Clinical Investigation
Radiation Dose Escalation or Longer Androgen Suppression to Prevent Distant Progression in Men With Locally Advanced Prostate Cancer: 10-Year Data From the TROG 03.04 RADAR Trial

https://doi.org/10.1016/j.ijrobp.2019.11.415Get rights and content

Purpose

To clarify the relative effects of duration of androgen suppression (AS) and radiation dose escalation (RDE) on distant progression (DP) in men with locally advanced prostate cancer.

Methods and Materials

Participants with locally advanced prostate cancer in the TROG 03.04 RADAR trial were randomized to 6 or 18 months AS ± 18 months zoledronic acid (Z). The trial incorporated a RDE program by stratification at randomization and dosing options were 66, 70, or 74 Gy external beam radiation therapy (EBRT), or 46 Gy EBRT plus high-dose-rate brachytherapy boost (HDRB). The primary endpoint for this study was distant progression (DP). Secondary endpoints included local progression, bone progression, prostate cancer-specific mortality and all-cause mortality. Effect estimates for AS duration and RDE were derived using Fine and Gray competing risk models adjusting for use of Z, age, tumor stage, Gleason grade group, prostate-specific antigen, and treatment center. Cumulative incidence at 10 years was estimated for each RDE group.

Results

A total of 1051 out of 1071 randomized subjects were eligible for inclusion in this analysis. Compared with 6 months AS, 18 months AS significantly reduced DP independently of radiation dose (subhazard ratio 0.70; 95% confidence interval [CI], 0.56-0.87; P = .002). No statistically significant interaction between effect of AS duration and RT dose was observed (Wald test P = .76). In subgroup analyses, DP was significantly reduced by the longer duration of AS in the 70 Gy and HDRB groups but not in the 66 Gy and 74 Gy. Compared with 70 Gy, HDRB significantly reduced DP (subhazard ratio 0.68 [95% CI, 0.57-0.80]; P < .0001) independently of AS duration. At 10 years, adjusted cumulative incidences were 26.1% (95% CI, 18.9%-33.2%), 26.7% (22.9%-30.6%), 24.9% (20.0%-29.8%) and 19.7% (15.5%-23.8%) for DPs in the respective radiation dose groups.

Conclusions

Compared with 6 months AS, 18 months AS reduced DP independently of radiation dose. Men treated with HDRB gained a significant benefit from a longer duration of AS. Evidence of improved oncologic outcomes for HDRB compared with dose-escalated EBRT needs to be confirmed in a randomized trial.

Introduction

Opinion remains divided on how much androgen suppression (AS) is necessary for men with locally advanced prostate cancer if they are treated with escalated radiation (RT) doses.

In our first report of our RT dose escalation substudy for the RADAR trial, we found that increasing AS and RT dose escalation independently reduced local progressions.1 We had insufficient data at that time, with minimum follow-up of 6.5 years after randomization, to determine whether a reduction in distant progressions and prostate cancer deaths had been achieved by either treatment modality. With minimum follow-up of 10 years, we now have sufficient data to address these outcomes. In this report our aims are (1) to test if longer AS influences distant progression and the other secondary endpoints independently of RT dose, (2) to estimate the effect of AS duration within strata of RT doses, and (3) to assess if there is an independent ordered effect of RT dose on outcomes.

Section snippets

Patients and treatment

Men with histologically confirmed adenocarcinoma of the prostate without lymph node or systemic metastases, and with cT2b-4 stage primary tumors or cT2a stage primary tumors with Gleason score ≥7 and baseline prostate-specific antigen (PSA) levels ≥10 ng/mL, were eligible to participate after providing informed consent. All subjects received the standard treatment of 6 months of leuprorelin (22.5 mg every 3 months, intramuscularly) commencing at randomization, 5 months before RT to the prostate

Results

Of the 1071 trial subjects, 1051 subjects who received radiation therapy as specified in the trial protocol were eligible for inclusion in these analyses. Four out of the 23 participating centers were equipped with HDRB facilities. Median follow-up duration from randomization was 10.5 years (interquartile range, 8.2-11.8 years). Baseline characteristics and RT dose assignment were well balanced between the AS groups (Table 1). There were some imbalances in baseline characteristics according to

Discussion

This study explores the duration of AS in the context of dose-escalated radiation therapy using 10-year data from the RADAR trial for locally advanced, high-risk PC. To our knowledge, RADAR is the first RCT to randomize subjects to short or longer AS after stratifying by radiation dose. Subjects received either 6AS or 18AS in combination with one of 4 RT dosing options: 66 Gy, 70 Gy, 74 Gy, or HDRB. Our study showed no evidence of an interaction between AS duration and RT dose and that

Conclusions

Our study showed that 18 months of AS significantly reduced distant progression compared with 6 months AS independently of RT dose. It also provides the first definitive evidence of the benefit of a longer duration of AS in men treated with EBRT plus HDR boost, confirming that extreme-dose escalated RT does not obviate the need for AS. Based on these findings, 18 months of AS together with EBRT plus HDR boost should be considered an effective option for men with locally advanced, high-risk PC.

References (27)

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This work was supported by the National Health and Medical Research Council of Australia (Project Application ID 300705, 455521 and 1099149); The Goodfellow Foundation, Auckland (New Zealand); Cancer Standards Institute of New Zealand; Novartis Pharmaceuticals Australia; and AbbVie Pharmaceuticals Australia.

Disclosures: J.W.D. reports grants from Novartis Pharmaceuticals and grants and nonfinancial support from AbbVie during the conduct of the study. All other authors declare no competing interests.

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