Abstract
Introduction
Prostate-specific membrane antigen (PSMA) radioguided surgery (RGS) is being tested to personalize lymph node dissection at radical prostatectomy and in the salvage settings.
Material and methods
We conducted a narrative review using the MEDLINE database (via PubMed), selecting key publications on the intravenous administration of PSMA to investigate lymph node involvement during surgery.
Results
This review provides an overview of the PSMA-RGS methodology and outcomes. The technique demonstrates high specificity, particularly in ex vivo settings, with a median ranging from 93.5% to 100%. However, sensitivity varies widely, with a median range of 50% to 100%, often limited by reduced detection of micrometastases. Detailed preoperative, perioperative, and oncological evaluations are summarized in tables.
Conclusions
PSMA-RGS is feasible and safe in both primary and salvage settings. In appropriately selected patients, it may contribute to longer therapy-free survival (36 months) and prolonged biochemical recurrence-free survival (19 months).
Keywords: radioguided surgery, prostate-specific membrane antigen, PSMA, pelvic lymph node dissection, lymph node metastases, prostate cancer
INTRODUCTION
The standard local therapies for early-stage prostate cancer (PCa) are radical prostatectomy (RP) or radiotherapy [1]. However, after the treatment, up to 50% of patients experience biochemical recurrence (BCR) caused by local recurrence or distant metastases [2]. Lymph nodes (LNs) are among the first sites for metastasis [3]. One of the possible solutions to remedy this was primary lymph node dissection (LND) during prostatectomy. However, its impact on survival and morbidity remains unclear. One promising advancement is radioguided surgery (RGS), which can improve LN sampling while minimizing side effects of extended LND [4].
When BCR occurs, management options include watchful waiting, salvage radiotherapy (SRT), or androgen deprivation therapy (ADT) [2]. Selecting the appropriate treatment requires balancing oncologic benefit with physical and mental aspects of patient quality of life [5].
Two key trials, STOMP and ORIOLE, explored whether metastasis-directed therapy (MDT) improves survival. The STOMP trial, a randomized multicenter study in Belgium, included 62 patients with oligometastatic PCa randomized to MDT or surveillance (2012–2015). After three years, ADT was delayed in the MDT group (21 vs 12 months; p <0.08) [6].
The ORIOLE trial (2016–2018, US) enrolled 54 patients with ≤3 asymptomatic metastases. Stereotactic ablative radiation (SABR) was compared to observation in a 2 : 1 ratio. Disease progression was defined as a PSA rise ≥2 ng/dl, radiologic progression, new symptoms, ADT initiation, or death. At 6 months, progression occurred in 19% (SABR) vs 61% (observation) [7]. These trials suggest MDT, including SABR or metastasectomy, may delay progression and improve cancer-specific survival (CSS) [6–8]. However, these are not targeted therapies – except for targeted salvage radiation.
RGS offers intraoperative localization and removal of metastatic lesions. It involves intravenous administration of a radiotracer that binds to prostate-specific membrane antigen (PSMA), a protein overexpressed in PCa cells [9, 10]. The radiotracer emits ionizing radiation (γ or β particles), detected during surgery with a handheld probe, providing visual and auditory cues. This allows for precise excision of metastatic sites, including those otherwise difficult to detect [11–15].
This review summarizes recent developments in RGS using PSMA-targeted tracers. It evaluates the potential of this approach as a therapeutic option for patients with lymph node involvement (LNI) in recurrent PCa.
Search strategy
The review’s search strategy and selection criteria were designed to ensure comprehensive coverage of PSMA RGS in recurrent PCa while maintaining methodological precision. The search strategy consisted of Medline database analysis (via PubMed). The papers needed to consider PSMA and RGS applied in in vivo settings to be eligible. We did not include papers concerning 11C-choline or conventional imaging to evaluate metastases. The work did not consider papers about sentinel lymph node dissection with or without fluorescence. Only articles written in English or German language were included.
TECHNIQUE CHARACTERISTICS AND THE COURSE OF THE PROCEDURE
RGS is a technique that enables the intraoperative identification of metastatic lesions. A radioactive tracer emitting either β or γ radiation binds to the PSMA, forming a PSMA-ligand. Administered intravenously, this tracer allows for the detection of PCa tissue even at low prostate-specific antigen (PSA) levels. Real-time visual and auditory feedback is provided via a read-out console positioned near the surgical field (Figure 1) [12, 16].
Figure 1.
Graphical representation of the procedure.
As part of preoperative staging, patients with BCR following primary therapy undergo Gallium-68 (68Ga) PSMA positron emission tomography (PSMA PET) imaging. This is currently considered the most specific modality for assessing LNI [17, 18]. A key advantage of preoperative imaging is the ability to determine the number and anatomical location of metastatic lymph nodes, enabling direct correlation with intraoperative tracer localization. This correlation helps reduce the risk of missing lesions during surgery.
However, it should be noted that despite its high specificity, 68Ga-PSMA PET demonstrates relatively low sensitivity, particularly in low-volume disease. Therefore, it cannot reliably determine the necessity of ePLND in all cases [19].
Approximately one day before surgery, patients receive an intravenous dose of either Indium-111 (111In) PSMA I&T or Technetium-99m (99mTc) PSMA-I&S [11, 19]. This is followed by single photon emission computed tomography/computed tomography (SPECT/CT) imaging, which serves as a quality control measure for radiotracer distribution and helps cross-validate the findings from prior PSMA PET imaging [20].
Preoperative PET imaging presents certain limitations compared to SPECT/CT. One major drawback is the complex process of obtaining 68Ga from the Ge-68/68Ga generator, which significantly restricts the number of patients who can be scanned. Additionally, the short half-life of 68Ga (68 minutes) necessitates on-site synthesis in a nuclear medicine laboratory [21]. In contrast, the 99mTc generator allows for higher radiotracer yield and can serve a substantially larger patient population [22]. Despite these logistical advantages, PSMA PET remains crucial due to the lower sensitivity of SPECT/CT.
For example, Rauscher et al. [23] found that 111In-PSMA I&T SPECT/CT detected only 48.3% of metastatic LNs (14 out of 29), while 68Ga-PSMA HBED-CC PET identified metastases in 59% of patients with early recurrent PCa (13 out of 22). Similarly, Lawal et al. [24] reported that in 14 patients, 68Ga PSMA PET/CT detected 46 lesions with increased PSMA uptake (10 prostate, 24 LNs, 12 bone), whereas 99mTc HYNIC PSMA SPECT/CT visualized only 36 of these 46 lesions (10 prostate, 15 LNs, 11 bone), failing to detect any new ones – even in the presence of high PSA levels (median 45.2 ng/ml).
The next step is the intraoperative detection of metastatic lesions. The previously administered PSMA radiotracer binds to overexpressed PSMA receptors, allowing for detection using a γ-probe during surgery [17]. The γ-probe, functioning as a scintillation counter, can identify small lesions (<10 mm) and locate PCa tissue even in atypical regions, as targeted by tracers like 99mTc-PSMA-I&S. The device provides both visual and auditory signals, with signal intensity proportional to the γ radiation concentration [12].
Schottelius et al. [25] compared the in vivo biodistribution of PSMA-I&T labeled with various radionuclides (111In, 68Ga, 177Lu) in LNCaP (human prostate adenocarcinoma cell line) xenograft-bearing mice. They observed that 111In-PSMA-I&T and 177Lu-PSMA-I&T exhibited similar uptake levels, while 68Ga-PSMA-I&T showed significantly lower uptake one hour after radiotracer injection. Despite its effective uptake, 111In-PSMA-I&T has notable limitations, including high cost and limited availability.
99mTc-PSMA-I&S addresses these issues. Robu et al. [26] evaluated the performance of 99mTc-PSMA-I&S in comparison with 68Ga-PSMA-I&T, 177Lu-PSMA-I&T, and 111In-PSMA-I&T. They found comparable internalization rates between 99mTc-PSMA-I&S and 111In-PSMA-I&T (93 ±3% vs 104 ±7% of the reference [125I-BA]KuE) in both in vitro LNCaP cell assays and in vivo CB17 LNCaP xenograft-bearing mice. Moreover, the study established that the optimal timing for RGS using 99mTc-PSMA-I&S is more than 5 hours post injection, ensuring a high lesion-to-background ratio, specifically referring to the contrast between radiotracer uptake in malignant tissue versus surrounding non-target tissue [26].
Ex vivo scintillation measurements confirm the successful intraoperative removal of malignant tissue [12].
OPEN SURGERY IN OLIGOMETASTATIC PROSTATE CANCER
Maurer et al. [12] conducted the first study utilizing PSMA in RGS, involving five patients (one with primary PCa and four with recurrent disease), all presenting with LNI confirmed by 68Ga-PSMA HBED-CC PET imaging. Building on this, Rauscher et al. performed a prospective study including 31 patients with recurrent PCa, reporting high sensitivity (92.3%), specificity (93.5%), and PPV (88.9%) for RGS using 111In-PSMA. Postoperative PSA levels dropped below 0.2 ng/ml in 20 of the 31 patients, and 13 patients remained free from BCR during a median follow-up of 13.8 months (range: 4.6–18.3 months). Only one patient experienced a complication exceeding grade 1 on the Clavien-Dindo scale (grade 3a), presenting with urosepsis and hydronephrosis [11].
Knipper et al. later published a retrospective study involving 364 patients who underwent PSMA-RGS without concomitant treatments. Metastatic lesions were successfully dissected in 343 of 364 patients (94%). Postoperative complications according to the Clavien-Dindo classification occurred in 24 patients (6.6%) within 3 months. BCR was observed in 225 patients, while 165 achieved complete biochemical response (cBR, PSA <0.2 ng/ml) within 2–16 weeks after surgery. Median biochemical-free survival (BFS) was 7.8 months (95% CI: 5.4–10.5), and treatment-free survival (TFS) was 35.5 months (95% CI: 25.9–45.9). Independent predictors of BCR following PSMA-RGS included higher preoperative PSA (HR: 1.07; 95% CI: 1.02–1.12), increased number of PSMA-avid lesions (HR: 1.23; CI: 1.08–1.40), multiple lesion localizations (pelvic and retroperitoneal) (HR: 1.90; CI: 1.23–2.95), and retroperitoneal involvement (HR: 2.04; CI: 1.31–3.18) [20].
In a more recent multicenter retrospective study, Knipper et al. analyzed data from 553 patients. Among them, 212 remained BCR-free for a median of 23.7 months (IQR: 10–36). Subgroup analysis revealed superior oncological outcomes for patients with PSA <0.1 ng/ml compared to those with PSA 0.1–<0.2 or ≥0.2 ng/ml, as reflected by TFS at 2-year follow-up: 81.1% vs 56.1% vs 43.1%, respectively (CI: 75.1–87.5% vs 43.6–72.1% vs 35.9–51.7%; p <0.001). Multivariable analysis identified predictors of TFS, including pT stage at RP, time from RP to PSMA-RGS, retroperitoneal metastasis location, number of PSMA PET-visible lesions, and postoperative PSA levels [27].
Details of additional studies are summarized in Tables 1–3 [13, 27–34]. Collectively, these studies suggest that PSMA-RGS is a promising tool for enhancing intraoperative detection of metastatic lesions in PCa, potentially leading to improved oncological outcomes. However, as salvage surgery in oligorecurrent PCa remains an experimental approach and RGS cannot substitute for ePLND or comprehensive histopathological evaluation, careful patient selection is critical.
Table 1.
Baseline characteristics of prostate cancer patients who underwent open surgery
| Study (number of patients) | Maurer et al. (n = 5) | Rauscher et al. (n = 31) | Horn et al. (n = 63) | Maurer et al. (n = 31) | Horn et al. (n = 121) | Knipper et al. (n = 40) | Mayr et al. (n = 50) | Knipper et al. (n = 364) | Knipper et al. (n = 553) |
| Hospital | Munich | Munich | Munich | Munich | Munich | Munich, Hamburg | Regensburg | Munich, Hamburg | Hamburg, Munich, Amsterdam |
| Publishing date | 2015 | 2017 | 2017 | 2019 | 2019 | 2021 | 2024 | 2023 | 2024 |
| Study type | Prospective | Prospective | Retrospective | Retrospective | Retrospective | Retrospective | Retrospective | Retrospective | Retrospective |
| Setting | Recurrent /Primary | Recurrent | Recurrent | Recurrent | Recurrent | Recurrent | Recurrent | Recurrent | Recurrent |
| Journal | European Urology | BJU international | Der Urologe | European Urology | European Urology | European Urology | World Journal of Urology | European Urology | European Urology Oncology |
| PSA at primary treatment (ng/ml), median IQR | 2.45 (0.46–4.36) | NA | 9.7 (NA) | NA | 9.5 (6.8–17.9) | 7.4 (5.3-10.8) | NA | 9 (6,16) | 9 (6-15) |
| pT stage at RP (%) | 29 RP | 61 RP | 31 RP | 121 RP | 40 RP | 50 RP | 364 RP | 553 RP | |
| pT2 | T2c 2 (40) | 12 (39) | 14 (45) | 41 (34) | 18 (45) | 21 (42) | 145 (40) | 221 (40) | |
| pT3a | 1 (20) | 16 (52) | 16 (52) | 78 (64) | 15 (38) | 14 (28) | 105 (29) | 144 (26) | |
| pT3b | 1 (20) | 7 (17) | 13 (26) | 107 (29) | 155 (28) | ||||
| pT4 | 1 (20) | 1 (3) | 0 | 0 | – | – | |||
| NA | 2 (6) | 63 (100) | 1 (3) | 2 (2) | 0 | 2 (4) | 7 (2) | 33 (6) | |
| Gleason grade group (%) | |||||||||
| I | 1 (20) | 5 (16) | 4 (13) | 13 (11) | 7 (18) | 30 (60) | 27 (7) | 31 (6) | |
| II | 1 (20) | 15 (49) | 8 (26) | 58 (48) | 12 (30) | 96 (26) | 135 (24) | ||
| III | 1 (20) | 7 (23) | 6 (15) | 127 (35) | 194 (35) | ||||
| IV | 1 (20) | 10 (32) | 5 (16) | 44 (36) | 7 (18) | 17 (34) | 40 (11) | 63 (11) | |
| V | 1 (20) | 7 (23) | 7 (18) | 60 (17) | 83 (15) | ||||
| NA | 1 (3) | 63 (100) | 6 (5) | 1 (3) | 3 (6) | 14 (4) | 47 (9) | ||
| pN stage (%) | |||||||||
| pN0 | 4 (80) | 21 (68) | 23 (74) | 90 (74) | 30 (75) | 41 (82) | 276 (75) | 395 (71) | |
| pN1 | 1 (20) | 6 (19) | 5 (16) | 25 (21) | 6 (15) | 7 (14) | 60 (17) | 98 (18) | |
| pNX | 4 (13) | 3 (10) | 6 (5) | 2 (5) | 2 (4) | 18 (5) | 27 (5) | ||
| NA | 63 (100) | 2 (5) | 0 | 10 (3) | 33 (6) | ||||
| Surgical margin status (%) | NA | NA | |||||||
| R0 | 3 (60) | 22 (71) | 78 (65) | 27 (68) | 35 (70) | 266 (73) | 386 (70) | ||
| R1 | 5 (16) | 22 (18) | 11 (28) | 9 (18) | 72 (20) | 112 (20) | |||
| RX | 2 (5) | 4 (8) | 11 (3) | 15 (3) | |||||
| NA | 2 (40) | 31 (100) | 63 (100) | 4 (13) | 21 (17) | 2 (4) | 15 (4) | 40 (7) | |
| Secondary treatment (%) | 4 (80) | 22 (71) | 30 (48) | 20 (65) | 83 (69) | 33 (83) | 33 (66) | ||
| RT after RP | 2 (40) | 20 (65) | 23 (37) | 18 (58) | 77 (64) | 33 (83) | 3 (6) | 224 (62) | 310 (56) |
| No | 2 (40) | 9 (29) | 38 (31) | 21 (42) | 140 (39) | 243 (44) | |||
| Salvage LND | 4 (13) | 3 (10) | 8 (7) | - | |||||
| RT & salvage LND | 1 (20) | 7 (11) | |||||||
| ADT | 8 (26) | 8 (26) | 8 (7) | 7 (14) | 0 (Exclusion criteria) | ||||
ADT – androgen deprivation therapy; IQR – interquartile range; LND – lymph node dissection; NA – not applicable; PSA – prostate-specific antigen; pN – pathological regional lymph node; pNX – pathological lymph node impossible to assess; pT – pathological primary tumor; RGS – radioguided surgery; RP – radical prostatectomy; RT – radiotherapy
Table 3.
Outcomes of prostate-specific membrane antigen radioguided surgery in open surgery group
| Study (patients number) | Rauscher et al. (n = 31) | Horn et al. (n = 63) | Maurer et al. (n = 31) | Horn et al. (n = 121) | Knipper et al. (n = 40) | Mayr et al. (n = 50) | Knipper et al. (n = 364) | Knipper et al. (n = 553) |
| Total number of specimens (total metastatic lesions) | 145 (51) | 277 (94) | 132 (58) | NA | 40 (0 – local recurrence) | 178 | NA | NA |
| RGS-positive specimens confirmed histologically (All histologically confirmed metastatic lesions) | 48 (52) | 94 (109) | 46 (58) | 180 (219) | 40 (40 – local recurrence) | (93) | 180 | NA |
| RGS-negative specimens confirmed histologically (All histologically non-metastatic lesions) | 87 (93) | 162 (168) | 74 (86) | NA | 0 | NA | 39 | NA |
| Sensitivity (%), 95% CI | 92 (83–97) | 86.2 | 83.6 (71–92) | NA | 100 | NA | NA | NA |
| Specificity (%), 95% CI | 94 (82–98) | 96 | 100 | NA | 100 | NA | NA | NA |
| PPV (%) 95% CI | 89 (73–96) | 94 | 100 | NA | 100 | NA | NA | NA |
| NPV (%) 95% CI | 96 (88–99) | 92 | 89 (78–95) | NA | 100 | NA | NA | NA |
| Number of BFS patients (%) | 18 (60) | 17 (27) | 13 (42) | 71 (59) | 18 (45) | 19 (38) | 139 (38) | 212 (38) |
| Median BFS months (follow-up range) | NA | 12 (7–32) | 14 (5–18) | 6 | 24 (12–42) | 10 (IQR: 5–21) | 8 (5–11) | 19 (CI: 7–36) |
| Number of TFS patients (%) | 20 (67) | 17 (27) | 20 (65) | 82 (68) | 28 (70) | 21 (42) | 243 (67) | 365 (66) |
| Median TFS months (follow-up range) | 9 (2–19) | 12 (7–32) | 12 (6–18) | 5 | 46 (12–42)* | 13 (6–21) | 36 (26–46) | 24 (10–36) |
Estimated survival probability based on Kaplan-Meier analyses
BFS – biochemical-free survival; CI – confidence interval; NGV – negative predictive value; PCa – prostate cancer; PPV – positive predictive value; RGS – radioguided surgery; TFS – treatment-free survival
Table 2.
Preoperative characteristics, pathological results, and complication rates of prostate cancer patients who underwent open surgery
| Study (number of patients) | Maurer et al. (n = 5) | Rauscher et al. (n = 31) | Horn et al. (n = 63) | Maurer et al. (n = 31) | Horn et al. (n = 121) | Knipper et al. (n = 40) | Mayr et al. (n = 50) | Knipper et al. (n = 364) | Knipper et al. (n = 553) |
| Median age at PSMA-RGS [yr], (IQR) | 75 (69–75) | 68.2 (52–76) | 69 (49–78) | 67 (61–74) | 70 (63–74) | 67 (63–74) | 70 (65–73) | 67 (62–71) | 67 (62–72) |
| Median time between RP and PSMA-RGS [mo], (IQR) | NA | NA | 54 (3–246) | NA | 52 (26–113) | 102 (72–122) | 44 (23–92) | 54 (28–93) | 49 (25–97) |
| Median PSA prior to PSMA-RGS [ng/ml], (IQR) | 1.46 (0.45–2.93) | 1.3 (0.57–2.53) | 1.29 (0.65–2.48) | 1.13 (0.71–2.35) | 1.13 (0.53–2.16) | 0.9 (0.5–1.7) | 1.2 (0.6–3.0) | 1.0 (0.5–1.90) | 0.81 (0.42–1,54) |
| Mean radiotracer activity (range MBq) | 146 MBq (110–169) | 150 MBq (86–298) | 150 MBq (110–190) | 571 MBq (221–857) | NA | NA | NA | NA | NA |
| PSMA PET – avid lesions (%) | Max 5 | NA | Max 4 | 175/171 detected in RGS +9 additional detected | Max. 4 | Equivocal findings 63 (11) | |||
| 0 | 6 (2) | ||||||||
| 1 | 2 (40) | 40 (100) | 25 (50) | 241 (66) | 350 (63) | ||||
| 2 | 1 (20) | 18 (36) | 76 (21) | 89 (16) | |||||
| 3 | 7 (14) | 24 (7) | ≥3 51 (9) | ||||||
| 4 | 1 (20) | 12 (3) | |||||||
| 5 | 4 (1) | ||||||||
| 6 | 1 (20) | 1 (<1) | |||||||
| Lesions localizations (%) | During RGs | During RGS | During RGS | 68Ga-PSMA-11 PET | PSMA PET/CT | During RGS | |||
| Unilateral pelvic | 4 | 16 (53) | 31 | 17 (54.8) Pelvic (iliaca ext., com., int., obturator) | 74 (61) | 26 (52) | 154 (42) | 299 (54) | |
| Bilateral pelvic | 6 | 12 (3) | |||||||
| Pelvic and presacral or retrovesical | 0 | 32 (9) | |||||||
| Presacral/pararectal | 3 | 6 (20) | 16 | 9 (29) | 31 (26) | 7 (14) 3 (6) + Pelvic |
48 (13) | ||
| Retrovesical/paravesiacal | 2 | 4 (13) | 10 | 9 (29) | 26 (22) | 40 (100) | Perivesical: 3 (6) | 54 (15) | 90 (16) |
| Retroperitoneal | 3 (10) | 5 | 2 (7) | 5 (4) | 6 (12) | 28 (8) | 125 (23) | ||
| Retroperitoneal and other location | 4 (8) | 27 (7) | |||||||
| Intra-abdominal | 1 (2) | 3 (<1) | |||||||
| Other | 1 Inguinal LN |
1 (3) inguinal | 8 (1) | ||||||
| None | 1 (3) | 6 (2) | 31 (6) | ||||||
| Number pathologically confirmed lesions (%) | NA | 94 | 58 | Unknown 19 (3) | |||||
| 0 | 21 (6) | 31 (6) | |||||||
| 1 | 2 (40) | 77 (64) | 40 (100) | 29 (58) | 145 (40) | 233 (42) | |||
| 2 | 1 (20) | 29 (24) | 14 (28) | 69 (19) | 94 (17) | ||||
| 3 | 15 (12) | 7 (14) | 34 (9) | ≥3 176 (32) | |||||
| 4 | 24 (7) | ||||||||
| 5 | 1 | 15 (4) | |||||||
| ≥6 | 1 (20) | 56 (15) | |||||||
| Clavien-Dindo complications (%) | NA | 10 (32) | 24 (38) | 13 (42) | 40 (33) | 7 (18) | 13 (26) | 118 (33) | NA |
| I | 6 (19) | 12 (39) | 29 (24) | 4 (10) | 4 (8) | 81 (22) | |||
| II | 1 (2) | 13 (4) | |||||||
| IIIa | 6 (10) | 1 (3) | 11 (9) | 3 (8) | 0 | 8 (2) | |||
| IIIb | 4 (13) | 8 (16) | 15 (4) | ||||||
| IVb | 1 (<1) | ||||||||
| V | 1 (<1) | ||||||||
IQR – interquartile range; LN – lymph node; MBq – megabecquerel; mo – months; PET – positron emission tomography; PSA – prostate-specific antigen; PSMA – prostate-specific membrane antigen; RGS – radioguided surgery; RP – radical prostatectomy; yr – years
Multiple studies have demonstrated that both pre- and postoperative PSA levels are significantly associated with longer BFS and treatment-free survival (TFS) [27, 29, 31, 35]. Notably, the most favorable long-term outcomes were observed in patients with PSA levels below 0.1 ng/ml [27]. The interval between RP and PSMA-RGS is another key factor, as are the number of PSMA-avid lesions and the count of histopathologically confirmed positive nodes [27, 31, 35].
Findings on other prognostic indicators, such as the impact of the pathological T stage at RP and the anatomical location of lesions, remain inconsistent across studies [27, 36].
ROBOT-ASSISTED SURGERY IN OLIGOMETASTATIC PROSTATE CANCER
Robot-assisted radioguided surgery (rRGS) has recently emerged as a key area of interest within RGS. Several studies have demonstrated its feasibility. As summarized in Tables 4–6, each study reported outcomes comparable to those of open RGS [36–42]. Ambrosini et al. compared rRGS (n = 24) to open RGS (n = 61), finding similar oncological outcomes between groups (12-month BFS: 41% vs 39%, p = 0.9). rRGS did not significantly reduce estimated blood loss (β = −40 ml; 95% CI: −103 to 22 ml; p = 0.2) and was associated with a significantly longer operative time (β = 28 min; 95% CI: 10–46 min; p = 0.002). No Clavien-Dindo grade III–V complications occurred in the rRGS group, compared to four cases (6%) in the open RGS group. Similar encouraging results were reported regardless of the gamma probe used [42]
Table 4.
Baseline characteristics of prostate cancer patients who underwent robot-assisted surgery
| Study (number of patients) | De Barros et al. (n = 20) | Quarta et al. (n = 30) | Gondoputro et al. (n = 12) | Schilham et al. (n = 20) | Gandaglia et al. (n = 12) | Mazzucato et al. (n = 13) | Falkenbach et al. (n = 37) |
| Hospital | Amsterdam | Milan | Darlinghurst Sydney | Nijmegen | Milan | Hamburg-Eppendorf | Hamburg-Eppendorf |
| Study type | Prospective | Prospective | Prospective | Prospective | Prospective | Retrospective | Retrospective |
| Setting | Recurrent | Primary | Primary | Primary | Primary | Recurrent | Repeat salvage surgery |
| Publishing date | 2022 | 2024 | 2022 | 2024 | 2022 | 2024 | 2023 |
| Journal | European Urology | European Journal of Nuclear Medicine and Molecular Imaging | Journal of Nuclear Medicine | Journal of Nuclear Medicine | European Urology | Cancers | World Journal of Urology |
| PSA at primary treatment (ng/ml), median IQR | NA | 8.5 (4.6–16) | 9.15 (6.0–21.2) | 22.2 (2.9–117) | 8.7 (4.8–15.5) | NA | 0,64 |
| pT stage at RP (%) | 15 RP, 5 RT | Clinical stage | 11 RARP + ePLND 9 ePLND + RP | 11 RP + ePLND 2 RP | 21 sLND 16 RGS | ||
| pT1 | 2 (17) | ||||||
| pT2 | 9 (30) | 6 (50) | |||||
| pT3a | 15 (50) | 1 (8) | 8 (67) | ||||
| pT3b | 6 (20) | 3 (25) | 4 (33) | ||||
| Gleason grade group (%) | NA | NA | Pathological | NA | NA | ||
| II | |||||||
| III | 8 (27) | 4 (33) | |||||
| IV | 12 (40) | 3 (25) | 2 (17) | ||||
| V | 10 (33) | 9 (75) | 6 (50) | ||||
| pN stage (%) | NA | Intermediate to high risk cN0 cM0 at conventional imaging | |||||
| pN0 | 21 (70) | 3 (25) | 4 (20) | 8 (67) | 9 (69) | 26 (70) | |
| pN1 | 9 (30) | 9 (75) | 1 (70) | 4 (33) | 2 (15) | 7 (19) | |
| pNX | 4 (11) | ||||||
| unknown | 2 (15) | ||||||
| PLND | 11 (85) | ||||||
| Surgical margin status (%) | NA | NA | NA | NA | NA | ||
| R0 | 24 (80) | 10 (83) | |||||
| R1 | 6 (20) | 2 (17) | |||||
| RX | |||||||
| NA | |||||||
| Secondary treatment (%) | NA | NA | 0 | 37 (100) | |||
| RT after RP | 5 (25) | 5 (38) | |||||
| Salvage Radiotherapy | 4 (20) 1 (5)* |
||||||
| Salvage radical prostatectomy | 1 (5) | ||||||
| No | 9 (45) | 5 (42) | 8 (62) | ||||
| Salvage LND | 1 (5) 1 (5)* |
21 (57) | |||||
| Radioguided surgery | 16 (43) | ||||||
| RT & ADT | 6 (50) | ||||||
| ADT | 2 (17) | 0 | |||||
| Lutetium PSMA | 1 (5)* | ||||||
Tertiary treatment
ADT – androgen deprivation therapy; ePLND – extended pelvic lymph node dissection; IQR – interquartile range; JNM – “The Journal of Nuclear Medicine”; LND – lymph node dissection; NA – not applicable; pN – pathological regional lymph node; pNX – pathological lymph node impossible to assess; PSA – prostate-specific antigen; PSMA – prostate-specific membrane antigen; pT – pathological primary tumor; RARP – robotic-assisted radical prostatectomy; RP – radical prostatectomy; RT – radiotherapy; RGS – radioguided surgery. sLND – salvage lymph node dissection
Table 6.
Outcomes of prostate-specific membrane antigen radioguided surgery in robot-assisted surgery group
| Study (patients number) | De Barros et al. (n = 20) | Quarta et al. (n = 30) | Gondoputro et al. (n = 12) | Schilham et al. (n = 20) | Gandaglia et al. (n = 18) | Mazzucato et al. (n = 13) | Falkenbach et al. (n = 37) |
| Total number of specimens (total number of metastatic lesions) | 75 | 174 (22) | 74 (22) | 49523 (45)30 | 96 (8) | 54 (19) | NA |
| RGS positive specimens confirmed histologically (all histologically confirmed metastatic specimens) | 19 (22) | 16 (22) | 16 (21) | 28 (30) | 4 (8) | 14 (19) | NA |
| RGS negative specimens confirmed histologically (all histologically non-metastatic specimens) | 56 (53) | 135 (152) | 36 (52) | 12 (13) | 87 (88) | 35 (35) | NA |
| Sensitivity (%), 95% CI | 86 (65–97) | 72 (50–89) | 76 (53–92)* 76 (53–92)** |
67 | 50 | 74 | NA |
| Specificity (%), 95% CI | 100 | 88 (83–89) | 69 (55–81)* 96 (87–99)** |
100 | 99 | 100 | NA |
| PPV (%) 95% CI | 100 | 48 (48–93) | 50* 89** |
97 | 80 | 100 | NA |
| NPV (%) 95% CI | 95 (86–98) | 96 (88–96) | 88* 91** |
97 | 96 | 88 | NA |
| Number of BFS patients (%) | 4 (21) | NA | 5 (42) | 3 (10) | 9 (75) | 12 (92) | 10 (27) |
| Median BFS months (follow-up range) | Max 15 | NA | NA | 12 | 1 | 4 | 9 (4–12) |
| Number of TFS patients (%) | NA | NA | 5 (42) | NA | 9 (75) | >12 (>92) | 19 (51) |
| Median TFS months (follow-up range) | NA | NA | 13 (4–21) | NA | 1 | 4 | 11 (6–25) |
in vivo
ex vivo
BFS – biochemical-free survival; CI – confidence interval; NA – not applicable; NGV – negative predictive value; PCa – prostate cancer; PPV – positive predictive value; PSA – prostate-specific antigen; RARP – robot-assisted radical prostatectomy; RGS – radioguided surgery; TFS – treatment-free survival
Table 5.
Preoperative characteristics, pathological results, and complication rates of prostate cancer patients who underwent robot-assisted surgery
| Study (number of patients) | De Barros et al. (n = 20) | Quarta et al. (n = 30) | Gondoputro et al. (n = 12) | Schilham et al. (n = 20) | Gandaglia et al. (n = 18) | Mazzucato et al. (n = 13) | Falkenbach et al. (n = 37) |
| Median age at PSMA-RGS [yr], (IQR) | 68 (66–72) | 68 (62–70) | 68 (range 57–69) | 69 (57–79) | 70 (66–71) | 71 (66–72) | 69 |
| Median time between RP and PSMA-RGS [mo], (IQR) | 26 (11–47)* | Simultaneous | Simultaneous | Simultaneous | Simultaneous | 49 (25–70) | 61 |
| Mean radiotracer activity (range MBq) | 541 MBq (526–578) | 734 MBq (730-738) | 500 MBq | 157 MBq (152-164) | 735 MBq (731 –738) | NA | NA |
| PSMA PET/CT- avid lesions (%) | 21 | NA | 11 | 18F-PSMA PET | 11 (PSMA PET/MRI) | 13 | |
| 0 | 0 | ||||||
| 1 | 18 (90) | 6 (55) | 3 (15) | 13 (100) | 22 (60) | ||
| 2 | 2 (10) | 9 (45) | 13 (35) | ||||
| 3 | 6 (30) | 1 | 2 (5) | ||||
| 4 | 2 (10) | ||||||
| 5 | 1 (9) | ||||||
| > 6 | 8 lesions 1 (<1) | ||||||
| Lesions localizations (%) | (during RGs) | PSMA PET/CT | 18F-PSMA PET | 68Ga-PSMA PET/MRI | PSMA PET/CT | ||
| Unilateral pelvic | 12 (60) | 2 (17) | 46 (94) | 1 (8) | 12 (92) | 30 (81) | |
| Bilateral pelvic | 1 (8) | ||||||
| Pelvic and presacral or retrovesical | 1 (8) | ||||||
| Presacral/ pararectal | 2 (10) | 4 (33) | 3 (6) | ||||
| Retrovesical/ paravesiacal | 1 (5) | ||||||
| Retroperitoneal | 7 (19) | ||||||
| Other | 5 local recurrences | 1 extrapelvic | |||||
| None | 10 (83) | ||||||
| Number pathologically confirmed lesions (%) | NA | NA | 22 | NA | |||
| 0 | 2 | ||||||
| 1 | 1 (25) | 6 (46) | 17 | ||||
| 2 | 3 (23) | 10 | |||||
| 3 | 2 (50) | ≥3 lesions 4 (31) | 4 | ||||
| 4 | ≥4 4 | ||||||
| 5 | |||||||
| ≥6 | 1 (25) | ||||||
| Clavien-Dindo complications (%) | 6 (30) | NA | 1 (8) | 1 (5) | 1 (8) | 100% <III | 3 (8) |
| I | 5 (25) | 1 (8) | 1 (5) | ||||
| II | |||||||
| IIIa | 1 (8) | 3 (8) | |||||
| IIIb | |||||||
| IVa | |||||||
| IVb | |||||||
| V | 1 (5) | ||||||
Median time from last treatment to RGS
CT – computed tomography; IQR – interquartile range; mo – months; MRI – magnetic resonance imaging; NA – not applicable; PET – positron emission tomography; PSMA – prostate-specific membrane antigen; RGS – radioguided surgery; RP – radical prostatectomy; yr – years
Mazzucato et al. identified an intriguing observation: radioactive uptake depends on tumor-occupied tissue. Nodal metastases exhibited higher radioactivity than soft tissue PCa lesions – potentially due to higher tumor cell concentration in lymph nodes. Further studies are needed to validate this finding [42].
Although current data do not show a definitive oncological advantage for rRGS, the technique improves access to local recurrences by enhancing visualization and surgical maneuverability, which may translate into greater precision than open RGS [43].
In a study by Quarta et al. [39], target-to-background (TtB) ratios were evaluated at three thresholds (≥2, ≥3, and ≥4) to assess implications for ePLND in RP settings. A TtB ratio ≥2 yielded the highest sensitivity (78%) but lower specificity (76%), compared to TtB ≥3 (66% sensitivity, 95% specificity) and ≥4 (55% sensitivity, 95% specificity). While a TtB ratio ≥2 could spare 60% of excised LNs and potentially replace ePLND, it risked missing 11% of patients with LNI [39]
Notably, the studies discussed did not report TFS or BFS outcomes. While improving LNI detectability is important, it remains unclear whether removing all metastatic LNs – including micrometastases – leads to improved survival or increased complication rates that may preclude repeat RGS in selected patients. Further well-designed studies are essential to establish robust clinical evidence.
RADIOGUIDED SURGERY VERSUS CONVENTIONAL SURGERY
The previously presented data must be evaluated alongside other therapeutic options to ensure that PCa patients receive the most effective treatment. Knipper et al. [44] compared conventional surgical approaches (CSA), which rely solely on preoperative 68Ga-PSMA PET imaging to identify affected LNs, with RGS in the context of salvage lymphadenectomy.
This prospective study included 42 patients with PCa recurrence confined to lymph nodes. Of these, 29 underwent CSA and 13 underwent 99mTc-PSMA RGS, using the radiotracer administered one day before surgery. The mean number of LNs removed was 17.8 (range: 1–65) in the CSA group and 19.3 (range: 2–53) in the RGS group. RGS successfully removed all metastatic LNs identified by 68Ga-PSMA PET, whereas CSA failed to confirm histological metastases in 9 patients (31%), despite a mean dissection of 13.6 LNs (range: 5–27). Six-week postoperative PSA levels were significantly lower in the RGS group compared to the CSA group (0.69 ng/ml [<0.01–3.3] vs 2.19 ng/ml [0.01–8.91], p <0.01). Notably, 95% of patients in this study did not receive ADT, allowing for a direct and unbiased comparison between the two surgical methods. These findings suggest the superiority of RGS over CSA. However, the small sample size limits the strength of these conclusions [44].
Furthermore, salvage surgery in oligorecurrent PCa remains an experimental approach, and RGS cannot replace ePLND or detailed histopathological analysis. Larger, well-designed comparative studies are necessary to establish the clinical value of RGS in salvage lymphadenectomy and to define appropriate patient selection criteria.
β RADIATION RADIOGUIDED SURGERY
The previously described RGS technique relies on γ radiation, although PET isotopes undergo both β+ and γ decay. While γ rays are highly penetrating, their effectiveness depends on low background radiation and minimal uptake by surrounding tissues, limiting the detectability of smaller metastases. To address this limitation, β+ emission has been explored, allowing for the development of smaller, lighter detectors with reduced collimation requirements [16].
Collamati et al. conducted a feasibility study using 68Ga with a β probe. In a retrospective analysis of 45 patients who underwent PET/CT with 68Ga-PSMA-11, the study demonstrated that β+ RGS is technically feasible, although it still requires prior PET imaging for accurate localization [16]. In another study involving seven patients, Collamati evaluated the signal-to-background ratio (SBR) during robot-assisted RGS. Lower SBR values (<2.5) indicated tumors located farther from the margin, while higher values correlated with closer proximity to tumor tissue. Of four LNs showing increased tracer uptake, three were histologically confirmed as metastatic [45].
Although further studies are necessary, β+ detectors show promise for enhancing intraoperative tumor margin assessment and improving the detection of metastatic LNs in PCa.
FUTURE DIRECTIONS
The sensitivity and specificity of PSMA-PET/CT are largely size-dependent; for metastases larger than 4.9 mm, the detection rate exceeds 90% [46]. According to the LN size distribution reported by Falkenbach et al., approximately 75% of metastases are detectable using PSMA-PET/CT [36]. Future research should prioritize technological innovations and the identification of reliable clinical or biological markers to improve patient selection. Emerging biomarkers, such as Cyr61 protein and circulating tumor cells, may enhance the sensitivity of PSMA-RGS, as explored in the BioPoP trial (NCT04324983). Additionally, defining the genetic background of patients could refine prognostic assessment and aid in identifying high-risk PCa patients who may benefit from intensified oncological surveillance or alternative strategies, including repeat RGS aimed at achieving minimal cancer burden [47].
Optimizing the tracer dose and incubation time to reduce background signal could further enhance the sensitivity of PSMA-RGS. Currently, no published data evaluate the impact of PSMA-RGS on ADT. It remains unclear whether short-term systemic ADT after PSMA-RGS can prolong BFS or if continued ADT is necessary until castration resistance develops. Preliminary insights may be available from the ongoing TRACE-II trial, which compares short-term ADT alone with PSMA-RGS combined with short-term ADT (NCT05555017).
Further investigation is also warranted to compare the outcomes of initiating ADT immediately after primary PSMA-RGS versus delaying ADT until BCR. A temporary ADT regimen may extend progression-free survival, as suggested by findings from earlier studies in radiotherapy settings [48].
Although RGS has demonstrated potential in treating recurrent or oligometastatic PCa, current evidence remains limited. One major challenge is the variability in sensitivity across studies, particularly in detecting micrometastases. Additionally, optimal patient selection criteria have yet to be clearly defined.
The role of micrometastatic disease in treatment outcomes is also ambiguous. However, according to Falkenbach et al., biochemical recurrence-free survival (bRFS) appears to correlate with metastasis size. Despite a potentially prolonged time to recurrence, micrometastases continue to present a treatment challenge [49]. Advancements in detection and clearer treatment protocols are needed.
Repeat salvage LND using RGS has shown comparable safety and efficacy to initial salvage LND [36]. Critical questions remain: Can MDT delay the initiation of systemic therapy or castration resistance? Might MDT even cure oligorecurrent PCa? Another avenue of exploration involves comparing oncological outcomes between repeated MDTs (e.g., PSMA-RGS or stereotactic ablative radiotherapy [SABR]) versus early ADT following primary MDT. This question is under investigation in the STORM trial, which compares MDT (surgical or radiotherapeutic) with MDT plus long-term ADT (NCT03569241).
An additional and largely unexplored application of RGS lies in focal therapy. PSMA PET/CT or PET/MR may offer reliable diagnostic capabilities for detecting BCR following focal therapy, potentially allowing precise metastasis-directed surgery to target local or distant recurrences [50].
CONCLUSIONS
PSMA-RGS has proven to be a feasible and safe technique for detecting nodal metastases in salvage surgery. Additionally, rRGS has recently gained attention for its enhanced visualization and maneuverability. While this method consistently demonstrates high specificity, its sensitivity remains variable, particularly in detecting micrometastases. It is important to emphasize that RGS does not replace ePLND based on template lymphadenectomy or thorough histopathological examination. Nevertheless, in carefully selected patients, this approach has the potential to prolong therapy-free intervals and extend biochemical recurrence-free survival. Further large-scale, well-structured studies are required to establish robust evidence and cost-effectiveness.
Funding Statement
FUNDING This research received no external funding.
CONFLICTS OF INTEREST
The authors declare no conflict of interest.
ETHICS APPROVAL STATEMENT
The ethical approval was not required.
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