Departments of a Radiology and b Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

Transcription

1 The Oncologist Cancer Imaging Utility of Radiolabeled Somatostatin Receptor Analogues for Staging/Restaging and Treatment of Somatostatin Receptor Positive Pediatric Tumors GEETIKA KHANNA, a DAVID BUSHNELL, a M. SUE O DORISIO b Departments of a Radiology and b Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Key Words. Somatostatin Scintigraphy Pentetreotide Embryonal tumors Neuroendocrine tumors Pediatric Disclosure: D.B. has acted as a consultant to Molecular Insight Pharmaceuticals within the last 2 years. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article. ABSTRACT In this paper, we review the pediatric oncologic applications of somatostatin receptor targeted imaging and therapy. Somatostatin receptors are expressed in high densities by embryonal tumors, such as neuroblastoma and medulloblastoma, and neuroendocrine tumors like carcinoids and islet cell tumors. We first review the distribution of these receptors in normal tissues and tumor cells. We then discuss the technique of somatostatin receptor scintigraphy (SRS) in the pediatric population. Next, the specific clinical applications of SRS with regard to the imaging of neuroblastoma, central nervous system tumors, and gastroenteropancreatic neuroendocrine tumors of childhood are discussed. Finally, we discuss the potential role of somatostatin receptor targeted radiotherapy for improving the duration and quality of life of children with these tumors. The Oncologist 2008;13: INTRODUCTION Somatostatin, a peptide hormone, is the most widely distributed of the hypothalamic regulatory hormones [1]. It is present in the central and peripheral nervous systems, the gastrointestinal tract, and the pancreas. Somatostatin receptors (sstrs) have been identified on the surface of several cell types, such as pancreatic islet cells and thyroid C cells, and on tumor cells like those of neuroendocrine tumors (NETs) and primitive neuroectodermal tumors (PNETs). To date, five subtypes of sstrs have been cloned in human tissues: sstr1, sstr2, sstr3, sstr4, and sstr5. Because the halflife of somatostatin is very short ( 2 minutes), its use for imaging is not practical. The availability of chelated synthetic analogues of somatostatin like indium-111 diethylentriaminepentaacetate ( 111 In-DTPA)-octreotide and 111 In- 1,4,7,10-tetraazacyclododecane-N,N,N,N -tetraacetic acid (DOTA)-lanreotide has enabled in vivo imaging of sstr-expressing tumors. These synthetic analogues of somatostatin have high affinity for sstrs, especially sstr2, and have a long half-life (on the order of several hours) allowing for their use as imaging agents. In adults, the primary application of somatostatin receptor scintigraphy (SRS) has Correspondence: Geetika Khanna, M.D., M.S., Department of Radiology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Telephone: ; Fax: ; geetika-khanna@uiowa.edu Received September 24, 2007; accepted for publication February 15, AlphaMed Press /2008/$30.00/0 doi: /theoncologist The Oncologist 2008;13:

2 Khanna, Bushnell, O Dorisio 383 been in the evaluation of gastroenteropancreatic NETs like carcinoids and islet cell tumors, meningiomas, and neural crest tumors like paragangliomas. Among the childhood cancers, SRS has shown the most potential in the evaluation of embryonal tumors such as neuroblastoma, medulloblastoma, and supratentorial PNETs as well as NETs like carcinoids and pancreatic NETs [2]. These malignancies remain among the most challenging of all pediatric cancers, with recurrence and metastases occurring in 50% of embryonal tumors, while outcomes for NETs in the pediatric and young adult populations are not well documented [3, 4]. Consequently, new treatment options such as molecularly targeted radiotherapy are beginning to offer new hope for improving both the length and quality of life for these children. SRS The somatostatin analogue octreotide can be labeled with 111 In through the DTPA ligand to form 111 In-octreotide, also referred to as 111 In-pentetreotide, or with iodine-123 ( 123 I) complexed with tyrosine, 123 I-Tyr 3 -octreotide. These radiopharmaceuticals bind with high affinity to sstr2 and with moderate affinity to sstr3 and sstr In-pentetreotide is the preferred radiopharmaceutical for the following reasons: 123 I is not readily available and labeling of 123 ItoTyr 3 is cumbersome, 123 I-Tyr 3 -octreotide has an initially longer plasma half-life, resulting in more background activity, and it is primarily cleared by the liver, resulting in more bowel activity [5 7]. The recommended administered activity of pentetreotide in children is 5 MBq/kg (0.14 mci/kg) with a maximum of 222 MBq (6 mci) in adults [8]. Images are acquired at 4 and 24 hours after injection. Planar and single photon emission computed tomography (SPECT) images are acquired using a gamma camera fitted with a mediumenergy collimator. Symmetrical 20% energy windows are centered over both photopeaks of 111 In (173 and 247 kev) and the data from both windows are added. Like any other radiopharmaceutical, knowledge of the normal tissue accumulation of 111 In-pentetreotide is essential in the interpretation of SRS. This tracer shows avidity for normal organs such as the pituitary, thyroid, spleen, liver, and renal parenchyma (Fig. 1). The gall bladder, bowel, renal collecting system, ureters, and bladder are seen as a result of clearance of 111 In-pentetreotide. SPECIFIC IMAGING APPLICATIONS IN PEDIATRIC MALIGNANCIES Neuroblastoma Neuroblastoma, the most common NETs of childhood, is a typical example of an embryonal tumor of childhood [9]. Figure 1. Normal distribution of 111 In-pentetreotide. Whole body 4-hour anterior image in a 4-year-old shows normal activity in the pituitary, liver, spleen, and kidneys, and some bowel activity. Neuroblastoma and related tumors (ganglioneuroblastoma and ganglioneuroma) arise from the neural crest cells that colonize the sympathetic ganglia and adrenal medulla in fetal life. These neoplasms are characterized by an array of biological and clinical features ranging from spontaneous regression and differentiation into benign neoplasms in infants to potentially aggressive dissemination in older children. Accurate detection of bone and bone marrow metastases is very important because therapy and prognosis relate directly to their presence. Other prognostic factors include age at diagnosis and biological features, such as histopathology, tumor ploidy, and N-myc amplification [10]. sstrs, specifically sstr1 and sstr2, have been identified on neuroblastoma tumor cells [11, 12]. This allows sstr imaging of neuroblastoma for staging and restaging purposes (Fig. 2). However, the normal uptake of pentetreotide by the liver and spleen and its excretion through the hepatobiliary and genitourinary systems limit the utility of SRS in the detection of neural crest tumors. Metaiodobenzylguanidine (MIBG) remains the current standard for scintigraphic evaluation of neuroblastoma. MIBG is a guanethidine derivative and is structurally similar to norepinephrine. It is concentrated in sympathetic ganglia and the adrenal medulla and stored in catecholamine storage vesicles. MIBG

3 384 Somatostatin Receptors in Pediatric Tumors Figure 2. Somatostatin receptor scintigraphy of neuroblastoma in a 9-year-old boy with newly diagnosed neuroblastoma. Shown is a whole-body planar anterior image obtained 24 hours after injection of 3.4 mci 111 In-pentetreotide. Multiple foci of metastatic disease are noted in the skull, spine, humeri, pelvis, and femurs, in addition to a large abdominal mass consistent with stage IV disease. scanning is considered by many investigators as the reference standard for detection of metastatic disease. It has been shown to have a sensitivity of 92% and specificity of 98% 100% for the detection of bone marrow metastases [13, 14]. The largest series comparing scintigraphy with 123 I-MIBG and SRS included 88 children with neuroblastoma and ganglioneuroblastoma [15]. The investigators found MIBG to be significantly more sensitive than SRS in tumor detection, with sensitivities of 94% and 64%, respectively. However, they showed that SRS provided significant prognostic information, with SRS positivity correlating with survival and event-free survival probability. The ratio of the activity of octreotide in the tumor versus the background on in vivo imaging, specifically the rate of increase in this ratio with time, has been shown to correlate with the density of sstr2 expression as determined by reverse transcription-polymerase chain reaction [16]. This allows for the use of SRS to determine sstr expression in the tumor in a noninvasive fashion. The clinical value of sstr2 as a prognostic marker lies in its ability to detect patients at low risk, independently of clinical stage, age at diagnosis, and N-myc amplification status [17]. In a series of 26 neuroblastoma patients, Briganti et al. [18] showed the density of sstr expression to be strongly related to survival, independently of N-myc oncogene amplification. They proposed that neuroblastoma imaging with SRS may have not only a diagnostic but also a prognostic value. O Dorisio et al. [11] also showed a correlation among the presence of sstrs, stage of disease, and patient survival in a series of 26 neuroblastoma patients by in vitro analysis. However, they did not find a correlation between the presence of sstrs and N-myc oncogene amplification. In summary, though MIBG scintigraphy remains the best scintigraphic method for the detection of neuroblastoma tissue, SRS has the potential to provide prognostic information in a minimally invasive fashion. Central Nervous System Tumors Brain tumors are the second most common pediatric malignancy, accounting for nearly 20% of all childhood tumors [19]. In the International Classification of Childhood Cancer, central nervous system (CNS) tumors are divided into six subgroups, with the main diagnostic groups being: astrocytomas, embryonal tumors, ependymomas, and other gliomas [20]. Embryonal tumors as a group have the worst prognosis and are comprised primarily of medulloblastoma and supratentorial PNETs. Embryonal tumors have consistently been shown to express the highest density of sstrs, specifically sstr2. This allows for promising applications of SRS in the diagnosis and surveillance of these tumors (Fig. 3). Initial reports on the application of SRS in the evaluation of CNS tumors focused on meningiomas and pituitary adenomas [21, 22]. This was followed by two reports, each reporting one case of medulloblastoma, suggesting high densities of sstrs in this neoplasm [23, 24]. In 1998, Müller et al. [25] reported on the expression of sstrs and the role of SRS in 20 children with medulloblastoma. All 14 medulloblastoma samples studied by autoradiography demonstrated uniformly high expression of sstrs in the tumor tissue. The sensitivity of SRS in this study was 88%, with a specificity of 100%. SRS was true negative in one patient with a false-positive magnetic resonance imaging (MRI) scan, and the only patient with a false-negative SRS had a small drop metastasis. High expression of sstrs in central PNETs was subsequently confirmed by Frühwald et al. [26, 27], who evaluated seven children with supratentorial PNETs and found SRS to be more sensitive than conventional imaging in the detection of relapse in select cases. In a series of 20 pediatric brain tumors, SRS was shown to be a useful adjunct to MRI in the surveillance of sstr-positive malignancies, especially when the MRI findings were equivocal [28]. Though MRI is the most sensitive imaging

4 Khanna, Bushnell, O Dorisio 385 Gastroenteropancreatic NETs Figure 3. Somatostatin receptor scintigraphy of a central nervous system embryonal tumor in a 3-year-old boy with headaches. (A): Axial T2-weighted magnetic resonance imaging scan demonstrates a mass occupying the fourth ventricle. (B): Axial 111In-pentetreotide single photon emission computed tomography image demonstrates intense radiotracer uptake within the mass. (C): Photomicrograph (20 ) of immunohistochemistry slide shows staining for somatostatin receptor (brown stain). This was proven to be a medulloblastoma at pathology. modality for the detection of residual/recurrent medulloblastoma, SRS has been shown to be more specific because of its high-affinity binding to sstrs [29]. These studies suggest that SRS can provide useful molecular imaging information that can complement the information obtained from MRI, though more evidence is needed before the routine use of SRS in the surveillance of embryonal tumors can be recommended. Data on the expression of sstrs on glial tumors are conflicting. While Reubi et al. [24] showed that sstrs are expressed by 82% of low-grade gliomas (World Health Organization [WHO] grade I and II) and only 2% of highgrade gliomas (WHO grade III and IV), these results have not been unanimously confirmed [30]. Mawrin et al. [31] demonstrated that the loss of differentiation of glial tumors was associated with greater expression of sstrs. Detection of glial tumors by SRS, however, depends not only on the Gastroenteropancreatic (GEP)-NETs arise from neuroendocrine cells found in the pancreas, the gut, and its derivatives like the bronchial tree. NETS encompass carcinoid tumors, islet cell tumors, and amine precursor uptake and decarboxylation tumors. GEP-NETs have traditionally been classified into pancreatic tumors and carcinoids, which are further subdivided based on location as foregut, midgut, or hindgut tumors. They may also be classified based on symptoms as functional or nonfunctional tumors. In 2000, however, a more prognostically useful classification system was proposed by the WHO, based on tumor histology: 1a, well-differentiated NETs, which show benign behavior; 1b, well-differentiated neuroendocrine carcinomas (NECs), which are characterized by low-grade malignancy; and 2, poorly differentiated NECs of high-grade malignancy [34]. GEP-NETs are rare in the pediatric population, accounting for 1% of all pediatric malignancies [35]. The most common sites of GEP-NETs in the pediatric population are the appendix and bronchial tree, and liver metastases with unknown primary [35, 36]. There is limited information in the pediatric literature regarding the imaging findings of GEP-NETs [37]. Most of the information regarding imaging of these tumors is obtained from adult studies. The quoted diagnostic performance of different imaging modalities in various studies is highly variable, depending on local expertise, different stages of technology development, and the imaging protocols used. The overexpression of sstrs and the presence of amine uptake and storage mechanisms allow targeted molecular imaging of NETs using SRS and MIBG, respectively. SRS has been shown to be more sensitive than MIBG scintigraphy in the detection of GEPNETs, with sensitivities in the range of 78% 100% and 36% 85%, respectively [38, 39]. Specifically, MIBG has been shown to have limited accuracy in the detection of expression of sstrs but also on the integrity of the blood brain barrier because pentetreotide is a polar, water-soluble peptide [32]. Schmidt et al. [22] concluded that, although nearly all gliomas express sstrs, only high-grade gliomas with disruption of the blood brain barrier show significant uptake of the radiopharmaceutical. Scintigraphic findings in gliomas should be interpreted with caution because uptake depends both on the status of the blood brain barrier and the expression of sstrs on the tumor. There is limited information on the expression of sstrs in ependymomas. Though ependymomas have been shown to express sstrs, predominantly sstr2, the level of expression is variable and generally lower than that seen in embryonal tumors [33].

5 386 Somatostatin Receptors in Pediatric Tumors pancreatic NETs, though it may be useful in the detection of midgut NETs [38]. Also, nonfunctional NETs have been shown to have lower affinity for MIBG than functional tumors; however, no such difference has been seen in pentetreotide uptake. SRS is currently the modality of choice in the detection of the primary tumor, the evaluation of the extent of disease, monitoring treatment effects, and selecting patients for targeted therapy (Fig. 4) [40]. However, there are limitations to SRS. There is considerable variation in sstr subtype expression among different tumor types and also heterogeneous expression in tumors of the same type [41]. Most gastrinomas, but only half of insulinomas, express sstrs. The small size of the primary tumor and their tendency to occur anywhere along the gastroenteropancreatic system can make tumor detection a challenge. Coregistration of data from molecular and anatomic modalities or hybrid imaging with SPECT-CT or position emission tomography (PET)-CT can aid in the accurate localization of disease, detection of small lesions, and determination of areas of physiologic uptake. Fusion imaging with SPECT-CT has been shown to be more accurate than either SPECT or CT alone and can result in management changes in 14% 28% of patients [42, 43]. The development of PET radiopharmaceuticals, like gallium- 68-labeled 1,4,7,10-tetraazacyclododecane-N,N,N,N tetraacetic acid-d-phe 1 -Tyr 3 -octreotide ( 68 Ga-DOTA- TOC), for detecting NETs is of great interest as they can offer better spatial resolution than with SPECT and the opportunity to evaluate various aspects of NET biochemistry in vivo [44]. The development of novel PET and SPECT radiopharmaceuticals and incorporation of fusion imaging in everyday practice could lead to further improvements in the detection and staging of GEP-NETs. Other Imaging Applications sstrs have been identified on lymphoma cells by in vitro studies, allowing for the in vivo evaluation of Hodgkin s disease and non-hodgkin s lymphoma by SRS [45]. However, with the increasing availability of fluorine-18-fluorodeoxyglucose ( 18 FDG)-PET at most centers, and better resolution of PET imaging compared with SPECT, 18 FDG- PET has essentially become the imaging modality of choice in the evaluation of lymphoma, even in children. SRS has been successfully used to image other malignancies like medullary thyroid carcinoma, pheochromocytoma, paragangliomas, and pituitary adenomas. These tumors are primarily seen in adults. However, occasionally they can occur in children, especially in the presence of multiple endocrine neoplastic syndromes like von Hippel-Lindau disease (GEP-NETs and pheochromocytoma), neurofibromatosis type I (pheochromocytoma), multiple endocrine neoplasia I Figure 4. Somatostatin receptor scintigraphy of a gastroenteropancreatic neuroendocrine tumor in a 6-year-old girl with a history of abdominal pain and diarrhea for several months. (A) Somatostatin receptor scintigraphy single photon emission computed tomography image obtained 24 hours after i.v. administration of 111 In-pentetreotide in the axial plane shows an intense focus of increased uptake adjacent to the gall bladder (G), which corresponds to a mass seen at the porta hepatis (arrow) on axial contrast-enhanced computed tomography (B). Also note the thickening of the gastric folds as a result of hypergastrinemia. This is a surgically proven pancreatic gastrinoma. (pituitary adenoma, pancreatic islet cells tumors), and multiple endocrine neoplasia II (medullary thyroid carcinoma, pheochromocytoma) [46]. THERAPEUTIC APPLICATIONS Besides imaging, radiolabeled analogues of somatostatin offer the potential for use in the treatment of patients with advanced stage sstr-expressing tumors. Although 111 In emits low-energy electrons that have some treatment potential, radionuclides such as yttrium-90 ( 90 Y) and lutetium-177 ( 177 Lu), which emit higher energy electrons through a process known as beta decay, are generally felt to be better suited for therapeutic purposes. 90 Y has been labeled to a Tyr 3 -octreopeptide identical, except for the Tyr 3, to the octreopeptide in the imaging agent 111 In-pentetreotide. For this therapeutic drug, a do-

6 Khanna, Bushnell, O Dorisio 387 decane tetraacetic acid derivative (DOTA) is used as the chelator to link 90 Y to the octreopeptide. DOTA provides a stronger bond between 90 Y and the octreopeptide, resulting in a more stable complex than the corresponding DTPA-linked molecule 111 In-pentetreotide. The resulting radioactive drug, 90 Y-DOTA-Tyr 3 -octreotide, is currently known generically as 90 Y-edotreotide (also referred to in the literature as SMT-487 or 90 Y-DOTATOC). 177 Lu has been linked to a very similar octreopeptide known as octreotate. Studies have demonstrated that 90 Y-DOTATOC has a several-fold higher binding affinity for sstr2 on most NETs relative to 111 In-pentetreotide [47]. Unlike other targeted radiotherapeutic drugs, including 131 I-MIBG, dosage-limiting normal organ toxicity is typically seen in the kidneys with 90 Y-DOTATOC, as opposed to the bone marrow. 90 Y-DOTATOC is administered i.v. over a 20- or 30-minute period, and is usually given in multiple 6 8 week cycles separated by 2 3 months in time. From a radiation safety standpoint, patients can be treated in an outpatient setting because 90 Y does not emit gamma radiation. 131 I-MIBG, 90 Y-DOTATOC, and 177 Lu-DOTA-Tyr 3 -octreotate (DOTATATE) have all shown substantial promise in treating adult patients with NETs not responsive to other treatments [48 52]. Although objective tumor response data are limited for 131 I-MIBG, studies have demonstrated similar overall response rates for these three agents in the range of 20% 50%, depending somewhat on tumor type and the specific administration protocol [53 55]. Currently, there is much greater experience treating adults with NETs using 90 Y-DOTATOC, or the similar agent 177 Lu-DOTATATE, than there is treating children. The results, however, in adults have been highly encouraging, with improvements seen in clinical status and quality of life in addition to evidence of prolonged survival even though, as stated above, overall objective response rates have been modest [56, 57]. The largest experience in the field of targeted radionuclide therapy in children with NETs, and more specifically chemotherapy-refractory neuroblastoma, has been with high-dosage 131 I-MIBG [58 60]. While results with this radioactive drug are often good, many children with chemotherapy-refractory disease do not respond significantly to 131 I-MIBG. Moreover, studies have demonstrated discordant uptake patterns of MIBG versus octreopeptides in some patients with NETs [61]. In adults at least, many patients with NETs, especially those with pancreatic tumors, show better targeting with the octreopeptides than with MIBG [62]. Consequently, there may be an important role in the pediatric setting for agents such as 90 Y-DOTATOC or 177 Lu-DOTATATE, which have distinctly different tumor cell targeting mechanisms than MIBG. Notably, successful treatment of a child with medulloblastoma using 90 Y-DOTATOC administered intrathecally was recently reported [63]. We are currently conducting a phase I trial of 90 Y- DOTATOC to treat children with advanced stage embryonal and neuroendocrine malignancies. The primary criterion for treatment in this study is tumor uptake equal to or greater than that of the liver on pretherapy 111 In-pentetreotide images. Side effects from this therapy have so far been limited to nausea/vomiting at the time of treatment because of the coadministration of an amino acid solution designed to reduce renal radiation exposure from 90 Y- DOTATOC, with no evidence to date of renal or bone marrow toxicity. In adults, a small fraction of individuals may go on to develop chronic renal insufficiency as a result of this treatment, with preliminary results suggesting less renal toxicity from 177 Lu-DOTATATE than from 90 Y- DOTATOC [64]. To help reduce the potential for renal toxicity from these agents, cationic amino acid solutions are routinely administered at the time of treatment. Such amino acid solutions have been shown to reduce kidney uptake of radiolabeled octreopeptides on the order of 20% 30% [65]. CONCLUSION In conclusion, radiolabeled octreopeptides have advanced our ability to care for children with sstr-expressing tumors, principally NETs. 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