based on the PSA level (> 10 ng/mL), Gleason score (7 to 10), and/or the 2002 American Joint Commission of Cancer8 clinical T category (T2b-4). However, whether treatment with AST and RT compared with RT will also prolong the time to PSA recurrence, PCSM, and ACM in men who experience a rapid PSA increase during the year before diagnosis remains unanswered. Specifically, the rapid increase in PSA during the year before diagnosis could be associated with prostate cancer that is already hormone refractory. Evidence to support that a rapid PSA increase may signal the presence of androgen-insensitive disease exists in the setting of PSA recurrence9-12 after RP, RT, or RT and AST. Specifically, in that setting a rapid as compared with a slow increase in PSA is associated significantly with a brief PSA response to AST and a correspondingly shorter time to PCSM and ACM after PSA recurrence, despite the use of AST. This latter point questions the clinical utility of treating men with AST and RT in the setting of a newly diagnosed patient with a rapid pretreatment increase in PSA. Therefore, in this study after adjusting for known prognostic factors, we evaluated whether treatment with 6 months of AST and RT compared with RT was associated with a prolonged time to PSA recurrence, PCSM, and ACM in men with newly diagnosed prostate cancer and a rapid increase in the pretreatment PSA.
Patient Selection, Staging, and Treatment Pretreatment and follow-up information were compiled on 702 men who were treated with RT with (n = 222) or without (n = 480) 6 months of AST at St Anne's Hospital (a Harvard Medical School affiliate, Fall River, MA), the Brigham and Women's Hospital (Boston, MA), or the Dana-Farber Cancer Institute (Boston, MA) from January 1, 1989, to December 1, 2002, for the following clinical categories listed by the 2002 American Joint Commission of Cancer8: T1c (nonpalpable), T2 (palpable), or T3 (extraprostatic) prostate cancer. A total of 66 men who had only a single measurement of PSA before RT and AST were excluded from the study, as were 157 men whose pretreatment PSA measurements were spaced less than 6 months apart. Of the remaining 479 men, 241 had a pretreatment PSA velocity more than 2 ng/mL/yr and comprised the study cohort. One genitourinary pathologist used the Gleason scoring system13 to assign a histologic grade to each man's prostate biopsy specimens, and the highest score assigned was used for all of the analyses performed in this study. Each man provided written informed consent before study entry; the St Anne's and Dana Farber–Harvard Cancer Center institutional review boards approved the study. The median age of the men at the time of initial therapy was 72 years (interquartile range, 67 to 76 years). Table 1 lists the baseline clinical characteristics of the men stratified by treatment received. All men had a computed tomographic scan of the pelvis and a bone scan that did not reveal evidence of regional or metastatic disease before treatment. The radiotherapeutic treatment technique and AST formulation have been described previously.4
Follow-Up The median follow-up for all study patients was 4.6 years (interquartile range, 2.8 to 6.4 years) and follow-up started on the last day of RT or RT plus AST and concluded on January 1, 2006, or the date of death, whichever was sooner; no patient was lost to follow-up. PSA recurrence was defined as two consecutive increasing PSA values more than 1.0 ng/mL and differing by more than 0.2 ng/mL to avoid scoring PSA failure from PSA increase due to testosterone rebound that can occur after the AST is discontinued. Before PSA recurrence, patients had a serum PSA measurement and an annual digital rectal examination at a median of every 6 months. After PSA recurrence, the serum PSA level was measured at a median of 3 months (range, 1 to 6 months). Any patient sustaining PSA recurrence was started on salvage hormonal therapy at a PSA level of approximately 10 ng/mL (median, 9.6 ng/mL; interquartile range, 7.6 to 11.6 ng/mL). Overall, there were 115 PSA recurrences and 62 deaths, of which 35 were as a result of prostate cancer. There were no deaths as a result of any cause during treatment and all patients' experienced PSA recurrence before death as a result of prostate cancer.
Cause of Death Determination
Statistical Methods
Comparison of baseline clinical characteristics and follow-up.
The initial treatments were compared on their distribution of the pretreatment clinical covariates. The Assessment of associations with recurrence and mortality. A Cox regression analysis17 was used to assess whether the treatment received, the PSA velocity before diagnosis, PSA level, age, biopsy Gleason score, and clinical T category at diagnosis were associated significantly with the time to PSA recurrence and ACM. The same assessment was made for the end point of time to PCSM using Gray's formulation, which accounts for competing causes of mortality.18 For the purpose of the Cox regression multivariable analyses, the PSA velocity and level and age were considered as continuous variables, whereas biopsy Gleason score, clinical tumor T category, and initial treatment were analyzed as categoric variables defined as Gleason 8 to 10 versus 7 versus 6 or less (baseline), T3 versus T2 versus T1c (baseline), and RT and AST versus RT (baseline), respectively. For all categoric variables, the cut points selected were made before the data were examined, and were based on established strata.4 For all Cox regression analyses, residuals19 were examined to check for the proportional hazards (PH) assumption and no violation again the PH assumption was found. Unadjusted and adjusted hazard ratios (HRs) and the associated 95% CIs and P values for probability estimates of time to PSA recurrence and ACM were calculated for all covariates using a Cox proportional hazards model,17 whereas a PH model18 that accounted for the subdistributions of competing risks (R version 2.1.1; R Foundation for Statistical Computing, Vienna, Austria) was used for all calculations pertaining to the cumulative incidence probability estimates of time to PCSM. SAS version 9.1.3 (SAS Institute, Cary, NC) was used for all remaining statistical analyses. Estimates of PSA recurrence and ACM after treatment with RT and AST or RT were computed and equal to the 1 –Kaplan and Meier estimate20 of PSA failure-free survival and 1 –Kaplan and Meier estimate of overall survival, respectively, and are displayed graphically. Comparisons of these estimates across treatments were made using the log-rank test.17 Estimates of PCSM after treatment with RT and AST or RT were computed using a cumulative incidence methodology,21 and are displayed graphically. Comparisons of these estimates across treatments were made using a K-sample test.22 All statistical tests were two sided and P < .05 was considered statistically significant.
Clinical Characteristics Stratified by Treatment As listed in Table 1, men who were treated using RT and AST compared with RT had a significantly higher proportion (P = .004) of Gleason score 7 (48% v 40%) and 8 to 10 (26% v 15%) cancers, longer median follow-up (5.8 v 3.3 years; P < .001), and a lower median age at diagnosis (70.9 v 72.7 years; P = .004). These men also had significantly more advanced clinical T category at diagnosis (P = .02), a higher proportion of PSA level more than 10 to 20 ng/mL (45% v 36%), and a lower proportion of PSA level more than 4 to 10 ng/mL (24% v 38%), which approached statistical significance (P = .09).
Factors Associated With Recurrence and Mortality
Recurrence and Mortality Estimates Despite the significantly longer median follow-up, younger age at diagnosis, higher proportion of Gleason 7 to 10, and advanced T-category cancers, significantly lower estimates of PSA recurrence (P < .001), PCSM (P = .007), and ACM (P < .001) were observed in men who were treated using RT and AST compared with RT, as shown in Figures 1A to 1C, respectively.
Increasing PSA values during the year before diagnosis were found to be associated with a shorter time to PSA recurrence, PCSM, and ACM after RT4 years after randomized studies5-7 were initiated that reported a prolongation in the time to these end points when RT and AST compared with RT was used to treat men with high-risk prostate cancer. As a result, these randomized studies5-7 did not stratify for or routinely collect the information necessary to estimate the pretreatment PSA velocity before random assignment to treatment. In addition, a rapidly increasing PSA compared with a slowly increasing PSA after RP, RT, or RT plus AST has been shown to be associated with a shorter time to PSA recurrence, PCSM, and ACM,9-12 despite the administration of AST after PSA recurrence, suggesting a hormone-refractory disease state. Therefore, the question remains unanswered whether a man with a rapid increase in PSA before diagnosis will experience a prolongation in the time to PSA recurrence, PCSM, and ACM when treated using RT plus AST compared with RT. In this study, men treated with RT and AST who also experienced a rapid increase in PSA during the year before diagnosis (ie, > 2 ng/mL/yr) had a significantly longer median follow-up, a younger median age, and a higher proportion of Gleason 7 to 10 and advanced clinical T-category cancers at diagnosis. In addition, there was an additional 2 months of survival time added to men treated with RT alone. This difference in survival time favoring patients treated with RT occurred because time zero was defined as the last day of treatment, and men who were treated using RT and AST continued AST for 2 months after the completion of RT. As a result, patients treated with RT had a survival time of 2 months when men treated with RT and AST had a survival time of 0 months. All of these factors would bias against an association with prolonged survival in men treated using RT and AST because longer follow-up in younger men with higher grade and more advanced cancers would be expected to lead to an increase in observed prostate cancer death. Yet, despite this bias against the men treated with RT and AST, the unadjusted estimates of time to PSA recurrence, PCSM, and ACM were significantly longer in men treated using 6 months of AST and RT compared with RT, as illustrated in Figures 1A to 1C, respectively. Moreover, after adjusting for all known prognostic factors, there was a significant association between treatment using 6 months of AST and RT compared with RT, and a prolongation in the time to PSA recurrence, PCSM, and ACM, as shown in Table 2. The significant association between treatment using 6 months of AST and RT compared with RT and the time to PSA recurrence remained whether the 1997 American Society for Therapeutic Radiology and Oncology definition23 or the more recent nadir + 2 ng/mL definition24 was used. The clinical significance of these findings is that a rapid increase in PSA before diagnosis does not necessarily suggest a hormone-refractory disease state and a shorter time to PCSM, as it does in the postoperative and postradiation settings. There are several considerations that warrant additional discussion. First, this study provides evidence to support, but does not prove the hypothesis that treatment using 6 months of AST and RT compared with RT in men with a pretreatment PSA velocity more than 2 ng/mL prolongs the time to PSA recurrence, PCSM, and ACM. Only a randomized study that can control for unknown confounding factors can provide proof that treatment using 6 months of AST and RT compared with RT prolongs the time to PSA recurrence, PCSM, and ACM in men with a rapid pretreatment PSA increase; the current study provides evidence to support this association. Second, the association between treatment using 6 months of AST and a prolongation in time to PSA recurrence, PCSM, and ACM provides evidence to support that a rapid increase in PSA before diagnosis does not necessarily suggest the presence of hormone-refractory disease, as it appears to in the settings of postoperative and postradiation PSA recurrence.9-12 This distinction is important clinically because it suggests that the hormone-refractory disease state results from progression over time and does not necessarily exist in all men who experience a rapid PSA increase during the year before diagnosis. Finally, as shown in Table 2, after adjusting for known prognostic factors, men with a biopsy Gleason score 7 or 8 to 10, compared with Gleason score 6 or less had a significantly shorter time to both PCSM and ACM. However, despite this shorter time to PCSM and ACM in men with high-grade compared with low-grade prostate cancer, men with Gleason 7 to 10 cancers treated using 6 months of AST and RT compared with RT also experienced a significantly longer time to PCSM and ACM, as illustrated in Figures 2A and 2B, respectively.
In conclusion, treatment with 6 months of AST to RT compared with RT in men with a pretreatment PSA velocity more than 2 ng/mL/yr was associated with a prolonged time to PSA recurrence, PCSM, and ACM. Therefore, in contrast to men with a rapidly increasing PSA after RP or RT who rapidly progress toward PCSM despite the use of AST after PSA recurrence, it appears that in men with a rapid increase in PSA before diagnosis, a survival benefit may exist when treatment using 6 months of AST and RT is used compared with RT.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. D'Amico AV, Chen M, Roehl K, et al: Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 351:125-135, 2005 2. Sengupta S, Myers RP, Slezak JM, et al: Preoperative prostate-specific antigen doubling time and velocity are strong and independent predictors of outcomes following radical prostatectomy. J Urol 174:2191-2196, 2005[CrossRef][Medline] 3. Patel DA, Presti JC Jr, McNBeal JE, et al: Preoperative PSA velocity is an independent prognostic factor for relapse after radical prostatectomy. J Clin Oncol 23:6157-6162, 2005 4. D'Amico AV, Renshaw AA, Sussman B, et al: Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 294:440-447, 2005 5. 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] 6. Denham J, Steigler A, Lamb DS, et al: Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: Results from the Tran-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol 6:841-850, 2005[CrossRef][Medline] 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. Greene FL. Prostate, in Greene FL, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging Manual (ed 6). New York, NY, Springer, 2002, pp 309-316 9. Lee AK, Levy LB, Cheung R, et al: Prostate-specific antigen doubling time predicts clinical outcome and survival in prostate cancer patients treated with combined radiation and hormone therapy. Int J Radiat Oncol Biol Phys 63:456-462, 2005[CrossRef][Medline] 10. D'Amico AV, Chen MH, Roehl K, et al: Identifying patients at risk for significant versus clinically insignificant postoperative prostate-specific antigen failure. J Clin Oncol 23:4975-4979, 2005 11. Freedland SJ, Humphreys EB, Mangold LA, et al: Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433-439, 2005 12. D'Amico AV, Moul J, Carroll P, et al: Surrogate marker for prostate cancer specific mortality following radical prostatectomy or radiation therapy. J Natl Cancer Inst 95:1376-1383, 2003 13. the Veterans Administration Cooperative Urological Research Group.Gleason DF, Histologic grading and staging of prostatic carcinoma, in Tannenbaum M (ed): Urologic Pathology. Philadelphia, PA, Lea & Febiger, 1977, pp 171-187 14. Kutner MH, Nachtscheim CJ, Neter J, et al: Simple linear regression, in Kutner MH, Nachtscheim CJ, Neter J, et al (eds): Applied Linear Statistical Models (ed 5). New York, NY, McGraw-Hill/Irwin, 2005, pp 1-99 15. Agresti A: Two-way contingency tables, in Agresti A (ed): An Introduction to Categorical Data Analysis (ed 2). New York, NY, John Wiley & Sons, 2002, pp 16-52 16. Hollander M, Wolfe DA: The two sample location problem, in Hollander M, Wolfe DA (eds): Nonparametric Statistical Methods (ed 2). New York, NY, John Wiley & Sons, 1999, pp 106-140 17. Klein JP, Moeschberger ML: Semiparametric proportional hazards regression with fixed covariates, in Klein JP, Moeschberger ML (eds): Survival Analysis: Techniques for Censored and Truncated Data (ed 2). New York, NY, Springer, 2003, pp 243-293 18. Fine JP, Gray RJ: A proportional hazards model for the sub distribution of a competing risk. J Am Stat Assoc 94:496-509, 1999[CrossRef] 19. Klein JP, Moeschberger ML. Regression Diagnostics, in Klein JP, Moeschberger ML (eds): Survival Analysis: Techniques for Censored and Truncated Data (ed 2). New York, NY, Springer, 2003, pp 353-392 20. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-500, 1958[CrossRef] 21. Gaynor JJ, Feuer EJ, Tan CC, et al: On the use of cause-specific failure and conditional failure probabilities: Examples from clinical oncology data. J Am Stat Assoc 88:400-409, 1993[CrossRef] 22. Gray RJ: A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1998[CrossRef] 23. Cox JD: Guidelines for PSA following radiation therapy: American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997[CrossRef][Medline] 24. Horwitz EM, Thames HD, Kuban DA, et al: Definitions of biochemical failure that best predict clinical failure in patients with prostate cancer treated with external beam radiation alone: A multi-institutional pooled analysis. J Urol 173:797-802, 2005[CrossRef][Medline] Submitted March 28, 2006; accepted July 10, 2006. This article has been cited by other articles:
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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
2 test
.009) and ACM (P 
