Research ArticleFEATURED ARTICLE OF THE MONTH

Prostate-Specific Membrane Antigen–Targeted Radioguided Pelvic Lymph Node Dissection in Newly Diagnosed Prostate Cancer Patients with a Suspicion of Locoregional Lymph Node Metastases: The DETECT Trial

Melline G.M. Schilham, Diederik M. Somford, Heidi V.N. Küsters-Vandevelde, Rick Hermsen, Jean Paul A. van Basten, Robert J. Hoekstra, Tom W.J. Scheenen, Martin Gotthardt, J.P. Michiel Sedelaar and Mark Rijpkema
Journal of Nuclear Medicine March 2024, 65 (3) 423-429; DOI: https://doi.org/10.2967/jnumed.123.266495

Abstract

Prostate-specific membrane antigen (PSMA)–targeted radioguided surgery (RGS) aims to optimize the peroperative detection and removal of PSMA-avid lymph node (LN) metastases (LNMs) and has been described in patients with recurrent prostate cancer (PCa). In newly diagnosed PCa patients undergoing pelvic LN dissections, PSMA RGS could guide the urologist toward PSMA-expressing LNMs as identified on preoperative 18F-PSMA PET/CT imaging. The objective was to evaluate the safety and feasibility of 111In-PSMA RGS in primary PCa patients with one or more suggestive LNs on preoperative 18F-PSMA PET/CT. Methods: This prospective, phase I/II study included 20 newly diagnosed PCa patients with at least 1 suggestive LN on preoperative 18F-PSMA PET/CT. PSMA RGS was performed 24 h after 111In-PSMA-I&T administration, and postoperative 18F-PSMA PET/CT was performed to verify successful removal of the suggestive lesions. The primary endpoint was determination of the safety and feasibility of 111In-PSMA RGS. Safety was assessed by monitoring adverse events. Feasibility was described as the possibility to peroperatively detect suggestive LNs as identified on preoperative imaging. Secondary outcomes included the accuracy of 111In-PSMA RGS compared with histopathology, tumor- and lesion-to-background ratios, and biochemical recurrence. Results: No tracer-related adverse events were reported. In 20 patients, 43 of 49 (88%) 18F-PSMA PET–suggestive lesions were successfully removed. 111In-PSMA RGS facilitated peroperative identification and resection of 29 of 49 (59%) RGS-target lesions, of which 28 (97%) contained LNMs. Another 14 of 49 (29%) resected LNs were not detected with 111In-PSMA RGS, of which 2 contained metastases. Conclusion: 111In-PSMA RGS is a safe and feasible procedure that allows peroperative detection of 18F-PSMA PET/CT–suggestive lesions in newly diagnosed PCa patients. The use of a radioactive PSMA tracer and a detection device (γ-probe) during surgery helps in identifying LNs that were suggestive of PCa metastases on the 18F-PSMA PET/CT before surgery and thus may improve the peroperative identification and removal of these LNs.

In newly diagnosed prostate cancer (PCa) patients, determination of the presence and localization of lymph node (LN) metastases (LNMs) is crucial for clinical decision-making and treatment planning, as nodal involvement correlates with recurrence and these patients could benefit from adjuvant therapies (1,2). To date, extended pelvic LN dissection (ePLND) is still considered the best available tool for nodal staging. Although the therapeutic impact of ePLND remains controversial, some evidence suggests that removal of all LNMs could maximize locoregional disease control and potentially impact oncologic outcomes in selected patients (3). The radicality of ePLND depends on the template’s extent and resection adequacy, and research indicated that up to one third of the nodes, including 13% with LNMs, can be missed (4,5).

Conventional imaging modalities have been of limited value in nodal staging, because of low sensitivity (<40%) (6). The introduction of PET tracers targeting the cell-surface glycoprotein prostate-specific membrane antigen (PSMA) has significantly altered imaging strategies in PCa (7). The overexpression of PSMA on most PCa cells makes it a valuable target for PSMA PET/CT, which is currently increasingly used to preoperatively detect and map potential LNMs. Although PSMA PET/CT improved the detection of potential LNMs compared with conventional imaging, its sensitivity remains insufficient (13%–85%) to completely replace ePLND (8–10). Nevertheless, recent studies have shown that the presence of suggestive LNs on preoperative PSMA PET/CT is associated with an increased risk of biochemical persistence and biochemical recurrence after robot-assisted radical prostatectomy combined with ePLND (2,11). This could to some extent be associated with inadequate detection and subsequent resection of all LNMs during surgery.

PSMA-targeted radioguided surgery (RGS) is a novel technique with the aim of optimizing peroperative detection and removal of PCa lesions. This technique uses PSMA ligands labeled with a γ-emitting radionuclide (e.g., 111In or 99mTc) to facilitate peroperative detection of PSMA-expressing PCa tissue, that is, LNM. Several studies have shown the safety and feasibility of PSMA RGS using different PSMA ligands in patients with recurrent PCa (12–17). Hence, the question was raised of whether 111In-PSMA RGS could also optimize ePLND in the primary setting. If so, 111In-PSMA RGS could increase the probability of complete removal and subsequent accurate staging and thus potentially improve prognosis in a selected group of pN1 patients with limited nodal involvement (3,18).

In this prospective study, we evaluated the safety and feasibility of 111In-PSMA-I&T RGS in 20 newly diagnosed PCa patients with at least 1 suggestive LN on preoperative 18F-PSMA PET/CT imaging, with the aim of peroperatively detecting the 18F-PSMA PET–suggestive lesions.

MATERIALS AND METHODS

Study Design and Patient Population

This investigator-initiated prospective study was approved by the Institutional Review Board (CMO-Arnhem-Nijmegen) and registered at ClinicalTrials.gov (NCT04300673). Between September 2020 and April 2022, 20 patients with histopathologically proven PCa were included. Written informed consent was obtained from all. We selected patients without prior active PCa treatment who were scheduled for ePLND with robot-assisted radical prostatectomy or ePLND before radiotherapy on the prostate and who had at least 1 PSMA-suggestive LN within the ePLND template on 18F-PSMA PET/CT. Exclusion criteria were unequivocal evidence of metastatic disease outside the pelvic region and prior pelvic nodal surgery. Adjuvant therapy (i.e., radiotherapy or androgen deprivation therapy) was applied in accordance with local guidelines.

Preoperative Procedure

Preoperative 18F-PSMA PET/CT was part of preoperative staging according to local protocols. Scans were reviewed by experienced nuclear medicine physicians. For suggestive lesions, anatomic location and level of suspicion were systematically reported. Level of suspicion was defined on a 5-point Likert scale expressing the probability of metastasis presence in a LN, based on tracer uptake, LN size, and location as described in the PSMA reporting and data system classification by Rowe et al. (19). LNs with a level of suspicion of at least 3 were defined as RGS-target lesions. One day before scheduled ePLND, a single dose of 157 MBq (range, 151.8–164.2 MBq) of 111In-PSMA-I&T was intravenously injected.

Surgical Procedure

All procedures were performed via a transperitoneal approach using the Da Vinci Xi robotic surgical system (Intuitive Surgical), and images were available in the operating theater (Figs. 1A and 1B). Radioguidance was achieved using a laparoscopic γ-probe (SOE-311-AL; Eurorad SA) connected to the Europrobe 3.2 control unit (Eurorad SA). The γ-probe was covered with a sterile sleeve and inserted in the abdominal peritoneal cavity through a 12-mm assistant’s port via the Alexis laparoscopic system (Applied Medical Corp.), placed above the right iliac crest. Real-time feedback of γ-probe measurements in response to 111In activity was provided both acoustically and numerically by the control unit. Background measurements at the lateral abdominal wall muscle served as a reference. Additionally, radiosignals were measured for structures near RGS-target lesions (ureters, iliac arteries, bladder, prostate, and intestines) to assess nonspecific tracer uptake.

FIGURE 1.
FIGURE 1.

(A and B) 18F-PSMA PET/CT 11 wk before surgery demonstrates presence of suggestive LNs in left and right obturator fossa in transversal plane (blue arrows, A) and on maximum-intensity projection (green arrows, B). (C) Laparoscopic γ-probe is inserted via Alexis laparoscopic system to make in vivo measurements to detect suggestive LNs. (D) Resected specimens are measured ex vivo at benchtop examination. (E) Histopathologic examination shows LNM on hematoxylin and eosin staining and strong PSMA expression. (F and G) 18F-PSMA PET/CT (F) and maximum-intensity projection (G) 11 wk after surgery show successful removal of both suggestive LNs.

Standard bilateral ePLND was performed, including obturator fossa, external iliac, internal iliac, common iliac, and, at the surgeon’s discretion, presacral and mesorectal regions. γ-probe measurements were taken in regions of interest in vivo to identify the RGS-target lesions (Fig. 1C). A lesion was considered positive if counts per second were at least twice the counts per second of the background reference. Directly after resection, ex vivo benchtop measurements were taken (Fig. 1D). Ex vivo, a lesion with at least 10 cps was considered suggestive and subsequently marked with a suture. If ex vivo measurements showed no activity (<10 cps), in vivo measurements were repeated. All resected specimens were assessed using the γ-probe ex vivo and likewise marked if at least 10 cps were measured. Specimens were collected separately according to the anatomic resection site.

Postoperative Histopathologic Analysis and Imaging

All specimens were fixed in formaldehyde (10%) and processed for paraffin embedding. The tissue blocks were cut at a 3-μm thickness, and slides were stained with hematoxylin and eosin (Figs. 1E and 1F). The total number and size of LNs (macroscopically) and LNMs (microscopically) per specimen per anatomic region were reported. PSMA staining was applied on the marked LNs and on LNs that showed metastases on hematoxylin and eosin staining. PSMA expression was classified according to the percentage of PSMA-positive tumor cells (0%, <10%, 10%–50%, 51%–80%, >80%) and staining intensity (none, 0; mild, 1; moderate, 2; strong, 3).

Postoperative 18F-PSMA PET/CT was used to confirm or reject successful removal of RGS-target lesions (Figs. 1G and 1H) and was performed approximately 6 wk after surgery (robot-assisted radical prostatectomy plus ePLND) or 2 wk after surgery (ePLND only), before adjuvant treatment (i.e., radiotherapy or androgen deprivation therapy).

Safety and Follow-up

During administration of 111In-PSMA-I&T, safety was assessed by clinical observation of the patients for 1 h after injection. Vital parameters (temperature, blood pressure, heart rate) were measured before and 5, 30, and 60 min after injection. Long-term safety was assessed by monitoring adverse events for 12 mo, including analysis of laboratory results from blood samples taken at baseline, 10 d, and 3 mo after tracer administration. Adverse events were reported according to the Common Terminology Criteria for Adverse Events version 5.0. Surgical complications were assessed according to the Clavien–Dindo classification. Follow-up consisted of clinical examination and PSA measurements at 6 wk and 3, 6, 9, and 12 mo after surgery.

Study Endpoints

The primary endpoint of this study was determination of the safety and feasibility of the RGS procedure with 111In-PSMA-I&T. Feasibility was defined as the ability to peroperatively detect the RGS-target lesions preoperatively identified on 18F-PSMA PET/CT. Secondary outcomes included the accuracy of 111In-PSMA RGS compared with histopathology, lesion-to-background ratios (LBRs) of identified RGS-target lesions, and tumor-to-background ratios (TBRs) of histopathologically proven LNMs. Ratios were calculated for identified RGS-target lesions and retrospectively histopathologically confirmed LNMs. Adjuvant treatment strategies and biochemical recurrence within 1 y were descriptively reported as they were not part of the primary aim of this study.

Statistical Analyses

All clinical data were collected in the Castor Electronic Data Capture system (https://castoredc.com). Quantitative data describing the feasibility of the procedure are presented as medians with interquartile ranges (IQRs) or means with total ranges and numbers with frequencies within groups, as appropriate. The sensitivity, specificity, positive predictive value, and negative predictive value on a per-lesion analysis of 111In-PSMA RGS compared with histopathology were derived from 2 × 2 contingency tables. LBRs and TBRs were compared using unpaired t tests. Statistical analyses were performed using the SPSS statistical software package (version 27.0; IBM Corp.) and Prism (version 9.0; GraphPad Software). A P value of less than 0.05 was considered statistically significant.

RESULTS

Primary Outcomes

Patient and Surgical Characteristics

The characteristics of the included patients (n = 20) are summarized in Table 1. In total, 49 suggestive LNs were identified on preoperative 18F-PSMA PET/CT and defined as RGS-target lesions. Surgical characteristics are described in Table 2. In total, 523 LNs were resected. Final histopathology concluded pN1 in 16 patients (80%).

View this table:
TABLE 1.

Demographics and Clinical Characteristics of Study Population at Diagnosis (n = 20)

View this table:
TABLE 2.

Peroperative Surgical and Oncologic Characteristics

Safety of 111In-PSMA-I&T RGS

No adverse events were recorded after the administration of 111In-PSMA-I&T (Table 2). Temperature, blood pressure, and heart rate remained stable in the hour after tracer injection (Supplemental Table 1; supplemental materials are available at http://jnm.snmjournals.org). One surgical complication (Clavien–Dindo grade 1) was observed and was managed conservatively (urinary leakage at the anastomosis of the bladder). No study-related adverse events were observed within 1 y of follow-up (Supplemental Table 2).

Feasibility of 111In-PSMA-I&T RGS: Peroperative Detection of 18F-PSMA PET–Suggestive Lesions

Twenty-nine of the 49 RGS-target lesions (59%) were identified with the γ-probe (in vivo or ex vivo), and successful removal was confirmed (Table 3). Of those, 28 LNs (97%) contained LNMs, with a mean size of 7.9 mm (range, 0.8–20.0 mm). One LN peroperatively measured an absolute count of 15 cps ex vivo yet was confirmed benign after complete sectioning. This 24-mm LN correlated with an RGS-target lesion with a level of suspicion of 3. Fourteen (of 49; 29%) RGS-target lesions could not be detected peroperatively, whereas postoperative imaging concluded successful surgical removal. Of those 14 LNs, 2 (14%) contained LNMs, both of which were no larger than 3 mm and were mild to moderate in PSMA expression. Those LNMs were matched on the basis of corresponding anatomic regions. The remaining 6 (of 49; 12%) RGS-target lesions could not be detected by PSMA RGS and were still visible and suggestive on postoperative 18F-PSMA PET/CT. Those lesions were located in surgically challenging regions (deep internal iliac regions and presacral regions).

View this table:
TABLE 3.

Peroperative γ-Probe Detection (In Vivo and Ex Vivo) and Characteristics of RGS-Target Lesions

Figure 2 depicts the in vivo and ex vivo LBRs of the RGS-target lesions. The in vivo and ex vivo median LBRs of detected RGS-target lesions (i.e., irrespective of histopathology) were 2.05 (IQR, 1.2–3.0) and 36 (IQR, 3.8–71), respectively (P = 0.0004). An overview of background measurements is provided in Supplemental Table 3.

FIGURE 2.
FIGURE 2.

In vivo and ex vivo LBRs of RGS-target lesions and comparison (unpaired t test) between in vivo and ex vivo ratios. Identification of RGS-target lesions during procedure was based on anatomic landmarks as indicated by preoperative imaging. To calculate LBR, maximum counts per second of identified RGS-target lesions were measured and divided by background counts per second both in vivo (A) and ex vivo (B). RGS-target lesion was considered γ-probe–positive if LBR > 2 in vivo or maximum counts per second ≥ 10 ex vivo. Results depicted in both A and B describe peroperative measurements, irrespective of histopathologic conclusions. ***P = 0.0004.

Secondary Outcomes

111In-PSMA RGS: Concordance Between Peroperative γ-Probe Findings and Histopathology

111In-PSMA RGS identified 2 lesions with increased counts per second that did not correlate with RGS-target lesions. Both contained LNMs on final histopathology (>3 mm and strong PSMA expression). Furthermore, histopathology identified 13 LNMs that were not identified on preoperative imaging or during 111In-PSMA RGS. These LNs were located at anatomic levels different from those of potentially missed RGS-target lesions. The mean size of those LNMs was 2.2 mm (range, 0.5–5.5 mm), and they showed strong, moderate, and no PSMA expression in 8 (62%), 4 (31%), and 1 (8%) cases, respectively.

The sensitivity, specificity, positive predictive value, and negative predictive value of 111In-PSMA RGS (in vivo and ex vivo combined) compared with histopathology on a per-lesion analysis were 66.7%, 99.8%, 96.8%, and 97.0%, respectively. The in vivo median TBR of LNMs was 2.3 (IQR, 1.3–3.1). The ex vivo median TBR of LNMs and benign LNs were 42 (IQR, 1.1–71) and 0 (IQR, 0.0–0.0), respectively (P = 0.0002) (Fig. 3).

FIGURE 3.
FIGURE 3.

Comparison of ex vivo TBRs between histopathologically proven metastatic LNs and nonmetastatic LNs (unpaired t test). To calculate TBR, maximum counts per second of all resected LNs were measured and divided by background counts per second. Results depicted in this figure are thus irrespective of whether lesion was RGS-target lesion. ***P = 0.0002.

Oncologic Outcomes and Follow-up

Although not part of the primary aim of this study, a description of oncologic outcomes and treatment strategies per patient up to 1 y is provided in Supplemental Table 4. A distinction was made between patients undergoing robot-assisted radical prostatectomy plus ePLND (n = 11) and patients undergoing ePLND before radiotherapy (n = 9). Of the 11 patients undergoing robot-assisted radical prostatectomy plus ePLND, 8 were staged pN1, yet 5 of those patients had undetectable PSA levels at 6 wk after surgery, of whom 2 patients eventually demonstrated biochemical recurrence, both 9 mo after surgery. The other 3 patients remained free of biochemical recurrence during 1 y of follow-up. Eight of 9 patients who underwent ePLND before radiotherapy were staged pN1, and all 8 received adjuvant radiotherapy to the pelvis and concomitant androgen deprivation therapy.

DISCUSSION

Whereas thus far the potential of PSMA RGS has been evaluated mainly for PCa patients undergoing salvage surgery for nodal recurrences, evidence regarding its feasibility in the primary setting is scarce. During ePLND in primary intermediate- and high-risk PCa patients, removal of PSMA PET–suggestive lesions is most likely to determine the presence of LNM. With this aim, 111In-PSMA RGS was evaluated in this phase I/II study on newly diagnosed PCa patients and showed that the administration of 111In-PSMA-I&T is safe and facilitates peroperative detection of 18F-PSMA PET–suggestive lesions. Overall, 88% of 18F-PSMA PET–suggestive RGS-target lesions were successfully removed. 111In-PSMA RGS facilitated peroperative identification of 59% of RGS-target lesions but missed 29% within the ePLND template. Successfully detected RGS-target lesions contained LNMs in 97% of cases, whereas the incidence of LNMs in the nondetected RGS-target lesions was considerably lower (14%). The critical role of patient selection for the PSMA RGS procedure is underlined by the fact that the majority (64%) of the surgically nondetected RGS-target lesions were level-of-suspicion 3 on preoperative 18F-PSMA PET/CT.

Another important finding from this study is the difference between in vivo and ex vivo performance of the γ-probe (Figs. 2 and 3), a finding that was also reported in previous series (14,20,21). The limited TBR in vivo is likely due to interfering physiologic tracer accumulation in the surrounding organs (i.e., the intestines, ureters, bladder, vasculature, and primary prostate tumor) (Supplemental Table 3); a longer interval between tracer administration and surgery could hypothetically improve TBR. As a result, γ-probe measurements in vivo are sensitive to the orientation toward an RGS-target lesion in relation to its surroundings (22).

Two series investigating PSMA RGS in the primary setting based feasibility on the diagnostic accuracy of probe measurements compared with histopathology (20,21). In the current study, accuracy of 111In-PSMA RGS was assessed as a secondary outcome. When our results are being compared with those series, the use of different tracers, incubation times, and γ-probes has to be kept in mind. Gondoputro et al. (20) reported a higher sensitivity (76%) and positive predictive value (89%) than we did, but they used a lower threshold for PSMA RGS positivity (LBR > 1.5, vs. 2 in our study). Preliminary results of Gandaglia et al. (21) were similar to our results (sensitivity, specificity, positive predictive value, and negative predictive value of 63%, 99%, 83%, and 96%, respectively).

From a clinical perspective, we focused specifically on 18F-PSMA PET–suggestive LNs, and the primary objective was to detect those lesions during 111In-PSMA RGS, irrespective of histopathologic results. A similar objective was recently described by Lunger et al. (23), who reported that PSMA RGS successfully facilitated resection of 70 of 78 (90%) 18F-PSMA PET–suggestive lesions in 35 patients. Of note, the reported SUVmax for 18F-PSMA PET–suggestive target lesions was considerably higher than in our series. Moreover, in our study postoperative imaging was applied in all patients to assess LN removal, whereas in the other studies postoperative imaging was not systematically applied and conclusions regarding LN removal were drawn indirectly on the basis of postoperative PSA levels only. Furthermore, resected 111In-PSMA RGS–suggestive lesions were marked during the procedure to ensure correlation between PSMA RGS findings and pathology on a node-to-node level. This more reliably indicates successful removal of specific lesions and justifies lesion-specific conclusions.

Most PSMA RGS feasibility studies (including ours) equally report the presence of additional microscopic LNMs found by histopathology that were missed by both 18F-PSMA PET/CT and PSMA RGS (13,20,21). This suggests that PSMA RGS, like PSMA PET/CT (24), underestimates the nodal burden in miN1 patients and that, at this point, sensitivity is not yet sufficient to facilitate omission of routine ePLND. However, some technical aspects that affect tracer retention in target tissue and interfering background tissue (e.g., optimal tracer dose and incubation time) could be further optimized to improve LBRs (25). At the same time, the high specificity of PSMA RGS regarding suggestive lesions, especially ex vivo, justifies use of the technique to directly confirm successful removal of suggestive lesions. Negative findings on ex vivo γ-probe measurements should trigger surgeons toward more extensive resection, especially in PSMA PET–suggestive regions. Furthermore, our results strengthen the suggestion as proposed by Gandaglia et al. (21) and Gondoputro et al. (20) that PSMA RGS in the primary setting is likely most productive for PSMA PET–suggestive lesions. This endorses the in vivo utility of PSMA RGS specifically to detect PMSA-avid LNs outside the standard ePLND template or in surgically challenging regions (e.g., pararectal and presacral), aiming to identify LNMs that would have been missed otherwise. Whether improved peroperative detection and resection of suggestive LNs using 111In-PSMA RGS leads to superior oncologic outcomes has yet to be determined by prospective trials.

Limitations of our study comprise the limited cohort size, which included both patients treated with ePLND combined with robot-assisted radical prostatectomy and patients treated with PLND only. In this proof-of-concept evaluation, our endpoint was defined as successful removal of suggestive lesions, whereas oncologic outcomes are more significant and should be considered in future prospective trials. Ideally, a comparison with standard-of-care ePLND should be made.

CONCLUSION

111In-PSMA RGS is a safe procedure that aids peroperative detection of lesions identified as suggestive on preoperative 18F-PSMA PET/CT in newly diagnosed PCa patients. This image-guided approach to detecting potential LNMs at ePLND may potentially improve nodal staging.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.

KEY POINTS

QUESTION: Is PSMA RGS feasible and safe in primary PCa with suggestive nodes on PSMA PET/CT?

PERTINENT FINDINGS: PSMA RGS facilitated peroperative identification and resection of 59% of PSMA PET–suggestive lesions, of which 97% contained LNMs in a total of 20 PCa patients. Only 2 metastases were found in 18F-PSMA PET–suggestive lesions that were not detected by PSMA RGS.

IMPLICATIONS FOR PATIENT CARE: PSMA RGS may improve nodal staging by peroperative identification and confirmation of successful removal of PSMA PET–suggestive lesions.

Footnotes

  • Published online Jan. 4, 2024.

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  • Received for publication August 10, 2023.
  • Accepted for publication November 7, 2023.
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