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Phase III Trial Comparing Whole-Pelvic Versus Prostate-Only Radiotherapy and Neoadjuvant Versus Adjuvant Combined Androgen Suppression: Radiation Therapy Oncology Group 9413

M. Roach, III, M. DeSilvio, C. Lawton, V. Uhl, M. Machtay, M.J. Seider, M. Rotman, C. Jones, S.O. Asbell, R.K. Valicenti, S. Han, C.R. Thomas, Jr, W.S. Shipley

From the University of California at San Francisco, San Francisco, and Radiology Associates of Sacramento, Sacramento, CA; Radiation Therapy Oncology Group Statistical Headquarters, University of Pennsylvania, Albert Einstein Medical Center, and Thomas Jefferson University, Philadelphia, PA; Medical College of Wisconsin, Milwaukee, WI; Akron City Hospital, Akron, OH; State University of New York Health Science Center at Brooklyn, Brooklyn, NY; Wayne State University, Detroit, MI; University of Texas Health Science Center at San Antonio, San Antonio, TX; and Massachusetts General Hospital, Boston, MA.

Address reprint requests to Mack Roach III, MD, University of California San Francisco, 1600 Divisadero St, Suite H1031, San Francisco, CA 94143-1708; email: roach{at}radonc17.ucsf.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: This trial tested the hypothesis that combined androgen suppression (CAS) and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAS and prostate-only (PO) RT. This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy (NCHT) improves PFS compared with adjuvant hormonal therapy (AHT) by 10%.

Materials and Methods: Eligibility included localized prostate cancer with an elevated prostate-specific antigen (PSA) 100 ng/mL and an estimated risk of lymph node (LN) involvement of 15%. Between April 1, 1995, and June 1, 1999, 1,323 patients were accrued. Patients were randomly assigned to WP + NCHT, PO + NCHT, WP + AHT, or PO + AHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease; PSA failure; or death for any cause.

Results: With a median follow-up of 59.5 months, WP RT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PO RT (P = .022). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (P = .56). When comparing all four arms, there was a progression-free difference among WP RT + NCHT, PO RT + NCHT, WP RT + AHT, and PO RT + AHT (60% v 44% v 49% v 50%, respectively; P = .008). No survival advantage has yet been seen.

Conclusion: WP RT + NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and compared with WP RT + AHT in patients with a risk of LN involvement of 15%.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
A LARGE number of men are treated with external-beam radiotherapy (RT) for localized prostate cancer based on the fact that recurrence rates at 5 years and survival rates at 5, 10, and 15 years appear to be similar to surgery when patients are matched by stage and tumor grade.^1–4 Several prospective randomized trials have recently demonstrated that adding androgen suppression to RT improves the results for patients with intermediate- and high-risk prostate cancer.^5–8 Radiation Therapy Oncology Group (RTOG) 8610 was the landmark study that demonstrated a survival benefit with neoadjuvant and concurrent hormonal therapy (NCHT) combined with RT.⁸ In this study, the benefits of short-term hormonal therapy consisting of combined androgen suppression (CAS) therapy were limited to patients with bulky disease and Gleason scores (GSs) of 2 to 6. However, in a combined analysis of RTOG trials, the benefit of short-term NCHT also appeared to extend to patients with T1-T2 and GSs of 7.⁹ Many other questions regarding the use of RT and CAS therapy remain. Among these questions is the role of prophylactic pelvic lymph node (LN) irradiation. Because a higher risk of complications and a higher cost might be expected with the addition of whole-pelvic (WP) RT, it would be desirable to omit this treatment if it is not beneficial. A previous prospective trial conducted by the RTOG failed to demonstrate a benefit with WP RT.¹⁰ However, this study included patients estimated to be at low risk for LN involvement, including some proven to be pathologically node-negative. Recent retrospective data indicate that patients with a risk of LN involvement of more than 15% might benefit from prophylactic WP RT.¹¹

Another important question is whether hormonal therapy should be delivered before, during, or after RT. Some, but not all, animal models suggested a biologic interaction between hormonal therapy and RT.^12,13 This multicenter, prospective, randomized phase III trial was designed to answer questions concerning the value of prophylactic WP RT in intermediate- to high-risk patients and the effect of the timing of hormonal therapy on progression-free survival (PFS).

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Eligibility included histologically confirmed, clinically localized adenocarcinoma of the prostate with an elevated prostate-specific antigen (PSA) 100 ng/mL. Patients were stratified by T stage (T1c, T2a v T1b, and T2b v T2c to T4), PSA (< 30 v 30 ng/mL), and GS (GS < 7 v 7 to 10). The PSA stratification chosen was based on the median PSA observed in an earlier high-risk patient study.^9,14 Eligible patients were also required to have an estimated risk of LN involvement of more than 15%, based on the equation +LN = (2/3) PSA + [(GS - 6) x 10].^15,16 Patients with T2c to T4 were also eligible if they had a GS 6, even if their calculated risk of LN involvement did not reach 15%, based on their risk as reported by Partin et al.¹⁷ Patients who were staged surgically were ineligible, as were patients with metastatic disease. Additional eligibility criteria included Karnofsky performance status 70%; no prior hormonal therapy, radiation, or chemotherapy; and liver function tests 1.2 times the upper limits of normal. All patients signed an informed consent before randomization.

All patients received CAS, which consisted of goserelin acetate 3.6 mg/mo subcutaneously or leuprolide acetate 7.5 mg/mo intramuscularly, and flutamide 250 mg tid orally for 4 months. Patients receiving NCHT began hormonal therapy 2 months before RT and continued to receive it during RT, whereas those receiving AHT began their drugs immediately following the completion of RT. All RT was given at 1.8 Gy per fraction to a total dose of 70.2 Gy. WP RT consisted of a conventional four-field technique with a minimum unblocked field size of 16 x 16 cm to a maximum central axis dose of 50.4 Gy. Patients receiving WP RT were treated with an additional 19.8 Gy to the prostate using a conedown boost technique. Prostate-only (PO) RT was limited to the prostate and seminal vesicles, with a maximum unblocked field size of 11 x 11 cm to a total of 70.2 Gy. A urethrogram was required as part of simulation, and the inferior field edge was to be placed at least 1 cm below the point where the contrast narrowed (apex of the penile urethra) to insure coverage of the prostate.¹⁸

Statistical Analysis
The trial used a 2 x 2 factorial design to test whether WP RT and CAS improved PFS compared with PO RT and CAS and whether NCHT and RT improved PFS compared with AHT and RT. Secondary objectives included comparing treatments with regard to local failure (LF), time to distant failure, and overall survival (OS). The design assumed no significant statistical interaction between the treatments. The study was designed to detect a 10% difference in the 5-year PFS rates with a significance level of 0.025 and a statistical power of 0.80. It was assumed that the PFS estimate was exponentially distributed. A two-sided log-rank test was used. The initial sample size was increased by 10% because of the possibility that patients may be found retrospectively ineligible or lost to follow-up. Thus, the targeted sample size for the study was 1,200 patients. PFS and OS were estimated with the Kaplan-Meier method, and the unstratified log-rank statistic was used to test for differences.¹⁹ No adjustments were made for further testing. Biochemical failure, LF, regional nodal failure, and distant metastases were estimated using the cumulative incidence method,²⁰ and Gray’s test was used to test for differences.²¹ These methods account for competing risks, such as death without experiencing an event. It is important to note that the analyses of local, regional nodal, distant, and biochemical failure do not take into account competing events, with the exception of death. Thus, the number of failures for the individual events do not sum to the total number of disease progressions for a given treatment arm. However, the analyses of time to first occurrence of an individual event (eg, LF) will account for other competing events. Thus, the sum of these individual failures will equal the number of disease progressions for each treatment arm. The RTOG toxicity scoring scale was used to assess treatment-related toxicity, as previously described.²²

End Point Definitions
The primary end point for this study was PFS, while secondary end points included OS, LF, distant metastases, and PSA failure. The failure event for PFS was defined as the first occurrence of local progression, regional nodal failure, distant failure, or biochemical (PSA) failure or death for any cause. The failure event for OS was defined as death for any cause. LF was defined as tumor recurrence (positive rebiopsy at least 2 years after treatment), tumor regrowth by 50%, or tumor that never cleared. RTOG 9413 was one of the first major trials to incorporate a biochemical (PSA) failure end point as part of the study design. The definition used was developed in 1994 as part of the study design before the American Society for Therapeutic Radiation and Oncology (ASTRO) consensus conference definition (a definition that was not designed to be used in patients receiving hormonal therapy).²³ An event for biochemical (PSA) failure was defined as two consecutive and significant PSA rises separated by at least 1 month. For a PSA level that was 1.5 ng/mL, an increase 0.3 ng/mL was considered a significant rise. For a PSA level that was more than 1.5 ng/mL, a significant rise was defined as an increase of 20% or more. For example, if the current PSA level was 2.0 ng/mL, an increase would be considered significant if the next recorded value (separated at least by 1 month) was 2.4 ng/mL. Patients with slowly rising PSAs (eg, < 20% per year) were considered free from PSA failure as long as their PSA remained less than 4.0 ng/mL. The decision to use a relatively high threshold value to define failure was based on the desire to use a definition with high specificity for a clinically meaningful outcome.²⁴ The decision to define failure as two rises reflected the desire to maintain high sensitivity. After completion of the primary statistical analysis using the definition of biochemical failure per the protocol, a definition based on the ASTRO consensus definition was applied to determine whether the major conclusions concerning the primary end point might be altered.²³

Data Monitoring
This study was approved by the National Cancer Institute and by the Committee on Human Subjects Research and the institutional review board at each participating RTOG institution. A formal RTOG Data Monitoring Committee was in place to oversee the study’s progress. The interim analysis results were presented to the Data Monitoring Committee in April 2001. Following this review, the study was deemed mature enough to warrant disclosure of the findings relative to the primary end point as stated in the study design. The O’Brien-Fleming^25,26 alpha-spending function boundary was 2.397, with a nominal significance level of 0.0165.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study was activated April 1, 1995, and closed June 1, 1999, with a total of 1,323 patients. Ninety-eight percent of the patients (1,292 of 1,323 patients) were considered eligible and properly entered onto the study. The pretreatment characteristics of the patients are summarized in Table 1. The median age was 70 years, and nearly 25% of patients were of African-American origin. The median PSA was 22.6 ng/mL, 67% of patients had T2c to T4 disease, and 72% had a GS of 7 to 10. The patients were balanced between all four arms for GS, PSA, stage, race, and estimated risk of LN involvement. The median follow-up since completion of therapy for all patients was 59.5 months.

View larger version (17K): [in this window] [in a new window]   Fig 1. Patients treated with whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate experienced a 4-year progression-free survival (PFS) of 54.2% compared with 47% in patients treated with prostate only (PO) RT (P = .022).

View larger version (16K): [in this window] [in a new window]   Fig 2. Demonstrates that there is no difference in 4-year progression-free survival (PFS) for patients treated with neoadjuvant and concurrent hormonal therapy (NCHT) compared with adjuvant combined androgen suppression (CAS; P = .56).

View larger version (25K): [in this window] [in a new window]   Fig 3. Four-year progression-free advantage for whole pelvic (WP) radiotherapy (RT) and neoadjuvant and concurrent hormonal therapy (NCHT)compared with prostate only (PO) RT and NCHT, and WP RT or PO RT and adjuvant hormonal therapy (AHT; 60 v 44, 49% and 50% respectively, P = .008).

View this table: [in this window] [in a new window]   Table 6. 4-Year Progression-Free Survival: Intermediate-Risk Patients (PSA < 30 & GS = 7–10 or PSA 30 & GS = 2–6)

View this table: [in this window] [in a new window]   Table 7. Acute and Late GU and GI RT Toxicity (Grade 3)*

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Could these findings result from the fact that a pelvic RT field is less likely to miss the prostate or seminal vesicles? This is not likely to explain our findings because, per protocol, fields as large as 11 x 11 cm covering the prostate and seminal vesicles were allowed on the PO RT arms, with no restrictions on the dose to the seminal vesicles. Furthermore, the patients randomly assigned to WP RT + AHT did no better than those treated by PO RT + AHT, indicating that the larger field size in the former was of no benefit without NCHT, despite a lower theoretical risk of missing the prostate.

How might the observations of this trial be affected by the benefits of higher doses of radiation? Although the incidence of clinically determined (digital rectal exam) local recurrences appeared to be low on all four arms, we know that the true incidence of local recurrences would be much higher if biopsies were systematically taken.³¹ Treatment probably failed for some patients from both arms who may have benefited from pelvic RT because of an inadequate dose to the prostate.³² If LFs were reduced with the use of higher doses, more of the patients treated on the PO RT arms, for whom treatment failed because of the lack of pelvic nodal treatment, would probably have become obvious. Thus, with higher doses of radiation, it is most likely that the benefits of WP RT would have been greater.

The follow-up thus far for RTOG 9413 is not mature enough to address the issue of OS. RTOG 8610, which compared NCHT + WP RT (same as arm 1 of 9413) to WP RT alone, failed to demonstrate a survival advantage until the follow-up was extended out to 8 years.⁸ The study included 471 eligible patients with bulky tumors (T2 to T4). At 8 years, NCHT was associated with improvements in local control (P = .016), disease-free survival (33% v 21%; P = .004), biochemical disease-free survival (P < .0001), and prostate cancer-specific mortality (23% v 31%; P = .05) and with a reduction in the incidence of distant metastases (P = .04). Subset analysis demonstrated that a beneficial effect of short-term androgen ablation on OS was seen in patients with GSs of 2 to 6 (NCHT + WP RT v WP RT alone, 70% v 52%; P = .015). The patients treated on the three arms of RTOG 9413 not including NCHT + WP RT would be expected to have an outcome no worse than the patients treated with RT alone (the control arm of RTOG 8610). Thus, if a survival advantage is shown between NCHT + WP RT and the other three arms, it is unlikely to appear any earlier or be as large as the survival advantage seen on RTOG 8610. Despite this fact, however, reducing the rate of progression without substantially increasing the risk of complications is likely to be beneficial because of delaying the need for salvage hormonal therapy and reducing anxiety related to treatment failure.

This study indicates that the greatest benefit to WP RT + NCHT may be seen in patients with intermediate- to high-risk disease compared with those with the lowest- or highest-risk disease (Table 6). This observation is consistent with two retrospective reports from the University of California, San Francisco.^11,33 These studies demonstrated that patients with a risk of LN involvement of 15% to 35% benefited the most from pelvic nodal RT, whereas those with a risk of less than 15% or more than 35% did not benefit from pelvic nodal RT. Thus, some patients may not benefit because their risk is too low, whereas others may not benefit because their risk of systemic disease is too high. The failure to identify an apparent benefit of pelvic nodal treatment in the lower-risk patients indicates that the lower-risk patients might be the most appropriate candidates for treatment with higher doses of radiation limited to the prostate. These findings have major implications for the large number of patients receiving RT and CAS for clinically localized prostate cancer. However, the failure to identify an apparent benefit of pelvic nodal treatment in the lower-risk patients may be caused by sample size, in that relatively few patients in this category were included in this study.

How do the conclusions of RTOG 9413 relate to those of RTOG 9202 and the trial reported by Bolla et al?⁵ Thus far, the OS curves for patients treated with long- and short-term hormonal therapy on RTOG 9202 are identical.⁶ Therefore, the OS curves for 9413 and 9202 are also likely to be identical because the short-term hormonal therapy arm of 9202 is identical to arm 1 of 9413. On the basis of the preliminary analysis of 9202, only the men with a GS 8 benefited from long-term hormonal therapy.⁶ However, a combined analysis of RTOG trials demonstrated that patients with a GS of 8 to 10 or a GS of 7 and T3 disease benefited from the use of long-term AHT.⁹ Thus, it is also probable that a subset of patients included in 9413 might have benefited from long-term AHT. In contrast to the intermediate-risk patients from 9413, who appeared to benefit the most from WP + NCHT (Table 6), those with a greater burden of systemic disease (GS >6 and PSA >30 ng/mL) may be included in the subset who require long-term AHT.

The failure to see an advantage to NCHT compared with AHT was unexpected given the evidence from animal models.^12,13 This could, in part, be the result of the fact that the patients entered on arms 3 and 4 received CAS during months 5 and 6, whereas patients from arms 1 and 2 completed CAS at the end of month 4. Thus, there could be a bias in assessing the time to PSA failure because the patients on arms 3 and 4 were being treated 2 months later (from the date of randomization) compared with patients treated on arms 1 and 2. The failure to see a benefit from NCHT compared with AHT in combination with PO RT could explain the observed lack of benefit to the use of NCHT in patients receiving PO brachytherapy.³⁴

In conclusion, this phase III trial demonstrates that WP RT + NCHT improves the freedom from progression compared with PO RT + NCHT, PO RT + AHT, and WP RT + AHT in patients with a risk of LN involvement of more than 15%. This study proves that there is a favorable biologic interaction between WP RT and NCHT, but no advantage to short-term NCHT compared with short-term AHT when only the prostate is irradiated. Longer follow-up is required to confirm the trends seen in this study as they apply to secondary end points, because the median survival is not likely to be reached for several more years.

View larger version (23K): [in this window] [in a new window]   Fig 4. Prostate-specific antigen (PSA) control favors whole-pelvic (WP) radiotherapy (RT) and neoadjuvant and concurrent hormonal therapy (NCHT) compared with prostate only (PO) RT and NCHT, and WP RT or PO RT adjuvant hormonal therapy (AHT; P = .048).

	NOTES

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.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted May 1, 2002; accepted January 16, 2003.

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				C. Kadoch, A. V. D'Amico, and R. H. Matthews When Prostate Brachytherapy Fails: A Case Report and Discussion Oncologist, November 1, 2005; 10(10): 799 - 805. [Abstract] [Full Text] [PDF]

				A. Zapatero, F. Valcarcel, F. A. Calvo, R. Algas, A. Bejar, J. Maldonado, and S. Villa Risk-Adapted Androgen Deprivation and Escalated Three-Dimensional Conformal Radiotherapy for Prostate Cancer: Does Radiation Dose Influence Outcome of Patients Treated With Adjuvant Androgen Deprivation? A GICOR Study J. Clin. Oncol., September 20, 2005; 23(27): 6561 - 6568. [Abstract] [Full Text] [PDF]

				A. V. D'Amico, A. A. Renshaw, B. Sussman, and M.-H. Chen Pretreatment PSA Velocity and Risk of Death From Prostate Cancer Following External Beam Radiation Therapy JAMA, July 27, 2005; 294(4): 440 - 447. [Abstract] [Full Text] [PDF]

				T. M. Pisansky External Beam Radiotherapy as Curative Treatment of Prostate Cancer Mayo Clin. Proc., July 1, 2005; 80(7): 883 - 898. [Abstract] [PDF]

				A. V. D'Amico, J. Manola, M. Loffredo, A. A. Renshaw, A. DellaCroce, and P. W. Kantoff 6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients With Clinically Localized Prostate Cancer: A Randomized Controlled Trial JAMA, August 18, 2004; 292(7): 821 - 827. [Abstract] [Full Text] [PDF]

				T. L. DeWeese Radiation Therapy and Androgen Suppression as Treatment for Clinically Localized Prostate Cancer: The New Standard? JAMA, August 18, 2004; 292(7): 864 - 866. [Full Text] [PDF]

				M. Roach III In Reply: J. Clin. Oncol., June 1, 2004; 22(11): 2255 - 2257. [Full Text] [PDF]

				A. Pollack A Call for More With a Desire for Less: Pelvic Radiotherapy With Androgen Deprivation in the Treatment of Prostate Cancer J. Clin. Oncol., May 15, 2003; 21(10): 1899 - 1901. [Full Text] [PDF]

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