Abstract
Background
Gallium-68 prostate-specific membrane-antigen positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) has recently emerged as a novel imaging modality, potentially improving oncologic outcomes for prostate cancer patients. This study aimed to assess the potential predictive factors associated with 68Ga-PSMA-11 PET/CT positivity following persistent prostate-specific antigen (PSA) levels and primary biochemical recurrence post-radical prostatectomy (RP), focusing on prostate specimen characteristics. Furthermore, we aim to identify predictive factors for locoregional recurrence.
Methods
We conducted a retrospective analysis of 230 prostate cancer patients treated with RP and without prior salvage or adjuvant radiotherapy or systemic treatments. All patients underwent 68Ga-PSMA-11 PET/CT scans to detect prostate cancer recurrence detection. Pathological findings were carefully examined and correlated with 68Ga-PSMA-11 PET/CT positivity and locoregional recurrence.
Results
Our analysis showed that 68Ga-PSMA-11 PET/CT positivity was associated with International Society of Urological Pathology (ISUP) grade group ≥3, presence of positive lymph node invasion at the time of RP, positive extra-prostatic extension, involvement of seminal vesicles and post-RP PSA levels ≥0.1 ng/ml. Additionally, we identified ISUP grade group 2 and ISUP grade group ≥3, whether with or without positive lymph node invasion, along with extra-prostatic extension, involvement of seminal vesicles and post-RP PSA ≥0.1 ng/ml were identified as factors associated with pelvic node recurrence.
Conclusion
Pathological findings emerge as robust predictors of 68Ga-PSMA-11 PET/CT positivity and locoregional recurrences in cases of initial biochemical recurrence or persistence without prior adjuvant or salvage treatment. This diagnostic approach facilitates potential adjustments in management strategies, such as PSMA-guided radiotherapy or PSMA-guided lymphadenectomy.
Keywords: Gallium Radioisotopes, Local, Neoplasm Recurrence, Positron-Emission Tomography, Prostate-Specific Membrane Antigen (PSMA), Prostatic Neoplasms
1. Introduction
Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the third leading cause of cancer-related mortality among males.1 Up to 5-20% of patients experience persistent prostate-specific antigen (PSA) levels post-treatment, and approximately one-third experience biochemical recurrence (BCR) after radical prostatectomy (RP). Both conditions increase the risk of distant metastases, as well as PCa-specific and overall mortality.2,3
Aggressive pathological characteristics and early detection of biochemical persistence or recurrence following RP typically led to initial adjuvant or salvage radiotherapy, either alone or coupled with androgen deprivation therapy (ADT).4,5 Despite early treatment, many patients still relapse owing to occult oligometastatic disease or PCa resistance mechanisms. Therefore, confirming potential sites of recurrence is critically important in such cases.
Recently, positron emission tomography/computed tomography (PET/CT) utilizing ligands targeting the prostate-specific membrane antigen (PSMA), such as the Gallium-68 PSMA (68Ga-PSMA-11 PET/CT), has become the leading imaging modality for diagnosing BCR in PCa. Notably, this radioligand received FDA approval for the evaluation of BCR in December 2020, significantly increasing the detection rate of metastatic disease, particularly oligometastatic recurrence, even at lower PSA levels.6
A recent meta-analysis obtained 68Ga-PSMA-11 PET/CT detection rates of 33%, 46%, 57%, 82%, and 97% for PSA categories of 0-0.19, 0.2-0.49, 0.5-0.99, 1-1.99, and ≥2 ng/ml, respectively, in the context of biochemical recurrence following prostatectomy.
This innovative PET imaging modality offers an opportunity to improve oncologic outcomes for PCa patients. However, further research is needed before it can be integrated into guideline recommendations. The studies exploring the characteristics to define optimal candidates for 68Ga-PSMA-11 PET/CT imaging are limited, which is crucial to maximize efficacy and minimize unnecessary testing. While several retrospective studies have tried to identify potential predictive factors, their findings have been limited by heterogeneous patient cohorts, spanning various primary treatments and stages of biochemical recurrence.7, 8, 9, 10, 11
Therefore, our objective was to assess potential predictive factors for 68Ga-PSMA-11 PET/CT positivity in a specific cohort of PCa patients who underwent RP without prior adjuvant or salvage treatment. In addition, we evaluated potential factors that could be associated with the recurrence location pattern detected in 68Ga-PSMA-11 PET/CT scans. This approach is important to optimize site-directed PSMA-guided therapies, such as targeted salvage radiotherapy or salvage lymph node dissection, which may delay the initiation of systemic therapies.12, 13, 14, 15
2. Materials and methods
In this retrospective cohort study, we analyzed a total of 2,172 68Ga-PSMA-11-PET/CT scans performed between December 2018 and December 2023. Our institution, the Department of Nuclear Medicine at Clinica Universidad de Navarra, was the first in Spain to have access to this advanced imaging tool. Patients were excluded if they met any of the following criteria: initial treatment other than radical prostatectomy (e.g., radiotherapy or focal therapy; insufficient patient medical history information; referral from external healthcare facilities; PET/CT conducted for primary staging purposes; or hormone-resistant or metastatic PCa at initial diagnosis. Patients who had previously received salvage or adjuvant treatment were also excluded to maintain the study population’s homogeneity and specificity.
All patients provided signed informed consent before undergoing PET/CT imaging.
Ethical approval for the study was granted by the Ethics Committee of the University of Navarra in April 2021 (number 2021.041).
The final analyses included a total of 230 PCa patients aged 18 years or older who had undergone RP without prior adjuvant or salvage treatment and with PET/CT study due to biochemical recurrence or persistence. The persistence or biochemical recurrence was defined as a detectable PSA post-RP or a rising PSA following an initially undetectable level. For patients with multiple PET/CT scans, only the most recent scan was included in the analyses.
The dependent variable was the 68Ga-PSMA-11-PET/CT result (positive of negative), while the potential determinants were ISUP (International Society of Urological Pathology) grade, positive lymph node invasion (LNI) at the time of RP, positive EPE (extra-prostatic extension), seminal vesicle invasion (SVI), surgical margin (SM), and PSA levels post-RP. These potential predictive factors were selected according to clinical criteria.
We focused on pathology findings as these are routinely available variables in patient histories and appear to significantly influence on the development of PCa recurrence and may represent the variables most closely associated to 68Ga-PSMA-11-PET/CT positivity in this patient group.
The patients received an intravenous injection of 150-200 MBq of the radiotracer, and PET/CT scans were conducted 70-80 minutes post-injection. Imaging covered the cervical, thoracic, abdominal, and pelvic regions, with standardized uptake value quantification performed according to European Association of Nuclear Medicine (EANM) 18F–fluorodeoxyglucose PET/CT EANM Resarch Ltd. accreditation standards. The analysis of radiopharmaceutical uptake included assessments of both the surgical bed and other anatomical and nodal structures.
All PET/CT scans underwent thorough analysis by experienced, board-certified nuclear medicine physicians. Lesions were confirmed through histological assessment, including bed/metastatic biopsy and salvage lymphadenectomy, and/or by visualization of lesions on additional standard imaging modalities such as CT or magnetic resonance imaging.
Patient characteristics were summarized using means and standard deviations for continuous variables, and frequencies and proportions for categorical variables. The associations between potential predictive factors and 68Ga-PSMA-11 PET/CT positivity were assessed using logistic regression models. Additionally, multinomial logistic regression analysis was used to evaluate the association between potential predictive factors and recurrence site pattern.
A significance level of <0.05 was set for all analyses. Statistical analyses were performed using IBM SPSS Statistic (version 28.0) and Stata (StataCorp. 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LLC).
3. Results
A total of 230 PCa patients who underwent RP without prior adjuvant or salvage treatment and subsequently underwent 68Ga-PSMA-11 PET/CT imaging to confirm potential recurrence were included in the study.
Patient demographics and tumor characteristics of RP specimens are presented in Table 1, comparing patients with positive and negative imaging findings. Out of the total cohort, visible lesions were observed on 68Ga-PSMA-11 PET/CT scans in 152 patients, resulting in a positivity rate of 66.1%. The mean age at RP was 64.1 years, and 76.1% of RP were robot-assisted. When considering prostate specimen characteristics, the rate of negative margins was slightly higher in patients with positive 68Ga-PSMA-11 PET/CT compared with those with negative 68Ga-PSMA-11 PET/CT (56.6% vs. 51.3%). Regarding functional outcomes, complete continence was achieved in 59.1% of the cases, while erectile function was preserved in only 32.2%.
Table 1.
Baseline characteristics and surgical pathology findings of patients treated with RP and who underwent 68Ga-PSMA-11 PET/CT for the detection of persistent or recurrent PCa.
| Variables | All patients (n = 230) | Positive 68Ga-PSMA PET/TC (n = 152) |
Negative 68Ga-PSMA PET/TC (n = 78) |
P |
|---|---|---|---|---|
| Age at RP (yr), mean (±SD) | 64.1 (±7.0) | 64.6 (±7.4) | 63.1 (±6.1) | 0.171 |
| PSA at diagnosis (ng/ml), mean (±SD) | 10.2 (±11.5) | 10.6 (±13.3) | 9.3 (±6.7) | 0.416 |
| Surgical approach of RP, n (%) | 0.744 | |||
| Open | 14 (6.1) | 8 (5.3) | 6 (7.7) | |
| Laparoscopic | 41 (17.8) | 28 (18.4) | 13 (16.7) | |
| Robotic | 175 (76.1) | 116 (76.3) | 59 (75.6) | |
| Preservation of NVB, n (%) | 108 (47) | 62 (40.8) | 46 (59) | 0.009 |
| LND at time of RP, n (%) | 0.044 | |||
| Nx | 126 (54.8) | 75 (49.3) | 51 (65.4) | |
| N0 | 77 (33.5) | 55 (36.2) | 22 (28.2) | |
| N1 | 27 (11.7) | 22 (14.5) | 5 (6.4) | |
| Pathologic T stage, n (%) | 0.015 | |||
| ≤T2c | 107 (46.5) | 62 (40.8) | 45 (57.7) | |
| ≥T3a | 123 (53.5) | 90 (59.2) | 33 (42.3) | |
| ISUP GG, n (%) | 0.006 | |||
| 1 | 47 (20.4) | 22 (14.5) | 25 (32.0) | |
| 2 | 73 (31.7) | 45 (29.6) | 28 (35.9) | |
| 3 | 55 (23.9) | 42 (27.6) | 13 (16.7) | |
| 4 | 24 (10.4) | 19 (12.5) | 5 (6.4) | |
| 5 | 31 (13.5) | 24 (15.8) | 7 (9) | |
| % of PCa involvement, mean (±SD) | 31.5 (±21) | 32.9 (±20.8) | 28.7 (±21.3) | 0.216 |
| MTD (mm), mean (±SD) | 21.4 (±12.6) | 21.5 (±9.6) | 21.2 (18.3) | 0.889 |
| Cribriform pattern, n (%) | 50 (21.7) | 41 (27) | 9 (11.5) | 0.007 |
| PNI, n (%) | 192 (83.5) | 130 (85.5) | 62 (79.5) | 0.243 |
| LVI, n (%) | 44 (19.1) | 32 (21.1) | 12 (15.4) | 0.301 |
| High-grade PIN, n (%) | 44 (19.1) | 25 (16.4) | 19 (24.4) | 0.149 |
| SM, n (%) | 0.445 | |||
| Negative | 126 (54.8) | 86 (56.6) | 40 (51.3) | |
| R1 | 104 (45.2) | 66 (43.4) | 38 (48.7) | |
| EPE, n (%) | 112 (48.7) | 82 (54) | 30 (38.5) | 0.026 |
| SVI, n (%) | 49 (21.3) | 38 (35) | 11 (14.1) | 0.056 |
| PSA after RP (ng/ml), mean (±SD) | 0.4 (±1.5) | 0.5 (±1.8) | 0.1 (±0.1) | 0.034 |
| Continence after RP, n (%)a | 0.028 | |||
| No | 3 (1.3) | 3 (2) | 0 | |
| Partial | 91 (39.6) | 68 (44.7) | 23 (29.5) | |
| Complete | 136 (59.1) | 81 (53.3) | 55 (70.5) | |
| EF after RP, n (%)a | 74 (32.2) | 46 (30.3) | 28 (35.9) | 0.387 |
68Ga-PSMA-11 PET/CT, Gallium-68 prostate-specific membrane-antigen positron emission tomography/computed tomography; EPE, extra-prostatic extension; EF, erectile function; GG, grade group; ISUP, International Society of Urological Pathology; LND, lymph node dissection; LVI, linfovascular invasion; MTD, maximum tumor diameter; NVB, neurovascular bundle; PCa, prostate cancer; PSA, prostate-specific antigen; PNI, perineural invasion; RP, radical prostatectomy; SD, standard deviation; SM, surgical margin; SVI, seminal vesicle invasion.
Continence and erectile function were assessed at the time of68Ga-PSMA PET/TC was indicated.
Table 2 focuses on 68Ga-PSMA-11-PET/CT results, specifically comparing patients with positive and negative findings on these scans. Most studies were conducted at PSA levels ranging from 0.2 and 0.49 ng/ml, representing 49.3% of the positive 68Ga-PSMA-11 PET/CT group and 53.8% of the negative 68Ga-PSMA-11 PET/CT group. When considering PSA doubling time, up to 60.9% of patients were classified as high risk for biochemical recurrence according to the EAU risk classification, with this proportion increasing to 63.2% among cases with positive 68Ga-PSMA-11 PET/CT findings. The median time from RP to scan imaging was 24.5 months (interquartile range [IQR] 25-75%: 6.75-48.25).
Table 2.
Distribution of PSMA parameters between positive and negative findings on68Ga-PSMA-11 PET/CT scans.
| Variables | All patients (n = 230) | Positive 68Ga-PSMA PET/TC (n = 152) |
Negative 68Ga-PSMA PET/TC (n = 78) |
P |
|---|---|---|---|---|
| Age at PSMA PET/CT (yr), mean (±SD) | 66.9 (±7.5) | 67.0 (±7.7) | 66.8 (±7.1) | 0.821 |
| PSA at PSMA PET/CT (ng/ml), n (%) | 0.498 | |||
| < 0.2 | 7 (3.0) | 4 (2.6) | 3 (3.8) | |
| 0.2–0.49 | 117 (50.9) | 75 (49.3) | 42 (53.8) | |
| 0.5–0.99 | 60 (26.1) | 40 (26.3) | 20 (25.6) | |
| 1–1.99 | 27 (11.7) | 17 (11.2) | 10 (12.8) | |
| > 2 | 19 (8.3) | 16 (10.5) | 3 (3.8) | |
| Risk group, n (%)a | 0.304 | |||
| Low risk | 54 (23.5) | 31 (20.4) | 23 (29.5) | |
| High risk | 140 (60.9) | 96 (63.2) | 44 (56.4) | |
| Unknown | 36 (15.6) | 25 (16.4) | 11 (14.1) | |
| Time from RP to PSMA (months), median (p25, p75) | 24.5 (6.8, 48.3) | 18.5 (4, 42.5) | 33 (14, 71.3) | 0.019 |
| Number of lesions on PSMA, mean (±SD) | 1.3 (±1.4) | 1.9 (±1.3) | 0 | <0.001 |
| Locoregional recurrence, n (%) | <0.001 | |||
| Negative | 83 (36.1) | 5 (3.3) | 78 (100) | |
| Prostate bed | 55 (23.9) | 55 (36.2) | 0 (0) | |
| Lymph node and prostate bed | 15 (6.5) | 15 (9.9) | 0 (0) | |
| Lymph node unilateral | 52 (22.6) | 52 (34.2) | 0 (0) | |
| Lymph node bilateral | 25 (10.9) | 25 (16.4) | 0 (0) | |
| Extra pelvic nodal recurrence, n (%) | 0.028 | |||
| Retroperitoneal | 8 (3.5) | 8 (5.3) | 0 (0) | |
| Mediastinal | 0 | 0 | 0 (0) | |
| Bone recurrence, n (%) | 0.051 | |||
| Single axial | 5 (2.2) | 5 (3.3) | 0 (0) | |
| Single extra-axial | 3 (1.3) | 3 (2) | 0 (0) | |
| Multiple axial | 4 (1.7) | 4 (2.6) | 0 (0) | |
| Multiple extra-axial | 5 (2.2) | 5 (3.3) | 0 (0) | |
| Visceral recurrence,n(%) | 0 | 0 | 0 (0) |
68Ga-PSMA-11 PET/CT, Gallium-68 prostate-specific membrane-antigen positron emission tomography/computed tomography; PSA, prostate-specific antigen; PSMA, prostate-specific membrane-antigen; PET/CT, positron emission tomography/computed tomography; RP, radical prostatectomy; SD, standard deviation.
BCR risk stratification system defined by the European Association of Urology. Low-risk BCR is defined as a PSA doubling time of more than 12 mo and a Gleason score of less than 8. High-risk BCR is defined as PSA doubling time of no more than 12 mo or a Gleason score of at least 8.
Analysis of potential predictive factors on 68Ga-PSMA-11 PET/CT positivity
We evaluated several factors as potential predictors of 68Ga-PSMA-11 PET/CT positivity, including ISUP grade, LNI at the time of RP, EPE, SVI, surgical margin, and PSA levels post-RP (Table 3). All these factors were associated with an increased risk of 68Ga-PSMA-11 PET/CT positivity, with the exemption of surgical margin (odd ratio (OR): 0.81; 95% confidence interval (95% CI): 0.47-1.40, P = 0.445).
Table 3.
Associations of surgical pathology findings and68Ga-PSMA-11-PET/CT positivity.
| Variables | OR (95% CI) | P |
|---|---|---|
| ISUP grade group | ||
| 1 | 1.0 (Ref) | |
| 2 | 1.83 (0.87-3.84) | 0.112 |
| ≥3 | 3.86 (1.87-7.99) | <0.001 |
| Lymph node invasion | ||
| Nx | 1.0 (Ref) | |
| N0 | 1.70 (0.92-3.13) | 0.088 |
| N1 | 2.99 (1.06-8.42) | 0.038 |
| Extra prostatic extension | ||
| Negative | 1.0 (Ref) | |
| Positive | 1.87 (1.07-3.27) | 0.027 |
| Seminal vesicle invasion | ||
| Negative | 1.0 (Ref) | |
| Positive | 2.03 (0.97-4.24) | 0.059 |
| Surgical margin | ||
| Negative | 1.0 (Ref) | |
| Positive | 0.81 (0.47-1.40) | 0.445 |
| PSA after RP (ng/ml) | ||
| <0.1 | 1.0 (Ref) | |
| ≥0.1 | 2.33 (1.23-4.41) | 0.010 |
68Ga-PSMA-11 PET/CT, Gallium-68 prostate-specific membrane-antigen positron emission tomography/computed tomography; CI, confidence interval; ISUP, International Society of Urological Pathology; OR, odds ratio; PSA, prostate-specific antigen; Ref, reference; RP, radical prostatectomy.
Patients in the highest category of ISUP grade (≥3) exhibited a higher risk of 68Ga-PSMA-11 PET/CT positivity (OR: 3.86, 95% CI: 1.87-7.99, P < 0.001) compared with patients with an ISUP grade of 1. Similarly, positive LNI at the time of RP (OR 2.99; 95% CI: 1.06-8.42; P = 0.038), positive EPE (OR 1.87; 95% CI: 1.07-3.27; P = 0.027), SVI (OR 2.03, 95% CI: 0.97-4.24, P = 0.059), and PSA levels post-RP ≥ 0.1 ng/ml (OR 2.33; 95% CI: 1.23-4.41, P = 0.010) seemed to be associated with 68Ga-PSMA-11-PET/CT positivity.
Patterns of recurrence on positive PSMA-PET/CT
Table 2 presents the distribution of locoregional recurrence patterns in patients with positive 68Ga-PSMA-11-PET/CT findings. Among the 152 patients with positive 68Ga-PSMA-11-PET/CT scans, 147 exhibited locoregional recurrence (96.7%). Within this group, the majority (92 out of 147, 62.6%) had pelvic lymph node recurrence, while 37.4% presented with exclusive fossa uptake. Notably, 15 out of 147 patients (10.20%) displayed concurrent pelvic lymph node and prostatic fossa recurrence, while 52 patients (35.4%) showed unilateral lymph node involvement and 25 patients (17.01%) exhibited bilateral lymph node involvement. Additionally, extra-pelvic recurrence, primarily retroperitoneal lymph node uptake, was observed in 5.3% of patients with positive 68Ga-PSMA-11-PET/CT findings (8 out of 152).
Regarding skeletal involvement, bone recurrence was observed in 17 patients (11.2%), with single axial (3.3%) and multiple extra-axial (3.3%) manifestations being the most common patterns of skeletal metastatic recurrence. Remarkably, no visceral recurrence was detected in our patient cohort.
Among cases of locoregional recurrence, 58.5% (86 out of 147) of patients presented a single positive lesion on imaging, while 41.5% (61 out of 147) displayed two or more positive lesions on 68Ga-PSMA-11-PET/CT.
Analysis of predictive factors for locoregional recurrence pattern and number of lesions on 68Ga-PSMA-11-PET/CT
The association between potential predictive factors and locoregional recurrence pattern was also explored using multinomial logistic regression models. The OR for an ISUP grade 2 was 2.32 (95% CI: 0.78-6.91; P = 0.130) and the OR for an ISUP grade 3 was 5.06 (95% CI: 1.79-14.34; P = 0.002) for having pelvic node recurrence versus prostate bed recurrence, compared with an ISUP grade 1.
Compared with lymph node invasion Nx, N1 showed higher odds for having pelvic node recurrence versus prostate bed recurrence (OR 20.43; 95% CI: 2.61-159.97; P = 0.004). Moreover, EPE (OR 3.28; 95% CI: 1.63-6.59; P = 0.001), SVI (OR 2.84; 95% CI: 1.19-6.77; P = 0.018), and PSA ≥0.1 ng/ml (OR 2.14; 95% CI: 1.04-4.41; P = 0.038) were also associated with an increased risk of pelvic node recurrence versus prostate bed recurrence (Fig. 1). In contrast, positive surgical margins showed an OR of 0.49 (95% CI: 0.25-0.96; P = 0.039), suggesting a higher risk of prostate bed recurrence versus pelvic node recurrence.
Fig. 1.
Factors associated with pelvic lymph node recurrence (reference: prostatic fossa recurrence).
EPE, extra-prostatic extension; ISUP, International Society of Urological Pathology; LNI, lymph node invasion; RP, radical prostatectomy; SM, surgical margin; SVI, seminal vesicle invasion.
The multivariable analysis attenuated some of these associations with the exemption of positive LNI (OR 10.9; 95% CI: 1.28-93.1; P = 0.029) and positive surgical margins (OR 0.35; 95% CI: 0.16-0.77; P < 0.009), which remained statistically significant.
When assessing the association between these potential risk factors and the number of detected lesions (≥2 lesions versus 1 lesion) on 68GA-PSMA-11 PET/CT, we observed links between EPE (OR 1.95; 95% CI: 0.99-3.81; P = 0.052), SVI (OR 3.34; 95% CI: 1.55-7.20; P = 0.002), and positive LNI (OR 4.66; 95% CI: 1.67-12.97; P = 0.003) with the presence of two or more positive lesions. In the multivariable analysis, the association was attenuated for EPE (OR 1.24; 95% CI 0.56–2.75) and remained for SVI (OR 2.71; 95% CI 1.18-6.20; P = 0.019) and positive LNI (OR 3.03; 95% CI 0.95-9.68; P = 0.062).
4. Discussion
To our knowledge, this is the first study to assess the impact of pathology findings on the likelihood of 68Ga-PSMA-11-PET/CT positivity in a specific study population of patients with PCa who underwent RP without prior adjuvant or salvage treatment.
The overall PSMA-PET/CT detection rate observed in our cohort was 66.1%, consistent with the rates reported in previous studies.6, 10 Notably, in our subgroup of patients with very low PSA (<0.5 ng/ml), the detection rate was 51.6%, slightly higher than the 35%-40% reported in previous studies.9,16, 17, 18
Numerous studies have tried to identify the key variables affecting the positivity rates.
Rauscher et al. developed a nomogram to predict PET/CT positivity, identifying PSA levels and concurrent ADT as the two most influential predictors in their multivariate analysis.7 Indeed, the existing literature has shown that PSA level at the time of recurrence significantly impacts PSMA-PET/CT detection rates, with higher detection rates observed at increasing PSA levels.6,11,18,19 Moreover, patients undergoing ADT appear to have higher detection rates compared with those not receiving ADT, likely due to the upregulation of PSMA expression during ADT.11, 19
Ceci et al. conducted a comprehensive assessment of positivity rates in 68Ga-PSMA-11-PET/CT scans across various clinical contexts, including first biochemical recurrence, BCR after salvage therapy, biochemical persistence after RP, and advanced-stage PCa prior to second-lines systemic therapies.20 Positivity rates ranged from 40.3% in cases of first biochemical recurrence to 86.9% in the advanced-stage PCa group, highlighting significant heterogeneity within the patient cohort. Multivariate analyses revealed identified ISUP grade, PSA levels, PSA doubling time, and clinical setting as independent predictors of scan positivity.
Our findings demonstrate considerable heterogeneity in the variables influencing PSMA-PET/CT positivity, which can be attributed to the diverse populations sampled across studies. Considering this, we endeavored to introduce clinically accessible variables, aiming to better understand the observed detection rates within our cohort.
In our study, several factors including ISUP grade group ≥3, positive LNI at time of RP, positive EPE, SVI and PSA after RP ≥ 0.1 ng/ml appear to predict 68Ga-PSMA-11-PET/CT positivity. These findings are consistent with the previous research on the main variables predicting PCa recurrence based on pathological data, such as those used in the post-surgical CAPRA-S score.21,22 Therefore, for this subset of patients experiencing first recurrence, it may be more reliable to prioritize pathological findings as predictors for PSMA positivity, and, by extension, for PCa recurrence.
Notably, positive surgical margins demonstrate a trend toward PSMA-PET/CT negativity, although this association was not statistically significant. Currently, limited literature explores the association between surgical margins and scan positivity rates. However, nerve-sparing surgery, particularly bilateral nerve-sparing, is well-documented to correlate with an elevated risk of positive SM, potentially increasing the risk of BCR.23,24 This may stem from selecting patients with preoperatively low ISUP grades upon prostate biopsy and clinical T1 staging. Therefore, the tendency toward positive surgical margins with scan negativity could be attributed to the performance of nerve-sparing radical prostatectomy in low-risk PCa patients, resulting in a higher incidence of positive surgical margins. In our cohort, 46.2% (48 out of 104) of patients with positive surgical margins were classified as ISUP <3 and 71.2% (74 out of 104) as ISUP ≤3. This could increase the likelihood of PSA recurrence but may not affect scan positivity.
Based on the foregoing, it can be concluded that patients presenting with more aggressive disease at the time of initial diagnosis are at higher risk of PSMA positivity and thus PCa recurrence.
Furthermore, the primary objective of this study was to define recurrence patterns in first BCR or persistence and to assess factors predictive of locoregional recurrence. This subset of patients is particularly challenging, given that PET/CT positivity is approximately 50%. Nevertheless, this presents a crucial opportunity to implement different recurrence-guided therapies with curative intent.
To our knowledge, only a limited number of other studies have explored site-specific relapse patterns in cases of first biochemical recurrence or persistence. For instance, Francolini et al.22 demonstrated that out of 52 patients with positive 68Ga-PSMA-11-PET/CT, 35 (67.3%) had locoregional only recurrence, with 12 exhibiting prostate bed recurrence, two of whom also had concomitant local and regional recurrence. In the study by Devos et al. (28), which included patients with BCR after primary RP alone, as well as RP with ADT or radiotherapy, 5.6% of those who underwent RP alone experienced prostate bed recurrence, while 84.5% presented lymph node recurrence on imaging, mostly below the common iliac bifurcation. Similarly, Grubmüller et al. (29) reported that, among 57 patients treated with primary RP alone, 79% experienced pelvic-only recurrence and 15.8% had extra-pelvic recurrence. Thus, our findings align with the existing literature, indicating that the most common pattern of recurrence observed was the locoregional involvement (147 out of 152 patients, 96.7%).
Having established that locoregional involvement was the predominant recurrence pattern in primary BCR and PSA persistence, our focus shifted to examining variables associated with relapse in both the prostatic fossa and pelvic nodes. Our results suggest that pathological factors can play a vital role in localizing locoregional relapse, particularly with positive lymphadenectomy significantly associated with pelvic node recurrence. Additionally, although with a lower level of significance, factors such as an ISUP ≥3, positive EPE, and SVI could also be included as predictors of lymph node recurrence. Moreover, surgical margins emerged as the sole factor displaying a strong association with prostate bed recurrence.
Identifying factors associated with nodal recurrence on PSMA-PET/CT scans opens avenues for tailored treatments, including guided lymphadenectomy or radiotherapy with a boost to the PET-positive lymph nodes. Further research is needed to evaluate additional therapeutic strategies following PET-positive lymph node detection. Additionally, studies are needed to determine the optimal timing of PET/CT scans and to assess the potential role of ADT in combination with salvage treatment.
Considering these advancements, it can be inferred that accurately predicting positivity rates and locoregional relapse or disease persistence in this specific clinical context can enable physicians to select the optimal management strategies. This approach holds the promise for achieving longer-lasting PSA responses and potentially improving cure rates.
This study has several limitations. First, it is a retrospective design. Second, for a subset of our cohort, the time from RP to PSMA did not align with the time from RP to BCR as some patients had to wait for 68Ga-PSMA-11-PET/CT availability at our center. Third, there is a recognized need to strengthen the confirmatory pathologic data for PSMA-PET/CT positive findings, which remains challenging in many cases due to ethical and practical constraints.
In conclusion, this study suggests that variables of prostate specimen analysis are associated with PSMA positivity, supporting the need to evaluate these factors in cases of first biochemical recurrence or persistence.
Additionally, our findings highlight the prevalence of locoregional recurrence within this population and underscore the value of the same pathological variables in predicting locoregional recurrence. Overall, these results may contribute to identify optimal candidates for 68Ga-PSMA-11-PET/CT imaging and to facilitate more targeted and personalized treatments for locoregional recurrence.
Conflict of interest
The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
References
- 1.Siegel R.L., Miller K.D., Wagle N.S., Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023 Jan;73(1):17–48. doi: 10.3322/caac.21763. [DOI] [PubMed] [Google Scholar]
- 2.Van den Broeck T., van den Bergh R.C.N., Arfi N., Gross T., Moris L., Briers E., et al. Prognostic value of biochemical recurrence following treatment with curative intent for prostate cancer: a systematic review. Eur Urol Elsevier B.V. 2019;75:967–987. doi: 10.1016/j.eururo.2018.10.011. [DOI] [PubMed] [Google Scholar]
- 3.Sood A., Keeley J., Palma-Zamora I., Arora S., Dalela D., Olson P., et al. Ten-year disease progression and mortality rates in men who experience biochemical recurrence versus persistence after radical prostatectomy and undergo salvage radiation therapy: a post-hoc analysis of RTOG 9601 trial data. Urol Oncol: Sem Orig Inves. 2020 Jun 1;38(6):599.e1–599.e8. doi: 10.1016/j.urolonc.2020.02.024. [DOI] [PubMed] [Google Scholar]
- 4.Carrie C., Hasbini A., de Laroche G., Richaud P., Guerif S., Latorzeff I., et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016 Jun 1;17(6):747–756. doi: 10.1016/S1470-2045(16)00111-X. [DOI] [PubMed] [Google Scholar]
- 5.Shipley W.U., Seiferheld W., Lukka H.R., Major P.P., Heney N.M., Grignon D.J., et al. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017 Feb 2;376(5):417–428. doi: 10.1056/NEJMoa1607529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Perera M., Papa N., Roberts M., Williams M., Udovicich C., Vela I., et al. Gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer—updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis. Eur Urol Elsevier B.V. 2020;77:403–417. doi: 10.1016/j.eururo.2019.01.049. [DOI] [PubMed] [Google Scholar]
- 7.Rauscher I., Düwel C., Haller B., Rischpler C., Heck M.M., Gschwend J.E., et al. Efficacy, predictive factors, and prediction nomograms for 68Ga-labeled prostate-specific membrane antigen–ligand positron-emission tomography/computed tomography in early biochemical recurrent prostate cancer after radical prostatectomy. Eur Urol. 2018 May 1;73(5):656–661. doi: 10.1016/j.eururo.2018.01.006. [DOI] [PubMed] [Google Scholar]
- 8.Ceci F., Castellucci P., Graziani T., Farolfi A., Fonti C., Lodi F., et al. 68Ga-PSMA-11 PET/CT in recurrent prostate cancer: efficacy in different clinical stages of PSA failure after radical therapy. Eur J Nucl Med Mol Imag. 2019 Jan 1;46(1):31–39. doi: 10.1007/s00259-018-4189-7. [DOI] [PubMed] [Google Scholar]
- 9.Deandreis D., Guarneri A., Ceci F., Lillaz B., Bartoncini S., Oderda M., et al. 68Ga-PSMA-11 PET/CT in recurrent hormone-sensitive prostate cancer (HSPC): a prospective single-centre study in patients eligible for salvage therapy. Eur J Nucl Med Mol Imag. 2020 Nov 1;47(12):2804–2815. doi: 10.1007/s00259-020-04809-8. [DOI] [PubMed] [Google Scholar]
- 10.Fendler W.P., Calais J., Eiber M., Flavell R.R., Mishoe A., Felix, et al. Assessment of 68 Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer A prospective single-arm clinical trial supplemental content. JAMA Oncol [Internet] 2019;5(6):856–863. doi: 10.1001/jamaoncol.2019.0096. https://jamanetwork.com/ Available from: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Afshar-Oromieh A., Holland-Letz T., Giesel F.L., Kratochwil C., Mier W., Haufe S., et al. Diagnostic performance of 68Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients. Eur J Nucl Med Mol Imag. 2017 Aug 1;44(8):1258–1268. doi: 10.1007/s00259-017-3711-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Ost P., Bossi A., Decaestecker K., De Meerleer G., Giannarini G., Karnes R.J., et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol Elsevier. 2015;67:852–863. doi: 10.1016/j.eururo.2014.09.004. [DOI] [PubMed] [Google Scholar]
- 13.Deek M.P., Van der Eecken K., Sutera P., Deek R.A., Fonteyne V., Mendes A.A., et al. Long-Term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic prostate cancer: analysis of STOMP and ORIOLE trials. J Clin Oncol [Internet] 2022;40:3377–3382. doi: 10.1200/JCO.22.00644. https://doi Available from: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bravi C.A., Heidenreich A., Fossati N., Gandaglia G., Suardi N., Mazzone E., et al. Combining PSA and PET features to select candidates for salvage lymph node dissection in recurrent prostate cancer. BJUI Compass. 2023 Jan 1;4(1):123–129. doi: 10.1002/bco2.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Rauscher I., Maurer T., Beer A.J., Graner F.P., Haller B., Weirich G., et al. Value of 68Ga-PSMA HBED-CC PET for the assessment of lymph node metastases in prostate cancer patients with biochemical recurrence: comparison with histopathology after salvage lymphadenectomy. J Nucl Med. 2016 Nov 1;57(11):1713–1719. doi: 10.2967/jnumed.116.173492. [DOI] [PubMed] [Google Scholar]
- 16.Farolfi A., Ceci F., Castellucci P., Graziani T., Siepe G., Lambertini A., et al. 68Ga-PSMA-11 PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy and PSA <0.5 ng/ml. Efficacy and impact on treatment strategy. Eur J Nucl Med Mol Imag. 2019 Jan 1;46(1):11–19. doi: 10.1007/s00259-018-4066-4. [DOI] [PubMed] [Google Scholar]
- 17.Van Leeuwen P.J., Stricker P., Hruby G., Kneebone A., Ting F., Thompson B., et al. 2015. Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment.https://bjui-journals.onlinelibrary.wiley.com/doi/10.1111/bju.13397 Available from. [DOI] [PubMed] [Google Scholar]
- 18.Artigas C., Diamand R., Shagera Q.A., Plouznikoff N., Fokoue F., Otte F.X., et al. Oligometastatic disease detection with 68 Ga-PSMA-11 PET/CT in hormone-sensitive prostate cancer patients (HSPC) with biochemical recurrence after radical prostatectomy: predictive factors and clinical. Impact. 2021 doi: 10.3390/cancers13194982. Available from: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Hoffmann M.A., Buchholz H.G., Wieler H.J., Höfner T., Müller-Hübenthal J., Trampert L., et al. 2019. The positivity rate of 68Gallium-PSMA-11 ligand PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer [Internet]www.oncotarget.com Available from. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Ceci F., Bianchi L., Borghesi M., Polverari G., Farolfi A., Briganti A., et al. Prediction nomogram for 68Ga-PSMA-11 PET/CT in different clinical settings of PSA failure after radical treatment for prostate cancer. Eur J Nucl Med Mol Imag. 2020 Jan 1;47(1):136–146. doi: 10.1007/s00259-019-04505-2. [DOI] [PubMed] [Google Scholar]
- 21.Cooperberg M.R., Hilton J.F., Carroll P.R. The CAPRA-S score: a straightforward tool for improved prediction of outcomes after radical prostatectomy. Cancer. 2011 Nov 15;117(22):5039–5046. doi: 10.1002/cncr.26169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Würnschimmel C., Wenzel M., Wang N., Tian Z., Karakiewicz P.I., Graefen M., et al. Radical prostatectomy for localized prostate cancer: 20-year oncological outcomes from a German high-volume center. Urol Oncol: Sem Orig Inves. 2021 Dec 1;39(12):830.e17–830.e26. doi: 10.1016/j.urolonc.2021.04.031. [DOI] [PubMed] [Google Scholar]
- 23.Komori H., Blas L., Shiota M., Takamatsu D., Matsumoto T., Lee K., et al. Impact of nerve sparing in robot-assisted radical prostatectomy on the risk of positive surgical margin and biochemical recurrence. Int J Urol. 2022 Aug 1;29(8):824–829. doi: 10.1111/iju.14900. [DOI] [PubMed] [Google Scholar]
- 24.Preston M.A., Breau R.H., Lantz A.G., Morash C., Gerridzen R.G., Doucette S., et al. The association between nerve sparing and a positive surgical margin during radical prostatectomy. Urol Oncol: Sem Orig Inves. 2015 Jan 1;33(1):18.e1–18.e6. doi: 10.1016/j.urolonc.2014.09.006. [DOI] [PubMed] [Google Scholar]