Radioiodine Therapy for Multinodular Toxic Goiter

ORIGINAL INVESTIGATION Radioiodine Therapy for Multinodular Toxic Goiter Birte Nygaard, MD, PhD; Laszlo Hegedu¨s, MD, PhD; Peter Ulriksen, MD; Kamilla Gerhard Nielsen, MD; Jens Mølholm Hansen, MD

Background: Radiolabeled iodine 131 therapy is used reduction in median thyroid volume from 56 mL (range, for treatment of multinodular toxic goiter, but long- 21-430 mL) to 44 mL (range, 15-108 mL), representing a term follow-up studies are lacking. 24% reduction related to the insufficient 131I dose. In all patients, the initial median thyroid volume of 44 mL (range, Methods: A prospective study of 130 consecutive 16-430 mL) decreased to 25 mL (range, 8-120 mL) patients (115 women) treated with 131I for multinodular (PϽ.005), representing a median reduction of 43%, 24 toxic goiter and followed by evaluation of thyroid vol- months after the last 131I dose. Hypothyroidism evaluated ume (determined using ultrasound) and thyroid func- using life-table analysis developed in 6% of patients who tion variables. did not receive antithyroid pretreatment and 20% who did (PϽ.005) after a median of 42 months (range, 3-60 Results: The patients were observed for a median of 72 months), the total hypothyroidism frequency being 14% months (range, 12-180 months). Sixty-six patients re- within 5 years of treatment. ceived antithyroid drug pretreatment; 64 did not. Iodine 131 treatment (3.7 MBq/g thyroid tissue corrected to a Conclusions: Ninety-two percent of patients with mul- 100% 24-hour 131I uptake) was given as a single dose in tinodular toxic goiter were cured with 1 or 2 treat- 81 patients, 2 doses in 38, and 3 to 5 doses in 11. One or ments. The thyroid volume was reduced by 43%, with 2 treatments cured 119 patients (92%), and 68 (52%) be- few side effects. Iodine 131 should be the choice of treat- came euthyroid within 3 months after 1 131I treatment. The ment in patients with multinodular toxic goiter. median 131I dose was 370 MBq (range, 93-1850 MBq). Forty-nine patients needing more than 1 131I dose had a Arch Intern Med. 1999;159:1364-1368

ULTINODULAR goiter is a We therefore wanted to evaluate the common cause of hy- long-term changes in thyroid function and perthyroidism, espe- volume using a precise and accurate ul- cially in areas of mild to trasonic technique18 in a large, prospec- moderate iodine defi- tive group of consecutive patients with ciency.1 In these patients, hyperthyroid- multinodular toxic goiter treated with 131I. M 131 ism cannot be expected to be permanently We used an algorithm for I dose calcu- cured by antithyroid drug treatment. Ra- lation, taking volume and 24-hour 131I up- diolabeled iodine 131 therapy is in prin- take into consideration. ciple an attractive treatment modality, since the suppressed extranodular thyroid tis- RESULTS sue is partly protected, and in recent years, the popularity of this treatment has in- Clinical data for the 130 patients are given creased. Therefore, it is of great impor- in Table 1. The median follow-up was 72 tance to evaluate the long-term effects and months (12-180 months). Patients pre- possible side effects of this treatment. A treated with antithyroid drugs did not dif- 1-year follow-up of 70 patients was pub- fer significantly from those not receiving lished from our department in 1986, dem- antithyroid pretreatment with regard to onstrating a 35% reduction of thyroid vol- age, sex, 131I dose, follow-up, or the pro- ume, and hypothyroidism developed in only portion needing more than 1 131I dose. The 1 patient.2 Studies evaluating the long- patients receiving antithyroid pretreat- 131 term effects of I treatment in patients with ment had significantly lower FT4I and FT3I Graves disease,3-7 autonomously function- at the time of 131I treatment than patients From the Departments of ing solitary hot or toxic thyroid nod- not receiving antithyroid pretreatment Endocrinology and Ultrasound, ules,8-12 and multinodular nontoxic goiter (Table 1). Thyroid function variables be- Herlev Hospital, University of have been performed.13-16 However, few fore antithyroid pretreatment were not Copenhagen, Herlev studies6,7,17 have described the long-term ef- available in all patients and are therefore (Drs Nygaard, Ulriksen, 131 Nielsen, and Hansen); and fects of I treatment in patients with mul- not given. The pretreated group had a sig- 131 Endocrinology, Odense tinodular toxic goiter, and a precise evalu- nificantly higher 24-hour I uptake (Table University Hospital, Odense ation of the long-term changes in thyroid 1). The median initial thyroid volume was (Dr Hegedu¨s), Denmark. volume is not available. higher in the pretreated group (59 mL [16-

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENTS AND METHODS corrected to 100% uptake of 131I after 24 hours. The maxi- mum single dose given was 740 MBq. Serum concentrations of T4 (reference range, 56-129 The study population consisted of 130 consecutive pa- nmol/L [4-10 µg/dL]) and T3 (reference range, 1.0-2.5 131 tients treated with I for a multinodular toxic goiter and nmol/L) and T3 resin uptake (reference range, 0.80-1.25 observed for a minimum of 1 year. Sixty-six patients were arbitrary units) were determined using in-house methods pretreated with antithyroid drugs, whereas 64 were not. An- (assay variation was 6%, 10%, and 5%, respectively). The other 15 patients were treated in this period but were FT4I (reference range, 62-158 arbitrary units) and FT3I unavailable for follow-up within 12 months (7 were given (reference range, 0.8-2.8 arbitrary units) were calculated antithyroid pretreatment). The patients were seen from No- as the total hormone concentration times the T3 resin vember 1, 1979, through April 31, 1994. Type of thyroid uptake. Serum concentrations of thyrotropin were deter- gland was determined using technetium Tc 99m– mined using different commercial assays as described pertechnetate scintigraphy and ultrasound, whereas the previously.3 Ultrasonic scanning and calculation of total diagnosis of hyperthyroidism was based on the clinical pic- thyroid volume (reference range, 9.6-27.6 mL) was per- 18 ture, elevated free triiodothyronine (T3) index (FT3I) and/or formed as previously described using a compound scan- free thyroxine (T4) index (FT4I), and suppressed serum thy- ner (type 3401 and type 1846; Bru¨ el and Kjær, Nærum, rotropin level. Denmark). Sixty-six patients received antithyroid drugs before 131I Thyroid function variables and the size of the thyroid treatment (propylthiouracil [n = 54], methimazole [n = 8], on ultrasonography were determined before and 3⁄4,11⁄2, and carbimazole [n = 4]). In these patients, antithyroid drug 3, 6, and 12 months after treatment, and thereafter, once treatment was discontinued 5 days before 131I therapy and every year. In patients becoming hypothyroid, no further not resumed after 131I treatment. Sixty-four patients did not volume or thyroid function data were included in the data receive antithyroid pretreatment. Pretreatment was based evaluation after hypothyroidism was diagnosed. on the degree of hyperthyroidism and the clinical status of Results are given as median and range or 25th and 75th the patients. percentiles. When percentage of change in thyroid vol- Permanent hypothyroidism was defined as decreased ume is used, the median values of the individual changes FT4I accompanied by an elevated serum thyrotropin con- are given. For statistical evaluation, Wilcoxon test for paired 2 centration. Euthyroidism was defined as FT4I and FT3I design, Mann-Whitney test for unpaired design, ␹ test, and within the reference range. The 131I dose was calculated as life-table analysis were used. The level of significance was 3.7 MBq/g total thyroid mass (evaluated using ultrasound), chosen as PϽ.05.

Table 1. Clinical Data in Patients With Multinodular Toxic Goiter Treated With Iodine 131*

Patients Receiving Patients Not Receiving Antithyroid Drug Pretreatment Antithyroid Drug Pretreatment (n = 66) (n = 64) P Age, y 65 (31-81) 64 (41-85) .92 No. of men/women 10/56 5/59 .14

FT4I, arbitrary units 84 (33-253) 179 (124-441) Ͻ.005

FT3I, arbitrary units 2.0 (0.7-5.0) 4.0 (1.5-12.4) Ͻ.005 Thyroid volume, mL 59 (16-430) 43 (18-125) .09 Initial 131I dose, MBq 290 (93-925) 315 (111-740) .97 24-h 131I uptake, % 57 (13-86) 45 (28-76) Ͻ.005 Total 131I dose, MBq 370 (93-1850) 385 (130-1547) .82 No. of 131I doses 14140 21919Ͼ.99 3-5 6 5

*FT4I indicates free thyroxine index; FT3I, free triiodothyronine index. Unless otherwise indicated, data are given as median (range).

430 mL] vs 43 mL [18-125 mL]), but the difference was The median time to become euthyroid after 131I therapy not significant (P = .09; Table 1). However, comparing was 5 weeks (range, 3 weeks to 24 months) after the last the initial volume in patients needing more than 1 131I 131I treatment (Table 2). There were no significant dif- dose, a highly significant difference was seen (74 mL [21- ferences between patients given antithyroid pretreatment 430 mL] in the pretreated group vs 47 mL [23-125 mL] and those who were not. Sixty-eight patients (52%) were in the group not pretreated) (PϽ.005). euthyroid within 3 months after the first 131I treatment. Eight The median initial 131I dose was 313 MBq (93-925 patients did not become euthyroid after 131I treatment. Three MBq), whereas the median total dose was 370 MBq (93- of these 8 patients had 1 131I treatment, 4 patients had 2 1850 MBq). More than 1 dose was given due to persis- treatments, and 1 patient had 3 treatments. These patients tent hyperthyroidism in 41 patients and to reduce goi- did not want subsequent 131I treatment and were given long- ter size in 8. term antithyroid drug treatment.

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 2. Effect of Iodine 131 on Thyroid Function in 130 Patients With Multinodular Toxic Goiter*

Patients Receiving Patients Not Receiving Antithyroid Drug Pretreatment Antithyroid Drug Pretreatment (n = 66) (n = 64) P Time to euthyroidism 5 wk (3 wk-12 mo) 6 wk (3 wk-24 mo) .60 Time to TSH† Ͼ4 mU/L, mo 12 (3-30) 23 (3-60) .52 No. of patients 17 9 .09 Time to hypothyroidism, mo 36 (3-60) 48 (36-60) .33 No. of patients 11 3 .03 Time from TSH Ͼ4 mU/L to hypothyroidism, mo 36 (30-39) 24 (0-42) .71

*Unless otherwise indicated, data are given as median (range). †TSH indicates thyrotropin.

60 64 61 5758 51 37 20 28 18 19 80 6655 53 60 51 32 20 20 16 16

50 60 40

30 40 Volume, mL Volume, Volume, mL Volume, 20 20 10

0 0 03 6 12 24 36 48 60 72 108 036 12 24 36 4860 72 108 Time, mo Time, mo

Figure 1. Changes in median thyroid volume (bars indicate 25th and 75th Figure 2. Changes in median thyroid volume (bars indicate 25th and 75th percentiles) after the last iodine 131 treatment in 64 patients not receiving percentiles) after the last iodine 131 treatment in 66 patients receiving antithyroid pretreatment. Thyroid volume was not measured every year in all antithyroid pretreatment. Thyroid volume was not measured every year in all patients. Numbers indicate number of observations. patients. Numbers indicate number of observations.

THYROID VOLUME IN PATIENTS RECEIVING than 1 131I dose. In these patients, 131I doses not leading ANTITHYROID PRETREATMENT to euthyroidism caused a 21% decrease in thyroid volume from a median of 47 mL (23-125 mL) to 44 mL Median initial thyroid volume was 59 mL (16-430 mL). (15-99 mL) (P = .03), and 24 months after the last 131I dose, Twenty-five of the 66 patients were treated with more than a further decrease to 29 mL (8-76 mL) (PϽ.005). The 1 131I dose. In these patients, 131I doses not leading to eu- median volume reduction after more than 1 131I dose was thyroidism caused a 27% decrease in thyroid volume from 32%. Thyroid volume before and after 131I therapy in re- a median of 74 mL (21-430 mL) to 50 mL (13-315 mL) lation to the latest 131I dose is demonstrated in Figure 2. (PϽ.005), and 24 months after the last 131I dose, a further A gradual 40% reduction from a median of 43 mL (15- decrease to 24 mL (8-108 mL) (PϽ.005). The median vol- 115 mL) to 27 mL (8-85 mL) 24 months after treatment ume reduction after more than 1 131I dose was 50%. Thy- was observed (PϽ.005). Hereafter, no further signifi- roid volume before and after 131I therapy in relation to the cant changes were observed. Within the observation pe- latest 131I dose is demonstrated in Figure 1. A gradual 45% riod, 3 patients became hypothyroid. In these patients, reduction from a median of 45 mL (13-315 mL) to 23 mL the median thyroid volume was reduced from 19 mL (8-120 mL) 24 months after treatment was observed (15-42 mL) to 10 mL (8-12 mL), measured at the time (PϽ.005). Hereafter, no further significant changes were hypothyroidism was diagnosed. Within the first 3 months observed. Within the observation period, 11 patients be- after 131I therapy, 72% of the total volume reduction was came hypothyroid. In these patients, the median thyroid seen. volume was reduced from 24 mL (17-66 mL) to 16 mL There was no significant difference between the pa- (8-72 mL) at the time when hypothyroidism was diag- tients receiving and those not receiving antithyroid drug nosed (P = .01). Within the first 3 months after 131I therapy, pretreatment in relation to changes in thyroid volume seen 68% of the total volume reduction was seen. after the 131I dose that cured the hyperthyroidism.

THYROID VOLUME IN PATIENTS NOT GIVEN SIDE EFFECTS ANTITHYROID PRETREATMENT Hypothyroidism occurred significantly more often in pa- Median initial thyroid volume was 43 mL (18-125 mL). tients pretreated with antithyroid drugs (11/66 [17%]) than Twenty-four of the 64 patients were treated with more in those not receiving such treatment (3/64 [5%]) (P = .03).

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 100 disseminated thyroid follicular cancer is too short to re- Series 1 Series 2 late the cancer to the 131I treatment. Series 1: 80 66 6257 4538 32 28 25 21 14 Series 2: COMMENT 64 5952 4740 37 34 32 29 25 60 The magnitude of thyroid volume reduction found in our study is of the same order as that seen after 131I therapy in 3 40 toxic diffuse and autonomous solitary toxic thyroid ad- 2,12 19,20 Hypothyroidism, % enomas as well as in nontoxic diffuse and nontoxic 13 20 multinodular goiter. As in these long-term follow-up studies,3,12,13 we found that the most pronounced reduction is seen within the first 3 months, with a continuous size- 131 01 2468103579 reducing effect of I on thyroid volume lasting 2 years. Time, y One could speculate that if the 131I is only taken up in the hyperfunctioning nodules, the reduction in the thyroid vol- Figure 3. Life-table analysis describing the hypothyroidism rate after iodine 131 therapy. Series 1 shows patients pretreated with antithyroid ume would be based on the changes in these nodules, leav- drugs; series 2, patients not pretreated with antithyroid drugs. Numbers ing the paranodular tissue unaffected with a potential of indicate number of observations. growth. The result could be a primary reduction of the thyroid volume followed by a reincrease related to growth of After evaluation using life-table analysis, hypothyroid- the paranodular tissue. We did not see this secondary re- ism was seen in 14% of the entire group within 5 years. growth of the thyroid volume in a rather long follow-up, Hereafter, no further cases of hypothyroidism occurred. indicating that the 131I affects not only the hyperfunction- Life-table analysis showed a hypothyroidism rate of 20% ing nodules but also the paranodular tissue. To our knowl- within 5 years in patients treated with antithyroid pre- edge, these are the first long-term data on thyroid volume medication, whereas patients in the group not given an- and function in multinodular toxic goiter, using an accu- tithyroid drug pretreatment had a significantly lower hy- rate thyroid size evaluation, and on 131I therapy, taking pothyroidism rate of 6% (PϽ.005) (Figure 3). thyroid size and 131I uptake into consideration. Hypothyroidism was diagnosed after a median of 42 months We demonstrated a cumulated risk for hypothyroid- (3-60 months). No significant differences in time to hy- ism of 14% within 5 years of 131I therapy. No cases of hypothyroidism, time to serum thyrotropin values greater than pothyroidism were seen beyond 5 years in this follow-up 4 µIU/mL, and time from these values to hypothyroidism ranging from 1 to 15 years. This pattern of hypothyroid- were seen between patients who were given antithyroid ism is different from that seen in patients treated with 131I drug pretreatment and those who were not (Table 2). In for Graves disease. In the latter group, hypothyroidism was Table 2, 12 patients are described as having serum values seen in approximately 20% within 1 year and thereafter with of greater than 4 µIU/mL without progression to overt hy- a constant incidence of 2% to 3% per year, eventually reach- pothyroidism. These patients had serum thyrotropin val- ing 100% if the patients lived long enough.3-5 In our study, ues in the range of 5 to 11 µIU/mL during follow-up (in 1 the incidence of hypothyroidism is similar to that found patient, a single measurement of 17 µIU/mL was found). in patients with other nonimmunological thyroid dis- In all patients, FT4I and FT3I were within the normal range, eases such as autonomously functioning solitary thyroid with no symptoms of hypothyroidism. nodules11,12 and nontoxic multinodular goiter.13 Few pub- Recurrence of hyperthyroidism after a longer pe- lished studies have addressed this issue in groups of pa- riod of euthyroidism without antithyroid drugs was tients all treated with 131I for multinodular goiter. Frank- seen in 1 patient treated with 400 MBq of 131I. The pa- lyn et al21 demonstrated hypothyroidism in 11.4% of 44 tient was euthyroid with a slightly suppressed serum patients with a 1-year follow-up. Danaci et al6 investi- thyrotropin level for 10 years; then hyperthyroidism re- gated 21 patients and found a cumulative 5-year hypo- curred and, after a further 131I dose, the patient again be- thyroidism rate of 24%, giving a fixed dose of 444 MBq. came euthyroid. Berg et al,7 giving a calculated dose of 100 Gy, found that None of the patients had symptoms of a radioio- 47% were given thyroxine treatment 48 months after treat- dine-induced thyroiditis. An increase (more than 5%) ment. On the other hand, Wiener,17 studying 88 pa- in thyroid volume was seen in 9 patients the first tients only, found 1 patient with hypothyroidism in a months after 131I treatment. The median increase was follow-up ranging from 1 to 17 years (average, 5.3 years). 23% (11%-60%). In these 9 patients, the median thy- We found a significantly higher hypothyroidism rate roid volume was 33 mL (19-133 mL) before treatment. in patients pretreated with antithyroid drugs (20%) com- The largest increase was seen in a patient with an initial pared with patients not given antithyroid premedication volume of 28 mL. None of these patients had increased (6%). An explanation could be that in patients given an- pressure symptoms, and none needed surgical interven- tithyroid drugs before 131I treatment, serum thyrotropin was tion. Three patients had a second 131I dose, not because not suppressed at the time of treatment, and the 131I was of compression symptoms, but because of continued taken up, not only in the hyperfunctioning nodules but in hyperthyroidism. the whole thyroid gland. In a recent study, Hancock et al22 In 1 patient, a disseminated follicular thyroid car- found a significantly higher failure rate in patients treated cinoma was diagnosed 3 years after 131I treatment of 488 with propylthiouracil until 4 to 7 days before 131I therapy MBq. The time from 131I treatment to the diagnosis of a for Graves disease compared with patients not given anti-

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