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The Journal of Clinical Endocrinology & Metabolism 87(9):4154 – 4159 Copyright © 2002 by The Endocrine Society doi: 10.1210/jc.2001-011762
Effectiveness of Thyroid Hormone Suppressive Therapy in Benign Solitary Thyroid Nodules: A Meta-Analysis M. REGINA CASTRO, PEDRO J. CARABALLO,
AND
JOHN C. MORRIS
Section of General Internal Medicine (M.R.C., P.J.C.) and Division of Endocrinology (M.R.C.), Albany Medical School and VA Healthcare Network Upstate New York, Albany, New York 12208; and Division of Endocrinology and Metabolism (J.C.M.), Mayo Clinic, Rochester, Minnesota 55905 The effectiveness of thyroid hormone suppressive therapy in reducing the volume of benign thyroid nodules is controversial. It is important to clarify this therapeutic effect of thyroid hormone, because its prolonged use needs to be carefully weighed against its potential deleterious effects in the skeletal and cardiovascular systems. To evaluate the best available evidence, we conducted a systematic review and metaanalysis of the randomized controlled trials that fulfill the following inclusion criteria: single thyroid nodules proven benign by fine needle aspiration, treatment, and follow-up of at least 6 months; documented suppression of TSH; measurement of thyroid nodule volume by ultrasound; and response to therapy defined as more than 50% volume reduction from baseline. Six randomized clinical trials published between
1987 and 1999, with 346 patients, were included in the metaanalysis. Ninety percent of the participants were female. Using a random effects model, the overall effect size showed a relative risk of 1.9 (95% confidence interval, 0.95–3.81) favoring a treatment effect. A sensitivity analysis showed significant changes in the results. Suppressive thyroid hormone therapy for longer than 6 months is associated with a trend toward a reduction of more than 50% in volume of benign thyroid nodules, without achieving statistical significance. The results are highly sensitive to changes in the statistical analysis, especially if the method used ignores heterogeneity among the effect sizes. More studies are needed before this therapy can be widely recommended. (J Clin Endocrinol Metab 87: 4154 – 4159, 2002)
A
benign, solitary thyroid nodules and to perform a metaanalysis of all randomized, controlled, clinical trials (RCT).
LTHOUGH BENIGN NODULAR thyroid disease is a very common disorder, significant controversy still exists regarding its management. Since the original publication by Astwood et al. in 1960 (1) reporting a reduction in nodule size with the use of thyroid hormone suppressive therapy in an uncontrolled trial, multiple reports have either confirmed (2, 3) or refuted these observations (4 –7). However, the majority of these reports were either uncontrolled trials or observational studies (8, 9). Furthermore, many of these studies included a heterogeneous group of patients with single benign thyroid nodules, colloid or cystic nodules, multinodular or simple adenomatous goiters; different treatment doses and length of therapy, often without clear documentation of TSH suppression with therapy (2, 3); and variable definitions of what constitutes a response to therapy, as well as different methods of assessment of nodule size [palpation vs. ultrasound (US)], all of which may explain the large variability in study results. Because prolonged thyroid hormone suppressive therapy has been associated with adverse effects on the skeletal and cardiovascular systems (10 – 13), the expected benefits of this treatment must be carefully weighed against the potential adverse effects, and careful review of the current evidence is needed to settle this controversy. The aim of this study is to systematically review the available evidence in the medical literature about the effectiveness of thyroid hormone suppressive therapy in patients with
Abbreviations: CI, Confidence interval; l-T4, levothyroxine; MNG, multinodular goiter; RCT, randomized, controlled, clinical trials; RR, relative risk; STN, single thyroid nodule; US, ultrasound.
Subjects and Methods Search and study selection We conducted a comprehensive, computerized search of the literature in MEDLINE from January 1985 until April 2001 and performed a hand search in the references of pertinent publications. The terms used in the search included: thyroid nodules, nodular thyroid disease, solitary thyroid nodules, goiter, nontoxic goiter, cold nodules combined with levothyroxine (l-T4) suppression, thyroid hormone suppression, suppressive therapy, and thyroxin. We searched for all publications reporting original data on the effect of thyroid hormone suppressive therapy on benign thyroid nodular disease. Studies that met the following criteria were considered for inclusion in the present report: RCT, with or without placebo; single thyroid nodule (STN) by palpation, proven benign by fine needle aspiration biopsy; documented suppression of TSH with thyroid hormone therapy; measurement of thyroid nodule volume by US; response to suppressive therapy defined as greater than 50% reduction in nodule volume from baseline; and treatment duration and follow-up of at least 6 months. Two publications (6, 14) that reported data on the same patient population were considered as one. Another study (15) reported results of suppressive therapy in patients with benign single nodules and multinodular goiter (MNG), but only results pertaining to those patients with STN were considered in the current report. Information from the studies was tabulated by one reviewer (M.R.C.) and subsequently confirmed by a second reviewer (P.J.C.). The following data were collected from each study: 1) publication data, first author’s last name, year of publication, and country of the population studied; 2) study design; 3) duration of treatment in months; 4) characteristics of the exposed and unexposed groups, i.e. number of subjects in each group, diagnosis, gender, and age; and 5) treatment dose of l-T4 and documentation of TSH suppression. To assess the methodological quality of the studies, we performed an open review of all the studies initially identified by the search of the
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Castro et al. • L-T4 Therapy in Benign STN
literature. Studies that did not meet predetermined inclusion criteria were excluded from the final review.
Analysis We performed a meta-analysis on the effect of l-T4 suppressive therapy in patients with benign STNs. We considered only the studies that met all of the above-mentioned inclusion criteria, to avoid significant methodological differences in study design and treatment protocols. We calculated the effect size in each study using relative risk (RR) with their 95% confidence intervals (CI). The RR was calculated using the number of patients assigned to treatment vs. control group whose nodule volume decreased by more than 50%, as determined by US measurement. The effect sizes were pooled on the basis of a random effects model (16) that incorporates the statistical heterogeneity, if present, and provides a more conservative estimate of the pooled effect size (wider CI). If heterogeneity is not present, the fixed effect and random effects model provide similar results (17). Using this methodology we minimized the probability of an ␣ error (to conclude that the treatment is effective when, in fact, it is not), although it may result in an increased probability of a  error (concluding that the treatment is not effective, when in reality it is). We chose this method because of concern about the potential adverse effects of long-term suppressive thyroid hormone therapy. Heterogeneity of study results was evaluated by visual examination of a plot of the effect sizes (RR and 95% CI), where the degree of homogeneity is judged on the basis of the degree of overlapping of the CI. We also used a statistical test for homogeneity, which assesses the probability that the difference between the result of the studies is due to chance (the smaller the P value, the less homogeneity present among study results). To evaluate the impact of each selected study on the overall results of the meta-analysis, we performed a one-way (one study excluded at the time) and two-way sensitivity analysis (two studies excluded at a time). We recalculated the overall RR and 95% CI using a fixed effect model.
Results
Thirteen original clinical trials assessing the effect of l-T4 suppressive therapy on benign STNs were identified (4 –9, 14, 15, 18 –22). Of these, two studies (6, 14) reported data on the same population, and only one of them (6) was included for this analysis. Of the remainder, six other studies were excluded (Table 1) for not meeting predefined criteria with regard to: 1) study design, lack of randomization (8, 9, 15, 22) or of control groups (8, 9); 2) nodule size not assessed by US (20); and 3) definition of response to treatment (21). The remaining six studies were included in the metaanalysis (4 –7, 18, 19). All of these studies had at least 6 months of treatment/follow-up, and all were prospective RCT (Table 2). The dose of l-T4 used varied from 1.5–3 g/kg, and in every study appropriate suppression of TSH was documented, either by measurement of TSH by second or third generation assay or by TRH stimulation test. The studies were performed in the United States (4), Italy (6, 18), Spain (5), Brazil (19), and Iran (7). The publication dates of these studies ranged between 1987 and 1999. A total of 175 patients were assigned to the l-T4 treatment group, and 171 patients were assigned to the control group. The majority of patients (90%) were female, and their mean age ranged between 34 and 48 yr. Five of the six studies (4 –7, 19) reported no statistically significant response to l-T4 suppressive therapy by the end of the study period, although the proportion of patients whose nodule volume decreased by more than 50% was higher in the l-T4-treated groups (22%) than in the control groups (10%). The only study that reported a statistically significant difference between the treatment and control groups showed that none of the 22 patients
J Clin Endocrinol Metab, September 2002, 87(9):4154 – 4159 4155
in the control group responded with reduction in the nodule volume. This study, although controlled, did not use placebo and was the only study that included exclusively solid nodules (16), some of which were subsequently characterized as fibrotic, and none of which responded to suppressive therapy (23). Statistical homogeneity of the effect sizes was sufficient to allow the use of meta-analysis (Fig. 1); however, its degree was judged to justify the use of a random effects model (2 ⫽ 7.42; P ⫽ 0.19). The meta-analysis resulted in an overall RR of 1.9 favoring the treatment group, which did not reach statistical significance (95% CI, 0.95–3.81). Sensitivity analysis
To evaluate the robustness of the results of this metaanalysis, and due to the significant controversy surrounding this therapy, we performed a one-way sensitivity analysis. In this analysis, the overall homogeneity and effect size were calculated, removing one study at a time (Table 3). The RR achieves statistical significance only when the study by Gharib et al. (4) is excluded (RR, 2.35; 95% CI, 1.21– 4.57). On the other hand, the homogeneity improved in a similar way when the study by either Gharib et al. (4) or La Rosa et al. (18) was removed from the analysis (2 ⫽ 4.39, P ⫽ 0.355; and 2 ⫽ 4.19, P ⫽ 0.380, respectively). In a two-way sensitivity analysis, when both of these studies that introduce significant heterogeneity are excluded, the remainder of the studies become homogeneous (2 ⫽ 1.81; P ⫽ 0.6127), and the RR (2.08; 95% CI, 1.09 –3.06) approaches that seen when a fixed effects model is used including all the studies (RR, 2.2; 95% CI, 1.3–3.72). However, exclusion of these studies is arbitrary and may introduce unintentional bias. Discussion
The efficacy of l-T4 therapy to reduce thyroid nodule size has been a matter of controversy for many years. Because of growing concern about potential adverse effects of long-term suppressive doses of l-T4 on the cardiovascular and skeletal systems, it becomes imperative to analyze the current evidence in a more systematic way. This study systematically reviewed the six best RCT that evaluate the effectiveness of l-T4 suppressive therapy given for more than 6 months in decreasing volume of solitary nodules by more than 50%. We found an overall treatment response that did not achieve statistical significance (RR, 1.9; 95% CI, 0.95–3.81). This result is very sensitive to the small statistical heterogeneity of the effect sizes of the studies included in the meta-analysis. If we assume homogeneity (fixed effect model) or exclude outliers to improve homogeneity, the results become statistically significant. The clinical and methodological similarities of the studies make it difficult to assume these changes without jeopardizing the integrity of the systematic review and the meta-analysis. Although five of the six studies included in the metaanalysis showed no significant reduction in nodule volume with l-T4 suppressive therapy, most of them did show a trend in favor of l-T4 treatment (5–7, 19). The proportion of responders was greater in the l-T4 (mean, 22%; range, 14 – 39%) than in the placebo or control groups (mean, 10%; range, 0 –20%), but statistical significance was achieved in a
Prospective Nonrandomized Controlled No placebo
Prospective Nonrandomized Controlled No placebo
Double blind Randomized Placebo-controlled
Nonrandomized Noncontrolled
Nonrandomized Noncontrolled
Mainini 1995 Brazil (22)
Lima 1997 Brazil (15)
Berghout 1990 Netherlands (21)
Morita 1989 Japan (9)
Celani 1990 Italy (8)
6 –12
3
9 (⫹9 months follow-up)
12
24
18
Duration of treatment (months)
STN 2 PTC 7 Cysts STN
STN (Another subgroup with MNG was not included.)
Sporadic diffuse, nontoxic single nodule and MNG STN
STN
N ⫽ 55 T ⫽ 45 C ⫽ 10 N ⫽ 54 T ⫽ 34 C ⫽ 20
N ⫽ 78 (115-drop-outs) T ⫽ 26 C ⫽ 26 (L-T4 ⫹ CBZ ⫽ 26) N ⫽ 49 T ⫽ 49 C ⫽ 10 patients with neurosis N ⫽ 122
Diagnosis
N ⫽ 74 T ⫽ 37 C ⫽ 37
No. of subjects
200 g (⬃2.48 g/kg)
L-T4,
L-T4,
0.1– 0.2 mg
0.1 mg
Placebo
L-T4, 2.5 g/kg L-T4 ⫹ CBZ
L-T4,
68/122 responded 24/122 PR 16/122 NR
18/49 T ?/10 C
15/26 T ?/26 C
20/34 T (11/34 PR) 1/20 C (3/20 PR)
8/45 T 0/10 C
1.7 ⫾ 0.9 g/kg
L-T4,
14/37 T 13/37 C
Results responders
150 g, adjusted to suppress TSH response to TRH
L-T4,
Treatment
Does not state whether control group had thyroid nodules or just neurosis. Follow-up only 3 months.
Response defined as ⬎13% reduction in thyroid volume. Large drop-out rate.
Control group had contraindications for suppressive L-T43 selection bias. Low iodine intake area. TSH suppressed ⬍0.1. Nodule volume by US.
TSH suppression OK. Selection bias. Difference NS.
No US assessment. TSH suppression documented by TRH stimulation test.
Comments
J Clin Endocrinol Metab, September 2002, 87(9):4154 – 4159
N, Total subjects; T, treatment group; C, control group; PR, partial response (⬎20% but ⬍50%); NR, no response; ?, not reported; NS, difference not significantly significant; CBZ, carbimazole; PTC, papillary thyroid cancer.
Prospective Randomized Controlled
Study design
Cheung 1989 Hong Kong (20)
First author Year Country (Ref. no.)
TABLE 1. Summary of studies encountered that did not meet all inclusion criteria
4156 Castro et al. • L-T4 Therapy in Benign STN
Prospective Randomized Controlled No placebo No double blind
Prospective Randomized Placebo-controlled
Prospective Randomized Controlled No placebo Only US blinded
Prospective Randomized Double blind Placebo-controlled
Prospective Double blind Randomized Placebo-controlled
Reverter 1992 Spain (5)
Papini 1993 Italy (6)
LaRosa 1995 Italy (18)
Zelmanovitz 1998 Brazil (19)
Larijani 1999 Iran (7)
12
12
12
12
6 –12
6
Duration of treatment (months)
T ⫽ 42 ⫾ 15 C ⫽ 48.2 ⫾ 17
T ⫽ 40.1 ⫾ 8.2 C ⫽ 39.4 ⫾ 12.8
T ⫽ 43 ⫾ 10 C ⫽ 42 ⫾ 11
T ⫽ 35.7 ⫾ 11.6 C ⫽ 41 ⫾ 12.9
T ⫽ 44.8 ⫾ 10.3 C ⫽ 41.3 ⫾ 13.1
T ⫽ 34.4 ⫾ 9.4 C ⫽ 37.1 ⫾ 11.8
N ⫽ 53 (48) T ⫽ 28 (26) C ⫽ 25 (22) N ⫽ 40 (40) T ⫽ 20 (20) C ⫽ 20 (20)
N ⫽ 101 (90) T ⫽ 51 (46) C ⫽ 50 (44) N ⫽ 45 (45) T ⫽ 23 (23) C ⫽ 22 (22)
N ⫽ 45 (42) T ⫽ 21 (19) C ⫽ 24 (23) N ⫽ 62 (48) T ⫽ 32 C ⫽ 30
SD)
Age (yr, mean ⫾
No. of subjects (female)
STN
STN
STN
STN
STN
STN
Diagnosis
L-T4,
L-T4,
T0, 16.4 ⫾ 18.7 T1, 17.7 ⫾ 31.6 C0, 13.6 ⫾ 13.9 C1, 11.6 ⫾ 9.7 T0, 12.8 ⫾ 11.9 T1, 12.4 ⫾ 16.7 C0, 13.2 ⫾ 10.2 C1, 11.7 ⫾ 13.6
1.5–2.0 g/kg
T0, 5.9 ⫾ 5.7 T1, 4.5 C0, 5.7 ⫾ 5.8 C1, 6.5
100 g Increased to 1.8 g/kg, then adjusted to TSH ⬍ 0.3
L-T4,
2.5–3 g/kg
T0, 6.2 ⫾ 8.9 T1, 5.86 ⫾ 8.9 C0, 6.25 ⫾ 7.41 C1, 6.48 ⫾ 7.36
L-T4,
L-T4, 2 g/kg Adjusted to suppression
T0, 3.0 ⫾ 2.6 T1, 2.5 ⫾ 2.3 C0, 2.6 ⫾ 1.7 C1, 2.4 ⫾ 1.6 T0, 10.3 ⫾ 11.9 T1, 10.1 ⫾ 12.2 C0, 9.2 ⫾ 6.4 C1, 9.2 ⫾ 9.5
3 g/kg
Nodule volume (ml) and change in size
200 g Then adjusted to TSH suppression
L-T4,
Treatment
6/32 T 4/30 C NS
6/21 T 2/24 C NS
9/23 T 0/22 C S
10/51 T (13/51 PR) 3/50 C NS
4/20 T 3/20 C NS
4/28 T 5/25 C NS
Results responders
Assessed nodule volume by US. TSH suppression documented, also TRH-TSH.
Nodule volume by US. TSH suppression documented, also TRH-TSH.
Assessed nodule volume by US. TSH suppression noted (TSH ⬍ 0.3). A third group treated with KI, excluded from analysis.
Nodule size by US (and palpation-excluded). TSH suppression.
Nodule volume by US. TSH suppression documented.
Assessed nodule volume by US. TSH suppression noted, also TRH-TSH.
Comments
N, Total subjects; T, treatment group; T0, treatment group at baseline; T1, treatment group at end of study; C, control group; C0, control group at baseline; C1, control group at end of study; S, difference statistically significant; NS, difference not statistically significant; PR, partial response.
Prospective Randomized Double blind Placebo-controlled
Study design
Gharib 1987 USA (4)
First author Year Country (Ref. no.)
TABLE 2. Summary of all studies included in the meta-analysis
Castro et al. • L-T4 Therapy in Benign STN J Clin Endocrinol Metab, September 2002, 87(9):4154 – 4159 4157
4158
J Clin Endocrinol Metab, September 2002, 87(9):4154 – 4159
Castro et al. • L-T4 Therapy in Benign STN
FIG. 1. Meta-analysis of studies evaluating effectiveness of thyroid hormone suppressive therapy in reducing volume of STNs by more than 50% from baseline measurement. Each study effect size is presented as RR and 95% CI.
TABLE 3. Sensitivity analysis Study excluded
One way None Larijani (7) Reverter (5) Zelmanovitz (19) Papini (6) Gharib (4) La Rosa (18) Two way Gharib (4) & La Rosa (18)
Random effects model
Test of homogeneity
RR
(95% CI)
2 (df)
P value
1.90 2.13 2.11 1.73 1.69 2.35 1.64
0.95 –3.81 0.88 –5.17 0.90– 4.95 0.77 –3.87 0.74 –3.83 1.21– 4.57 0.91 –2.93
7.42 (5) 7.20 (4) 7.18 (4) 6.68 (4) 6.39 (4) 4.39 (4) 4.19 (4)
0.192 0.1256 0.1266 0.1537 0.1718 0.3557 0.3809
2.08
1.09 –3.96
1.81 (3)
0.6127
single study (18). Only one study (4) was clearly negative, with a RR less than 1. Although most studies included patients with exclusively (18) or predominantly solid nodules (5, 6, 19), which are known to be more responsive to l-T4 suppressive therapy, in the study by Gharib et al. (4) up to 38% of patients had predominantly cystic nodules (14% in the l-T4 group and 24% in the control group), which may at least partially explain the greater proportion of patients who failed to respond to therapy, when compared with other studies. A placebo-controlled study by McCowen et al. (24) demonstrated lack of efficacy of l-T4 suppressive therapy in preventing recurrence of cystic nodules after aspiration. The study by Larijani et al. (7) also included a significant proportion of patients with mixed or predominantly cystic nodules, although the relative proportion of nodules in each of these two categories is not clearly defined. The results of this meta-analysis are in contrast to those reported by Zelmanovitz et al. (19). However, some significant differences between these meta-analyses need to be pointed out, which may explain the contradictory results of the two studies. Zelmanovitz et al. included seven trials in their meta-analysis (4 – 6, 15, 18, 19, 22), five of which are also included in our current report (4 – 6, 18, 19). We excluded the studies by Mainini et al. (22) and Lima et al. (15) because they did not meet one or more of our inclusion criteria. Specifi-
cally, on detailed review of these studies, the trial reported by Mainini et al. (22) was not a randomized study, and therefore, potential for selection bias existed. The second study, by Lima et al. (15), was also a nonrandomized trial in which the control group had specific contraindications to l-T4 therapy. In this study, which included 101 patients, only 54 of them (rather than 74, as stated in that meta-analysis) had a diagnosis of STN, the rest being patients with MNG. Finally, our study includes an additional trial by Larijani et al. (7) published in 1999, not included in the previous meta-analysis. Contradicting results of multiple previous reports on this topic are likely the result of extensive and significant methodological differences in study design. Many of these studies were uncontrolled (8, 9), often conducted in endemic goitrogenous areas (8) in which the therapeutic effect of TSH suppression may be enhanced; an otherwise well designed study was flawed by lack of an objective method of assessment of nodule volume (20). It has been demonstrated that US measurement is far more sensitive and accurate for estimating number and size of thyroid nodules than palpation (25, 26). Our study attempts to overcome these flaws by establishing very well defined inclusion criteria to minimize, in as much as possible, these methodological differences and ensure a certain degree of homogeneity in the design of the studies included in our report. However, despite our efforts to minimize these methodological differences, a test for homogeneity demonstrated that there remained between-study heterogeneity that cannot be accounted for by the above criteria. Also, results of the meta-analysis differed depending on the model used to analyze the result, suggesting meaningful discrepancies (heterogeneity) among the studyspecific effect estimates. Although the results of our meta-analysis do not demonstrate a statistically significant difference in nodule size after 6 –12 months of l-T4 suppressive therapy, when compared with control group, there is a clear trend favoring the treatment group, and a larger proportion of patients in the l-T4 group responded with more than 50% reduction in nodule volume. Also, in one study, l-T4 has been shown to signif-
Castro et al. • L-T4 Therapy in Benign STN
icantly decrease the number of new nodules forming in the gland (14). It is possible, therefore, that a subgroup of patients, not easily identifiable on the basis of pretreatment characteristics, may, in fact, benefit from this therapy. Certain nodule features may predict a better response to l-T4 therapy, such as small nodular volume (⬍10 ml) and abundant colloid on fine needle aspiration (23). Patients with exclusively or predominantly solid nodules may also be more responsive to this therapy than those with a major cystic component, because thyroid cysts have been shown to recur after aspiration despite treatment with l-T4 suppression (24). Although, on the basis of the results of our study, l-T4 suppressive therapy cannot be generally recommended for treatment of single benign thyroid nodules, with the expectation of achieving significant reduction in their size, it may still be reasonable to offer this option to carefully selected patients whose risk for development of potential adverse effects is low, and consider discontinuation of treatment if no objective response is seen after a predetermined period of time. Further carefully designed studies including a larger number of patients are needed to provide a clear answer to this important clinical question.
J Clin Endocrinol Metab, September 2002, 87(9):4154 – 4159 4159
8. 9.
10. 11. 12. 13. 14.
15.
16.
Acknowledgments 17.
Received November 2, 2001. Accepted June 7, 2002. Address all correspondence and requests for reprints to: M. Regina Castro, M.D., Stratton VA Medical Center, 113 Holland Avenue, Albany, New York 12208. E-mail:
[email protected].
19.
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20.
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