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ProtecT trial

Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. 

Localized prostate cancer was diagnosed in 2664 men. 

1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy.

At a median follow-up of 15 years comparison of  the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes) were established.

More than one third of the men had intermediate or high-risk disease at diagnosis. 

Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group.

Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. 

Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. 

Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. 

In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. 

No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. 

No treatment complications were reported after the 10-year analysis.

After 15 years of follow-up, prostate cancer–specific mortality was low regardless of the treatment assigned. 

Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer.

The treatment of localized prostate cancer, management of the disease remains controversial. 

The challenging aspects of risk stratification continue to drive both overtreatment and undertreatment of localized PC.

Since the U.S. Preventive Services Task Force updated its recommendations in 2012 and 2018, the incidence of localized disease has declined, whereas the incidences of regional and advanced cases have increased.

During this period, cancer-specific mortality has remained unchanged.

In the United Kingdom between 1999 and 2009, a total of 82,429 men between the ages of 50 and 69 years at nine centers were enrolled in the Prostate Testing for Cancer and Treatment (ProtecT) trial to evaluate the effectiveness of conventional treatments in clinically localized prostate cancer that was detected on prostate-specific antigen (PSA) testing. 

Localized prostate cancer was diagnosed in 2664 men who had a life expectancy of at least 10 years and who were eligible for treatment. 

Of these men, 1643 underwent randomization to receive active monitoring (545 men), prostatectomy (553 men), or radiotherapy (545 men). 

The median age at diagnosis was 62 years (range, 50 to 69), and the median PSA level was 4.6 ng per milliliter (range, 3.0 to 18.9). 

No material clinicopathological differences were seen among the randomized groups.

At a median follow-up of 15 years, the relative effectiveness of active monitoring, prostatectomy, and radiotherapy on prostate cancer–specific and all-cause mortality, metastases, disease progression, and the initiation of long-term androgen-deprivation therapy was evaluated 

At the time of diagnosis, approximately 77% of the men were deemed to have low-risk disease.

In the active-monitoring group, an increase of at least 50% in the PSA level during a 12-month period or any concern on the part of the patient or clinician triggered a review, with management options that included continued monitoring or further testing and radical or palliative treatments. 

Radical intervention was defined as prostatectomy or radiotherapy. 

In the prostatectomy group, the use of 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. 

Radiotherapy was delivered along with neoadjuvant androgen-deprivation therapy for 3 to 6 months with three-dimensional conformal radiotherapy at 74 Gy in 37 fractions.

Management review was triggered if the PSA level increased by at least 2.0 ng per milliliter over the nadir level or concern was raised about disease progression. 

Androgen-deprivation therapy was discussed if the PSA level increased to 20 ng per milliliter.

The primary outcome was death from prostate cancer, and secondary outcomes were death from any cause, metastases, as confirmed on imaging or a PSA level of ≥100 ng per milliliter, clinical progression, a composite of metastases, clinical T3 or T4 disease, initiation of long-term androgen-deprivation therapy, ureteric obstruction, rectal fistula, or urinary catheterization because of tumor growth. and long-term androgen-deprivation therapy alone. 

At baseline, 77.2% of the men were in Gleason grade group 1 (Gleason score, 3+3=6); 76.0% had stage T1c cancer. 

369 men (24.1%) had intermediate disease and 147 (9.6%) had high-risk disease.

Among the 488 men who had undergone prostatectomy within 12 months after assignment to any group, 138 (28.5%) had an increase in the pathological cancer stage to pT3 or pT4: 155 (32.0%) had an increase in tumor grade, and 245 (50.5%) had a Gleason score of 7 (3+4, grade group 2) or higher.

Of the 13 men who had undergone prostatectomy but died of prostate cancer, all had an increase in the tumor stage and 76.9% had an increase in the tumor grade.

Of the 104 men in whom metastases developed, 53 (51.0%) had Gleason grade group 1 disease at baseline, and 49 (47.6%) were identified has having low-risk disease according to the CAPRA criteria.

After median follow-up of 15 years, 45 patients (2.7%) had died of prostate cancer: 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group.

No significant difference in prostate cancer mortality was found among the trial groups.

Thus, prostate cancer–specific survival was approximately 97% regardless of the trial-group assignment.

In the ProtecT trial of 15 years no significant difference in prostate cancer mortality was found in patients with localized prostate cancer managed by active monitoring, surgery or radiation.

Death from any cause occurred in 356 patients (21.7%), with a similar distribution across the three groups.

Of the 104 men (6.3%) in whom metastases were diagnosed, 51 (9.4%) were in the active-monitoring group, 26 (4.7%) in the prostatectomy group, and 27 (5.0%) in the radiotherapy group.

The difference was most apparent among men with metastatic disease in regional nodes: 14 (2.6%) in the active-monitoring group and 4 (<1%) in each of the radical treatment groups.

Of 9.2% men who received long-term androgen-deprivation therapy, 12.7% were in the active-monitoring group, 7.2% in the prostatectomy group, and 7.7%min the radiotherapy group.

Of the 259 men (15.8%) with local progression, 141 (25.9%) were in the active-monitoring group, 58 (10.5%) the prostatectomy group, and 60 (11.0%) the radiotherapy group (Fig. S4). 

Staging as a measure of local progression, T3 or T4 disease was found in 12.7% of men in the active-monitoring group, 2.7% in the prostatectomy group, and 3.1%) in the radiotherapy group.

Probability of Undergoing Radical Intervention during the Follow-up Period.

By the end of the median 15-year follow-up, radical treatment had been performed in 92.5% in the radiotherapy group and in 90.4% in the prostatectomy group.

This finding compares 61.1% who received radical treatment in the active-monitoring group, an absolute increase of 6.3 percentage points from 54.8% who had received radical treatment at 10 years.

By the end of follow-up, 24.4% in the active-monitoring group were alive and had neither received radical treatment nor started androgen-deprivation therapy. 

Of these men at the time of diagnosis, 12.8% were considered to have intermediate or high-risk disease.

The relative risk of death from prostate cancer in the three groups differed according to the men’s age at diagnosis. 

Among the men who were under the age of 65 years, those who had undergone either active monitoring or prostatectomy had a lower risk of death from prostate cancer than those who had undergone radiotherapy.

Among those who were 65 years of age or older, those who had undergone prostatectomy or radiotherapy had a lower risk of death from prostate cancer than those who had undergone active monitoring.

The higher incidence of metastatic disease in the active-monitoring group at 10 years was anticipated to have an effect on prostate cancer–specific mortality at 15 years, but this was not the case. 

Among the 40 men in whom metastatic disease had been diagnosed at 10 years, the risk of death from prostate cancer was lower among those in the active-monitoring group (13.6%) than in either the prostatectomy group (25.0&) or the radiotherapy group (70.0%).

The current 15-year analysis provides evidence of a high percentage of long-term survival in the trial population (97% from prostate cancer–specific death and 78% from death from any cause), regardless of treatment group. 

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.

The findings indicate that depending on the extent of side effects associated with early radical treatments, more aggressive therapy can result in more harm than good. 

Clinicians may avoid overtreatment by ensuring that men with newly diagnosed, localized prostate cancer consider critical trade-offs between short-term and long-term effects of treatments on urinary, bowel, and sexual function, as well as the risks of progression.

The trial was initiated in 1999, and when the baseline data were published, it appeared that more than three quarters of the men had features suggesting low-risk disease on the basis of the risk-stratification methods that were being used at the time.

Contemporary methods of risk stratification have shown that up to 34% of the ProtecT cohort actually had intermediate or high-risk prostate cancer at the time of diagnosis.

Furthermore, pathological data from men who had undergone prostatectomy within 12 months after diagnosis revealed that one third went on to have an increase in both the grade and stage of prostate cancer and one half had Gleason grade group 2 disease or higher, which suggests that more intermediate-risk disease was present across the cohort than was previously thought.

An analysis of data from the 13 men who had undergone prostatectomy but later died of prostate cancer further revealed the limitations of risk-stratification methods, because 46% were diagnosed with Gleason grade group 1 disease at baseline; all the men had an increase in stage and 77% had an increase in grade.

More than three quarters of these men underwent surgery within 2 years after diagnosis and 84% received salvage radiotherapy, treatments that indicated the aggressive nature of their disease. 

Despite multimodality treatments, these men who died from prostate cancer must have harbored features of lethality that were not identified at diagnosis or affected by treatment. 

Furthermore, of the 104 men in whom metastases developed, 51% were classified as being at low risk (Gleason grade group 1) at baseline and 47% were considered to be at low risk according to the CAPRA criteria.

Thus, additional prediction tools are needed, with better understanding and alignment of the tumor phenotype with its genotype, as well as the natural history of disease progression.

Even though the incidence of metastases increased, the number of prostate cancer deaths remained low and the intervals between metastases and death continued to extend from 10 to 20 years in some cases, particularly in the active-monitoring group.

Of the 40 men in whom metastases had been diagnosed at 10 years, 14% had died of prostate cancer in the active-monitoring group by 15 years as compared with 25% in the prostatectomy group and 70% in the radiotherapy group. 

New systemic therapies for progressive disease have become increasingly available, and it is likely that these treatments contributed to lengthening survival in the men with metastases in our trial. 

When the sites of metastatic disease were analyzed, 29% of the men in the active-monitoring group had regional lymph-node involvement, as compared with 15% in each of the prostatectomy and radiotherapy groups.

The incidence of visceral and distant lymph-node involvement was low and similar in the three groups. 

Skeletal metastases accounted for a similar percentage of cases in the active-monitoring group (31%) and the prostatectomy group (35%), with a lower percentage in the radiotherapy group (15%). 

This finding may be due to the presence of occult micrometastatic disease at diagnosis that was subsequently suppressed by neoadjuvant androgen-deprivation therapy given before the administration of radiotherapy. 

Local progression incidence of clinical restaging with active monitoring (13%) was higher by a factor of 4 than that with radical treatments (3%), but Many of these cases were based on subjective digital rectal examinations or computed tomographic (CT) imaging, methods that provide the weakest justification for the initiation of radical treatment.

By the 15-year follow-up, 90 to 92% of the men had undergone either prostatectomy or radiotherapy according to the randomized assignment. 

In the active-monitoring group, 61% had undergone either prostatectomy or radiotherapy. 

Change-of-management rates were similar to those in other active surveillance programs, with approximately 30% of the patients undergoing either prostatectomy or radiotherapy within 3 years, a percentage that increased to 55% at 10 years and 61% at 15 years. 

Decisions to change the management approach in the early years were often made without evidence of progression, which probably reflected anxiety on the part of either the patients or their physicians. 

At 15 years, 39% of the men in the active-monitoring group had not undergone radical treatment, and 24% were alive without either radical treatment or androgen-deprivation therapy. 

Of these men at the time of diagnosis, 11% had a Gleason grade group of 2 to 5 or a CAPRA score of 3 to 5 and stage T2 disease.

The Prostate Cancer Intervention versus Observation Trial (PIVOT), which showed no survival benefit of radical treatment in men with a high number of coexisting illnesses.

The Scandinavian Prostate Cancer Group Study 4 investigators found consistent benefits of radical treatment as compared with watchful waiting among patients with clinical symptoms, half of whom had evidence of disease outside the prostate. 

Survival after PSA-detected prostate cancer is long, regardless of the patient-stratification method that was used, and that lethal disease is not easily affected by radical treatment.

No evidence of differential treatment effects on prostate cancer mortality among subgroups that were defined according to tumor grade at diagnosis, aggregate or maximum tumor length, tumor stage, PSA level, or risk-stratification method.

Men who were at least 65 years of age at the time of diagnosis appeared to have benefited from early radical treatment, whereas those who were younger than 65 years of age benefited more from active monitoring or surgery than from radiotherapy.

This finding could reflect potential benefits of prompt radical treatment among older men but should be interpreted cautiously.

Trials limitations: Since its inception, treatments and diagnostic methods have evolved. 

Investigators were not using contemporary multiparametric MRI or positron-emission tomography with prostate-specific membrane antigen, and biopsies were not image-targeted.

At a median follow-up of 15 years the  mortality from PSA-detected prostate cancer remained very low regardless of whether men had been assigned to receive active monitoring, prostatectomy, or radiotherapy. 

Radical treatment resulted in a lower risk of disease progression than active monitoring but did not lower prostate cancer mortality. 

Even though the active-monitoring protocol was perceived as less intensive than contemporary active surveillance, one quarter of the men in the active-monitoring group were alive without having received any form of treatment. 

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.

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