For more than two decades, the Prostate Testing for Cancer and Treatment (ProtecT) study has been evaluating the effectiveness of contemporary treatments among men with prostate specific antigen (PSA)-detected, clinically localised prostate cancer. The 15-year follow-up analysis provides evidence of a high percentage of long-term survival in the study population with 97% prostate cancer–specific death and 78% 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 (ADT) by half as compared with active monitoring. However, these reductions did not translate into differences in mortality at 15 years, a finding that emphasises the long natural history of this disease.
Clinicians may avoid overtreatment by ensuring that men with newly diagnosed, localised 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 findings are reported by Dr. Freddie Hamdy of the Nuffield Department of Surgical Sciences, University of Oxford in Oxford, UK and colleagues of the ProtecT Study Group at the 38th Annual Congress of the European Association of Urologists (10-13 March 2023, Milan, Italy) along simultaneous publication on 11 March 2023 in The New England Journal of Medicine.
The authors wrote in the background that despite recent advances in early detection and treatment of localised prostate cancer, management of the disease remains controversial. Although multiparametric magnetic resonance imaging (MRI) and targeted biopsies may reduce the diagnosis of indolent disease, the challenging aspects of risk stratification continue to drive both overtreatment and undertreatment.
Between 1999 and 2009, a total of 82429 men between the ages of 50 and 69 years at 9 centres in the UK were enrolled in the ProtecT study to evaluate the effectiveness of conventional treatments in clinically localised prostate cancer that was detected on PSA testing. Localised 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 randomisation 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 mL (range, 3.0 to 18.9). No material clinicopathological differences were seen among the randomised groups or among the men who accepted or declined to undergo randomisation.
In the current phase of the study at a median follow-up of 15 years (range, 11 to 21), the study team evaluated the relative effectiveness of active monitoring, prostatectomy, and radiotherapy with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term ADT (secondary outcomes). At the time of diagnosis, approximately 77% of the men were deemed to have low-risk disease. Thus, the study team performed a comprehensive analysis using several risk-stratification systems, including the Cancer of the Prostate Risk Assessment (CAPRA) and scoring systems of D’Amico and the Cambridge Prognostic Group, to assist in the interpretation of the 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%), in particular in 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 3 groups.
Metastases developed 51 men (9.4%) in the active-monitoring group, 26 (4.7%) in the prostatectomy group, and 27 (5.0%) in the radiotherapy group. Long-term ADT 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%). 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, tumour stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis.
The authors noted that their study has several limitations. Since its inception, treatments and diagnostic methods have evolved. During the study recruitment, investigators were not using contemporary multiparametric MRI or positron emission tomography (PET) with prostate specific membrane antigen (PSMA), and biopsies were not image-targeted. They commented that longer-term follow-up to 20 years and beyond will be crucial to continue to evaluate possible differential effects of various treatments and that their findings provide evidence that greater awareness of the limitations of current risk-stratification methods and treatment recommendations in guidelines is needed.
In an accompanied editorial article, Prof. Oliver Sartor of the Departments of Medicine and Urology, Section of Hematology and Medical Oncology, Tulane Medical School in New Orleans, Louisiana, US wrote that today, if a patient has an elevated PSA level, data suggest that the clinician may use multiparametric MRI to selectively biopsy only patients with a score of 3 to 5 on the Prostate Imaging Reporting and Data System, which classifies a lesion on a scale from 1 to 5, with higher scores indicating a higher suspicion of cancer. A targeted biopsy appears to be sufficient to diagnose tumours in grade groups 3 to 5.
Additional risk-stratification methods beyond clinical stage, PSA level, and Gleason score are also readily available. Genomic classifiers can provide important prognostic information and help guide treatment decisions. Germline genomic assessments are also endorsed by expert groups in patients with higher-grade tumours or selected family histories. PSMA PET scans are now approved to better assess staging in patients with unfavourable intermediate or high-risk localised disease. In certain circumstances, PSMA PET scans may also be useful in determining appropriateness for biopsy. Once risk stratification regarding the tumour is complete, clinicians can undertake appropriate action based on additional factors, such as age, family history, coexisting conditions, and (possibly most important) patient preference.
Prof. Sartor underlined that active monitoring as performed in the ProtecT trial should not be used today, as we can do better by adding serial multiparametric MRI assessments. The increased rate of metastasis that was noted in the active-monitoring group would likely be diminished with the active surveillance protocols that are being used today. The management of localised prostate cancer has undergone a change since the ProtecT study was started. Still, the results provide valuable data to inform decision making in the large group of men with low- or intermediate-risk prostate cancer.
The study was supported by the Health Technology Assessment Program of the National Institute for Health and Care Research, with the University of Oxford as sponsor.
References
- Hamdy FC, Donovan JL, Lane JA, et al. for the ProtecT Study Group. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. NEJM; Published online 11 March 2023. DOI: 10.1056/NEJMoa2214122
- Sartor O. Localized Prostate Cancer — Then and Now. NEJM; Published online 11 March 2023. DOI: 10.1056/NEJMe2300807