Snowballs rolling down a hill growing in size representing rapid PSA doubling time
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At biochemical recurrence (BCR), rapid PSA doubling time (PSADT) may suggest a path to poor outcomes.1-4

Following definitive therapy, a rising prostate-specific antigen (PSA) level is a sign of heightened risk for development of symptomatic metastatic disease.At the time of BCR in non-metastatic hormone-sensitive prostate cancer (nmHSPC), 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

Download these hypothetical patient profiles to help you further understand high-risk BCR, or click a patient below to explore these profiles.

Not actual patients.

This site is intended only for Healthcare Professionals who are interested in the management of prostate cancer

I AM NOT A HEALTHCARE PROFESSIONAL

This website is an educational scientific resource, funded and developed by Astellas Pharma AG. MAT-CH-NON-2024-00036 DOP: February 2024.

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UNDERSTANDING High-Risk BCR

PSADT is a critical indicator of risk at the time of BCR

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.1-5

A rapid PSADT ≤ 9-12 months indicates a high risk of disease progression

This rate of PSA doubling has been shown in clinical studies and recognised by European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines to be correlated with the risk of prostate cancer metastasis and mortality.1–4,6

Pound CR et al. JAMA 19995

One of the first real world–evidence based studies to assess the relationship between BCR in prostate cancer following radical prostatectomy (RP) and disease progression

Methods: This was a retrospective cohort study of 1997 men who underwent radical prostatectomy to treat localised 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 analysed 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.

Chart Likelihood of Metastasis-Free Survival (MFS) over 15 Year Period Following PSA Recurrence

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 analysed 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.5

Freedland SJ et al. JAMA 20057

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).

Chart Fifteen-Year Actuarial Kaplan-Meier Prostate Cancer-Specific Survival Curves by PSADT

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 randomised, 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 generalisability 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.7

Guidelines recommend options for monitoring PSA levels after definitive treatment

Following treatment with curative intent for localised prostate cancer, serial PSA measurements with clinical evaluation can be important during follow-up.4,6 These measurements enable the determination of PSA doubling time, which is a reliable indicator of the risk for disease progression.1-3

The options recommended for PSA testing by the NCCN Clinical Practice Guidelines in Oncology, Prostate Cancer are:4

Patients at high risk of recurrence:

every 3 months

Three calendar icons representing monitoring PSA levels in patients at high risk of recurrence of prostate cancer

Other patients: Every 6 to 12 months

Twelve calendar icons representing monitoring PSA levels in other prostate cancer patients

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.4

What does BCR mean in prostate cancer?

Guidelines offer direction for signs of BCR following radical prostatectomy (RP) and radiation therapy (RT)4,6:

AFTER RP:

EAU Guidelines6

PSA should be undetectable (<0.1 ng/mL) A PSA of >0.1 ng/mL is a signal of residual prostate tumour tissue After an undetectable PSA is obtained, a PSA ≥0.4 ng/mL and rising, best predicts further metastases

NCCN Guidelines*4

Persistent disease:

PSA level never drops to undetectable levels

PSA recurrence:

PSA undetectable, followed by a detectable PSA level on 2 or more occasions

AFTER RT:

EAU Guidelines6

PSA ≥2 ng/mL

above post-RT nadir

NCCN Guidelines4

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.4

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.4

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Review an example timeline graph showing the relationship between PSADT and high-risk BCR

To help visualise the risk of recurrence related to PSADT, we created a data simulation using a 12-month PSADT* to illustrate how serial PSA measurements are interpreted, based on a hypothetical initial posttreatment PSA value of 0.5 ng/mL.

Select “High-Risk” or “Low-Risk” to visualize how subsequent PSA measurements would be interpreted.

Timeline-based representation of PSADT less than 12 months

This second PSA value of 1.1 ng/mL at 6 months after the initial measurement—or any PSA value in the shaded area—would be considered a rapid PSADT, indicative of a higher risk of prostate cancer recurrence.

Timeline-based representation of PSADT greater than 12 months

This second PSA value of 0.8 ng/mL at 11 months after the initial measurement—or any PSA value in the shaded area—would not be considered a rapid PSADT. This would be indicative of a lower risk of prostate cancer recurrence.

This visualiser is meant for educational purposes only. It does not constitute medical advice. It is not intended to replace a healthcare professional’s independent medical judgment regarding the management of individual patients. It is not intended for use in clinical practice.

*Rapid PSADT is often defined as either <9 months or <12 months —but there is no universal consensus on this definition.1-3 This visualiser is based on the <12-month criterion from the 2023 EAU Guidelines.6

Biochemical recurrence of prostate cancer without metastatic disease is defined in the EAU Guidelines as a PSA >0.1 ng/mL after radical prostatectomy and the PSA nadir value + 2.0 ng/mL after radiation therapy.6

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HYPOTHETICAL High-Risk BCR Patient Profiles

Not actual patients.

Hypothetical nmCSPC patient 2.8 months PSADT
ROBIN

HIGH-RISK BCR

PSADT: 2.8 months

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PERSONAL AND SOCIAL HISTORY

Robin works as an architect. He is married and has 3 children.

PROSTATE CANCER HISTORY

Initial diagnosis was 2 years ago. Treated with radical prostatectomy followed by salvage radiation therapy. Currently has a rapidly rising PSA.

PATIENT PERSPECTIVE

Concerned about his high-risk BCR status and the chance his prostate cancer will progress.

Hypothetical nmCSPC patient 2.8 months PSADT disease progression chart

Drag the arrow to explore Robin's progression

Hypothetical nmCSPC patient 5 months PSADT
ANDREAS

HIGH-RISK BCR

PSADT: 5 months

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PERSONAL AND SOCIAL HISTORY

Andreas works as a pharmacist. He has 1 daughter and 3 grandchildren. His father died of prostate cancer at age 67.

PROSTATE CANCER HISTORY

Andreas 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. 

PATIENT PERSPECTIVE

With no immediate plans to retire, Andreas wants to understand his potential prostate cancer recurrence risk. 

Hypothetical nmCSPC patient 5 months PSADT disease progression chart

Drag the arrow to explore Andreas's progression

Hypothetical nmCSPC patient 11 months PSADT
URS

HIGH-RISK BCR

PSADT: 11 months

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PERSONAL AND SOCIAL HISTORY

URS has been living with prostate cancer for the last 4 years. He and his husband are volunteers at an animal shelter.

PROSTATE CANCER HISTORY

Initial diagnosis in May of 2018. One year after external beam radiation therapy, Urs’s PSA began to rise and has been rising steadily since July of 2019.

PATIENT PERSPECTIVE

Urs enjoys an active lifestyle and loves to take his dogs to the beach. He is motivated to learn more about high-risk BCR.

Hypothetical nmCSPC patient 11 months PSADT disease progression chart

Drag the arrow to explore Urs's progression

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RESOURCES

These guidelines recommend options for the evaluation of patients with a biochemical recurrence of non-metastatic, castration-sensitive prostate cancer.4,6

Please see EAU Guidelines for complete information

Available at www.uroweb.org/guidelines/prostate-cancer

Please see NCCN Guidelines for complete information

Available at www.nccn.org

Snowballs rolling down a hill growing in size representing rapid PSA doubling time

The referenced data and publications will be made available upon request.

 

References:
1.
Paller CJ et al. Management of biochemically recurrent prostate cancer after local therapy: evolving standards of care and new directions Clin Adv Hematol Oncol 2013;11(1):14-23.
2. Ward JF et al. The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy J Urol 2003; 170(5):1872-1876.
3. Freedland SJ et al. A phase 3 randomised study of enzalutamide plus leuprolide and enzalutamide monotherapy in high-risk non-metastatic hormone-sensitive prostate cancer with rising PSA after local therapy: EMBARK study design BMJ Open 2021; 11(8):e046588.
4. NCCN Guidelines. Prostate Cancer. Version 1. 2023.
5. Pound CR et al. Natural history of progression after PSA elevation following radical prostatectomy JAMA1999; 281(17):1591–1597.
6. EAU. Available at: https://uroweb.org/guidelines/prostate-cancer. Date accessed: July 2023.
7. Freedland SJ et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy JAMA 2005;294(4):433–439.