21Archivio Italiano di Urologia e Andrologia 2021; 93, 1 ORIGINAL PAPER No conflict of interest declared. DOI: 10.4081/aiua.2021.1.21 apy are among the treatments of choice for localized PCa. However, between 27% and 53% of all patients develop a rising PSA and experience biochemical recur- rence (BCR) (2). PSA elevation is highly predictive of clinical recurrence but not all patients with BCR after treatment with curative intent have local relapse. Therefore, it is very important to distinguish the ones that may benefit from local salvage treatment from those that don’t. BCR is defined as 2 consecutive PSA values equal or superior to 0.2 ng/mL after radical prostatecto- my, or a PSA increase equal or superior to 2 ng/mL above the nadir after radiotherapy (3, 4). However, the indica- tion for further treatments should not be based solely on a pre-determined PSA threshold but should be decided on the individualized risk of progression (5). In BCR, conventional imaging, such as computed tomog- raphy (CT), magnetic resonance imaging (MRI) and bone scintigraphy, has limited accuracy for the detection of recurrence sites (local, regional or systemic), especially at low PSA levels, while it is known that the optimal therapeutic window for salvage treatment in BCR is below 0.5-1 ng/mL (6). On the one hand, salvage radio- therapy (SRT) is considered the treatment of choice for PCa patients with BCR after radical prostatectomy. Its efficacy depends on early detection of disease limited to the prostatic fossa. On the other hand, distant metastases require systemic therapies, such as hormonal therapy or chemotherapy (7), whereas local treatment may lead to unnecessary side effects (8). Therefore, to achieve the best possible results while avoiding unjustified therapies and side effects, treatment must be individualized for each patient. In this field, molecular imaging techniques offer a great potential. In 2011, the Heidelberg group introduced [68Ga] Ga-PSMA- 11 (also known as HBED-CC, Glu-urea- Lys(Ahx)- HBED-CC and PSMA-HBED-CC) in Germany for clinical imaging of PCa. Prostate specific membrane antigen (PSMA) is a membrane glycoprotein codified by the PSMA gene (FOLH1) located on the short arm of chro- mosome 11. Despite the name “specific”, PSMA is also expressed in other tissues such as the brain, salivary glands, liver, kidney, small intestine, ganglia and neovas- culature of some solid tumors, but in very lower levels. Concerning prostate, PSMA is expressed in normal, benign and malignant prostatic epithelium but its expres- Objectives: Clinical approach of prostate cancer (PCa) biochemical recurrence (BCR) is an ever-changing topic. Prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11 PET-CT- PSMA PET-CT) has shown good potential in this field. The aim is to evaluate PSMA PET-CT detection rate in PCa BCR and assess its impact on clinical outcome. Material and methods: Out of 319 patients with PCa who underwent PSMA PET-CT between October 2015 and June 2019, 70 had developed BCR after treatment with curative intent. Two groups were created: one with BCR after surgery (RP group) (N: 48; 68.6%) and other with BCR after radio- therapy (RT group) (N: 22; 31.4%). Clinical, analytical, patho- logical and PSMA PET-CT results were evaluated. Results: Initial age was different between groups (p = 0.008). RP patients were mainly at intermediate risk (85.1% vs 42.9%, p = 0.001) while RT patients were at low risk of recurrence (8.5% vs 47.6%, p = 0.001). In RP and RT groups, PSMA PET- CT detected, respectively, pelvic relapse in 31.3% and 63.6%, and extrapelvic relapse in 18.8% and 31.8%. Salvage treat- ment was performed in 61.9% (n = 26) of RP patients and in 15% (n = 3) of RT patients, p < 0.001. Of RP patients submit- ted to salvage treatment, 59.1% achieved complete remission. Concerning these patients, local radiotherapy led to complete remission in 68.4% (n = 13). Of RT patients submitted to sal- vage treatment, two had complete remission and one had par- tial remission.Concerning detection rate, PSMA PET-CT was positive for pelvic relapse when pre-PET PSA ≥ 0.8 ng/mL (RP) or ≥ 2.3 ng/mL (RT) and for extrapelvic relapse when PSA ≥ 0.4 ng/mL (RP) or ≥ 3.5 ng/mL (RT), p > 0.05. Conclusions: Biochemical persistence rate after salvage thera- py was similar (30-40%). The cut-off PSA values for pelvic relapse detected on PSMA PET-CT were ≥ 0.8 ng/mL (RP) and ≥ 2.3 ng/mL (RT). KEY WORDS: Biochemical recurrence; PSMA PET-CT; Salvage treatment; Prostate cancer. Submitted 18 July 2020; Accepted 28 July 2020 INTRODUCTION Prostate cancer (PCa) is the second most commonly diag- nosed cancer in men, with an estimated 1.1 million new cases worldwide in 2012, accounting for 15% of all can- cers diagnosed (1). Radical prostatectomy and radiother- [68Ga]Ga-PSMA-11 PET-CT: Local preliminary experience in prostate cancer biochemical recurrence patients Summary João Carvalho 1, 2, Pedro Nunes 1, 2, Edgar Tavares da Silva 1, 2, Rodolfo Silva 2, 3, João Lima 1, 2, Vasco Quaresma 1, 2, Arnaldo Figueiredo 1, 2 1 Department of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal; 2 Faculty of Medicine, Coimbra University, Coimbra, Portugal; 3 Department of Nuclear Medicine; Coimbra University Hospital Center, Coimbra, Portugal. Archivio Italiano di Urologia e Andrologia 2021; 93, 1 J. Carvalho, P. Nunes, E. Tavares da Silva, R. Silva, J. Lima, V. Quaresma, A. Figueiredo 22 sion in PCa is 100-1000-fold of what is observed in nor- mal cells (9, 10). The localization of the catalytic site of PSMA in the extracellular domain allows the develop- ment of small specific inhibitors that are internalized after ligand binding (11). Over the last years, many articles concerning the use of [68Ga] Ga-PSMA-11 PET/CT (PSMA PET-CT) in this scenario have been published and the results appear to be promising (12-17), leading to treatment plan changes in up to 87.1% of patients (6). A meta-analysis revealed detection rates of 48% at PSA levels of 0.2 ng/mL, increasing to 56% and 70% at levels of 0.5 and 1.0 ng/mL, respectively. These results were quite superior to those observed with conventional imag- ing techniques and even [18F] Choline PET/CT (18). This study aims to evaluate PSMA PET-CT detection rate in prostate cancer patients with BCR after treatment with curative intent and assess its impact on clinical outcome. MATERIAL AND METHODS This study followed the rules of the local ethics commit- tee and were in accordance with the Helsinki Declaration. It was a preliminary cross-sectional study of prostate cancer patients with BCR after treatment with curative intent at our institution. Within a total of 319 PCa patients who underwent PSMA PET-CT between October 2015 and June 2019, 70 developed BCR after treatment with curative intent. [68Ga]Ga-PSMA-11 was synthesized locally, at ICNAS (Instituto de Ciências Nucleares Aplicadas à Saúde). 68Ga-PSMA-HBEDCC (Glu- NH-CO-NH-Lys-(Ahx)-[[68Ga]Ga(N,N’-bis-[2-hydroxy- 5 (carboxyethyl)benzyl]ethylenediamine-N,N’-diacetic- acid]) (68Ga-PSMA-11) was prepared in a similar proce- dure as described by Eder et al. (19). All patients under- went a whole-body PET-CT acquisition (Siemens Biograph, Siemens Healthcare, Gemini GXL Philips, Philips) 60 minutes after intravenous injection of 2 MBq/Kg of [68Ga]Ga-PSMA-11. PSMA PET-CT scans were acquired in three-dimensional mode with 4 minutes per bed posi- tion. Patients were well hydrated and voided immediate- ly before the scan. No adverse effects were reported. PSMA PET-CT images were independently interpreted by two nuclear medicine physicians. In case of disagree- ment, the final diagnosis was reached by requesting a third opinion. The main criteria of positivity for PSMA PET-CT scans were: any area of focal uptake of the radio- tracer (single or multiple), higher than the surrounding background, that did not correlate with physiologic trac- er uptake. PSMA PET-CT positive lesions were classified as “pelvic relapse” [prostate/prostate bed relapse and/or pelvic lymph nodes, excluding common iliac nodes (LNs)] or “extrapelvic relapse” (inguinal LNs and/or above common iliac bifurcation LNs and/or bone lesions and/or other visceral lesions). PSMA PET-CT negative scans were considered false negative by definition. Two groups were created: patients submitted to surgery (RP group) (N: 48; 68.6%) and patients treated with radiotherapy (RT group) (N: 22; 31.4%). Clinical, ana- lytical, pathological and PSMA PET-CT results were eval- uated. All continuous variables were reported as mean and standard deviation. Categorical variables were described according to their frequency and percentage. Descriptive analysis of demographic and clinical vari- ables was performed. Chi-square test was used for cate- gorical variables. Continuous variables were compared using the T student. The detection rate of PSMA PET-CT was assessed. All tests performed were 2-sided. Statistical significance was taken at a p value of less than 0.05. All data were analysed using the Statistical Package for the Social Sciences (SPSS) 23.0 (IBM SPSSS Statistics Corp.; Armonk, New York, USA). RESULTS Demographic and clinical data (Table 1) showed that RT patients were older than RP patients (66 ± 6.5 vs 69 ± 6.2 years, p = 0.008), but PSA was similar between groups (8.7 ± 5.7 vs 7.5 ± 5.8 ng/mL, p = 0.4). Patients were divided according to the European Association of Urology (EAU) risk group classification for BCR of localised PCa: Low-risk were defined by PSA < 10 ng/mL and Gleason score < 7 (ISUP grade 1) and cT1-2a; Intermediate-risk was defined by PSA 10-20 ng/mL or Gleason score 7 (ISUP grade 2/3) or cT2b and High-risk was defined by PSA > 20 ng/mL or Gleason score > 7 (ISUP grade 4/5) or cT2c (12). Most patients in RP group were in the intermediate-risk category (85.1%), while in the RT group the low-risk cat- Table 1. Demographic and clinical data. Data RP group (n: 48) RT group (n: 22) p Age at PCa diagnosis (years) 66 ± 6.5 69 ± 6.2 0.008 Initial PSA (ng/mL) 8.7 ± 5.7 7.5 ± 5.8 0.4 EAU risk groups for BCR of localised PCa 0.001 - Low-risk 8.5% 47.6% - Intermediate-risk 85.1% 42.9% - High-risk 6.4% 9.5% Time between initial treatment and BCR (months) 23.5 ± 42.7 44.5 ± 42.5 0.09 RP group: group previously submitted to surgery; RT group: group previously submitted to radiotherapy; PCa: prostate cancer; EAU: European Association Urology; BCR: biochemical recurrence. Table 2. Relapse pattern between groups. Data RP group (n: 48) RT group (n: 22) p Pelvic relapse 15 (31.3%) 14 (63.6%) 0.001 Extrapelvic relapse 9 (18.8%) 7 (31.8%) No disease 24 (50%) 1 (4.5%) Global SUVmax 8.4 ± 5.7 [3.3-16.7] 5.6 ± 3.9 [2.7-17.4] 0.3 RP group: group previously submitted to surgery; RT group: group previously submitted to radiotherapy; SUVmax: maximum standardized uptake values of [68Ga]Ga-PSMA-11. Table 3. PSA value in pelvic and extrapelvic relapse between groups if positive PSMA PET-CT. Data PSA value in pelvic PSA value in extrapelvic p relapse (ng/mL) relapse (ng/mL) RP group + positive PSMA PET-CT 0.99 ± 0.9 1.0 ± 13.2 0.6 RT group + positive PSMA PET-CT 3.0 ± 2.1 4.5 ± 5.4 0.2 RP group: group previously submitted to surgery; RT group: group previously submitted to radiotherapy. egory was the most prevalent (47.6%), with this differ- ence being statistically significant (p = 0.001). The time interval between initial treatment and BCR was similar between groups (Table 1). In RP patients, final pathology revealed pT2a in six (13.4%), pT2c in 16 (33.3%), pT3a in 14 (28.9%) and pT3b in 12 cases (24.4%). N status was N0 in 29 (60.4%), N1 in 13 (27.1%) and Nx in six cases (12.5%). R status revealed R0 in 41 (85.4%) and R1 in seven cases (14.6%). In RP and RT groups, PSMA PET-CT detected pelvic relapse in 31.3% and 63.6% of patients and extrapelvic relapse in 18.8% and 31.8%, respectively. PSMA PET-CT was negative in 24 (50%) of RP group and in one case (4.5%) of RT group. The maximum stan- dardized uptake value (SUVmax) of the lesion with the highest [68Ga]Ga-PSMA-11 uptake per patient was also analysed, and no statistical significant difference was found between groups (Table 2). In positive PSMA PET- CT, PSA values were not able to distinguish between pelvic and extrapelvic disease in either groups (Table 3). Salvage treatment was performed in 61.9% (n = 26) of RP group (local radiotherapy in 54.7%, radiotherapy to a sin- gle bone metastasis in 2.4% and lymphadenectomy in 4.8%) and in 15% (n = 3) of RT group(radical prostatec- tomy with bilateral pelvic lymphadenectomy in two and high-dose brachytherapy in one case), p < 0.001. Out of all RP patients submitted to salvage treatment, 59.1% achieved complete remission. Concerning these patients, local radiotherapy led to complete remission in 13 cases (68.4%). Neither extended lymphadenectomy nor radio- therapy to the single bone metastasis led to complete remission. In fact, none of the removed nodes harboured tumour cells. Out of the three RT patients submitted to salvage treatment, two had complete remission (both sub- mitted to radical prostatectomy with bilateral pelvic lym- phadenectomy) and one had partial remission (targeted high-dose brachytherapy). Pathology obtained from sal- vage radical prostatectomy revealed ISUP grade 2 pT3bN1M0R0 and ISUP grade 2 pT3bN0M0R0. In both cases, the initial biopsy specimens firstly done before radiotherapy revealed an ISUP grade 1. Concerning detection rate, PSMA PET-CT was positive for pelvic relapse when pre-PSMA PET-CT PSA ≥ 0.8 ng/mL (RP) or ≥ 2.3 ng/mL (RT) (Tables 4, 5) and for extrapelvic relapse when PSA ≥ 0.4 ng/mL (RP) or ≥ 3.5 ng/mL (RT), p > 0.05 (Tables 6, 7). DISCUSSION This study showed the preliminary experience of PSMA PET-CT in real-world PCa patients that experienced BCR after treatment with curative intention. In BCR patients, 68-Ga PSMA avidity in the pelvic region was higher in the radiotherapy than in prostatectomy cohort (63.6% vs 31.3%), in line with other studies that showed a propor- tion of 52% vs 22% (14). The negativity of PSMA PET- CT was almost exclusive of RP patients (50% versus 4.5%). Gallium 68-PSMA, similarly to most other PSMA based agents, has a significant urinary tracer excretion with high activity often seen in the bladder. This could 23Archivio Italiano di Urologia e Andrologia 2021; 93, 1 PET in prostate cancer biochemical recurrence Table 4. Detection rate of PSMA PET-CT for pelvic relapse in RP patients. Sensibility and specificity of PSMA PET-CT for pelvic relapse in RP patients PSA value (ng/mL) Sensibility Specificity p 0.2 93.3% 3% 0.06 0.3 80% 18.2% 0.4 73.3% 33.3% 0.5 73.3% 60.6% 0.6 73.3% 63.6% 0.7 73.3% 66.6% 0.8 73.3% 72.7% 0.9 66.7% 78.8% 1.0 46.7% 78.8% RP group: group previously submitted to surgery. Table 6. Detection rate of PSMA PET-CT for extrapelvic relapse in RP patients. Table 7. Detection rate of PSMA PET-CT for extrapelvic relapse in RT patients. Sensibility and specificity of PSMA PET-CT for extrapelvic relapse in RP patients PSA value (ng/mL) Sensibility Specificity p 0.2 88.9% 2.6% 0.9 0.3 77.8% 17.9% 0.4 66.7% 30.8% 0.5 55.6% 41% 0.6 44.4% 51.3% 0.7 44.4% 53.8% 0.8 44.4% 59% 0.9 44.4% 66.7% 1.0 44.4% 74.4% RP group: group previously submitted to surgery. Sensibility and specificity of PSMA PET-CT for extrapelvic relapse in RT patients PSA value (ng/mL) Sensibility Specificity p 0.9 100% 13.3% 0.2 1.8 85.7% 20% 2.0 85.7% 33.3% 2.3 71.4% 33.3% 3.0 71.4% 53.3% 3.5 71.4% 60% 4.0 57.1% 80% 4.5 42.9% 80% RT: group previously submitted to radiotherapy. Table 5. Detection rate of PSMA PET-CT for pelvic relapse in RT patients. Sensibility and specificity of PSMA PET-CT for pelvic relapse in RT patients PSA value (ng/mL) Sensibility Specificity p 0.9 92.9% 12.5% 0.5 1.8 85.7% 25% 2.0 71.4% 25% 2.3 71.4% 37.5% 3.0 50% 37.5% 3.5 42.9% 50% RT: group previously submitted to radiotherapy. Archivio Italiano di Urologia e Andrologia 2021; 93, 1 J. Carvalho, P. Nunes, E. Tavares da Silva, R. Silva, J. Lima, V. Quaresma, A. Figueiredo 24 interfere with the evaluation of the postprostatectomy bed/seminal vesicle bed regions as well as lower pelvic lymph nodes. Salvage treatment in patients previously submitted to radiotherapy was done only after re-biopsy and confir- mation of tumour persistence. In our limited experience, radical prostatectomy could portend better results than high-dose brachytherapy. The final pathological upgrad- ing compared to the pre-radiotherapy biopsy has to be seen with caution, given the difficulties in evaluating the Gleason score after radiotherapy. Concerning RP patients, radiotherapy was the only effective salvation treatment. Other attempts to reach complete remission were not succeeded, even extended lymphadenectomy did not reveal ganglia metastases. In fact, according to Budaus et al., the comparison between preoperative PSMA PET-CT lymph nodes findings with histologic work-up after radical prostatectomy performed for high risk prostate cancer only detected 33.3% of the patients as being true positive for lymph node metastasis, and 66.7% of the patients as a false negative. Our population had a reduced incidence of high-risk patients, so we must presume that our results were following the low sensitivity (33.3%) and high specificity (100%) rate of PSMA PET-CT for detection of lymph node metastasis in this work (15). The SUVmax value in our population was low, in line with the findings of Demerci et al. (16). They showed that SUV max values correlated significantly with grade groups of primary tumours. The EAU risk groups for BCR of localised PCa in RP and RT were predominantly intermediate and low-risk respectively. This explained the lower SUVmax detected in RT patients compared with RP patients. The optimal cut-off PSA values for pelvic relapse detect- ed on PSMA PET-CT were ≥ 0.8 ng/mL (RP) and ≥ 2.3 ng/mL (RT). The optimal cut-off values for extrapelvic relapse detected on PSMA PET-CT were ≥ 0.4 ng/mL (RP) and ≥ 3.4 ng/mL (RT). Sanli et al concluded that a PSA value of 0.83 ng/ml was the optimal cut-off value for distinguishing between positive and negative PSMA PET- CT in general (17). EAU Guidelines (5) include a weak recommendation for offering PSMA PET-CT scan to men with a persistent PSA > 0.2 ng/mL to exclude metastatic disease. According to our results, this cut-off seems too low. However, it was a preliminary study with few patients and we hope to increase our experience in this setting to see if this cut- off is applied to our population. It has also been report- ed that patient’s prognosis was improved when salvage therapy was initiated before the PSA level exceeds 0.5 ng/mL (20). In our population, the cut-off of 0.5 ng/mL for RP patients was associated with a sensibility of 73.3% and specificity of 72.7% in pelvic relapse and with a sensi- bility of 55.6% and specificity of 30.8%. Literature showed that these cut-off values can differ from 17.5% to 61.5% (6). In other studies, the detection sensitivity of PSMA PET- CT is dependent on the PSA at the time of imaging, with detection sensitivities in the range of 50-60% when the PSA is as low as 0.2 to 0.5 ng/mL (21, 22). However, the cut-off value for PSA performing PSMA PET-CT has yet to be defined, and thus prospective studies are required to recommend PSMA PET-CT for patients with BCR. With increasing use of PSMA PET-CT scan, its value must be balanced critically with cost and clinical benefit. Given the high costs and limited availability of PSMA PET-CT scan, choline PET-CT is still widely used in patients with prostate cancer relapse, despite its low sen- sibility for low PSA levels. A meta-analysis by Han et al. (23) showed that PSMA PET-CT altered the management in 54% of patients. They reported that the use of PSMA PET-CT imaging lead to an increase in the proportion of patients receiving radiotherapy (from 56% to 61%), sur- gery (from 1% to 7%), focal therapy (from 1% to 2%), and multimodal treatment (from 2% to 6%), and to a decrease in patients receiving systemic treatment (from 26% to 12%) and no treatment (from 14% to 11%). The evidence for introducing management changes as a result of PSMA PET-CT findings is low, and prospective studies are required. The risk of early treatments causing more harm than good, as well as the long-term effects on progression-free and overall survival rates are still unclear (24). An interesting potential benefit of PSMA PET-CT could be to select, with higher accuracy, patients to high- dose radiotherapy for oligometastatic disease. In our study, there was one patient who underwent radiothera- py to a single bone metastasis, yet no complete remission was achieved. Whether this approach improves patient outcomes remains unclear, the impact of potentially avoiding androgen deprivation therapy and its toxicity would definitely be important. Some limitations must be also elicited as they could influence results and conclusions. The small number of patients, different size groups and the monocentric nature of the study could limit the applicability of these results. Population studied was heterogeneous: patients submitted previously to radiotherapy were fewer, older and belonged to a lower risk group for BCR instead of patients submitted previously to radical prostatectomy were almost the double and belonged to an intermediate- risk group. The lack of PSA kinetics and the lack of comparison with standard conventional imaging could introduce a bias: the majority of patients did not have a simultaneous approach with conventional imaging. However, the available literature supports PSMA PET-CT superiority over conventional imaging in this setting (13). CONCLUSIONS PSMA PET-CT has shown good potential for using in patients with BCR, but most studies are limited by their retrospective design. Despite the limited information in major guidelines, it could be standard in patients with recurrent PCa, mainly with low PSA. PSA level is associ- ated with the positivity rate of PSMA PET-CT. The cut-off PSA values for pelvic relapse detected on PSMA PET-CT were ≥ 0.8 ng/mL (RP) and ≥ 2.3 ng/mL (RT). However, PSA levels could not discriminate between PSMA PET- CT positivity for pelvic or extrapelvic relapse. Biochemical persistence rate after salvage therapy was similar between groups (30-40%). 25Archivio Italiano di Urologia e Andrologia 2021; 93, 1 PET in prostate cancer biochemical recurrence REFERENCES 1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359-86. 2. Freedland SJ, Humphreys EB, Mangold L, et al. 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