Men ‘protected’ regardless of Tx choice for localized prostate cancer

Whatever choice of therapy men with localized prostate cancer may have initially — surgery, radiation, or active monitoring — they would likely have a good 15-year outcome as shown in the ProtecT* trial.

At 15 years, survival from localized prostate cancer remained high at 96 to 97 percent, irrespective of the treatment those men received. Rates of prostate cancer death or all-cause mortality were also comparable among them. [EAU 2023 plenary session; N Engl J Med 2023; 388:1547-1558]

“Although prostatectomy or radiotherapy reduced the incidence of metastasis, local progression, and long-term androgen-deprivation therapy (ADT) by half compared with active monitoring, these reductions did not translate into differences in mortality at 15 years, a finding that emphasizes the long natural history of the disease,” said study investigator Dr Freddie Hamdy, Nuffield Professor of Surgery, Professor of Urology, and Head, Nuffield Department of Surgical Sciences at the University of Oxford, UK.

“Men with metastases do not necessarily die of prostate cancer,” he added. “Those who die have lethality features that have yet to be identified and are not easily impacted by multimodality treatment approaches.”

Putting this into perspective, Hamdy said men with localized prostate cancer and their physicians can take their time to “carefully consider the trade-offs between the benefits and harms of treatments” when making decisions for care.

Which treatment approach is effective?

Between 1999 and 2009, 82,429 men from the UK were screened for prostate cancer using a prostate specific antigen (PSA) test. Of these men, 2,664 were diagnosed with localized prostate cancer. More than a third had intermediate or high-risk disease.

At least 1,643 men were enrolled in ProtecT to assess the efficacy of treatments. They were randomly assigned to undergo active monitoring (n=545), prostatectomy (n=553), or radiotherapy (n=545) on top of 3-6 months of ADT.

Those assigned to prostatectomy who had positive surgical margins, extracapsular disease, or a residual postoperative PSA of ≥0.2 ng/mL were given the option of adjuvant or salvage radiotherapy.

At a median follow-up of 15 years, the primary outcome of mortality from prostate cancer occurred in 45 men. Rates were low regardless of the treatment received (3.1 percent with active monitoring, 2.2 percent with prostatectomy, and 2.9 percent with radiotherapy).

Mortality from any cause occurred in 356 men, with no significant difference among the three treatment groups.

More metastases occurred in men assigned to active monitoring (9.4 percent) than in those treated with prostatectomy (4.7 percent), or radiation (5 percent).  Long-term ADT was initiated in 69 men (12.7 percent, 7.2 percent, and 7.7 percent, respectively).

Additionally, more men on active monitoring had clinical progression (with 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 tumour growth) than those treated with surgery or radiation.

“However, the differences in disease progression in the active monitoring group vs the surgery or radiotherapy groups did not translate to differences in OS,” explained Hamdy.

“At the end of the follow-up, 133 men (24.4 percent) were alive without any prostate cancer treatment in the active-monitoring group.”

Is it safe to delay treatment?

“It is an important message for patients that delaying treatment is safe as that means delaying the side effects as well,” commented Dr Peter Albers, professor and chairman of the Department of Urology, Heinrich-Heine-University Düsseldorf, Germany.

“However, we still don’t know enough about the biology of this disease to determine which cancers will be the most aggressive. We need more research on this,” he pointed out.

As active monitoring and biopsy protocols are more advanced today than when the ProtecT trial was conducted, “it is possible we could improve on these outcomes further,” Albers added.

How can we do better today?

Dr Oliver Sartor from Tulane Medical School in New Orleans, Louisiana, US couldn’t agree more. In an accompanying editorial, he said active monitoring as performed in the trial should not be solely relied on today. [N Engl J Med 2023;388:1617-1618]

Screening, diagnosis, and management of prostate cancer have substantially evolved since the ProtecT trial. In the active monitoring group, for example, a 50-percent increase in the PSA level over 1 year “or any concern from the patient or clinician” would merit a review, with the patient either continuing with monitoring or requiring further testing to guide decisions for radiotherapy, radical prostatectomy, or palliative care, he pointed out.

“We can do better today by adding serial multiparametric magnetic resonance imaging assessments,” Sartor added. “The increased rate of metastasis in the ‘active monitoring’ group would likely be reduced with the active surveillance protocols that we utilize today.”

Additionally, he said the findings disclosed inadequacies in disease staging at that time. “Many patients in the trial were at low risk or favourable intermediate risk, who would be appropriate candidates for active surveillance today.”

Hamdy, for his part, said the long survival of men with screen-detected prostate cancer in ProtecT – regardless of treatment or metastases – does not support the introduction of population testing for early detection.

“The indications for active monitoring and surveillance can be safely expanded to intermediate-risk disease,” he said. “Treatment decisions need to balance the trade-offs between reduction of metastases, long-term hormones, and local progression with radical treatments against their short, medium-, and long-term impacts on sexual, urinary, and bowel functions,” he pointed out.