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‘Very Good News’ About Localized Prostate Cancer: ProtecT Results

MILAN — Men newly diagnosed with localized prostate cancer can rest assured that whatever their initial choice of therapy — whether surgery, radiation, or active monitoring — all will have a high probability for good long-term outcomes.

That’s the welcome take-home message from investigators in the massive Prostate Testing for Cancer and Treatment (ProtecT) trial, in which more than 82,000 men were screened with prostate specific antigen (PSA) testing from 1999 through 2009.

Among these screened men, 2664 were diagnosed with localized prostate cancer, and 1643 men in this group were then randomly assigned to receive either radical prostatectomy, radiotherapy, or active monitoring.

At a median 15 years of follow-up there were no significant differences among the treatment groups in either prostate cancer death or all-cause mortality rates, the researchers report.

“Radical treatments (prostatectomy or radiotherapy) reduced the incidence of metastasis, local progression, and long-term androgen-deprivation therapy by half as compared with active monitoring. However, these reductions did not translate into differences in mortality at 15 years, a finding that emphasizes the long natural history of this disease,” note the authors, led by Freddie C. Hamdy, MD, from Oxford University the United Kingdom.

The study was published online March 11 in New England Journal of Medicine to coincide with presentation of the data at the European Association of Urology (EAU) Congress in Milan, Italy, in-person and virtually.

“The fact that the greater progression of disease seen under active monitoring didn’t translate into higher mortality will be both surprising and encouraging to urologists and patients,” commented Peter Albers, MD, a urologist at Düsseldorf University in Germany and chair of the EAU’s Scientific Congress Office.

“Active monitoring and biopsy protocols today are much more advanced than at the time this trial was conducted, so it’s possible we could improve on these outcomes still further. It’s an important message for patients that delaying treatment is safe, especially as that means delaying side effects as well,” he said. “It’s also clear that we still don’t know enough about the biology of this disease to determine which cancers will be the most aggressive, and more research on this is urgently needed.”

Balancing Act

Given the similarities in long-term survival outcomes regardless of the treatment assigned at baseline, the choice of therapy involves weighing

trade-offs between benefits and harms associated with treatments for localized prostate cancer, Hamdy and colleagues concluded.

In an editorial accompanying the study, Oliver Sartor, MD, from Tulane Medical School in New Orleans, Louisiana, notes that the authors’ recommendation for men and their clinicians to weigh the benefits and harms of treatment is “perhaps not the hoped-for conclusion for treatment advocates, given the duration and size of the trial.”

“The side effects of radical prostatectomy and radiation therapy are well annotated, and many men have substantial sexual or urinary dysfunction after definitive local treatments,” he continued. “Today, as ever, less intensive approaches to the treatment of prostate cancer are clearly needed.”

Indeed, the investigators found that the adverse effects of radiotherapy and surgery on sexual and urinary function persisted for up to 12 years.

Sartor also pointed out, however, that prostate cancer screening, diagnosis, and management have evolved substantially since the ProtecT trial was initiated in 1999.

For example, in the active monitoring group, an increase of at least 50% in the PSA level over 1 year “or any concern on the part of the patient or clinician” would then trigger a review, with the patient then either continuing on monitoring or going on to further testing and either radiotherapy, radical prostatectomy, or palliative care.

“Active monitoring as performed in the ProtecT trial should not be used today. We can do better by adding serial multiparametric MRI assessments. The increased rate of metastasis that was noted in the ‘active monitoring’ group would likely be diminished with the active surveillance protocols that are being used today,” Sartor stated.

The study results also laid bare inadequacies in disease staging, he added, pointing out that the “vast majority of the trial patients were at low risk or favorable intermediate risk and would today be considered appropriate candidates for active surveillance.”

ProtecT Details

The study enrolled 1643 men diagnosed with localized prostate cancer and with a life expectancy of more than 10 years, randomly assigning them to receive either active monitoring (545 patients), radical prostatectomy (553), or external-beam radiotherapy (545).   

Patients assigned to radiotherapy also received neoadjuvant androgen-deprivation therapy (ADT) for 3 to 6 months, and patients assigned to surgery who had positive surgical margins, extracapsular disease, or a residual postoperative PSA of 0.2 ng/mL or higher were offered the option of adjuvant or salvage radiotherapy.

Remarkably, follow-up was complete for 1610 (98%) of all patients enrolled and randomized.

In all, 45 men died from prostate cancer. The rates of prostate cancer deaths by treatment type were 3.1% with active monitoring, 2.2% with prostatectomy, and 2.9% with radiotherapy (P = .53). Rates of death from any cause were 16.2, 15.0, and 15.0 per 1000 person-years, respectively, and did not differ significantly between the treatment groups.

Significantly more metastases occurred among men who were assigned to active monitoring, at 9.4% compared with 4.7% assigned to prostatectomy (hazard ratio (HR), 0.47) and 5% assigned to radiation (HR, 0.48).

More men assigned to active monitoring started on long-term ADT (12.7%) compared with 7.2% assigned to prostatectomy and 7.7% assigned to radiation. The HR for ADT use compared with active monitoring was 0.54 in both the surgery and radiation groups, and these differences were statistically significant.

In addition, significantly more men on active monitoring had clinical progression (evidence of metastatic disease, initiation of long-term ADT, diagnosis of clinical T3 or T4 disease, ureteric obstruction, rectal fistula, or urinary catheterization because of tumor growth) than men treated with surgery (HR, 0.36) or radiation (HR, 0.35).

However, the researchers emphasize that these significant differences in disease progression in the group on active monitoring compared with the other two groups who had either surgery or radiotherapy did not translate to differences in overall survival.

Overall, the results showed that “men with newly diagnosed, localized prostate cancer and their clinicians can take the time to carefully consider the trade-offs between harms and benefits of treatments when making management decisions,” the investigators write.

The ProtecT trial was supported by the Health Technology Assessment Program of the National Institute for Health and Care Research (NIHR), with the University of Oxford as sponsor. Hamdy reports acting as editor-in-chief for BJU International and as a consultant for Intuitive Surgical UK; most co-authors have no disclosures; the full list can be found with the original article. Sartor acts as a consultant for numerous pharmaceutical companies.

European Association of Urology Annual Congress (EAU 2023). Presented in oral session March 12, 2023.

N Engl J Med. Published online March 11, 2023. Abstract, Editorial

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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