What treatment and monitoring strategies are recommended for patients with biochemical recurrence without PSA rise?
Executive summary
Biochemical recurrence that is suspected or imaged without a concomitant rise in standard PSA levels is unusual but documented, and management balances early salvage intent against risks of overtreatment; current guideline and observational data favor targeted imaging (PSMA-PET), consideration of early salvage radiotherapy when clinically indicated even with negative scans, risk-stratified active surveillance for low‑risk cases, and selective systemic escalation for high‑risk M0 recurrence [1] [2] [3] [4].
1. Defining the clinical puzzle: recurrence without a clear PSA signal
True local or symptomatic recurrence without an accompanying PSA rise is rare but reported in the literature, and biochemical recurrence most commonly manifests as a rise in PSA after curative therapy, with definitions after prostatectomy typically using a confirmatory threshold (eg, ≥0.2 ng/mL) while other centers use ultrasensitive assays and variable cut points [1] [5] [6].
2. First-line reconnaissance: PSMA-PET and the limits of imaging
Contemporary management begins with high‑sensitivity molecular imaging—PSMA-targeted PET/CT or PET/MRI—because these tracers detect recurrent disease at lower PSAs and find lesions missed by conventional imaging, but detection rates drop at very low PSA and a negative PET does not rule out clinically meaningful microscopic disease (PSMA detection rates vary by PSA level and are substantially lower when PSA <0.5 ng/mL) [3] [7].
3. When imaging is negative: why guidelines still often favor salvage radiotherapy
Guideline panels conclude that a negative PSMA-PET should not automatically preclude or delay salvage prostate‑bed radiotherapy when other clinical indications exist, because PET/CT sensitivity at low PSA is insufficient to exclude microscopic local disease and outcomes with salvage RT have been similar whether PET was locally positive or negative in reported series [3] [8].
4. Risk‑stratified surveillance versus intervention
For men judged low risk by clinical and pathologic features and by PSA kinetics, active observation with regular PSA monitoring and repeat imaging is an accepted strategy and has been associated with low prostate‑cancer mortality in selected cohorts; conversely, patients with rapid PSA doubling time, higher absolute PSA, adverse pathology, or nodal status should be considered for earlier salvage RT or intensified therapy [4] [9] [10].
5. Systemic and metastasis‑directed options when occult spread is suspected
When micrometastatic disease is suspected despite no PSA rise or with equivocal imaging, guidelines reserve systemic escalation for defined high‑risk M0 biochemical recurrence (eg, short PSA‑DT or PSA thresholds described by EAU/NCCN), and trials have shown benefit to adding next‑generation AR pathway inhibitors in some high‑risk M0 settings; metastasis‑directed therapies (eg, stereotactic RT or salvage lymphadenectomy) have been used selectively but yield variable biochemical control in observational series [2] [9] [11].
6. Practical monitoring and testing nuances
Clinicians may use ultrasensitive PSA assays selectively in high‑risk patients but should confirm trends before committing to invasive therapy; repeat PSMA imaging when PSA rises or kinetics worsen is common practice because PET sensitivity rises with PSA and can change management, yet there is no universal evidence defining perfect timing for testing [8] [3] [2].
7. Uncertainties, tradeoffs and the patient‑level decision
Evidence gaps remain: heterogeneity of BCR definitions, limited prospective randomized data on imaging‑directed versus empiric salvage strategies, and variable follow‑up durations in observational cohorts mean decisions require candid discussion of tradeoffs—risk of missing an early curative window versus risk of overtreatment and morbidity—with leading sources (AUA/ASTRO/SUO, EAU, ASCO reviews) emphasizing a tailored, risk‑based approach [8] [2] [9].