¹¹¹In-DTPA⁰-octreotide (Octreoscan), ¹³¹I-MIBG and other agents for radionuclide therapy of NETs

This paper is a critical review of the literature on NET radionuclide therapy with (111)In-DTPA(0)-octreotide (Octreoscan) and (131)I-MIBG, focusing on efficacy and toxicity. Some potential future applications and new candidate therapeutic agents are also mentioned. Octreoscan has been a pioneering agent for somatostatin receptor radionuclide therapy. It has achieved symptomatic responses and disease stabilization, but it is now outperformed by the corresponding β-emitter agents (177)Lu-DOTATATE and (90)Y-DOTATOC. (131)I-MIBG is the radionuclide therapy of choice for inoperable or metastatic phaeochromocytomas/paragangliomas, which avidly concentrate this tracer via the noradrenaline transporter. Symptomatic, biochemical and tumour morphological response rates of 50-89%, 45-74% and 27-47%, respectively, have been reported. (131)I-MIBG is a second-line radiopharmaceutical for treatment of enterochromaffin carcinoids, mainly offering the benefit of amelioration of hormone-induced symptoms. High specific activity, non-carrier-added (131)I-MIBG and meta-astato((211)At)-benzylguanidine (MABG) are tracers with potential for enhanced therapeutic efficacy, yet their integration into clinical practice awaits further exploration. Amongst other promising agents, radiolabelled exendin analogues show potential for imaging and possibly therapy of insulinomas, while preclinical studies are currently evaluating DOTA peptides targeting the CCK-2/gastrin receptors that are overexpressed by medullary thyroid carcinoma cells.     

Successful and unsuccessful approaches to imaging carcinoids: Comparison of a radiolabelled tryptophan hydroxylase inhibitor with a tracer of biogenic amine uptake and storage,and a somatostatin analogue

A mouse mastocytoma model was used to determine the biodistribution and tumour uptake of four radiopharmaceuticals developed to target the serotonin synthetic pathway in carcinoid tumours. Three of the compounds were competitive inhibitors of the rate-limiting enzyme of serotonin synthesis, tryptophan hydroxylase. Radiolabelled iodo-dl-phenylalanine (iodine-131 PIPA) was found to have the highest uptake and tumourto-liver ratio. Four patients with known carcinoid tumours were then injected with 0.5 mCi¹³¹I-PIPA and imaged at 1, 4, 24 and 48 h post-injection. The radiopharmaceutical, however, failed to localize in the known tumour sites. This result was in contrast to the authors' experience of¹³¹I- and¹²³I-MIBG imaging of carcinoid tumours. Seven patients with known metastatic carcinoid tumours, two patients with symptoms of recurrence following tumour resection, one patient with completely resected disease, and two patients with a flushing syndrome of uncertain aetiology were studied with¹³¹I-MIBG. Three of the seven patients with known metastatic disease had positive¹³¹I-MIBG scans. Both patients with clinical evidence of recurrent disease had negative scans, as did the patient who was considered to have had complete resection of her primary tumour. The two patients with idiopathic flushing syndrome also had negative scans. Among seven patients imaged with¹²³I-MIBG there were four true-negative scans and one falsenegative, the latter in a patient with biochemical and CT evidence of recurrence. In a seventh patient with distant metastases there was variable uptake in some of the lesions. Four patients were studied with indium-111 penetetreodide. Two patients with metastatic carcinoid disease had positive scans, although hepatic metastases were not seen in one. Another two with idiopathic flushing syndrome had normal studies. The literature suggests that up 50% of carcinoid tumour cases are detected with¹³¹I-MIBG, compared to a sensitivity of 87% reported with somatostatin receptor imaging using¹¹¹In-pentetreotide. The experience with¹²³I-MIBG is much less extensive. The mechanisms of carcinoid tumour localization for each of the three classes of radiotracers are discussed and contrasted to their varying sensitivities. The relative success of¹³¹I-MIBG and¹¹¹In-pentetreotide relative to¹³¹I-PIPA may be related to the fact that¹³¹I-MIBG is actively taken up and stored by the enterochromaffin cells of the tumours and¹¹¹In-pentetreotide binds to cell surface receptors, whereas¹³¹I-PIPA binds to tryptophan hydroxylase, which may be present in quantities too small to permit tumours to be imaged.     

Nuclear medicine therapy of neuroblastoma.

Specific targeting of radionuclides to neuroblastoma, a neural crest tumour occurring predominantly in young children and associated with a relatively poor prognosis, may be achieved via the metabolic route (MIBG), receptor binding (peptides) or immunological approach (antibodies). The clinical role of 131I-MIBG therapy and radioimmunotherapy in neuroblastoma is discussed. In recurrent or progressive metastatic disease after conventional treatment modalities have failed, 131I-MIBG therapy, with an overall objective response rate of 35%, is probably the best palliative treatment, as the invasiveness and toxicity of this therapy compare favourably with that of chemotherapy, immunotherapy and external beam radiotherapy. In patients presenting with inoperable stage III and IV neuroblastoma, 131I-MIBG therapy at diagnosis is at least as effective as combination chemotherapy but is associated with much less toxicity. In patients with recurrent disease 131I-MIBG therapy in combination with hyperbaric oxygen therapy proved feasible and encouraging effects on survival have been observed. Attempts to intensify the treatment in relapsed patients by combination of 131I-MIBG therapy with high dose chemotherapy and/or total body irradiation have met with considerable toxicity. Developments in MIBG therapy aiming at improving the therapeutic index are mentioned. Early results of radioimmunotherapy using 131I-UJ13A or 131I-3F8 monoclonal antibodies have shown moderate objective response and considerable side effects in patients with stage IV neuroblastoma, who had relapsed or failed conventional therapy. New developments in radioimmunotherapy of neuroblastoma include the use of chimaeric antibodies, the enhancement of tumour uptake by modulation of antigen expression or by increasing the tumour perfusion/vascularity/permeability, the use of other labels and multistep targeting techniques, e.g. using bispecific monoclonal antibodies.     

Enhancement of 131I-MIBG uptake in carcinoid tumours by administration of unlabelled MIBG

Iodine-131 metaiodobenzylguanidine (131I-MIBG) has been used with success for the palliation of symptomatic, metastatic carcinoid tumours. However, only 70% of cases are MIBG-avid and tumour uptake is not always sufficient for therapy. At The Netherlands Cancer Institute 34 carcinoid patients with no or insufficient uptake were treated with escalating doses of unlabelled ('cold') MIBG. No objective remissions were recorded, but a palliative effect (i.e. subjective disappearance of symptoms and/or reduction of medication by more than 50%) was observed in 60% of cases (mean duration 4.5 months). In 24 of the patients undergoing therapy with 'cold' MIBG, total body scintigraphy using 37 MBq 131I-MIBG was performed before and after infusion of 'cold' MIBG. The biodistribution of 131I-MIBG and its tumour to non-tumour ratios were compared. After 'cold' MIBG the 131I-MIBG uptake in the salivary glands was suppressed in all patients, myocardial uptake in 21, and uptake in normal liver tissue in 14. Pulmonary uptake was increased in 13 patients. More importantly, the tumour to non-tumour (T/NT) ratios improved in 17 of the 24 cases (by 7.8-111.4% at 24 h). Of the initial six patients demonstrating a significant increase in the T/NT ratio, five have subsequently received combined treatment of 7.4 GBq 131I-MIBG following the administration of 'cold' MIBG (both by 4 h intravenous infusion), resulting in a good palliative response in four of them. These patients had previously been excluded from therapy with 131I-MIBG only. It is concluded that the administration of unlabelled MIBG may not only provide palliation to patients with carcinoid tumours, but may also alter the biodistribution of MIBG, enabling 131I-MIBG therapy to be used in cases not qualifying for this treatment due to insufficient tumour uptake.     

<Superscript>131</Superscript>I-MIBG Therapy in metastatic phaeochromocytoma and paraganglioma

Purpose ¹³¹Iodine metaiodobenzylguanidine (¹³¹I-MIBG) is a radiopharmaceutical used for scintigraphic localisation of phaeochromocytomas and paragangliomas. The experience with its therapeutic use is limited. We report our experience for the treatment of malignant phaeochromocytoma and paraganglioma. Materials and methods The charts of 19 patients with malignant phaeochromocytoma (n = 12) or paraganglioma (n = 7), who were treated with ¹³¹I-MIBG, were retrospectively reviewed. Four patients (21%) received radiotherapy, three (16%) chemotherapy, and in one patient (5%), both chemotherapy and radiotherapy was given before ¹³¹I-MIBG therapy. Response to ¹³¹I-MIBG treatment was evaluated by objective as tumour response, biochemical and subjective response. Results Of the 19 patients, 13 (68%) were men, 6 (32%) were women. Ages ranged from 22 to 68 years (median, 47). The median initial dose was 7.4 GBq (200 mCi; range, 6.7 GBq–25.9 GBq, 180–700 mCi); median cumulative dose was 22.2 GBq (600 mCi; range, 6.8 GBq–81.4 GBq, 183–2200 mCi). Objective tumour response was achieved in 47% of the patients. Biochemical response rate was 67%, and symptomatic response was seen in 89% of the patients. Overall median follow-up was 29 months, with a range of 3–93 months. Haematologic complications were the most common side effects and were observed in 26% of the patients. Conclusion Our data support that symptomatic and biochemical response can be reached with ¹³¹I-MIBG therapy in patients with metastatic phaeochromocytoma and paraganglioma. Although complete tumour response was not observed, the palliation and control of tumour function by ¹³¹I-MIBG therapy may be valuable for the patients.     

Role of 131I-metaiodobenzylguanidine (MIBG) in the treatment of neuroendocrine tumours. Experience of the National Cancer Institute of Milan.

BACKGROUND: 45 patients with neuroendocrine tumours (22 neuroblastomas, 10 phaeochromocytomas, 3 para-gangliomas, 6 medullary thyroid carcinomas and 4 carcinoids) underwent 131I-MIBG therapy. METHODS: All patients, with the exception of 5 phaeochromocytoma cases with nonoperable disease, had previously been treated with conventional therapies. Patients had a previous diagnostic scintigraphy with 131I-MIBG (activity 20-44.4 MBq) or with 123I-MIBG (activity 74-222 MBq). The therapeutic activity for adults ranged from 3.7 to 7.4 GBq of 131I-MIBG; for children from 2.7 to 5.5 GBq. All treatments were repeated at not less than 4-weekly intervals. The neuroblastoma patients were divided into two groups: the first included 14 patients with advanced metastatic disease not responding to previous treatments; the second included 8 patients with documented residual neuroblastoma tissue that could not be surgically removed after first-line therapy. RESULTS: In neuroblastoma patients with advanced disease resistant to previous therapies 2 out of 14 showed a partial response, 9 stable disease and 3 progression of cancer. In neuroblastoma patients with residual disease (7 evaluable out of 8) we obtained 3 partial responses; a stable response was observed in 3 patients. The results of MIBG therapy in the group of phaeochromocytoma patients (9 evaluable out of 10) consisted of 3 partial responses, 5 stable disease and 1 progression. Evaluation of the response carried out on the basis of biochemical parameters increased the responses and MIBG therapy showed good effectiveness in controlling the functional symptoms. In the group of paraganglioma patients we observed 1 complete, 1 partial and 1 stable response. In patients with medullary thyroid carcinoma a partial response was observed in 1 patient with mediastinal metastases and 2 disease stabilisations were seen in another 2 patients. Patients with carcinoids who underwent MIBG therapy showed 3 disease stabilisations. The overall toxicity was acceptable, especially considering that the majority of our patients had had previous myelotoxic treatments (chemotherapy and/or radiotherapy, alone or in combination). CONCLUSIONS: On the basis of our experience we can conclude that 131I-MIBG therapy is effective and also well tolerated.     

Nuclear medicine therapy of pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas are rare catecholamine-producing tumors which arise from chromaffin tissue. When a pheochromocytoma/paraganglioma is suspected, biochemical confirmation is based on 24-hour urinary excretion rates of catecholamines and their metabolites (metanephrines, VMA, etc.). Following biochemical confirmation non invasive imaging techniques such as CT and/or MR of the abdomen and 123I-MIBG scintigraphy are performed to localize the tumor. 111In-octreotide may also be applied, mainly to localize head and neck chemodectomas. Malignant paragangliomas of either adrenal or extra-adrenal origin show a variable natural history: from a locally invasive indolent tumor to a highly aggressive malignancy. Surgery with complete resection or debulking of the primary tumor is the standard treatment. External radiotherapy and chemotherapy are usually scarcely effective. An alternative treatment is 131I-MIBG therapy which is performed with high specific activity 131I-MIBG. Usually a standardized dose ranging from 3.7 to 9.1 GBq of 131I-MIBG is administered by slow i.v. infusion. In advanced stage cases 131I-MIBG therapy aims at symptom palliation and tumor function reduction as well as at tumor arrest or tumor regression. In these cases MIBG therapy allows prolonged survival and good quality of life. In less advanced cases the purpose of MIBG therapy is to complement surgery and to achieve the total eradication of the tumor. Non functioning malignant paraganglioma can some time also concentrate MIBG and can be treated with high doses of the tracer. 131I-MIBG therapy is a safe treatment and is usually well tolerated by the patient (with rather low myelotoxicity).     

Present status and progress of endocrine nuclear medicine

The author reviewed present status and progress of endocrine nuclear medicine including thyroid, parathyroid, adrenocortical, adrenomedullary and somatostatin receptor imaging and also radionuclide therapy of Basedow's disease, metastatic foci of post-operative thyroid cancer and malignant neural crest tumor. Relatively new imaging agents include 99mTc-MIBI and 99mTc-tetrofosmin for parathyroid imaging and 111In-pentetreotide for somatostatin receptor imaging. It is hoped that therapy of malignant neural crest tumors such as metastatic pheochromocytoma and neuroblastoma with 131I-MIBG and somatostatin receptor imaging will be available in Japan as soon as possible.     

Stable disease and improved health-related quality of life (HRQoL) following fractionated low dose 131I-metaiodobenzylguanidine (MIBG) therapy in metastatic paediatric paraganglioma: observation on false "reverse" discordance during pre-therapy work up and its implication for patient selection for high dose targeted therapy

The incidence of paraganglioma in the paediatric population is exceedingly rare, accounting for < 0.1% of childhood cancers. We report here the response and toxicity profile in a case of malignant paraganglioma which was treated with what is currently perceived as an unconventional and non-standard approach, using three consecutive low doses of 131I-MIBG (a cumulative dose of 11 647.6 MBq). The patient had a stable disease at the end of 42 months follow-up following the first treatment with 131I-MIBG. Excellent symptomatic and hormonal responses were observed. The only adverse effect was mild nausea in the first 24 h after therapy. In addition to the potentially primary end point of radiological and biochemical response measurement, we, in this paper, endeavoured to look for a quality of life evaluation for this form of treatment. Given the rarity of this condition, the experience gained by this therapeutic approach is intriguing from response and toxicity standpoints and may be extrapolated to malignant pheochromocytoma as well. An apparent "reverse discordance" between 131I-MIBG scintigraphy and 99Tc(m)-MDP bone scan encountered during pre-therapy work up is also described with possible explanations. This draws attention to an important clinical issue in selecting patients for high dose targeted therapy.     

Enhanced tumor uptake in neuroendocrine tumors after intraarterial application of 131I-MIBG.

131I-labeled metaiodobenzylguanidine (MIBG) is an established treatment modality for neuroendocrine tumors. Because of low tumor doses, it has a predominantly palliative character. Our approach was to investigate whether intraarterial application of 131I-MIBG has the potential to enhance tumor uptake. METHODS: Seventeen patients with primary or metastasized neuroendocrine tumors received intraarterial treatment with 131I-MIBG, and 12 of these patients also had intravenous treatment. Every patient underwent intravenous 131I-MIBG whole-body scanning before therapy. For quantification, a tumor-to-whole-body ratio was calculated from the diagnostic and 24-h posttreatment scans. RESULTS: Compared with the intravenous application, intraarterial 131I-MIBG treatment provided an up to 4-fold higher tumor uptake. Mean uptake was enhanced by 69%, but this varied widely between patients. We did not observe any immediate complications from catheterization. Carcinoid-related side effects were noted in 7 of 17 patients and were not different from those seen with intravenous application. CONCLUSION: Intraarterial treatment with 131I-MIBG is a safe alternative to intravenous application and provides a 69% higher mean tumor uptake. We propose to attempt intraarterial MIBG treatment in every patient to assess its potential benefit.     

A comparison of targeting of neuroblastoma with mIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

Iodine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targeting ability in neuroblastoma patients. The SK-N-SH tumour cells used in the mouse experiments show good MIBG uptake and provide a relatively low number of 6,300 binding sites/cell for mAb chCE7. Tumours were treated with single injections of 131I-MIBG (110 MBq) and with 131I-labelled mAb chCE7 (17 MBq) and both agents showed antitumour activity. After therapy with 131I-chCE7, the subcutaneous tumours nearly disappeared; treatment with 131I-MIBG was somewhat less effective, resulting in a 70% reduction in tumour volume. A calculated tumour regrowth delay of 9 days occurred with a radioactivity dose of 17 MBq of an irrelevant control antibody mAb 35, which does not bind to SK-N-SH cells, compared with a regrowth delay of 34 days with 131I-mAb chCE7 and of 24 days with 131I-MIBG. General toxicity appeared to be mild, as assessed by a transient, approximate 10% maximum decrease in body weight during the treatments. The superior growth inhibition achieved by 131I-chCE7 compared with 131I-MIBG can be explained by its prolonged retention in the tumours, due to slower normal tissue and plasma clearance. Cross-reaction of mAb chCE7 with L1-CAM present in normal human tissues was investigated by direct binding of radioiodinated mAb to frozen tissue sections. Results showed a strong reaction with normal human brain tissue and weak but detectable binding to normal adult kidney sections. Seven patients with recurrent neuroblastoma were sequentially imaged with 131I-MIBG and 131I-chCE7. The results underlined the heterogeneity of neuroblastoma and showed the two imaging modalities to be complementary. 131I-chCE7 scintigraphy may have clinical utility in detecting metastases which do not accumulate 131I-MIBG, and the antibody may hold potential for radioimmunotherapy, either by itself or in combination with 131I-MIBG.     

Whole-body iodine-131 metaiodobenzylguanidine imaging for detection of bone metastases in patients with paraganglioma: comparison with bone scintigraphy

Iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) therapy is an effective treatment for patients with malignant paraganglioma for which surgical resection is not indicated. We performed high-dose ¹³¹I-MIBG therapy on two patients with malignant paraganglioma and multiple bone metastases. The bone metastases were diagnosed by magnetic resonance imaging (MRI). Metastatic bone lesions were evaluated by whole-body ¹³¹I-MIBG imaging and bone scintigraphy. Whole-body ¹³¹I-MIBG imaging showed extensive metastatic bone lesions, whereas conventional bone scintigraphy did not. There was a remarkable discrepancy between ¹³¹I-MIBG imaging and bone scintigraphy in the diagnosis of metastatic bone lesions of malignant paraganglioma in our two patients. High-dose ¹³¹I-MIBG imaging may detect early stages of bone metastases, compared with bone scintigraphy, in patients with malignant paraganglioma.     

Long-term efficacy of low activity meta-[131I]iodobenzylguanidine therapy in patients with disseminated neuroendocrine tumours depends on initial response

BACKGROUND: meta-[131I]Iodobenzylguanidine (131I-MIBG) has been used to treat patients with disseminated neuroendocrine tumours (NET). However, so far there is limited information related to the efficacy of this agent beyond the normal 6-month assessment period. Before we can assume that such treatment would be beneficial to patients with these tumours the outcome of the patients over a longer time course should be determined. In many centres financial or radiation protection constraints mean that lower activities of 131I-MIBG have to be used at each administration, therefore instead of giving a single administration of a higher activity 131I-MIBG a series of multiple lower activity administrations are used. METHODS: The case records of 25 patients who had received 131I-MIBG over a 4-year period, from 1 June 1997 to 30 June 2001, were reviewed. Overall time of clinical follow-up range from 1 to 60 months, with a mean of 16 months). There were 16 female and nine male patients (mean age 55.6 years; range, 30-79 years). Most of patients had carcinoid (17), two had phaeochromocytoma, two gastrinoma and two an undifferentiated NET, one had malignant paraganglioma and one had medullary cell carcinoma of the thyroid. All had avid uptake for 123I-MIBG on diagnostic scanning. The minimum number of treatments received was 1 in 4 patients (with activities of 2.0 to 3.4 GBq); the maximum was 11 treatments (with cumulative activities as high as 29.1 GBq). Treatment was given using an infusion pump and was normally repeated at 12- to 16-week intervals (mean number of treatments per patient, 4). Response to therapy was determined by changes in the size of the tumour on computed tomography and/or magnetic resonance imaging using the response evaluation criteria in solid tumours (RECIST). Toxicity was measured using blood and urine tests of renal, hepatic, thyroid and bone marrow function. The median time from the last treatment to progression of disease and death (if applicable) was also calculated. RESULTS: No significant or long-lasting toxicity was encountered. At 6 months after the patient's last treatment, 18 patients (72%) had no evidence for progression. Twelve months after their last treatment 12 (48%) patients had no evidence for progression. At 18 months after the patient's last treatment, only seven patients (28%) had no progression of their disease. Overall, the median progression-free survival was 15 months. In those patients with stability or response at 6 months there was a prolonged progression-free survival and overall survival. In those with progression of disease at 6 months, at the 6-month assessment point, there had been four deaths (16%), at 12 months, there were three additional cancer deaths and finally at 18 months, there were a further five deaths. The median survival was 18 months. In those patients who died the mean time interval between disease progression and death was 4.6 months (range 0-12 months). CONCLUSION: Of the patients treated with low-activity 131I-MIBG 68% had significant benefit for at least 6 months post-treatment. In these patients with progressive and extensive disease this technique provided prolonged progression-free and overall survival with minimal side effects especially if an initial response to treatment was seen.     

Meta[131I]iodobenzylguanidine therapy for patients with metastatic and unresectable pheochromocytoma and paraganglioma

IntroductionPheochromocytomas (PHEOs) and paragangliomas (PGLs) are tumors that can exhibit a malignant behavior. Targeted radiotherapy with ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) has proven useful in patients with unresectable, metastatic and/or relapsed disease.MethodsWe review the literature and our experience at UCSF to highlight important characteristics of PHEO/PGL and the use of ¹³¹I-MIBG in the treatment of this disease.ResultsThese tumors are rare, with a diagnosed incidence of only two to four cases per million annually; 40% are discovered at autopsy. Clinical manifestations are caused by excess secretion of catecholamines, although some PGLs are nonsecretory. Approximately 25% of patients with PHEO/PGLs have an underlying genetic predisposition. The risk of a germline mutation is higher in children. Diagnostic evaluation should include serial determinations of fractionated metanephrines and serum chromogranin A. Staging requires both ¹²³I-MIBG and full-body magnetic resonance imaging or ¹⁸FDG-PET scanning. The primary treatment for PHEO/PGL is resection. Patients may be candidates for treatment with ¹³¹I-MIBG if they have unresectable or metastatic tumors that are avid for MIBG. Such patients usually respond to this targeted radioisotope therapy and many achieve a durable remission. Myelosuppression is a dose-related side effect that can be treated with transfusions or autologous hematopoietic stem cells. Late side effects can include infertility, myelodysplasia and second cancers.ConclusionsTreatment with ¹³¹I-MIBG can be considered for patients if surgery is not feasible. There are significant risks associated with this treatment, but the majority of patients will respond. Treatment with ¹³¹I-MIBG should be done at institutions with experience in delivering targeted radiotherapeutics.     

Neuroblastoma imaging using a combined CT scanner-scintillation camera and 131I-MIBG.

High-dose administration of 131I-metaiodobenzylguanidine (131I-MIBG) continues to be a promising treatment for neuroblastoma. However, currently used methods of estimating 131I-MIBG uptake in vivo may be too inaccurate to properly monitor patient radiation exposure doses. To improve localization and uptake measurements over currently practiced techniques, we evaluated different methodologies that take advantage of the correlated patient data available from a combined CT-scintillation camera imaging system. METHODS: Serial CT and radionuclide scans of three patients were obtained on a combined imaging system. SPECT images were reconstructed using both filtered backprojection and maximum-likelihood expectation maximization (MLEM). Volumes of interest (VOIs) were defined on anatomic images and automatically correlated to spatial volumes in reconstructed SPECT images. Several radionuclide quantification methods were then compared. First, the mean reconstructed values within coregistered SPECT VOIs were estimated from MLEM reconstructed images. Next, we assumed that reconstructed activity in SPECT voxels were linear combinations of activities present in individual objects, weighted by geometric factors derived from CT images. After calculating the weight factors by modeling the SPECT imaging process with anatomically defined VOIs, least-squares fitting was used to estimate the activities within lesion volumes. We also estimated the lesion activities directly from planar radionuclide images of the patients using similar linearity assumptions. Finally, for comparison, lesion activities were estimated using a standard conjugate view method. RESULTS: Activities were quantified from three patients having a total of six lesions with volumes ranging from 0.67 to 117 mL. Methods that used CT data to quantify lesion activities gave similar results for planar and tomographic radionuclide data. Estimating activity directly from mean VOI values in MLEM-reconstructed images alone consistently provided estimates lower than CT-aided methods because of the limited spatial resolution of SPECT. Values obtained with conjugate views produced differences up to fivefold in comparison with CT-aided methods. CONCLUSION: These results show that anatomic information available from coregistered CT images may improve in vivo localization and measurement of 131I-MIBG uptake in tumors.     

Evaluation of (111)In-pentetreotide, (131)I-MIBG and bone scintigraphy in the detection and clinical management of bone metastases in carcinoid disease

Bone metastases are assumed to be rare in carcinoid disease and to be associated mainly with bronchial primaries. The aim of the present study was to evaluate the occurrence of bone metastases in patients with metastatic carcinoid tumours, and the role of various nuclear medicine modalities (bone scintigraphy, (111)In-pentetreotide and (131)I-MIBG) in its detection and clinical management. Nine (2 women, 7 men, median age 65 years) out of 86 consecutive carcinoid patients treated between 1987 and 1998 developed bone metastases (10%) with a median interval of 37 months between the diagnosis of metastatic carcinoid and bone metastases. Seven of them had non-bronchial primaries. (111)In-pentetreotide scintigraphy failed to detect the bone lesions in 50% of the cases, and (131)I-meta-iodobenzylguanidine(MIBG) scintigraphy in almost 80% of cases. Standard bone scintigraphy, however, was positive in all. Pain relief of bone metastases by means of radiation therapy was obtained in 5 of 6 patients. In another patient palliation of pain symptoms was obtained with Rhenium-186-hydroxyethylidene diphosphonate. Octreotide, Interferon of MIBG were ineffective for this purpose. It is concluded that bone metastases in carcinoid patients may be missed on (131)I-MIBG and (111)In-pentetreotide scintigraphy. Bone scintigraphy is a sensitive imaging technique. Diagnostic nuclear medicine modalities may be helpful in the clinical management of carcinoid disease.     

Long-term efficacy of radionuclide therapy in patients with disseminated neuroendocrine tumors uncontrolled by conventional therapy.

Therapeutic options in patients with advanced-stage gastroenteropancreatic (GEP) neuroendocrine tumors are limited. We compared the efficacy of radionuclide therapy with 111In-pentetreotide and 131I-metaiodobenzylguanidine (MIBG) in 20 patients (group A) with the outcome of similar patients who could not be treated for nonmedical reasons (group B, n = 12). The intent was to treat all patients because of uncontrolled tumor disease (n = 21), contraindication to chemotherapy or surgery (n = 7), or uncontrolled and badly tolerated clinical symptoms (n = 4). METHODS: Group A patients received 3 monthly administrations of 3.7-7.4 GBq of 131I-MIBG (n = 5) or 7 GBq of 111In-pentetreotide (n = 15), according to the best tracer uptake. Clinical evaluation, biologic tests, and conventional imaging were performed at 3, 6, 12, 18, and 24 mo. Therapy was considered beneficial if clinical status improved, laboratory tests for secreting tumors improved by >20%, tumor progression was halted, the size of the most significant localization had decreased by >25%, and the dosage of analgesic and cold somatostatin therapy could be lowered. Pejorative events were defined as side effects due to therapy, relapse in clinical symptoms, tumor progression, tumor laboratory marker increase, and death. RESULTS: The overall survival rate at 3 mo was significantly higher in group A (P = 0.05). Radionuclide therapy was beneficial in 14 patients (73% of group A), with only 1 significant side effect. The average time before relapse was 16.1 +/- 7.8 mo. The overall Kaplan-Meier survival rate and cumulative progression-free and cumulative event-free survival rates during the first 15 mo were significantly higher in patients receiving radionuclide therapy (P = 0.019, P = 0.024, and P = 0.019, respectively). CONCLUSION: Radionuclide therapy is feasible and safe and significantly defers the occurrence of fatal and nonfatal events in patients clinically uncontrolled by conventional therapy.     

Radionuclide therapy in the United Kingdom in 1995.

A postal survey was conducted in the UK in 1996 to determine the facilities available and the level of activity at centres where radionuclide therapy was practised in 1995. A response rate of 79% indicated that 102 centres were providing radionuclide therapy, with 339 clinicians holding ARSAC certificates, 57% of whom were clinical oncologists. There were 84 beds available for therapy and the total number of patients treated was 11,435. Patient numbers treated by disease or procedure were: haematological, 569 (5%); benign thyroid disease, 9059 (79.2%); malignant thyroid disease, 911 (8%); bone pain palliation, 425 (3.5%); radiosynovectomy, 321 (2.8%); neuroendocrine tumour therapy, 76 (0.7%); and intra-cavitary, 56 (0.5%). The total amounts of activity of individual radiopharmaceuticals administered in GBq were: 131I, 16,695; 90Y-colloid, 88; 32P, 94.6; 131I-MIBG, 646; 89Sr, 57.6; and 186Rh-HEDP, 16. Average waiting times varied from 1 to 5 weeks, with a range of 0 to 52 weeks for some therapies. Most centres had the services of a physicist available. Compared with teaching hospitals, the 61 district hospitals had fewer allocated beds, but treated almost half of all patients. The numbers of therapies undertaken were increasing at many centres and this has implications for long-term planning.     

Evaluation of suspected recurrent papillary thyroid carcinoma with [18F]fluorodeoxyglucose positron emission tomography

We evaluated 10 patients with suspected recurrent papillary thyroid cancer using [18F]fluorodeoxyglucose positron emission tomography (FDG PET). Prior therapy included total (n = 8) or subtotal (n = 2) thyroidectomy, radiation therapy (n = 2) and radioiodine ablation (n = 2). All patients had an 131I scan and one or more of the following imaging studies: 99Tcm-sestamibi scan. 111In-octreotide scan, sonography (US), computed tomography (CT) and magnetic resonance imaging (MRI). Both the PET and 131I scans were negative in four patients. The PET and 131I scan results were discordant in six patients. Of the six discordant cases, five had true-positive PET scans and false-negative 131I studies. Three of these patients underwent neck lymph node dissection that showed positive histology for metastatic papillary carcinoma. Another patient had fine-needle aspiration (FNA) of a parapharyngeal mass that was also positive for papillary carcinoma. One patient was treated with radiation to the thyroid surgical bed based on an elevated serum thyroglobulin and a positive PET finding. Tumour response with a decrease in the size of the lesion was documented by a follow-up MRI scan. The remaining patient had a presumed false-positive PET scan, since a difficult hypocellular FNA of a small palpable lymph node was negative for tumour. We conclude that FDG PET is useful in the evaluation of patients with suspected recurrent papillary thyroid cancer when the 131I scan is negative.