Abstract
Radioguided surgery (RGS) allows a surgeon to intraoperatively identify the lesions of interest. This technique relies on the accumulation of a radiotracer in the lesion(s) of interest. Such accumulation can occur via the local administration of the radiotracer, followed by local staining or passive drainage via the lymphatic system, or can occur via the systemic administration followed by retention or targeted accumulation of the radiotracer. The range of radiotracers applied in RGS varies from the radioactive isotope itself, to small molecules, peptides, antibodies, and colloids. The choice of the radionuclide depends on various factors, such as half-life, desired radiation type and energy, and (chemical) means to attach it to an active entity. An often overlooked factor is the radiation burden for the patient and the medical personnel. The introduction of optical imaging technologies, such as fluorescence and Cherenkov imaging, expands the utility of RGS.
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Keywords
- Sentinel Lymph Node
- Sentinel Lymph Node Biopsy
- Positron Emission Tomography Imaging
- Neuroendocrine Tumor
- Medical Personnel
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
1 Introduction
The concept of radioguided surgery (RGS) can provide the operating specialist with information regarding the location and margins of target lesions during surgery and as such can help improve the accuracy of the surgical procedure (Fig. 5.1). RGS requires two things: (1) the availability of a tracer emitting a nuclear signal (possibly accompanied by and optical signal) that accumulates at the site of interest and (2) (portable) detectors that can detect the tracers nuclear signal, thereby providing the surgeon with acoustic or visual feedback regarding its location. Fully integrated whole body preoperative (nuclear) imaging and intraoperative RGS using the same radiotracer (single injection) is the most superior way to perform RGS as it allows the nuclear medicine physician and surgeon to jointly generate a (virtual) roadmap regarding the location of the lesions, thereby also enabling the identification of unexpected lesions at distant locations (Fig. 5.1). During the intervention, radioguidance, possibly in combination with an optical component, can provide the surgeon with real-time information regarding the location of the lesions and helps confirm accurate lesion resection. In combination with state-of-the-art navigation equipment, the preoperative nuclear information can provide additional (virtual) intraoperative guidance to improve RGS (Fig. 5.1) [1]. The technical approach and the detectors required for RGS will be discussed in further chapters.
Schematic representation of the possibilities with radio- and hybrid tracers
This chapter discusses the radio- and hybrid tracers applied in the field of RGS. Hereby we only focus on tracers that have been used in a clinical setting.
2 General Categories and Routes of Administration for Radiotracers
The radiotracers applied in RGS can roughly be divided into four general categories: (1) radiocolloids (Fig. 5.2), (2) small molecules (Fig. 5.3), (3) peptides (Fig. 5.4), and (4) antibodies and antibody fragments (Fig. 5.5). Radiotracers can be administered locally, e.g., when using a radiocolloid for sentinel lymph node (SLN) biopsy, or intravenously, e.g., when using targeted antibodies.
Radiocolloids applied in RGS
Small-molecule radiotracers applied in RGS
Peptide-based radiotracers applied in RGS
Radiolabeled antibodies and antibody fragments applied in RIGS
2.1 Local Administration
The most widespread application of RGS is the SLN biopsy procedure. For this application, radiolabeled colloid particles (Fig. 5.2) are injected into or directly surrounding the primary tumor, from which they drain via the local lymphatic pathways to the SLN(s). These lymph nodes can then be removed via RGS to be examined at pathology for the presence of metastases. Although the mechanism may differ, upon reaching the SLN(s), these radiocolloids become entrapped via interaction with macrophages and histiocytes lining the sinuses of the nodes [2]. In SLN identification applications, movement of the tracer to the SLN is a physical phenomenon driven by lymphatic flow. Hence, when the lymphatic flow is abundant, e.g., following the injection of a large volume of tracer, saturation of the SLN can occur, leading to overflow into higher-echelon nodes. This effect is similar to pouring a bottle of champagne on a pyramid of champagne glasses. Initially only the first glass will fill up, but when more champagne is added, eventually all glasses will fill up. However, when the injected volume is limited and the SLN procedure is combined with dynamic imaging, retention of radiocolloid allows for accurate identification of the SLN(s).
For the radioguidance toward the sentinel lymph node in SLN biopsies in various cancer types, 99mTc-labeled radiocolloids are widely applied (Fig. 5.2). Radiocolloid labeling occurs via the complexation of 99mTc via various donor atoms in the colloids. The size of the colloidal particles is probably the most important variable and determines the tracer dynamics. Particles with a diameter above 500 nm show very limited drainage via the lymphatic system [3]. On the other side, particles between 5 and 12 nm can penetrate the capillary membranes and rapidly migrate through the lymphatic system and thus require targeting mechanisms using, e.g., mannose to be retained in the SLN [4–6]. Obviously here the chance of overflow to higher-echelon nodes is greatest. Medium-sized colloidal particles ranging between 10 and 200 nm are reported to show the best balance between drainage kinetics via the lymphatics and retention in the SLN(s) [2, 7]. An overview of the different SLN tracers and their sizes has been provided by van den Berg et al. [8].
A local injection, guided by ultrasound or X-ray imaging, with, e.g., (large) 99mTc-labeled colloidal particles, can also be used to mark non-palpable (breast) tumors, essentially providing temporary radioactivity–based tattoos. This approach was shown a valid alternative to wire-guided localization (WGL), in which a hooked wire is placed preoperatively to locate the tumor during surgery [9]. The procedure that applies radioactive signatures of a radiocolloid to intraoperatively excise the tumors under RGS is called radioguided occult lesion localization (ROLL) [10]. A similar procedure, where a radioactive titanium seed is placed to locate the tumor, is called radioguided seed localization (RSL). If this procedure is performed with a radiolabeled colloidal particle that also drains to the SLN(s), ROLL can be combined with a SLN biopsy procedure, which has been named sentinel node and occult lesion localization (SNOLL) [10, 11].
2.2 Intravenous Administration
The class of small molecule-based radiotracers is the oldest and most diverse class of tracer used in medicine. It consists of radiolabeled molecules mimicking hormones, such as metaiodobenzylguanidine (MIBG) [12]; amino acids, such as 3,4-dihydroxyphenylalanine (DOPA) [13], glucose, such as fluorodeoxyglucose (FDG) [14]; and mimicking building blocks, such as bisphosphonates (Fig. 5.3) [15]. In general these tracers are widely available and/or easy to prepare locally. After distribution through the patients’ venous system, these tracers show increased uptake in diseased areas based on the increased metabolism and/or increased proliferation of malignant cells in comparison to healthy tissue.
Although somewhat larger than the small molecules, the relatively small size of receptor targeting peptides (Fig. 5.4) means that they have favorable kinetics. Since they can be produced synthetically, this class of compounds is relatively cheap compared to, e.g., antibodies. Moreover, the variety in which peptide sequences can be produced, and thus the variety of receptors that can potentially be targeted using such compounds, is endless.To introduce a radionuclide in peptide tracers, in most tracers a bifunctional linker is introduced (Fig. 5.4). Such a bifunctional linker consists of donor atoms or groups that can form a complex with the radionuclide and a reactive group to allow conjugation to the targeting peptide. The introduction of the isotope can be performed just before applying the radiotracer. Generally receptor targeted peptides are injected intravenously to allow distribution via the blood circulation and finally targeting of a disease specific receptor.
In radioimmunoguided surgery (RIGS), radiolabeled antibodies or antibody fragments (Fig. 5.5) are used to target receptor molecules expressed on the lesion(s) of interest. Such antibodies are raised against a specific biomarker that is overexpressed in certain malignancies. The advantages of using an antibody as targeting moiety are their high specificity, affinity, and avidity for the biomarker it has been raised against. Conversely, nonspecific uptake in organs such as the liver and spleen may increase the radiation burden for the patient. At the same time, long circulation times of antibodies demand a long time interval between administration and imaging and/or RIGS. This interval can vary significantly from 2 to 24 days to allow sufficient clearance of unbound antibodies [16–18]. Several options are available to deal with the circulation times: (1) use of isotopes with a long half-life such as 89Zr, 111In, or 125I, to ensure the presence of a radioactive signal after multiple days; (2) pretargeting, which is the use of a reactive or bivalent antibody, followed after a couple of days with the (reactive) radioisotope [19, 20]; and (3) use antibody fragments that show an increased clearance rate [21]. To introduce a radionuclide in the antibodies, three options are available. Either the radionuclide is complexed by donor atoms of the antibody itself (e.g., 99mTc) via covalent conjugation to amino acids in the antibody (e.g., 125I) or via the before mentioned bifunctional linkers (e.g., 111In) (Fig. 5.5).
To accommodate an additional optical signal, any one of the above tracer types may be converted into hybrid entities that include dyes [22]. Alternatively, the generation of Cherenkov light by beta-emitting isotopes can also enable optical guidance [23].
3 Radionuclides
Numerous radionuclides are available, or can be produced, for applications in nuclear imaging, RGS, radiotherapy, or combinations hereof. The choice for the (ideal) radionuclide is based on the availability of the radionuclide and the application for which it will be used. Ideally, a balance between the clinical demands (e.g., half-life, radiation type, radiation energy) and the ability to (chemically) attach the radionuclide to the tracer is found. Table 5.1 contains the physical characteristics of the radionuclides applied in RGS to date.
For the selection of an isotope, radiation exposure of the patient and the medical personnel is also a major factor that needs to be taken into account. Not only is it necessary that the (long-term) benefits for the patient outweigh the possible side effects of radiation exposure, the dose received by the surgical staff during the intervention may also limit the amount of procedures that they can perform on a yearly basis. Table 5.2 contains the range of radiation doses both patients and medical personnel receive upon a RGS procedure with a certain radionuclide. Although this table shows the upper limits and possibly overestimates the dose, it clearly illustrates the differences between various radionuclides.
The patient dose clearly increases upon increased gamma-radiation energy (0.94 mSv for 100 MBq 99mTc compared to 8.1 mSv for 111In) or by applying β-particle emitting isotopes (7.0 mSv for 370 MBq 18F and 13 Sv for 550 MBq 131I). The patient dose is generally justified by the benefits the patient obtains from accurate imaging, radiation therapy (e.g., 131I), and/or RGS. Nevertheless, the choice for the radionuclide should be made carefully. For instance, the choice for applying 89Zr results in a considerable radiation dose (22.2 mSv for 37 MBq 89Zr). Radionuclides emitting β−-particles only show a high radiation burden for the patient, because this radiation has a very limited penetration. Radionuclides emitting β+-particles and gamma-emission also generate a radiation burden for the medical personnel.
The radiation dose received by the medical personnel, e.g., the surgeon and the OR personnel, upon RGS, also deserves careful consideration. In contrast to the justification for the patient, medical personnel has no obvious benefit from the chosen procedure or radionuclide used during the procedure except for achieving an accurate resection. Nevertheless during the, generally long, surgical procedures (multiple hours), they stand in close proximity to the patient and expose themselves to the tracer-based radiation. Based on the level of training, medical personnel is allowed to be exposed to certain levels of radiation, generally divided in maximum exposures of 20, 5, and 1 mSv per year; general surgeons and OR personnel belong to the last group. Because these values represent the upper limits of radiation exposure that is legally allowed, this may influence the amount of procedures that can be performed on a yearly basis. For example, RGS with 18F (370 MBq at 1 h postinjection) results in 35 μSv.h−1. This means that personnel not trained in radiation hygiene can only be present at the operation table for 29 h a year (Table 5.2). An average operation to remove malignant lesions takes 4 h, which means that this person can only perform/attend seven procedures a year. A similar procedure with 99mTc (100 MBq at 1 h postinjection) allows untrained personnel to attend 129 4-h procedures per year (Table 5.2). An important factor in these calculations is the half-life of the isotope used and the time between injection and the RGS procedure. When the accumulation of the radiotracer allows a longer time between injection and RGS, a large reduction in the radiation exposure for medical personnel can be obtained (Table 5.2). This said, often a strong signal is required during surgery to allow for RGS.
3.1 Gamma-Radiation
The workhorses of nuclear medicine, and in particular RGS, are radionuclides that emit γ-photons (Fig. 5.6). Gamma-emitting radionuclides allow whole body imaging using planar scintigraphy and/or single-photon emission tomography (SPECT). Especially isotopes that emit low-to-medium energy (27–245 KeV) photons, such as 99mTc, 111In, and 125I, have been widely used for RGS. Reasons for their popularity are: (1) availability, (2) compatibility with clinically available gamma detectors, (3) well-developed (chemical) procedures for introducing these nuclides into radiotracers, and (4) energy-dependent tissue attenuation. A high-energy γ-emitter has a higher tissue penetration, improving the accuracy of preoperative imaging, but also results in a higher chance of background signals during RGS. Furthermore, high-energy γ-emissions demand a thickly shielded detector to improve the spatial resolution. The combination of low-to-medium energy photon emission with a short-to-medium half-life of the radionuclide results in a limited radiation burden for both the patient and medical personnel.
Application of γ-emitters in RGS. (i) Whole body nuclear imaging by SPECT; (ii) intraoperative gamma tracing with acoustic gamma probe; (iii) intraoperative gamma imaging with gamma camera; (iv) virtual navigation based on preoperative SPECT imaging or intraoperative freehand γ-detection
3.1.1 99m-Technetium
By far the most widely applied and available radioisotope is 99mTc. 99mTc has a half-life of 6 h and emits γ-photons of 141 keV, which is in the ideal range (100–200 KeV) for γ-detection by commercially available detectors. Due to this medium energy γ-radiation, the radiation burden for both patient and medical personnel is relatively low (Table 5.2). Pertechnetate (99mTcO4 −) can be collected from 99Mo/99mTc generators by elution with saline and there is a range of possibilities for conjugation of this isotope to generate the desired radiotracers [37, 38]. Labeling of most 99mTc-based radiotracers is performed by reducing the pertechnetate obtained from the generator with Sn(II)-based reducing agents in the presence of the coordinating agent of choice. Technetium can be stabilized through coordination to several donor atoms, e.g., N, O, P, S, and As [38]. Direct metal coordination can be achieved by small molecules that form the radiotracer together with 99mTc (such as hexakis-2-methoxy-2-methyl-isonitrile complex (MIBI) (Fig. 5.3)) [39], or it can be the functional part of a peptide, protein, or inorganic tracer itself (such as 99mTc-UBI29–41 [40], 99mTc-nanocolloid, and 99mTc-sulfur colloid (Fig. 5.2) [30, 41]). Other than direct metal coordination, metal coordination can also occur through bifunctional chelates, for example, by applying hydrazinonicotinic acid (HYNIC) and diethylene triamine pentaacetic acid (DTPA) [42, 43].
Numerous materials have been applied to form radiocolloids for local injection, resulting in a large size range. Several inorganic particles are clinically applied for SLN biopsy and SNOLL applications such as 99mTc-sulfur colloid (15–5000 nm unfiltered or 15–400 nm filtered) [7, 11, 44, 45] (the United States) and 99mTc-antimony trisulfide (3–30 nm) [7, 45, 46] (Australia and Canada) (Fig. 5.7). 99mTc–tin colloids have also been applied, mainly in Japan. Their size can be controlled by the concentration of stannous chloride and 99mTc, resulting in particles of 50–1500 nm (Fig. 5.7) [45]. In some cases, like with 99mTc-rhenium sulfide (NanoCis) (20–100 nm), the stability and the formation of micro aggregates have limited use of the tracer [7, 46, 47]. Also organic-based colloid particles are applied for radioguided SLN biopsies. 99mTc-phytate particles (Fig. 5.2) are formed by the interaction of stannous phytate with Ca2+ present in serum. The size of these particles depends on the calcium concentration and in vitro experiments showed a size range of 150–1500 nm [45]. In Europe, 99mTc-labeled human serum albumin (HSA)-based colloids are most widely used for SLN biopsy procedures. HSA-nanocolloid (Nanocoll; mean diameter 20 nm; range 10–100 nm, Fig. 5.2) has shown to provide a superior retention in the SLN compared to radiolabeled HSA (vasculosis; mean diameter 7 nm) and is therefore widely applied [6, 30]. Next to the SLN biopsy, Nanocoll is also often used for ROLL and SNOLL procedures [48], sometimes in combination with large 99mTc-labeled albumin aggregates (e.g., 99mTc-MAA (10–90 μm) for-tumor demarcation [10]. Even the larger HSA-nanocolloid (SentiScint; mean diameter 205 nm; range 100–600 nm; Fig. 5.2) has shown promising results during SLN procedures [49, 50]. 99mTc-labeled dextran-based nanoparticles (14 nm) have been used for lymphatic mapping in, e.g., colon and breast cancer [51, 52]. A small dextran-based colloid (7 nm) with DTPA and mannose moieties conjugated to its structure has been developed for SLN mapping (Tilmanocept) (Fig. 5.2) [53–55]. This tracer is claimed to show faster clearance from the injection site and to have a stronger interaction with phagocytes [42].
Various size ranges of radiocolloids applied in RGS
Next to local administration, 99mTc-labeled compounds can also be administered intravenously. The most simple form herein is the ability of “free” 99mTc-pertechnetate to accumulate in the thyroid, due to its resemblance to iodine. Next to thyroid scintigraphy to evaluate for hot/cold nodules, pertechnetate can also be used for radioguidance during thyroidectomy [56].
Conjugated to six methoxyisobutylisonitrile ligands, 99mTc forms the hydrophobic and positively charged 99mTc-sestamibi (Fig. 5.3), which is rapidly taken up by mitochondria in (hyper)active cells. Next to its common application in cardiac imaging [57], 99mTc-sestamibi was also shown to allow the evaluation of tumor margins in patients with breast cancer showing promising results for the detection of small foci [58]. Furthermore, the normal distribution of 99mTc-sestamibi was evaluated in 5 volunteers followed by the RGS of one patient suspected of a brain tumor. 99mTc-sestamibi-based RGS resulted in the accurate detection and removal of the brain lesions diagnosed as metastases of renal cell carcinoma [59]. Due to its uptake in (hyper)active cells, 99mTc-sestamibi has also been applied in the detection of abnormalities in the (para)thyroid [60–64].
99mTc-dimercaptosuccinic acid (DMSA) (Fig. 5.3) is believed to accumulate in tumors due to their acidic environment [65]. Therefore, 99mTc-DMSA has been applied for the detection of thyroid cancer. In a study it was compared in 25 patients to 111In-pentetreotide (see below) [66]. Although better results were found for 99mTc-DMSA, it is no longer commercially available [67].
Bisphosphonates have a high affinity for hydroxyapatite, the mineral present in bones. Bisphosphonates especially tend to accumulate in sites of active bone formation, which occurs in bone lesions. Therefore, 99mTc-labeled bisphosphonates have been applied for radioguided biopsies and surgery of bone lesions. RGS based on 99mTc-medronic acid (MDP) and 99mTc-oxidronate (HDP) (Figs. 5.3 and 5.8) was shown to reduce the procedure time and to improve the localization of the lesions [15, 68–70].
Patient with a sternal metastasis, resected via 99mTc-MDP RGS
Coordinated by HYNIC and ethylenediamine N,N’-diacetic acid (EDDA), 99mTc has also been conjugated to receptor targeting peptides such as the somatostatin analogue octreotate (Fig. 5.4). Upon intravenous administration, the peptide targets the somatostatin receptors, commonly overexpressed on neuroendocrine tumors. This radiotracer was used for RGS of four carcinoids and five pancreatic neuroendocrine tumors, resulting in accurate detection of the lesions and an increased detection of lymph node metastases [43].
99mTc has also been used to label antibodies, e.g., SM3 against polymorphic epithelial mucin and H17E2 against placental- and germ cell alkaline phosphatases; both are biomarkers that are overexpressed in ovarian cancer (Fig. 5.5). In 16 patients (1 patient for H17E2 and 15 patients for SM3), these labeled antibodies were shown to allow detection of ovarian cancer, both in vivo and in excised tissue specimens [71]. An 99mTc-labeled antibody fragment against carcinoembryonic antigen (CEA) (IMMU 4-Fab) (Fig. 5.5) was applied for RIGS in 65 patients with colorectal tumors resulting in more accurate diagnosis and in determining the extent of the lesion and possible lymph node intrusion [72]. 99mTc labeled anti-CEA antibody fragment F023C5 was unsuccessful in the detection of lesions in one lung cancer patient, but did show an increased uptake of radioactivity ex vivo [67, 73].
3.1.2 111-Indium
111In is a γ-emitter with a half-life of 2.8 days. Similar to 99mTc, the photon energies of 111In (171 and 245 keV) are in the optimum range for commercial gamma cameras. Due to the higher energy γ-radiation and the longer half-life, the radiation burden for patients and medical personnel is higher compared to 99mTc (Table 2). 111In is produced by proton irradiation of 112Cd and can be incorporated in radiotracers via bifunctional chelates such as DTPA and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), which can be chemically conjugated to targeting moieties such as a peptides, antibodies, and proteins.
For the RGS toward, e.g., neuroendocrine tumors, thyroid carcinomas, and meningiomas, 111In-labeled somatostatin analogues are widely applied (Fig. 5.4) [31, 66, 74–78]. The mechanism of tracer uptake is based on intravenous administration of the tracer, followed by specific binding to the somatostatin receptor. Panareo et al. reported that use of 111In-DTPA-D-Phe1-octreotide (111In-pentetreotide) resulted in the excision of non-palpable neuroendocrine breast tumors that were not detected by conventional imaging techniques [31]. The use of a gamma probe in 111In-DTPA-D-Phe1-octreotide RGS towards midgut carcinoid and endocrine pancreatic tumors in 21 patients allowed detection of all tumor lesions >5 mm, while SPECT failed to detect lesions <9 mm [75].
Intravenous administration of 111In-labeled anti-TAG72 (a tumor-associated glycoprotein) antibodies has been used for RIGS of colorectal carcinoma (37 patients) and ovarian cancer (5 patients). This resulted in the detection of several lesions that would have been missed by standard surgical exploration [79, 80]. RIGS towards prostate-specific membrane antigen (PSMA) using the antibody 111In-capromab pendetide has been reported in one patient, which resulted in the excision of a tumor positive lymph node (Fig. 5.5) [81]. RIGS with 111In has also been performed via a pretargeting approach [20]; in 13 patients with thyroid carcinoma, approximately 4 days after injection of a bivalent antibody directed against CEA and DTPA, 111In-di-DTPA-tyrosyl-lysine was injected [82]. 3 ± 1 days after injection of the radiotracer, patients underwent RGS. Small lesions with a diameter below 0.3 cm could be detected successfully using this approach [19].
3.1.3 57-Cobalt
57Co is mainly a γ-emitter that emits photons of 122 and 136 keV. This radionuclide has a long half-life of 271.8 days. Due to its long half-life and the emission of low-energy β−-particles, the radiation burden for the patient is high (Table 2). This radioisotope is produced by proton irradiation of natural iron and nickel. Bleomycin, a cytostatic, was labeled with 57Co via complexation of the bivalent cobalt ion by the molecule itself. 21 lung cancer patients were injected intravenously with bleomycin (Fig. 5.3), which was labeled via complexation of the divalent 57cobalt ion [83]. Bleomycin itself binds and damages DNA and is therefore most active against fast dividing cells, such as in malignant tissue. 57Co-labeled bleomycin was shown to allow the detection of lung tumors that would otherwise be missed [25]. However, the long half-life of 57Co prevented dissemination of this technology.
3.1.4 67-Gallium
67Ga is a γ-emitter (93, 184, and 300 keV) with a half-life of 3.26 days. Due to its medium half-life, high γ-energy emission (300 keV), and β−-emission, the use of 67Ga results in a considerable radiation burden for the patient (Table 5.2). 67Ga is produced by the irradiation of 68Zn by charged particles, e.g., protons. After production the gallium is coordinated with citric acid to form gallium citrate (Fig. 5.3), which in itself is administered as radiotracer. 67Ga-citrate is often used as radiotracer to detect inflammatory lesions, based on the transchelation of the 67Ga to lactoferrin and siderophores released by leukocytes and microorganisms located at the site of infection [84, 85]. 67Ga citrate has also been reported by Schattner et al. in the RGS toward extranodal lymphoma in one patient, where accumulation in the lesion was most likely caused by necrotic tissue and inflammatory responses [26].
3.1.5 123-Iodine
123I is mainly a γ-emitter that emits photons of 27, 31, and 159 keV. Also this radionuclide emits β−-particles of 23 and 127 keV. The isotope has a half-life of 13.2 h. Due to its short half-life, the radiation burden caused by using this isotope is relatively low, although it is higher than 99mTc (Table 5.2). 123I is produced by proton irradiation of 124Xe, resulting in 123Xe that subsequently decays to 123I. Radioiodination, with all isotopes of iodine, is mainly performed by electrophilic substitution, which requires the (in situ) generation of I+ species. These species can be obtained by the generation of mixed halogen species. Examples of applied oxidizing reagents that can generate mixed radiohalogen species are chloramine-T, iodogen, and N-chlorosuccinimide [86]. Mixed radiohalogen species (XCl) readily react with activated aryl compounds, such as phenols, resulting in mono- or disubstitution at positions ortho to the hydroxyl group. Proteins can be radioiodinated due to the presence of tyrosine residues, although also histidine, tryptophan, and cysteine are sensitive to radioiodination [86, 87]. Non-activated aryl compounds can be radioiodinated via isotopic exchange, in which a non-radioactive iodine isotope is exchanged for a radioactive isotope, or via the electrophilic substitution of a stannylated precursor [88, 89]. Finally also radioiodine-labeled prosthetic groups can be added to the targeting moiety via a selective reaction, for instance, via conjugation to amine reactive groups [86, 87].
123I has been used for RGS of thyroid cancer, both as Na123I and as 123I-MIBG (Fig. 5.3) [32, 90]. Injection of Na123I will result in the accumulation in hyperactive regions of the thyroid, while 123I-MIBG will accumulate in adrenergic tissue such as thyroid tumors. Because 131I (see below) is less expensive, better available, and also often used for therapy, this isotope often replaces 123I in thyroid-related procedures [67]. 123I-MIBG has been applied for RGS-based detection of neuroblastoma (41 procedures) [12, 91] and for the detection of neuroendocrine tumors (4 patients) [66, 92].
3.1.6 125-Iodine
125I is a γ-emitter with a half-life of 60.1 days that emits low-energy photons (35 keV). The low-energy photon emissions makes this isotope less suitable for whole body imaging, but well suited for RGS due to its low background radiation. 125I is produced by neutron irradiation of 124Xe, which leads to 125Xe that then decays to 125I. The labeling chemistry for this isotope essentially is identical to that of 123I.
For RGS using the sodium salt to detect thyroid malignancies, generally other iodine isotopes are applied. 125I has been used for the labeling of MIBG (Fig. 5.3). In a direct comparison between 123I-MIBG (36 cases) and 125I-MIBG (30 cases) for RGS in neuroblastoma patients, 125I-MIBG showed a higher specificity. This difference can be explained by the low-energy emission of 125I, which resulted in a lower background signal from surrounding tissue [91, 93].
There are also examples where iodination was used in combination with targeting peptides. For example, the somatostatin analogue 125I-Lanreotide was used in 13 patients with breast carcinoma resulting in accurate positive margin resection [94]. Furthermore it was applied in 2 patients with gastrinomas, which are gastrin-secreting tumors that also overexpress the somatostatin receptor [95]. A different somatostatin analogue, 125I-Tyr3-octreotide, was applied in 12 patients suspected of neuroendocrine tumors or gastrinomas showing promising results in tumor-specific accumulation and intraoperative detection (Fig. 5.4) [96].
The long half-life of 125I makes it ideal for RIGS with complete antibodies (Fig. 5.5). Most clinical radioiodinated RIGS studies using 125I have been performed with antibodies targeting the tumor-associated glycoprotein 72 (anti-TAG-72), e.g., primarily in colorectal cancer but also in gastric, pancreatic, ovarian, lung, prostate, and breast cancer. It started with the murine B72.3 antibody, followed by the second-generation antibodies: CC49 and the humanized HuCC49 (for an extensive review, see ref. [67]). Alternatively, A5B7 (52 patients) [97] and CL58 (29 patients), targeting the carcinoembryonic antigen (CEA), resulted in the detection of colorectal cancer lesions [98]. 125I-labeled F(ab’)2 antibody fragments, containing both binding domains of a whole antibody without the Fc region, directed against CEA (F023C5) were explored for RIGS. In a small patient group, F023C5 was used to identify breast and colorectal cancer. However, due to a low tumor detection rate during RGS (40 %), the investigators advised the use of more specific antibodies [99, 100]. Antibodies against the tumor-associated antigen 17-1A (EpCAM) has been radiolabeled with 125I and applied in multiple patients to assist in locating non-palpable colorectal tumors or aiding in determining the resection margins [101–103]. Wang et al. intravenously injected 125I-labeled antibodies (3H11) against human gastric cancer cells in 35 patients and showed high specificity and accuracy in detecting the lesions [67, 104].
Although little chemistry is involved, a completely different application of 125I can be found in 125I-labeled titanium seeds [105–107]. In a procedure called radioguided seed localization (RSL), these seeds are placed under ultrasound or X-ray guidance to mark non-palpable breast tumors. It can be considered an alternative to WGL and ROLL and is of particular interest for use in a neoadjuvant setting. The systemic treatment, applied in the neoadjuvant setting to reduce the tumor volume before surgery, demands a considerable time (several weeks) between tumor localization and the actual surgery. WGL and ROLL are not ideal as they require the insertion of a twisted marker before treatment and/or the injection of 99mTc-labeled colloids just before surgery. 125I-labeled seeds require only one procedure to place them and they remain detectable after >30 weeks [108]. Studies evaluating RSL showed a reduction in reoperations due to positive tumor margins and an increased patient convenience compared to the WGL [9, 109]. In comparison with ROLL, RSL showed the same surgical outcome in breast-conserving surgery [108].
3.1.7 131-Iodine
131I emits both γ- and β−-radiation of 364 and 606 keV, respectively, and has a half-life of 8 days. 131I is produced by neutron irradiation of natural tellurium. The labeling chemistry for this isotope resembles that of 123I. 131I induces a large radiation burden for the patient, as a result of its β−-emission. This, in combination with the accumulation of sodium iodide in the thyroid, has led to the therapeutic use of this isotope against thyroid malignancies. Due to the γ-emission, the isotope can be used for RGS, but caution is necessary with respect to the exposure of the medical personnel due to the large dosages (>1 GBq) used for therapeutic applications.
One of the first RGS studies reported in the literature applied 131I-labeled diiodofluorescein (Fig. 5.3) to locate brain tumors [110, 111]. Fluorescein was shown to distribute throughout the body, but was slower cleared form the malignant tissue, which resulted in a detectable signal from the tumor between 3 and 8 h postinjection [112]. This observation led to the development of radioiodinated fluorescein. In 340 patients suspected of a space-occupying brain lesion, the detection of diiodofluorescein by a Geiger-Müller tube had an accuracy of 95 % [111].
131I is the most used isotope to treat abnormalities of the thyroid and RGS towards, thyroid cancer [113–115]. However, after iodine-based therapy, many recurrent thyroid cancers are iodine insensitive and therefore other tracers have to be used for imaging and RGS (such as 99mTc-MIBI and 99mTc-DMSA). For the detection of neuroendocrine tumors, the use of 131I-MIBG (Fig. 5.3) was shown feasible [116]. However, hepatic clearance can result in high background signals overshadowing the lesion of interest, which limits the application of all iodine-labeled MIBG tracers for the detection of neuroendocrine tumors in the area of the adrenal gland [66].
131I has also been used for labeling of antibodies and antibody fragments, which resulted in the accurate detection of small lesions and allowed the evaluation of the resection margins (Fig. 5.5) [16, 35, 117, 118]. However, due to its β−-emission and relatively high-energy γ-photons, 131I has been replaced by other iodine isotopes, such as 125I, for RIGS applications.
3.1.8 201-Thallium
201Tl is a γ-emitter that emits photons of 71 and 167 keV. T and the isotope has a half-life of 73 h. 201Tl causes a considerable radiation dose for the patient, although the exposure for the medical personnel is relatively low (Table 5.2).
The radionuclide is produced by proton irradiation of 203Tl, which yields 201Pb that then decays into 201Tl. An intravenous injection of 201Thallous chloride (TlCl; Fig. 5.3) has been used in one RGS case towards parathyroid adenoma [36]. Since 201Tl showed an increased uptake in areas of high cellular density with increased regional blood flow, the authors claim it allowed removal of the tumor, which was not detected by visible inspection.
3.2 Positron Radiation
A prominent part of nuclear medicine, and radiochemistry, focuses on radionuclides that emit β+-particles or positrons in combination with positron emission tomography (PET). The emitted positrons travel a maximum of a couple of millimeters through human tissue before they reach thermal energies and annihilate with an electron [119]. This annihilation results in the emission of two high-energy photons of 511 keV, which travel in opposite direction from the point of annihilation (180 ± 0.25°). Compared to SPECT imaging, PET imaging has a higher sensitivity and spatial resolution in whole body imaging. Because of these advantages, and their abundant clinical use, positron emitters have also been explored for RGS (Fig. 5.9).
Application of β-emitters in RGS. (i) Whole body nuclear imaging by PET; (ii) intraoperative gamma and beta tracing with acoustic probes; (iii) virtual navigation based on preoperative PET imaging or intraoperative freehand β-detection
Unfortunately, the advantages that apply for whole body imaging cannot be directly translated to RGS. Accurate localization of high-energy photons requires extensive shielding of the detectors, which generally converts them into heavy (and relatively large) devices. An interesting alternative is the selective detection of the positrons themselves. Due to the very limited range of positrons in tissue (<2 mm), this may yield a superficial detection technique that could allow for the accurate delineation of tumor margins. The fact that it is not straightforward to detect β+-particles over the background of high-energy photons is underlined by the fact that there are only few reports that describe the intraoperative use of a β+-selective probe [33, 120].
3.2.1 18-Fluorine
The most widely used β+-emitter is 18F, which emits β+-particles of 634 keV and has a half-life of 110 min. Although high-energy photons (511 keV) are generated by the annihilation of the β+-particles, the effective dose for the patient is relatively low. However, the high-energy photons result in a relatively high radiation burden for the medical personnel (Table 5.2). 18F is generated by proton irradiation of H2 18O or 18O2 [121] and can be covalently incorporated in radiotracers via nucleophilic or electrophilic introductions, for which multiple reagents have been developed, e.g., [18F]-F−-kryptofix [121]. An alternative approach would be to incorporate 18F (in the form of aluminum fluoride) in a chelate (NOTA), thereby allowing labeling of tracers by simple mixing just before administration [122].
2-Deoxy-2-(18F)fluoro-D-glucose (18F-FDG) (Fig. 5.3), a glucose in which the hydroxyl group at the 2-position is replaced via nucleophilic substitution by 18F, is the most widely applied tracer in modern nuclear medicine and can be used to highlight areas with a high metabolic activity. 18F-FDG has also been applied for RGS approaches because of its widespread use and tumor accumulating characteristics. Yet, due to its short half-life, the interval between tracer administration and surgery is limited. Furthermore certain (metabolic active) organs and tissues are known to accumulate 18F-FDG, e.g., the heart, brains, and bladder, which may obscure detection of lesions in these anatomies.
Early 18F-FDG RGS studies have been performed with non-optimized gamma cameras (detection windows around 124, 150, 200, and 255 KeV), resulting in low-radiation detection [14]. More optimized high-energy gamma detectors have later been used to locate, e.g., colorectal tumors and lymphoma, which resulted in the removal of non-palpable and difficult to locate lesions [120, 123–125]. Next to high-energy gamma detectors, also β-sensitive probes were applied [120]. Although the authors claim the selective detection of β-particles, the detection up to 6 cm raises some questions about the selectivity of the probe [120].
A case study has also been reported regarding RGS with 18F-L-DOPA (Fig. 5.3). Increased uptake of 18F-L-DOPA in tumors is caused by the upregulation of amino-acid transporters, to supply the malignancy in their demand for nutrients. The application of 18F-L-DOPA in RGS with a high-energy gamma detector resulted in the successful removal of multiple neuroendocrine tumors and metastases [13].
3.2.2 68-Gallium
68Ga is a positron emitter that emits β+-particles of 1.9 MeV and has a half-life of 67.7 min. We were not able to find information about the effective dose for patients; a high radiation burden can be expected based on the high-energy β+-particles and the 511 keV photons generated by positron annihilation. For the medical personnel the radiation burden is caused by the 511 keV photons and is therefore similar for most β+-emitters (Table 5.2). 68Ga can be eluted from a 68Ga-generator; a stationary phase with absorbed 68Ge is eluted with an acidic mobile phase, which takes the generated 68Ga with it. Such a generator can be maintained at location, e.g., a nuclear facility in a medical center. For RGS applications similar advantages and disadvantages can be expected as described above for 18F. From the chemical perspective, 68Ga can, however, be more easily incorporated in a radiotracer via chelation by a bifunctional chelate conjugated to the targeting moiety. DOTA has been the chelate of choice in the clinically used 68Ga-based radiotracers, although other and possibly better chelates are available, e.g., NOTA and TRAP [126, 127]. Due to the requirement of a chelate in combination with a short half-live, 68Ga has been predominantly used in combination with peptide constructs. For RGS applications, 68Ga was incorporated in the somatostatin analogues DOTA-NOC and DOTA-octreotate (DOTA-TATE) (Fig. 5.4). These radiotracers have been successfully used for RGS towards gastroenteropancreatic neuroendocrine tumors. In 9 patients, the RGS approach with a high-energy gamma detector allowed detection of 94 % of lesions (up to 5 mm tumors) compared to 69 % by preoperative PET imaging and 50 % by surgical palpation [27].
3.2.3 89-Zirconium
89Zr has both β+- and γ-emissions of 389 and 909 keV, respectively, and has a half-life of 78.4 h. Due to the high-energy emissions and medium half-life, 89Zr causes a considerable radiation burden for the patient. Also the radiation dose for the medical personnel is slightly higher compared to other β+-emitters due to the additional γ-emission. 89Zr is produced by proton irradiation of 89Y and can be incorporated in a radiotracer via the bifunctional chelate desferrioxamine.
In a pilot study with 89Zr-desferioxamine-nanocolloid (Fig. 5.2) for SLN mapping by Heuveling et al., a higher resolution in the preoperative nuclear imaging (PET vs SPECT) was observed [28]. The authors claim that, by using a β-selective probe, RGS based on 89Zr-desferrioxamine-nanocolloid should provide a similar or better intraoperative detection, compared to 99mTc-nanocolloid, especially for localization of a SLN near the injection site. This was however not (yet) shown.
3.2.4 124-Iodine
124I is a γ- and β+-emitter that emits photons of 0.6 and 1.7 MeV and β+-particles of 1.5 and 2.1 MeV. 124I has a half-life of 4.18 days. Due to its little use in (clinical) research, we were not able to find information about the effective dose for patients. A high radiation burden can be expected based on the high-energy emissions and long half-life. The exposure for medical personnel is considerable (Table 5.2). 124I is produced by proton irradiation of 124Te. The conjugation chemistry for this isotope is similar to that of the other iodine isotopes reported above.
Although 124I is mainly used for PET imaging, this isotope has been applied in RIGS tracing both the positrons and the high-energy photons (511 keV) originating from 124I-labeled antibodies against A33 transmembrane glycoprotein (huA33) and against carbonic anhydrase IX (cG250) [33]. Detection was performed by both a high-energy gamma detector and a β-selective detector. In four patients a high correlation between γ- and β+-detection was determined and the authors claim that the β-probe showed a higher tumor to background signal compared to the high-energy gamma probe.
3.3 Electron Radiation
β−-particle or electron-emitting radionuclides have been applied for RGS for two reasons. The first reason is the clinical application of β−-emitters for radiotherapy, which allows RGS toward the residual lesion based on other emissions of the radionuclide. The second reason for using a (pure) β−-emitter in combination with a β−-specific detector for RGS is the very limited range of β−-particles in tissue. Any uptake in nearby healthy tissue or radiation of a nearby injection site is attenuated before reaching the detector. This would result in a lower background and a better delineation of the margins around the lesion of interest. Unfortunately a (pure) β−-emitter does not allow preoperative whole body imaging for surgical planning and an approximate location of the lesion of interest has to be known to be able to locate it with a β−-specific probe.
3.3.1 32-Phosphorus
32P emits β−-particles of 690 keV and has a half-life of 14.3 days. Due to its limited use in clinical research, we were not able to find information about the effective dose for patients or medical personnel. 32P is produced by neutron irradiation of 32S. One of the first studies on RGS reported on in 1949, applying a Geiger-Müller device, was performed with 32P-PO4 2− (Fig. 5.3). The accumulation and turnover of the phosphate ion were found higher in tumor tissue compared to healthy brain tissue, thereby allowing the identification of cerebral gliomas in 14 patients [24]. Due to its β−-emission, 32P has not been widely applied for RGS, but for research purposes, multiple methods are available to label all kind of tracers with this isotope [128, 129].
3.3.2 90-Yttrium
90Y emits β−-particles of 2.3 MeV and has a half-life of 64 h. The high-energy β—emission results in a high radiation burden for the patient, and therefore, this isotope is mainly used for therapeutic purposes. However, the additional X-ray generation and the use of high therapeutic dosages cause considerable radiation exposure for the medical personnel. 90Y is a decay product of 90Sr, which is produced upon uranium and plutonium fission in nuclear power plants. Small-scale 90Y generators based on 90Sr have been developed, which can be used for the production of 90Y with high specific activity [130]. These generators can be operated at the local nuclear facility of medical centers. Although 90Y is almost purely a β−-emitter, SPECT imaging has been performed based on Bremsstrahlung, which originates from the loss of kinetic energy from the high-energy electrons (β−) resulting in the emission of photons [131]. Also PET imaging is possible due to the rare (1 in 32 million transitions) β−/β+-pair formation, of which the β+ can subsequently annihilate with an electron to produce two photons of 511 keV [132, 133]. 90Y can be incorporated in radiotracers by binding it to the bifunctional chelate DOTA, which can be conjugated to a variety of targeting moieties.
Recently the use of a β−-specific probe in combination with the 90Y-labeled somatostatin analogue DOTA-TOC (Fig. 5.4) was suggested for the detection of meningioma and high-grade glioma [29]. In this study, PET imaging was performed with 68Ga-DOTA-TOC and provided quantitative information about the uptake of the tracer. Based on this information, the required dosage of 90Y-DOTA-TOC was calculated to discriminate the lesion of interest from the surrounding healthy tissue with a β−-specific probe [29]. Based on this preoperative 68Ga-based imaging and calculations, the authors concluded that RGS based on 90Y-DOTA-TOC should be possible [29].
4 Hybrid Imaging and Detection Platforms (Table 5.3)
Hybrid imaging combines two imaging modalities, e.g., nuclear and luminescence imaging, in a single approach. It was already introduced in 1948 by Moore et al. who radiolabeled diiodofluorescein, resulting in a tracer that has both a nuclear and a fluorescent component. Luminescence imaging in the clinic has been performed based on fluorescence and Cherenkov luminescence (CL) and can provide high-resolution imaging in the operating theatre to aid the surgeon in detecting the lesion of interest (Fig. 5.11b). The advantage of luminescence-guided surgery over radioguided surgery lies in the limited tissue attenuation of visible light [138]; like with β−-particle or electron-emitting radionuclides, imaging of optical signals is less hindered by background signals originating from the injection site or from tracer accumulation in the vicinity of the lesion of interest. However, due to the limited tissue penetration of light (<1 cm) [138], luminescence imaging is not suitable for whole body imaging. Therefore, the application of a radio- and luminescent tracer combines the best of both worlds.
Hybrid imaging tracers applied in RGS
Two subclasses of hybrid tracers have been reported for clinical use, being the combination of a radionuclide and a fluorescent label on a single tracer (Fig. 5.11a) or the detection of the Cherenkov luminescence (CL) emitted by β+/β−-emitting isotopes (Fig. 5.11b). Fluorescence imaging is based on the excitation of a fluorescent label with light, which results in the emission of light of a longer wavelength. The advantage of fluorescence imaging is that it provides real-time high-resolution information. Yet, fluorescence imaging requires the addition of a fluorescent label to the imaging tracer, the excitation light has to be blocked from reaching the camera, and background fluorescence can occur originating from endogenous fluorophores.
Cherenkov photons (Cherenkov Luminescence; CL) originate from charged particles (β+ /β− ) that travel through a medium faster than the speed of light in that same medium. CL occurs in tissue when the emitted charged particles have energies higher than 0.21 MeV. The intensity of CL is around three orders of magnitude lower than that obtained with fluorescence imaging, but during the decay of the isotope, it provides a continuous spectrum with peak emission in the UV range [140]. The advantage of CL is that no additional label is required next to the β -particle emitting radionuclide and that there is virtually no background signal because no external excitation light is required. However, since the CL intensity is tracer dose dependent, it may negatively influence the dose received by the patient and surgical staff [23 ]. Furthermore, low signal intensity means long acquisition times and absolute darkness are needed to generate an image and thus real-time guidance is not possible.
Application of hybrid tracers in RGS. (a) Hybrid tracers combining nuclear imaging with fluorescence imaging: (i) whole body nuclear imaging; (ii) intraoperative tracing with acoustic probe; (iii) intraoperative fluorescence imaging. Real-time fluorescence overlaid with white-light image. (b) Hybrid imaging based on Cherenkov luminescence emitted by β+/β−-emitting isotopes: (i) whole body nuclear imaging; (ii) intraoperative tracing with acoustic probe; (iii) intraoperative optical imaging. CL images overlaid with white-light photograph. With kind permission from Springer Science and Business Media [139]
The earliest example of a hybrid tracer of the first subclass is 131I-diiodofluorescein (Fig. 5.10), which was reported by Moore et al. in 1948. Fluorescein was already reported for the detection of malignant tissue by UV-light irradiation and visible detection of the fluorescence (λem = 520 nm) by eye [112]. By radioiodination, this fluorescent tracer could be detected using a Geiger-Müller tube [110, 111]. Both the radiosignal and the fluorescence detection could be used to localize brain lesions [134].
The radioiodinated (123I, 125I, and 131I) derivative of methylene blue (Fig. 5.10), a blue dye commonly used for optical visualization of the lymphatic ducts, has been used for lymphatic mapping and RGS toward SLN(s), which resulted in the successful removal [135, 141–143]. Although methylene blue was shown to possess fluorescence properties [144], these were not exploited within the clinical studies.
For SLN biopsy procedures, the hybrid radioactive and fluorescent tracer indocyanine green (ICG)-99mTc-nanocolloid was introduced (Fig. 5.10). The tracer was formed via the non-covalent interaction between the near-infrared fluorescent dye ICG and the albumin components of 99mTc-nanocolloid [6, 136]. An early reproducibility study showed the behavior of the hybrid tracer being identical to its parental compound 99mTc-nanocolloid [145]. Next to preoperative SLN mapping, intraoperative radioguidance and fluorescence guidance to the SLN(s) were facilitated. The latter allowing the optical verification of the location of the SLN, which was not possible with the parental compound [146, 147]. The addition of real-time fluorescence imaging during the RGS procedure was considered especially valuable during the detection of SLNs close to the injection site of the radiocolloid [148], and enabled optical detection of SLN(s) failed to accumulated the traditionally used blue dye [146].
Cherenkov photons originate from charged particles (β+/β−) that travel through a medium faster than the speed of light in that same medium. CL occurs in tissue when the emitted charged particles have energies higher than 0.21 MeV. The intensity of CL is around three orders of magnitude lower than that obtained with fluorescence imaging, but during the decay of the isotope, it provides a continuous spectrum with peak emission in the UV range [140]. The advantage of CL is that no additional label is required next to the β-particle emitting radionuclide and that there is virtually no background signal because no external excitation light is required. However, since the CL intensity is tracer dose dependent, it may negatively influence the dose received by the patient and surgical staff [23]. Furthermore, low signal intensity means long acquisition times and absolute darkness are needed to generate an image and thus real-time guidance is not possible.
For CL imaging, all β+- and β−-emitters used in clinical practice can potentially be used. This said, the amount of clinical reports on CL imaging is limited. Recently clinical studies with 131I (for thyroid) and 18F-FDG (for various malignancies) have been reported, showing the clinical feasibility of CL imaging [137, 139, 149]. In these studies superficial lesions were visualized through the skin. Technical camera development for CL imaging is moving toward endoscopic use and a laparoscopic camera for CL imaging was recently evaluated in four patients with colorectal cancer [139].
5 Future Perspectives
Although this chapter discusses radiotracers that have already been applied for RGS in patients, in principle all clinically used radiotracers can be applied for RGS. This includes also the tracers that are currently investigated for diagnostic imaging purposes, such as 18F-fluorothymidine (18F-FLT; visualizes cell proliferation), 18F- and 99mTc-annexin V (visualizes cell apoptosis/necrosis), 68Ga-prostate-specific membrane antigen ligand (68Ga-PSMA; visualizes the prostate-specific membrane antigen), 99mTc-etarfolatide (visualizes epithelial tumor cells), and various antibodies labeled with 89Zr [150–152]. Also in the preclinical field, several promising radio- and hybrid tracers are being developed that might be applicable in RGS and image-guided surgery [153–158]. Although the recent reemergence of image-guided surgery has boosted the preclinical activities regarding tracer development for this application, the “from molecule to man” translation of these activities remains limited.
Interesting recent developments in the choice of radionuclides for RGS are the steps toward the application of β+- (e.g., 18F and 89Zr) and β−-emitters (90Y) for RGS. Especially the selective detection of the β-particles can potentially improve the resolution in RGS. However, the application of these radionuclides increases the radiation dosages obtained by patients (both β−- and β+-emitters) and medical personnel (mainly β+-emitters). This aspect needs to be resolved in order to implement such RGS procedures in an everyday clinical practice. One suggestion would be to improve the specificity and especially the sensitivity of the imaging modalities, both nuclear and optical, which would allow the application of lower dosages of these radiotracers.
6 Concluding Remarks
As can be concluded from the described applications of radioisotopes in RGS, the most used radioisotopes are 99mTc (radiocolloids and 99mTc-sestamibi), 111In (111In-somatostatin analogues), and 125I (125I-MIBG and 125I-labeled antibodies). This originates mainly from their easy availability, their preferred medium to low-energy photon emission, and their ease of incorporation into radiotracers. Interesting new developments are focusing on surgical guidance toward β-emitters and the inclusion of optical guidance methods. A critical point in the development of new RGS procedures and the use of certain radionuclides is the radiation exposure of the surgical staff. Especially the need for isotopes with high-energy emissions may limit the clinical application due to restrictions in the radiation exposure of the medical personnel.
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This work was financially supported by a Netherlands Organisation for Scientific Research VIDI grant (NWO; STW BGT 11272).
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Bunschoten, A., van den Berg, N.S., Valdés Olmos, R.A., Blokland, J.A.K., van Leeuwen, F.W.B. (2016). Tracers Applied in Radioguided Surgery. In: Herrmann, K., Nieweg, O., Povoski, S. (eds) Radioguided Surgery. Springer, Cham. https://doi.org/10.1007/978-3-319-26051-8_5
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