European Nuclear Medicine Guide
The expanding role of radioguided surgery in interventional Nuclear Medicine.
As the main clinical modality for molecular imaging purposes, Nuclear Medicine has been rapidly expanding its impact on patient care. This impact has mainly been achieved by gaining ground in the early identification of disease. Modern examples herein are the routine use of [18F]FDG- and [18F]PSMA- PET during cancer diagnosis and staging. Through its tracer-enabled diagnostic support, Nuclear Medicine aids the treating disciplines e.g. oncologists, radiotherapists and surgeons in their decision-making process. The rise of theranostics and matching out-patient clinics in European Nuclear Medicine departments, underscores that the medical impact of nuclear medicine can be expanded to the delivery of therapy. This opens a range of unique new possibilities for our field. When looking at Radiology departments in Europe, one can conclude that imaging has also proven its value by guiding interventions such as local-therapy delivery (e.g. liver embolization) and tissue-biopsy, so-called Interventional Radiology. Given the increasing desire to perform interventions on early molecular disease there is a growing demand for interventional molecular imaging technologies. This has driven the emergence of interventional nuclear medicine (INM).
The disciplines of INM describe the use of nuclear medicine-based technologies to guide the implementation of medical interventions e.g. local-therapy delivery, smart-biopsy or image-guided surgery. Of these three pillars in INM, the first two are strongly based on a collaboration with our colleagues in Interventional Radiology. The last one, image-guided surgery, requires a direct collaboration with our surgical colleagues. Radio-guided surgery, the use of radiopharmaceutical accumulation to drive lesion identification, aims to support precision surgery by improving the surgical detection accuracy, while reducing operation time and procedure related side-effects and promoting minimally invasive procedures.
In this chapter, we aim to provide an update on the INM discipline radioguided surgery, and we place these efforts in perspective to other image-guided surgery technologies.
Radioguided surgery (RGS) has seen a substantial growth in the last decades and constitutes a wide range of procedures. To date, RGS has been successfully applied in a variety of clinical indications, mostly oncological. Three distinct methods, all of them based on the accumulation of an administered radiotracer in a target or index lesion, are used [219]:
The ability to preoperatively detect and quantify radioactivity using non-invasive scintigraphy, i.e. SPECT or PET, besides intraoperative identification, is the basis of all RGS indications. In fact, one could state that the penetration of radiation through tissue sets RGS apart from the other main interventional molecular imaging strategy, namely fluorescence-guided surgery. This feature provides the operating surgeon with a roadmap towards the lesions of interest, while fluorescence can only be applied in a superficial manner [220].
When using gamma-emitting radioisotopes such as 99mTc, the effective dose to the patient and surgical staff’s exposure can be considered negligible. The radiation exposure, however, increases using other radioisotopes e.g. 111In. When positron-emitting radioisotopes are used, the occupational exposure to the surgical staff needs to be taken into consideration [221].
The rationale of SLN biopsy in solid tumours is based on the concept that initial lymphatic spread to locoregional lymph nodes. During the last 25 years, SLN biopsy has been extended from applications in patients with breast cancer and cutaneous melanoma to a wide variety of other solid epithelial malignancies such as head and neck cancers, gynaecological cancers, and urological malignancies.
In this application, a variety of nano-sized (7-200nm; 10-150 MBq) radiopharmaceuticals is used depending on the availability and country e.g. nanocolloid, sulphur colloid, rhenium sulphite or dextran particles [222]. These particles drain from the injection site via lymphatic vessels and accumulate in the SLN by phagocytosis of macrophages and/or retention due to particle size. Lymphoscintigraphy following interstitial radiocolloid injection is essential to visualize the drainage kinetics and to precisely differentiate SLN’s from higher echelon LNs and to provide surgeons with an intraoperative roadmap. Intraoperative detection of SLN’s has been boosted by the availability of new imaging modalities such as dedicated (DROP-IN) gamma probes, portable gamma cameras and freehandSPECT cameras [223,224].
This has resulted in a SLN identification rate being close to 100%. Nevertheless, false negative of this procedure exist and remain difficult to identify. An analysis of false-negative procedures has revealed that the major pitfalls were: 1) Failure of the radiopharmaceutical to drain to all potential drainage basins e.g. by blockage of the lymphatic drainage due to prior surgery or neoadjuvant therapy, 2) Injection site of the tracer, 3) “Failure” to detect a SLN a different lymphatic basin other than predictable one which was not included in the field of view, or 4) Inability to surgically identify the preoperatively identified lesions. Furthermore, literature suggests that the false-negative rate is, at least partly, related to the experience of the lymphatic mapping team (nuclear medicine physicians, surgeons and pathologists combined), whereby the success of SLN biopsy increases as a centre gains experience [225].
When using radioactivity to guide surgical interventions, radiation exposure is often put forward as limitation. However, the patient’s effective dose for [99mTc]-colloids is 1.2-2.0 µSv/MBq, that corresponds to 0.04 mSv after an injection of 20 MBq of [99mTc]-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) [226].
In recent years, the use of SPECT/CT imaging for SLN detection has increased, thus driving up the patient exposure. The additional effective dose from the CT component of SPECT/CT imaging, however, varies and depends mainly on the characteristics of the CT scan and characteristics (e.g. weight) of the patient [227]. For a low dose CT for attenuation correction, an effective dose of a maximum of 2.4 mSv has been reported.
Scientific innovations in SLN biopsy focus on enhancing the pre- and intraoperative detection accuracy. This has resulted in the extension of RGS towards fluorescence guided surgery and has resulted in the explorative use of PET radiocolloids for SLN biopsy [228,229]. The latter, however, also has an impact on the patient’s effective dose and occupational exposure of surgical staff. It is interesting to note that the technical developments that are being pursued for lymphatic mapping may also find their way to other RGS indications.
The radioguided occult lesion localization (ROLL) approach has been used as alternative to guidewires for non-palpable tumour lesions in breast cancer, lung cancer and other isolated lesions that are visible on morphological scanning modalities e.g. mammography, ultrasound or CT [230].
ROLL involves the intralesional injection of a small amounts of radioactive microspheres (e.g. [99mTc-]MAA; 2–15 MBq) that are too large to migrate from the site of injection. Alternatively, the local retention of [99mTc]-radiocolloid can be explored for lesion demarcation in combination with SLN procedures (SNOLL). Using the same gamma-tracing modalities as for SLN -procedures, surgeons can accurately localize the target lesion as a hot-spot and can harvest it with minimal excision of healthy tissue.
A practical alternative to ROLL relies on the use of sealed radioactive seeds (4x0.8 mm titanium capsule containing 125I (t1/2 = 59.4 days; EC-decay), so-called radioguided seed localization (RSL) [231].
In general, the seeds are placed in the centre of the lesion using an 18G needle and radiologic guidance. Excision of the lesion is guided by using a handheld gamma probe that is modified to sensitively detect photons around 30 keV. Unique for the RSL technology is that it can also be used as a reference for the original lesion location in a neoadjuvant setting.
At the age of precision medicine, the magic words are “targeted tracers”, and the same is true for RGS. Here, the tracers used to realize radioguidance actively accumulate in lesions following iv tracer administration. Although radioguidance can work with a broad range of gamma-emitting isotopes, the most frequently used radioisotopes are 99mTc, 111In and 123I due to their availability, their medium to low-energy photon emission, their relative long half-life, and their ease of incorporation into radiotracers. Of these isotopes, 99mTc is most practical and yields the lowest radiation exposure to the patients and surgical staff.
Clinical applications have been reported in parathyroid surgery ([99mTc]-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]HDP) or in lymphatic metastases in prostate cancer ([99mTc]PSMA I&S) [232–236].
Recently, there has been an increasing focus on the use of beta emitters such as the therapeutic isotope 90Y and traditional PET tracers for surgical guidance, e.g.18F-FDG (metabolically active tumours) or [68Ga]/[18F]PSMA-ligands (prostate cancer) [237–240].
When using PET tracers, the detection technique becomes a challenge, requiring high-energy gamma-probes, beta-probes or even the highly sensitive light detection [223,241].
An important issue in the development of new RGS procedures and the use of beta-emitting radionuclides is the occupational exposure of the surgical staff (isotopes with high-energy emissions may limit the clinical application due to dose limit for occupational exposure). However, some examples have been based on PET/CT detection and high-energy gamma photon probe guidance (NET surgery using [68Ga]-labelled somatostatin analogues, [18F]FDG-avid tumour lesions) [242–244].
Another potential use for PET tracers is detection of optical Cerenkov photons emitted by those tracers with dedicated optical cameras, which potentially can be used intraoperatively to guide cancer surgery in various malignancies (e.g. assessing tumour margin status). Cerenkov light can provide a resolution of <2 mm but, unfortunately, light suffers heavily from tissue‐induced signal attenuation. This also limits the signal penetration of even near‐infrared dyes to <1 cm (fluorescence imaging in vivo signal attenuation severely limits the detection sensitivity).
Finally, new approaches are based on PET/CT detection and pairing with tracers for SPECT/CT and standard gamma counting ([68Ga]-PSMA-11 and [99mTc]- or [111In]PSMA-I&S in prostate cancer patients for regional lymph node resection) [245].
Advantages of RGS with its preoperative route map and deep tissue signal-penetration intraoperatively, helps surgeons identify the disease spread in front and may help select the least invasive surgical approach accurately. Despite the strong advantages provided by RGS, it is obvious that in the case of gamma emissions, background signals may be prominent and prevent the surgeon from accurately detecting the lesions of interest. One way to overcome such weaknesses is to include the use of complementary guidance technologies into the same procedure.
Compared to radioguidance, optical‐guidance has a superior spatial resolution and is even detectable down to the microscopic level. The major asset of fluorescence imaging is its capability to accommodate the surgeons desire to optically identify the lesions in real‐time.
Fluorescent tracers such as fluorescein and ICG (optical imaging) can provide such intraoperative visualization, as fluorescence signals can be used to accurately demarcate a superficial lesion. Based on the complementary sensitivity to activity detection and the fact that surgeons are used to obtaining real-time visual feed-back, fluorescence provides a logical candidate for further expansion of RGS [220,246].
The current evolution in the field of hybrid imaging technologies and tumour-targeted hybrid tracers opens up exciting new possibilities. Based on clinical studies, the advantages of the hybrid approach rely on the fact that a hybrid tracer (e.g. ICG-[99mTc]-nanocolloid) allows preoperative imaging and accurate intraoperative guidance (hybrid surgical navigation concepts have been used to successfully integrate nuclear guidance (i.e. SPECT/CT or freehandSPECT) with fluorescence guidance in vivo) [247].
Moreover, luminescent signals remain visual in pathological specimens at a high resolution and can thus be used to aid pathological examination of surgical specimens [248].
While clinical demand drives the field of interventional nuclear medicine and its section of radioguided surgery, technological innovations play an instrumental part in the progression of these efforts. The availability of radiotracers plays a crucial role in refining the existing procedures and expanding radioguidance to other indications. Here we can observe an increasing shift towards hybrid tracer designs, where the radiotracers, next to a radioisotope, also contain an alternative imaging label e.g. for fluorescence imaging. Next to the radiopharmaceutical advances, significant strides have been made in engineering of hardware and software. Through engineering efforts, modalities have become available for non-99mTc radionuclides (e.g. 90Y), and modalities have been designed for specialist surgical procedures e.g. robotic surgery. At the same time, the surgical roadmaps provided by nuclear medicine are increasingly being used to provide surgeons with augmented-, mixed- or virtual-reality displays that support navigation during radioguidance procedures.