[131-I-meta-iodo-benzyl-guanidine therapy in childhood neuroblastoma.] / Gyermekkori neuroblastoma kezelésében alkalmazott 131-I-meta-jodo-benzil-guanidin terápia.

Neuroblastoma, representing one-tenth of childhood malignancies, is a clinically and prognostically heterogeneous disease. Survival in cases with poor prognosis has recently been significantly improved by rapidly evolving multimodal therapy. Our 4-year-old patient presented with bitemporal swelling and the diagnostic workup confirmed stage IV neuroblastoma (bone marrow and multiple bone metastases). While the tumor responded well to the initial treatment, it relapsed during post-consolidation therapy. As part of the salvage therapy for this high-risk disease with poor prognosis, 131-I-meta-iodo-benzyl-guanidine treatment was performed for the first time in our country, in a case of pediatric neuroblastoma. Neuroendocrine tissue cells express a norepinephrine transporter capable of uptaking the catecholamine analog meta-iodo-benzyl-guanidine. This mechanism makes it an adequate molecule for the imaging (123-I-meta-iodo-benzyl-guanidine) and target therapy (131-I-meta-iodo-benzyl-guanidine) of neuroendocrine tumors, including neuroblastoma. Treatment with 131-I-meta-iodo-benzyl-guanidine requires specific personnel and infrastructural equipment, particularly in pediatric cases. Careful organization and cooperation between nuclear medicine specialists and collaborating clinicians (pediatric oncologists and adult internists if necessary) are essential. Meta-iodo-benzyl-guanidine therapy, already routinely used abroad, has been considered as part of salvage therapy for recurrent neuroblastoma until now, but ongoing clinical trials suggest that it may become part of the first-line treatment soon. As the indications broaden, it is necessary to make it available for more and more children in our country. Orv Hetil. 2023; 164(39): 1550-1555.

Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP.

PURPOSE: We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of 131 I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL). METHODS: Patients received 131 I-mIBG on day 1, with intravenous topotecan daily on days 1-5. A second activity of 131 I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21-25. Peripheral blood stem cells were infused on day 31. RESULTS: Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2-20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1-26). Median number of prior lines of treatment was 3 (1-7). Objective response rate was 13% (95% confidence interval [CI]: 4-31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6-32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years). CONCLUSION: MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

Response to targeted radionuclide therapy with [131I]MIBG AND [177Lu]Lu-DOTA-TATE according to adrenal vs. extra-adrenal primary location in metastatic paragangliomas and pheochromocytomas: A systematic review.

Purpose: Targeted radionuclide therapy (TRT) with [131I]MIBG and [177Lu]Lu-DOTA-TATE is an alternative treatment to the classic schemes in slow progressive metastatic/inoperable paraganglioma (PGL) and pheochromocytoma (PHEO). There is no consensus on which treatment to administer and/or the best sequence in patients who are candidates for both therapies. To clarify these questions, this systematic review assesses the prognostic value of [131I]MIBG and [177Lu]Lu-DOTA-TATE (PRRT-Lu) treatments in terms of progression-free survival (PFS) both globally and considering the primary location. Methods: This review was developed according to the PRISMA Statement with 27 final studies (608 patients). Patient characteristics, treatment procedure, and follow-up criteria were evaluated. In addition, a Bayesian linear regression model weighted according to its sample size and an alternative model, which also included an interaction between the treatment and the proportion of PHEOs, were carried out, adjusted by a Student's t distribution. Results: In linear regression models, [131I]MIBG overall PFS was, on average, 10 months lower when compared with PRRT-Lu. When considering the interaction between treatment responses and the proportion of PHEOs, PRRT-Lu showed remarkably better results in adrenal location. The PFS of PRRT-Lu was longer when the ratio of PHEOs increased, with a decrease in [131I]MIBG PFS by 1.9 months for each 10% increase in the proportion of PHEOs in the sample. Conclusion: Methodology, procedure, and PFS from the different studies are quite heterogeneous. PRRT-Lu showed better results globally and specifically in PHEOs. This fact opens the window to prospective trials comparing or sequencing [131I]MIBG and PRRT-Lu.

Failure modes and effects analysis of pediatric I-131 MIBG therapy: Program design and potential pitfalls.

BACKGROUND: There is growing interest among pediatric institutions for implementing iodine-131 (I-131) meta-iodobenzylguanidine (MIBG) therapy for treating children with high-risk neuroblastoma. Due to regulations on the medical use of radioactive material (RAM), and the complexity and safety risks associated with the procedure, a multidisciplinary team involving radiation therapy/safety experts is required. Here, we describe methods for implementing pediatric I-131 MIBG therapy and evaluate our program's robustness via failure modes and effects analysis (FMEA). METHODS: We formed a multidisciplinary team, involving pediatric oncology, radiation oncology, and radiation safety staff. To evaluate the robustness of the therapy workflow and quantitatively assess potential safety risks, an FMEA was performed. Failure modes were scored (1-10) for their risk of occurrence (O), severity (S), and being undetected (D). Risk priority number (RPN) was calculated from a product of these scores and used to identify high-risk failure modes. RESULTS: A total of 176 failure modes were identified and scored. The majority (94%) of failure modes scored low (RPN <100). The highest risk failure modes were related to training and to drug-infusion procedures, with the highest S scores being (a) caregivers did not understand radiation safety training (O = 5.5, S = 7, D = 5.5, RPN = 212); (b) infusion training of staff was inadequate (O = 5, S = 8, D = 5, RPN = 200); and (c) air in intravenous lines/not monitoring for air in lines (O = 4.5, S = 8, D = 5, RPN = 180). CONCLUSION: Through use of FMEA methodology, we successfully identified multiple potential points of failure that have allowed us to proactively mitigate risks when implementing a pediatric MIBG program.

Phase I/II clinical trial of high-dose [131I] meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding single myeloablative chemotherapy and haematopoietic stem cell transplantation.

PURPOSE: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose 131I-meta-iodobenzylguanidine (131I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan. METHODS: Patients received 666 MBq/kg of 131I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with 131I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and 123I-mIBG scintigraphy. Response was evaluated after engraftment. RESULTS: We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dose 131I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively. CONCLUSION: 131I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT. TRIAL REGISTRATION NUMBER: jRCTs041180030. NAME OF REGISTRY: Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 . DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 12/01/2018.

Theranostics in Neuroblastoma.

Theranostics combines diagnosis and targeted therapy, achieved by the use of the same or similar molecules labeled with different radiopharmaceuticals or identical with different dosages. One of the best examples is the use of metaiodobenzylguanidine (MIBG). In the management of neuroblastoma-the most common extracranial solid tumor in children. MIBG has utility not only for diagnosis, risk-stratification, and response monitoring but also for cancer therapy, particularly in the setting of relapsed/refractory disease. Improved techniques and new emerging radiopharmaceuticals likely will strengthen the role of nuclear medicine in the management of neuroblastoma.

131I-MIBG negative progressive symptomatic metastatic paraganglioma: response and outcome with 177Lu-DOTATATE peptide receptor radionuclide therapy.

OBJECTIVE: The primary aim of this study was to evaluate the long-term outcome of 177Lu-DOTATATE PRRT in terms of clinical, biochemical and imaging response rates, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in 131I-metaiodobenzylguanidine (MIBG) negative progressive/symptomatic locally advanced or metastatic paragangliomas (PGL). The secondary aims of this study were to determine clinical toxicity of 177Lu-DOTATATE and association of PFS with various variables. MATERIALS AND METHODS: 131I-MIBG negative PGL with progressive/symptomatic locally advanced or metastatic disease that underwent 177Lu-DOTATATE PRRT from 2012 to 2019 in our institute were evaluated. Standard dose activity of 5.55-7.4 GBq per cycle of 177Lu-DOTATATE was administered in somatostatin receptor (SSTR) positive PGL. Post-PRRT response was evaluated under three broad categories: (a) symptomatic, (b) biochemical, and (c) imaging (molecular and anatomic imaging). The PFS and OS since first 177Lu-DOTATATE cycle were determined. Associations of PFS with various variables were also investigated. The clinical toxicities of 177Lu-DOTATATE in PGL were determined. RESULTS: Amongst a total of 9 PGL patients, response to 177Lu-DOTATATE was seen in six patients, two patients, four patients and three patients on symptomatic, biochemical, molecular and anatomical based imaging response evaluation categories respectively with DCR of 67%. The median PFS and OS were not reached at a median follow-up of 40 months. Estimated PFS rate of 63% (95% CI 30-96%) and OS rate of 65% (95% CI 32-97%) were noticed at 40 months. Significant association of PFS was found for site of PGL (non-HNPGL), total cumulative dose of PRRT (> 22.2 GBq), and number of PRRT cycles patient received (≥ 4cycles). 177Lu-DOTATATE was well tolerated without acute catecholamine crisis, nephrotoxicity or bone marrow suppression of any grade or high-grade (grade ≥ 2) hematological toxicities. CONCLUSION: Our study showed favorable results with minimal low-grade and easily manageable side effects of 177Lu-DOTATATE in patients of PGL. Thus, 177Lu-DOTATATE may be considered as promising therapeutic option in 131I-MIBG negative and SSTR positive subset of PGL cases. However, further prospective study in a large number of patients is required for validation of our study results.

High-dose 131I-mIBG as consolidation therapy in pediatric patients with relapsed neuroblastoma and ganglioneuroblastoma: the Japanese experience.

OBJECTIVE: Children with relapsed neuroblastoma have a poor prognosis despite modern multimodality therapy. Novel and more effective therapeutic strategies are required for relapsed neuroblastoma. We retrospectively examined the utility of consolidation therapy with high-dose 131I-meta-iodo-benzyl-guanidine (131I-mIBG) in relapsed neuroblastoma or ganglioneuroblastoma patients with complete response (CR) to induction therapy as demonstrated by diagnostic 123I-mIBG scintigraphy. METHODS: Between December 2009 and 2014, five patients with relapsed neuroblastoma and one with relapsed ganglioneuroblastoma received high-dose 131I-mIBG therapy. Overall and progression-free survival rates at five years after 131I-mIBG therapy were analyzed by the Kaplan-Meier method. RESULTS: During follow-up, three children showed no signs of disease relapse, whereas three died. One child without a relapse died from post-transplant side effects, and two children with a relapse died owing to tumor progression. The 5-year progression-free and overall survival rates after 131I-mIBG therapy were 44% and 67%, respectively. CONCLUSIONS: Consolidation therapy with high-dose 131I-mIBG for patients with 2nd CR showed good overall and progression-free survival. While the risks of radiation exposure must be considered, high-dose 131I-mIBG therapy as consolidation therapy needs to be further investigated.

MIBG Therapy for Neuroblastoma: Precision Achieved With Dosimetry, and Concern for False Responders.

Neuroblastoma causes 15% of cancer mortality in children. High risk neuroblastoma has poor prognosis, with high relapse rate and mortality despite multimodal treatment. 123-I-meta-iodo-benzyl-guanidine (mIBG) scintigraphy is one of the current standard diagnostic procedures in neuroblastoma. mIBG can also be used therapeutically, labeled with 131-I, as a radiopharmaceutical agent, delivering targeted radiotherapy to tumoral sites. But published data of this strategy show heterogeneous results. One concern is that in most reports the infused activity is only based in body-weight, which could lead to infra or over-treatment, depending on inter-patient variability in radiation absorption. Activity adjustment by whole-body dosimetry can be used to homogeneize the treatment. Also, mIBG avid tumors may lose avidness along the treatment. As mIBG is used both for treatment and response evaluation, this could result in undetected progressions in patients with apparent complete response. We present a retrospective single-center review of neuroblastoma patients who received therapeutic 131-I-mIBG, focusing on cases with dosimetry-adjusted activity. Dosimetry allowed for a more precise delivery of radiation, reducing 81.1% of deviation from absorption target of 4 Gray (Gy), from 23.4% (±0.936 Gy) to 4.4% (± 0.176 Gy). Patients who showed partial or complete response had better and longer survival. Relapse/progression in non-responders was an early event (within 3 months from treatment). We also present one case of progression with apparent complete response due to loss of mIBG avidness, detected in our series.

Radiation exposure in nurses during care of 131I-MIBG therapy for pediatric patients with high-risk neuroblastoma.

OBJECTIVE: 131I-meta-iodo-benzyl-guanidine (131I-MIBG) therapy has been used in children with high-risk neuroblastoma, who, in Japan, are cared for by trained nurses. To determine the safety of occupational radiation exposure in nurses, we retrospectively examined radiation exposure during therapy. METHODS: Sixty-two nurses who received radiation exposure during 131I-MIBG therapy were assessed for the daily percentage of total radiation exposure received using the formula, daily radiation exposure/total radiation dose × 100; self-care score of children was evaluated. RESULTS: Fifty-four 131I-MIBG treatments (592 ± 111 MBq/kg) were performed in neuroblastoma patients (M/F; 27 /27, mean age at 131I-MIBG treatment; 7 ± 2 years), who were isolated for 5 ± 1 days. Average total (0.36 ± 0.18 mSv; range 0.09-0.97 mSv) and daily (0.07 ± 0.05 mSv/day; range 0.02-0.32 mSv/day) radiation exposure to nurses per patient care. The daily percentage of total radiation exposure significantly decreased in 3 days after 131I-MIBG treatment (days 0, 1, and 2 was 38.2 ± 14.7%, 26.9 ± 12.6%, and 15.3 ± 7.1%, respectively), and the average self-care score was 12.2 ± 3.5 (10-27) for all patients. Higher self-care score was significantly related to younger patients' age and higher daily radiation exposure in nurses. CONCLUSION: Individual exposure to radiation was well controlled. Nurses who care for pediatric patients needing daily assistance must be aware of the radiation exposure risks, which can be reduced by establishing a care system and monitoring radiation exposure.

Dosimetry-based high-activity therapy with 131I-metaiodobenzylguanidine (131I-mIBG) and topotecan for the treatment of high-risk refractory neuroblastoma.

PURPOSE: Patients with high-risk neuroblastoma have an increased risk of recurrence and relapse of disease and a very poor prognosis. 131I-metaiodobenzylguanidine (131I-mIBG) in combination with topotecan as a radiosensitizer can be an effective and relatively well-tolerated agent for the treatment of refractory neuroblastoma. The aim of this retrospective study was to evaluate response and outcome of combined therapy with 131I-mIBG and topotecan. METHODS: Ten patients, between 3 and 20 years of age, were included. Nine patients had been refractory to several lines of chemotherapy and radiotherapy. One patient with a very high-risk neuroblastoma had received only induction therapy. Response was graded according to the International Neuroblastoma Staging System. RESULTS: Regarding treatment response, two patients achieved complete remission, one with relapse at 16 months, five achieved a partial remission, four showed progression at between 1 and 18 months; two showed stable disease with progression at between 1 and 5 months, and one showed progressive disease. Eight of the ten patients died with overall survival between 4 and 63 months, and two patients were still alive without disease at the time of this report: 52 and 32 months (patient had received only induction therapy). Acute and subacute adverse effects were mainly haematological, and one patient developed a differentiated thyroid cancer. CONCLUSION: In patients with high-risk refractory neuroblastoma, administration of high activities of 131I-mIBG in combination with topotecan was found to be an effective therapy, increasing overall survival and progression-free survival. Further studies including a larger number of patients and using 131I-mIBG for first-line up-front therapy are warranted.

Assessment of the dicentric chromosome assay as a biodosimetry tool for more personalized medicine in a case of a high risk neuroblastoma 131I-mIBG treatment.

PURPOSE: The aims of this study were to estimate the whole - body absorbed - dose with the Dicentric Chromosome Assay (DCA) (biodosimetry) for 131I - metaiodobenzylguanidine (131I - mIBG) therapy for high - risk neuroblastoma, and to obtain an initial correlation with the physical dosimetry calculated as described by the Medical Internal Radiation Dosimetry formalism (MIRD). Together both objectives will aid the optimization of personalized targeted radionuclide therapies. MATERIAL AND METHODS: A 12 year-old child with relapsed high-risk neuroblastoma was treated with 131I-mIBG: a first administration with activity <444 MBq/kg was used as a tracer in order to calculate the activity needed in a second administration to achieve a whole body prescribed dose of ∼4 Gy. Blood samples were obtained before and seven days after each administration to analyze the frequency of dicentrics. Moreover, consequent estimations of retained activity were done every few hours from equivalent dose rate measurements at a fixed position, two meters away from the patient, in order to apply the MIRD procedure. Blood samples were also drawn every 2- to -3 days to assess bone marrow toxicity. RESULTS: For a total activity of 22,867 MBq administered over two phases, both biological and physical dosimetries were performed. The former estimated a whole-body cumulated dose of 3.53 (2.58-4.41) Gy and the latter a total whole-body absorbed dose of 2.32 ± 0.48 Gy. The patient developed thrombocytopenia grade 3 after both infusions and neutropenia grade 3 and grade 4 (based on CTCAE 4.0) during respective phases. CONCLUSION: The results indicate a possible correlation between biodosimetry and standard physical dosimetry in 131I-mIBG treatment for high-risk neuroblastoma. A larger cohort and refinement of the DCA for internal irradiation are needed to define the role of biodosimetry in clinical situations.

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

OBJECTIVE: 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. METHODS: We studied 15 patients with pheochromocytoma (14/15) or ganglioneuroma (1/15), who were treated initially with 7.4 GBq of I-131-MIBG. Isolated lymphocytes collected from patients 10 days 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 2 years 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 2 Gy and studied with the same method. RESULTS: 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 ± 0.3 Gy 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 2 years. CONCLUSIONS: 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 7.4 GBq of I-131-MIBG in pheochromocytoma or ganglioneuroma patients is limited and reversible.

Local recurrence of pheochromocytoma in multiple endocrine neoplasia type 2A: a diagnostic and therapeutic challenge.

In a patient with multiple endocrine neoplasia type 2A (MEN2A), an inverted physiological ratio between urinary normetanephrines and metanephrines is an early marker of recurrence in epinephrine-secreting pheochromocytoma, and 131I MIBG treatment appears to be a useful therapeutic option in order to avoid multiple invasive surgical procedures in pheochromocytomatosis.

Feasibility of Administering High-Dose (131) I-MIBG Therapy to Children with High-Risk Neuroblastoma Without Lead-Lined Rooms.

BACKGROUND: Although (131) I-metaiodobenzylguanidine ((131) I-MIBG) therapy is increasingly used for children with high-risk neuroblastoma, a paucity of lead-lined rooms limits its wider use. We implemented radiation safety procedures to comply with New York City Department of Health and Mental Hygiene regulations for therapeutic radioisotopes and administered (131) I-MIBG using rolling lead shields. PROCEDURE: Patients received 0.67 GBq (18 mCi)/kg/dose (131) I-MIBG on an IRB-approved protocol (NCT00107289). Radiation safety procedures included private room with installation of rolling lead shields to maintain area dose rates ≤0.02 mSv/hr outside the room, patient isolation until dose rate <0.07 mSv/hr at 1 m, and retention of a urinary catheter with collection of urine in lead boxes. Parents were permitted in the patient's room behind lead shields, trained in radiation safety principles, and given real-time radiation monitors. RESULTS: Records on 16 (131) I-MIBG infusions among 10 patients (age 2-11 years) were reviewed. Mean ± standard deviation (131) I-MIBG administered was 17.67 ± 11.14 (range: 6.11-40.59) GBq. Mean maximum dose rates outside treatment rooms were 0.013 ± 0.008 mSv/hr. Median time-to-discharge was 3 days post-(131) I-MIBG. Exposure of medical staff and parents was below regulatory limits. Cumulative whole-body dose received by the physician, nurse, and radiation safety officer during treatment was 0.098 ± 0.058, 0.056 ± 0.045, 0.055 ± 0.050 mSv, respectively. Cumulative exposure to parents was 0.978 ± 0.579 mSv. Estimated annual radiation exposure for inpatient nurses was 0.096 ± 0.034 mSv/nurse. Thyroid bioassay scans on all medical personnel showed less than detectable activity. Contamination surveys were <200 dpm/100 cm(2) . CONCLUSIONS: The use of rolling lead shields and implementation of specific radiation safety procedures allows administration of high-dose (131) I-MIBG and may broaden its use without dedicated lead-lined rooms.

Arsenic Trioxide as a Radiation Sensitizer for 131I-Metaiodobenzylguanidine Therapy: Results of a Phase II Study.

UNLABELLED: Arsenic trioxide has in vitro and in vivo radiosensitizing properties. We hypothesized that arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent (131)I-metaiodobenzylguanidine ((131)I-MIBG) and tested the combination in a phase II clinical trial. METHODS: Patients with recurrent or refractory stage 4 neuroblastoma or metastatic paraganglioma/pheochromocytoma (MP) were treated using an institutional review board-approved protocol (Clinicaltrials.gov identifier NCT00107289). The planned treatment was (131)I-MIBG (444 or 666 MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25 mg/m(2)) intravenously on days 6-10 and 13-17. Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria, version 3.0. Response was assessed by International Neuroblastoma Response Criteria or (for MP) by changes in (123)I-MIBG or PET scans. RESULTS: Twenty-one patients were treated: 19 with neuroblastoma and 2 with MP. Fourteen patients received (131)I-MIBG and arsenic trioxide, both at maximal dosages; 2 patients received a 444 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide; and 3 patients received a 666 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide. One did not receive arsenic trioxide because of transient central line-induced cardiac arrhythmia, and another received only 6 of 10 planned doses of arsenic trioxide because of grade 3 diarrhea and vomiting with concurrent grade 3 hypokalemia and hyponatremia. Nineteen patients experienced myelosuppression higher than grade 2, most frequently thrombocytopenia (n = 18), though none required autologous stem cell rescue. Twelve of 13 evaluable patients experienced hyperamylasemia higher than grade 2 from transient sialoadenitis. By International Neuroblastoma Response Criteria, 12 neuroblastoma patients had no response and 7 had progressive disease, including 6 of 8 entering the study with progressive disease. Objective improvements in semiquantitative (131)I-MIBG scores were observed in 6 patients. No response was seen in MP. Seventeen of 19 neuroblastoma patients continued on further chemotherapy or immunotherapy. Mean 5-year overall survival (±SD) for neuroblastoma was 37% ± 11%. Mean absorbed dose of (131)I-MIBG to blood was 0.134 cGy/MBq, well below myeloablative levels in all patients. CONCLUSION: (131)I-MIBG plus arsenic trioxide was well tolerated, with an adverse event profile similar to that of (131)I-MIBG therapy alone. The addition of arsenic trioxide to (131)I-MIBG did not significantly improve response rates when compared with historical data with (131)I-MIBG alone.

Long-term outcome and toxicity after dose-intensified treatment with 131I-MIBG for advanced metastatic carcinoid tumors.

UNLABELLED: Reported experience with systemic (131)I-metaiodobenzylguanidine ((131)I-MIBG) therapy of neuroendocrine tumors comprises different dosing schemes. The aim of this study was to assess the long-term outcome and toxicity of treatment with 11.1 GBq (300 mCi) of (131)I-MIBG per cycle. METHODS: We performed a retrospective review of 31 patients with advanced metastatic neuroendocrine tumors (20 with carcinoid tumors and 11 with other tumors) treated with (131)I-MIBG. Treatment outcome was analyzed for patients with carcinoid tumors (the most common tumors in this study), and toxicity was analyzed for the entire patient cohort (n = 31). Treatment comprised 11.1 GBq (300 mCi) per course and minimum intervals of 3 mo. The radiographic response was classified according to modified Response Evaluation Criteria in Solid Tumors. Toxicity was determined according to Common Terminology Criteria for Adverse Events (version 3.0) for all laboratory data at regular follow-up visits and during outpatient care, including complete blood counts and hepatic and renal function tests. Survival analysis was performed with the Kaplan-Meier curve method (log rank test; P < 0.05). RESULTS: The radiographic responses in patients with carcinoid tumors comprised a minor response in 2 patients (10%), stable disease in 16 patients (80%; median time to progression, 34 mo), and progressive disease in 2 patients (10%). The symptomatic responses in patients with functioning carcinoid tumors comprised complete resolution in 3 of the 11 evaluable symptomatic patients (27%), partial resolution in 6 patients (55%), and no significant change in 11 patients. The median overall survival in patients with carcinoid tumors was 47 mo (95% confidence interval, 32-62), and the median progression-free survival was 34 mo (95% confidence interval, 13-55). Relevant treatment toxicities were confined to transient myelosuppression of grade 3 or 4 in 15.3% (leukopenia) and 7.6% (thrombocytopenia) of applied cycles and a suspected late adverse event (3% of patients), myelodysplastic syndrome, after a cumulative administered activity of 66.6 GBq. The most frequent nonhematologic side effect was mild nausea (grade 1 or 2), which was observed in 28% of administered cycles. No hepatic or renal toxicities were noted. CONCLUSION: Dose-intensified treatment with (131)I-MIBG at a fixed dose of 11.1 GBq (300 mCi) per cycle is safe and offers effective palliation of symptoms and disease stabilization in patients with advanced carcinoid tumors. The favorable survival and limited toxicity suggest that high cycle activities are suitable and that this modality may be used for targeted carcinoid treatment--either as an alternative or as an adjunct to other existing therapeutic options.