Participants

A total of 545 men were randomly assigned to active monitoring, 553 to radical prostatectomy, and 545 to radiotherapy. The median age of the participants was 62 years (range, 50 to 69), the median PSA level at the prostate-check clinic was 4.6 ng per milliliter (range, 3.0 to 19.9), 77% had tumors with a Gleason score of 6 (on a scale from 6 to 10, with higher scores indicating a worse prognosis), and 76% had stage T1c disease; there were no meaningful differences at baseline among the three randomized groups.6 Information on baseline demographic and clinical characteristics according to assigned treatment group is provided in Table S2 in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Trial Design and Oversight

Figure 1. Figure 1. Randomization, Treatment, and Follow-up. A total of 88% of the men assigned to active monitoring, 71% of the men assigned to surgery, and 74% of men assigned to radiotherapy received the assigned treatment within 9 months after randomization. A total of 14 patients were lost to follow-up for secondary outcomes, but data on deaths were captured for all participants.

Details of the screening, randomization, and follow-up of patients in the ProtecT trial were published previously6 and are shown in Figure 1. Approval for the trial was obtained from the U.K. East Midlands (formerly Trent) Multicenter Research Ethics Committee (01/4/025). The trial was overseen by an independent trial steering committee and a separate data and safety monitoring committee. All the participants provided written informed consent. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol, available at NEJM.org.

Randomization

Treatment options were discussed with the men, and 1643 men (62% of the eligible participants) agreed to undergo randomization. Treatment assignments were stratified according to site, with stochastic minimization to improve the balance across the groups with respect to age, Gleason score (<7, 7, or 8 to 10 points), and the mean of the baseline and first biopsy PSA test results together (<6.0, 6.0 to 9.9, or >9.9 ng per milliliter). After randomization, clinicians and participants were aware of the group assignments.

Treatment Procedures and Clinical Management

Clinical management was standardized with the use of trial-group–specific pathways. The purpose of active monitoring was to minimize the risk of overtreatment by avoiding immediate radical intervention and by monitoring disease progression regularly, so that radical treatment with curative intent could be given as necessary. Triggers to reassess patients and consider a change in clinical management were based largely on changes in PSA levels. This was very different from “watchful waiting” in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) and in the U.S. Prostate Cancer Intervention versus Observation Trial (PIVOT), which had no planned protocol for curative radical intervention on disease progression.2,4 Serum PSA levels were measured every 3 months in the first year and every 6 to 12 months thereafter. Changes in PSA levels were assessed. An increase of at least 50% during the previous 12 months triggered a review. Management options included continued monitoring or further tests and radical or palliative treatments as required.

The radiotherapy protocol included neoadjuvant androgen-deprivation therapy for 3 to 6 months before and concomitantly with three-dimensional conformal radiotherapy delivered at a total dose of 74 Gy in 37 fractions. The protocol for quality assurance followed the RT01 trial procedures.7-9 The trial oncologist held a review appointment with participants if PSA levels rose by at least 2.0 ng per milliliter above the nadir or if concerns were raised about progression. Management options included continued monitoring, additional testing, salvage therapy, or palliative treatments.

In men assigned to surgery, postoperative PSA levels were measured every 3 months for the first year, every 6 months for 2 years, and yearly thereafter. Adjuvant or salvage radiotherapy was discussed with patients who had positive surgical margins, extracapsular disease, or a postoperative PSA level of 0.2 ng per milliliter or higher. In all groups, androgen-deprivation therapy was offered when PSA levels reached 20 ng per milliliter or less, if indicated. Imaging of the skeleton was recommended if the PSA level reached 10 ng per milliliter.

Clinical Outcome Measures

The primary outcome measure was prostate-cancer mortality at a median of 10 years of follow-up, with prostate-cancer–related deaths defined as deaths that were definitely or probably due to prostate cancer or its treatment. The process for ascertaining cause of death was adapted from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC).10-12 The independent cause-of-death evaluation committee, whose members were unaware of the treatment assignments, reviewed summaries of anonymized records. Deaths were categorized as definitely, probably, possibly, probably not, or definitely not due to prostate cancer.13,14

Secondary outcomes included all-cause mortality and the rates of metastases, clinical progression, primary treatment failure, and treatment complications. Metastatic disease was defined as bony, visceral, or lymph-node metastases on imaging or PSA levels above 100 ng per milliliter. Patients were considered to have clinical progression if they had any of the following: evidence of metastases, diagnosis of clinical T3 or T4 disease, long-term androgen-deprivation therapy, ureteric obstruction, rectal fistula, or the need for a urinary catheter owing to local tumor growth. Primary treatment failure after surgery was defined as a PSA level of 0.2 ng per milliliter or higher at 3 months after surgery, and primary treatment failure after radiotherapy was defined according to the Phoenix Consensus Conference recommendations.15

Although some events of clinical progression such as metastases could be reported uniformly, manifestations of local progression could differ between men receiving radical treatment and those receiving active monitoring because of differences in treatment assignments. After surgery, the serious intervention-related complications that were recorded were death, transfusion of more than 3 units of blood, thromboembolic or cardiovascular events, rectal injury, and anastomotic problems requiring intervention. After radiotherapy, the complications that were recorded were death and any treatment-related toxic effect resulting in major surgical intervention. Intervention-related complications within 90 days after the completion of treatment were recorded.

Statistical Analysis

A prespecified statistical analysis plan was developed before the data for the primary analysis were accessed16 (see the Supplementary Appendix). The primary outcome of prostate-cancer mortality (the rate of death due to prostate cancer or its treatment) was compared among the three assigned treatment groups on an intention-to-treat basis with the use of Cox proportional-hazards regression adjusted for trial center, age at baseline, Gleason score, and PSA level at baseline (log-transformed). The results of an alternative cumulative-incidence approach with competing risks regression are shown in Figs. S1 and S2 and Table S1 in the Supplementary Appendix. Prostate-cancer–specific mortality is reported with 95% confidence intervals for each treatment group, and pairwise significance tests were planned if a test of the null hypothesis of no difference in 10-year disease-specific risk of death across all three groups yielded a P value of less than 0.05. This conditional approach was designed to keep the overall false positive rate at 5%.17 The primary analysis approach was adapted as necessary for secondary outcomes. Four prespecified subgroup analyses were conducted with the use of relevant interaction terms: age, clinical stage, Gleason score, and PSA level. All analyses were conducted with the use of Stata software, version 14.1 (StataCorp).