PSA as the driving biomarker to manage low- and intermediate-risk prostate cancer patients in clinical practice

Prostate cancer risk stratification relies on several clinical factors. Low-risk patients, characterized by T1–T2a stage, Gleason score (GS) ≤6, and prostate-specific antigen (PSA) <10 ng ml⁻¹, exhibit an excellent prognosis and are suitable for active surveillance (AS). Regular monitoring is essential for these patients, including PSA tests every 3–6 months, annual digital rectal exams (DRE), and prostate biopsies every 6–12 months, followed by less frequent biopsies every 2–5 years. Epstein criteria, which consider GS ≤6, PSA density (PSAD) <0.15 ng ml⁻², limited tumor involvement in cores, and absence of high-risk features, help predict pathologic and biochemical relapse-free survival and guide AS management.1

Intermediate-risk patients, with T2b–T2c stage and GS 7 (3 + 4 or 4 + 3), undergo radical prostatectomy (RP) with or without lymph node dissection (LND), radiotherapy (RT), and hormone therapy (HT). RP + LND is indicated for tumors confined to the prostate gland (T1–T2), especially in nonelderly patients (<65 years) and those at intermediate risk. RT is an effective alternative to RP for localized prostate cancer, providing comparable long-term outcomes in disease control.

Comprehensive diagnostic technique includes PSA, DRE, transrectal prostate ultrasound, multiparametric nuclear magnetic resonance (NMR), computed tomography (CT), bone scans, and choline or prostate-specific membrane antigen (PSMA)–positron emission tomography (PET). Restaging involves choline–positron emission tomography (PET), if PSA ≥1 ng ml⁻¹ or PSA-doubling time (PSA-DT) <6 months, or PSMA-PET, especially if PSA <1 ng ml⁻¹, to detect recurrence or metastasis.2,3

Multidisciplinary evaluation by urologists, radiologists, radiotherapists, and medical oncologists is crucial. Treatment strategies should consider clinical stage, GS, age, and comorbidity status. Personalized care improves outcomes and ensures a continuum of patient support. Some GS 6 and GS 7 patients present with locally advanced or node-positive/metastatic disease and require multidisciplinary interventions, including RP, RT, and HT.

In clinical practice, age and comorbidity influence treatment decisions. Our experience incorporates a clinical evaluation based on age categories (nonelderly, young-elderly, and old-elderly) and comorbidity status (assessed using the Cumulative Illness Rating Scale [CIRS]) integrated with performance status.4,5 In our investigations, we explored various studies and real-life experiences to tailor individualized treatment approaches for patients who are not suitable for standard therapies. Additionally, we introduced the concept of toxicity syndromes (TS) to comprehensively assess treatment-related adverse events, particularly considering age and comorbidities.

Specifically, we defined two types of TS: limiting TS-single sign (TS-ss), occurring when a patient experiences only one limiting toxicity; and limiting TS-multiple signs (TS-ms), if the limiting toxicity is associated with other nonlimiting toxicities (Grade ≤ 2), or the patient experiences multiple limiting toxicities simultaneously. Across different cancer types, limiting TS-ms was more prevalent and significantly affected elderly patients compared to nonelderly individuals. These findings highlight the importance of considering toxicity burden when designing personalized treatment strategies.6

PSA BIOMARKER TO PROPERLY MANAGE LOW- AND INTERMEDIATE-RISK PROSTATE CANCER PATIENTS IN CLINICAL PRACTICE

PSA, a glycoprotein produced by the prostatic glandular tissue, serves as a crucial diagnostic and clinical biomarker in prostate cancer management. Both benign and malignant prostatic diseases can elevate PSA levels in the blood. In clinical practice, PSA typically drops to undetectable values within 2 months after RP, while it gradually declines to less than 1 ng ml⁻¹ after RT. Failing to achieve these values is associated with an increased risk of disease recurrence and reduced survival rates (with a 5.6-fold higher risk of death if PSA exceeds 0.2 ng ml⁻¹). The average PSA value and time to reach PSA nadir can vary significantly.7

To enhance the accuracy of PSA assessment, PSA-DT has been evaluated. PSA-DT defines the interval (in month) for PSA doubling and is commonly used in clinical practice. A PSA-DT of <3 months is considered relevant. After RP, RT, or salvage therapy following PSA failure or during AS, PSA-DT correlates with patient outcomes. Detecting a PSA-DT of ≤10 months in patients with nonmetastatic castration-resistant (CR) prostate cancer identifies a risk factor for developing bone metastases. This PSA-DT threshold now allows access to HT such as apalutamide, darolutamide, and enzalutamide.8 PSA-DT plays a crucial role in monitoring prostate cancer progression. Here are its key applications.

AS for low-risk prostate cancer

For patients with low-risk (GS 6) prostate cancer confined to the prostate gland, assessing PSA-DT is valuable. If PSA-DT is less than 10 months in nonmetastatic disease, it prompts multidisciplinary treatment evaluations. Diagnostic evaluations (ultrasound, NMR, and choline-PET) are considered before making treatment decisions.

Follow-up after RP or RT

Posttreatment monitoring involves evaluating PSA-DT. Proper diagnostic assessments (ultrasound, NMR, and choline-PET) are recommended based on PSA levels: if PSA ≥ 1 ng ml⁻¹, consider ultrasound, NMR, and choline-PET; if PSA < 1 ng ml⁻¹, consider more sensitive PSMA-PET.

PSA-DT is assessed to guide HT decisions in hormone-sensitive (HS) nonmetastatic disease.

HT monitoring in advanced settings

In adjuvant and metastatic HS and CR prostate cancer, PSA-DT is useful to monitor HT effectiveness. Patients receiving chemotherapy or polyadenosine diphosphate-ribose polymerase (PARP) inhibitors due to breast

cancer gene 1 and 2 (BRCA1/BRCA2) mutations should evaluate PSA-DT. HT will be adjusted if PSA-DT is less than 3 months.9 Additionally, PSAD is defined as the ratio between circulating PSA value and prostate gland size (measured by NMR). Notably, PSAD predicts histological progression during AS; it indicates reduced risk of aggressive disease in patients with equivocal NMR; and increased PSAD (cut-off values of 0.12–0.15 ng ml⁻²) is associated with higher prostate cancer risk.10 While other diagnostic and prognostic biomarkers are being studied, their clinical application remains uncertain, and guidelines vary across different contexts.

CONCLUSIONS

To date, PSA, as an absolute value and derived as PSA-DT, is the driving biomarker for managing prostate cancer patients in clinical practice. It assumes specific, differential prognostic and predictive relevance in the different settings of low- and intermediate-risk patients, allowing for the proper proposition of AS and different treatment strategies, personalized according to age, comorbidity status, expected multidisciplinary treatment-related adverse events and toxicity syndromes observed in the individual patient.

Different PSA-DT evaluations can be useful for clinically managing the individual patient, depending on different disease settings: (1) AS of low-risk (GS 6) prostate cancer limited to the prostate gland, to prolong it if PSA-DT ≥10 months, or add multidisciplinary treatment strategies if PSA-DT <10 months; (2) follow-up of early prostate cancer patients treated by RP with or without RT, and with or without adjuvant HT to add more sensitive receptor-mediated PSMA-PET if PSA >0.5 ng ml⁻¹ and <1 ng ml⁻¹, and to treat HS-disease with newer androgen receptor inhibitors, also in absence of detected metastases if PSA-DT <10 months; and (3) monitoring of HT in the adjuvant, and metastatic HS and CR settings and in patients associating chemotherapy or PARP-inhibitors due to BRCA1/BRCA2 mutations, to detect metastatic disease as early as possible and treat HS-disease and, thereafter, CR-disease, by adding or cross HT if PSA-DT <3 months.

Thus, PSA analysis and PSA-DT are useful to manage patients of low- and intermediate-risk prostate cancer in clinical practice.

AUTHOR CONTRIBUTIONS

ER proposed and wrote the manuscript. CM and FS contributed to integration of specific information concerning each disease setting. GB revised the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.