The natural history of a delayed detectable PSA after radical prostatectomy

In this study of 3348 men treated with RP for clinically localized prostate cancer, we found that 14.3% of patients had immediate PSA persistence while 19.1% developed biochemical recurrence ≥6 months within 10 years of primary treatment. Median time to BCR in the delayed detectable PSA group was 25 months (IQR 15-43), and PSA at time of failure was <0.10 ng/mL for 65.7% of patients. Increasing CAPRA-S score was a risk factor associated with development of delayed detectable PSA. CAPRA-S score is computed from preoperative PSA, pathologic Gleason score, extracapsular extension, lymph node involvement, positive surgical margin, and seminal vesicle invasion [9]. Previous studies have similarly found that seminal vesicle invasion, pathologic Gleason score, and positive surgical margin are significant prognostic factors for biochemical recurrence [6, 10, 11]. As such, we included CAPRA-S in our analysis rather than its component parts. Overall, long-term oncologic outcomes were excellent for the delayed detectable PSA group, with MFS 92%, PCSM 3%, and ACM 6% at 10 years. PCSM is similar to previously published outcomes [12].

Of those with a delayed detectable PSA, 46% underwent salvage treatment within 10 years after RP. This is higher than our previously published CaPSURE cohort treatment rate of 34% for BCR [5]. Several differences between the cohorts may explain this finding: the CaPSURE study included patients treated between 1995-2002 with BCR defined as PSA ≥ 0.2 ng/mL whereas this study involves a more contemporary group with a lower PSA cut-off of 0.03 ng/mL. The majority of those patients had biopsy Gleason score 2-6 (66.8%) versus 18% in this study. Furthermore, median follow up in the CaPSURE group was shorter, at 63.5 months compared to 72 months.

The median PSA of patients undergoing salvage therapy was 0.08 ng/mL (IQR 0.05, 0.14) and median time to treatment was 29 months (IQR 19, 46). Though the PSA level at time of salvage therapy in our cohort is lower than the PSA trigger level of 0.2 ng/mL in the RAVES and GETUG-AFU 17 randomized trials, our findings similarly support salvage treatment in appropriately selected patients, with favorable long-term oncologic outcomes of MFS 86% and PCSM 5% [13].

Most patients who received salvage treatment underwent radiation with or without ADT (95.1%), while the remainder were placed on ADT alone. We found that a high Decipher score (HR 2.34, CI 1.21–4.51, p = 0.1), an increasing CAPRA-S score (HR 1.09, CI 1.02-1.17, p = 0.02) and PSA-DT of <6 months (HR 7.58, CI 5.42-10.6, p < 0.01) were associated with risk of receiving salvage treatment. In a review on management of BCR after primary treatment, Artibani et al reported that a PDA-DT of <3 months was associated with high risk of metastases and PCSM [3].

Shahait et al recently analyzed the use of post-prostatectomy Decipher risk stratification in two prospective observational cohorts and found that those with a high Decipher score were more likely to receive secondary therapy compared to those with low/intermediate Decipher risk, with OR 6.84 [14]. We also found that a high Decipher score was associated with risk of salvage treatment (HR 2.34), but not with recurrent PSA failure.

After salvage treatment, 62% of men had recurrent PSA failure within 10 years, at a median of 34 months. PSA-DT < 6 months after salvage therapy was associated with risk of second PSA failure. Of those receiving tertiary treatment, 78.7% had ADT alone while 8.5% received systemic therapy, including enzalutamide, abiraterone, ketoconazole, chemotherapy, and immunotherapies. Tumati et al reported on a smaller cohort of 286 patients who underwent salvage RT between 1986 and 2013 and subsequently developed second BCR. At a median of 6.1 years after second BCR, metastasis, PCSM and ACM were 41%, 17.7% and 27.1%, respectively [15]. Similarly, for those who received tertiary treatment for recurrent PSA failure in our cohort, we found MFS was 54%, PCSM 23% and ACM 23% at 10 years’ time. Remarkably, some patients who progress through salvage and tertiary therapy may expect a prolonged clinical course rather than a rapid decline.

Our study has several strengths, including a more contemporary definition of detectable PSA as ≥0.03 ng/ml and a median follow-up period of 6 years for the delayed BCR cohort. Additionally, our database includes patients who had a second BCR after salvage treatment as well as data on tertiary treatments. Limitations include the retrospective nature of this study within a single-center experience of patients who underwent surgery. As UCSF is a tertiary referral center, it is likely that patients with a detectable PSA will continue their care at our institution while those without recurrence may be at higher risk of loss to follow-up at UCSF. Additionally, the clinical generalizability of our findings is limited by our institutional use of Decipher and CAPRA scores, which may not be widely adopted in the community setting. Furthermore, detailed information on how decisions for salvage and tertiary treatment were made are lacking in this natural history study.

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