Active surveillance data in prostate cancer show frequent upgrading, rare mortality

Badar M. Mian, MD

In “Journal Article of the Month," Badar M. Mian, MD, offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, New York.

Active surveillance (AS) strategies for prostate cancer with low-risk features, such Grade Group 1 (GG1), are increasingly being utilized to avoid treatment-related complications. Due to the long natural history of prostate cancer and low risk of progression, long-term risk of metastasis or death is not well defined, resulting in some uncertainty about patient selection for AS. A recent study by Maggi et al noted that although reclassification of the initial biopsy Grade Group or switch from surveillance to active treatment occurred frequently, less than 1% of men died of prostate cancer.¹ They analyzed the data from a large, prospectively maintained AS cohort to identify the variables associated with disease progression and metastases while on AS.

The investigators identified 1450 men on AS between 1990 and 2018 who met the inclusion criteria of low- or intermediate-risk prostate cancer. AS eligibility criteria included organ-confined disease with biopsy GG1, 33% or less positive biopsy cores, and PSA density (PSAD) lower than 0.15 ng/mL/cm3. However, few selected patients with GG2 and/or higher PSAD were also enrolled into the AS program. 1303 patients (90%) were diagnosed with initial biopsy GG1 and 147 (10%) with GG2. Median PSA at initial biopsy was 5.4 ng/mL, with median PSAD of 0.13 ng/mL/cm3. Median age was 62 years and median follow-up was 77 months. Additional testing such as Genomic Prostate Score (GPS) was performed in 34% of men (mean GPS 25), whereas multiparametric magnetic resonance imaging (mpMRI) was performed in 46% of men, of whom 24% had lesions classified as Prostate Imaging Reporting and Data System (PI-RADS) 4-5.

The primary outcome of interest was emergence of metastatic prostate cancer noted on imaging or pathology of delayed prostatectomy. Secondary outcomes included upgrading on surveillance biopsy to GG2 or greater, receipt of active treatment, and prostate cancer-specific and overall survival. For this analysis, patients were divided into 3 subgroups based on the initial biopsy GG and PSA. Of these, GG1 with PSAD lower than 0.15 was noted in 57%, GG1 with PSAD of 0.15 or higher in 32%, and GG2 in 10%.

At 7 years, biopsy GG upgrade-free survival was 40%, and median time to biopsy GG upgrade was 25 months. The 7-year upgrade-free survival was higher in patients with initial GG1 with PSAD lower than 0.15 (47%) compared with those with GG1 with PSAD of 0.15 or higher (28%) or initial GG2 (44%) (log rank P < .01). The 7-year treatment-free survival was 59%, with a median time to receiving active treatment of 32 months. The 7-year treatment-free survival was higher in patients with initial GG1 with PSAD lower than 0.15 (69%) compared with those with GG1 with PSAD of 0.15 or higher (46%) or initial GG2 (42%) (log rank P < .01).

At 7 years, metastasis-free survival was 99%, and median time to metastases was 62 months. Of the 15 patients who developed metastases, 2 were lost to follow-up, 9 had lymph node metastasis, 2 had lymph node and bone metastasis, 1 had bone metastasis, and 1 had bone and visceral organ metastasis. Initial biopsy GG2 disease was associated with lower 7-year metastasis-free survival (96%) than those with GG1 with PSAD lower than 0.15 (99 %) and with GG1 with PSAD of 0.15 or higher (100%) (log rank P < .01). On multivariable analysis, risk factors for increased risk of metastases included initial GG2, PSA velocity, and PI-RADS 4-5 lesion. However, age, PSAD, and GPS did not increase the risk of metastases. Of note, in those who did not develop metastases, the median follow-up was quite sufficient at 77 months.

Overall, 64 of 1450 patients died at a median of 84 months. The 7-year overall survival was 97% for the entire cohort. Overall survival rates differed by sub-groups: GG1 with PSAD lower than 0.15 (98%) compared to those with GG1 with PSAD of 0.15 or higher (96%) or initial GG2 (87%). Only 4 of 64 patients in this AS program died of advanced prostate cancer. The 7-year prostate cancer-specific survival was greater than 99%.

This report is based on one of the few large AS cohorts with long-term follow-up. Although 60% of patients experienced upgrading on subsequent biopsies, only 41% underwent deferred treatment, suggesting that upgrading alone may not necessitate immediate treatment. The goal of AS protocols is to avoid or delay treatment for those who may not benefit from it, and still maintain the curative intent through early capture of any disease progression. The success of AS protocol is evident from the data showing that 1% of men with low-risk prostate cancer developed metastases, and only 0.27% died of prostate cancer.

Further details about other prognostic variables in patients with initial GG2, such as age, focality, or percentage of Gleason pattern 4, would have been instructive in identifying the optimal candidates for AS. Additionally, this AS protocol included variable diagnostic testing and surveillance protocol during the study period. Should patients with GG2 on AS be managed with a more strict or intensive surveillance program than those with GG1? Although most of the patients in this study were Caucasian (92%) and the general applicability may be questioned, recent studies have highlighted the safety of AS in African American men with low-risk prostate cancer.

The boundaries of AS inclusion criteria are being expanded to include selected men with GG2 prostate cancer. Incorporating mpMRI, and perhaps genomic tests, will further facilitate the selection of appropriate candidates for AS, thus increasing its acceptability by urologists and patients. Despite some heterogeneity in the type and frequency of testing during the surveillance period, these results provide reassurance and increased confidence in the safe utilization of AS protocols for men with low-risk GG1, and selected GG2, prostate cancer.

Reference

1. Maggi M, Cowan JE, Fasulo V, et al. The long-term risks of metastases in men on active surveillance for early stage prostate cancer. J Urol. 2020;204(6):1222-1228. doi:10.1097/JU.0000000000001313