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Following definitive therapy, a rising prostate-specific antigen (PSA) level is a sign of heightened risk for development of symptomatic metastatic disease.1 At the time of BCR in nonmetastatic castration-sensitive prostate cancer (nmCSPC), PSADT has been shown to be one of the most reliable indicators of the risk for further progression.1,3 A rapid PSADT ≤9-12 months indicates an increased risk of prostate cancer-related morbidity and mortality.1,3,5
Not actual patients.
PSADT refers to the time it takes for PSA levels to double. PSADT has been shown to be highly correlated with the development of metastatic disease and survival outcomes.1-3,6
This rate of PSA doubling has been shown in clinical studies and recognized by American Urological Association (AUA) Guidelines and NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) to be correlated with the risk of prostate cancer metastasis and mortality.1-6
Pound CR et al. JAMA 19996
One of the first real world–evidence based studies to assess the relationship between BCR in prostate cancer following RP and disease progression
Methods: This was a retrospective cohort study of 1997 men who underwent radical prostatectomy to treat localized prostate cancer. None of the men included in the study received neoadjuvant radiation or hormonal therapy. Postoperative follow-up included serum PSA level testing every 3 months for 1 year, semiannually during the next year, and yearly thereafter. Several approaches to PSADT calculation were analyzed by recursive partitioning (a form of multivariable analysis). A Cox proportional hazards regression model was used to determine the optimal PSADT for predicting disease progression.
Results: This graph presents the likelihood of developing metastatic disease among the 304 men in the study who had BCR. It is based on 103 (34%) of those 304 men who had developed distant metastases during the study period. PSADT in this group was calculated based on all PSA results within 2 years of the first elevated value (>0.2 ng/mL).
The PSADT cutoff point of 10 months provided the most significant prediction of time to development of metastatic disease following PSA elevation.* The study also found that a Gleason score of 8-10 and an initial PSA elevation within 2 years of surgery were significantly associated with a higher actuarial risk of developing metastatic disease.
Limitations: This study is subject to the limitations of retrospective cohort studies, which include data quality factors (e.g., missing data) and loss of patients to follow-up. In addition, the size of the group analyzed for PSADT in this study was relatively small. Results should be considered preliminary and not definitive.
*Metastases were defined in this study as distant metastases detected by a positive bone scan or other radiographic or histologic (eg, lymph node biopsy) evidence.6
Freedland SJ et al. JAMA 20055
Conducted by the same research group that published the study by Pound and colleagues, this study further defined outcomes in men who develop BCR in prostate cancer following RP
Methods: This was a retrospective cohort study of 379 men with prostate cancer treated by radical prostatectomy at Johns Hopkins Hospital. Inclusion criteria: BCR (defined by PSA ≥0.2 ng/mL), and measurement of at least 2 PSA values at least 3 months apart within 2 years of BCR. Exclusion criteria: preoperative radiation, hormonal therapy, or salvage radiation therapy with a durable PSA response of >2 years. Postoperative follow-up included serum PSA level testing every 3 months for 1 year, semiannually during the next year, and yearly thereafter. PSADT was based on all PSA values within 2 years of BCR (PSA ≥0.2 ng/mL).
Results: During follow-up, the prostate cancer mortality rate was 17% (66 of 379 men).† Based on multivariable analysis, three factors were significantly associated with mortality: pathological Gleason score (8-10), time of BCR (≤3 years) and PSADT, as a continuous variable. This Kaplan-Meier graph illustrates the researchers’ exploration of different PSADT cut-off points, using 3- and 6-month intervals. Each PSADT subgroup was significantly associated with prostate-cancer specific mortality; the more rapid the PSADT, the greater the risk.
Limitations: This study was subject to the limitations of retrospective cohort studies, which include data quality factors (e.g., missing data) and loss of patients to follow-up. Because this study was not randomized, its results are subject to potential confounding by unmeasured variables and sampling biases. The authors identify other limitations of the study, including (1) small subgroup size and large confidence intervals; (2) a predominantly white population limiting generalizability of results to a more racially diverse population; and (3) calculation of PSADT based on the assumption that PSA levels increase exponentially (at least during the first 2 years after recurrence), although it is plausible that, in the long term, PSADT values may not be stable. They note that external validation from other, similar studies, or from prospective clinical trials is necessary.
†Prostate cancer death was defined in this study as death occurring in a patient who had metastases that progressed following hormonal therapy.5
Following treatment with curative intent for localized prostate cancer, serial PSA measurements with clinical evaluation can be important during follow-up.2,4 These measurements enable the determination of PSA doubling time, which is a reliable indicator of the risk for disease progression.1,3,5
The NCCN Guidelines suggest the option of considering tumor stage, Gleason score, and initial PSA when determining if a patient is at high risk of recurrence.2
Guidelines offer direction for signs of BCR following radical prostatectomy (RP) and radiation therapy (RT)2,4:
PSA = 0.2 ng/mL
plus a confirmatory value of ≥0.2 ng/mL
Persistent disease:
PSA level never drops to undetectable levels†
PSA recurrence:
PSA undetectable, followed by a detectable PSA level on 2 or more occasions†
PSA ≥2 ng/mL
above post-RT nadir
PSA ≥2 ng/mL above post-RT nadir
*The NCCN Guidelines include a third category in addition to persistent disease and PSA recurrence. The third group comprises patients with persistent, low PSA levels, attributed to either slow PSA metabolism or residual benign tissue. NCCN Guidelines suggest that this group does not require further evaluation unless PSA increases.2
†The NCCN Guidelines note that there is no consensus definition of a threshold for a truly undetectable PSA level. They recommend the option that clinicians evaluate patients with persistent disease and PSA recurrence for metastatic disease.2
Select “High-Risk” or “Low-Risk” to visualize how subsequent PSA measurements would be interpreted.
*Rapid PSADT is often defined as either <9 months or <12 months—but there is no universal consensus on this definition.1,3,5 This visualizer uses the <12-month criterion from the 2021 AUA Guidelines.4
†Biochemical recurrence of prostate cancer without metastatic disease is defined as a PSA ≥0.2 ng/mL after radical prostatectomy and the PSA nadir value + 2.0 ng/mL after radiation therapy.4
Not actual patients.
HIGH-RISK BCR
PSADT: 2.8 months
HIGH-RISK BCR
PSADT: 5 months
HIGH-RISK BCR
PSADT: 11 months
HIGH-RISK BCR
PSADT: 2.8 months
Gregory works as an architect. He is married and has 3 children.
Initial diagnosis was 2 years ago. Treated with radical prostatectomy followed by salvage radiation therapy. Currently has a rapidly rising PSA.
Concerned about his high-risk BCR status and the chance his prostate cancer will progress.
HIGH-RISK BCR
PSADT: 5 months
Nicolas works as a pharmacist. He has 1 daughter and 3 grandchildren. His father died of prostate cancer at age 67.
Nicolas underwent a radical prostatectomy, followed by radiation therapy, shortly after he was diagnosed in November of 2020. His PSA has continued to rise since July of 2022.
With no immediate plans to retire, Nicolas wants to understand his potential prostate cancer recurrence risk.
HIGH-RISK BCR
PSADT: 11 months
Hector has been living with prostate cancer for the last 4 years. He and his husband are volunteers at an animal shelter.
Initial diagnosis in May of 2018. One year after external beam radiation therapy, Hector’s PSA began to rise and has been rising steadily since July of 2019.
Hector enjoys an active lifestyle and loves to take his dogs to the beach. He is motivated to learn more about high-risk BCR.
These guidelines recommend options for the evaluation of patients with a biochemical recurrence of non-metastatic, castration-sensitive prostate cancer.2,4
Please see AUA Guidelines for complete information
Available at www.auanet.org/guidelines-and-quality/guidelines
Please see NCCN Guidelines for complete information
Available at www.nccn.org
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