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

BACKGROUND:

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 (¹³¹I‐MIBG). Therefore, ¹³¹I‐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.

METHODS:

The authors performed a retrospective analysis of 39 consecutive patients aged ≥10 years with recurrent or refractory neuroblastoma who were treated with ¹³¹I‐MIBG monotherapy at the University of California at San Francisco under phase 1, phase 2, and compassionate access protocols.

RESULTS:

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 ¹³¹I‐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).

CONCLUSIONS:

The findings of the current study suggest that ¹³¹I‐MIBG is a highly effective salvage agent for adolescents and adults with neuroblastoma. Cancer 2011;. © 2011 American Cancer Society.     

Promising therapeutic targets in neuroblastoma

Neuroblastoma, the most common extracranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease and have a 5-year event-free survival of <50%. New approaches with targeted therapy may improve efficacy without increased toxicity. In this review we evaluate 3 promising targeted therapies: (i) (131)I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical that is taken up by human norepinephrine transporter (hNET), which is expressed in 90% of neuroblastomas; (ii) immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, which is expressed on 98% of neuroblastoma cells; and (iii) inhibitors of anaplastic lymphoma kinase (ALK), a tyrosine kinase that is mutated or amplified in ~10% of neuroblastomas and expressed on the surface of most neuroblastoma cells. Early-phase trials have confirmed the activity of (131)I-MIBG in relapsed neuroblastoma, with response rates of ~30%, but the technical aspects of administering large amounts of radioactivity in young children and limited access to this agent have hindered its incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also shown activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small-molecule inhibitor of ALK has shown promising preclinical activity for neuroblastoma and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma.     

Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with 131I-metaiodobenzylguanidine

Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with ¹³¹I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after ¹³¹I-MIBG have not been defined.This is a multi-institutional retrospective review of patients with neuroblastoma treated with ¹³¹I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to ¹³¹I-MIBG. A competing risk regression was used to identify potential risk factors for SMN.The analytical cohort included 644 patients treated with ¹³¹I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4–13.0%) and 14.3% (95% CI, 8.3–23.9%) at 5 and 10 years from first ¹³¹I-MIBG, respectively. No increase in SMN risk was found with increased number of ¹³¹I-MIBG treatments or higher cumulative activity per kilogram of ¹³¹I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first ¹³¹I-MIBG, bone disease, disease status at time of first ¹³¹I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1–0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma.The cumulative risk of SMN after ¹³¹I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk.     

Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age

PurposeTo determine the response to radionuclide targeted therapy with I-131-metaiodobenzylguanidine (¹³¹I-MIBG) as induction therapy in high-risk neuroblastoma patients.Patients and methodsThe protocol dictated at least two cycles of ¹³¹I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months.ResultsOf 44 consecutive patients, 41 were evaluable after two courses of ¹³¹I-MIBG. The objective response rate at this point was 66%. In 24 patients, ¹³¹I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%.ConclusionFirst line ¹³¹I-MIBG-targeted therapy is a valuable tool in the treatment of MIBG-positive high-risk neuroblastoma patients.     

(131)I-MIBG radionuclide therapy is safe and cost-effective in the control of symptoms of the carcinoid syndrome.

BACKGROUND: The standard treatment used to control the symptoms of carcinoid syndrome (CS) involves subcutaneous injections of the somatostatin analogue octreotide. This is expensive (US $8000--16,000 per year), and treatment may be for many years. The aim of this study was to evaluate the efficacy and cost-effectiveness of our experience over the last 5 years with 1-131-labelled metaiodobenzylguanidine (MIBG) radionuclide therapy in the palliation of patients with CS. METHODS: A consecutive series of 20 symptomatic patients (referred between 1994 and 1999) with CS were evaluated. Fifteen of them underwent(123)I-MIBG scanning. Of the 13 patients with significant tracer uptake in metastatic deposits compared to background, 12 underwent a course of therapeutic(131)I-MIBG (one patient refused). Symptoms, biochemical markers, CT scans, follow-up(123)I-MIBG scans, and the requirement for octreotide were used to assess outcome of treatment. Costs of(131)I-MIBG and octreotide treatments were compared. RESULTS: MIBG treatment was well tolerated in all with only transient side-effects. Ten patients showed a measurable clinical improvement. Seven had a complete clinical response. The mean duration of response was 15.4 months. Octreotide was not required or was reduced in eight patients. Treatment with(131)I-MIBG resulted in a saving of US $1000 per patient, with effective symptom control, when compared to octreotide. CONCLUSION: 1-131 MIBG therapy is a safe and cost-effective therapeutic option to successfully control symptoms in patients with carcinoid syndrome. Copyright Harcourt Publishers Limited.     

Improved radiation protection of the thyroid gland with thyroxine,methimazole, and potassium iodide during diagnostic and therapeutic use of radiolabeled metaiodobenzylguanidine in children with neuroblastoma

BACKGROUND: During radiolabeled metaiodobenzylguanidine (MIBG) administration in children with neuroblastoma, the thyroid is protected from (123/131)I uptake by potassium iodide. Despite this protection, up to 64% of patients develop thyroid dysfunction. The authors introduce a new method of radiation protection for the thyroid gland. METHODS: In a prospective cohort study, 34 children with neuroblastoma who received MIBG were given thyroxine, methimazole, and potassium iodide for protection of the thyroid gland. Protection started 1 day before the start of diagnostic 123I-MIBG and was continued until 4 weeks after the last therapeutic 131I-MIBG dose. Follow-up measurements were performed every 3 months after the protection was stopped. Visualization of the thyroid on MIBG images was reviewed by three nuclear medicine physicians. Results were compared with a historic control group of children who had received potassium iodide for thyroid protection during MIBG administration. RESULTS: After a mean follow-up of 19 months, there were 23 evaluable patients. Thyroid function was normal in 86% of survivors compared with 44% of children in the historic control group (P=0.011; Pearson chi-square test). Scintigraphic visualization of the thyroid diminished substantially after the new protection (21.5% vs. 5.3%, respectively; P=0.000). CONCLUSIONS: The results of the current study indicate that compared with potassium iodide alone, combined thyroxine, methimazole, and potassium iodide protect the thyroid more effectively against radiation damage from (123/131)I during diagnostic and therapeutic MIBG administration in children with neuroblastoma.     

Impact of metaiodobenzylguanidine scintigraphy on assessing response of high-risk neuroblastoma to dose-intensive induction chemotherapy.

PURPOSE: The International Neuroblastoma Response Criteria (INRC) recommend, but do not make mandatory, metaiodobenzylguanidine (MIBG) scans. We present the first report on the effect of MIBG scans on the classification of response to dose-intensive induction therapy. PATIENTS AND METHODS: After dose-intensive induction and before consolidative therapy, 162 Memorial Sloan-Kettering Cancer Center (MSKCC) patients with high-risk neuroblastoma (NB) had MIBG scans (99 with (131)I, 63 with (123)I), computed tomography, (99m)Tc-bone scan, bone marrow (BM) tests, and urine catecholamine measurements. Induction included high-dose cyclophosphamide (140 mg/kg) plus other agents and high-dose cisplatin (200 mg/m(2))/etoposide (600 mg/m(2)). RESULTS: In 90 patients treated with dose-intensive therapy from diagnosis at MSKCC, the use of MIBG scintigraphy increased the incomplete response numbers from 14 (15.5%) to 20 (22%), giving a complete remission/very good partial remission (CR/VGPR) rate of 78%. In 72 patients treated before referral to MSKCC for intensified therapy, MIBG findings changed the response classification of one patient; the CR/VGPR rate was 43%. MIBG scans showed no BM disease in 15 of 38 patients with histologically evident NB in BM but did show uptake consistent with BM involvement in five patients who had no NB observed in BM tests. CONCLUSION: With the less effective therapy consequent to the intensification of induction only after initial exposure to standard-dose chemotherapy, MIBG scintigraphy merely confirms the findings of other staging modalities for detection of relatively widespread residual NB. However, when dose-intensive therapy is initiated at diagnosis, the reliable achievement of major disease responses makes extensive BM testing and MIBG scintigraphy prerequisites for accurate determination of disease status.     

Second malignancies in children with neuroblastoma after combined treatment with 131I-metaiodobenzylguanidine

BACKGROUND: (131)I-metaiodobenzylguanidine ((131)I-MIBG) is selectively taken up by cells of neural crest origin, allowing targeted radiotherapy of tumors such as neuroblastoma (NB) and pheochromocytoma. Radiotherapy may provide additional benefits in the treatment of NB, with moderate side effects such as hematologic and thyroid toxicity. However, with longer follow-up, other complications might occur. We describe our experience with second cancers occurring in children treated with (131)I-MIBG and chemotherapy. METHODS: The clinical records of 119 consecutive NB cases treated with (131)I-MIBG at a single institution between 1984 and 2001 were reviewed for the occurrence of a second malignant neoplasm (SMN). RESULTS: Overall, five cases of SMN occurred in the study patients. In particular, two cases of myeloid leukemia, one of angiomatous fibrous histiocytoma, one of malignant schwannoma, and one case of rhabdomyosarcoma were detected. The schwannoma and the rhabdomyosarcoma developed within the residual neuroblastic mass after first-line therapy. CONCLUSIONS: Should (131)I-MIBG treatment become more broadly employed in the therapeutic strategy for neuroblastoma, the risk of second cancer will have to be taken into consideration. The organization of an international registry of subjects treated with (131)I-MIBG might better define the frequency and features of second malignancies following this radiometabolic approach.     

Radionuclide therapy of adrenal tumors

Adrenal tumors arising from chromaffin cells will often accumulate radiolabeled metaiodobenzylguanidine (MIBG) and thus are amenable to therapy with I-131 MIBG. More recently, therapy studies have targeted the somatostatin receptors using Lu-177 or Y-90 radiolabeled somatostatin analogs. Because pheochromocytoma (PHEO)/paraganglioma (PGL) and neuroblastoma (NB), which often arise from the adrenals, express these receptors, clinical trials have been performed with these reagents. We will review the experience using radionuclide therapy for targeting PHEO/PGL and NBs. J. Surg. Oncol. 2012; 106:632-642. ? 2012 Wiley Periodicals, Inc.     

Pharmacokinetics and intracellular distribution of the tumor-targeted radiopharmaceutical m-iodo-benzylguanidine in SK-N-SH neuroblastoma and PC-12 pheochromocytoma cells

Radiodinated meta-iodobenzylguandine (MIBG) is increasingly used for the diagnosis and targeted radiotherapy of neuro-adrenergic tumors. We have investigated various conditions for specific tumor loading and prolonged retention of this radiopharmaceutical in poorly differentiated SK-N-SH neuroblastoma and highly differentiated PC-12 pheochromocytoma cells. At a constant value of drug concentration x incubation time, short incubations were superior to protracted incubations for maximal cell loading. This effect was most pronounced in the SH-N-SH neuroblastoma cells. In highly differentiated pheochromocytoma cells, the levels of MIBG storage remained high and unchanged during incubations up to 46 hr in label-free medium, while primitive SK-N-SH cells lost 40-50% of accumulated drug by diffusion. In PC-12 cells, susceptibility of stored MIBG to exocytotic release induced by acetylcholine or K+ was similar to that of natural norepinephrine (NE) and prevented by the Ca(++)-channel blockers verapamil and nifedipine. Conversely, granule-poor SK-N-SH cells were insensitive to exocytotic release of MIBG. Uptake and retention capacities were minimally impaired by an externally delivered radiation dose of 5 Gy to mimic the radiobiological effect of 131I-MIBG in tumors. In pre-irradiated cultures, drug uptake was even stimulated, probably due to enrichment in non-proliferating cells. An autoradiographic comparison of the (sub)cellular distributions of 3H-norepinephrine and 125I-MIBG showed that routine conditions of cell fixation and sample processing do not yield reliable results regarding localization of MIBG.     

Role of adrenal imaging in surgical management

Adrenal imaging using radiopharmaceuticals is a functional test that can contribute significantly to surgical management and follow-up of patients with either benign or malignant conditions of the adrenal cortex and medulla. Imaging of the cortex is achieved by iodine-131-labeled iodomethyl nor-cholesterol (NP-59), while adrenal medulla imaging can be successfully accomplished by 131I-metaiodobenzylguanidine (MIBG), which localizes in the adrenergic nerve terminal with norepinephrine. Both tests carry high sensitivity and specificity for functional tumors and hyperplasia, and often better than CT scanning. This article reviews the current status and clinical utility of nuclear imaging of the adrenal cortex in congenital hyperplasia, low renin hypertension and aldosteronism, and Cushing's syndrome. Adrenal medulla imaging is reviewed in light of our experience at the University of Texas M.D. Anderson Cancer Center in pheochromocytoma, neuroblastoma, and other neuroectodermal tumors. Investigation of 131I-MIBG therapy of metastatic tumors of neuroectodermal origin potentially offers a means of at least controlling symptoms of hormonal secretion in these patients.     

Combining anatomic and molecularly targeted imaging in the diagnosis and surveillance of embryonal tumors of the nervous and endocrine systems in children

Combining anatomical and functional imaging can improve sensitivity and accuracy of tumor diagnosis and surveillance of pediatric malignancies. MRI is the state-of-the-art modality for demonstrating the anatomical location of brain tumors with contrast enhancement adding additional information regarding whether the tumor is neuronal or glial. Addition of SPECT imaging using a peptide that targets the somatostatin receptor (Octreoscan) can now differentiate medulloblastoma from a cerebellar pilocytic astrocytoma. Combined MRI and Octreoscan is now the most sensitive and accurate imaging modality for differentiating recurrent medulloblastoma from scar tissue. CT is the most common imaging modality for demonstrating the anatomical location of tumors in the chest and abdomen. Addition of SPECT imaging with either MIBG or Octreoscan has been shown to add important diagnostic information on the nature of tumors in chest and abdomen and is often more sensitive than CT for identification of metastatic lesions in bone or liver. Combined anatomical and functional imaging is particularly helpful in neuroblastoma and in neuroendocrine tumors such as gastrinoma and carcinoid. Functional imaging with MIBG and Octreoscan is predictive of response to molecularly targeted therapy with 131I-MIBG and 90Y-DOTA-tyr3-Octreotide. Dosimetry using combined anatomical and functional imaging is being developed for patient-specific dosing of targeted radiotherapy and as an extremely sensitive monitor of response to therapy. Both MIBG and Octreotide are now being adapted to PET imaging which will greatly improve the utility of PET in medulloblastoma as well as increase the sensitivity for detection of metastatic lesions in neuroblastoma and neuroendocrine tumors.     

Improved effect of 131I-MIBG treatment by predosing with non-radiolabeled MIBG in carcinoid patients, and studies in xenografted mice

Background: ¹³¹I-meta-iodobenzylguanidine (MIBG) hasbeen used with success for the palliation of metastatic carcinoid. To qualifymore patients for this treatment, we evaluated the effect of predosing withnon-radiolabeled MIBG on ¹³¹I-MIBG tumour targeting in carcinoidpatients and in mice with BON human carcinoid xenografts. Patients and methods:Ten carcinoid patients with a faint tumourimaging on a diagnostic ¹³¹I-MIBG scan (1 mCi = 37 MBq, 5 mg MIBG)received non-radiolabeled MIBG prior to a second scintigraphy. In case ofimproved tumour targeting patients were treated with 200 mCi (7.4 GBq)¹³¹I-MIBG following a pharmacological predose of 20–40mg/m² MIBG. Results:In six patients, highly increased tumour/non-tumour ratios were seen due to reduced levels in normal tissues and increased tumouraccumulation. The combined treatment applied in five patients, considerablyimproved symptoms in all (duration 6–12 months), accompanied bybiochemical response in three. In BON carcinoid xenografted mice, MIBG wasinjected intraperitoneally followed by intravenous ¹²⁵I-MIBG withsimilar findings: increased tumour/non-tumour radioactivity ratios by1.5–3-fold. Conclusion:Predosing with non-radiolabeled MIBG resulted inimproved ¹³¹I-MIBG tumour targeting, prolonged palliation andencouragingly often biochemical responses in carcinoid.     

131I]MIBG and topotecan: a rationale for combination therapy for neuroblastoma

MIBG is selectively concentrated in neuroblastoma cells, and radioiodinated MIBG has been used with some success for targeted radiotherapy. However, long-term cure remains elusive, and the topoisomerase I inhibitor topotecan may improve upon existing [131I]MIBG therapy. While synergistic killing by combinations of ionising radiation and topoisomerase I inhibitors has been reported, there is no consensus on optimal scheduling. Furthermore, there has been no attempt to demonstrate radio-potentiation by topoisomerase I inhibitors and targeted radiotherapy. We are investigating various scheduled combinations of topotecan and [131I]MIBG on neuroblastoma cells, and preliminary data suggests that topotecan induces increased accumulation of [131I]MIBG in vitro.     

Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma.

PURPOSE: The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining (131)I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue. PATIENTS AND METHODS: Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received (131)I-MIBG 12 mCi/kg on day -21, followed by carboplatin (1,500 mg/m(2)), etoposide (800 mg/m(2)), and melphalan (210 mg/m(2)) administered from day -7 to day -4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated. RESULTS: The (131)I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil (> or = 0.5 x 10(3)/microL) and platelet (> or = 20 x 10(3)/microL) engraftment were 10 and 28 days, respectively. For the eight patients treated with metastatic disease, three achieved complete response and two had partial responses by day 100 after transplantation. CONCLUSION: Treatment with (131)I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.     

Different outcomes for relapsed versus refractory neuroblastoma after therapy with 131I-metaiodobenzylguanidine (131I-MIBG)

Background¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) is a targeted radiopharmaceutical with significant activity in high-risk relapsed and chemotherapy-refractory neuroblastoma. Our primary aim was to determine if there are differences in response rates to ¹³¹I-MIBG between patients with relapsed and treatment-refractory neuroblastoma.MethodsThis was a retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with ¹³¹I-MIBG at UCSF between 1996 and 2014. Results were obtained by chart review and database abstraction. Baseline characteristics and response rates between relapsed patients and refractory patients were compared using Fisher exact and Wilcoxon rank sum tests, and differences in overall survival (OS) were compared using the log-rank test.ResultsThe response rate (complete and partial response) to ¹³¹I-MIBG-based therapies for all patients was 27%. There was no difference in response rates between relapsed and refractory patients. However, after ¹³¹I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients (p = 0.02). Among all patients, the 24-month OS was 47.0% (95% confidence interval (CI) 39.9–53.9%). The 24-month OS for refractory patients was significantly higher at 65.3% (95% CI 51.8–75.9%), compared to 38.7% (95% CI 30.4–46.8%) for relapsed patients (p < 0.001).ConclusionsAlthough there was no significant difference in overall response rates to ¹³¹I-MIBG between patients with relapsed versusrefractory neuroblastoma, patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after ¹³¹I-MIBG compared to patients with refractory disease.     

Influence of cisplatin and doxorubicin on 125I-meta-iodobenzylguanidine uptake in human neuroblastoma cell lines

The combination of 131I-meta-iodobenzylguanidine (MIBG) with chemotherapy has recently been employed in the treatment of advanced stage neuroblastoma with encouraging results. However, the mechanisms underlying the interaction between these two different modalities of treatment have not yet been explored. In this study, human neuroblastoma cell lines pretreatment with cisplatin and doxorubicin increased cellular 125I-MIBG accumulation in a dose-dependent manner. Cell cycle analysis showed that increased 125I-MIBG accumulation correlated with the drug-induced G2/M phase block. Northern blot analysis demonstrated an increase in gene expression of the noradrenaline transporter induced by doxorubicin, but not by cisplatin treatment. Increased 125I-MIBG accumulation was also observed in murine xenografts of the human neuroblastoma cell line SK-N-DZ or BE(2)M17 treated intraperitoneally (i.p.) with cisplatin or doxorubicin, respectively. These results suggest that the combination of 131I-MIBG and these drugs could selectively increase radiation doses delivered to neuroblastomas.     

Scintigraphic response by 123I-metaiodobenzylguanidine scan correlates with event-free survival in high-risk neuroblastoma.

PURPOSE: To investigate whether response to induction therapy, evaluated by metaiodobenzylguanadine (MIBG) and bone scintigraphy, correlates with event-free survival (EFS) in children with high-risk neuroblastoma (NB). PATIENTS AND METHODS: Twenty-nine high-risk NB patients were treated prospectively with an intensive induction regimen and consolidated with three cycles of high-dose therapy with peripheral blood stem-cell rescue. The scintigraphic response was evaluated by MIBG and bone scans using a semi-quantitative scoring system. The prognostic significance of the imaging scores at diagnosis and following induction therapy was evaluated. RESULTS: A trend associating worse 4-year EFS rates for patients with versus without osteomedullary uptake on MIBG scintigraphs at diagnosis was seen (35% +/- 11% v 80% +/- 18%, respectively; P =.13). Similarly, patients with positive bone scans at diagnosis had worse EFS than those with negative scans, although the difference did not receive statistical significance (34% +/- 10% v 83% +/- 15%, respectively; P =.06). However, significantly worse EFS was observed in patients with a postinduction MIBG score of >/= 3 compared to those with scores of less than 3 (0% v 58% +/- 11%; P =.002). There was no correlation between bone scan scores and outcome following induction therapy. CONCLUSION: MIBG scores >/= 3 following induction therapy identifies a subset of NB patients who are likely to relapse following three cycles of high-dose therapy with peripheral blood stem-cell rescue, local radiotherapy, and 13-cis-retinoic acid. Alternative therapeutic strategies should be considered for patients with a poor response to induction therapy.     

核素靶向治疗在转移性甲状腺髓样癌治疗中的价值

目的 评价放射性同位素^90Y标记的奥曲肽（^90Y-DOTATOC）及^131I标记的间碘苄胍（^131I-MIBG）在治疗转移性甲状腺髓样癌中的价值。方法 12例经病理学检查证实的转移性甲状腺髓样癌患者均进行了^131In-奥曲肽和^131I-MIBG或^123I-MIBG联合显像。根据显像结果,分别选择奥曲肽显像阳性或MIBG显像阳性的患者行^90Y-DOTATOC或^131I-MIBG内照射靶向治疗。内照射靶向治疗方案为：静脉滴注3．33GBq ^90Y．DOTATOC,治疗间期为6周;或11．1GBq ^131I-MIBG,治疗间期3个月以上。结果 12例患者联合显像均为阳性,其中奥曲肽显像阳性8例,MIBG显像阳性6例。根据联合显像结果,筛选出4例采用^90Y-DOTATOC治疗,5例采用^131I-MIBG治疗。经过3-5个疗程的治疗,随访15～36个月,9例核素治疗的患者中,3例部分缓解,6例病情稳定,有效率为33．3％（3／9）,反应率为100％（9／9）,未见明显副作用。结论 核素标记的奥曲肽及MIBG靶向治疗转移性甲状腺髓样癌安全有效,可作为改善患者预后的一种方法。