Metaiodobenzylguanidine Therapy Research Articles

Peripheral Blood Biomarkers Associated With Toxicity and Treatment Characteristics After 131I- Metaiodobenzylguanidine Therapy in Patients With Neuroblastoma

Few tools exist to predict clinical outcomes after radiopharmaceutical therapy. Our goal was to identify associations between blood-based biomarkers of radiation effect and clinical outcomes after 131I-metaiodobenzylguanidine (131I-MIBG) therapy in patients with neuroblastoma. We conducted a prospective, single-center cohort study in children with advanced neuroblastoma treated with 131I-MIBG as monotherapy or in combination with systemic putative radiation sensitizers. We collected serial peripheral blood samples after 131I-MIBG infusions and quantified a panel of protein and messenger RNA markers. We plotted relative change from baseline to assess degree of modulation over time and then evaluated association of marker modulation with toxicity and response endpoints. The cohort included 40 patients (30 male/10 female; median age 7years). We observed significant modulation of the majority of markers between baseline and hour 72 after 131I-MIBG. Greater fold increase of plasma FLT3 ligand was associated with subsequent grade 4 neutropenia (P=.039). Modulation of peripheral blood BCLXL and DDB2 was associated with grade 3+nonhematologic toxicity (P=.043 and .048, respectively). No markers were associated with tumor response. Greater plasma FLT3 ligand, BCLXL, and BCL2 modulation was observed in patients receiving 131I-MIBG in combination with radiation sensitizers. Among 9 patients who received 2 courses, the degree of modulation in serum amylase was significantly lower after the second course (P=.012). Peripheral blood biomarkers relevant to radiation exposure are significantly modulated during the acute period after 131I-MIBG. The degree of modulation of a subset of these markers is associated with toxicity and receipt of concomitant radiation sensitizers.

Estimated Internal and External Radiation Exposure of Caregivers of Patients With Pediatric Neuroblastoma Undergoing 131I Metaiodobenzylguanidine Therapy: A Prospective Pilot Study.

Current recommendations suggest that family members should participate in the care of children receiving in-hospital I metaiodobenzylguanidine (MIBG) therapy for neuroblastoma. The present study aimed to measure the external radiation exposure and estimate the internal radiation exposure of caregivers during the hospital stay for I MIBG therapy. Caregivers received radiation safety instructions and a potassium iodide solution for thyroid blockade before patient admission. External radiation exposure was determined using a personal pocket dosimeter. Serial 24-hour urine samples were collected from caregivers during the hospital stay. Estimated internal radiation exposure was calculated based on the urine activity. Twelve cases (mean age, 6.2 ± 3.5 years; range, 2-13 years) were enrolled. The mean administered activity was 233.3 ± 74.9 (range, 150.0-350.0) mCi. The mean external radiation dose was 5.8 ± 7.2 (range, 0.8-19.9) mSv. Caregivers of children older than 4 years had significantly less external radiation exposure than those of children younger than 4 years (1.9 ± 1.0 vs 16.4 ± 5.0 mSv; P = 0.012). The mean estimated internal radiation dose was 11.3 ± 10.2 (range, 1.0-29.8) μSv. Caregivers receive both external and internal radiation exposure while providing in-hospital care to children receiving I MIBG therapy for neuroblastoma. However, the internal radiation exposure was negligible compared with the external radiation exposure.

Feasibility, toxicity and response of upfront metaiodobenzylguanidine therapy therapy followed by German Pediatric Oncology Group Neuroblastoma 2004 protocol in newly diagnosed stage 4 neuroblastoma patients

Aim of the studyRadiolabelled meta-iodobenzylguanidine (MIBG) is an effective option in treatment of neuroblastoma (NBL) tumours. We studied feasibility, toxicity and efficacy of upfront 131I-MIBG and induction treatment in stage 4 NBL patients. Patients and methodsRetrospective, multi-centre (AMC and EMC) pilot regimen (1/1/2005–2011). Newly diagnosed stage 4 NBL patients, were treated with 2 courses of 131I-MIBG, GPOH 2004 NBL protocol, myeloablative therapy (MAT) and autologous stem cell rescue (ASCT). 131I-MIBG was administered in a fixed dose. Response rate (RR) was defined as complete remission, very good partial response and partial response. ResultsThirty-two patients, (median age [range] 2.9 [0–11.4] years), 21 received 131I-MIBG therapy, 11 did not because of: MIBG non-avid (N = 5) and poor clinical condition (N = 6). In 95% of eligible patients 131I-MIBG treatment was feasible within 2 weeks from diagnosis. Interval between chemotherapy courses was 25 days (131I-MIBG group) versus 22 days (chemotherapy group). No stem cell support was needed after 131I-MIBG therapy. Stem cell harvest in both groups was feasible, neutrophil recovery was comparable, but platelet recovery post MAT, ASCT was slower for 131I-MIBG-treated patients. RR post 131I-MIBG was 38%, post MAT + ASCT was 71% (131I-MIBG group), 36% (chemotherapy group) and overall 59%. ConclusionsInduction therapy with 131I-MIBG before the HR GPOH NB 2004 protocol is feasible, tolerable and effective in newly diagnosed stage 4 NBL patients. 131I-MIBG upfront therapy induces early responses.

Evaluation of cytological radiation damage to lymphocytes after I-131 metaiodobenzylguanidine therapy by the cytokinesis-blocked micronucleus assay.

The purpose of this study was to evaluate the degree of cytological radiation damage to lymphocytes occurring after I-131 metaiodobenzylguanidine (MIBG) therapy as determined by the cytokinesis-blocked micronucleus assay. The chromosomal damage to lymphocytes induced by I-131 in vivo should result in augmentation of the number of cells with micronuclei. We studied 15 patients with pheochromocytoma (14/15) or ganglioneuroma (1/15), who were treated initially with 7.4GBq of I-131-MIBG. Isolated lymphocytes collected from patients 10days after the therapy were harvested and treated according to the cytokinesis-blocked method of Fenech and Morley. Serial blood samples were obtained periodically only from two patients for 2years after therapy. Micronucleus number of micronuclei per 500 binucleated cells was scored by visual inspection. As controls, lymphocytes from the same patients before the therapy were also studied. In an in vitro study, lymphocytes from eight normal volunteers were exposed to doses varying from 0.5 to 2Gy and studied with the same method. The mean number (mean±SD) of micronuclei after treatment was significantly increased (p<0.001) as compared to control subjects (49.4±8.2 vs. 11.3±6.4). Internal radiation absorbed doses estimated for the 15 patients were 1.6±0.3Gy in this external irradiation study. The frequency of micronuclei post-administration of I-131-MIBG gradually decreased to near baseline (i.e., pre-therapy) levels by 2years. The relatively low frequency of lymphocyte micronuclei induced by I-131-MIBG in vivo and reversal of the increasing frequency of lymphocyte micronuclei after therapy suggest that the short-term non-stochastic damage induced by this therapy with 7.4GBq of I-131-MIBG in pheochromocytoma or ganglioneuroma patients is limited and reversible.

Individualized 131I-mIBG therapy in the management of refractory and relapsed neuroblastoma

ObjectiveIodine-131-labelled meta-iodobenzylguanidine (131I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach.Materials and methodsA review of 44 treatments in 25 patients treated with 131I-mIBG therapy was performed. Patients received 131I-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients.ResultsThe mean administered activity was 11089±7222 MBq and the mean whole-body dose for a single administration was 1.79±0.57 Gy. Tumour-absorbed doses varied considerably (3.70±3.37 mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease.ConclusionA highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized 131I-mIBG therapy.

Update of the Israeli Experience With Iodine-131 Metaiodobenzylguanidine Therapy for Patients With Malignant Pheochromocytoma, Paraganglioma, and Other NETs

Update of the Israeli Experience With Iodine-131 Metaiodobenzylguanidine Therapy for Patients With Malignant Pheochromocytoma, Paraganglioma, and Other NETs

Iodine-131 metaiodobenzylguanidine therapy for neuroblastoma: reports so far and future perspective.

Neuroblastoma, which derives from neural crest, is the most common extracranial solid cancer in childhood. The tumors express the norepinephrine (NE) transporters on their cell membrane and take in metaiodobenzylguanidine (MIBG) via a NE transporter. Since iodine-131 (I-131) MIBG therapy was firstly reported, many trails of MIBG therapy in patients with neuroblastoma were performed. Though monotherapy with a low dose of I-131 MIBG could achieve high-probability pain reduction, the objective response was poor. In contrast, more than 12 mCi/kg I-131 MIBG administrations with or without hematopoietic cell transplantation (HCT) obtain relatively good responses in patients with refractory or relapsed neuroblastoma. The combination therapy with I-131 MIBG and other modalities such as nonmyeloablative chemotherapy and myeloablative chemotherapy with HCT improved the therapeutic response in patients with refractory or relapsed neuroblastoma. In addition, I-131 MIBG therapy incorporated in the induction therapy was proved to be feasible in patients with newly diagnosed neuroblastoma. To expand more the use of MIBG therapy for neuroblastoma, further studies will be needed especially in the use at an earlier stage from diagnosis, in the use with other radionuclide formations of MIBG, and in combined use with other therapeutic agents.

Abstract B72: Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. A phase II pilot window study (AMRO-NB-HR-2000/01)

Abstract Purpose: Patients with high-risk (HR) neuroblastoma (NBL) have a poor prognosis and new treatment strategies are needed. 131I- Meta-Iodobenzylguanidine (MIBG) therapy alone has a significant antitumor efficacy against NBL. Topotecan (TPT) is a radio-enhancer and can potentiate radiation-induced cytotoxicity and up-regulate the uptake of MIBG in vitro. We designed a clinical study with upfront 131I-MIBG therapy and Topotecan for HR-NBL. We evaluated short term clinical response rate and outcome. Clinical response was scored according to International Neuroblastoma response Criteria (INRC) and Curie score (MIBG) after 2 courses of MIBG/TPT and after induction chemotherapy and HD ASCT. Haematological toxicity and the effect on harvesting/ feasibility performing autologous stem cell transplantation (ASCT) was evaluated. Topoisomerase-1 activity (Topo-1) levels were measured. Methods: Multi-centre, prospective (window phase II) study performed between 2000-2003 in HR NBL patients treated with 2 cycles of upfront 131I-MIBG therapy followed by the addition of TPT 0.7 mg/m2 for 5 days after each course. Thereafter, patients received 4 courses of VECI chemotherapy, followed by surgery and HD ASCT. Results: Sixteen patients (10 male), median age 2, 8 yrs. NMYC amplified 8/14 (57%) and LOH1P in 7/15 (47%). Surgery performed in 12/16 (75%) patients. Clinical response after 2x MIBG/TPT 15/16 (94%, VGPR/ PR/ MR), 1 PD; after 4x VECI 11/16 (69%, CR/ VGPR/ PR/MR), 3 PD, 1 death and 1 unknown. More than 50% reduction in MIBG Curie score after 2x MIBG/ TPT and subsequent 4x VECI courses in most cases. Overall outcome 2/16 currently alive. Long term follow up was limited, possibly related to low intensity induction chemotherapy as used in this study. Harvesting of stem cells in 13/16 patients (79%), mean yield 2, 2 CD34 pos/ kg, 9/16 (56%) underwent HD ASCT. Haematological toxicity was limited, median platelet recovery after HD ASCT was 73 days. Topo-1 activity was measured in 10/16 tumors, increased compared to reference level. Conclusion: Upfront treatment of HR-NBL with MIBG/TPT is feasible and highly effective after 2 courses. The toxicity is limited (haematological). Stem cell harvesting and HD ASCT are manageable. Citation Format: Max M. van Noesel, Kathelijne CJM Kraal, Jan de Kraker, Berthe LF van Eck-Smit, Godelieve AM Tytgat, Huib N. Caron. Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. A phase II pilot window study (AMRO-NB-HR-2000/01). [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B72.

Radionuclide therapy of endocrine-related cancer

This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50% and the 15-year survival rate for these patients is approximately 90%. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in >30% and symptom control in almost 80% of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes.

Management of neuroblastoma. Comparative study between first- and second-line radioionated meta-iodobenzylguanidine therapy and chemotherapy alone

Context: Neuroblastoma is a high-grade malignancy of childhood; it is chemo- and radio-sensitive, but prone to relapse after initial remission. Aim : The aim of this study was to document the impact of first- or second-line radioionated [ 131 I] meta-iodobenzylguanidine ( 131 I-MIBG) therapy or chemotherapy alone on the short-term response and long-term survival in untreated children and to further characterize the side-effects of MIBG treatment. Materials and Methods: In this interventional randomized controlled study, 123 children with advanced neuroblastoma were divided into three groups according to the treatment strategy: 65 were treated by chemotherapy alone (group I), 30 children who were not responding or had relapsed after chemotherapy were treated by second-line 131 I-MIBG (group II), and 28 children were treated by 131 I-MIBG as first-line from the start (group III). External beam radiotherapy was given to bone and brain secondaries when detected. Staging work up was done before, during, and after management with a follow-up period of 5 years. Statistical Analysis Used: All statistical tests were done using Whitney test for the continuous variants to compare the same group pre- and post-therapy. Total actuarial survival and disease-free survival were calculated using Kaplan-Meier analysis. Results: The number of treatments with 131 I-MIBG varied between 1 and 4 per patient (mean 3). Toxicity was seldom severe. Mainly myelosuppression was noticed. Response was documented before surgery for the primary tumor was performed. There was 9, 6, and 14 complete response (CR); 10, 18, and 16 partial responses (PR); 3, 2, and 23 with a stable disease (SD); and 6, 4, and 12 progressed in each group, respectively. Total actuarial survival was found to have a median of nearly 60, 55, and 33 months for groups I, II, and III, respectively, with a statistical significant difference between the three groups. Conclusion: The current study showed the effectiveness of MIBG as a first-line treatment in the management of locally advanced neuroblastoma cases with limited metastasis as initial response and long-term survival for the cases was favorable, while in cases with multiple metastases, chemotherapy should be given first-line and, in case of failure or relapse, second-line MIBG therapy is warranted.

A Catecholamine-Secreting Skull Base Sinonasal Paraganglioma Presenting with Labile Hypertension in a Patient with Previously Undiagnosed Genetic Mutation

Sinonasal paragangliomas are very uncommon neuroendocrine tumors that can present as skull base lesions. Functional paragangliomas are exceedingly rare. They can be associated with genetic mutations that have been associated with increased risk of head and neck paragangliomas. We present a case of a rare functioning sinonasal paraganglioma of the skull base in a patient with distant history of prior abdominal paragangliomas. The patient underwent subtotal endoscopic resection of the skull base lesion limited by carotid encasement of the tumor. They were treated with postoperative adjuvant radiation and therapeutic metaiodobenzylguanidine (MIBG) therapy. Genetic testing revealed succinate dehydrogenase B (SDHB) mutation. Skull base paragangliomas are rare tumors that may preclude complete surgical resection. 131Iodine-MIBG can be used as adjuvant therapy in postoperative external beam radiation and in MIBG avid tumors. Long-term follow-up is needed given locally aggressive nature of these tumors, especially for patients with history of genetic mutations such as SDHB mutations as recurrent paragangliomas may develop.

131I]Metaiodobenzylguanidine therapy in neural crest tumors

To evaluate the response of [¹³¹I] metaiodobenzylguanidine ([¹³¹I]MIBG) therapy in patients with neuroectodermal tumors and to assess their quality of life using the functional assessment of cancer therapy - general quality-of-life questionnaire for patients who are on follow-up after MIBG therapy. Thirty-two patients diagnosed with various subtypes of neuroectodermal tumors and treated with [¹³¹I]MIBG were included in this retrospective analysis. Response to therapy was evaluated objectively by comparing pretherapy and posttherapy biochemical markers, radiological investigations, and follow-up MIBG scans. Symptomatic response and quality of life were also evaluated in the follow-up visits. In seven patients with stage III neuroblastoma, an objective response rate was seen in 57% and a symptomatic response rate was seen in 29% of the patients. Among 11 patients with stage IV neuroblastoma, an objective response was observed in 36% and a symptomatic response in 36% of the patients. Among 12 patients with pheochomocytoma and paraganglioma, an objective response was noticed in 8%, but symptomatic improvement and stabilization of disease were seen in 75% of the patients belonging to this category. One patient with medullary carcinoma of the thyroid and one patient with mediastinal carcinoid did not show an objective response but had a stable disease; both patients showed symptomatic improvement. Quality of life has improved in all 11 patients who are still on follow-up. [¹³¹I]MIBG therapy can be of significant value in the treatment of patients with chemotherapy-resistant stage III and IV neuroblastomas who demonstrate good tracer uptake in diagnostic scans. MIBG therapy has the potential to stabilize the disease and provide symptomatic improvement in patients with metastatic/recurrent pheochomocytoma/paraganglioma and medullary carcinoma thyroid and carcinoid in which there is evidence of tracer accumulation in the tumor. Both single high dose or multiple fractionated doses are equally effective in improving the quality of life in metastatic/recurrent pheochomocytoma/paraganglioma.

Response, survival, and toxicity after iodine‐131–metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults

Adolescent and adult patients with neuroblastoma appear to have a more indolent disease course but a lower survival rate compared with their younger counterparts. The majority of neuroblastoma tumors specifically accumulate the radiolabeled norepinephrine analogue iodine-131-metaiodobenzylguanidine ((131) I-MIBG). Therefore, (131) I-MIBG has become increasingly used as targeted radiotherapy for patients with recurrent or refractory neuroblastoma. The objective of the current study was to characterize the toxicity and activity of this therapy in older patients. The authors performed a retrospective analysis of 39 consecutive patients aged ≥10 years with recurrent or refractory neuroblastoma who were treated with (131) I-MIBG monotherapy at the University of California at San Francisco under phase 1, phase 2, and compassionate access protocols. Sixteen patients were aged ≥18 years at the time of MIBG treatment initiation, whereas 23 patients were ages 10 to 17 years. The median cumulative administered dose of (131) I-MIBG was 17.8 millicuries (mCi)/kg. The majority of treatments led to grade 3 or 4 hematologic toxicities (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3]) that were similar in frequency among age strata. Three patients subsequently developed a hematologic malignancy or myelodysplasia. The overall rate of complete plus partial response was 46%. Patients aged ≥18 years at the time of first MIBG treatment had a significantly higher response rate compared with patients ages 10 to 17 years (56% vs 39%; P = .023). The median overall survival was 23 months with a trend toward longer overall survival for the subgroup of patients aged ≥18 years (P = .12). The findings of the current study suggest that (131) I-MIBG is a highly effective salvage agent for adolescents and adults with neuroblastoma.

Childhood phaeochromocytoma and paraganglioma: 100% incidence of genetic mutations and 100% survival

Introduction The aim is to identify the incidence of genetic mutations and outcome of children presenting with phaeochromocytoma/paraganglioma (PGL) to a single paediatric surgical service to determine the need for genetic counselling in associated kindreds. Methods A retrospective case note review was undertaken of all cases treated between 1998 and 2008 with particular reference to presentation, management, and predisposing genetic conditions. Results Seven cases (4 male, 3 female) were identified (median age, 13 years; interquartile range, 9-16). Three cases had a family history of phaeochromocytoma/PGL. All presented with neurologic symptoms related to hypertension, including headaches (n = 5), hemiparesis (n = 2), facial palsy, and hemianopia. All underwent surgical resection. Five patients had meta-iodobenzylguanidine (MIBG) therapy for apparently malignant features. All cases were found to have a predisposing genetic mutation: von Hippel-Lindau (n = 3), succinate dehydrogenase mutations (n = 3), and multiple endocrine neoplasia (n = 1). All patients are alive after a median follow-up of 5 (interquartile range, 2-7) years. Conclusions All 7 cases had a familial genetic mutation identified, and none arose de novo. We advocate genetic counselling for all families of children diagnosed with phaeochromocytoma/PGL with lifelong surveillance tailored to the underlying syndrome because of the increased risk of synchronous and metachronous tumours associated with these genetic syndromes.

Low-Dose Iodine-131 Metaiodobenzylguanidine Therapy for Patients With Malignant Pheochromocytoma and Paraganglioma

The following is a report on the clinical experience of an Israeli referral center for iodine-131 metaiodobenzylguanidine (131-MIBG) therapy for malignant pheochromocytoma (MPCC) and malignant paraganglioma (MPGG). The charts of 10 patients with MPCC (n = 7) and MPGG (n = 3) treated between 2000 and 2008 were reviewed. Response to 131-MIBG therapy was evaluated by tumor, hormone, and symptomatic relief criteria. The median follow-up was 18 months (2-48 months). The number of 131-MIBG treatments ranged from 1 to 4 (mean: 2.1). The average single dose of 131-MIBG was 5.4 +/- 0.2 GBq (145 +/- 5.0 mCi). The average cumulative dose was 11.6 +/- 1.6 GBq (310 +/- 44.0 mCi). There were no complete responses. Three patients (30%) had partial tumor response, 5 (50%) had stable disease, and 2 (20%) progressed after therapy. Five patients (50%) experienced symptomatic response. Hormone response was noted in 5 patients (50%). Progression-free survival was 17.5 months (2-47 months). One patient (10%) had thrombocytopenia and 2 patients (20%) developed subclinical hypothyroidism. Hormonal and symptomatic relief can be achieved with 131-MIBG therapy in patients with MPCC and MPGG with minor side effects.

Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy

Imaging of neuroendocrine tumours (NET) poses significant challenges because of the heterogeneous biology of the tumours that are represented by this class of neoplasia. NET can range from benign lesions to highly aggressive cancers. Structural imaging techniques have suboptimal sensitivity in most published series and diagnosis is often delayed until metastatic disease is present. Current guidelines emphasise the importance of functional imaging for evaluating the extent of NET. The mainstay of this type of imaging has been somatostatin receptor scintigraphy (SRS) with [111In]diethylenetriaminepentaacetic acid-octreotide (Octreoscan™). Routine use of single-photon emission computed tomography (SPECT) and particularly of hybrid SPECT/computed tomography (CT) has significantly improved localisation of tumour sites and evaluation of somatostatin receptor (SSTR) expression, which is important for predicting the likelihood of response to somatostatin analogues (SSA). Positron emission tomography (PET) can also now be used for evaluating SSTR expression. There are a number of peptides that have been evaluated but [68Ga]tetraazocyclodecanetetraacetic acid (DOTA)-octreotate (GaTate) PET/CT, which has been shown to be significantly more sensitive for detecting small lesions than Octreoscan™, is now probably the preferred agent because high uptake in known sites of disease provides a diagnostic pair for assessing suitability of patients for [177Lu]DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT). A range of other radiolabelled SSA has also been used for PRRT. Lesions without SSTR expression require alternative imaging and therapeutic strategies. Although fluorodeoxyglucose (FDG) uptake in low-grade NET is not generally increased relative to normal tissues, the loss of differentiation that often accompanies loss of SSTR expression may be associated with a significant increase in glycolytic metabolism and an accompanying improvement in the diagnostic sensitivity of FDG PET/CT. High FDG avidity is associated with a poorer prognosis but increases the likelihood of response to chemotherapy. Functioning tumours also require substrates for their secreted products. This can be exploited for NET imaging with amine precursor uptake being imaged using [18F]3,4-dihydrophenylalanine and serotonin-secreting tumours being sensitively detected using [11C]5-hydroxytryptamine. Both these agents are suitable for imaging with PET. [123I]meta-Iodo-benzyl-guanidine (MIBG) SPECT/CT may also be useful as a staging technique, particularly for NET of the sympathetic neuronal chain, and can identify patients who may be suitable for [131I]MIBG therapy. In the future, paradigms guided by clinical and biopsy features should allow personalised imaging paradigms aligned to therapeutic options.

Twenty-Eight Years Survival with Metastatic Phaeochromocytoma Treated by Repeated [131I] Metaiodobenzylguanidine Therapy

Pheochromocytoma is a rare neuroendocrine tumour. The prognosis after metastasis is poor, but there have been rare cases of prolonged survival of up to 26 years. Treatments for malignant phaeochromocytoma include surgical debulking, pharmacological control of hormone-mediated symptoms, 131I-metaiodobenzylguanidine (MIBG) therapy, chemotherapy and hormone therapy such as somatostatin analogues. We report the case of a patient, treated only with 131IMIBG therapy, who has survived 28 years since her diagnosis in 1981. The primary lesion was removed in 1982 by adrenectomy. In 1987, urinary catecholamines began to rise, heralding the onset of multiple bone and lung metastases. Her only treatment has been six doses of 131I-MIBG therapy between 1988 and 2003, (total of 22,804MBq). These treatments have relieved pain and led to the resolution of some of the metastatic lesions. She is now 81 years old and is currently very well and asymptomatic, despite evidence of residual thoracic and lumbar vertebral metastases.

Is aggressive local treatment necessary for diffuse liver involvement in patients with progression of stage 4s neuroblastoma to stage 4?

Three patients with stage 4S neuroblastoma without MYC-N amplification who progressed to stage 4 with persistent liver involvement, were treated with iodine 131–meta-iodobenzylguanidine therapy, chemotherapy, and surgery. Successive histologic examination of the liver showed differentiation of the tumor in 2 patients and fibrosis in the third. One patient died of brain metastases at the age of 30 months. The other 2 patients are alive at 50 and 44 months. Diffuse liver involvement in patients with stage 4 progression of previous stage 4S without MYC-N amplification may differentiate after treatment. The aim of this report is to draw attention to major liver surgery that it may not be necessary in tumors without MYC-N amplification, despite the persistence of lesions in the liver.

Hepatic absorbed radiation dosimetry during I-131 Metaiodobenzylguanadine (MIBG) therapy for refractory neuroblastoma

To compare the prediction of therapeutic hepatic radiation-absorbed dose rates from tracer imaging plus a linearity assumption to estimation based on intra-therapy imaging in (131)I metaiodobenzylguanidine (MIBG) therapy of refractory neuroblastoma. Conjugate-view images of the liver were obtained before therapy for seven patients at seven times after a tracer infusion of (131)I MIBG and at three times after the therapy infusion. Measured liver activities were converted to dose-rate estimates. Three statistical models of the rates assuming double exponential dependences on time were examined. One of the three models allowed for a multiplicative correction to the therapeutic late-phase dose-rate amplitude. Results from that model: (1) the tracer prediction of the late-phase absorbed-dose-rate amplitude was a factor of 1.75 times the intra-therapy-estimated value, and (2) the difference between tracer prediction of the radiation-absorbed dose and intra-therapy estimation of it was statistically significant, and (3) the liver radiation-absorbed dose did not reach 30 Gy. A statistical modeling analysis finds that the radiation-absorbed dose after therapy appears to be lower than that which is predicted from the linear scaling with administered activity of the tracer radiation-absorbed dose. Hepatocyte toxicity is the most likely reason but it is not high enough to produce clinically observable results.

Current Treatment of Malignant Pheochromocytoma

Pheochromocytomas are rare tumors of predominantly adrenal origin that often produce and secrete catecholamines. Malignancy occurs in a variable percentage of cases depending on genetic background and tumor location. Definitive diagnosis relies on the detection of distant metastases. Treatments for malignant pheochromocytoma include surgical debulking, pharmacological control of hormone-mediated symptoms, targeted methods such as external irradiation, and systemic antineoplastic therapy. Different agents and protocols for this purpose are reviewed, and their therapeutic potential is discussed. Literature on antineoplastic therapies for malignant pheochromocytoma was identified by searching the PubMed database with restriction to articles published in English during the past 30 yr. Because of the rarity of the condition, no randomized clinical trials concerning the treatment of malignant pheochromocytoma have been performed. The strategy established best is [131I]meta-iodobenzylguanidine (MIBG) therapy, which is well tolerated. Similar to cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine, MIBG can induce remission for a limited period in a significant proportion of patients. Octreotide as a single agent seems to be largely ineffective. MIBG radiotherapy and cyclophosphamide, vincristine, and dacarbazine chemotherapy are comparable with respect to response rate and toxicity. It is unclear whether combining both can improve the outcome. Future developments may include new multimodal concepts with focus on inhibition of angiogenetic factors and heat shock protein 90. Any present or new therapeutic approach must take into account the highly variable natural course of the disease.