99mTc-labelled PSMA ligand for radio-guided surgery in nodal metastatic prostate cancer: proof of principle

Abstract

Purpose Intraoperative identification of prostate cancer (PCa) lymph node (LN) metastases (LNM) detected by preoperative PSMA PET/CT may be facilitated by PSMA radio-guided surgery (RGS) with use of a γ-probe. Earlier we demonstrated excellent performance of the 111In-labelled PSMA ligand DKFZ-617 ([111In]In-PSMA-617) in RGS for ex situ distinction of LN vs LNM at lymphadenectomy (LA) at a single LN level. In comparison with indium-111, technetium-99m has better physical properties for γ-probe measurements, better availability and lower radiation exposure for patients and medical personnel. Against this background, we evaluated the uptake of 99mTc-PSMA-I&S ligand at the level of single LN and its power to discriminate between unaffected LN and LNM. Methods Six patients with PCa with the suspicion of LNM on preoperative PSMA-PET/CT underwent [99mTc]Tc-PSMA-I&S RGS (4 salvage LA, 2 primary LA) with intravenous injection of [99mTc]Tc-PSMA-I&S 24 h prior to surgery. Resected samples were isolated manually aiming at the level of single LN. Uptake measurements were done ex situ with a high-purity germanium detector. Receiver operating characteristic (ROC) analysis was performed based on [99mTc]Tc-PSMA-I&S uptake expressed as lean body mass standard uptake value (SUL). Results Separation of the tissue samples from 73 subregions resulted in 498 single samples. After final histopathology 356 LN, 160 LNM und 11 non-nodal PCa samples were identified. Median SUL of tumor-free samples (0.26) and samples with cancer (3.5) was significantly different (p < 0.0001). ROC analysis revealed an area under the curve (AUC) of 0.917 (95% CI 0.89–0.95). Using a SUL cutoff of 1.1, sensitivity, specificity, positive predictive value, and negative predictive values were 76.6%, 94.4%, 89.4% and 86.9%. Conclusion Ex situ analysis of [99mTc]Tc-PSMA-I&S uptake at single LN level showed good diagnostic performance for the ex situ distinction of tumor-bearing vs tumor-free LN during RGS.

Synthesis and preclinical evaluation of novel 99mTc-labeled PSMA ligands for radioguided surgery of prostate cancer

“…However, RGS is performed around 20–24 h p.i. in patients [ 13 , 19 , 36 ] and, based on the rule of thumb of approximately fourfold faster metabolism in mice compared to men, we chose a distribution time of 6 h to simulate TBR at the time of surgery as accurately as possible. In that context, our preclinical findings on the in vivo performance of [ 99m Tc]Tc-N4-PSMA ligands represent a remarkable development.…”

“…While similar high uptake in LNCaP-xenografts was observed at 6 h p.i., the clearance of the novel ligands from most background tissue was significantly improved compared to [ 99m Tc]Tc-PSMA-I&S. In addition, drastically and favorably reduced kidney retention compared to [ 99m Tc]Tc-PSMA-I&S was found to be a common feature of the new ligands, which can probably be attributed to their shared molecular scaffold derived from rhPSMA-compounds [ 23 , 24 ], while being pronounced by the use of the hydrolyzed SiFA moiety. This finding is of particular interest, as high renal activity accumulation may interfere with accurate lesion detection during RGS [ 36 ]. Nevertheless, clinical studies are necessary to validate whether our preclinical findings also apply to the human situation.…”

Extra‐peritoneal oligometastatic renal cell carcinoma: atypical pattern of metastasis and novel localization techniques

“…7 Additionally, modalities which improve detection of metastatic lymph nodes in RCC are required, with figures in the current literature of CT accuracy being as low as 60% 8 and PSMA PET/CT may therefore prove to be useful in this context. Furthermore, PSMA-based radioguided surgery for nodal metastasis has demonstrated promising evidence in prostate cancer, 9,10 which may extend to RCC nodal metastases.…”

PSMA-PET und „radio-guided surgery“ bei zervikaler Lymphadenektomie

“…Für die "PSMA-radio-guided surgery" von abdominellen und pelvinen Lymphknotenmetastasen bei Prostatakarzinomrezidiven existieren bereits vielversprechende Ergebnisse bezüglich der Metastasendetektion [6,7]. Maurer et al konnten intraoperativ zwischen tumorinfiltrierten und gesunden Lymphknoten unterscheiden (Sensitivität 83,6 %; Spezifität 100 %), gefolgt von einer vollständigen Entfernung aller im präoperativen PSMA-PET detektierten Läsionen [5].…”