“Very good news” concerning localized prostate cancer: the results of ProtecT

MILAN – Men newly diagnosed with localized prostate cancer can rest assured that whatever their initial choice of treatment – be it surgery, radiation therapy or active surveillance – all will have a high probability of good long-term results.

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

Of these screened men, 2,664 were diagnosed with localized prostate cancer, and 1,643 men from this group were then randomly assigned to receive either radical prostatectomy, radiation therapy, or active surveillance.

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

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

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

“The fact that the greater disease progression observed under active surveillance has not translated into higher mortality will be both surprising and encouraging for urologists and patients,” commented Peter Albers, MD, urologist at the University of Düsseldorf in Germany and President of the EAU. Office of the Scientific Congress.

“The active monitoring and biopsy protocols are now much more advanced than when this trial was conducted, so it is possible that we could improve these results even further. It is an important message for patients that delaying treatment is safe, especially since it means delaying the 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 further research on this is urgently needed.”

Balancing law

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

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

In an editorial accompanying the studyOliver Sartor, MD, of Tulane Medical School in New Orleans, Louisiana, notes that the authors’ recommendation for men and their clinicians to weigh the pros and cons of treatment is “perhaps not the conclusion expected for treatment advocates, given the length and size of the trial.

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

Indeed, the researchers found that the adverse effects of radiation therapy 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 significantly since the launch of the ProtecT trial in 1999.

For example, in the active follow-up group, an increase of at least 50% in the PSA level over 1 year “or any patient or clinician concern” would then trigger a review, with the patient then either continuing follow-up or switching from other tests and either radiation therapy, radical prostatectomy or palliative care.

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

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

ProtecT details

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

Patients assigned to radiation therapy 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 residual postoperative PSA of 0.2 ng/mL or greater were offered the option of adjuvant or salvage radiotherapy.

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

In all, 45 men died of prostate cancer. Prostate cancer death rates by treatment type were 3.1% with active surveillance, 2.2% with prostatectomy, and 2.9% with radiation therapy (P = 0.53). All-cause death rates were 16.2, 15.0, and 15.0 per 1000 person-years, respectively, and did not differ significantly between treatment groups.

Significantly more metastases occurred in men who were assigned to active surveillance, at 9.4% versus 4.7% assigned to prostatectomy (relative risk (HR), 0.47) and 5% assigned to radiotherapy (HR, 0.48).

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

Additionally, significantly more men on active surveillance had clinical progression (evidence of metastatic disease, initiation of long-term ADT, diagnosis of T3 or T4 clinical disease, ureteral obstruction, rectal fistula or urinary catheterization due to tumor growth) than men treated with surgery (HR, 0.36) or radiotherapy (HR, 0.35).

However, the researchers point out that these significant differences in disease progression in the active surveillance group compared to the other two groups that underwent either surgery or radiation therapy did not translate into 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 taking management decisions,” the researchers write.

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

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

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

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

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