European Nuclear Medicine Guide
The range of applications wherein iMI is having clinical impact is increasing. There are a significant development in the design of optical- (e.g., fluorescence, Cherenkov, optoacoustics, Raman) and radionuclide-based (e.g., gamma rays and beta particle-based) agents [26].
99mTc (140 keV) and, to a lesser extent, 111In (gamma rays with photon energies of 171 and 245 keV) have been established as the most favorable radioisotopes for clinical use in i.e. radioguided surgery applications for sentinel nodes, somatostatin receptor overexpressing lesions and prostate specific membrane antigen (PSMA) expressing lesions. Recent examples of implemented agents are [99mTc]Tc-PSMA-I&S, (ICG-)[99mTc]Tc-nanocolloid and [111In]In-octreotide] [27-30].
The ability to preoperatively detect and quantify radioactivity using non-invasive scintigraphy, i.e., using SPECT or PET, is complemented by the ability of (gantry-based or gantry-free) identification of radiopharmaceuticals during the intervention. In fact, one could state that the effective penetration of radiation through tissue sets iNM apart from the other main interventional molecular imaging strategies, namely fluorescence-guided surgery [27]. The tissue penetration of the radiopharmaceutical provides the operating surgeon with in-depth radioguidance towards the lesions of interest, while fluorescence is optimally applied in superficial applications (detection of lesions located < 1cm deep in tissue) [31].
Despite its limitations, fluorescence is often pursued as an intraoperative detection method as it does not expose the patient to ionizing radiation. However, low energy gamma-emitting radionuclides such as 99mTc, only provide a negligible effective dose to both patient and surgical staff. The exposure, however, increases when using mid-energy radionuclides (e.g., 111In) or even high-energy positron-emitting radionuclides (e.g. 18F, 68Ga). When these are used, the occupational exposure to the surgical staff can limit the number of procedures that can be performed on a yearly basis. For instance, the skin dose rate from a 5-mL syringe containing 1 GBq of 68Ga is approximately 8.7 mSv/s [109], indicating that the annual skin dose limit of 500 mSv could be reached in less than a minute of contact without adequate protection. Effective protective measures such as shielding and maintaining distance are challenging and impractical to implement within the operating room. However, reduction of the administered activity for use in RGS (approximately 30 MBq) compared to the activity that is applied for preoperative PET imaging (150-350 MBq, dependent on the target tissue) is a viable option to minimize exposure for β+-emitters can help maintain safety standards. The patient’s effective dose for [99mTc]Tc-nanocolloids is 1.2-2.0 µSv/MBq, that corresponds to 0.04 mSv after an injection of 20 MBq of [99mTc]Tc-nanocolloid. Estimates of exposures to surgeons and pathologists have been reported, ranging from 0.37 to 0.56 mSv/year (in a workload of 100 patients) [7, 32].
In the current era of precision medicine, the magic words are “targeted tracers”, and the same is true for iNM. Targeted tracer surgery is an evolving technique within iNM that uses radiopharmaceuticals (targeted tracers) to enhance the intraoperative visualization of tumors and metastatic lesions. These radiolabeled tracers bind specifically to tumor-associated biomarkers, facilitating real-time or ex vivo identification of malignant tissues during surgery. The goal is precise delineation of primary tumor margins, accurate local recurrence detection, and complete surgical resection.
Clinical applications have been reported in parathyroid surgery ([99mTc]Tc-MIBI), radioiodine uptake in recurrences/metastases from differentiated thyroid carcinoma (123I), receptor-mediated uptake of radiolabelled agents by tumours such a neuroendocrine tumours or paragangliomas (99mTc or 111In labelled-pentetreotide), accumulation of bone-seeking agents for radioguided excision of isolated bone metastasis ([99mTc]Tc-HDP) or in lymphatic metastases and local recurrences in prostate cancer ([99mTc]Tc-PSMA I&S) [33-37].
In recent years, there has been a renewed interest on the use of beta emitters such as the therapeutic radionuclides 90Y and 166Ho for image-guided radioablation and traditional PET tracers for surgical guidance, e.g. 2-[18F]FDG, [68Ga]Ga-DOTA-TATE or [68Ga]Ga/[18F]F-PSMA-ligands [38].
In addition, new approaches are being used that are based on pairing PET and SPECT tracers for preoperative PET/CT detection and intraoperative standard low-energy gamma detection techniques. Here huge successes have been obtained in PSMA targeted surgery by combining e.g. [68Ga]Ga-PSMA-11 and [99mTc]Tc- or [111In]In-PSMA-I&S in prostate cancer patients for regional lymph node resection and local recurrences. Recent advances in drop-in gamma and beta probes further expand the utility of these tracers [44-49].
Ex vivo specimen scanning has been used to expand tissue assessment in the operating room, by allowing detailed assessment of margins and evaluation of whether residual tumor remains in the surgical bed. Tracer uptake can be detected using the same detection devices as used intraoperatively, but this set-up also provides the opportunity to evaluate novel approaches such as an intraoperative PET/CT device or freehand SPECT combined with 3D Lidar scanning. Imaging data can be relayed back to the operating surgeon, potentially guiding further resection [14, 39-43].
Hybrid radiopharmaceuticals that incorporate both a radio- and fluorescent label are increasingly being explored to support best-of-both-worlds iNM guidance strategies. The major asset of fluorescence imaging using e.g., the fluorescent dyes Fluorescein or Indocyanine green (ICG) is the capability to accommodate the surgeon's desire to optically identify the lesions in real‐time. Compared to radioguidance, fluorescence‐guidance has a spatial resolution that could even be detectable down to the microscopic level, but detection is limited to lesions located <1cm beneath the tissue surface due to tissue attenuation. However, the visual feedback provided by fluorescence could particularly be valuable when investigating margins. A widely used example of effective incorporation of fluorophores into radiopharmaceuticals is the hybrid SLN tracer ICG-[99mTc]Tc-nanocolloid [26]. Targeted hybrid tracers are currently being developed and translated towards the clinical setting [50, 51]. When using a hybrid tracers that includes both a radio- and fluorescent-imaging label the benefits of fluorescence imaging can be aligned with preoperative imaging roadmaps and approaches that help provide in depth target detection during surgery such as navigation, gamma-probe tracing, and gamma-imaging (mobile gamma-camera or freehand SPECT). Both fluorescent and radioactive signals can both be detected in ex vivo tissue specimens, but the resolution with which they can be detected will vary [26, 51-54].