Clinical Investigation
An Update of the Phase III Trial Comparing Whole Pelvic to Prostate Only Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression: Updated Analysis of RTOG 94-13, With Emphasis on Unexpected Hormone/Radiation Interactions

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Purpose

This trial was designed to test the hypothesis that total androgen suppression and whole pelvic radiotherapy (WPRT) followed by a prostate boost improves progression-free survival (PFS) by ≥10% compared with total androgen suppression and prostate only RT (PORT). This trial was also designed to test the hypothesis that neoadjuvant hormonal therapy (NHT) followed by concurrent total androgen suppression and RT improves PFS compared with RT followed by adjuvant hormonal therapy (AHT) by ≥10%.

Methods and Materials

Patients eligible for the study included those with clinically localized adenocarcinoma of the prostate and an elevated prostate-specific antigen level of <100 ng/mL. Patients were stratified by T stage, prostate-specific antigen level, and Gleason score and were required to have an estimated risk of lymph node involvement of >15%.

Results

The difference in overall survival for the four arms was statistically significant (p = 0.027). However, no statistically significant differences were found in PFS or overall survival between NHT vs. AHT and WPRT compared with PORT. A trend towards a difference was found in PFS (p = 0.065) in favor of the WPRT + NHT arm compared with the PORT + NHT and WPRT + AHT arms.

Conclusions

Unexpected interactions appear to exist between the timing of hormonal therapy and radiation field size for this patient population. Four Phase III trials have demonstrated better outcomes when NHT was combined with RT compared with RT alone. The Radiation Therapy Oncology Group 9413 trial results have demonstrated that when NHT is used in conjunction with RT, WPRT yields a better PFS than does PORT. It also showed that when NHT + WPRT results in better overall survival than does WPRT + short-term AHT. Additional studies are warranted to determine whether the failure to demonstrate an advantage for NHT + WPRT compared with PORT + AHT is chance or, more likely, reflects a previously unrecognized biologic phenomenon.

Introduction

Combining hormonal manipulation with radiotherapy for patients with clinically localized intermediate- and/or high-risk prostate cancer has become a standard of care on the basis of the results from multiple prospective randomized trials 1, 2, 3, 4. Four Phase III randomized trials used short-term neoadjuvant hormonal therapy (NHT) in combination with external beam radiotherapy (RT), and all demonstrated an improvement in either overall survival (OS) or freedom from prostate-specific antigen (PSA) failure 2, 5, 6, 7. In three of these studies, only the prostate was irradiated 5, 6, 7. To date, all the studies using long-term hormonal therapy for high-risk disease incorporated whole pelvic (WP) RT 1, 3, 4. However, some investigators believe it is not necessary to treat the pelvic lymph nodes, either because they believe that lymph node disease is tantamount to distant metastasis or, potentially, that hormonal manipulation will address microscopically involved lymph nodes, because it appears to help prevent and/or treat potential microscopic distant metastasis.

In addition to the scope of the radiation required, the question of timing of androgen suppression remains. Is NHT better or worse than adjuvant hormonal therapy (AHT) or are they equivalent?

The Radiation Therapy Oncology Group (RTOG) study 94-13 was designed to answer both questions. This trial was a multicenter prospective randomized trial designed to answer the questions concerning the value of prophylactic whole pelvic radiotherapy (WPRT) in patients who had an assessed risk of lymph node involvement of >15% (Roach formula) (8). It was also designed to answer the question of the timing of hormonal therapy (neoadjuvant vs. adjuvant) on progression-free survival (PFS). This analysis is an update of the results of RTOG 94-13 with specific focus on the unexpected interaction between field size and the timing of hormonal therapy.

Section snippets

Eligibility

Patients eligible for this trial included those with histologically confirmed, clinically localized adenocarcinoma of the prostate with an elevated PSA level of ≤100 ng/mL. Patients were stratified by T stage (T1c-T2a vs. T1b-T2b vs. T2c-T4), PSA level (<30 vs. ≥30 ng/mL), and Gleason score (<7 vs. 7–10). PSA stratification was determined from the median PSA level observed in an earlier high-risk patient study 9, 10. Additionally, eligible patients were required to have an estimated risk of

Results

This study was activated April 1, 1995, and closed June 1, 1999, with a total of 1,323 patients accrued. Of the 1,323 patients, 1,292 (98%) were considered eligible and properly entered into the study. The pretreatment characteristics of the patients are summarized in Table 1. The median age was 70 years, and nearly 23% were of African-American descent. The median PSA level was 22.6 ng/mL, and two-thirds of the patients had clinical disease Stage T2c–T4, with 73% having a Gleason score of ≥7.

Discussion

Questions regarding the timing of hormonal therapy, as well as radiation field size, in patients with adenocarcinoma of the prostate with a risk of lymph node involvement of >15% were the primary goals of this study. PFS (Fig. 1) showed that no difference resulted in PFS according to the timing of hormonal therapy. Figure 2 showed that no difference resulted in PFS by radiation field size. However, a lack of a benefit for WPRT vs. PORT or AHT vs. NHT in this group of patients was not likely to

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