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 131
I-MIBG, free iodide contamination of the product, and the biologic degradation of 131
I-MIBG by the liver, free radioiodide is released and may be taken up by the thyroid gland, leading to radiation damage. [21
] In order to prevent damage to the thyroid, stable, non-radioactive iodide ion such as potassium iodide is administered to patients prior to 131
I-MIBG therapy to pre-saturate the thyroid. However, based on a study by Picco and colleagues, primary hypothyroidism occurred in 12/14 patients after 131
I-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 131
I-MIBG treatment in children was less effective than expected. In van Santen’s study, up to 64% of 42 children with neuroblastoma treated with 131
I-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 131
I-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 131
I-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 (). 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 131
I-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 131
Family history and the effects of prior therapy, as well as other treatments received after 131
I-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 131
I-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
The liver is also a target organ for 131
I-MIBG concentration. [37
] Uptake within the organ has been consistently shown on conjugate planar imaging and one third of injected 131
I-MIBG is found within the liver following diagnostic and therapeutic doses. 131
I-MIBG is uniformly taken up by the liver, reaching maximum uptake within 15 minutes after an intravenous injection of 131
I-MIBG, and is rapidly eliminated. Therefore, hepatic toxicity following 131
I-MIBG therapy has been closely monitored in neuroblastoma patients. Although symptomatic hepatic toxicity has not been reported in patients receiving single agent 131
I-MIBG dosing <12 mCi/kg, there is less information on the effect of 131
I-MIBG exposure to the liver for patients receiving ≥12 mCi/kg of 131
] A recent dosimetry study supports the lack of toxicity seen in our study, as it showed that giving 18 mCi/kg of 131
I-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.