Measurement of serum PSA is the cornerstone in follow-up after primary curative treatment for PCa. Rising PSA values are helpful to identify patients with recurrence and it is directly correlated with tumor burden [7]. However, it cannot distinguish between local and systemic recurrence, and thus continuously rises some degree of clinical interpretation difficulties. PSMA-PET has been proposed as a tool which overcomes these shortcomings in the post-treatment setting. The aim of this part is to answer the following questions: What are the detection rates of PSMA PET/CT and at which PSA-thresholds is PSMA PET/CT able to identify positive lesions in a reasonable number of patients? Do clinical parameters beyond PSA exist, that are associated with higher detection rates (Table 1)?

Looking at a broad spectrum of patients and a wide range of PSA values, PSMA PET/CT has detection rates ranging from 27.3% to 96% at PSA levels below 0.5 and ≥10 ng/mL, respectively. Afshar-Oromieh et al [8] evaluated PSMA PET/CTs of a large number of men (n=1,007) with BCR after different primary and secondary treatments (i.e., RP, RT, androgen deprivation therapy [ADT], chemotherapy and/or high-intensity focused ultrasound). The overall detection rate of any lesion, including all PSA levels, was 79.5% – slightly lower than in previous studies of the same group, supposedly due to a lower median PSA level [9].

Of note, ADT was found to be significantly associated with positive PSMA PET/CTs (both p<0.001). ADT plays a relevant role in PSMA-based imaging since it is known to increase PSMA expression of PCa cells [6]. This phenomenon does not only increase the number of visualized lesions in patients on ADT compared to patients without ADT, but may also be of clinical importance regarding PSMA-targeting therapies. While the strength of this study lies in its large sample size, the rather heterogeneous spectrum of recurrent PCa patients represents a limitation regarding validity of PSMA-PET/CT detection rates. However, the results are being corroborated by the largest prospective study, conducted by Caroli et al [10], who examined PSMA PET/CTs from 314 men after RP or primary RT and without ADT within 6 months before imaging. If results from ¹⁸flourine (F)-choline PET/CTs performed within one month prior to PSMA PET/CT were available, only patients with negative or “dubious” scans were included. In their study, the overall detection rate of any positive lesion was 62.7%, ranging from 27.3% for PSA values of 0–0.2 ng/mL to 94.8% for PSA values above 2 ng/mL. In comparison to the results from the previous mentioned retrospective study, the overall detection rate, as well as detection rates for PSA levels <0.5 and 1 to 2 ng/mL, was lower. These differences may be explained by the study design: results from prospective evaluations are less prone to unmeasured confounding. Also, the mean PSA was as low as 0.83 ng/mL, explaining the lower overall detection rate. Taken together, the study by Caroli et al [10] confirms higher PSA levels to be significantly associated with positive scans, while the impact of ADT could not be assessed due to study design.

When focusing on more homogeneous cohorts and low PSA levels for which reliable imaging modalities are desperately needed, PSMA-PET/CT still reveals lesions in more than 50% of the patients. A group from Munich investigated 272 patients with very low (0.2–0.5 ng/mL) and low (>0.5–1.0 ng/mL) PSA values after RP only [11]. Detection rates of any lesion in PSMA-PET/CT, stratified by PSA-levels, were as high as 55% vs. 74% for very low and low PSA values, respectively. These important findings were in line with other retrospective evaluations making the clinician understand that diagnostic PSMA PET/CT scans may be of use if imaging will have an impact in treatment strategy at PSA-levels below 0.5 ng/mL [1213].

Interestingly, even in patients with very low PSA-values <0.5 ng/mL, two studies from Munich found distant lesions in ~18% of the patients. This finding suggests that clinicians are facing a rather palliative setting in almost every 5th to 6th patient with such low PSA levels. Furthermore, this finding underscores evidence from previous studies showing better outcomes only in 80% of patients undergoing salvage RT at low PSA levels [14].

Evidence for the value of PSMA PET/CT after RT as a primary treatment is low. Distinguishing between men who do and do not benefit from further – and to some extent morbid – treatment is exactly what diagnostic tools should be able to do. This is even more crucial in patients who had undergone RT as primary treatment since treatment options for patients with local recurrence after RT are associated with higher morbidity compared to those after primary RP. Unfortunately, to date there is only one study available that exclusively focused on patients with BCR after RT and found an overall detection rate of 90.7% for PSMA PET/CT at a comparatively high median PSA of 6.4 ng/mL. Evidence of distant disease in 59.8% of the patients suggests a certain potential to tailoring further treatment [15]. However, more in-depth investigations are needed to better understand the value and impact of PSMA PET/CT in the management of patients with BCR after RT.

In summary, the overall detection rates for patients with PSA-recurrence after primary local therapy for PCa range from 63% to 91%. Unsurprisingly, detection rates are higher among men with higher PSA levels. However, PSMA PET/CT demonstrates promising detection rates of >50% up to 74% for men with PSA levels <0.5 ng/mL and between 0.5 and <1 ng/mL, respectively. At these PSA levels, at which early salvage RT is recommended according to current guidelines, distant disease are found in ~18%.

For men with higher PSA ≥1 ng/mL detection rates were >80% in almost all studies. Besides higher PSA-level, ADT is significantly associated with positive scans which may be explained by its ability to increase PSMA expression on PCa cells. The major limitation of all of the aforementioned studies is the missing verification of positive lesions PSMA PET/CT: the true rate of positive lesions remains uncertain. More importantly, it remains unanswered whether the additional effort and expense translates into an alteration of the management and a clinical benefit in a long-term-perspective.

Even a highly accurate diagnostic test is only useful if it impacts clinical management. Thus, in addition to defining the accuracy of this test, one clinical relevant question is whether PSMA PET/CT influences clinical decision-making of men with BCR of PCa. Decision making might be particularly challenging when treatment recommendations before and after PSMA PET/CT are conflicting, boiling down to the question whether or not a therapy should be changed based on the results of PSMA PET/CT scans. For example: Does a men with BCR after primary RP and negative results on PSMA PET/CT still require salvage RT? Another rising debate addresses the management of oligometastatic diseases. The treatment of solitary or few metastases in patients with PCa showed longer ADT-free survival in a randomized phase II clinical trial [16]. However, do clinical decisions change in patients with oligometastatic disease seen in PSMA PET/CT? Table 2 summarizes the results of six retrospective and three prospective studies that observed changes in the management of recurrent PCa following PSMA PET/CT [171819202122232425].

In patients planned for salvage RT after primary RP, results from PSMA PET/CT lead to modification of the initially planned RT strategy in up to one third of the patients: Calais et al [17] aimed to determine how often positive lesions seen in PSMA PET/CTs were covered by the prostate fossa clinical target volume for post-prostatectomy RT. This volume is defined by the Radiation Therapy Oncology Group and represents a minimum volume to be irradiated in a common postoperative scenario [26]. Calais et al [17] examined 270 men with BCR after RP and PSA levels of less than 1 ng/mL, who were planned for RT according to current guidelines [32728]. A total of 19% were identified to harbor at least one positive lesion that was not covered by the consensus clinical target volume. Of those, 12% had extrapelvic lesions (mostly bone lesions) and thus salvage RT as initially planned would not lead to curative treatment. Seven percent had positive lesions within the pelvis, which could have led to an extension of the radiated field. Unfortunately, due to lack of follow-up, the question whether or not these results ultimately led to a change of management remains unclear. However, the true clinical impact was examined in a prospective setting by van Leeuwen et al [25] Positive lesions were detected in 54% of 70 consecutive men with PSA levels between 0.05–1.0 ng/mL following RP. The management was altered in 28.6% because of lesions that were located in either regional lymph nodes or bones that would not have been included in a conventional salvage RT field to the prostatic bed. Notably, the authors emphasize that in 18 men (25%) with positive lesions within the pelvis, consideration might also have been given to focused treatment to a higher dose, using the ⁶⁸Ga-PSMA fused with the planning CT to allow a simultaneous integrated boost or dose painting.

While current EAU guidelines recommend PSMA PET/CT in patients with PSA values ≥1 ng/mL after RP [3], better long-term outcomes have been observed following early salvage RT in patients with PSA levels <0.5 ng/mL [328].

Astonishingly, Farolfi et al [18] found similar modification rates in patients at these PSA levels. For example 24% became candidates for stereotactic body radiation therapy (SBRT; compared to 0% before PSMA PET/CT), while ADT was avoided in 14.3%. SBRT is currently under debate as a treatment option for oligometastatic PCa. It constitutes a non-invasive high-dose external beam radiotherapy, typically delivered in only a few fractions that allow for relative sparing of nearby normal tissues [29]. While there is evidence for a benefit in progression free survival from the treatment of oligomeatastatic disease, studies also show high distant failure rates over time [30].

Active treatment of local recurrence and/or oligometastatic disease and avoidance of definitive treatment in patients with distant disease are common postimaging changes. Findings from several retrospective and survey-based studies show that when investigating a broader spectrum of patients with BCR after different primary treatment modalities, changes occur in up to three quarters of patients [19202123]. The largest retrospective study revealed that >90% of all negative scans resulted mostly in surveillance instead of administration of ADT [20]. In 34% of the patients, oligometastatic disease was actively treated. These findings on the impact of PSMA PET/CT on management decisions are further supported by a prospective study by Zacho et al [24] In the setting of BCR after RP, RT or RP plus salvage RT, they found that the management changed in 30/69 patients (43.5%) according to results from PSMA PET/CT [24]. Likewise, the prevailing change was avoidance of ADT, favouring selective lymph node dissection in men found to have positive lymph node disease. Also, in six out of nine patients with negative scans, salvage RT was omitted. It is important to note that all patients had BCR and that surveillance is only recommended in patients with favourable risk factors, while salvage RT represents the standard of care in patients with BCR after RP [3]. One has to question the meaningfulness of changing management decisions based on PSMA PET/CT as long as no long-term clinical outcomes are available and as long as there is no intention to investigate these.

In our review, out of nine studies, positive and negative PSMA PET/CT results influenced clinical decision making in 19% to 76% of cases, mainly by steering patients away from ADT towards more individual treatment, as for example by altering the initially planned radiation strategy. To what, if any, extent these decisions might impact clinical outcomes in a long-term perspective is uncertain due to missing follow-up investigations. This said, patients facing changes in their management due to results from PSMA PET/CT must be informed that these must not necessarily translate into a long-term clinical benefit.

Along with higher detection rates of recurrent PCa, salvage lymphadenectomy, has gained increasing interest. There is a growing body of literature analyzing the sensitivity, specificity, positive and negative predictive value, and accuracy of PSMA PET diagnostics for patients undergoing salvage lymphadenectomy [4849505152]. Compared to the above mentioned detection rates, these investigations additionally aim to analyze the accuracy for the detection of lymph node metastases by comparing the results seen in PSMA PET/CT with histopathologic findings. Are lesions seen in PSMA PET/CT actually positive in histopathology? Or even more crucial: Are negative lesions truly negative? To answer these questions, it is most important to not exclusively remove positive lesions when undertaking a lymph node dissection (as done in some of the aforementioned studies), but to perform a bilateral extended lymph node dissection beyond positive lesions [50].

When performing standardized lymph node dissections, the current sensitivity and specificity of PSMA-PET/CT are not high enough to justify a salvage lymphadenectomy solely of the PET-positive regions, instead a complete (extended) bilateral salvage lymphadenectomy may be performed.

In the largest retrospective study conducted by Rauscher et al [52], standardized predefined lymph node template fields in 48 patients with positive results in PSMA PET/CT, PET/MR of morphologic imaging were evaluated. Regarding the predefined fields (so called field-based), sensitivity, specificity, positive predictive value, negative predictive value and accuracy of ⁶⁸Ga-PSMA PET were 77.9%, 97.3%, 94.6%, 87.8%, and 89.9% whereas these results were 100%, 50%, 93.3%, 100%, and 93.8% on a patient-based analysis. PSMA based results outclassed morphologic imaging results especially in terms of sensitivity, which was <35% in both field- and patient-based analysis. Hence, PSMA PET/CT identifies patients with negative results more reliably compared to morphologic imaging, but still doesn't reach levels to which selective lymph node dissection only should be suggested as almost ¼ of negative lesions in PSMA PET/CT were ultimately positive in histological evaluation. The field-based results seen in Rauscher et al's study [52], however, are comparable to those seen in smaller studies (Table 5) [484951]. Interestingly, the results also translated into results seen in a real world investigation by Mandel et al [50]. While most other investigators looked at imaging results from their home institution, Mandel et al [50] evaluated PSMA PET/CT or PET/MR from 13 different nuclear medicine centers. Often, study settings largely differ from real world settings: When investigating imaging results, differences may occur throughout the process due to different imaging policies across practices and institutions. By including results from different nuclear medicine centers the results yield in a higher generalizability.

Difficulties in comparing the results from the above-mentioned studies arise from discrepancies in used references for the analyses (number of patients, number of lymph nodes removed or the anatomic boundaries). Moreover, it is of note that in many cases only patients with positive results underwent surgery resulting in selection bias due to imaging-derived pre-selection and possible overestimation of sensitivity results. Furthermore, it remains debatable whether or not salvage lymphadenectomy should be performed based on findings from PSMA PET/CT at all. Of note, according to current guidelines, any kind of salvage lymphadenectomy should only be offered to highly selected patients and its impact on long-term oncologic outcomes is still controversial [353].

With the attempt to further tailor therapy, new PSMA-targets have lately been developed to possibly guide salvage treatment in oligometastatic patients: Instead of labeling PSMA with positron emitting isotopes for imaging purposes, it can also be targeted by gamma-radiation emitting isotopes [54]. The emitted radioactivity can be detected during surgery with the use of gamma probes giving an acoustic feedback. In an experimental setting, radio guided salvage lymph node dissection might be a promising approach for the future as it can lead to a beneficial BCR-free survival compared to “standard” salvage lymphadenectomy.

Clinical outcomes and safety of this new and experimental procedure were first evaluated by a group from Munich, Germany [55]. The investigators compared intra-operative gamma probe radioactivity with histopathological results of dissected specimen of 31 men with oligometastatic recurrence within the pelvic or retroperitoneal lymph nodes. Ex vivo measurements (positive vs. negative) with gamma probes resulted in a sensitivity, specificity and accuracy of 92.3%, 93.5% and 93.1%, respectively. The positive and negative predictive values were 88.9% and 95.6%. Of all men with complete follow-up information, a PSA reduction of >50% and 90% were observed in 76.6% and 53.3%, respectively. Two thirds remained without therapy after a median follow-up of 337 days. Another 31 men were analyzed in a similar setting, but using ^99mTc based PSMA to guide surgery [56]. Sensitivity was lower (83.6%) with a specificity of 100% in 132 tissue specimen removed. Accuracy reached 93%. After surgery, PSA-reduction to ≤0.2 ng/mL was seen in 20 patients (64.5%) of whom 13 (65%) stayed BCR free after 13 months. In concordance with the aforementioned results, 20 men (64.5%) continued being therapy-free after a median follow-up of 12.2 months. These results are further strengthened by a short term follow-up study by Knipper et al [57] PSA reduction >50% and >90% within six weeks of surgery was significantly higher in 13 patients who underwent radio guided salvage lymph node dissection compared to 29 patients who underwent surgery based on PSMA PET/CT results only (p<0.01). These findings underscore the potential of radio guided salvage lymph node dissection in the future. However, one must bear in mind that the studies examined very small and highly-selected patients. Furthermore, the follow-up time of a maximum of 13 months has to be considered as rather short. Before a final evaluation of this new procedure can be made, further, larger cohorts with longer follow-up need to be investigated.