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Original Studies |
Departments of Endocrinology (S.J.B., L.H.), Nuclear Medicine (H.B., J.M.), Radiology (P.B.A., D.U.K.), and Oncology (L.B.), Odense University Hospital, DK-5000 Odense, Denmark
Address all correspondence and requests for reprints to: Steen Bonnema, M.D., Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: steen.bonnema{at}dadlnet.dk
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Abstract |
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Five patients (22%) developed hypothyroidism. Thyroid volumes were at baseline, after 1 week, and after 1 yr [mean ± SEM, 311 ± 28, 314 ± 26 (P = NS), and 215 ± 26 (P < 0.01) mL]. The relative changes 1 week after therapy ranged from -14.1% to 15.3%. After 1 yr the mean size was reduced by 33.9% (range, 13.5–61.4%). Only the initial goiter size showed a significant negative correlation to the percent reduction. The smallest cross-sectional area of the trachea decreased 9.2% within 1 week after treatment, but eventually emerged with a 17.9% larger area [mean ± SEM, 84.3 ± 4.8, 75.5 ± 5.1 (P < 0.01), and 98.2 ± 6.0 (P < 0.01) mm2]. The inspiratory parameter, FIF50%, improved after an initial insignificant decline [baseline therapy, after 1 week, after 3 months, and after 1 yr (mean ± SEM), 2.37 ± 0.24, 2.20 ± 0.21 (P = NS), 2.51 ± 0.23 (P = NS), and 2.76 ± 0.25 (P = 0.01) L/s]. FIF50% correlated significantly with the smallest cross-sectional tracheal area (baseline, 1 week, and 1 yr: r = 0.74; P < 0.001, r = 0.63; P < 0.005, and r = 0.46; P < 0.05). Changes in tracheal anatomy did not correlate with changes in either lung dynamics or goiter size. In conclusion, very large goiters can be reduced by a third, on the average, with high dose 131I therapy without any initial clinically significant tracheal compression. Tracheal cross-sectional area as well as pulmonary inspiratory capacity improve. No serious adverse effects are seen.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the period from 1995–1997, 27 patients with very large goiter were initially recruited and treated with high dose 131I. Twenty-three patients (2 men and 21 women) with a median age of 67 yr (range, 42–86 yr) completed the examinations during the study period, and data from these subjects are included in the results. Subtotal thyroidectomy had previously been performed in 8 patients. The goiters, all multinodular, were larger than 150 mL, except for one gland that was only 100 mL. The patient in question was chosen to be treated according to the protocol because the goiter was located almost entirely intrathoracically. We intended to monitor the symptoms by use of a visual analog scale, but this tool had to be omitted due to poor compliance by several of the elderly patients. Therefore, we are not able objectively to correlate the anatomical changes with the relief of the discomfort after treatment. However, all patients had major complaints from cervical and tracheal pressure and presented an urgent need for treatment. A few patients reported of exercise dyspnea and intermittent stridorous respiration. At the initial examination in the hospital, stridor was not a dominant feature in any patient, nor did anybody suffer from dyspnea at rest.
Surgery would normally be the treatment of choice for very large goiters, but this was not feasible because of concomitant medical disorders, previous neck surgery, and/or personal aversions. There was no clinical suspicion of malignancy in any of the patients. If scintigraphy showed dominant hypoactive nodules, fine needle aspiration biopsy was performed (n = 5). Six patients had been treated for thyrotoxicosis with antithyroid drugs (methimazole or propylthiouracil) for various lengths of time. The medication was discontinued 4 days before 131I therapy, and it was not routinely resumed afterward. Another two patients were slightly thyrotoxic at the time of treatment. Eight patients had subclinical thyrotoxicosis. The remaining seven patients were euthyroid. The study was approved by the ethics committee of the county of Funen, Denmark (Journal 95/67). All patients provided signed informed consent before inclusion in the study.
131I therapy
131I was given as a single oral dose to the hospitalized isolated patient according to the official irradiation regulatives. The intended thyroid irradiation was 100 Gy. Initially, dose calculation was based on the following algorithm: dose [megabecquerels (MBq)] = thyroid weight (g) x 5.55 (MBq/g) x 100/24-h 131I uptake (%). Subsequently, to optimize the intended thyroid irradiation, an elaborated algorithm was used in 17 patients: dose (MBq) = thyroid weight (g) x 22.4(days x MBq/g) x 100/[t1/2 (days) x 24-h 131I uptake (%)]. An estimate of the iodine half-life was achieved by a 96-h 131I uptake. After the administration of 131I, the patients had daily measurements of thyroid 131I activity by a Geiger counter in a distance of 1 m, and subsequently, the kinetics of 131I (24-h uptake and half-life) were calculated. For practical reasons, the calculated doses had to be reduced in four patients to keep hospitalization within 14 days. However, this reduction resulted in no appreciable difference from the intended irradiation of 100 Gray.
Thyroid function
Blood tests were taken before, 3 weeks, 6 weeks, 3 months, 6 months, 9 months, and 12 months after therapy. They included serum total T4 (RIA; Diagnostic Products, Los Angeles, CA; normal range, 65–135 nmol/L)), serum T3 (RIA; Johnson & Johnson, Amersham Pharmacia Biotech, Aylesbury, UK; normal range, 1.00–2.10 nmol/L), and serum TSH (DELFIA, Wallac Oy, Turku, Finland; normal range, 0.30–4.0 mU/L). Free T4 and free T3 indexes were calculated multiplying the total values by the percent T3 resin uptake. Serum antithyroid peroxidase antibodies (anti-TPO) were determined by the RIA DYNO test (Brahms Diagnostics, Berlin, Germany; normal range, <200 U/L). If thyrotoxicosis remained persistently posttreatment, thyroid-stimulating antibodies were measured (Medi-Lab, Copenhagen, Denmark).
Anatomy of the thyroid gland and the trachea
Thyroid 99mTc scintigraphy was performed in all patients. Goiter size was estimated by magnetic resonance imaging (MRI) that was performed on a superconducting system (Gyroscan T5II, Philips, Eindhoven, The Netherlands) operating at 0.5 Tesla. T1-weighted images [TR (repetition time) = 270 ms; TE (echo time) = 15 ms] were obtained in the axial, coronal, and sagittal planes using a standard neck coil. The slice thickness was 8 mm, with an interslice gap of 0.8 mm covering the entire thyroid gland. On each axial slice the cross-sectional area of the thyroid and trachea was measured manually by drawing a line along the outer contours of the thyroid and tracheal lumen. To calculate the thyroid volume we multiplied the measured areas by the slice thickness and interslice gap. The smallest cross-sectional area of the tracheal lumen was measured, and the total tracheal volume was calculated by multiplying the sum of the areas along the initial thyroid extension by the slice thickness and gap. MRI was performed before, 1 week after, and 1 yr after therapy. Results are the mean of blinded double measurements made by two independent observers. The precision of thyroid volume estimates by MRI is high, and the interobserver coefficient of variation has been estimated to 4.1 ± 2.2% (11).
Pulmonary function
Flow volume loop curves were obtained before therapy and 1 week, 3 months, and 1 yr after treatment. On each occasion, the patient performed at least three respiratory maneuvers, consisting of forced maximal expiration followed by forced maximal inspiration. Air flow rates and lung volumes were recorded instantaneously by a precision pneumotachograph (Vitalograph, Spiropharma, Copenhagen, Denmark). Parameters extracted from the best performed curves were FEV1 (forced expiratory volume in 1 s), FVC (forced vital capacity), FEV1/FVC (Tiffeneau index), FIF50% (forced inspiratory flow at 50% of the vital capacity), and FEF50% (forced expiratory flow at 50% of the vital capacity). Upper airway obstruction, i.e. tracheal compression, causes a compromised inspiration reflected by a FEF50%/FIF50% ratio greater than 1.2 (12). The maximal values of each of the parameters were included in the data analyses, even if they were obtained from different curves. The results were compared to reference values in a database of age- and sex-matched subjects.
Statistical analysis
Statistical analyses were performed using a statistical software program (WINKS) on a personal computer. If not otherwise specified, the results are presented as the mean ± SEM or the median/range. Friedman’s two-way ANOVA was used to test paired data. Multiple regression analysis and Spearman’s rank correlation were employed to test for correlation. Logarithmic values of the data were used if correlation analysis involved ratios.
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Results |
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Twenty-four-hour 131I uptake was 48.6 ± 16.7% (±SD). The median 131I dose was 2281 MBq (61.6 mCi); the range was 988-4620 MBq (26.7–124.9 mCi). The mean thyroid irradiation was 99.1 ± 35.9 Gy (±SD).
Thyroid function
Eight patients, of whom seven had toxic or subtoxic goiter before treatment, showed a transient elevation of free T4 index and/or free T3 index above the normal range 3 weeks after therapy (maximum values noticed were 223 and 3.53 nmol/L, respectively). Thereafter, the thyroid function of these patients decreased, and subsequently, euthyroidism or hypothyroidism appeared. Manifest radiation thyroiditis, defined as severe tenderness of the neck accompanied by increasing thyroid hormone levels and sedimentation rate, was not observed in any patient. Pretreatment anti-TPO antibodies were present in two patients and were found in another single patient posttreatment. Of the eight pretreatment thyrotoxic patients, five became euthyroid, and two developed hypothyroidism. One patient remained toxic and resumed antithyroid drug therapy. In this case, the persistent hyperfunction was regarded merely as an insufficient 131I treatment of the multinodular goiter, as there was no indication of a transition into an autoimmune disease (the goiter in question was reduced by 37.5% after 1 yr). None developed thyroid-stimulating antibodies. All eight patients with subclinical thyrotoxicosis achieved normalized serum TSH. Altogether, five patients (22%), two of whom were anti-TPO positive, developed hypothyroidism during the observation period, and consequently, these patients were prescribed T4 substitution. Seventeen patients were euthyroid without medication 1 yr after 131I therapy.
Anatomy of thyroid gland and trachea
Fourteen patients had a major intrathoracic extension of their
goiter in the sense that ultrasound volume estimation was impossible or
unreliable. Based on MRI, the mean initial goiter size was 311 ±
28 mL (range,100–703 mL). One week after the
131I treatment, half of the goiters had
decreased, but the mean volume was not significantly changed at
314 ± 26 mL (range, 110–604 mL; P = NS). The
relative changes ranged from -14.1% to 15.3% (Fig. 1
). At 1 yr after treatment, the mean
volume was 215 ± 26 mL (range, 67–586 mL; P <
0.01). The mean individual reduction was 33.9%, ranging from
13.5–61.4% (Fig. 2). The magnitude of
the thyroid irradiation had no influence on the percent reduction. In
fact, in a multiple regression analysis, including age, absorbed dose,
and initial goiter size, only the latter showed a significant negative
correlation with the percent reduction 1 yr after treatment (Fig. 2).
No difference in effect was seen among patients with suppressed and
normal TSH values. The smallest tracheal cross-sectional area decreased
significantly 1 week after treatment from 84.3 ± 4.8
mm2 (range, 37.5–126.0
mm2) to 75.5 ± 5.1
mm2 (range, 32.0–128.5
mm2; P < 0.01). The mean and the
greatest percent reduction were 9.2% and 32.7%, respectively. Only
three patients showed an acute increase in the tracheal area; in two
subjects this was only insignificantly, but, paradoxically, the patient
among all patients with the largest goiter (703 mL) increased the
tracheal area by as much as 51.4%. In fact, no correlation was seen
between the acute effect on the trachea and the initial size of the
surrounding goiter. Eventually, 1 yr after therapy, the tracheal area
was increased to 98.2 ± 6.0 mm2 (range,
53.0–164.5 mm2; P < 0.01)
corresponding to a 17.9% increase compared to baseline (range,
-18.3–56.4%). The data for the tracheal volume along the initial
thyroid extension showed the same pattern as for the area data,
although not as pronounced. Data are summarized in Table 1.
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Inspiratory data were not obtained from one patient due to an oral
deformity. After an initial insignificant decline in FIF50%, this
parameter increased after 1 yr compared to baseline (P
= 0.01; data shown in Table 1
). The median intraindividual change of
FIF50% 1 week after treatment was -1.2% (range, -32.8% to 31.0%),
and after 1 yr 21.7% (range, -40.3% to 141.7%). Only six patients
had a FEF50%/FIF50% ratio above the cut-off limit of 1.2 (defining
upper airway obstruction), and in none of these did the ratio normalize
after therapy. No patient suffered from any severe respiratory distress
caused by the treatment. In the early phase following therapy, however,
five patients complained of a worsening of pressure symptoms, two of
whom were given 25 mg prednisolone for a short period of time with a
satisfactory relief of the discomfort. Three of these five patients, in
fact, had the smallest cross-sectional tracheal area among all in this
acute phase, and to some degree this also applied to FIF50%
(32.0/0.70; 41.0/1.35; 44.5/2.12
mm2/L/s-1, respectively). Also, the
pretreatment tracheal areas for these individuals were in the lowest
range. For the whole study population, FIF50% correlated significantly
with the smallest cross-sectional tracheal area before treatment
(r = 0.74; P < 0.001; n = 22; Fig. 3). This correlation persisted in the
follow-up period, but with reduced strength (1 week after treatment:
r = 0.63; P < 0.005; 1 yr after treatment: r
= 0.46; P < 0.05). Looking at the relative changes in
FIF50% in each individual at the end of the observation period, no
correlation existed to the changes in either tracheal area or goiter
size. Cases were seen in which FIF50% improved despite unchanged or
even slightly reduced cross-sectional area and vice versa.
The expiratory parameters FEF50%, FVC, and FEV1 were unaltered
throughout the study (Table 1).
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Discussion |
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In patients with very large goiters, MRI (or computer tomography) instead of ultrasound is the method of choice for volume estimation, particularly because the gland often extends intrathoracically. Thus, previous studies (16, 17, 18, 19) of 131I therapy of large goiters, in which only ultrasound, scintigraphy, or clinical judgment is employed for assessment of the treatment effect, should be interpreted with caution. MRI was used by Huysmans et al. (20) in treating 19 patients with very large compressive multinodular goiters (mean volume, 269 mL) with high dose 131I. They obtained a 40% reduction (range, 19–68%) after 1 yr. The small difference (34% in our study) is most likely explained by the larger goiters in our patients and the fact that we did not routinely use posttreatment L-T4. We did not include a control group, and this implies that we may have underestimated the size reduction, as the growth potential is up to 10–20%/yr (7). Whether goiter reduction continues beyond 1 yr needs further study, but is suggested by recent investigations (5, 21).
In our study, the frequency of hypothyroidism was 22% after 1 yr. This is higher than the 8% observed in smaller multinodular goiters treated with 131I (4). However, we do not consider subsequent hypothyroidism to be a major concern, as L-T4 therapy, in doses that normalize serum TSH, rarely results in adverse effects.
Among patients referred for a moderately enlarged goiter, upper airway obstruction evaluated by flow volume loops was found among 33% (22). Surprisingly, there seems to be no difference in the prevalence of compressive symptoms in patients with and without upper airway obstruction (22). It is also our impression that there is a poor correlation between symptoms and the measures for inspiratory capacity, although we would have liked to be more quantitative about this variable. Considering that only 6 of 23 patients in this study had a FEF50%/FIF50% ratio above the limit of 1.2, we find it questionable if this ratio is better than FIF50% to reflect upper airway obstruction. With regard to detecting upper airway obstruction, it has been proved that flow volume loop curves are superior to x-ray of the trachea (23, 24, 25). Thus, a pulmonary function test should be considered in patients complaining of compressive symptoms. We suggest that FIF50% alone can be used when monitoring the inspiratory capacity among patients without other severe pulmonary diseases. Thyroidectomy has been shown to improve the inspiratory capacity (23, 24, 26). Also, 131I therapy has a favorable effect on upper airway resistance, as demonstrated by Nygaard et al. (25) in a study including patients with moderately enlarged goiters.
One matter of great concern when treating large goiters with 131I, and thereby restricting its use, has been the fear of an early enlargement caused by edema. Theoretically, this might lead to a worsening of tracheal compression and acute respiratory distress. It has been shown (27) that the use of 131I in smaller multinodular goiters does not result in any significant acute enlargement of the gland. In a few subjects, however, a volume increment up to 25% may be seen (27). Our results are comparable to the observations in smaller goiters. One week after treatment, the largest increase noticed was 15%, whereas several of the patients had goiter reduction already at this time. No cases of irradiation thyroiditis were seen, but the incidence of this complication is probably around 3% within the first month of 131I (28), nor did we encounter any cases of 131I-induced Graves’ disease as recently described in patients with toxic as well as nontoxic multinodular goiter (28, 29).
Our study is the first that has focused on the changes of the tracheal anatomy as well as the pulmonary function immediately after high dose 131I therapy. We find it imperative to clarify the possible adverse effects of 131I therapy on the respiratory capacity. The vast majority of our patients had a reduction in the smallest cross-sectional tracheal area 1 week after treatment, but despite this, no patient had severe respiratory distress or required ventilatory assistance. However, in patients with a very small cross-sectional tracheal area (for example, <50–60 mm2), glucocorticoids should be initiated as edema prophylaxis, considering the fact that of the five patients complaining of exacerbation of the goiter pressure in the days following therapy, three had a tracheal dimension in the lowest range. We cannot exclude that respiratory complications may occur, but having this precaution in mind, the presence of even marked tracheal compression before intervention does not in itself contraindicate 131I therapy in our opinion.
After 1 yr, the tracheal area had enlarged by 17.9%. This is less than the 36% found by others (20). A small tracheal area has great impact on the upper airway resistance. Consistent with this fact, the tracheal area and the inspiratory capacity showed a positive correlation before treatment. Even a small increment in the diameter of the trachea will result in a tremendous improvement in the airflow capacity according to Poiseuilles Law (flow proportional to radius4). This explains why the correlation between these two parameters became weaker after therapy. However, no correlation existed between the relative changes. Some of our patients actually improved their inspiratory capacity despite unchanged or even reduced tracheal dimensions. Thus, other factors, e.g. laryngospasms, may be of importance.
The 34% volume reduction after high dose 131I therapy still leaves the patient with a very large gland. However, even a minor reduction of the goiter may be sufficient to relieve the compressive symptoms. The results from MRI as well as the pulmonary function tests clearly seem to prove the beneficial effect of high dose 131I therapy. In support of this, all of our patients except one expressed their satisfaction with the result of the treatment. According to our protocol, high dose 131I therapy is cumbersome and quite costly. The 131I dose might be fractionated, thereby avoiding hospitalization (19). However, the efficacy of this modification fails solid documentation. In view of these considerations and the slow and limited effect of the treatment, high dose 131I remains a secondary option to surgery to be used in highly selected cases.
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Footnotes |
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Received April 26, 1999.
Revised June 14, 1999.
Accepted July 1, 1999.
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