Background
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. Of these 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.
Methods
At a median follow-up of 15 years (range, 11 to 21), we compared 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).
Results
Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that 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 (P = 0.53 for the overall comparison). 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.
Conclusions
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. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.).
Prostate cancer generally has a long natural history. The Prostate Testing for Cancer and Treatment (ProtecT) trial is a UK-based milestone study that recruited men 50 to 69 years old. From 1999 to 2009, 82,429 men had a PSA test; 2,664 had a diagnosis of localised prostate cancer. Finally, a total of 545 men were randomly assigned to receive active monitoring, 553 to radical prostatectomy, and 545 to radiotherapy.
Results at a median of 10-year follow-up were published in the NEJM in 2016 showing that prostate-cancer–specific mortality was low, with no significant difference among study arms. Surgery and radiotherapy were associated with a lower disease progression and metastases as compared to active monitoring. Overall, there were 17 prostate-cancer–specific deaths – (8 in the active-monitoring group, 5 in the surgery group and 4 in the radiotherapy group (p=0.48)). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths in total). Metastasis was more common in men from the active-monitoring group (33 men) than in those from the surgery group (13 men) or the radiotherapy group (16 men) (P=0.004). 44% of the patients who were assigned to active monitoring did not receive radical treatment and avoided side effects.
This year, the update at 15-year median follow-up was published in the April issue of the NEJM. Trial compliance remained remarkably high with a follow-up being complete for 1,610 patients (98%).
Again, death from prostate cancer almost tripled compared to 10-years but still remained low, occurring 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 (P=0.53 for the overall comparison). Death from any cause was observed in 356 men (21.7%). 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 was reported for 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 the follow-up. No differential effect on cancer-specific mortality was noted in relation to the baseline PSA level, tumour stage or grade, or risk-stratification score.
The authors concluded that after 15 years of follow-up, prostate cancer–specific mortality remained low regardless of the treatment assigned. Thus, the choice of therapy should incorporate weighing trade-offs between benefits and harms associated with specific treatment option for localised prostate cancer.
The study adds relevant information for the current prostate cancer management strategies. Notably, more than one third of the men had intermediate or high-risk disease at diagnosis. Importantly, the percentage of intermediate or high-risk disease included is likely under-estimated compared to the modern prostate cancer diagnostic era due to several changes compared to 15 years ago. Firstly, the ISUP classification that was previously scored as gleason score 6 would now be gleason score 7 cancers. Secondly, new imaging modalities. The use of mpMRI and mpMRI targeted biopsy significantly reduces risk of upgrading/staging which, for biopsies during the trial recruitment may have been as high as 30%. This is well reflected amongst those who underwent radical prostatectomy with 28.5% having an increased pathological stage (to pT3 or pT4), 32.0% increase tumour grade and 50.5% a gleason score of 7 (3+4, grade group 2) or higher. The use of PSMA-PET nowadays also increases the ability of staging localised disease. Third, active monitoring was less stringent compared to modern active surveillance protocols which may have resulted in increased treatment rates but potentially, also increased disease control in terms of metastasis and progression. Whilst recommendation for ISUP 1 prostate cancer now universally recognises surveillance as the gold standard management, the trial provides milestone information for managing newly diagnosed localised prostate cancer overall, as well as selected intermediate and high-risk disease.