European Nuclear Medicine Guide
During the last 30 years, SLN biopsy has been extended from applications in clinically node negative (cN0) 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. While included in guidelines for a number of indications [55-59], in others its application remains in clinical trials only [60-63]. The procedure has, however, served as the steppingstone for many novel iNM technologies [64, 65].
In SLN biopsy 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 [64, 66]. Hybrid tracer variants are based on non-covalent binding between ICG and albumin, and thus solely applicable for albumin based nanocolloids. Lymphoscintigraphy following interstitial radiocolloid injection is essential to visualize the lymphatic drainage kinetics and to precisely differentiate SLNs from higher echelon nodes and to provide surgeons with a pre- and intraoperative roadmap. Intraoperative detection of SLNs has been boosted by the availability of new technological modalities such as dedicated (DROP-IN) gamma probes, portable gamma cameras, freehand-SPECT cameras and intraoperative navigation. [65, 67]
This has resulted in a SLN identification rate being close to 100% for most indications. Nevertheless, false negatives rates (FNR) for this procedure (e.g. in breast cancer patients) are between 1 and 14% [68, 69]. The major pitfalls for the FNR are: 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 in 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 center gains experience [69]
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 [70, 71].
Targeted tracer surgery plays a pivotal role in identifying macro-metastatic nodal involvement in patients who are clinically node-positive (cN+). In such patients, imaging techniques and palpation may suggest lymph node involvement, but intraoperative confirmation and precise resection remain crucial to prevent under- or over-treatment.
Targeted tracers address this problem by using radiolabeled molecular targets (e.g., PSMA ligands, somatostatin analogues, or tumor-specific antibodies) that accumulate selectively in metastatic lymph nodes via overexpressed receptors or antigens. During surgery, handheld gamma or PET probes help localize tracer-positive nodes, which are more likely to harbor metastatic disease.
As examples, in cN+ prostate cancer patients, 99mTc-labeled or 111In-labeled PSMA ligands allow preoperative imaging (e.g., SPECT/CT) to map involved nodes and intraoperative detection using gamma probes. This has led to the concept of salvage surgery in recurrent or persistent nodal disease. Maurer et al. demonstrated the clinical use of [111In]111In-PSMA-I&T- in patients with PSMA-PET positive nodes. Intraoperative gamma probe localization allowed targeted removal of PSMA-positive macro-metastatic lymph nodes, leading to PSA decline postoperatively [72].
iNM has become a cornerstone of modern oncologic practice for diagnosing and assessing primary tumor margins and detecting local recurrences. It leverages imaging modalities to accurately sample tissue from suspicious lesions while minimizing invasiveness and morbidity. Importantly, it also plays a role in evaluating residual disease after treatment or biopsy of tissue adjacent to surgical margins to confirm complete tumor excision [18, 73].
Pathology, and frozen section analysis herein, remains the gold standard for assessing whether a so-called R0 or R1 resection is obtained, respectively referring to the absence or presence of tumour cells at or close to the surgical margin [74, 75].
The pathology exam requires several time-consuming steps. Positive margins may imply consequences for the patients, such as re-intervention, additional radio-or chemotherapy, or increased relapse rates. Use of fluorescent tracers or mobile intraoperative PET/CT device or other devices such as freehand SPECT have been designed to solve this issue [16, 43, 76].
Recent reports have demonstrated promising results in thyroid cancer, bladder cancer, renal cell carcinoma, prostate and skin cancer [39, 43, 77, 78].
Modern oncology requires precise tumor assessment to drive effective therapies. Image-guided biopsies are the current standard of care to characterize molecular alterations safely and effectively, but have inherent limitations due to tumor heterogeneity and accessibility, as well as from procedure related risks.
In the search for a non-invasive method to characterize tumor, researchers have turned to medical imaging as a repeatable alternative to quantify tumoral heterogeneity, albeit with a lower spatial resolution. The benefits of non-invasive imaging compared to invasive image-guided biopsy include reduced inherent risk to the patient and the potential to characterize the tumor as a whole as opposed to a focal biopsy.
Percutaneous image-guided tumor biopsy remains the standard method to acquire samples for analysis of both tumoral and non-tumoral tissue. Image-guided biopsy provides a minimally invasive technique with very good results for routine diagnostic purposes, as well as for precision cancer diagnostics. While overall less invasive than surgical biopsy, image-guided needle biopsy still presents potential procedure related risks and complications, reported to be below 5–10% [75].
Examples of application of image-guided biopsy include tracers such as [99mTc]Tc-HDP in combination with Freehand SPECT has been used to guide percutaneous skeletal lesions that were preoperatively identified on bone scintigraphy [18].
MRI-guided core biopsy has been shown to change the surgical management in women with a new diagnosis of breast cancer [79].
PET/CT-guided biopsy of suspected lung lesions was shown to outperform CT-guided biopsy by reducing the rate of rebiopsy due to inconclusive results [80].
The application of such a technique has been applied to multiple scenarios (thyroid remnants, osteoid osteoma, neuroendocrine tumors, oligometastasis, parathyroid, breast cancer, etc…), with excellent results and minimizing the surgery required [82-86].
The radioguided occult lesion localization (ROLL) approach has been used as alternative to guidewires for non-palpable tumor lesions in breast cancer, lung cancer and other isolated lesions that are visible on morphological scanning modalities e.g. mammography, ultrasound or CT [64, 87].
In most cases, ROLL involves the intralesional injection of a small number of radioactive microspheres (e.g. [99mTc-]Tc-MAA; 2–15 MBq) that are too large to migrate from the site of injection. However, when 99mTc-radiolabeled nanocolloids are used, most of the tracer also remains at the injection site, providing an interesting alternative that allows for the exploration of 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 (RSL) [88].
In general, the seeds are placed preoperatively in the center 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 low-energy gamma photons around 30 keV. Unique for the RSL technology, due to the longer radionuclide half-life and small formfactor, is that it can also be used as a reference for the original lesion location in a neoadjuvant setting, where the seed remains in the lesion throughout the length of the therapy process.
Liver radioembolization, also known as selective internal radiation therapy (SIRT), is a minimally invasive treatment primarily used for unresectable liver tumors, including hepatocellular carcinoma (HCC) and liver metastases (especially from colorectal cancer). It involves the delivery of radioactive microspheres via the hepatic artery to target tumors while sparing healthy liver tissue.
The SARAH Trial (2017), a randomized Phase III, open label, included 459 patients with advanced HCC in France. It was compared SIRT with ⁹⁰Y vs. oral sorafenib. The median overall survival was 8.0 months in the SIRT arm vs 9.9 months with sorafenib (ns). However, grade ≥3 adverse events were 26% (SIRT) vs. 61% (sorafenib) with a better quality of life in the SIRT arm [89].
The EPOCH Trial (2021), a randomized Phase III trial involving 428 patients with liver-dominant metastatic colorectal cancer (mCRC), refractory to first-line chemotherapy, was the first positive Phase III study in mCRC for SIRT. The progression free survival was 8.0 months in the SIRT arm vs 7.2 months in the control arm (statistically significant but clinically modest), with no differences in the overall survival [90].
The HEPAR PLuS Trial (2022) is the first clinical study using a scout activity of 166Ho microspheres (same product) for pre-treatment planning. Unlike ⁹⁰Y, which uses [99mTc]Tc-MAA (a different compound) for planning, 166Ho scout activity is identical to therapeutic activity and allows exact simulation of treatment distribution. However, it is still in the early-phase and its clinical impact on long-term outcomes are under study [91].