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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Cancer. Author manuscript; available in PMC 2012 September 15.
Published in final edited form as:
PMCID: PMC3125487

Response, Survival and Toxicity after 131I-MIBG Therapy for Neuroblastoma in Pre-Adolescents, Adolescents and Adults



Adolescent and adult patients with neuroblastoma appear to have a more indolent disease course but a lower survival than their younger counterparts. The majority of neuroblastoma tumors specifically accumulate the radiolabeled norepinephrine analogue 131I-metaiodobenzylguanidine (MIBG). 131I-MIBG has therefore become increasingly used as targeted radiotherapy for relapsed or refractory neuroblastoma. The aim of this study was to characterize the toxicity and activity of this therapy in older patients.


We performed a retrospective analysis of 39 consecutive patients ages 10 years and older with relapsed or refractory neuroblastoma who were treated with 131I-MIBG monotherapy at UCSF under Phase I, Phase II, and compassionate access protocols.


Sixteen patients were ≥18 years old at MIBG treatment initiation, whereas twenty-three were 10–17 years old. The median cumulative administered dose of 131I-MIBG was 17.8 mCi/kg. The majority of treatments led to grade 3 or 4 hematologic toxicities which were similar in frequency among age strata. Three patients subsequently developed hematologic malignancy or myelodysplasia. The overall rate of complete plus partial response was 46%. Patients ≥18 years old at time of first MIBG treatment had a significantly higher response rate compared to patients 10–17 years old (56% vs 39%, p=0.023). Median overall survival was 23 months with a trend toward longer overall survival for the ≥18 year old subgroup (p = 0.12).


Our findings suggest that 131I-MIBG is a highly effective salvage agent for adolescents and adults with neuroblastoma.

Keywords: neuroblastoma, adult, adolescent, MIBG, radiopharmaceutical


Neuroblastoma is the most common extracranial solid tumor of childhood, with a median age at diagnosis of approximately 17 months.1 The tumor derives from primitive sympathetic nervous system tissue2 and thus typically arises in the adrenal glands or in sympathetic ganglia. Age at diagnosis is a key prognostic factor for patients with disseminated disease. Patients < 18 months of age have a more favorable outcome1 and a subset of infants with metastatic disease may demonstrate spontaneous tumor regression.3 By contrast, older patients with advanced neuroblastoma remain difficult to cure in spite of recent advances in aggressive multi-modality therapy.4,5

Neuroblastoma is only rarely diagnosed beyond the first decade of life.6 Previous studies have indicated that this older patient population may have a distinctive natural history with frequent late relapses and a prolonged, relapsing-remitting, but ultimately fatal course.7 These patients tend to be highly resistant to the cytotoxic chemotherapies that are associated with significant response rates in a younger patient population.8

Ninety percent of neuroblastoma tumors express the norepinephrine transporter and therefore take up the sympathomimetic metaiodobenzylguanidine (MIBG).9,10 Clinical trials conducted with high-dose 131I-MIBG used as monotherapy or in combination with other agents for relapsed or refractory high-risk neuroblastoma have demonstrated promising response rates.11 The largest of these was a multi-institution phase II monotherapy trial with 164 patients receiving a prescribed dose of 12 mCi/kg or 18 mCi/kg of 131I-MIBG.12 The overall response rate was 36%, with another 34% of patients exhibiting stable disease. Univariate analysis of these findings indicated that age over 12 years at time of treatment was a positive prognostic factor for response compared to the patients who were 22 months-6 years of age.

To further explore the use of 131I-MIBG in an older patient population, we have conducted a retrospective review of treatment outcomes and toxicities of 39 consecutive patients with relapsed or refractory neuroblastoma ages 10 years and older at the time of treatment with 131I-MIBG monotherapy on Phase I, Phase II and compassionate access protocols at UCSF. The aims of this analysis were to evaluate the response, survival, and toxicity of 131I-MIBG therapy in older patients and to compare these parameters between adolescent patients 10–17 years old and adult patients ages 18 years or older at time of 131I-MIBG therapy.

Patients and Methods

Patients treated with 131I-MIBG therapy were identified from a UCSF database of 131I-MIBG monotherapy trials. Patients were eligible for the current analysis if they received their first therapeutic 131I-MIBG at age 10 years or older. Patients who had previously received MIBG as part of a combination therapy protocol were still eligible for this analysis (n=1), as were patients who were previously treated with MIBG at institutions other than UCSF (n=1). One patient received subsequent treatment on NANT protocol 0701 ( # NCT00659984) with no carrier-added 131I-MIBG. This patient had previously received standard 131I-MIBG on the compassionate access protocol and only details related to the compassionate access treatment are included here. Institutional review board approval was obtained for this retrospective analysis and for the original, prospective 131I-MIBG treatment protocols administered to the patient population described in this work. All patients or parents/guardians signed informed consent for participation in the therapy trials.

Patient characteristics, including gender, race and ethnicity, tumor location and stage at diagnosis, MYCN gene amplification status and Shimada histology where available, and extent of prior treatment were obtained from UCSF pediatric oncology records. Hematologic toxicity was assessed by neutrophil and platelet nadir within 8 weeks of treatment, duration of neutropenia and requirement for platelet transfusions. Liver toxicity was assessed by grade of ALT, AST and total bilirubin elevations within 8 weeks of treatment. Assessment of thyroid toxicity included assessment of thyroid function tests at any point following therapy. Other non-hematologic toxicities noted in the medical records were also recorded. Toxicities were graded according to CTCAE v.3.13

Patients were treated according to previously described protocols used in Phase I14 and Phase II12 studies of high-dose 131I-MIBG monotherapy for relapsed or refractory neuroblastoma. Compassionate access patients were treated similarly to the Phase II protocol. Twenty-seven of the thirty-nine patients included in this report had previously been included in the reports of overall results on the Phase I (n=8) and II (n=19) 131I-MIBG therapy trials. All of the remaining twelve patients were treated on a compassionate access protocol.

Patients were eligible for the studies if they had high-risk neuroblastoma and failed to achieve complete response with standard induction therapy, or developed relapsed or progressive disease. MIBG uptake by tumors in soft tissue or bone on diagnostic MIBG scan was required for treatment. Adequate hematologic, renal, cardiac, and hepatic function, as well as adequate time since prior therapy were other criteria for treatment.12,14

131I-MIBG was synthesized in the radio pharmacy at UCSF under IND 32,147 for patients on the Phase I and II studies, and was purchased from NDP Pharmaceuticals (New Jersey, USA) for compassionate access patients. Patients were treated with a single or multiple infusions of 131IMIBG, depending on response and interim toxicity. Patients received intravenous 131I-MIBG infusions over two hours with hydration, thyroid protection with KI and KClO4, and placement of a Foley catheter to avoid accumulation of radioactive urine in the bladder.12 Hematologic toxicities were managed with blood product transfusions, G-CSF for absolute neutrophil counts of < 500/μL, and hematopoietic stem cell infusions for prolonged myelosuppression. Total body radiation doses were calculated using multiple measurements from handheld or ceiling-mounted Geiger counters.15

Response was assessed six to eight weeks after treatment using MIBG imaging, CT/MRI imaging, as well as bone marrow analyses and urine catecholamine levels. The International Neuroblastoma Response Criteria were used to assess response to each treatment and overall best response.16 Time from treatment to date of last patient contact and date of death were also recorded.

Statistical Methods

Descriptive statistics were generated for patients [greater, double equals] 18 years and 10–17 years of age at first 131I-MIBG treatment. For patients who underwent multiple on-study MIBG treatments, overall response was reported as the response to the most successful treatment. In statistical analysis of response rates, a response was defined as a partial response or better. The observed difference in response rates between age groups was evaluated statistically using the Fisher exact test. The Kaplan-Meier method was used to estimate overall survival from the time of first 131I-MIBG treatment. The median follow-up time for the analyzed cohort was 78 months. Comparisons in overall survival between age groups were made using the log-rank test. Statistical analyses were performed using Stata version 10.1 (College Station, Texas).


Patient Characteristics

A total of 39 neuroblastoma patients 10 years and older at the time of first 131I-MIBG monotherapy treatment and meeting inclusion criteria were identified from UCSF study databases (Table 1). Twenty-three patients were between 10 and 17 years of age when they received their first MIBG treatment; these patients make up the adolescent age subgroup in our analysis. Of note, this subgroup included 14 patients who were between 10 and 13 years of age at first MIBG treatment who therefore may be described as pre-adolescent. Sixteen patients were 18 years of age or older at the time of their first MIBG treatment and make up the adult subgroup in our study. For all patients, there was a 1.8:1 male:female ratio, and the median age of diagnosis was 11.6 years (range, 0.4–40.1 years). Most patients had primary tumor sites in the abdomen. Only one of 17 patients had a known MYCN-amplified neuroblastoma. Thirteen patients had documented unfavorable histology neuroblastoma, and 7 patients had unfavorable ganglioneuroblastoma. The latter histology was more frequently encountered in patients age 18 and over at the time of their first MIBG treatment (five patients out of seven total).

Table 1
Characteristics of 39 patients with neuroblastoma treated with 131I-MIBG at age ≥ 10 years.

The median age at time of first 131I-MIBG treatment was 15.5 years (range, 10.0–45.5). The median interval from initial neuroblastoma diagnosis to first 131I-MIBG treatment was 2.7 years (range, 0.5–18.9). Patients undergoing their first treatment as adults had a substantially longer median interval from diagnosis (4.7 years) than did adolescents (2.3 years), consistent with the known more indolent course of the disease in older patients.7 Twenty-one patients (54%) had undergone hematopoietic stem cell transplants; two of these patients had also received total body irradiation as part of their conditioning regimen. The median number of treatment regimens received prior to 131I-MIBG therapy was 3 (range 1–8). Twenty-two patients (56%) had disease involving both osteomedullary and soft tissue sites at the time of first on-study MIBG treatment.

Treatment Characteristics

Data were available on a total of 59 MIBG treatments administered at UCSF that met study inclusion criteria. Twenty-five patients received a single 131I-MIBG treatment, nine patients received two treatments, four patients received three treatments, and one patient received four treatments (Table 2). One of the patients receiving three MIBG treatments at UCSF had previously received an additional three treatments at another institution, which were not subject to review in this analysis. The maximum number of lifetime MIBG treatments, including those provided at outside institutions and not subject to analysis here, was six.

Table 2
Treatment details for 39 patients treated with MIBG at age ≥ 10 years.

For all treatments, the median total dose administered per treatment was 11.9 mCi/kg, with a range of 2.6 to 18.8 mCi/kg. The median whole body radiation dose per treatment was 201 cGy, with a range of 54–490 cGy (Table 2). Although individual treatment doses were specified in advance by the particular treatment protocol, when first MIBG treatments were compared to subsequent treatments, median total MIBG doses, per-kilogram MIBG doses, and whole body radiation indices progressively declined for the second and ≥ third treatments. For patients receiving their first on-study treatment at 10–17 years of age, the median cumulative dosage was 720 mCi (range, 327–2409) or 17.8 mCi/kg (range, 6.3–36.3), with a median cumulative whole body index of 240 cGy (range, 79–506). These patients received a median of 1 treatment. For patients receiving their first on-study treatment at ≥ 18 years of age, the median cumulative dosage was 857 mCi (range, 342–2287) or 16.9 mCi/kg (range, 9.0–43.0), with a median cumulative whole body index of 387 cGy (range 97–490). These patients received a median of 2 treatments.

Treatment Toxicities

Grade 3 or 4 toxicities from each cycle of MIBG therapy were similar to those previously reported, and consisted chiefly of myelosuppression (Table 3). Sixty percent of treatments resulted in grade 4 thrombocytopenia, while an additional 17% resulted in grade 3 thrombocytopenia. Only 18/55 treatments could be administered without platelet transfusion support; 25 treatments required transfusion support for less than 8 weeks after MIBG infusion, while 12 treatments resulted in platelet transfusion dependence at the end of 8 weeks following treatment. Grade 4 neutropenia occurred in 45% of the treatments, with an additional 29% resulting in grade 3 neutropenia. G-CSF support was provided following 46% of the treatments, and 29% of the treatments were followed by infusion of hematopoietic stem cells for persistent myelosuppression. There was no apparent difference in grade 3 or 4 hematologic toxicity in patients ages 10–17 and ≥18 years of age at the time of treatment.

Table 3
Hematologic and non-hematologic toxicities observed in 59 courses of 131I-MIBG therapy in 39 patients ≥ 10 years of age at time of treatment.

Non-hematological toxicity was minimal, with one patient who had grade 3 ALT elevation within 6 weeks of 131I-MIBG treatment. Minor, frequently reported side effects included nausea and vomiting shortly after MIBG infusion, dry mouth, occasional parotitis, and fatigue.

Significant late effects of treatment included new-onset thyroid dysfunction in four patients, including one diagnosis of thyroid carcinoma. Three patients developed secondary leukemia or myelodysplastic syndrome; two of these have been described previously.17

Response and Outcome

The overall response rate was 46% (Table 4). Two patients (5%) had a complete response and one patient had a very good partial response (3%). Fifteen patients had a partial response (39%) and two patients had a minimal response (5%). Stable disease was observed in seventeen patients (44%), while two patients developed progressive disease (5%). Patients ≥ 18 years of age at first 131I-MIBG therapy had a higher overall response rate (56%) compared to patients 10–17 years of age (39%; p = 0.023).

Table 4
Best objective response following 131I-MIBG therapy according to age at time of treatment.

The median overall survival time for the analyzed cohort was 23 months, with an estimated overall survival rate at 3 years of 32.8% (95% confidence interval, 18.1 – 48.5%; Figure 1A). The median overall survival time for patients ≥ 18 years was 36 months, with an estimated overall survival rate at 3 years of 43.2% (95% confidence interval, 17.4 – 66.9%). The median overall survival time for patients < 18 years was 19.7 months, with an estimated overall survival rate at 3 years of 19.4% (95% confidence interval, 6.1 – 38.3%). Therefore, there was a trend towards longer overall survival in patients ≥ 18 years at time of first 131I-MIBG compared to patients < 18 years, though this difference did not reach the usual level of statistical significance (log-rank p-value = 0.12; Figure 1B).

Figure 1Figure 1
Overall survival after first on-study MIBG treatment for all patients (A) and according to age at first on-study treatment (B, age 10–17 years versus age 18+ years).


Our findings demonstrate that 131I-MIBG is an effective salvage therapy in adolescent and adult neuroblastoma patients. The patients described in our study were heavily pretreated with conventional or other experimental therapies (median of 3 regimens), and the majority had widely disseminated disease at the time of first 131I-MIBG treatment. The overall response rate was 46%, and median overall survival following treatment was 23 months, with a higher response rate observed in older patients. As in younger patients,18 the main serious toxicity was myelosuppression, with 60% of treatments resulting in grade 4 thrombocytopenia and 45% resulting in grade 4 neutropenia. Late effects included leukemia or myelodysplastic syndrome in 3 patients (8%), and one case of thyroid carcinoma. As has been previously reported, it is impossible to determine the causative effect of MIBG vs. other treatments received by these patients that are known to predispose to second cancers.17,19

The adult patient subgroup in our series (≥18 years of age at time of MIBG treatment initiation) had a significantly higher response rate to MIBG therapy than did the adolescent subgroup (ages 10–17). Furthermore, adult patients demonstrated a trend toward improved overall survival post-MIBG as compared to adolescents. The adult patients had a longer median latency from diagnosis to MIBG treatment initiation than did adolescents (4.7 years vs. 2.3 years), although the median number of previous treatments was identical for the two groups. This pattern is consistent with other reports of a more indolent disease course in older high-risk patients.7,20 There was no significant difference in the toxicity profile between the two groups.

The overall response rate in our series of adolescent and adult patients (46%) exceeds that reported in five out of six published Phase I and II trials of 131I-MIBG monotherapy for patients of all ages (0%–56%, n=312, reviewed in11). The largest of these, a Phase II trial, enrolled 164 patients, and showed an overall response rate of 36%, with a more favorable response rate of 55% in patients ages 12–30 years (n=31).12 This age-dependent pattern in overall response is replicated in our case series of patients ages 10–45. We have extended this finding to also demonstrate that adult patients appear to have a higher response rate than adolescent patients. Our results are consistent with the body of literature showing that 131I-MIBG is an effective salvage agent in high-risk neuroblastoma,11 and indicate that this modality is particularly effective for older patients. Of note, however, only 6 of 16 adult patients (38%) had received high-dose therapy with stem cell rescue prior to first on-study 131I-MIBG treatment, whereas 15 of the 23 patients ages 10–17 (65%) had received such therapy. By contrast, 78% (128/164) patients described in the previously published Phase II study (which encompassed patients ages 1.8–30.2 years) had received prior treatment with stem cell transplant.12 As such, the differential response rate between adults and adolescents may reflect different prior treatment intensity.

This study is limited by its retrospective, single-institution nature. However, neuroblastoma is very rarely diagnosed past the age of 10 years6 and patients described in our series traveled to UCSF for MIBG treatment from many regions of the U.S. and overseas. In order to obtain an adequate cohort of older patients for analysis, we pooled data from three consecutive treatment protocols, which may have introduced heterogeneity in our results. In addition, there was a substantial male predominance in our adolescent patient subgroup, whereas the adult patient subgroup was evenly matched by gender. While prior reports do not show a significant difference in response to MIBG according to gender,12 we cannot rule out this effect in the present study. Patients who tolerated the treatment poorly were unlikely to get a repeat infusion, thus likely underestimating treatment toxicity in all patients. Finally, it is difficult to assess the contribution of MIBG treatment to overall survival, and to reliably define event-free survival in this setting, since many patients who were treated with MIBG promptly moved on to other treatments, prior to eventual tumor progression. It is also unclear to what extent the trend to an improved survival advantage in older patients can be attributed to the effect of 131I-MIBG vs. subsequent treatments, or the more indolent natural history of disease in older patients.7 Our study does suggest additional evidence for the latter, manifested by a longer time period from diagnosis to MIBG treatment in the adult patient subgroup compared to the adolescent subgroup, and consistent with a trend reported previously.12

In conclusion, we have analyzed the response rate, overall survival, and toxicity of 131I-MIBG monotherapy for relapsed or refractory neuroblastoma in 39 patients ages 10 years or older who underwent Phase I, Phase II, or compassionate access 131I-MIBG treatment at a single institution. We found that nearly half of these high-risk patients responded to MIBG therapy, with a significantly higher response rate and a trend to longer overall survival in the adult vs. the adolescent patient subset. There was no evidence of increased toxicity in the older age groups. Our results support the clinical utility of this treatment in adolescent and adult neuroblastoma patients. The incorporation of 131I-MIBG into induction or myeloablative regimens has the potential to improve the survival for this subgroup of neuroblastoma patients, who have historically had a very poor outcome.

Condensed Abstract

We present a retrospective, single-institution case series of 39 adolescent and adult patients ages 10 years and over with relapsed or refractory neuroblastoma treated with 131I-MIBG. While the overall treatment response rate (46%) is high for all patients, we find that adults have a significantly higher treatment response rate and exhibit a trend to longer post-treatment overall survival as compared to adolescents, indicating that 131I-MIBG is a promising salvage agent for neuroblastoma in this patient population.


We thank Ruby Ha, Qiu Ming Chen, and Alekist Quach for assistance in data gathering. We thank the patients and families who participated in the treatment trials as well as the nursing staff involved in their care.

Funding: This research was funded by the Campini Foundation, Alex Lemonade Stand Foundation, the Dougherty Family Foundation, and NIH/NCRR UCSF-CTSI UL1 RR024131.


The authors have no financial disclosures.


1. London W, Castleberry R, Matthay K, et al. Evidence for an Age-Cutoff Greater than 365 days for Neuroblastoma Risk Group Stratification in the Children's Oncology Group (COG) J Clin Oncol. 2005;23:6459–6465. [PubMed]
2. Hoehner J, Gestblom C, Hedborg F, Sandstedt B, Olsen L, Pahlman S. A developmental model of neuroblastoma: differentiating stroma-poor tumors' progress along an extra-adrenal chromaffin lineage. Lab Invest. 1996;75:659–675. [PubMed]
3. D'Angio G, Evans A, Koop C. Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet. 1971;297:1046–1049. [PubMed]
4. Yu A, Gilman A, Ozkaynak M, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324–1334. [PMC free article] [PubMed]
5. Maris J, Hogarty M, Bagatell R, Cohn S. Neuroblastoma. Lancet. 2007;369:2106–2120. [PubMed]
6. Refaat M, Idriss S, Blaszkowsky L. Case Report: An Unusual Case of Adrenal Neuroblastoma in Pregnancy. The Oncologist. 2008;13:152–156. [PubMed]
7. Franks L, Bollen A, Seeger R, Stram D, Matthay K. Neuroblastoma in adults and adolescents: an indolent course with poor survival. Cancer. 1997;79:2028–2035. [PubMed]
8. Kushner B, Kramer K, Modak S, Qin L, Cheung N. Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer. 2010;116:3054–3060. [PubMed]
9. Carlin S, Mairs R, McCluskey A, et al. Development of a real-time polymerase chain reaction assay for prediction of the uptake of meta-[(131)I]iodobenzylguanine by neuroblastoma tumors. Clin Cancer Res. 2003;9:3338–3344. [PubMed]
10. Treuner J, Feine U, Niethammer D, et al. Scintigraphic imaging of neuroblastoma with [131-I] iodobenzylguanidine. Lancet. 1984;1:333–334. [PubMed]
11. DuBois S, Matthay K. Radiolabeled metaiodobenzylguanine for the treatment of neuroblastoma. Nuc Med Biol. 2008;35(S1):35–48. [PMC free article] [PubMed]
12. Matthay K, Yanik G, Messina J, et al. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol. 2007;25:1054–1060. [PubMed]
13. US Department of Health and Human Services . Common Terminology Criteria for Adverse Events (CTCAE) 2006.
14. Matthay K, DeSantes K, Hasegawa B, et al. Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol. 1998;16:229–236. [PubMed]
15. Matthay K, Panina C, Huberty J, et al. Correlation of tumor and whole-body dosimetry with tumor response and toxicity in refractory neuroblastoma treated with (131)I-MIBG. J Nucl Med. 2001;42:1713–1721. [PubMed]
16. Brodeur G, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11(8):1466–1477. [PubMed]
17. Weiss B, Vora A, Huberty J, Hawkins R, Matthay K. Secondary myelodysplastic syndrome and leukemia following 131I-metaiodobenzylguanidine therapy for relapsed neuroblastoma. J Pediatr Hematol Oncol. 2003;25(7):543–547. [PubMed]
18. DuBois S, Messina J, Maris J, et al. Hematologic toxicity of high-dose iodine-131-metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol. 2004;22(12):2452–2460. [PubMed]
19. Garaventa A, Gambini C, Villavecchia G, et al. Second malignancies in children with neuroblastoma after combined treatment with 131I-metaiodobenzylguanidine. Cancer. 2003;97(5):1332–1338. [PubMed]
20. Kaye J, Warhol M, Kretschmar C, Landsberg L, Frei Er. Neuroblastoma in adults. Three case reports and a review of the literature. Cancer. 1986;58(5):1149–1157. [PubMed]