In the era of precision medicine, integrated diagnostics is employed for selecting appropriate and optimal therapies tailored for patients’ individual characteristics. Today, a highly debated and heterogeneous clinical scenario is how to manage the patients who underwent whole-gland therapy for prostate cancer, such as radical prostatectomy, radiation therapy, and are experiencing rising PSA and biochemical recurrence (BCR).

The available diagnostic tools to further evaluate these patients should be utilized according to patients’ individual conventional risk factors such as the serum PSA level and PSA kinetics, pathological Gleason grade group, and clinical stage. The oncologic outcome for patients with localised and locally advanced prostate cancer who might experience BCR after treatment with curative intent has been defined by the European Association of Urology (EAU) as low-, intermediate-, and high-risk [1], whereas the new BCR risk groups proposed by Van den Broeck et al in 2019 stratify patients with BCR into low and high-risk categories for predicting oncologic outcome [2].

The two imaging modalities recommended by European guidelines for patients at risk of developing prostate cancer recurrence are basically magnetic resonance imaging for patients treated with radiation therapy, and prostate-specific membrane antigen-based (PSMA) targeting Positron Emission Tomography for patients treated with radical prostatectomy. There is a variety of nuclear medicine radiotracers tracers for patients with BCR, such as choline and fluciclovine, each of which aims to target different biologic processes.

In 2021, a panel of genitourinary radiology experts created the Prostate Imaging for Recurrence Reporting (PI-RR) system, just like the other existing RADS systems, to standardize image acquisition, interpretation, and structured reporting of MRI in prostate cancer local recurrence after therapies with curative intent [3]. PI-RR also aimed to represent a clinical guide to improve the management of men with recurrent prostate cancer by achieving better diagnostic performance and personalised treatment tailored for individual patients. PI-RR system has been recently validated in a multi-reader study, providing an accurate evaluation of local recurrence after definitive therapy for prostate cancer [4]. Indeed, for radiation therapy, the area under the receiver operating characteristic curve (AUC) for PI-RR ranged from 0.77 to 0.92 across different readers, and for radical prostatectomy, and the AUC ranged from 0.80 to 0.88, with an intraclass correlation coefficient of 0.87 for both groups. While MRI has been documented to be useful to detect local recurrence after surgery and radiation therapy, the evaluation for nodal and distant metastasis is limited. Based on the research in the last half decade, PSMA targeting PET/CT has been proven to be a highly sensitive imaging modality for detecting local recurrence after radical prostatectomy and for systemic disease assessment. Moreover, PSMA-PET/CT has been documented to impact patient management [5, 6]. However, PSMA-PET/CT lacks specificity, especially for the assessment of local recurrence confined to the prostate gland due to false positive post-radiotherapy treatment effect-related changes in the prostate [7]. Also, urinary excretion of these agents can significantly limit the assessment of anastomotic locally recurrent disease due to confounding radiotracer activity within the bladder (Fig. 1).

Fig. 1
figure 1

MRI case example in the post-RP setting of a 68-year-old male experiencing BCR (PSA 10.6 ng/ml) after salvage RP in 2019 (pT2c R0 N0). Axial T2W MRI shows a mass-like hypointense focus at 6-8 o’clock) (arrow) (A), with focal early enhancement on DCE (arrows) (B, subtracted image; C, non—subtracted image), and with focal marked hyperintensity on high b-value DWI (D) and marked hypointensity on the ADC map (E) (arrows), the resultant PI-RR category is 5 for this lesion. On the PSMA-PET/CT (F) no focal tracer uptake is present, likely secondary to urinary excretion of the radiotracer that obscures the evaluation. The assessment for pelvic lymph nodes was negative for both the pelvic MRI and the PET scan. RP, radical prostatectomy; BCR, biochemical recurrence; T2W, T2-weighted; MRI, magnetic resonance imaging; DCE, dynamic contrast enhanced; DWI, diffusion-weighted imaging; ADC, apparent diffusion coefficient; PSMA-PET/CT, prostate-specific membrane antigen-based targeting positron emission tomography

Full size image

Both MRI and PSMA-PET/CT have pros and cons in the evolution of local recurrence in post-surgery and radiation BCR patients. Joint use of the two techniques has been reported to improve diagnosis [8]. To further assist this joint use, PSMA targeting PET/MRI or software-based fusion of MRI with PET/CT scans can be considered during assessment for both local and distant prostate cancer recurrence. The use of PET/MRI scanners can be quite limited and impractical due to availability and high cost; however, software-based fusion of MRI and PET data can be a practical and cheaper solution.

For all these reasons, when proposing individualized pathways based on risk, BCR patients can be stratified into groups and can be triaged to four different possible pathways (Fig. 2):

  • Pathway 1 (for low-risk pre-treatment and BCR EAU groups): MRI first. If MRI is negative the patient is monitored over time with serum PSA, if MRI is positive the patient should undergo targeted biopsy and/or salvage therapy, after multidisciplinary consultation.

  • Pathway 2 (for low-risk BCR and intermediate-risk pre-treatment EAU groups): MRI first. If MRI is negative, the patient should be directed to nuclear medicine imaging, preferably PSMA-PET/CT scan, if PSMA-PET/CT is positive the patient should undergo targeted biopsy and/or salvage therapy, based on a multidisciplinary board decision.

  • Pathway 3 (for high-risk BCR and low-risk pre-treatment EAU groups or for low-risk BCR and high-risk pre-treatment EAU groups): MRI first. If MRI is negative, the patient should be directed to nuclear medicine imaging, preferably PSMA-PET/CT scan, if PSMA-PET/CT is positive the patient can be directed to salvage therapy.

  • Pathway 4 (for high-risk BCR and intermediate/high-risk pre-treatment EAU groups): Nuclear medicine imaging first, PSMA-PET/CT scan if available. If PSMA-PET/CT is negative, the patient should undergo a pelvis MRI based on PI-RR requirements, and if indicated whole-body MRI, if MRI is positive the patient should be directed to salvage therapy.

Fig. 2
figure 2

Proposed risk-adapted diagnostic pathways to address the patient with suspicion of recurrent prostate cancer. EAU, European Association of Urology; BCR, biochemical recurrence; MRI, magnetic resonance imaging; PET, positron emission tomography; P, pathway; FP, false positive; Neg, negative; Pos, positive

Full size image

In summary, those who are at low risk of developing recurrence based on EAU guidelines, with a favourable prognostic profile can be evaluated with MRI as first-line study, due to the low risk of distant metastasis. On the contrary patients with an intermediate or high risk of BCR with a less favourable prognostic profile based on EAU guidelines should be preferably investigated using PSMA-PET/CT.

The advantages of addressing recurrent disease according to a risk-adapted strategy rely on several factors, seeing precision diagnostics as “ground-truth”: (i) equipment availability in both public and private practices; (ii) triaging the right patient to the right imaging modality along with the natural history of the disease; (iii) nuclear medicine imaging-related costs and availability; and (iv) most importantly, making an accurate diagnosis in the less-invasive possible way. These pathways can be proposed only to well-informed men meeting the criteria outlined in the current EAU guidelines [1], able to understand the diagnostic work-up of their disease. Finally, to bridge the gap from PSA rise after treatment with curative intent to the detection of recurrence and salvage therapies, interdisciplinary education and communication between radiologists, urologists, nuclear medicine physicians, oncologists, and radiation oncologists is needed.