From Pages to Practice

By Mridula Nadamuni, MD

Published June 16, 2023


Men who receive a diagnosis of low- or intermediate-risk clinically localized prostate cancer can live for decades. Each treatment option is associated with different effects on quality of life and sexual, urinary, and bowel function. To compare the effectiveness of these treatments, 1643 men (98% white; age range, 50–69 years) in the U.K. with a diagnosis of prostate cancer based on prostate-specific antigen (PSA) testing between 1999 and 2009 were randomized to prostatectomy, radiotherapy, or active monitoring. Previously reported 10-year outcomes for prostate cancer–specific mortality and overall mortality were similar in the three groups. Researchers have now reported 15-year outcomes.

The incidence of the primary endpoint of death from prostate cancer remained similar and low (≈3%) in all three groups, although the incidence of metastases was higher in the active-monitoring group (≈9% vs. 5% in the prostatectomy and radiotherapy groups). By the end of the study, 61% of men randomized to active monitoring had ultimately undergone prostatectomy or radiotherapy and nearly 25% never required further intervention for prostate cancer. Interestingly, 34% of men younger than 65 years in the active-monitoring group changed management to prostatectomy compared with 15% of men 65 years and older.

Although these data suggest that men with low-risk prostate cancer can safely opt for active monitoring over early intervention, some caveats must be noted. The overwhelmingly white study population limits the relevance of the results in diverse populations. Further, the standard of care for evaluating PSA and the tools available for monitoring and characterization of prostate cancer have changed during the 15 years since the trail began. In 1999, the standard of care was to sample the PSA, biopsy those with an elevated PSA level, and then treat. Today, obtaining a multiparametric magnetic resonance image (mpMRI) is standard for grading tumors of the prostate and specific membrane antigen positron-emission-tomographic (PET) scans can better assess staging. That taken together with genomic assessments helps more precisely identify which patients receive biopsy. Finally, new systemic therapies for progressive disease continue to advance.

In sum, men with PSA-detected localized prostate cancer who received active surveillance over radical intervention continued to have similarly low mortality rates after 15-years of follow up. Clinicians can use this information when discussing therapy options with patients.

Read the following NEJM Journal Watch summary for more details of this study.

Treating Localized Prostate Cancer: Long-Term Outcomes from a Randomized Trial

Allan S. Brett, MD, reviewing Hamdy FC et al. N Engl J Med 2023 Mar 11 Sartor O. N Engl J Med 2023 Mar 11

In the ProtecT trial, 1643 men with localized, mostly low-risk prostate cancer (77% with Gleason score of 6) were randomized to radical prostatectomy, radiotherapy with neoadjuvant androgen deprivation, or active surveillance based primarily on serial prostate-specific antigen (PSA) testing. In previously published findings, prostate cancer–specific mortality (≈1%) and overall mortality (≈10%) were similar in the three groups at 10 years (NEJM JW Gen Med Nov 1 2016 and N Engl J Med 2016; 375:1415, 1425).

Now, researchers report outcomes after median follow-up of 15 years:

  • Prostate cancer–specific mortality was similar in the three groups (≈3%).

  • Overall mortality was similar in all groups (≈22%).

  • Metastases developed more commonly in the active-surveillance group (9.4%) than in the other two groups (≈5%).

  • 61% of active-surveillance patients had transitioned to prostatectomy or radiotherapy.

  • Reevaluation of risk status suggested that one third of patients had intermediate- or high-risk disease at baseline; nevertheless, prostate cancer–specific mortality in these men was not significantly higher with active surveillance than with prostatectomy or radiotherapy.

In a separate article, long-term patient-reported symptoms are described. The data are complex because symptoms changed somewhat over time, and more than half of active-surveillance patients eventually transitioned to radical treatment. But between years 7 and 12 of follow-up, urinary leakage and lack of firm erections remained more common in the prostatectomy group than in the other groups (by ≈5–10 percentage points), and fecal leakage was more common in the radiotherapy group (by ≈5 percentage points).

Comment: Patients were enrolled in this trial between 2001 and 2009; since then, much has changed in evaluating elevated PSA, managing prostate cancer, and intensity of active surveillance. Nevertheless, the trial confirms favorable outcomes with active surveillance of low-risk localized prostate cancer. Active surveillance also appeared comparable to initial radical treatment in patients whose tumors were not low-grade, but the study was underpowered to reach definitive conclusions for that subgroup.

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Mridula Nadamuni, MD, is a 2022–2023 NEJM Editorial Fellow. She completed her internal medicine/pediatrics residency and chief residency at UT Southwestern Medical Center.
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