Endocrinology, Mubarak Al Kabeer Teaching Hospital & Faculty of Medicine, Kuwait University, Jabriya, Kuwait

Nuclear Medicine Divisions, Mubarak Al Kabeer Teaching Hospital & Faculty of Medicine, Kuwait University, Jabriya, Kuwait

Abstract

Background

The current status of radioiodine-131 (RaI) dosimetry for Graves' hyperthyroidism is not clear. Recurrent hyperthyroidism and iatrogenic hypothyroidism are two problems which interact such that trying to solve one leads to exacerbation of the other. Optimized RaI therapy has therefore begun to be defined just in terms of early hypothyroidism (ablative therapy) as physicians have given up on reducing hypothyroidism.

Methods

Optimized therapy is evaluated both in terms of the greatest separation of cure rate from hypothyroidism rate (non-ablative therapy) or in terms of early hypothyroidism (ablative therapy) by mathematical modeling of outcome after radioiodine and critically discussing the three common methods of RaI dosing for Graves' disease.

Results

Cure follows a logarithmic relationship to activity administered or absorbed dose, while hypothyroidism follows a linear relationship. The effect of including or omitting factors in the calculation of the administered I–131 activity such as the measured thyroid uptake and effective half-life of RaI or giving extra compensation for gland size is discussed.

Conclusions

Very little benefit can be gained by employing complicated methods of RaI dose selection for non-ablative therapy since the standard activity model shows the best potential for cure and prolonged euthyroidism. For ablative therapy, a standard MBq/g dosing provides the best outcome in terms of cure and early hypothyroidism.

Introduction

Radioiodine-131 (RaI) therapy has been increasingly used for the treatment of hyperthyroid Graves' disease. Many factors contribute to the current popularity of this treatment modality as a primary and secondary management option, especially the recurrence of Graves' disease after drug therapy. Initially, the dosage (radioactivity) administered was worked out by a trial-and-error method but with increasing experience over the last century, RaI treatment methods evolved

Thyroid ablation, as defined above based only on cure rates, has not been adopted universally since many workers in the field do not see this as the optimal approach, but rather as an ablative one, and insist on defining as optimum the protocol in which the administered RaI dosage provides the best possible separation of cure rate from hypothyroidism rate. In this situation, the looming threat of recurrent hyperthyroidism and inevitability of hypothyroidism coexist with the fact that there is no consensus on their definition. Clinicians have expressed frustration with such optimization repeatedly

Methods

The hypothyroidism model

Using RaI, the thyroid can be irradiated to very large doses of several thousand grays that induce acute cell destruction (interphase death)

The clinical effect of RaI was best demonstrated in the Cooperative Thyrotoxicosis Follow-up Study

Therefore, the incidence of hypothyroidism at any given time is directly proportional to the magnitude of the initial effect. In other words, if a higher proportion of patients are rendered hypothyroid initially using a particular method of dose selection, then subsequent hypothyroidism proceeds from this point in the remainder with a shorter period to complete hypothyroidism. To assess the outcome of RaI therapy for the achievement of optimum hypothyroidism will then require assessment of first year hypothyroid (FYH) outcomes to the initial dose since subsequent development of hypothyroidism is predictable and independent of dose. A linear hypothyroidism dose model can therefore adequately predict first year hypothyroidism rates.

The cure model

Failure rates should also be defined at one year since the initial dose dependent effect of RaI has been shown to occur in this period and patients still hyperthyroid at this time will need re-treatment. However, in contrast to hypothyroid rates, cure rates tend to plateau out as administered activity or absorbed dose increases. This is because cure is the combination of euthyroidism and hypothyroidism rates and while the latter increases with dose, the former increases and then subsequently decreases as dose is increased. This leads to a lesser and lesser rise in cure rates with the same increment in RaI dose. Studies that have looked at this cure dose response demonstrate that this relationship is logarithmic. In a prospective, randomized multi-center study ^{2} = 0.99; outcome at 6 months). As the absorbed dose is increased so too does the average activity administered and hence with a fixed administered activity, cure can be expected to follow the same relationship to dose. Again the study of Nordyke and Gilbert^{2} = 0.97; data extrapolated from figure 1 and omitting 3 mCi) the logarithmic model explained 97% of the variability in cure rates. Therefore, a logarithmic cure dose model can adequately predict cure rates.

The final model demonstrating the relationship between euthyroid rates at 1 year and failure rates (of treatment) at 1 year at various dose levels for the three methods of dose selection.

The final model demonstrating the relationship between euthyroid rates at 1 year and failure rates (of treatment) at 1 year at various dose levels for the three methods of dose selection. This relationship is derived from the logarithmic cure-dose and linear hypothyroid-dose models described in the text where: Euthyroid rate = Cure – hypothyroidism rate Failure rate = 100 – cure rate The slanted line demarcates the level below which cure rates are predominantly due to hypothyroidism and vice-versa and serves as the upper limit for non-ablative dosing.

Data collection and statistical analysis

The first year outcome to varying doses of RaI was determined from the medical literature for the three methods of dose selection. Search for articles was via PubMed using the MESH term "iodine radioisotopes" and either of the terms Graves', hyperthyroidism or thyrotoxicosis. Additional articles were retrieved via manuscript reference review. We then independently reviewed potentially relevant manuscripts, subject to availability through our resources, and inclusion was restricted to studies in which the first year outcome was available in terms of treatment failure (or cure). Articles that reported outcome after RaI treatment of multinodular goiters, solitary toxic nodules or euthyroid goiters were excluded. Studies were selected irrespective of RaI use as the primary or secondary modality (after drug therapy) and irrespective of variations in iodine intake or gland size differences as our preliminary analysis suggested that dose alone accounted for 70–80% of the variation in cure rates or hypothyroidism rates. Our target for the search was at least 10 studies to fit each model. This target was reached once the number of selected manuscripts reached a total of thirty-four published studies on a first available basis (thirty-one of these studies had the data on hypothyroidism rates at one year) and the search was then discontinued. Individual studies were not graded nor did we attempt to keep a record of the total number of studies reviewed or excluded from the analysis since we did not intend this to be a systematic review. Our selected studies were analysed in three groups based on the method of dose selection given below and results of individual studies in each group were then pooled using a linear (hypothyroid) or logarithmic (cure) model:

Studies using the AbsD, used mass of the gland (measured or estimated), and measurements of the effective half-life of RaI in the thyroid to deliver a radiation absorbed dose to the thyroid which is usually given by Eq 1 _{eff} is the effective half-life in days and MBq_{T} is the activity of RaI deposited in the thyroid. C is a constant representing factors such as the average absorbed energy from the beta and gamma rays in MeV (which for RaI is 0.203 MeV) _{T} = MBq_{A}X(%uptake/100)) (Eq 1):

The target radiation absorbed dose for effective RaI therapy for hyperthyroid Graves' disease should be at least 60–70 Gy and this is commonly referred to as a conventional dose

Studies using CalA based dose selection were based on the lesser variability found in the value of the effective half time (T_{eff}) in Eq 1. This lesser influence of T_{eff} is because variation in the biologic half-life of RaI in the thyroid, makes only a small difference to its effective half-life. For example, a variation from 20 to 60 days in the biologic half-life would only increase the effective half-life from about 6 to 7 days assuming a physical half-life of 8 days. _{eff}, most patients will have a higher T_{eff} than the mean, albeit in a smaller range. Therefore more patients given CalA with the assumption of a constant half-life (of about 5–6 days) are liable to be given a slightly larger activity than with the corresponding AbsD, usually in the region of 30%

Many centers use this method of dose selection that assumes a constant half-life so that approaches to dosage adjustment usually include a factor for gland size, a standard dose in MBq/g (or microCuries per gram), and a correction to account for 131-I uptake

Studies using a FixA method gave fixed activities of RaI irrespective of thyroid mass or T_{eff}. From studies of thyroid size and goitre frequency in hyperthyroidism, it is clear that such patients will show wide variation

The relationship between cure or hypothyroidism and RaI dose for all three methods was analysed by simple regression using Statgraphics Plus for Windows 3.0, (Statistical Graphics Corp., Englewood Cliffs, N.J.) and applying a logarithmic model for cure rates and a linear model for hypothyroid rates. A visual analysis of the residuals versus dose plot was done to ensure that the pattern was random. A lack of fit test was performed by comparing the variability of the chosen model residuals to the variability between observations at replicate values of the independent variable (administered activity or absorbed dose). This was designed to determine whether the selected model was adequate to describe the observed data. The P-value for lack-of-fit in the analysis of variance was greater or equal to 0.10, for all three methods of dose selection in the cure model suggesting that they were adequate for the observed data. With the hypothyroidism model, there was significant lack of fit at the 90% level for AbsD and FixA, but this was seen also after consideration of ten alternative and more complicated models with better correlation. The linear model was therefore considered most appropriate as it has a clear biological basis previously outlined.

Results

The logarithmic cure model

The pooled analysis demonstrated that as higher doses are delivered, cure rates tend to reach a plateau so that the relationship between cure and dose was indeed logarithmic for all three methods of dose selection. The P-value in the analysis of variance for all three models was less than 0.01, indicating that there was a statistically significant relationship between cure and dose at the 99% confidence level. The R-Squared statistic indicated that the model as fitted explained 70%, 76% & 97% of the variability in cure respectively. This relationship was given by:

**CR = 23LN(Gy) - 38.5** (r^{2} = 0.7) for AbsD

**CR = 28.7LN(MBq/g) + 21.2** (r^{2} = 0.75) for CalA

**CR = 21.7LN(MBq) - 42.9** (r^{2}= 0.96) for FixA

The cure rates for CalA are consistent with cure rates at equivalent AbsD assuming that 0.06 MBq/g delivers 1 Gy as previously calculated. However, with FixA a given cure requires administration of less activity than that required with AbsD (on the average 30% lower) for the same cure. The reason for this is that even though the actual RaI activity given to the patient is less, the most common gland sizes are actually getting higher absorbed doses. For example, it has been shown that after a fixed dose of only 75 MBq, (which delivers a low average of 30–40 Gy) there is a 16-fold range of absorbed doses delivered (6–98 Gy) and 20% of patients actually receive doses greater than 60 Gy

The linear hypothyroidism model

A pooled analysis from thirty-one of the previously cited studies (those with data on hypothyroidism rate) revealed a linear relationship between FYH and all methods of dose selection (AbsD, CalA & FixA). The P-value in the analysis of variance for all three models was less than 0.01, indicating that there was a statistically significant relationship between cure and dose at the 99% confidence level. The R-Squared statistic indicated that the model as fitted explained 92%, 82% & 78% of the variability in cure respectively. This relationship was given by:

**FYH = 0.36(Gy) - 13.4** (r^{2} = 0.92) for AbsD

**FYH = 8.8(MBq/g) - 10.3** (r^{2} = 0.82) for CalA

**FYH = 0.13(MBq) + 0.412** (r^{2}= 0.78) for FixA

When effective RaI half-life is disregarded in the calculation of the RaI activity for treatment on a MBq/g basis, the FYH is higher for the same cure level as compared to the AbsD. The FYH rises from 25 to 95% for doses of 4 to 12 MBq/g respectively, compared to a rise from 15 to 60% after equivalent AbsD of 70 to 200 Gy. This again is explained by the effective half-life differing with a range from 1.6–7.5 days giving a possible difference in AbsD by a factor of 4.6

Conversely euthyroid rates with a FixA are relatively more at every cure level than what is observed after AbsD except for fixed activities of less than 140–150 MBq (see figure

The final model

From the cure model, failure rates are defined as 100-cure%. Similarly from both models, euthyroidism is defined as cure%-hypothyroidism%. The final model is plotted in figure

One useful feature of the euthyroid rates is that they can be used to provide a clinically useful definition of the optimized non-ablative regimens. A lower limit for such regimens would be at the point where euthyroid rates peak (turning point at which the euthyroid rates begin to fall off, see figure

The dose and outcome ranges for optimized therapy

Method

Outcome

Dose range

Cure%

Euthy%

Hypo%

(min/max)

(min/max)

(peak/min)

(min/max)

Non-ablative

AbsD

70Gy

58%

48%

10%

140Gy

76%

38%

38%

FixA

180 MBq

70%

46%

24%

310 MBq

82%

41%

41%

Ablative

CalA

~ 11.4 MBq/g

91%

1%

90%

The data is based on a combination of both models described in the text and depicted in figure

Discussion

The current status of RaI treatment regimens for Graves' hyperthyroidism suffer from inevitable induction of hypothyroidism and the risk of recurrence of thyrotoxicosis. Optimization of RaI treatment regimens aims at selection of the administered radioactivity that gives the highest cure and lowest euthyroid rate (ablative) or the former with a maximum euthyroidism (non-ablative). The way to achieve the latter has been addressed making use of available reports in the literature and a critical appraisal of the patterns of cure and induction of hypothyroidism. It is clear that for all three methods of dose selection, the euthyroid rates initially rise as the dose increases and then falls off as hypothyroidism ensues. The best outcome in terms of separation of cure rates from hypothyroidism rates is for a FixA between 185–310 MBq. The maximum euthyroid rates possible are about 40–45% and cure between 70–80%. Assuming a cumulative hypothyroid rate of 3% per year, the median time to hypothyroidism (for those euthyroid at 1 year) would be about 7 years. This is achieved at the expense of one patient out of every five treated needing re-treatment with radioiodine.

On the other hand, if only preventing re-treatment is considered optimal, clearly any method of dosing could be used and similar cure can be achieved by administering 11 MBq/g as CalA or 250 Gy as AbsD or 500 MBq as FixA. However, if in addition to high cure, early hypothyroidism is also required (ablative treatment), the only suitable method is through administration of a CalA, as at 11 MBq/g less that 5% of patients will be euthyroid at one year, compared to 10% given 250 Gy and 20% given 555 Mbq. From the model, a dose of 11–12 MBq/g predicts a 90% hypothyroidism rate at one year.

For any further improvement in these non-ablative optimized regimens, what is required is some modification that increases cure while at the same time blunting the rise in hypothyroidism. This method came to attention when it was noticed that doses estimated to deliver an AbsD or CalA to the thyroid (after linear adjustment for size) still resulted in higher hypothyroid rates in those patients with smaller goiters, and lower rates with increasing size of the goiter

Several workers have since used extra (non-linear) compensation for the size of the thyroid, by giving an increasing CalA (range 1.5 – 3.7 MBq/g) individualized to thyroid size (lower CalA for smaller glands and vice versa).

As the evidence in favor of such extra non-linear compensation per gram of thyroid became clear, it also became evident that it is not the activity of RaI per gram deposited in the thyroid that determines the outcome in a particular gland, but rather the total activity actually deposited. This is evident from the fact that smaller glands require more activity per gram than larger glands since CalA dosing leads to a steep rise in hypothyroidism rates with increasing dose (see fig 2). What would probably work more efficiently in this instance is to start off with a small FixA then step it up in multiples of a FixA so that the total dose increases with gland mass. One way to do this is to start with a small dose of 185 MBq and then step it up in multiples of 74 MBq with increasing gland size. Since (as described above) the relation between cure and activity/gram is non-linear, the fixed extra compensation will result in a greater than proportional step-up in administered activity.

Trials of such graded FixA

Suggested FixA Ral regimen for optimized non-ablative dosing

Thyroid grade

Standard

Expected

activity

Outcome of therapy

0

185 Mbq

85% cure and less than

Not easily visible even with neck

extension. Just palpable (Est 10 g)

10% hypothyroid at 1

I

259 MBq

year.

Visible only with neck extension but easily

Palpable (Est 20 g)

II

370 MBq

Visible without neck extension (Est 40 g)

III

444 MBq

Visible easily from afar (Est 80 g)

Adapted from the data of Zaini et al 1992 [68]. Only palpation was used to decide dosing in this study. The assumption made is that grades I - II goiters have median weights of 20–40 g [76], with the grade 0 goiter having a median weight of about 8 g [76,77] and grade III goiters a median weight of 80–100 g. [76] This regimen needs to be formally evaluated, especially in a study that uses a more accurate method of thyroid size assessment.

It is clear that if the target of RaI therapy is a prolonged period of euthyroidism, the increased effort and expenditure involved in calculating the precise activity of RaI for a target radiation absorbed dose, do not improve upon a FixA and in fact result in worse outcomes. It would seem that a return to a simple regimen utilizing FixA is inevitable for such a goal. Grading such FixA can be expected to markedly improve on the euthyroid rates (but not on overall cure rates) and in final assessment, the regimen in table

Competing Interests

None declared

Pre-publication history

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