Results of a randomized trial of treatment modalities in patients with low or early-intermediate risk prostate cancer (PREFERE trial)

Thomas Wiegel, Peter Albers, Detlef Bartkowiak, Roswitha Bussar-Maatz, Martin Härter, Glen Kristiansen, Peter Martus, Stefan Wellek, Heinz Schmidberger, Klaus Grozinger, Peter Renner, Fried Schneider, Martin Burmester, Michael Stöckle, Thomas Wiegel, Peter Albers, Detlef Bartkowiak, Roswitha Bussar-Maatz, Martin Härter, Glen Kristiansen, Peter Martus, Stefan Wellek, Heinz Schmidberger, Klaus Grozinger, Peter Renner, Fried Schneider, Martin Burmester, Michael Stöckle

Abstract

Purpose: The optimal treatment for patients with low to early-intermediate risk prostate cancer (PCa) remains to be defined. The randomized PREFERE trial (DRKS00004405) aimed to assess noninferiority of active surveillance (AS), external-beam radiotherapy (EBRT), or brachytherapy by permanent seed implantation (PSI) vs. radical prostatectomy (RP) for these patients.

Methods: PREFERE was planned to enroll 7600 patients. The primary endpoint was disease specific survival. Patients with PCa stage ≤ cT2a, cN0/X, M0, PSA ≤ 10 ng/ml and Gleason-Score ≤ 3 + 4 at reference pathology were eligible. Patients were allowed to exclude one or two of the four modalities, which yielded eleven combinations for randomization. Sixty-nine German study centers were engaged in PREFERE.

Results: Of 2251 patients prescreened between 2012 and 2016, 459 agreed to participate in PREFERE. Due to this poor accrual, the trial was stopped. In 345 patients reference pathology confirmed inclusion criteria. Sixty-nine men were assigned to RP, 53 to EBRT, 93 to PSI, and 130 to AS. Forty patients changed treatment shortly after randomization, 21 to AS. Forty-eight AS patients with follow-up received radical treatment. Median follow-up was 19 months. Five patients died, none due to PCa; 8 had biochemical progression after radical therapy. Treatment-related acute grade 3 toxicity was reported in 3 RP patients and 2 PSI patients.

Conclusions: In this prematurely closed trial, we observed an unexpected high rate of termination of AS and an increased toxicity related to PSI. Patients hesitated to be randomized in a multi-arm trial. The optimal treatment of low and early-intermediate risk PCa remains unclear.

Keywords: Active surveillance; External beam radiotherapy; Permanent seed implantation; Prostate cancer; Prostatectomy; Randomized clinical trial.

Conflict of interest statement

The author declares that there is no competing interest.

Figures

Fig. 1
Fig. 1
Flow chart of the PREFERE trial, recruiting from September 2012 to December 2016. AS active surveillance, RP radical prostatectomy, EBRT External beam radiotherapy, PSI Permanent seed implantation
Fig. 2
Fig. 2
Kaplan–Meier estimates for a the cumulative probability of undergoing radical intervention during the follow-up period, stratified by treatment, including immediate changes. AS curve: Active treatment for confirmed progression; b freedom from biochemical progression. For patients who discontinued active surveillance, analysis starts at the time of active treatment. AS: active surveillance; EBRT: external beam radiotherapy; PSI: permanent seed implantation; RP: radical prostatectomy
Fig. 3
Fig. 3
Toxicity (CTCAE) after radical treatment, including patients who discontinued active surveillance. a Acute toxicity (N = 220); b toxicity 12 months after radical treatment (N = 178). RP: radical prostatectomy; PSI: permanent seed implantation; EBRT: external beam radiotherapy
Fig. 4
Fig. 4
Quality of life of PREFERE patients at various times after trial entry (including men who changed trial arm immediately after randomization). a Overall quality of life according to QLQ C30 questionnaires; b sexual activity according to QLQ PR 25 questionnaires. Mean values with 95% confidence intervals are shown. Identical X-values slightly offset to improve legibility. AS active surveillance, EBRT external beam radiotherapy, PSI permanent seed implantation, RP radical prostatectomy

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