In this study the first steps are made towards integration of beta radioguided surgery within the robot-assisted setting. Using the DROP-IN concept, the surgeon has full control of probe placement, yielding autonomy and great maneuverability during radioguidance (8–11). Direct beta detection provides, thanks to its specificity and sensitivity, a useful way to probe prostate margins and suspect lymph nodes.
This initial ex vivo validation of the DROP-INβ probe concept showed a high signal to background (> 5) for tumors located < 1 mm from the resected surface, suggesting that the technique has the potential to support robotic surface scanning of primary tumor margins in prostate cancer. Even more precise characterization of the possible lesion depth with respect to the surgical margin might be possible with future developments in the underlying detection software algorithms (24). In addition, confirming PSMA-positive lymph nodes (S/B > 3), the DROP-INβ probe concept might also support the intraoperative identification of metastatic lymph nodes.
Compared to the previously reported use of a DROP-INγ probe in combination with the tracer [99Tc]Tc-PSMA-I&S (i.e. salvage procedures for lymphatic metastases) (10), the use of a DROP-INβ probe in combination with [68Ga]Ga-PSMA-11 possesses some unique advantages. First of all, this approach supports the use of more widely available PET tracers. Secondly, the limited tissue penetration of β particles (only a few mm’s) allows for an accurate surface scanning of the primary tumor margins (12), thus highlighting possible tumor localizations on the prostate surface. Indeed, in the current study beta radiation was severely attenuated when > 1.5 mm of healthy tissue was located between the surface of the prostate specimen and the pathological tumor margins. In this sense, β-tracing benefits from similar positive features as fluorescence imaging (25): i.e. no ‘shine-through’ of neighboring or deeper lying tracer-uptake and a superior spatial resolution (12,26). These features are essential when the extracapsular spread of PSMA-overexpressing tumor lesions is pursued in a prostate with (significant) default PSMA-expression (27). Consequently, β-tracing could provide a superior means for margin assessment during e.g. nerve sparing surgery (28,29). Alternative to investigated beta-radiation detection for tumor margin assessment on the prostate surface, fully matured ex vivo technologies are available (e.g. NeuroSAFE (30)) and alternative β-emission based imaging technologies are being explored (e.g. Cerenkov (22)). Future research, and in particular randomized trials, will have to show which technology is superior, or if different technologies can work in synergy.
Potential limitations of the proposed [68Ga]Ga-PSMA-11 guided surgery concept are the radiation dose for the surgical staff (currently limited to about 62 procedures a year) and the contamination of the prostate margins by tracer containing urine. The DROP-INβ probes ability to detect lesions using < 70 MBq doses helps limit the exposure of the surgical staff. It is worth highlighting in particular that injecting the radiotracer directly in the operating room allowed ex vivo examination after ~ 2.5xt1/2 (3 h, t1/2 = 68 m). Hence future in vivo application e.g. 1 h p.i. would allow an even lower activity to be used to achieve a similar detection sensitivity, namely of the order of 40 MBq. Regarding the urine contamination of the samples, as stated previously, the accumulation of PSMA tracers in healthy organs and in particular urine may yield background signals that complicate intraoperative margin detection (20). However, the direct detection of beta particles performed with a detector substantially transparent to gamma rays, as suggested in this paper, should drastically reduce the impact of such a background; only the signal originating from few millimeters around the detector should be detected (i.e. thus only a small urine layer must be considered (24,31)). Nonetheless, acknowledgement of this effect by radiochemists (32,33) and the reduced renal clearance of for example [18F]F-PSMA tracers (34,35) may in the future help to overcome these issues. In addition, the influence of renal clearance might also be overcome by using β-emitting isotopes that have a longer half-life, allowing the tumor resection to take place after all renal clearance of non-bound tracer is realized, e.g. using alternative PET isotopes such as 64Cu (t1/2 = 12.7 hours), or even theranostic isotopes such as 67Cu (t1/2 = 2.5 days), 90Y (t1/2 = 2.66 days) or 177Lu (t1/2 = 6.6 days) (36,37).