Search

Recent technical advances and implementation of novel radiotracers have further increased the potential of radioguided surgery for a broad variety of malignancies. Indeed, the possibilities for future applications of novel radiotracers in diverse oncological strategies has become more promising than ever. This literature review aims to provide a contemporary update on a selected group of radiotracers and evaluates the usability of radioguided surgery and sentinel node procedures, focusing on most promising advances. For example, the impact of targeted radiotracers on prostate specific membrane antigen (PSMA), CD206 receptor-targeted agents ( 99m Tc-tilmanocept), and hybrid tracers adding fluorescence to radioguidance (ICG- 99m Tc-nanocolloid) as well as targeting hypoxia-induced carbonic anhydrase IX (CAIX) will be covered. Furthermore, future outlooks on the implementation of gold nanoparticles (AuNP's), but also technical advances in improved radiotracer detection by hybrid gamma devices will be discussed.

The sentinel lymph node (SLN) biopsy is probably the most well-known radioguided technique in surgical oncology. Today SLN biopsy reduces the morbidity associated with lymphadenectomy and increases the identification rate of occult lymphatic metastases by offering the pathologist the lymph nodes with the highest probability of containing metastatic cells. These advantages may result in a change in clinical management both in melanoma and breast cancer patients. The SLN evaluation by pathology currently implies tumor burden stratification for further prognostic information. The concept of SLN biopsy includes pre-surgical lymphoscintigraphy as a "roadmap" to guide the surgeon toward the SLNs and to localize unpredictable lymphatic drainage patterns. In addition to planar images, SPECT/CT improves SLN detection, especially in sites closer to the injection site, providing anatomic landmarks which are helpful in localizing SLNs in difficult to interpret studies. The use of intraoperative imaging devices allows a better surgical approach and SLN localization. Several studies report the value of such devices for excision of additional sentinel nodes and for monitoring the whole procedure. The combination of preoperative imaging and radioguided localization constitutes the basis for a whole spectrum of basic and advanced nuclear medicine procedures, which recently have been encompassed under the term "guided intraoperative scintigraphic tumor targeting" (GOSTT). Excepting SLN biopsy, GOSTT includes procedures based on the detection of target lesions with visible uptake of tumor-seeking radiotracers on SPECT/CT or PET/CT enabling their subsequent radioguided excisional biopsy for diagnostic of therapeutic purposes. The incorporation of new PET-tracers into nuclear medicine has reinforced this field delineating new strategies for radioguided excision. In cases with insufficient lesion uptake after systemic radiotracer administration, intralesional injection of a tracer without migration may enable subsequent excision of the targeted tissue. This approach has been helpful in non-palpable breast cancer and in solitary pulmonary nodules. The introduction of allied technologies like fluorescence constitutes a recent advance aimed to refine the search for SLNs and tracer-avid lesions in the operation theatre in combination with radioguidance.

Conventional sentinel node (SN) mapping is performed by injection of a radiocolloid followed by lymphoscintigraphy to identify the number and location of the primary tumor draining lymph node(s), the so-called SN(s). Over the last decade research has focused on the introduction of new imaging agents that can further aid (surgical) SN identification. Different tracers for SN mapping, with varying sizes and isotopes have been reported, most of which have proven their value in a clinical setting. A major challenge lies in transferring this diagnostic information obtained at the nuclear medicine department to the operating theatre thereby providing the surgeon with (image) guidance. Conventionally, an intraoperative injection of vital blue dye or a fluorescence dye is given to allow intraoperative optical SN identification. However, for some indications, the radiotracer-based approach remains crucial. More recently, hybrid tracers, that contain both a radioactive and fluorescent label, were introduced to allow for direct integration of pre- and intraoperative guidance technologies. Their potential is especially high when they are used in combination with new surgical imaging modalities and navigation tools. Next to a description of the known tracers for SN mapping, this review discusses the application of hybrid tracers during SN biopsy and how the introduction of these new techniques can further aid in translation of nuclear medicine information into the operating theatre.

The popularity gained by the sentinel lymph node (SLN) procedure in the last two decades did increase the interest of the surgical disciplines for other applications of radioguided surgery. An example is the gamma-probe guided localization of occult or difficult to locate neoplastic lesions. Such guidance can be achieved by intralesional delivery (ultrasound, stereotaxis or CT) of a radiolabelled agent that remains accumulated at the site of the injection. Another possibility rested on the use of systemic administration of a tumour-seeking radiopharmaceutical with favourable tumour accumulation and retention. On the other hand, new intraoperative imaging devices for radioguided surgery in complex anatomical areas became available. All this a few years ago led to the delineation of the concept Guided intraOperative Scintigraphic Tumour Targeting (GOSTT) to include the whole spectrum of basic and advanced nuclear medicine procedures required for providing a roadmap that would optimise surgery. The introduction of allied signatures using, e.g. hybrid tracers for simultaneous detection of the radioactive and fluorescent signals did amply the GOSTT concept. It was now possible to combine perioperative nuclear medicine imaging with the superior resolution of additional optical guidance in the operating room. This hybrid approach is currently in progress and probably will become an important model to follow in the coming years. A cornerstone in the GOSTT concept is constituted by diagnostic imaging technologies like SPECT/CT. SPECT/CT was introduced halfway the past decade and was immediately incorporated into the SLN procedure. Important reasons attributing to the success of SPECT/CT were its combination with lymphoscintigraphy, and the ability to display SLNs in an anatomical environment. This latter aspect has significantly been improved in the new generation of SPECT/CT cameras and provides the base for the novel mixed reality protocols of image-guided surgery. In these protocols the generated virtual SPECT/CT elements are visually superimposed in the body of the patient in the operating room to directly facilitate, by means of visualization on screen or using head-mounted devices, the localization of radioactive and/or fluorescent targets by minimal invasive approaches in areas of complex anatomy. All these technological advances will play an increasing role in the future extension and the clinical impact of the GOSTT concept.

Beside the classical applications of sentinel lymph node mapping, some new procedures are emerging and showing feasibility and clinical utility. In this chapter, we will report on sentinel lymph node mapping in 1) malignancies of the female reproductive system (cervical cancer, endometrial cancer, vulvar cancer and ovarian cancer); 2) malignancies of the male reproductive system (prostate cancer, penile cancer and testicular cancer); 3) malignancies in kidney and bladder. This paper presents the uncommon applications of sentinel lymph node mapping in urogenital neoplasms.

Radioguided surgery has been investigated and applied to almost any neoplastic disease that is surgically treated. The impact of radioguided surgery on the surgical management of cancer patients includes relevant and real-time information to the surgeon regarding the location and extent of the disease, as well as regarding the assessment of surgical resection margins. Despite the fact that sentinel lymph node biopsy has been worldwide accepted as a highly accurate staging method for various solid cancers (among which breast cancer and cutaneous melanoma), some potential intraoperative drawbacks still remain. This article provides an update on currently available perioperative techniques regarding the use of radiotracers for radioguided surgery and sentinel lymph node mapping and biopsy, in particular in combination with vital dyes or other agents. The integration of computer technology and data processing makes it possible to integrate anatomic and functional images together with 3D rendering systems. This facilitates the targeted-tissue perioperative localization, especially in anatomically complex areas. Furthermore, we provide an update on advances in the integration of intraoperative imaging devices as well as optical tracers for the surgical management of patients. Evidence is emerging that these devices, together with new potential tracers, may improve intraoperative identification of sentinel nodes and/or tumors. A detailed presentation on a portable gamma camera in breast cancer patients, and the application of perioperative imaging devices in gynaecological cancers are included. Other important procedures, such as ROLL and RSL for occult lesion excision in the breast and other organs, are extensively discussed.

A few years ago SPECT/CT was successfully incorporated into the sentinel node (SN) procedure for breast cancer and melanoma. Important contributions of SPECT/CT in these two malignancies were the anatomical localization of SNs already visualized on planar images, the detection of additional SNs in aberrant basins, and the depiction of SNs in cases with no visualization on planar images. Recently, in a large series of melanoma patients the use of SPECT/CT was associated with the detection of more metastatic SNs and a higher rate of disease-free survival. Following the experiences in breast cancer and melanoma, SPECT/CT has been applied in oral cavity cancer as well as in urological and gynaecological malignancies. In the areas of lymphatic drainage of these malignancies (head and neck, pelvis, and upper abdomen) SPECT/CT appears to be essential to localize SNs, providing surgeons with helpful anatomical landmarks to plan SN biopsies. In gastrointestinal and lung malignancies SPECT/CT has only incidentally been used. With the improvement of the CT component in the second generation of SPECT/CT gamma cameras, nuclear physicians today can identify lymph nodes corresponding with the radioactive SNs. This is possible using a display of SPECT/CT similar to that of conventional tomography. Multiplanar reconstruction enables to correlate radioactive sentinel nodes seen on fused SPECT/CT with lymph nodes seen on CT, and the use of cross-reference lines allows the navigation between axial, coronal and sagittal views. This visual information is helpful for the intraoperative procedure and for post-excision assessment using portable devices. Fused SPECT/CT images may also be three-dimensionally displayed, improving anatomical SN localisation and recognition. This recent imaging improvement is leading to a new paradigm of "see and open" in contraposition to the former "open and see" in the SN procedure. The new mixed reality protocols which are able to transfer SPECT/CT to the operating room for surgical navigation will reinforce this "see and open" concept. However, a comprehensive interpretation of SPECT/CT together with lymphoscintigraphy is necessary to identify radioactive lymph nodes as sentinel nodes and classify them into different categories that are important for the intraoperative procedure.

Aim: Recently, a high-resolution dedicated PET system for hanging breast imaging (MAMMI PET) has been developed to improve primary tumor detection and characterization. The aim of this pilot study was to assess its feasibility for tumor detection and FDG uptake measurements in patients with stage II and III breast cancer., Methods: Thirty-two patients with invasive breast cancer (26 ductal, 4 lobular, 2 other), prior to and/or during neoadjuvant chemotherapy, underwent both conventional PET/CT and MAMMI PET in prone position with hanging breasts. Conventional PET/CT and MAMMI PET were performed 60±10 min and 110±10 min after injection of 180-240 MBq of FDG, respectively. Primary tumor detection was assessed and FDG uptake, expressed as maximum standardized uptake value (SUVmax), was calculated., Results: Both MAMMI PET and conventional PET/CT visualized the primary tumor in 31 patients (97%). The mean distance from the tumor to the pectoral muscle was 26.4mm (smallest distance 3.3mm). Agreement in FDG uptake between PET/CT and MAMMI PET was high (r=0.86, 95% CI 0.69-0.94). However, SUVmax as assessed with MAMMI PET was consistently higher than with PET/CT in all patients with an average ratio of 2.7., Conclusion: The dedicated high-resolution breast PET with hanging breast technique is able to visualize approximately all breast tumors in stage II and III breast cancer patients, including tumors in the vicinity of the thoracic wall. This may enable its sequential use in the assessment of response in breast cancer patients receiving neoadjuvant systemic therapy, although SUVmax values are not directly comparable to standard PET/CT.

The observed response to [131I]MIBG therapy in advanced neuroblastoma after conventional therapy, the noninvasiveness of the procedure, and the high metabolic activity which is frequently observed in untreated tumors led to the concept of substituting [131I]MIBG therapy for combination chemotherapy at diagnosis prior to surgery in patients with advanced disease/high risk neuroblastoma. The objective of this approach is to reduce the tumor volume, enabling adequate surgical resection of the tumor, and to avoid toxicity and the induction of early drug resistance. Chemotherapy is reserved to treat minimal residual disease postoperatively. Thirty-one children who presented with inoperable neuroblastoma were treated according to this protocol. After an objective response to [131I]MIBG therapy at diagnosis, 19 of 27 evaluable patients (70%) had complete or > 95% resection of the primary tumor or did not require surgery at all. Only mild hematological toxicity was observed. It is concluded that [131I]MIBG therapy of neuroblastoma at diagnosis is feasible; its effectiveness in attaining operability of the primary tumor is at least equal to that of combination chemotherapy, but its toxicity is considerably less.

From cumulative reported data the sensitivity of [131I]metaiodobenzylguanidine (131I-MIBG) scintigraphy of carcinoids appears to be greater than 60%; at our Institute 131I-MIBG scintigrams were positive in 51 of 70 patients with metastatic carcinoid. Twenty patients with symptomatic, metastatic disease have received 7.4 GBq doses of 131I-MIBG for palliation. Most of these patients had multiple large metastases showing no response to other therapies. No objective response (greater than 50% tumor volume reduction) was ever observed; however, 13 patients were relieved of symptoms, such as flushes, diarrhea, anorexia and pain. Palliation in some of these patients was meaningful and long lasting. Possible explanations for a palliative effect in the absence of objective remission are discussed. Treatment with escalating doses of stable MIBG (up to 80 mg) in 9 patients does not support the hypothesis that the palliation is due to a purely pharmacological effect. Palliation might be explained by the observation that carcinoid liver metastases may present both as hot and cold lesions; 131I-MIBG therapy will thus target exclusively at metabolically active metastases, which are responsible for the patient's symptoms.

[131I]Metaiodobenzylguanidine (131I-MIBG) is used for diagnostic scintigraphy and targeted therapy in a range of neural crest tumors, which exhibit an active uptake-1 mechanism at the cell membrane and cytoplasmatic storage in neurosecretory granules. A good and selective concentration and a long retention in the tumor, as is generally the case in neuroblastoma, are the basis for successful 131I-MIBG treatment. At The Netherlands Cancer Institute a phase II study was carried out in 53 patients with progressive recurrent disease after conventional therapy had failed. Despite the unfavorable basis for treatment, 131I-MIBG therapy induced 7 complete remissions, 23 partial remissions and arrest of disease (no change) in 10. Nine patients had progressive disease and one patient was lost to follow-up. The palliative effect of the treatment under these conditions was impressive. The duration of remissions varied from 2 to 38 months. The best results were obtained in patients with voluminous soft tissue disease. In general the treatment was well tolerated by children and the toxicity was mild, provided the bone marrow was not invaded by the disease. It is concluded that 131I-MIBG therapy has a definitive place in the treatment of neuroblastoma after conventional treatment has failed. As the invasiveness and toxicity of this therapy compare favorably with that of chemotherapy, immunotherapy and external beam radiotherapy, 131I-MIBG therapy is the best palliative treatment for patients with advanced recurrent neuroblastoma.

In recent years several radiopharmaceuticals have become available, offering new possibilities for the diagnosis and therapy of medullary thyroid carcinoma (MTC). For the diagnosis and follow-up 201TI-chloride and 99mTc(V)-DMSA are the tracers of choice. Imaging with [131I]metaiodobenzylguanidine (131I-MIBG) and 131I-anti-CEA or anti-calcitonin antibodies or fragments is less sensitive but very specific. These tracers can be used to evaluate their potential therapeutic use. Cumulative reported data on the diagnostic use of 131I-MIBG in 178 MTC patients indicate that overall 34.5% of medullary cancers concentrate MIBG. At The Netherlands Cancer Institute 131I-MIBG scintigraphy was positive in 8 of 23 patients with MTC. Four of these patients have received therapeutic amounts of 131I-MIBG, resulting in 1 partial remission and meaningful palliation in 3 patients with metastatic MTC. It is concluded that, although the preliminary experience suggests that the objective response of MTC to 131I-MIBG therapy is limited, the palliation provided to these patients, for whom there is little other treatment, may be very meaningful.

The observed response of [131I]metaiodobenzylguanidine (131I-MIBG) therapy in advanced neuroblastoma after conventional therapy had failed, the noninvasiveness of the procedure, and the high metabolic activity of untreated tumors led to a new protocol to use 131I-MIBG therapy in newly diagnosed patients instead of combination chemotherapy prior to surgery. The objectives of this study are to improve the overall outcome of patients with neuroblastoma by introducing 131I-MIBG therapy as the first therapy in the treatment schedule, in order to reduce the tumor volume, enabling adequate surgical resection and avoiding toxicity and the induction of early drug resistance. The advantages of this approach are that the child's general condition is unaffected before surgical resection is performed and that chemotherapy is reserved to treat minimal residual disease. So far, 13 patients with inoperable neuroblastoma (stage III and IV) were treated with 131I-MIBG initially and then submitted to surgery. More than 50% decrease of the volume of the primary tumor was noted in 7 of 10 evaluable patients; 8 patients have so far been operated with complete resection in 2, greater than 95% resection in 5 and 80% resection in one patient. Three patients are still undergoing 131I-MIBG treatment. The toxicity of 131I-MIBG de novo is in contrast with the previous experience of 131I-MIBG therapy after conventional therapy: only 4 patients had thrombocytopenia and only 1 of 7 patients with bone marrow involvement developed bone marrow depression.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant pheochromocytoma may present as a widespread metastatic disease, which is little or non-responsive to external beam radiotherapy and chemotherapy. The prognosis of these patients is bad due to both the progressive metastasis and the secretion of excess catecholamines which may cause hypertensive episodes. For these conditions [131I]metaiodobenzylguanidine (131I-MIBG) therapy may be an alternative treatment modality to induce both tumor remission and reduction of hormonal activity of the disease. The experience with 131I-MIBG therapy in four patients with metastatic malignant pheochromocytoma at The Netherlands Cancer Institute is reviewed. One patient with abdominal tumor recurrence and metastases to the lymph nodes and lungs had a partial remission of disease for 3 years; a second had a mixed response together with palliation and two other patients had stable disease, but were relieved of bone pain and severe hypertension, respectively. It is essential to be aware of the medication the patient is using, as many drugs are known or may be expected to interfere with the uptake and/or retention of 131I-MIBG by the tumor cells. The case of a significant reduction of 131I-MIBG uptake and retention by Labetalol in one of the patients is discussed. It is concluded that 131I-MIBG therapy may induce objective remission in patients with malignant pheochromocytoma and is certainly meaningful in the reduction of hormonal activity, the control of hypertension and the relief of pain from metastases.