Long-term carbimazole pretreatment reduces the efficacy of radioiodine therapy

Abstract

Introduction:

Data from several studies suggest that pretreatment with antithyroid drugs (ATD) before ¹³¹I increases the risk of treatment failure. This effect has been demonstrated more consistently with propylthiouracil than with carbimazole (CMZ) or methimazole (MMI). Men with Graves’ disease (GD) have a lower rate of remission with ¹³¹I compared to women and the impact of long-term ATD pretreatment on the success of ¹³¹I is unknown. The objective of our study was to compare the efficacy of fixed doses of radioiodine between patients with and without long-term CMZ pretreatment.

Materials and Methods:

We performed a retrospective study on 335 male patients with GD treated with ¹³¹I from 1998 to 2008. 148 patients had been pretreated with CMZ, and the remaining 187 patients received ¹³¹I without pretreatment. We compared the success rate of a single dose of ¹³¹I, between patients with and without long-term CMZ pretreatment.

Results:

The success rate of a single dose of ¹³¹I was significantly higher in patients without pretreatment than in patients who were pretreated with CMZ (91.4% vs. 82.3%, P = 0.01). The rate of hypothyroidism in the first 6 months after ¹³¹I therapy was significantly higher in patients without pretreatment (55.1% vs. 44.6%, P = 0.05). There was also a trend for higher cumulative rate of hypothyroidism at last follow-up in nonpretreated patients (78.1% vs. 69.7%).

Conclusion:

Male patients with Graves’ hyperthyroidism pretreated with CMZ have lower efficacy with 131I therapy compared to nonpretreated patients. CMZ pretreatment given for a prolonged period reduces the efficacy of ¹³¹I therapy.

INTRODUCTION

Radioactive iodine (RAI) therapy has been used as a first line of treatment for Graves’ hyperthyroidism (Graves’ disease [GD]) for more than seven decades and is still the treatment of choice in many parts of the world.[1] It's a common practice to pretreat patients with antithyroid drugs (ATD) prior to radioiodine ablation, to restore euthyroidism and to prevent exacerbation of the thyrotoxic state seen in some patients after radioiodine therapy.[2] ATD have a radioprotective effect and pretreatment with ATD has been shown to increase the risk of treatment failure with subsequent ¹³¹I.[3,4] This effect has been demonstrated more consistently with propylthiouracil (PTU) than with carbimazole (CMZ) or methimazole (MMI).[5,6,7,8,9] It has been recommended that ATD should be stopped 3–5 days before ¹³¹I to reduce the interference of ATD with the efficacy of radioiodine therapy. Men with GD have a lower rate of remission compared to women[10] and the impact of long-term pretreatment with ATD on the efficacy of radioiodine treatment in men has not been adequately evaluated. The objective of this retrospective study, in men with GD, was to compare the efficacy of fixed doses of radioiodine between patients with and without long-term CMZ pretreatment.

MATERIALS AND METHODS

We reviewed the case records of 464 male patients with GD treated at M. S. Ramaiah Medical College, Bangalore, with ¹³¹I, in the period between 1998 and 2008. GD was defined as the occurrence of biochemical hyperthyroidism (raised serum total/free T4 concentration and undetectable/low thyroid stimulating hormone [TSH]) together with the presence of at least two of the following: a palpable diffuse goiter, diffusely increased uptake on the technetium 99 m thyroid scan, elevated titers of thyroid peroxidase and/or TSH receptor autoantibodies, and/or the presence of ophthalmopathy. The inclusion criteria were: radionuclide studies and thyroid function tests consistent with GD, a recipient of ¹³¹I therapy, at least 1-year of follow-up data available post ¹³¹I therapy and discontinuation of CMZ therapy at least 5–7 days before radioiodine administration. Exclusion criteria included therapy with any ATD other than CMZ or ATD therapy during radioiodine therapy. Patients pretreated for <3 months were also excluded. Patients were divided into two groups-patients pretreated with CMZ as a primary long-term therapy that subsequently received ¹³¹I and untreated newly diagnosed patients who were given ¹³¹I alone without ATD pretreatment. In patients opting for ATD as primary therapeutic option, our policy was to administer them for 12–24 months and patients who were biochemically hyperthyroid or who required a dosage of >10 mg/d of CMZ to maintain euthyroidism at the end of therapy would then be advised to take ¹³¹I therapy.

Three hundred and thirty-five patients met the study criteria. Of the 335 patients, 148 patients had been pretreated with ATD and remaining 187 patients received ¹³¹I without pretreatment. Mean duration of ATD therapy before ¹³¹I was 23.1 months. Patients were treated with a single fixed dose of ¹³¹I based on the uptake of radioiodine and thyroid size. The dose of ¹³¹I varied from 5 to 15 millicurie (mCi). In patients pretreated with ATD, the drugs were withdrawn 5–7 days before radioiodine therapy. Following RAI treatment, thyroid status was monitored every 2–3 months during the 1^st year and 3–6 monthly thereafter. All the patients within the study group were followed up for at least 12 months after treatment. Cure of hyperthyroidism after ¹³¹I was defined as euthyroid status for 6 months off treatment or the need for levothyroxine replacement for biochemical hypothyroidism.

Statistical methods

Data are reported as mean and standard deviation for the continuous variables, number and percentage for the categorical variables. Student's t-test (unpaired t-test) was used to compare the outcome results between drug-naïve patients and patients who were previously on ATD. Chi-squared test was used to compare the observed frequencies of palpable goiter and ophthalmopathy between the two study groups. Two sample proportion test was used to compare the success rate of a single dose of ¹³¹I and differences in the rates of worsening of ophthalmopathy (%) between the study groups. Statistical analyses were done using StataCorp 12. P < 0.05 was set as statistically significant.

RESULTS

The baseline demographic, clinical, and laboratory characteristics of the cohort are summarized in Table 1. The prevalence of ophthalmopathy was not significantly different between the two groups. The overall success rate of a single dose of ¹³¹I for the entire cohort was 80.2% (275/335) and the cumulative rate of hypothyroidism at 1-year was 64.5%.

Table 1.

Baseline characteristics of the two study groups

A mean dose of ¹³¹I administered was similar in the two groups. The success rate of a single dose of ¹³¹I was significantly higher in patients without pretreatment than in patients who were pretreated with CMZ (91.4% vs. 82.3%, P = 0.01) [Figure 1]. The rate of hypothyroidism within the first 6 months after ¹³¹I therapy was significantly higher in patients without pretreatment (55.1% vs. 44.6%, P = 0.05). The rate of hypothyroidism between 6 months and 1-year after ¹³¹I therapy was not significantly different between the two groups (12.2% vs. 16.9%, P = 0.2). There was a trend for a higher cumulative rate of hypothyroidism at last follow-up in the drug-naïve patients (78.1% vs. 69.7%), though it did not quite achieve the threshold for statistical significance (P = 0.08) [Table 2]. There was also a nonsignificant trend for a shorter mean duration for the development of hypothyroidism in the drug-naïve patients. The rate of worsening of ophthalmopathy was not significantly different between the two groups. Cumulative rates of hypothyroidism between 1 and 6 months and 6 and 12 months were 55.1% and 12.2% respectively. 13.3% of drug-naïve patients and 12.8% of patients who had previously received ATD before ¹³¹I were euthyroid at the last follow-up without the need for levothyroxine replacement.

Figure 1.

Comparison of rates of hypothyroidism and euthyroidism between the two groups (P < 0.05, significant)

Table 2.

Comparison of outcome measures between the two groups

DISCUSSION

Our data demonstrate that male patients with Graves’ hyperthyroidism pretreated with CMZ have reduced efficacy with subsequent ¹³¹I therapy. Cumulative hypothyroidism and hypothyroidism within 6 months after ¹³¹I were also lower in them compared to patients who were not pretreated.

Although radioiodine is considered a safe and effective treatment for GD, controversies remain on the optimal method for calculating the dose and the most appropriate dose regimen. Achieving long-term euthyroidism appears to be a futile objective and most series report high rates of cumulative hypothyroidism after ¹³¹I.[10,11,12] Our findings are in concurrence with these studies, with two-thirds of patients developing hypothyroidism within 1-year. In our study, the success rate of ¹³¹I without ATD pretreatment was 91%. Cure rates of 67–95% have been reported after different doses of ¹³¹I (5–12.3 mCi) and studies employing higher doses (>10 mCi) have reported success rates between 86% and 95%.[10,11,12,13,14,15,16,17] A study from south India reported a success rate of 95% with a fixed dose of 10 mCi in GD.[18]

A cure rate of 82% seen in patients pretreated with CMZ. The results are comparable to a previous study of 58 patients that reported a success rate of 82% of a fixed dose of RAI in patients on long-term CMZ.[19] Another study of 61 patients found a success rate of 80% in patients pretreated with MMI.[7] A retrospective study in patients of GD on long-term PTU reported a success rate of 83% for ¹³¹I when PTU was stopped at least a week before ¹³¹I therapy and 71% when PTU was stopped for 4–7 days. ¹³¹I administered without PTU pretreatment had a success rate of 91%.[20] A prospective study reported a success rate of 83% at 1-year in patients pretreated with CMZ when it was stopped 3 days before ¹³¹I.[21]

Simultaneous use of ATD with RAI has consistently been shown to result in lower efficacy and higher failure rate than treatment with RAI alone.[21,22,23,24,25] However, studies have demonstrated that pretreatment with ATD leads to a higher failure rate even if the drugs are discontinued 4–7 days before RAI therapy and not restarted posttherapy. This effect has been demonstrated consistently with PTU and studies on CMZ/MMI yielded conflicting results. Hancock et al., found that PTU discontinued 4–7 days before radioiodine dosing was associated with a significant increase in the failure rate of subsequent radioiodine therapy.[20] Two other studies also reported that PTU pretreatment significantly reduced the efficacy of ¹³¹I therapy.[8,26] Imseis et al., found that PTU (but not MMI) may reduce the therapeutic efficacy of subsequent ¹³¹I when they were discontinued 5–55 days before radioiodine treatment.[5]

Goolden and Fraser found equal cure rates from ¹³¹I with and without CMZ pretreatment, when CMZ was discontinued 3–5 days before ¹³¹I therapy.[27] Two randomized controlled trials (RCTs) reported that MMI pretreatment didn’t interfere with the efficacy of ¹³¹I therapy.[7,28] Another study found no interference of CMZ treatment with the efficacy of I131 when it was discontinued 5–7 days before radioiodine therapy, but the success rate was much lower if it was simultaneously administered with ¹³¹I therapy.[22] In another study, pretreatment with MMI reduced the efficacy of ¹³¹I only when it was administered on the day of ¹³¹I therapy.[25]

However, a few other studies have reported that CMZ or MMI pretreatment reduces the efficacy of ¹³¹I. Connell et al., reported that CMZ stopped 5 days before ¹³¹I reduced the rate of hypothyroidism at 1-year compared to nonpretreated patients.[29] Two other studies reported that CMZ pretreatment reduced the efficacy of ¹³¹I therapy.[4,30] ATD, including CMZ, given within 1-week after radioiodine treatment was found to reduce the efficacy of I131 in a retrospective study of 206 patients.[31] A retrospective study of 360 patients with hyperthyroidism, with a follow-up range of 2–10 years, reported that ATD, including both PTU and CMZ pretreatment reduces the efficacy of radioiodine therapy. In that study, the response rate was significantly higher in the group without pretreatment (95%) as compared to patients with pretreatment (80.9%), much similar to the results of our study.[32] Another retrospective study of 449 patients with hyperthyroidism using a 550MBq fixed dose regimen found that CMZ pretreatment stopped 1-week before radioiodine therapy reduced the efficacy of radioiodine treatment.[33] Finally, a meta-analysis of 14 RCT reported that adjunctive ATD, including CMZ, were associated with an increased risk of treatment failure with ¹³¹I and reduced risk for hypothyroidism.[3]

Antithyroid drugs are used in the management of GD either as primary therapy for several months while awaiting remission of the disease or as pretreatment for several weeks prior to definitive RAI therapy. ATD are believed to have a radioprotective effect and hence interfere with and reduce the efficacy of ¹³¹I therapy. Radio resistance conferred by thioureas is believed to be due to their sulfhydryl groups.[34] As CMZ does not have a sulfhydryl group, it was proposed that it confers no radioresistance.[29,34] In many of the studies examining the effect of ATD on ¹³¹I, PTU or CMZ were used as pretreatment for several weeks before ¹³¹I and very few studies examined the effects of long-term ATD used as a primary therapy for several months of GD. The mean duration of CMZ therapy in our study was 23.08 months. Our study results suggest that CMZ pretreatment also reduces the efficacy of subsequent ¹³¹I like PTU. Although the success rate of ¹³¹I in patients pretreated with CMZ noted in our study was similar to that reported in previous studies, we also found that CMZ pretreatment reduced the efficacy of subsequent ¹³¹I unlike them. The apparent discrepancy in our results could be due to several reasons. First, CMZ was used for a longer duration in our patients than in many other studies. In a previous study, MMI given for more than 4 months before radioiodine therapy was shown to reduce the efficacy of subsequent ¹³¹I therapy.[12] Similar finding was reported by another study.[35] Second, the radioprotective effect could be gender divergent, and we studied only male patients. Male patients have been shown to have a significant poor response after ¹³¹I therapy as compared to female patients, and the response may be worse after pretreatment with ATD.[10,15,36] A mean dose of ¹³¹I in patients pretreated with ATD was 8.7 mCi that is lower than that used in many other studies. There is evidence to suggest that radio resistance-conferring effects of ATD are more commonly seen at lower doses and radioprotective effect of ATD can at least partly be overcome by increasing the dose of ¹³¹I.[10,37,38]

The merits of our study are a large number of patients and an uniform study group. We have only examined the outcome of radioiodine therapy in a retrospective analysis. A large prospective randomized control study is warranted to further clarify the effect of pretreatment with CMZ on the efficacy of ¹³¹I therapy.

CONCLUSIONS

Male patients with Graves’ hyperthyroidism pretreated with CMZ have lower efficacy with ¹³¹I therapy compared to nonpretreated patients. CMZ pretreatment given for a prolonged period interferes with the efficacy of ¹³¹I therapy.