Has it already been 15 years since the Prostate Testing for Cancer and Treatment (ProtecT) trial began? The authors of that landmark trial recently published an important update in the New England Journal of Medicine.1 Their study’s premise is based on the significant emphasis placed on the detection and treatment of localized prostate cancer. There have been significant changes over the last 15 years, including the increased use of multiparametric magnetic resonance imaging (mpMRI) and targeted biopsy to improve the specificity of diagnosing clinically significant prostate cancer. The authors note that “since the US Preventive Services Task Force updated its recommendations in 2012 and 2018,2 the incidence of localized disease has declined, whereas the incidences of regional and advanced cases have increased.3 During this period, cancer-specific mortality has remained unchanged.”4 The authors have previously reported on the 10-year follow-up of the ProtecT trial.5
The ProtecT trial included 82,429 patients between the ages of 30 and 69 years across multiple centers in the United Kingdom between 1999 and 2009. The goal of the trial was to evaluate the effectiveness of conventional treatment options, including active monitoring, surgery, and radiation for patients with clinically localized prostate cancer. The study comprised 2664 patients with a life expectancy of 10 years or more, with 1643 men randomized to active monitoring, prostatectomy, or radiation. This most recent study examined 15-year follow-up, evaluating the effectiveness of the 3 treatment approaches and their impact on prostate cancer-specific mortality, all-cause mortality, metastasis-free survival, disease progression, and the initiation of systemic therapy such as androgen deprivation therapy (ADT).
Prostate-specific antigen (PSA) levels were measured every 3 months for the first year and every 6 to 12 months after that. Patients were followed annually. Of note, patients in the active monitoring arm were followed by PSA level, and if the level increased by at least 50% in a 12-month period, or if the patient or clinician were concerned, it would trigger a review and subsequent discussion about management, including possible further monitoring, testing, or treatment. Patients who underwent surgery and had positive surgical margins, extracapsular disease, or a postoperative PSA of 0.2 ng/mL or higher underwent discussion of the possible use of salvage or adjuvant radiotherapy. Patients who underwent radiation received neoadjuvant ADT for 3 to 6 months with 3-dimensional conformal radiotherapy at 74 Gy in 37 fractions. Review was triggered by a 2 ng/mL rise in PSA level over the nadir or other concern for disease progression.
The authors note that in all groups, bone scintigraphy was recommended if PSA increased to 10 ng/mL, and ADT was discussed if PSA increased to 20 ng/mL.
Death from prostate cancer was the primary outcome. Secondary outcomes included all-cause mortality, evidence of metastatic disease on imaging or a PSA level higher than 100 ng/mL, long-term ADT alone, or clinical progression, which the authors defined as a composite of metastasis, clinical T3 or T4 disease, initiation of long-term ADT, ureteric obstruction, rectal fistula, or urinary catheterization because of tumor growth.
Several subgroup analyses were also investigated, including age, Gleason grade group (GG), PSA, disease stage, aggregate tumor length in biopsies, maximum tumor length in a single biopsy, and risk stratification score.
At a median follow-up of 15 years, data were collected for 98% of patients. A total of 1643 men were randomized to active monitoring (n=545), prostatectomy (n=553), or radiation (n=545). The median age at diagnosis was 62 years, and median PSA was 4.6 ng/mL. Of the patients included in the study, 76% had stage T1c disease. A total of 77% of patients had Gleason GG 1 disease at the time of diagnosis, while 24.1% had intermediate-risk disease and 9.6% had high-risk disease based on D’Amico classification system criteria. Of the 488 patients who underwent a radical prostatectomy, 28.5% had an upstage to pT2 or pT4 disease, 32% had an increase in tumor grade, and 50.5% had Gleason GG 7 or higher disease. A total of 13 patients underwent prostatectomy and ultimately died of prostate cancer. All 13 patients had an increase in tumor stage, and 77% had an increase in tumor grade. Of the 104 patients who developed metastatic disease, 51% had Gleason GG 1 disease at baseline and 47.6% had low-risk disease according to Cancer of the Prostate Risk Assessment criteria.
Of the 2.7% of patients who died of prostate cancer, 3.1% were in the active monitoring cohort, 2.2% were in the radical prostatectomy cohort, and 2.9% were in the radiation cohort. No significant difference in prostate cancer mortality was appreciated. The authors note that “prostate cancer-specific survival was approximately 97% regardless of trial group assignment.”
All-cause mortality was 21.7%, largely from cardiovascular or respiratory disease (51.6%), with no statistical difference appreciated across groups. Metastatic disease was seen in 6.3% of patients (9.4%, 4.7%, and 5% in the active monitoring, prostatectomy, and radiation cohorts, respectively). Nodal disease was seen in 2.6% of patients who underwent active monitoring compared with <1% for both the surgery and radiation cohorts. A total of 9.2% of patients were started on ADT (12.7%, 7.2%, and 7.7% in the monitoring, prostatectomy, and radiation cohorts, respectively), and 15.8% of patients experienced local progression (26%, 10.5%, and 11% in the monitoring, prostatectomy, and radiation cohorts, respectively). T3 or T4 disease was found in 12.7%, 2.7%, and 3.1% of patients in the active monitoring, prostatectomy, and radiation cohorts, respectively.
The authors then addressed change of management and found that in the radiation and surgery cohorts, radical treatment was performed in >90% of patients, while only 31.1% of patients underwent a radical therapy in the active monitoring cohort (down from 54.8% at 10-year follow-up). In the active monitoring cohort, 24.4% of patients did not receive radical therapy or had been started on ADT. A total of 12.8% of these patients had intermediate- or high-risk disease, and 10.4% had GG2 or higher disease at time of diagnosis.
Next, the authors evaluated the subgroup analyses and found that men younger than 65 years in the active monitoring and surgery cohorts had a lower risk of prostate cancer death compared with patients who had undergone radiation. Patients older than 65 years who had undergone radiation or surgery had a lower risk of prostate cancer death compared with those who underwent active monitoring. No treatment effects were appreciated when analyzing PSA level, clinical stage, Gleason GG, tumor length, or risk stratification.
“For more than 2 decades, our trial has been evaluating the effectiveness of contemporary treatments among men with PSA-detected, clinically localized prostate cancer,” the authors emphasize. The data showed a high percentage of long-term survival regardless of treatment modality; however, radical therapy did decrease the incidence of metastatic disease, local progression, and need for long-term ADT by 50% compared with active monitoring. The authors note that these findings are consistent with what is known about prostate cancer, namely that it has a long natural history.
According to the authors, these data indicate it is possible that more aggressive therapy can do more harm than good, a fact that should be considered when counseling patients about their options for managing prostate cancer. The authors also note that in contrast to major guidelines, this study shows that many more patients who would have been diagnosed with low-risk disease conventionally actually had intermediate- or high-risk disease, and “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.” The authors also note that there have been significant advances in the management of metastatic disease, which could explain the difference between the incidence of metastasis compared with the rate of prostate cancer-specific mortality.
Limitations of this study include the lack of mpMRI, prostate-specific membrane antigen imaging, and non-image-targeted biopsies at the time of diagnosis.
Still, the authors conclude their “findings provide evidence that greater awareness of the limitations of current risk-stratification methods and treatment recommendations in guidelines is needed. Men with new diagnoses of localized prostate cancer and their clinicians can take the time to carefully consider the tradeoffs between harms and benefits of treatments when making management decisions.”
David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.
References:
- Hamdy FC, Donovan JL, Lane JA, et al; ProtecT Study Group. Fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med. doi:10.1056/NEJMoa2214122
- US Preventive Services Task Force; Grossman DC, Curry SJ, Owens DK, et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319(18):1901-1913. doi:10.1001/jama.2018.3710
- Desai MM, Cacciamani GE, Gill K, et al. Trends in incidence of metastatic prostate cancer in the US. JAMA Netw Open. 2022. doi:10.1001/jamanetworkopen.2022.2246
- Jemal A, Culp MB, Ma J, Islami F, Fedewa SA. Prostate cancer incidence 5 years after US Preventive Services Task Force recommendations against screening. J Natl Cancer Inst. 2021;113(1):64-71. doi:10.1093/jnci/djaa068
- Hamdy FC, Donovan JL, Lane JA, et al; ProtecT Study Group. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375(15):1415-1424. doi:10.1056/NEJMoa1606220
