Elsevier

European Urology

Volume 66, Issue 2, August 2014, Pages 243-250
European Urology

Platinum Priority – Prostate Cancer
Editorial by Bruce J. Trock on pp. 251–252 of this issue
Adjuvant Radiotherapy Versus Wait-and-See After Radical Prostatectomy: 10-year Follow-up of the ARO 96–02/AUO AP 09/95 Trial

https://doi.org/10.1016/j.eururo.2014.03.011Get rights and content

Abstract

Background

Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy.

Objective

To determine the efficiency of ART after a 10-yr follow-up in the ARO 96–02 study.

Design, setting, and participants

After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional conformal ART with 60 Gy. The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP (ITT2 population)—that is, 159 WS plus 148 ART men.

Outcome measurements and statistical analysis

The primary end point of the study was progression-free survival (PFS) (events: biochemical recurrence, clinical recurrence, or death). Outcomes were compared by log-rank test. Cox regression analysis served to identify variables influencing the course of disease.

Results and limitations

The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p < 0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred.

Conclusions

Compared with WS, ART reduced the risk of (biochemical) progression with a hazard ratio of 0.51 in pT3 PCa. With only one grade 3 case of late toxicity, ART was safe.

Patient summary

Precautionary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors.

Introduction

For patients with localized prostate cancer (PCa), radical prostatectomy (RP) and external-beam radiotherapy (RT) enable an adjusted 10-yr overall survival (OS) of 83% and 89%, respectively [1]. After prostatectomy, 15–25% of the patients experience recurrence [2]. With adverse risk factors such as high serum levels of prostate-specific antigen (PSA), pT3, positive surgical margins (R1), and Gleason score ≥8, the 10-yr biochemical recurrence rates may grow to 75% [3]. Although not all PSA-relapsing patients will develop clinical progression, surgery alone may be inadequate for specific subgroups [4].

Three randomized prospective trials—SWOG 8794, European Organization for Research and Treatment of Cancer (EORTC) 22911 (10-yr data), and ARO 96–02 (5-yr data)—reported improved (biochemical) progression-free survival (PFS) after adjuvant RT (ART) with hazard ratios (HRs) between 0.43 and 0.53 [5], [6], [7]. Only SWOG also found a profit in OS and metastasis-free survival (MFS). As PSA recurrence precedes clinical progression by a median of 8 yr, long-term results of these studies are of major interest [8]. In this paper, we report the 10-yr follow-up of the ARO/AUO trial. Exclusively including patients who achieved an undetectable PSA after RP, the ARO/AUO trial is the one truly adjuvant trial among the three. Different from the two older trials, ARO 96–02 consistently incorporated three-dimensional (3D) conformal treatment planning, improving comparability with recent techniques.

Section snippets

Trial design and participants

Tumor stages were determined according to the 1992 International Union Against Cancer criteria [9]. Patients had histologically proven cT1–cT3N0 PCa preoperatively. Before entry, all patients underwent preoperative and postoperative PSA testing, bone scan, and chest radiography. Eligible patients had histologically proven adenocarcinoma of the prostate with no known distant metastases and a pathologic stage pT3–4 pN0 with positive or negative surgical margins. Patients had to be <76 yr, with a

Results

From 1997 to 2004, 388 patients entered the trial after RP but before achieving an undetectable PSA: 194 patients were assigned to the WS policy (arm A), and 194 patients were assigned to ART (arm B). Three patients were excluded because of immediate HT (Fig. 1). Seventy-eight patients (20%) who did not achieve an undetectable PSA were stated to have progressive disease (arm A, 33 patients; arm B, 45 patients). Of these 78 patients, 74 underwent RT; 4 patients refused RT. In this paper, we

Discussion

Concordant with earlier results and other prospectively randomized clinical trials, our data show an improved PFS after ART that reduced the relative risk of long-term biochemical relapse by 51% [5], [6], [7]. Our study differs from the SWOG and the EORTC trials in that achieving an undetectable PSA after RP (<0.5 ng/ml) was mandatory for inclusion. Thus, the ITT2 cohort demonstrates directly that PSA-negative patients do profit from ART after RP. Indirectly, this finding had also been deduced

Conclusions

We demonstrated that ART can improve biochemical PFS after RP for pT3 PCa. RT-related toxicity was rare and largely mild to moderate. Men with positive surgical margins are the most likely candidates to profit from adjuvant treatment. However, proving an effect on hard end points may require larger patient cohorts and longer follow-up.

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