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Meta-Analysis
. 2014 Jun 18;2014(6):CD004098.
doi: 10.1002/14651858.CD004098.pub2.

Levothyroxine or minimally invasive therapies for benign thyroid nodules

Elizabeth Bandeira-Echtler  1 , Karla Bergerhoff, Bernd Richter
Affiliations
Meta-Analysis

Levothyroxine or minimally invasive therapies for benign thyroid nodules

Elizabeth Bandeira-Echtler et al. Cochrane Database Syst Rev. .

Abstract

Background: Thyroid nodules (TN) are common in the adult population. Some physicians use suppressive levothyroxine (LT4) therapy to achieve a reduction in the number and volume of TN. In addition, minimally invasive treatments, such as percutaneous ethanol injection (PEI) sclerotherapy, laser photocoagulation (LP), and microwave (MW), radiofrequency (RF) and high-intensity focused ultrasound (HIFU) ablation, have been proposed, especially for pressure symptoms and cosmetic complaints, as an alternative to surgery. However, the risk to benefit ratio of all treatments for benign TN is currently unknown.

Objectives: To assess the effects of LT4 or minimally invasive therapies (PEI, LP, and RF/HIFU/MW ablation) on benign TN.

Search methods: We identified studies from computerised searches of The Cochrane Library, MEDLINE, EMBASE and LILACS (all performed up to April 2014). We also searched trial registers, examined reference lists of included randomised controlled trials (RCTs) and systematic reviews, and contacted study authors.

Selection criteria: We included studies if they were RCTs of LT4, PEI, LP, RF, HIFU or MW therapy in participants with an established diagnosis of benign TN. We excluded trials investigating the prevention of recurrence of thyroid disease after surgery, irradiation or treatment with radioiodine.

Data collection and analysis: Two review authors independently extracted data, assessed studies for risk of bias and evaluated overall study quality utilising the GRADE instrument. We assessed the statistical heterogeneity of included studies by visually inspecting forest plots and quantifying the diversity using the I² statistic. We synthesised data using random-effects model meta-analysis or descriptive analysis, as appropriate.

Main results: Thirty-one studies randomised 2952 outpatients to investigate the effects of different therapies on benign TN. Studies on LT4, PEI, LP and RF ablation therapy randomised 2083, 607, 192 and 70 participants, respectively. We found no RCTs of HIFU or MW ablation therapy in benign TN. The duration of treatment varied according to the applied therapies: up to five years for LT4 and one to three PEI ablations, one to three LP sessions and one or two RF sessions. Median follow-up was 12 months for LT4 and six months for minimally invasive therapies. Evidence was of low-to-moderate quality, and risk of performance and detection bias for subjective outcomes was high in most trials.No study evaluated all-cause mortality or health-related quality of life. Only one LT4 study provided some data on the development of thyroid cancer, reporting no abnormal cytological findings. One LP study provided limited information on costs of treatment.LT4 compared with no treatment or placebo was associated with a nodule volume reduction of 50% or more in 16% compared with 10% of participants after 6 to 24 months of follow-up (risk ratio (RR) 1.57 (95% confidence interval (CI) 1.04 to 2.38); P = 0.03; 958 participants; 10 studies; moderate-quality evidence). Pressure symptoms or cosmetic complaints were not investigated in LT4 studies. LT4 therapy was generally well tolerated: three studies provided quantitative data on signs and symptoms of hyperthyroidism, which were observed in 25% of LT4-treated versus 7% of placebo-treated participants at 12 to 18 months of follow-up (269 participants; 3 trials; low-quality evidence).PEI compared with cyst aspiration only was associated with a nodule volume reduction of 50% or more in 83% compared with 44% of participants after 1 to 24 months of follow-up (RR 1.83 (95% CI 1.32 to 2.54); P = 0.0003; 105 participants; 3 studies; low-quality evidence). Improvements in neck compression symptoms after 6 to 12 months of follow-up were seen in 78% of participants receiving PEI versus 38% of those in comparator groups. No reliable summary effect estimate could be established, RR ranged from 1.0 to 3.06 in favour of PEI (370 participants; 3 trials; low-quality evidence). In all trials, participants experienced periprocedural cervical tenderness and light-to-moderate pain usually lasting from minutes to several hours. As a result of the PEI procedure, 26% of participants reported slight-to-moderate pain compared with 12% of those receiving cyst aspiration only (RR 1.78 (95% CI 0.62 to 5.12); P = 0.28; 104 participants; 3 studies; low-quality evidence).One study comparing LP with LT4 showed a nodule volume reduction of 50% or more in favour of LP after 12 months of follow-up in 33% of LP participants versus 0% of LT4 participants, respectively (62 participants; 1 trial; low-quality evidence). A total of 82% of LP-treated versus 0% of untreated participants showed improvements in pressure symptoms after 6 to 12 months of follow-up (RR 26.65 (95% CI 5.47 to 129.72); P < 0.0001; 92 participants; 3 trials; low-quality evidence). Around 20% of LP-treated participants reported light-to-moderate cervical pain lasting 48 hours or more (97 participants; 3 trials; low-quality evidence).One trial with 40 participants, comparing RF with no treatment, resulted in a mean nodule volume reduction of 76% in the RF group compared with 0% of those in the no-treatment group at six months of follow-up (low-quality evidence). These RF-treated participants had fewer pressure symptoms and cosmetic complaints after 12 months of follow-up compared with untreated participants (a 2.8 decrease versus a 1.1 increase on a six-point scale, respectively, with higher values indicating more severe symptoms; low-quality evidence). All participants complained of pain and discomfort during RF, which disappeared when the energy was reduced or turned off (low-quality evidence).

Authors' conclusions: No study evaluated all-cause mortality, health-related quality of life or provided systematic data on the development of thyroid cancer. Longest follow-up was five years and median follow-up was 12 months. Nodule volume reductions were achieved by PEI, LP and RF, and to a lesser extent, by LT4. However, the clinical relevance of this outcome measure is doubtful. PEI, LP and RF led to improvements in pressure symptoms and cosmetic complaints. Adverse events such as light-to-moderate periprocedural pain were seen after PEI, LP and RF. Future studies should focus on patient-important outcome measures, especially health-related quality of life, and compare minimally invasive procedures with surgery. RCTs with follow-up periods of several years and good-quality observational studies are needed to provide evidence on the development of thyroid cancer, all-cause mortality and long-term adverse events.

PubMed Disclaimer

Conflict of interest statement

EBE: none known.

BR: none known.

KB: none known.

Figures

1
1
Study flow diagram
2
2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies Outcomes were classified into: subjective (i.e. pressure symptoms, cosmetic complaints, tolerability, adverse events, health‐related quality of life); (semi)objective (i.e. compliance, nodule volume reduction ≥ 50%); objective (i.e. all‐cause mortality, thyroid cancer, laboratory measurements of thyroid function, socioeconomic effects)
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study Outcomes were classified into: subjective (i.e. pressure symptoms, cosmetic complaints, tolerability, adverse events, health‐related quality of life); (semi)objective (i.e. compliance, nodule volume reduction ≥ 50%); objective (i.e. all‐cause mortality, thyroid cancer, laboratory measurements of thyroid function, socioeconomic effects)
4
4
Forest plot of comparison: 1 Levothyroxine versus control (no treatment, placebo), outcome: 1.1 Nodule volume reduction ≥ 50%.
5
5
Funnel plot of comparison: 1 Levothroxine versus comparator, outcome: 1.1 Nodule volume reduction ≥ 50%
1.1
1.1. Analysis
Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 1 Nodule volume reduction ≥ 50%.
1.2
1.2. Analysis
Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 2 Adverse events: participants without signs of hyperthyroidism.
1.3
1.3. Analysis
Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 3 Adverse events: participants without a nodule volume increase > 50%.
1.4
1.4. Analysis
Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 4 Thyrotropin (TSH) (end of study values).
1.5
1.5. Analysis
Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 5 Total thyroxine (T4) (end of study values).
2.1
2.1. Analysis
Comparison 2 Percutaneous ethanol instillation versus control (cyst aspiration, isotonic saline, levothyroxine, radiofrequency ablation), Outcome 1 Improvement of pressure symptoms (end of study).
2.2
2.2. Analysis
Comparison 2 Percutaneous ethanol instillation versus control (cyst aspiration, isotonic saline, levothyroxine, radiofrequency ablation), Outcome 2 Nodule volume reduction ≥ 50%.
2.3
2.3. Analysis
Comparison 2 Percutaneous ethanol instillation versus control (cyst aspiration, isotonic saline, levothyroxine, radiofrequency ablation), Outcome 3 Adverse events: slight to moderate pain.
3.1
3.1. Analysis
Comparison 3 Laser photocoagulation versus no treatment, Outcome 1 Improvement/disappearance of pressure symptoms (end of study).
3.2
3.2. Analysis
Comparison 3 Laser photocoagulation versus no treatment, Outcome 2 Adverse events: light to moderate cervical pain (≥ 48 hours).
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Update of

  • doi: 10.1002/14651858.CD004098

References

References to studies included in this review

LP Dossing 2005 {published data only}
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LP Dossing 2006 {published data only}
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LP Dossing 2013 {published data only}
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LP Gambelunghe 2006 {published data only}
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LP Papini 2007 {published data only}
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LT4 Cesareo 2010 {published data only}
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LT4 Grineva 2003 {published data only}
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LT4 Larijani 2005 {published data only}
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LT4 Papini 1998 {published data only}
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LT4 Reverter 1992 {published data only}
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LT4 Tsai 2006 {published data only}
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LT4 Wemeau 2002 {published data only}
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LT4 Zelmanovitz 1998 {published data only}
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PEI Bennedbaek 1998 {published data only}
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PEI Bennedbaek 1999 {published data only}
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PEI Bennedbaek 2003 {published data only}
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PEI Chu 2003 {published data only}
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PEI Sung 2013 {published data only}
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PEI Valcavi 2004 {published data only}
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PEI Verde 1994 {published data only}
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RF Faggiano 2012 {published data only}
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RF Huh 2012 {published data only}
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References to studies excluded from this review

Baek 2010 {published data only}
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Dossing 2002 {published data only}
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References to ongoing studies

LP Dossing 2001 {published data only}
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LP Pacella 2008 {published data only}
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LT4 Shih 2007 {published data only}
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RF Baek 2013 {published data only}
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