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

Colleen A. Lawton, M.D. IJROBP 2007;69:646
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. 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. In three of these studies, only the prostate was irradiated To date, all the studies using long-term hormonal therapy for high-risk disease incorporated whole pelvic (WP) RT 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). 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.

Methods and Materials

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. Additionally, eligible patients were required to have an estimated risk of lymph node involvement of >15%, according to the equation: . Patients with T2c-T4 tumors were also eligible if they had a Gleason score of ≥6, even if their calculated risk of lymph node involvement did not reach 15%. Patients who underwent surgical staging or who had metastatic disease were ineligible. Other eligibility criteria included a Karnofsky performance status of ≥70%; no prior hormonal therapy, radiotherapy, or chemotherapy; and liver function test results ≤1.2 times the upper limit of normal. In addition, all patients provided written consent before randomization.

All patients in the trial underwent total androgen suppression (TAS), which consisted of goserelin acetate 3.6 mg/mo subcutaneously or leuprolide acetate 7.5 mg/mo intramuscularly and oral flutamide 250 mg three times daily for 4 months. Patients receiving NHT began hormonal therapy 2 months before RT and continued to receive it during RT. Those patients receiving AHT began it immediately after RT completion.

Radiotherapy was given at 1.8 Gy/fraction to a total dose of 70.2 Gy calculated at the isocenter. Radiotherapy WPRT consisted of conventional four-field box technique with a minimal unblocked field size of 16 × 16 cm to a maximal central axis dose of 50.4 Gy. Patients undergoing WPRT were treated with an additional 19.8 Gy to the prostate using a cone-down boost technique. Prostate-only RT (PORT) was limited to the prostate and seminal vesicles, with a maximal unblocked field size of 11 × 11 cm to a total central axis dose of 70.2 Gy. A urethrogram was required as part of the simulation, and the inferior edge of the field was to be placed ≥1 cm below the point at which the contrast narrowed (apex of the penile urethra) to ensure coverage of the prostate.

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 showed that no difference resulted in PFS according to the timing of hormonal therapy. 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 be found, because in the design of the study it was assumed that no interaction would occur between the field size and the timing of hormonal therapy. Clearly, this exists, and therefore, the analysis of this study becomes more complex.

What is clear is that the study was not powered to compare the four treatment arms one against the other. However, when one considers the WPRT + NHT arms vs. PORT + NHT arm, a trend is seen toward statistical significance in the endpoints of PFS (p = 0.066), and biochemical failure using the Phoenix definition (nadir + 2 ng/mL; p = 0.0098). This suggests that if one chooses to use NHT for this population of prostate cancer patients, WPRT appears to provide a benefit compared with PORT. To expand on the concept of NHT using the data presented in this study,  shows the PFS curves for WPRT + NHT vs. the other three arms of this trial. This analysis was not statistically valid based on the design of the trial, but it seemed reasonable to evaluate as we tried to understand the interactions between the timing of hormonal therapy and the field size. one certainly could make an additional argument in favor of WPRT + NHT that would correspond to the results of RTOG 92-02 and 86-10. This result is further supported by a subset analysis of Arms 1 and 2 of RTOG 94-13 by Roach. This analysis showed a clear benefit in both biochemical control and PFS in favor of WPRT. Given the results of RTOG protocol 92-02 and 86-10  it seems reasonable that for this population one would chose NHT.

Another clear observation is that WPRT + AHT is the least desirable option with regard to OS. shows that WPRT and AHT had a trend toward worse OS compared with the other three arms (p = 0.019 vs. WPRT + NHT, p = 0.019 vs. PORT + NHT, and p = 0.01 vs. PORT + AHT).  The observation that WPRT + AHT would offer a worse outcome is somewhat surprising given the results of WPRT + NHT. Yet when one evaluates the published randomized data suggesting the use of hormonal therapy in this group of patients, none of the data to date have looked at short-course AHT. Therefore, the result, although unexpected, was not incongruous with previous data, because the previous data for AHT used only long-term AHT (i.e., 2–3 years).

Therefore, why would WPRT appear to be beneficial when hormonal therapy is given neoadjuvantly and concurrently as in Arm 1, yet detrimental to survival when given adjuvantly? Also, the reason no interaction was seen in the PORT arms (Arms 2 and 4) is unclear.

One possible explanation for the benefit of WPRT + NHT compared with WPRT + AHT could lie in the immune modulation of antiandrogen therapy. Mercader have shown that antiandrogen ablation therapy results in T-cell infiltration of the prostate, increasing apoptosis. This peaks at about 3–4 weeks into treatment with hormonal therapy. It might be that T-cell infiltration occurs within the involved lymph nodes, such that an increase in apoptosis occurs before and during RT, making RT more effective at the doses used to treat the lymph nodes. Because we did not see a statistically significant difference between PORT + NHT and PORT + AHT, the above phenomena could be dose dependent, such that the dose of 70 Gy is great enough that we could not see the effects. Other investigators have noted a beneficial effect of intratumoral T cells in other malignancies such as ovarian carcinoma.

Given that it is not questioned that an interaction exists between the timing of hormonal therapy and the RT field size in this patient population, one is left with how best to treat these patients. This study could not answer this question definitely, because it was not powered to compare the four arms separately. More studies are needed to determine the best treatment for these patients. We are left with the other prospective randomized data that exist for the treatment of locally advanced/high-risk prostate cancer. Data from the RTOG trial 92-02 showed that neoadjuvant, concurrent, and long-term hormonal therapy with RT is superior to neoadjuvant plus concurrent hormonal therapy with RT for this patient population (4). Given those data and the other long-term hormonal therapy trials, all of which have used WPRT 1, 3, WPRT with long-term hormonal therapy remains the standard against which future trials should be developed.