Patients with prostate cancer experienced prostate cancer-specific mortality at a low rate regardless of assigned treatment.
Patients with prostate cancer experienced prostate cancer-specific mortality at a low rate regardless of assigned treatment, underscoring the benefit to harm trade-off considerations clinicians must weigh when choosing a treatment for localized prostate cancer, according to long-term follow-up data from the phase 3 ProtecT trial (NCT02044172). The results were published in the New England Journal of Medicine.1
Findings from the trial showed that at a median follow-up of 15 years (range, 11-21), follow-up was complete for 1610 patients with prostate cancer. According to a risk-stratification analysis, intermediate-risk (24.1%) or high-risk (9.6%) disease was present in over one-third of patients. Death from prostate cancer was reported in 17, 12, and 16 patients in the active-monitoring (n = 545), prostatectomy (n = 553), and radiotherapy (n = 545) groups, respectively (P = .53 for the overall comparison). Metastases occurred in 9.4%, 4.7%, and 5.0% of patients, respectively.
Additionally, long-term androgen-deprivation therapy (ADT) was initiated in 12.7%, 7.2%, and 7.7% of patients in the active-monitoring, prostatectomy, and radiotherapy arms, respectively. Clinical progression was reported in 25.9%, 10.5%, and 11.0% of patients, respectively. Notably, among patients treated with active monitoring, 24.4% of patients were still alive without any prostate cancer treatment at the end of follow-up.
Differential effects on cancer-specific mortality were not linked to baseline prostate-specific antigen (PSA) level, tumor stage/grade, or risk-stratification score. Study authors did not report any treatment complications following their 10-year analysis.
To conduct the study, investigators collected data from 82,429 men aged between 50 years and 69 years spanning from 1999 to 2009 in the United Kingdom. Localized prostate cancer was diagnosed in 2664 patients, 1643 of whom were enrolled in the trial to evaluate the efficacy of different treatments. Patients needed to have a life expectancy of at least 10 years and be eligible for treatment. Patients were randomly assigned 1:1:1 to receive either active monitoring, prostatectomy, or radiotherapy.
Overall, the median age at diagnosis was 62 years (range, 50-69) and the median PSA level was 4.6 ng/mL (range, 3.0-18.9). Most patients had low-risk disease (77%) at the time of diagnosis. Clinicopathological differences among the groups were deemed to be minimal.
In the active-monitoring arm, most patients had a Gleason score of 6 (77%), stage T1c disease (75%), and were White (99%). Similarly, among patients who received surgery, these rates were 76%, 74%, and 99%, respectively. Finally, in the radiotherapy arm these rates were 78%, 79%, and 98%, respectively.2
As part of ProtecT, clinical management was standardized via the use of trial-specific pathways and PSA levels were measured every 3 months during the first year and every 6 to 12 months subsequently. Annual evaluation was also performed every year by trial-group assignment. Specific to the active-monitoring arm, an increase of 50% in PSA level during any year-long period or concern from the patient or clinician triggered a further review.1
Among patients treated with prostatectomy, adjuvant or salvage radiotherapy was considered for patients with positive surgical margins, extracapsular disease, or a PSA level of 0.2 ng/mL or higher after surgery. Radiotherapy was given with neoadjuvant ADT for 3 to 6 months and a management review occurred if PSA levels increased by a minimum of 2.0 ng/mL over the nadir level or if disease progression was suspected.
In the overall population, bone scintigraphy was recommended if PSA levels increased to 10 ng/mL. ADT was considered in the event PSA levels increased to 20 ng/mL.
The primary outcome of the study was death from prostate cancer. Secondary outcomes included death from any cause, metastases, clinical progression, and long-term ADT use.1
Additional findings from the trial revealed that among the 488 patients who received prostatectomy within a year of assignment to any group, 28.5% displayed an increase in pathological stage to pT3 or pT4. Less than half (32%) experienced an increase in tumor grade and 50.5% had a Gleason score of 7. Among patients who underwent prostatectomy and subsequently died of prostate cancer (n = 13), all saw an increase in their tumor stage and the majority (76.9%) experienced a rise in tumor grade.1
Patients who were treated with prostatectomy had a 34% reduction in the risk of death compared with those in the active monitoring arm (HR, 0.66; 95% CI, 0.31-1.39). This risk was reduced by 12% among patients who received radiotherapy compared with active monitoring (HR, 0.88; 95% CI, 0.44-1.74).
In terms of death from any cause, prostatectomy and radiotherapy offered a slight benefit compared with active monitoring. Patients in the prostatectomy arm experienced an 11% reduction in the risk of death by any cause (HR, 0.89; 95% CI, 0.69-1.15); this figure was 12% in the radiotherapy arm (HR, 0.88; 95% CI, 0.68-1.13).
The chance of metastatic disease was also reduced in both the surgery and radiotherapy arms compared with active monitoring. The chance of metastatic disease was lessened by 53% (HR, 0.47; 95% CI, 0.29-0.76) and 52% (HR, 0.48; 95% CI, 0.30-0.77) in the prostatectomy and radiotherapy arms, respectively.
Prostatectomy and radiotherapy also reduced the chance that ADT was used compared with active monitoring. The chance of ADT being used decreased by 46% (HR, 0.54; 95% CI, 0.37-0.80) and 46% (HR, 0.54; 95% CI, 0.36-0.79), respectively.
The most significant benefit of both prostatectomy and radiotherapy vs active monitoring was regarding clinical progression. The risk of clinical progression compared with active monitoring was reduced by 64% (HR, 0.36; 95% CI, 0.27-0.49) and 65% (HR, 0.35; 95% CI, 0.26-0.48), respectively.
Overall, the prostate cancer survival rates recorded as part of the study were high at both 10 and 15 years. The 10-year prostate cancer survival rates were 98.7% (95% CI, 97.2%-99.4%), 99.0% (95% CI, 97.7%-99.6%), in the active monitoring, prostatectomy, and radiotherapy groups, respectively. At 15 years, these rates were 96.6% (95% CI, 94.4%-98.0%), 97.2% (95% CI, 94.8%-98.5%), and 97.7% (95% CI, 95.5%-98.8%).
Study authors concluded that although radical treatments such as prostatectomy or radiotherapyreduced the incidence of metastasis, local progression, and long-term ADT by approximately 50% compared with active monitoring, these reductions did not translate into significant differences in 15-year mortality rates, underscoring the long natural history of the disease. They contended that their findings indicate that, when the extent of adverse effects associated with early radical therapy are considered, more aggressive therapy can sometimes be associated with more harm than good. Thus, clinicians can 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, they wrote in summation.