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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Pediatr Blood Cancer. Author manuscript; available in PMC 2012 February 1.
Published in final edited form as:
PMCID: PMC3006009
NIHMSID: NIHMS220378

Thyroid and Hepatic Function After High Dose 131I-Metaiodobenzylguanidine (131I-MIBG) Therapy for Neuroblastoma

Abstract

Background

131I-Metaiodobenzylguanidine (131I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and MIBG is concentrated in the liver after MIBG therapy. The aim of our study was to analyze the effects of 131I-MIBG therapy on thyroid and liver function.

Procedure

Pre and post therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with 131I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined.

Results

In patients who presented with Grade 0 or Grade 1 thyroid toxicity at baseline, 12±4% experienced onset or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by two years after 131I-MIBG therapy. At two years post 131I-MIBG therapy, 76±4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23±5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity usually was transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies.

Conclusion

The prophylactic regimen of potassium iodide and potassium perchlorate with 131I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following 131I-MIBG therapy were primarily reversible and did not result in late toxicity. 131I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction.

Keywords: Neuroblastoma, 131I-MIBG, Hypothyroidism

INTRODUCTION

Neuroblastoma, the most common extra-cranial solid tumor in children, is an embryonal tumor derived from the peripheral sympathetic nervous system. It is highly malignant, with metastatic disease at diagnosis in half of cases. Despite improvement in outcome with intensification therapy and treatment of minimal residual disease, 15% of patients have disease that is refractory to induction chemotherapy, and more than 50% of patients who achieve initial remission ultimately relapse and die as a result of their disease. [1]

Metaiodobenzylguanidine (MIBG) is a guanethidine derivative and analogue of norepinephrine with specific affinity for neural crest tissues. When labeled with iodine-131 (131I-MIBG), MIBG has shown activity against neuroblastoma, with response rates for refractory disease varying from 20%-37%. [2-10] In a Phase II clinical trial of 164 patients, the response rate (complete and partial) for all patients was 36%. [2] While 131I-MIBG has typically been used as a single agent in relapsed disease, several groups have increasingly used 131I-MIBG alone earlier in the course of disease or combined with chemotherapy. [11-16] With this expanding role, an understanding of the late toxicity of 131I-MIBG has become increasingly important.

The most common toxicities associated with high dose 131I-MIBG targeted radiotherapy are primarily hematologic, with almost all patients requiring at least one platelet or red cell transfusion and with most patients developing neutropenia. Approximately 36% of patients also require autologous hematopoietic stem-cell rescue (ASCR) after 131I-MIBG treatment. [17] The chief non-hematological toxicities reported with 131I-MIBG therapy include transient nausea and vomiting, sialoadenitis, transient hepatic abnormalities, later adrenal insufficiency (<1%), and variable rates of hypothyroidism. [18-24] Secondary malignancies such as acute myelogenous leukemia and myelodysplastic syndrome have also been reported in 3-5% of children who have received MIBG therapy to treat relapsed or refractory neuroblastoma. [2,25-26]

Thyroid function and liver function after 131I-MIBG therapy are of particular interest because the radioactivity is often concentrated in these organs. Both the thyroid and the liver can be visualized on the post-96 hour 131I-MIBG scan after 131I-MIBG therapy and the dissociated anion may be specifically concentrated in the thyroid. However, limited data is available to assess the acute and late effects of 131I-MIBG therapy on thyroid and liver function. Reports of hypothyroidism following 131I-MIBG therapy have been highly variable, with incidence rates ranging from 15-64% of patients. There has also been little systematic examination and no reports of late liver dysfunction associated with 131I-MIBG therapy. [19-23]

We report here an analysis of thyroid and liver function for neuroblastoma patients with follow-up data after receiving therapy with 131I-MIBG. We examined the relationship between liver and thyroid toxicity incidence and cumulative 131I-MIBG dose/kg, number of treatments, sex, and patient age at the time of therapy. We also analyzed the relation of thyroid dysfunction with thyroid visualization on post therapy 96 hour scans.

METHODS

Study Subjects

All evaluated patients either failed to achieve partial or complete response with standard induction therapy or developed progressive disease at any time prior to 131I-MIBG therapy. All patients had demonstrated MIBG uptake in skeletal or soft tissue prior to treatment. The vast majority of patients were heavily pre-treated, with a median of three prior regimens, and almost all had prior radiation therapy and surgery. All patients had total bilirubin ≤2x normal for age and AST and ALT <5x normal for age. All patients were fully recovered from the toxic effects of prior therapy.

Eligibility for inclusion in this analysis included evaluation of baseline thyroid and liver function and at least one post therapy value for thyroid function tests (TSH, Free T4 or T4) and/or liver function tests (AST, ALT, total bilirubin). Patients were enrolled on therapeutic trials with 131I-MIBG, and appropriate informed consent was obtained for all patients with approval by the institutional human research review board and radiation safety committee at treating institutions.

Treatment

Patients were treated between August 30, 1996 and May 1, 2008 on six clinical trials using 131I-MIBG therapy. These studies included patients from the following clinical trials: A multi-institutional Phase II study of 18 mCi/kg [2], an ongoing UCSF compassionate use study of 131I-MIBG, NANT 99-01 - a Phase I study of 131I-MIBG with myeloablative chemotherapy [11], NANT 2000-01 - a double infusion of 131I-MIBG (24-42 mCi/kg)[27], NANT 2001-02 131I-MIBG (12 mCi/kg) with myeloablative chemotherapy, and NANT 2004-06 - Irinotecan and Vincristine with 131I-MIBG (8-15 mCi/kg) (http://www.nant.org).

The 131I-MIBG for the studies was supplied either by the Michigan Memorial Phoenix Laboratory at the University of Michigan (investigational new drug 17,239; Ann Arbor, MI), Draximage Radiopharmaceuticals (investigation new drug 76,227; Kirkland, Quebec, Canada), or the University of California at San Francisco (Investigational New Drug 32,147; San Francisco, CA). Patients received 131I-MIBG infusions at the University of California, San Francisco, Children’s Hospital of Philadelphia, University of Michigan, and Cincinnati Children’s Hospital Medical Center. All 131I-MIBG products had a free iodide content of less than 5%. Patients who were treated on NANT 99-01, NANT 2001-02, and NANT 2004-06 received chemotherapy in combination with 131I-MIBG therapy, and were therefore excluded from liver function analyses.

Patients were treated with one to three therapeutic doses of 131I-MIBG, given intravenously over one to two hours with hydration and a Foley catheter for bladder protection. All patients remained in radiation-protected isolation for two to seven days until radiation emissions met institutional regulations. The dose of radiation to the whole body from 131I-MIBG was calculated for every patient using multiple measurements from a hand-held or ceiling-mounted Geiger counter. [28]

Thyroid Protection

To protect the thyroid from any dissociated 131-Iodide from the therapeutic doses of 131I-MIBG, patients were given an oral loading dose of 6 mg/kg of KI solution 8-12 hours prior to 131I-MIBG infusion, then 1 mg/kg every 4 hours on day 0-6, and 1 mg/kg/day through day 45 post infusion. Potassium perchlorate was also given as an additional oral blocking agent for 5 days post infusion with a loading dose of 8 mg/kg, then 2 mg/kg every 6 hours on days 0-4, beginning 4 hours after the start of 131I-MIBG infusion.

Monitoring

Patients on all studies were monitored weekly for a minimum of 6 weeks or until recovery from toxicity. Tumor response evaluations and hematologic, hepatic, renal and endocrine toxicity evaluations were required at 3 month intervals for one year, then every 6 months, or until the patient died or went on to other therapy. Baseline abnormalities were noted if available.

Scan Review

A post infusion 131I-MIBG scan (median time of 96 hours post infusion, (range: 72-120 hrs) was performed for all patients receiving 131I-MIBG therapy. Post therapy scans were reviewed by a nuclear medicine radiologist at the University of California for thyroid visualization. MIBG uptake in the thyroid was semi-quantitatively scored using a point scale: 0 = No Uptake, 1 = Faint Uptake, 2 = Definite Uptake, 3 = Intense Uptake. For patients who had more than one scan available, the scan with the highest review assessment was used in the analyses.

Evaluation of Thyroid Dysfunction at Baseline and after 131I-MIBG therapy

Pre and post therapy thyroid stimulating hormone (TSH) and T4 (free T4 when available) values were collected from medical records. Any symptomatology and/or use of thyroid hormone replacement therapy were noted. Abnormal thyroid function at baseline or time points after 131I-MIBG treatment was defined as TSH and/or T4 concentrations outside of the institutional normal ranges or if patients were noted to be receiving thyroid hormone replacement therapy at that time. Toxicity grade was determined based on CTC v3.0. For TSH and T4 lab values that did not have normal ranges, national age and sex adjusted normal ranges were used. If one of the two thyroid function measures was not available for a particular time point, only the available measure was evaluated for thyroid function. This type of missing data was very limited, and treating missing TSH or T4 values as normal did not significantly influence the results of the analyses.

Evaluation of Liver Dysfunction at Baseline and after 131I-MIBG therapy

Liver function tests, including aspartate transaminase (AST), alanine transaminase (ALT), and total bilirubin, were closely monitored and recorded pre-therapy and then weekly for the first six weeks after therapy and repeated at 3 month intervals for one year, then every 6 months, or until the patient died or went on to other therapy. Pre and post therapy liver functions were collected and hepatic toxicity was compared to the institutional normal ranges and graded using CTC v2.0 or CTC v3.0 per study protocol. If a normal range at a time point was missing for a patient, the normal range from another time point for the same patient was used, considering that the normal ranges were very similar across different time points. If one or two of the three liver function measures were not available for a particular time point, only the available measures were evaluated for liver toxicity. This type of missing data was limited, and treating missing lab values as normal did not significantly influence the results of the analyses

Statistical Methods

The cumulative incidence function over time was estimated for both thyroid and liver toxicities. [29] In the analysis of the thyroid data, we evaluated a) the onset or worsening of thyroid toxicity to Grade 2 (the highest grade of thyroid toxicity in our data) after 131I-MIBG therapy, and b) the onset or worsening of thyroid toxicity to any grade (Grade 1 or Grade 2) after 131I-MIBG treatment. In a), a change from baseline Grade 0 or Grade 1 to Grade 2 thyroid toxicity post 131I-MIBG therapy was considered an event. In b), a change from baseline Grade 0 to Grade 1 or Grade 2 after 131I-MIBG treatment, or a change from baseline Grade 1 to Grade 2 after 131I-MIBG treatment was considered an event. Patients who did not experience events defined above were censored at the time of the last test date. Patients with Grade 2 thyroid abnormality at baseline were excluded from the cumulative incidence analysis because medical management of thyroid abnormality made it unlikely for these patients to experience a further worsening of thyroid function after 131I-MIBG treatment. Similarly, in the analysis of the liver data, we evaluated a) the onset or worsening of liver toxicity to Grade 3 and Grade 4 after 131I-MIBG treatment, and b) the onset or worsening of liver toxicity to any grade (Grade 1, 2, 3 or 4). In a), a change from baseline Grade 0, Grade 1, or Grade 2 liver abnormality to Grade 3 or Grade 4 after 131I-MIBG therapy was considered an event, and in b), a change from baseline Grade 0 to Grade ≥1, or a change from baseline Grade 1 to Grade ≥2, or a change from baseline Grade 2 to Grade ≥3 was considered an event. Patients who did not experience an event defined above were censored at the time of the last test date. The “time 0” reference for all cumulative incidence analysis was the date of the first 131I-MIBG treatment.

Analysis of toxicity cumulative incidence and its dependence on patient and disease characteristics was based on the logrank test, product-limit (Kaplan-Meier) estimator, and univariate and multivariate Cox regression analysis. [30] The cumulative dose of 131I-MIBG/kg was included as a time-dependent covariate in the Cox regression analysis. Missing data for variables used in multivariate analysis were included in the models as a “missing” category. All p-values are two sided. Estimates of hazard ratio are presented with 95% confidence intervals. Statistical computation was performed using Stata 9.2. [31]

RESULTS

Analysis Cohort

A total of 194 patients were reviewed for thyroid and liver function. Of these patients, 160 had documented thyroid function values before and after 131I-MIBG therapy and were evaluable for thyroid toxicity, and 136 had documented liver function values before and after 131I-MIBG therapy and were evaluable for liver toxicity (Table I). Thyroid and liver data were both available in 102 patients.

TABLE I
Characteristics of Patients with Thyroid and/or Liver Data

Table I, patient characteristics, shows that this was a heavily pre-treated group of patients, and that approximately 25% of them had more than one MIBG therapy. The median cumulative 131I-MIBG dose was 18.2 mCi/kg (range: 5.0, 54.2). The median time to the last follow up thyroid function test was 3.5 months, but 36 patients had follow-up thyroid function test results that were obtained 12 months or more after 131I-MIBG therapy. Thirty-eight (24%) patients presented with abnormal thyroid function values at baseline, including one patient with an x-linked TBG deficiency that predisposed him to hypothyroidism, and seven patients who were on L-thyroxine prior to receiving 131I-MIBG therapy. Among the 136 patients evaluable for liver toxicity, the distribution of age, sex, the number of prior regimens and cumulative 131I-MIBG dose was very similar to that with thyroid data (Table I). Thirty-eight (28%) patients showed baseline liver function abnormality.

Thyroid Abnormalities Following 131I-MIBG Therapy

Of the 160 patients evaluable for thyroid function following 131I-MIBG therapy, seven patients had Grade 2 thyroid toxicity at baseline and remained Grade 2 after 131I-MIBG treatment. Thirty-one had grade 1 abnormalities at baseline, and of these six progressed to grade 2 hypothyroidism, and 14 normalized without intervention. Of the 122 patients with normal baseline thyroid function, three developed grade 2 hypothyroidism and one patient developed Grave’s Disease and had subsequent thyroidectomy. In all, 36 patients experienced an onset or worsening of thyroid function tests after 131I-MIBG therapy, including nine who developed grade 2 hypothyroidism requiring treatment with L-thyroxine (Figure 1).

FIGURE 1
Flowchart of All Patients with Pre and Post Therapy Thyroid Data

Table II and Figure 2A summarize cumulative incidence of onset or worsening of thyroid toxicities after 131I-MIBG therapy and its relationship with other factors. The 7 patients who had Grade 2 thyroid function abnormality at baseline were excluded from the cumulative incidence analysis. In the remaining patients, 15±5% had experienced onset or worsening to Grade 2 hypothyroidism or hyperthyroidism by two years after 131I-MIBG treatment, and 40±7% of patients had experienced onset or worsening to any grade (Figure 2A). In univariate and multivariate Cox regression analyses, the risk of Grade 2 toxicity was significantly higher in patients with baseline grade 1 thyroid abnormality compared to those with normal baseline thyroid function (Table II). The two-year cumulative incidence rates in these two groups were 35±14% and 10±5% respectively. In the analyses of onset or worsening to any grade thyroid toxicity, there was no significant association with baseline thyroid function. Age, sex, the number of previous chemotherapy and biotherapy regimens, thyroid uptake and cumulative 131I-MIBG dose did not have a significant impact on thyroid toxicity.

FIGURE 2
Cumulative Incidence of Increased Thyroid and Liver Toxicity after 131I-MIBG Treatment (see Statistical Methods section)
TABLE II
Cox Proportional Hazards Model of Cumulative Incidence of Onset or Worsening of Thyroid Toxicity from the Start of 131I-MIBG Treatment

Analysis of the cumulative incidence of hypothyroidism alone after 131I-MIBG therapy showed that at two years after treatment, 32±6% of patients experienced an onset or worsening of any grade hypothyroidism, and 12±4% had experienced onset or worsening to Grade 2 hypothyroidism.

Liver Function Following 131I-MIBG Therapy

Out of the 136 patients with documented liver function values following 131I-MIBG therapy, 98 had normal liver function at baseline, of whom 20 remained normal after 131I-MIBG therapy, 14 experienced Grade 3 or Grade 4 hepatic toxicities, and 64 experienced Grade 1 or Grade 2 toxicity after treatment. Thirty-eight patients had Grade 1 or Grade 2 liver toxicity at baseline, of whom 7 worsened to Grade 3 or Grade 4 after 131I-MIBG therapy, 7 worsened from Grade 1 to Grade 2, 17 remained the same grade, 1 decreased from Grade 2 to Grade 1, and 6 normalized without intervention. No patient had Grade 3 or Grade 4 liver abnormalities at baseline. Of the 136 patients, a total of 18 patients experienced Grade 3 elevation of at least one measure, and a total of 3 patients experienced Grade 4 elevations (Table III).

TABLE III
Summary of Grade 3 and 4 Liver Toxicities Post 131I-MIBG Therapy

At two years post 131I-MIBG therapy, 76±4% patients had experienced onset or worsening of hepatic toxicities to any grade (Grade 1, 2, 3, or 4) (Figure 2B). Most of these toxicities were of Grade 1 or Grade 2. 23±5% of patients had experienced onset or worsening to Grade 3 and Grade 4 liver toxicity (Figure 2B). Table IV summarizes the relationship between cumulative incidence of onset or worsening of liver toxicities after 131I-MIBG treatment and the other factors among patients reviewed for liver function. In Cox regression analysis, there was no significant association between baseline liver function and the risk of Grade 3 or Grade 4 liver toxicity (Table IV). However, there was a significant association between baseline liver functioning and onset or worsening to any grade liver toxicity. Patients with abnormal liver function at baseline had a significantly lower risk progressing to a higher grade toxicity than patients with normal liver function at baseline (p<0.0001 in both the univariate and multivariate analyses (Table IV). By two years after 131I-MIBG treatment, 84±4% of patients with normal liver function at baseline and 48±10% of patients with abnormal liver function at baseline had progressed to higher grade toxicity. The above results indicated that the risk of worsening into Grade 3 or Grade 4 liver toxicity post 131I-MIBG treatment was similar between patients with normal (Grade 0) or abnormal (Grade 1 or 2) baseline liver function, but the risk of worsening into Grade 1 or Grade 2 after 131I-MIBG treatment for patients who were normal at baseline was higher than the risk of worsening into Grade 2 for patients who had Grade 1 liver abnormality at baseline. Age, gender, and the number of previous chemotherapy or biotherapy regimens were not significantly associated with onset or worsening to Grade 3 and Grade 4 or onset or worsening to any grade hepatic toxicity. However, cumulative 131I-MIBG dose showed a trend to be associated with onset or worsening to liver toxicities of any grade (p=0.079 in the univariate analysis, and was significantly associated (p=0.027) in the multivariate analysis), but it was not associated with incidence of Grade 3 and Grade 4 hepatic toxicity.

TABLE IV
Cox Proportional Hazards Model of Cumulative Incidence of Onset or Worsening of Liver Toxicity from the Start of 131I-MIBG Treatment

Of the 21 patients who had Grade 3 or Grade 4 hepatic toxicities after 131I-MIBG therapy, only 8 were considered to be possibly related to the 131I-MIBG therapy; the remainder were coded as “unlikely”. For these 8 patients, the median follow-up time to the date of first abnormality was 1 month (range: 0.5-9 months). All abnormal values returned to normal after a median time of 15 days (Table III). The Grade 3 or 4 toxicities for the remaining 13 patients were deemed to be unlikely related to the 131I-MIBG therapy (Table III). The recorded abnormal post therapy values for those 13 patients occurred at a median time of six (range 2-44) months post 131I-MIBG. The factors that probably contributed towards the occurrence of the Grade 3 or Grade 4 liver toxicities among those 13 patients included: other subsequent therapy for neuroblastoma (N=4), active infections (N=2), progressive disease (N=3), or progressive disease and receiving other therapy (N=4). Other therapies included hu14.18-IL2, myeloablative chemotherapy in preparation for hematopoietic cell transplant, and 13-cis-retinoic acid [32].

DISCUSSION

This large follow up study including 194 patients after 131I-MIBG therapy shows that with proper preventive therapy, damage to the thyroid gland is uncommon and rarely clinically significant. Permanent serious damage to the liver was not evident; most changes were reversible and not clinically significant. In our study, the onset of symptomatic (grade 2) hypothyroidism at 2 years post therapy was only 12±4%, while worsening of thyroid function of any degree occurred in 40±7% of children by two years after MIBG therapy. Elevations of liver function tests were more common, with elevations to grade 3 or 4 seen in 23±5% of patients by two years. The liver toxicity, however, was significantly confounded by other contributing conditions, including other therapies, infections, and disease progression. Out of the 136 patients evaluated for liver toxicity, only 8 had early 131I-MIBG-related Grade 3 and/or Grade 4 hepatic toxicity, without other concomitant conditions, almost always transient.

Due to some dissociation of 131I-MIBG, free iodide contamination of the product, and the biologic degradation of 131I-MIBG by the liver, free radioiodide is released and may be taken up by the thyroid gland, leading to radiation damage. [21,33] In order to prevent damage to the thyroid, stable, non-radioactive iodide ion such as potassium iodide is administered to patients prior to 131I-MIBG therapy to pre-saturate the thyroid. However, based on a study by Picco and colleagues, primary hypothyroidism occurred in 12/14 patients after 131I-MIBG therapy, typically within 6-12 months of administration, despite using potassium iodide as a thyroid blocking agent. [22] In another study of 10 patients conducted by Brans and colleagues, 40% of patients developed hypothyroidism after a mean follow up time of eleven months, indicating that potassium iodide administration alone was inadequate to protect the thyroid. [23] H.M. van Santen and colleagues similarly concluded in a separate study that using potassium iodide only for radiation protection of the thyroid gland during 131I-MIBG treatment in children was less effective than expected. In van Santen’s study, up to 64% of 42 children with neuroblastoma treated with 131I-MIBG (median three therapies) developed TSH elevation, indicating thyroid dysfunction, after an average of 2.3 years. [21]

To decrease hypothyroidism in patients who receive 131I-MIBG therapy, van Santen conducted another study using a combination of thyroxine, methimazole, and potassium iodide for thyroid protection and demonstrated that this combination appeared more effective than using potassium iodide alone. With the combination of thyroxine, methimazole, and potassium iodide, the hypothyroidism rate in 23 patients with median follow-up of 19 months dropped to 14% thyroid dysfunction following 131I-MIBG therapy. [20]

Using CTC v.3 criteria, the results of our study revealed a 40±7% cumulative incidence rate of onset or worsening of thyroid toxicity to any grade at 2 years after 131I-MIBG therapy in the patients who used a thyroid protection regimen of both potassium iodide and potassium perchlorate. The cumulative incidence rate of onset of or worsening to symptomatic hypothyroidism alone was 12±4%. Using thyroid toxicity evaluation criteria similar to that of Picco and van Santen who both used elevated TSH to determine thyroid toxicity in their studies, our study showed 12 out of 122 patients with normal baseline thyroid function presented with Grade 1 compensated hypothyroidism after 131I-MIBG therapy, and 3 out of 122 patients required hormone replacement therapy after treatment, including one patient with a family history of hypothyroidism.

The most significant difference between prior studies and the current study was the thyroid blocking regimen used before and after 131I-MIBG treatment. Rather than using potassium iodide alone or in combination with thyroxine and methimazole, prolonged six weeks of administration of potassium iodide was used with five days of potassium perchlorate in all six clinical trials reviewed for this study. Based on the decreased incidence of symptomatic hypothyroidism observed in this study, the combination of potassium iodide and potassium perchlorate appears to be more effective than most of the previously used regimens in protecting the thyroid from 131I-MIBG therapy. However, even with the use of potassium iodide and potassium perchlorate, 29% of patients with evaluable immediate post therapy scans showed definite or strong thyroid uptake, and 19% of patients showed faint thyroid uptake. However, none of the three patients with normal baseline who were treated with L-thyroxine post-therapy had definite or intense thyroid uptake on their post therapy scans. Cox regression analyses did not reveal significant association between thyroid uptake and the cumulative incidence of onset or worsening of thyroid toxicity (Table II). This is consistent with van Santen, who also reported no correlation between thyroid dysfunction and thyroid visualization after 131I-MIBG administration.

In addition to the thyroid blocking regimen, the lower rate of hypothyroidism reported in this study may also be attributed to a shorter median time from 131I-MIBG therapy to thyroid function follow-up, and a fewer median number of therapies. While other studies report the appearance of thyroid dysfunction half a year or more after 131I-MIBG treatment, the median time to follow-up for this study was 3.5 months. However, 36 patients in this study were followed for more than 1 year. In addition, in only two of the patients who developed asymptomatic elevation of TSH did this occur more than one year post therapy; for the three patients with both elevated TSH and low T4, including two who required hormone therapy, the abnormality developed less than 6 months post MIBG treatment. Because the patient population consisted of refractory or relapsed neuroblastoma patients, many patients either moved on to another therapy shortly after 131I-MIBG treatment or died, which limited the amount of long-term endocrine data collected and available for analysis.

A number of patients (n=38; 24%) presented with abnormal thyroid function at baseline. This baseline abnormality may again have had to do with the study population, which included a majority of patients who had already been heavily pre-treated prior to 131I-MIBG therapy. Non-thyroidal illnesses that cause transient disruption in thyroid function may have also played a role in some of the aberrant thyroid functions collected at baseline and may have contributed to some of the thyroid function abnormalities seen after 131I-MIBG therapy.[34]

Family history and the effects of prior therapy, as well as other treatments received after 131I-MIBG therapy, such as IL-2 or neck irradiation also may have been contributory factors to thyroid function abnormalities. Overall, the prophylactic regimen of potassium iodide and potassium perchlorate with 131I-MIBG therapy is an effective method of protecting the thyroid, resulting in a low incidence rate of clinically significant hypothyroidism. Long term multi-year follow up of patients receiving MIBG will be necessary as this therapy is moved to front-line, to determine if thyroid cancer, as yet unreported, is also a risk, as this is a known late consequence of radiation therapy to the neck or whole body.[35-36]

The liver is also a target organ for 131I-MIBG concentration. [37] Uptake within the organ has been consistently shown on conjugate planar imaging and one third of injected 131I-MIBG is found within the liver following diagnostic and therapeutic doses. 131I-MIBG is uniformly taken up by the liver, reaching maximum uptake within 15 minutes after an intravenous injection of 131I-MIBG, and is rapidly eliminated. Therefore, hepatic toxicity following 131I-MIBG therapy has been closely monitored in neuroblastoma patients. Although symptomatic hepatic toxicity has not been reported in patients receiving single agent 131I-MIBG dosing <12 mCi/kg, there is less information on the effect of 131I-MIBG exposure to the liver for patients receiving ≥12 mCi/kg of 131I-MIBG. [32,38-39] A recent dosimetry study supports the lack of toxicity seen in our study, as it showed that giving 18 mCi/kg of 131I-MIBG results in <30 Gy of radiation to the liver, below liver toxicity range.[39]

Liver function abnormalities following 131I-MIBG therapy were more prevalent than thyroid function abnormalities, with 76±4% of patients experiencing onset or worsening of hepatic toxicity of any grade. Of these patients, only 23±5% experienced Grade 3 and/or 4 liver function abnormalities by 2 years after 131I-MIBG therapy. However, 13 of 21 cases with onset or worsening of Grade 3 and/or 4 liver toxicity were deemed unlikely related to 131I-MIBG therapy and attributed to another etiology. Therefore, less than 10% of patients with evaluable post therapy liver data had Grade 3 and/or 4 liver toxicity that was possibly attributed to their 131I-MIBG therapy.

Patients with Grade 3 and 4 liver toxicity who did not die shortly after due to progressive disease had their normalization of liver function after a median of 15 days. There were no cases of long-term hepatic complications related to liver function elevation after 131I-MIBG therapy. Grade 1 and 2 liver toxicities attributable to 131I-MIBG therapy were transient in patients with extended follow-up information and resolved without intervention.

Although age, gender, and the number of prior cancer treatments were not significantly associated with worsening of hepatic function, a strong correlation was seen between patient baseline liver function and the onset or worsening of any grade liver toxicity. In our analysis, the relative risk of onset or worsening to grade 3 or 4 hepatic toxicity after 131I-MIBG therapy showed a non-significant but positive association with baseline grade, but the relative risk of any onset or worsening of hepatic toxicity was significantly negatively associated with baseline grade. The latter result suggests that worsening of toxicity by 1 grade level is more likely in patients with normal liver function than for patients with grade 1 or grade 2 toxicity at baseline. This apparent paradox may be a result of the fact that so many factors may cause mild elevation of transaminase levels, such as antibiotics and other medications or infections.

In conclusion, the prophylactic regimen of potassium iodide and potassium perchlorate with 131I-MIBG therapy is an effective thyroid blocking regimen, with a relatively low incidence rate of symptomatic hypothyroidism when compared to prior studies. Liver abnormalities following 131I-MIBG therapy are primarily transient and do not appear to pose a long-term threat to children who receive 131I-MIBG therapy for neuroblastoma. Therefore, 131I-MIBG therapy is a promising treatment for children with refractory or relapsed neuroblastoma with a relatively low rate of significant late thyroid or hepatic dysfunction.

ACKNOWLEDGEMENTS

Supported in part by NIH grants NCI R21 CA97758, NCI PO1 81403, NCRR UCSF-CTSI UL1 RR024131, and the Dougherty Foundation, Alex’s Lemonade Stand Foundation, Campini Foundation, V-Foundation, Mildred V. Strouss Chair, Conner Fund, and Ciesam Foundation.

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