Levothyroxine or minimally invasive therapies for benign thyroid nodules

  • Review
  • Intervention

Authors


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.

Résumé scientifique

La lévothyroxine ou les thérapies mini-invasives pour les nodules thyroïdiens bénins

Contexte

Les nodules thyroïdiens (NT) sont fréquents dans la population adulte. Certains médecins utilisent la thérapie suppressive par lévothyroxine (LT4) afin d'obtenir une réduction du nombre et du volume des NT. En outre, des traitements mini-invasifs ont été proposés à titre d'alternative à la chirurgie, en particulier pour les symptômes de pression et la gêne esthétique : la sclérothérapie par injection percutanée d'éthanol (IPE), la photocoagulation au laser (PL), et l’ablation par micro-ondes (MW pour « microwave »), radiofréquence (RF) et ultrasons focalisés de haute intensité (HIFU pour « high-intensity focused ultrasound »). Cependant, le rapport bénéfices/risques de l’ensemble des traitements des NT bénins est actuellement inconnu.

Objectifs

Évaluer les effets du traitement par LT4 ou des thérapies mini-invasives (IPE, PL, ou ablation par RF/HIFU/MW) sur les NT bénins.

Stratégie de recherche documentaire

Nous avons identifié des études en effectuant des recherches informatiques dans la Bibliothèque Cochrane, MEDLINE, EMBASE et LILACS (toutes effectuées jusqu'en avril 2014). Nous avons également effectué des recherches dans les registres d'essais cliniques, examiné les références bibliographiques des essais contrôlés randomisés (ECR) inclus et des revues systématiques, et contacté les auteurs des études.

Critères de sélection

Nous avons inclus les études si elles étaient des ECR utilisant des traitements par LT4, IPE, PL, RF, HIFU ou MW chez les participants avec un diagnostic établi de NT bénins. Nous avons exclu les essais portant sur la prévention de la récidive de la maladie thyroïdienne après une intervention chirurgicale, une radiothérapie ou un traitement par iode radioactif.

Recueil et analyse des données

Deux auteurs de la revue ont, de façon indépendante, extrait les données, évalué le risque de biais des études et évalué la qualité globale des études en utilisant l'instrument GRADE. Nous avons évalué l'hétérogénéité statistique des études incluses par l'inspection visuelle des graphiques en forêt et en quantifiant la diversité avec la statistiqueI². Nous avons synthétisé les données en effectuant une méta-analyse avec un modèle à effets aléatoires ou une analyse descriptive, selon les cas.

Résultats principaux

Trente-et-une études randomisaient 2 952 patients externes pour étudier les effets de différentes thérapies sur les NT bénins. Les études sur les traitements d’ablation par LT4, IPE, PL et RF randomisaient respectivement 2 083, 607, 192 et 70 participants. Nous n'avons trouvé aucun ECR sur l’ablation par HIFU ou MW dans le traitement des NT bénins. La durée du traitement variait selon les traitements appliqués : jusqu'à cinq ans pour les traitements par LT4 et une à trois séances pour l’ablation par IPE, une à trois séances de PL, et une ou deux séances de RF. Le suivi médian était de 12 mois pour les LT4 et six mois pour les thérapies mini-invasives. La qualité des preuves était faible à modérée, et le risque de biais de performance et de détection pour les résultats subjectifs était élevé dans la plupart des essais.

Aucune étude n'a évalué la mortalité toutes causes confondues ou la qualité de vie liée à la santé. Une seule étude sur la LT4 fournissait des données sur le développement du cancer de la thyroïde et ne rapportait aucun résultat cytologique anormal. Une étude sur la PL a fourni des informations limitées sur les coûts de traitement.

Par rapport à l'absence de traitement ou un placebo, la LT4 était associée à une réduction du volume du nodule de 50 % ou plus chez 16 % des participants (contre 10 %) après 6 à 24 mois de suivi (risque relatif (RR) 1,57 (intervalle de confiance (IC) à 95 % de 1,04 à 2,38) ; P = 0,03 ; 958 participants ; 10 études ; preuves de qualité modérée). Les symptômes de pression ou la gêne esthétique n'ont pas été étudiés dans les études sur la LT4. La thérapie LT4 était généralement bien tolérée : trois études ont fourni des données quantitatives sur les signes et symptômes de l'hyperthyroïdie, qui ont été observés chez 25 % des patients traités par LT4 contre 7 % dans le groupe placebo sur 12 à 18 mois de suivi (269 participants ; 3 essais ; données de faible qualité).

Le traitement par IPE par rapport à l'aspiration du kyste seulement était associé à une réduction du volume du nodule de 50 % ou plus chez 83 % des participants (contre 44 %) après 1 à 24 mois de suivi (RR 1,83 (IC à 95 % de 1,32 à 2,54) ; P = 0,0003 ; 105 participants ; 3 études ; données de faible qualité). Des améliorations des symptômes de compression du cou au bout de 6 à 12 mois de suivi ont été observées chez 78 % des participants recevant des IPE contre 38 % des patients dans les groupes de comparaison. Aucune estimation résumée des effets fiable n'a pu être établie, le RR allait de 1,0 à 3,06 en faveur des IPE (370 participants ; 3 essais ; données de faible qualité). Dans tous les essais, les participants ont ressenti une sensibilité cervicale péri-procédurale et des douleurs légères à modérées sur une durée variant de quelques minutes à plusieurs heures. Conséquemment à la procédure d'IPE, 26 % des participants ont signalé une douleur légère à modérée par rapport à 12 % de ceux bénéficiant uniquement d’une aspiration du kyste (RR de 1,78 (IC à 95 % de 0,62 à 5.12) ; P = 0,28 ; 104 participants ; 3 études ; données de faible qualité).

Une étude comparant la PL avec la LT4 a montré une réduction du volume du nodule de 50 % ou plus en faveur de la PL après 12 mois de suivi chez 33 % des participants versus 0 % des participants du groupe LT4 (62 participants ; 1 essai ; données de faible qualité). Un total de 82 % des patients traités par la PL versus 0 % des participants non traités ont montré des améliorations des symptômes de pression après 6 à 12 mois de suivi (RR 26,65 (IC à 95 % de 5,47 à 129,72) ; P < 0,0001 ; 92 participants ; 3 essais ; données de faible qualité). Environ 20 % des participants du groupe PL ont mentionné une douleur cervicale légère à modérée pendant 48 heures ou plus (97 participants ; 3 essais ; données de faible qualité).

Un essai avec 40 participants, comparant la RF avec l'absence de traitement, entraînait une réduction du volume nodulaire moyen de 76 % dans le groupe RF, par rapport à 0 % dans le groupe ne recevant pas de traitement, au bout de six mois de suivi (preuves de faible qualité). Ces participants traités par RF avaient moins de symptômes de pression et de gêne esthétique après 12 mois de suivi par rapport aux participants non traités (respectivement, une diminution de 2,8 contre une augmentation de 1,1 sur une échelle de 6 points, où de fortes valeurs indiquent des symptômes plus sévères ; données de faible qualité). Tous les participants se sont plaints de douleur et d'inconfort pendant la RF, ces symptômes disparaissant lorsque l'énergie était réduite ou éteinte (preuves de faible qualité).

Conclusions des auteurs

Aucune étude n'a évalué la mortalité toutes causes confondues ou la qualité de vie liée à la santé, ni fourni des données systématiques sur le développement du cancer de la thyroïde. La période de suivi la plus longue était de cinq ans et le suivi médian était de 12 mois. Une réduction du volume des nodules a été obtenue par l'IPE, la PL et la RF et, dans une moindre mesure, par la LT4. Cependant, la pertinence clinique de cette mesure de résultat est douteuse. L'IPE, la PL et la RF ont amélioré les symptômes de pression et la gêne esthétique. Des événements indésirables tels qu’une douleur péri-procédurale légère à modérée ont été observés après l'IPE, la PL et la RF. Les futures études devraient se concentrer sur des mesures de résultats importants pour le patient, en particulier la qualité de vie liée à la santé, et comparer les procédures mini-invasives avec la chirurgie. Des ECR avec des périodes de suivi de plusieurs années et des études observationnelles de bonne qualité sont nécessaires pour fournir des preuves sur le développement du cancer de la thyroïde, la mortalité toutes causes et les effets indésirables à long terme.

Notes de traduction

Traduction réalisée par le Centre Cochrane Français

Plain language summary

Thyroid hormone therapy or minimally invasive treatments for benign thyroid nodules

Review question

What are the effects of thyroid hormone treatment (levothyroxine) and minimally invasive procedures on benign thyroid nodules?

Background

Nodules (lumps) within the thyroid gland are common and usually benign. They are more frequent in women, the elderly and in iodine-deficient areas. Thyroid nodules are often observed as an incidental finding in the course of ultrasonography of the thyroid, nodules of more than 1 cm in size are usually detected by palpation of the thyroid gland during a physical examination. Thyroid nodules may occur as a single nodule or as multiple nodules and may contain fluid (cyst). About 5 in 100 palpable thyroid nodules have a risk of becoming malignant (thyroid cancer). Thyroid nodules are often treated with thyroid hormones in order to reduce the size of the nodule. If thyroid nodules cause problems such as pressure symptoms or cosmetic complaints, surgery may be performed. Other therapies try to destroy the thyroid nodule by means of minimally invasive procedures (techniques which are less invasive than open surgery) and are usually performed on an outpatient basis.

Study characteristics

We identified 31 randomised controlled trials for this systematic review. Altogether 2952 participants were allocated to the various intervention and comparator groups. In total, 16 studies lasting six months to five years investigated the effects of levothyroxine therapy. Eight studies lasting 1 to 12 months investigated the efficacy of injections, mostly of ethanol, into thyroid nodules from which fluid had been slowly removed. Laser therapy (one or up to three sessions) was applied to nodules in five studies lasting 6 to 12 months. Two studies investigated the application of one or two radiofrequency (high-frequency radiowaves) sessions over 6 to 12 months.

Key results

None of the interventions investigated death from any cause, the development of thyroid cancer or health-related quality of life. Nodule volume reductions were achieved by all therapies; however, the clinical relevance of this outcome is doubtful. Minimally invasive treatments resulted in improvements in pressure symptoms and cosmetic complaints. Some side effects such as light-to-moderate pain were observed after minimally invasive procedures.

Quality of the evidence

Most study results were of overall low quality, mainly because only a few people were investigated, findings were imprecise or measurements were prone to bias. Future studies should investigate more patient-important outcomes, such as health-related quality of life, and should compare minimally invasive therapies with surgery. Studies with longer follow-up periods are needed to provide evidence on the development of thyroid cancer, death from any cause and long-term side effects of treatments.

Currentness of data

This evidence is up to date as of April 2014.

Laički sažetak

Levotiroksin ili minimalno invazivno liječenje benignih čvorova štitnjače

Što se istražuje?

Koji su učinci liječenja hormonima štitnjače (levotiroksin) i minimalno invazivnih postupaka kod čvorova u štitnjači?

Dosadašnja saznanja

Čvorovi (kvržice) u štitnjači uobičajena su pojava i najčešće su dobroćudni (benigni). Češće se javljaju u žena, u starijih i u krajevima s manjkom joda. Čvorovi u štitnjači se najčešće slučajno otkriju pri pregledu ultrazvukom, a čvorovi veći od 1 cm se najčešće otkriju palpacijom štitnjače pri fizikalnom pregledu. Ove tvorbe mogu biti u obliku pojedinačnih čvorova ili više njih, te neki mogu imati tekući sadržaj (cista). Prosječno 5 od 100 palpabilnih (koji se može napipati) čvorova štitnjače imaju rizik postati zloćudni (karcinom štitnjače). Čvorovi u štitnjači se često liječe hormonima štitnjače sa svrhom njihovog smanjenja. U slučaju da ovi čvorovi vrše pritisak na okolne strukture ili su kozmetički problem, uklone se kirurškim zahvatom. Drugi oblici liječenja djeluju uništavajuće putem minimalno invazivnih postupaka (tehnike koje su manje invazivne od kirurških zahvata otvaranja tijela) i uglavnom se obavljaju ambulantno.

Osobitosti istraživanja

Nađena je 31 randomizirana klinička studija za ovaj Cochrane sustavni pregled. Ukupno je obuhvaćeno 2952 bolesnika u kojih su provedeni različiti oblici liječenja i praćeni različiti pokazatelji. Učinak levotiroksina je ispitivan u 16 kliničkih studija u trajanju od 6 mjeseci do 5 godina. U osam studija koje su trajale 1 – 12 mjeseci ispitivan je učinak injekcija, uglavnom etanola, ubrizganih u čvorove štitnjače iz kojih je polako odstranjen tekući sadržaj. Liječenje laserom (u jednog do tri navrata) je primijenjeno u pet istraživanja u trajanju 6 – 12 mjeseci. Dva istraživanja su ispitivala višekratnu primjenu jedne ili dviju radiofrekvencija (radiovalovi visoke frekvencije) tijekom 6 – 12 mjeseci.

Ključni rezultati

Nijedno od istraživanja nije uključilo analizu smrti iz bilo kojeg razloga, nastanak karcinoma štitnjače ili kvalitetu života uvjetovanu zdravstvenim stanjem. Smanjenje volumena čvorova je postignuto svim oblicima liječenja, ali je kliničko značenje ovih rezultata upitno. Minimalno invazivno liječenje je imalo dobar ishod na simptome pritiska na okolne strukture i kod kozmetičkih smetnji. Neke nuspojave, primjerice blaga do umjerena bolnost, zabilježene su kod minimalno invazivnih postupaka.

Kvaliteta dokaza

Rezultati većine studija su općenito niske kakvoće, uglavnom zbog malog broja uključenih ispitanika, a rezultati su neprecizni ili je procjena ishoda pristrana. Daljnja istraživanja bi morala biti usmjerena na ishode važne za bolesnike, primjerice kakvoća života uvjetovana zdravstvenim stanjem, te na usporedbu minimalno invazivnog liječenja s kirurškim liječenjem. Potrebne su studije s duljim razdobljem praćenja kako bi se dobili dokazi o razvoju karcinoma štitnjače, smrti od bilo kojeg uzroka i dugoročnim nuspojavama liječenja.

Aktualnost podataka

Analizirani su dokazi objavljeni do travnja 2014. godine.

Bilješke prijevoda

Hrvatski Cochrane ogranak.
Prevela: Vesna Kušec

Résumé simplifié

La thérapie aux hormones thyroïdiennes ou les traitements mini-invasifs pour les nodules thyroïdiens bénins

Question de la revue

Quels sont les effets du traitement par une hormone thyroïdienne (la lévothyroxine) et des procédures mini-invasives sur les nodules thyroïdiens bénins ?

Contexte

Les nodules (boursouflures) au sein de la glande thyroïde sont courants et habituellement bénins. Ils sont plus fréquents chez les femmes, les personnes âgées et dans les régions déficitaires en iode. Les nodules thyroïdiens sont souvent détectés de façon fortuite lors d’une échographie de la thyroïde, les nodules de plus de 1 cm étant généralement détectés par la palpation de la glande thyroïde pendant un examen physique. Les nodules thyroïdiens peuvent être uniques ou multiples et peuvent contenir du liquide (kyste). Environ 5 nodules thyroïdiens palpables sur 100 ont un risque de devenir malins (cancer de la thyroïde). Les nodules thyroïdiens sont souvent traités par des hormones thyroïdiennes afin de réduire la taille du nodule. Si les nodules thyroïdiens entraînent des problèmes tels que des symptômes de pression ou une gêne esthétique, une chirurgie peut être effectuée. D'autres thérapies essayent de détruire les nodules thyroïdiens par des procédures mini-invasives (techniques moins invasives que la chirurgie ouverte) et sont généralement réalisées en ambulatoire.

Caractéristiques des études

Nous avons identifié 31 essais contrôlés randomisés pour cette revue systématique. Au total, 2 952 participants ont été assignés aux différents groupes d'intervention et de comparateur. Au total, 16 études d'une durée de six mois à cinq ans ont examiné les effets du traitement par lévothyroxine. Huit études d'une durée de 1 à 12 mois ont examiné l'efficacité des injections, principalement de l’éthanol, dans les nodules dont le liquide a été lentement retiré. Le traitement au laser (en une ou jusqu'à trois séances) a été utilisé sur les nodules dans cinq études d'une durée de 6 à 12 mois. Deux études ont étudié l'application d'une ou deux séances de radiofréquences (ondes radio à haute fréquence) sur 6 à 12 mois.

Principaux résultats

Aucune des interventions n’a examiné la mortalité toute cause, le développement d’un cancer de la thyroïde ou la qualité de vie liée à la santé. La réduction du volume des nodules était obtenue par tous les traitements ; cependant, la pertinence clinique de ce résultat est douteuse. Les traitements mini-invasifs ont amélioré les symptômes de pression et la gêne esthétique. Certains des effets secondaires tels que des douleurs légères à modérées ont été observées après les procédures mini-invasives.

Qualité des preuves

La plupart des résultats des études étaient globalement de faible qualité, principalement parce que seul un petit nombre de personnes avait été étudié, les résultats étaient peu précis ou les mesures étaient sujettes à un biais. Les études futures devraient examiner davantage de critères de jugement importants pour les patients, tels que la qualité de vie liée à la santé, et devraient comparer les thérapies mini-invasives à la chirurgie. Des études avec des périodes de suivi plus longues sont nécessaires pour fournir des preuves sur le développement du cancer de la thyroïde, le décès toutes causes confondues et les effets secondaires à long terme des traitements.

Actualité des données

Les preuves sont à jour en date d’avril 2014.

Notes de traduction

Traduction réalisée par le Centre Cochrane Français

Summary of findings(Explanation)

Summary of findings for the main comparison. Summary of findings (levothyroxine treatment)
  1. aAssumed risk was derived from the event rates in the comparator groups
    bDowngraded by two levels because of few participants and only one study investigating this outcome
    cDowngraded by two levels because of inconsistency, few participants and high risk of detection bias
    dDowngraded by one level because of indirectness (surrogate outcome parameter)

Thyroid hormone treatment compared with placebo or no treatment for benign thyroid nodules

Participant: participants with benign thyroid nodules

Settings: outpatients

Intervention: thyroid hormone treatment (levothyroxine (LT4))

Comparison: placebo or no treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskaCorresponding risk
Placebo or no treatmentLevothyroxine
All-cause mortalitySee commentSee commentNot estimableSee commentSee commentNot investigated
Thyroid cancer
Follow-up: 12 and 24 months
See commentSee commentNot estimableSee comment

⊕⊕⊝⊝

lowb

One study confirmed benignity of some treated nodules through FNAB and cytological re-evaluation in the non-responder group, defined as participants with constant or increasing nodule volume (33/58 participants)
Health-related quality of lifeSee commentSee commentNot estimableSee commentSee commentNot investigated

Adverse events

Follow-up: 12 to 18 months

See commentSee commentNot estimable269 (3)

⊕⊕⊝⊝

lowc

LT4 therapy was generally well tolerated. One of three studies reported more signs and symptoms of hyperthyroidism after LT4, a reliable effect estimate could not be established
Pressure symptoms / cosmetic complaintsSee commentSee commentNot estimableSee commentSee commentNot investigated

Nodule volume reduction ≥ 50%

Follow-up: 6 to 24 months

98 of 1000

154 of 1000

(102 to 233)

RR 1.57 (1.04 to 2.38)958 (10)⊕⊕⊕⊝
moderated
-
Socioeconomic effectsSee commentSee commentNot estimableSee commentSee commentNot investigated
*The basis for the assumed risk (e.g. the median comparator group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; FNAB: fine-needle aspiration biopsy; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Summary of findings (percutaneous ethanol injection sclerotherapy)

Summary of findings 2. Summary of findings (percutaneous ethanol injection sclerotherapy)
  1. aAssumed risk was derived from the event rates in the comparator groups
    bDowngraded by two levels because of imprecise results (CI includes null effect and appreciable benefit or harm) and high risk of detection bias
    cDowngraded by two levels because of inconsistency, high risk of performance bias and high or unclear risk of detection bias
    dDowngraded by one level because of few participants and indirectness (surrogate outcome parameter)

Percutaneous ethanol injection compared with aspiration, levothyroxine or isotonic saline for benign thyroid nodules

Participant: participants with benign thyroid nodules

Settings: outpatients

Intervention: percutaneous ethanol injection (PEI)

Comparison: aspiration, levothyroxine, isotonic saline

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskaCorresponding risk
AspirationPEI
All-cause mortalitySee commentSee commentNot estimableSee commentSee commentNot investigated
Thyroid cancerSee commentSee commentNot estimableSee commentSee commentNot investigated
Health-related quality of lifeSee commentSee commentNot estimableSee commentSee commentNot investigated

Adverse events

Follow-up: 6 to 12 months

118 of 1000209 of 1000
(73 to 602)
RR 1.78 (0.62 to 5.12)104 (3)

⊕⊕⊝⊝

lowb

In all studies participants experienced periprocedural cervical tenderness and light-to-moderate pain lasting from minutes to several hours

Pressure symptoms / cosmetic complaints

Follow-up: 6 to 12 months

See commentSee comment RR range 1.00 to 3.06370 (3)

⊕⊕⊝⊝

lowc

No reliable effect estimate because of unexplained considerable heterogeneity

Nodule volume reduction ≥ 50%

Follow-up: 1 to 12 months

442 of 1000809 of 1000
(584 to 1123)
RR 1.83 (1.32 to 2.54)105 (3)

⊕⊕⊕⊝

moderated

-

Socioeconomic effects

Follow-up: 6 months

See commentSee commentNot estimableSee commentSee commentNot investigated
*The basis for the assumed risk (e.g. the median comparator group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Summary of findings (laser photocoagulation)

Summary of findings 3. Summary of findings (laser photocoagulation)
  1. aAssumed risk was derived from the event rates in the comparator groups
    bDowngraded by two levels because of inconsistency, few participants and high risk of performance bias
    cDowngraded by two levels because of wide CIs, few participants and high risk of performance bias
    dDowngraded by two levels because of few participants, one study only, an unclear risk of detection bias and indirectness (surrogate outcome parameter)
    eDowngraded by two levels because of few participants, one study only and no formal cost-benefit analysis

Laser photocoagulation compared with no treatment or levothyroxine for benign thyroid nodules

Participant: participants with benign thyroid nodules

Settings: outpatients

Intervention: laser photocoagulation (LP)

Comparison: no treatment, levothyroxine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskaCorresponding risk
No treatmentLaser photocoagulation
All-cause mortalitySee commentSee commentNot estimableSee commentSee commentNot investigated
Thyroid cancerSee commentSee commentNot estimableSee commentSee commentNot investigated
Health-related quality of lifeSee commentSee commentNot estimableSee commentSee commentNot investigated

Adverse events

Follow-up: 6 to 12 months

See commentSee commentSee comment97 (3)

⊕⊕⊝⊝

lowb

Three studies reported that 10/49 (20%) participants treated by laser photocoagulation experienced light to moderate pain lasting 48 hours and more

Pressure symptoms / cosmetic complaints

Follow-up: 6 to 12 months

See commentSee comment 26.65 (5.47 to 129.72)92 (3)

⊕⊕⊝⊝

lowc

No participant in the no-treatment comparator group showed signs of improvement

Nodule volume reduction ≥ 50%

Follow-up: 12 months

See commentSee commentNot estimable62 (1)

⊕⊕⊝⊝

lowd

One study investigated laser therapy versus LT4 or no treatment and showed that 7/21 (33%) treated participants compared with no participants (0/41) in either comparator groups achieved this outcome

Socioeconomic effects

Follow-up: 12 months

See commentSee commentNot estimable62 (1)

⊕⊕⊝⊝

lowe

The costs of laser photocoagulation therapy including equipment, medical team, and disposable kits was about €450 (approx. US$550, September 2012 conversion)
*The basis for the assumed risk (e.g. the median comparator group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; LT4: levothyroxine; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 Summary of findings (radiofrequency ablation)

Summary of findings 4. Summary of findings (radiofrequency ablation)
  1. aDowngraded by two levels because of few participants, one study only and high risk of performance bias
    bDowngraded by two levels because of few participants, one study only and high risk of performance bias
    cDowngraded by two levels because of few participants, one study only and an unclear risk of detection bias

Radiofrequency ablation compared with no treatment

Participants: participants with benign thyroid nodules

Settings: outpatients

Intervention: radiofrequency ablation (RF)

Comparison: no treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Radiofrequency ablationNo treatment
All-cause mortalitySee commentSee commentNot estimableSee commentSee commentNot investigated
Thyroid cancerSee commentSee commentNot estimableSee commentSee commentNot investigated
Health-related quality of lifeSee commentSee commentNot estimableSee commentSee commentNot investigated

Adverse events

Follow-up: 12 months

See commentSee commentNot estimable40 (1)

⊕⊕⊝⊝

lowa

All participants complained of pain and discomfort during radiofrequency ablation which disappeared when the energy was reduced or turned off

Pressure symptoms / cosmetic complaints

Follow-up: 12 months

Scale: sum of individual scores including pressure symptoms in the neck, difficulty in swallowing, aesthetic complaint (0: absent, 1: moderate, 2: severe; range 0 to 6)

See commentSee commentNot estimable40 (1)

⊕⊕⊝⊝

lowb

Intervention group: decline from 3.4 (SD 1.3) at baseline to 0.6 (SD 0.5)

No-treatment group: increase from 3.0 (SD 1.3) at baseline to 4.1 (SD 0.9)
Difference between groups: P < 0.0001

Nodule volume reduction ≥ 50%

Follow-up: 12 months

See commentSee commentNot estimable40 (1)

⊕⊕⊝⊝

lowc

Statistically significant differences in favour of RF at 3, 6 and 12 months
Socioeconomic effectsSee commentSee commentNot estimableSee commentSee commentNot investigated
*The basis for the assumed risk (e.g. the median comparator group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; SD: standard deviation
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Nodular thyroid disease is common. Thyroid nodules are more frequent in women, the elderly and in iodine-deficient areas, becoming malignant possibly more often in men and especially in individuals aged over 70 years (Belfiore 1992). Palpable thyroid nodules were detected in 4% to 7% of individuals in the USA (Mazzaferri 1993) and in 0.8% of adult men and 5.3% of adult women in Northeast England (Tunbridge 1977). Thyroid nodules are even more common when detected using ultrasonography of the thyroid (Brander 1991), with prevalence rates varying from 20% to 60% (Galofré 2008). Many nodules are thyroid incidentalomas, which are discovered when neck structures are imaged for other reasons (Daniels 1996). In the Framingham study population, new nodules appeared in 0.1% of participants per year during a 15-year follow-up period (Vander 1968).

A clinically solitary thyroid nodule is a discrete swelling within an otherwise palpable normal thyroid gland. The overwhelming majority of these nodules are composed of irregularly enlarged follicles containing abundant colloid (benign adenomatous nodules). About half of individuals with clinically apparent solitary nodules are found to have multinodular goitres (MNGs) at surgery. The risk of cancer in people with true solitary nodules confirmed at surgery has been reported to be about the same as that in those with MNGs (McCall 1986). In contrast, however, a recent systematic review and meta-analysis found MNGs to be associated with a lower risk of thyroid cancer than solitary nodules (odds ratio (OR) 0.8 (95% confidence interval (CI) 0.67 to 0.96); 44,288 participants; 14 longitudinal and cross-sectional observational studies) (Brito 2013).

Thyroid nodules are often hypofunctioning, as determined by radionuclide scanning (termed 'cold' nodules), are incompletely encapsulated and sometimes poorly demarcated. Some authors consider a 'warm' TN as a distinct entity, although most distinguish nodules that are autonomously functioning as 'hot' from those that are 'cold'. Using this definition, virtually all thyroid cancers are cold. However, approximately 95% to 97% of cold nodules are benign (Daniels 1996). Benign thyroid nodules are commonly caused by thyroid adenomas, cysts and thyroiditis.

The discovery of a thyroid nodule leads to concerns that the nodule may develop into thyroid cancer. Factors that favour the development of thyroid cancer include a history of neck irradiation, rapid tumour growth, male sex, age younger than 20 years or older than 70 years, a family history of thyroid cancer or features suggestive of neoplasia. The incidence of cancer in individuals with clinical features suggestive of malignancy (e.g. firm, fixed nodule, enlarged cervical lymph nodes, recurrent laryngeal nerve palsy in the absence of previous surgery) is high, but most do not have these features (Hamming 1990). From a clinical viewpoint, fewer than 5% of palpable thyroid nodules are malignant. Nodule growth alone, however, does not predict malignancy. Alexander 2003 found that cystic nodules grew less than those with more solid components, and that malignity was proved after repeated fine-needle aspiration (FNA) in 1 of 74 nodules.

Well-differentiated thyroid carcinomas (papillary and follicular) comprise 80% of all thyroid cancers (Kaplan 1990). The annual incidence is approximately 4 in 100,000 persons (0.004%), with an estimated prevalence of 1 in 1000 persons (0.1%) (Daniels 1996). Many more people have clinically silent thyroid cancers: up to 35% of thyroid glands removed at autopsy (Mazzaferri 1988) or surgically (Pelizzo 1990) contain small (less than 1.0 cm), thought to be clinically insignificant, papillary carcinomas. Despite an increasing incidence in the detection of papillary carcinomas, mortality from thyroid cancer between 1973 and 2002 remained stable (Davies 2006). In the USA, approximately 37,200 cases of new thyroid cancers were estimated to be diagnosed in 2009, with about 1630 deaths resulting from the disease (Jemal 2009).

Recent developments, such as the use of FNA biopsy (FNAB), the application of high-resolution ultrasonography and sensitive thyroid-stimulating hormone (TSH) assays, have resulted in important advances in the diagnosis and management of thyroid nodules. Many publications have defined and classified nodules according to cytological features, described techniques for monitoring thyroid functional status in the course of TSH suppression and raised concerns about the potential complications of suppressive therapy.

Description of the intervention

It is unclear whether asymptomatic thyroid nodules should be treated because in most cases they are benign, small and can be managed by active surveillance (Gharib 2007). However, some thyroid nodules grow and can cause pressure and other symptoms as well as cosmetic complaints, and hence require treatment. Until recently, surgical approaches have been used for the management of nodules causing severe symptoms; however, the risk of complications persists and there may be a problem with the availability of experienced thyroid surgeons. Thyroid hormone suppression therapy with levothyroxine (LT4) is an alternative option for the treatment of thyroid nodules. In addition, a number of minimally invasive therapies, all guided by ultrasound imaging, are increasingly employed in the treatment of symptomatic thyroid nodules.

LT4 therapy

The use of thyroid hormone suppressive therapy in individuals with thyroid nodules and nodular goitre is based on the presumption that TSH (thyroid stimulating hormone also known as thyrotropin) is a growth factor for thyroid tissue (Burch 1995; Morita 1989). The rationale for TSH suppression (i.e. that thyroid nodules and nodular goitre are caused by TSH stimulation as the main stimulator of thyroid function or growth) has never been clearly proven (Cooper 1995). Despite considerable controversy among experts about its efficacy, suppressive therapy of the thyroid nodule with thyroxine, with the goal of suppressing TSH production and reducing the size of the nodule, has gained wide acceptance. The efficacy of thyroid hormone suppressive therapy for nodules and goitre is supported by extensive anecdotal clinical experience as well as numerous uncontrolled trials (Daniels 1996). Thyroid hormone suppression therapy for thyroid nodules resurfaced as a legitimate therapy with the publication of uncontrolled experiences in 1960 (Astwood 1960). Over the next decades, discordant reports about the efficacy of this therapy were published, possibly being associated with the aetiological heterogeneity of thyroid nodules and their unpredictable patterns of growth. With time, solitary nodules may enlarge, shrink or even disappear spontaneously (Kuma 1992), but most do not change appreciably (Vander 1968). Similarly, the possible presence of cystic nodules, which can either resolve or grow spontaneously, was not taken into consideration in some studies. Moreover, confounding variables, such as the lack of a comparator population, a short period of follow-up, an inaccurate quantification of nodule size and the lack of proof of effective TSH suppression, did not allow conclusive results. By definition, LT4 suppressive therapy is a dose of levothyroxine sufficient to suppress pituitary TSH secretion to concentrations that are below the lower limits of normal (Gharib 1998). Although the optimal level of TSH suppression has not been clearly defined, complete suppression of serum TSH concentrations to less than 0.1 mIU/L is thought to be unnecessary in individuals with benign thyroid disease (Burch 1995).

Percutaneous injection sclerotherapy

Percutaneous ethanol injection (PEI) is an ultrasound-guided minimally invasive therapeutic procedure suggested for the non-surgical management of benign thyroid nodules in individuals with pressure symptoms or cosmetic complaints. PEI was first proposed in 1990 as a possible alternative to surgery and radioiodine therapy for the treatment of autonomously functioning thyroid nodules in outpatients (Bennedbaek 1997; Livraghi 1990; Papini 1995). The procedure is currently described as effective in the treatment of benign thyroid cysts and complex nodules with a dominant fluid component. The method should not be performed in solitary solid nodules, whether hyperfunctioning or not, or in MNGs (AACE/AME/ETA Guidelines 2010). The Latin American Thyroid Society (LATS) also does not recommend PEI for the routine treatment of thyroid nodules other than cysts in their recent guidelines (LATS 2009). However, some authors have described satisfactory results with PEI for the treatment of thyroid solid nodules in individuals with pressure symptoms or cosmetic complaints who refuse surgery or are at surgical risk, reporting an overall nodule volume reduction of 43% (Bennedbaek 1995). Mainly ethanol is injected into the thyroid cysts, some investigators however use other substances such as the antibiotic tetracycline.

Technique: The individual lies on his/her back with the neck hyperextended. The nodule is identified by ultrasound. After applying local anaesthesia (optional), the operator inserts a needle that is connected to a syringe into the cyst. The cyst fluid is smoothly and slowly aspirated and the contents are extracted totally. Sterile ethanol 95% is then injected carefully into the cyst to refills the cavity. The quantity of ethanol injected is usually equivalent to 50% to 70% of the cystic fluid extracted. The alcohol (deposited within the cyst) is gradually reabsorbed during the next 24 to 48 hours without major discomfort. Alcohol causes permanent tissue ablation by local necrosis and thrombosis of small intranodular vessels. Experience is imperative for the performance of neck ultrasound and ultrasound-guided PEI because the manoeuvre is safe only in expert hands (PEI Valcavi 2004).

Another variation of the PEI technique was proposed by Bennedbaek et al, which involves subtotal cyst aspiration, washing with ethanol and subsequent complete fluid aspiration after two minutes (without removing the needle) under ultrasound control (PEI Bennedbaek 2003 ). The authors report treatment failure in 18% of participants. Such individuals subsequently underwent hemithyroidectomy; in one of them the surgeon mentioned that periglandular fibrosis resulting from the ethanol injection made the surgical procedure more difficult.

Ultrasound-guided interstitial laser photocoagulation

Interstitial laser photocoagulation (LP), also called percutaneous laser ablation, is described as a rapid, minimally invasive technique, and proposed as an alternative to thyroidectomy for benign thyroid lesions causing compressive symptoms or cosmetic complaints. The procedure is highly effective for achieving volume reductions in thyroid lesions, and is usually performed in selected cases (individuals at high-surgical risk) and in specialised centres (Filetti 2006). In most individuals with thyroid nodules, one to three sessions of LP induce a significant decrease in nodule volume and the amelioration of local symptoms (AACE/AME/ETA Guidelines 2010). Two new studies with three and five years of follow-up observed comparable nodule volume reductions of about 50% and 75%, with an improvement in pressure symptoms (Dossing 2011). Because of potential complications, thermal ablation procedures should be performed only by experienced operators (AACE/AME/ETA Guidelines 2010).

Technique: Under sterile conditions the individual undergoes local anaesthesia and light sedation to avoid abrupt movements. Ultrasound-guided, the laser fibre is positioned in the thyroid nodule through the lumen of one small or multiple (up to four) needles. The needle is then withdrawn 20 mm leaving the end of the fibre in direct contact with the tissue. After the penetration of the laser light, absorbed energy produces heat (temperatures of up to 180°C to 200°C), inducing tissue charring and necrosis with subsequent volume decrease. To avoid injuries from the thermal effects of LP, a safety distance of at least 15 mm from the neurovascular bundle is required (Pacella 2000). Before the procedure is terminated, three or four areas are treated.

A variation of this procedure has also been described as effective (LP Gambelunghe 2006): during the manoeuvre a small needle is moved from the initial position in steps of 2 to 5 mm, to a distance of 10 mm from the cranial portion of the capsule. The energy applied varies from 100 J to 400 J per step, based on the extent of the hyperechoic area produced by photocoagulation.

Ultrasound-guided radiofrequency ablation therapy

Ultrasound-guided radiofrequency (RF) ablation therapy has been investigated in elderly individuals with benign, compressive and large thyroid nodules (Spiezia 2009). RF ablation therapy, using small needles and internally cooled electrodes, enables the therapist to prevent scar formation without skin incision (Baek 2010). This procedure has previously been used for treating primary and secondary malignant neoplasms and liver tumours. RF energy is applied in 3.8 to 4 MHz quantities, and tissues are heated at temperatures between 60°C and 100°C resulting in subsequent cell death. The needles utilised are generally larger than those used for LP (Spiezia 2009) and this method is ordinarily performed under conscious sedation. Some authors have used single-hook needles (Baek 2010) and others prefer multiple expandable hook needles (RF Faggiano 2012). Safety and efficacy in prospective randomised controlled trials (RCTs) have yet to be adequately investigated, so RF ablation is currently not recommended in the routine management of benign thyroid nodules (AACE/AME/ETA Guidelines 2010).

High-intensity focused ultrasound ablation therapy

This procedure is employed in the ambulatory setting and has been used to treat localised prostate cancer. The technique has been shown to lower costs and shorten hospitalisation, and represents an interesting alternative for individuals in whom surgery is contraindicated (Esnault 2008). High-intensity focused ultrasound (HIFU) ablation is a process of delivering a large amount of heat energy to a restricted space, where ultrasound produces necrosis with a minimum effect on surrounding structures. The first human feasibility study was an open-label, non-randomised and uncontrolled trial performed in 25 participants who were scheduled for thyroid surgery two weeks later. No serious adverse events were observed, especially those affecting the recurrent nerves or the trachea (Esnault 2011). Histological analysis provided some preliminary results about the efficacy of this method and studies are ongoing to asses the changes in nodules at longer follow-up (Esnault 2011).

Ultrasound-guided microwave ablation therapy

This procedure has been used to treat benign and malignant tumours of the liver, kidneys, adrenal glands, spleen and lungs (Feng 2012). The technique has been performed on an inpatient basis under continuous control of blood pressure, partial oxygen pressure and electrocardiography. Under local anaesthesia, a small incision (< 2 mm in length) was made to introduce the internally cooled needle antenna into the thyroid nodule. After placement of the antenna, the ultrasound-guided microwave (MW) procedure was then performed under intravenous anaesthesia (Feng 2012). A power output of 20 W to 30 W was used during MW ablation. The penetration of the microwaves into the tissue is the consequence of a fast rotation of the molecules, growth of local energy and a rapid increase in temperature in the focused area (Gharib 2013). One small feasibility, non-randomised trial, performed in 11 participants with compressive neck symptoms, 9 with pain due to nodular goitre and 2 with Hashimoto’s thyroiditis demonstrated a nodule volume decrease of more than 50% and an improvement in cosmetic complaints (Feng 2012). Currently, MW is currently considered an experimental procedure for the treatment of thyroid nodules (Gharib 2013).

Known adverse effects of the intervention

LT4

The majority of thyroid hormone studies were of short duration and severe adverse effects were not observed despite adequate TSH inhibition under LT4 suppressive therapy (Mainini 1995). Studies investigating cardiovascular and osteoporosis risks sparked several controversies about the possibilities of fractures with long-term LT4 therapy, especially in postmenopausal women (Bauer 2001; Leese 2011; Stall 1990; Uzzan 1996). LT4 suppressive treatment is also reported to increase pulse rate, left ventricular mass and the frequency of atrial arrhythmias (Biondi 1993).

PEI

Adverse effects were mostly few and transient, and generally related to the percutaneous injection of ethanol into solid nodules rather than cysts (Bennedbaek 1997). Perinodular fibrosis due to ethanol injection into solid nodules may seriously hamper subsequent surgery (Bennedbaek 1997). In almost all studies, pain was of mild-to-moderate intensity lasting for one or two days. Other observed effects were: local burning sensation and transient dysphonia (Alcantara-Jones 2006; Braga-Brasaria 2002; Kanotra 2008; Kim 2005; Lima 2007; Zingrillo 1998). Severe complications, such as permanent dysphonia and infections, were not observed.

LP

Documented complications were mostly mild-to-moderate pain lasting for up to days (Dossing 2007; Papini 2004), sometimes requiring additional medication (Dossing 2002; Dossing 2011). Usually, no serious adverse effects, such as dysphonia, local infections, vocal cord paralysis or hypothyroidism, were noted.

RF

The most frequently described complications were pain of different intensities and durations, usually occurring during the procedure (Baek 2009; Baek 2010; Deandrea 2008; Jeong 2008; Kim 2006; Spiezia 2009). Haematoma and fever were also observed. Generally, complications resolved without sequela.

HIFU

Commonly reported adverse effects were local pain, skin burns, blisters and cough. It is hoped that safety can be improved by implementing technological improvements (Esnault 2011).

MW

Currently, the evidence base for MW ablation therapy is scarce. After MW ablation, 8 of 11 participants complained of a sensation of heat in the neck, slight pain, or both, at the ablated site. All participants could tolerate the symptoms and needed no analgesics (Feng 2012). One participant complained of coughing and choking when drinking and a small change in voice six hours after ablation. Laryngoscopic evaluation demonstrated ipsilateral vocal cord palsy. The participant's voice recovered within two months after corticosteroid therapy (Feng 2012).

Why it is important to do this review

Thyroid nodules are a frequent problem seen in a medical practice, and the primary objective of their management - if not causing pressure symptoms or cosmetic complaints - is to exclude malignancy. Uncertainties about aetiology, pathophysiology and prognosis complicate the choice of an efficient and safe treatment. In addition, there is considerable interest in finding therapeutic alternatives to surgery.

We identified several systematic reviews and meta-analyses investigating the effects of thyroid hormone therapy for benign thyroid nodules (Castro 2002; Richter 2002; Sdano 2005; Yousef 2010; Zelmanovitz 1998). Since the publication of these reviews, new studies have been carried out making it necessary not only to re-analyse data on thyroid hormone treatment, but also to establish evidence for all available treatment options for benign thyroid nodules.

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

RCTs. We excluded RCTs investigating the prevention of the recurrence of thyroid disease after surgery, irradiation or treatment with radioiodine.

Types of participants

Participants with an established diagnosis of benign thyroid nodule(s).

Diagnostic criteria

Benign thyroid nodules had to be identified by ultrasonography and FNAB with cytology. Additional investigations included physical examination, thyroid hormone measurements and scintigraphy.

Types of interventions

We looked for the following comparisons:

Interventions

(a) LT4.

(b) PEI.

(c) LP.

(d) RF ablation.

(e) HIFU ablation.

(f) MW ablation.

Comparator interventions
  • Placebo compared with (a) or (b).

  • Cyst aspiration only compared with (b).

  • No treatment compared with (a), (b), (c), (d), (e) or (f).

  • Any other treatment compared with (a), (b), (c), (d), (e) or (f).

  • Another treatment regimen for (a), (b), (c), (d), (e) or (f).

Types of outcome measures

Primary outcomes
  • Pressure symptoms, cosmetic complaints, or both.

  • Nodule volume reduction of 50% or more.

  • Adverse events.

Secondary outcomes
  • Compliance.

  • Tolerability.

  • Thyrotropin (TSH), thyroxine (T4) and tri-iodothyronine (T3) serum levels.

  • Thyroid cancer.

  • All-cause mortality.

  • Health-related quality of life.

  • Socioeconomic effects.

Method and timing of outcome measurement
  • Pressure symptoms, cosmetic complaints, or both: as measured by questionnaires in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

  • Nodule volume reduction of 50% or more: as measured by ultrasonography in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

  • Adverse events (such as infection, severe cervical pain, bone loss and risk of fractures, atrial fibrillation, signs of hyperthyroidism): measured in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

  • Compliance: as measured by questionnaires or pill count in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

  • Tolerability of the procedure: as measured by questionnaires in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

  • TSH, T4 and T3 serum levels: laboratory measurements in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

  • Thyroid cancer: as measured by clinical or register data in the long-term (≥ 12 months).

  • All-cause mortality: as measured by clinical or register data in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

  • Health-related quality of life (measured using a validated instrument) and indicators of well-being: measured in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

  • Socioeconomic effects (e.g. hospital stay, sick leave days, avoidance of surgery, costs): as measured by clinical or register data in the short-term (≤ 6 months), medium-term (6 to 12 months) and long-term (≥ 12 months).

'Summary of findings' table

The following outcomes are listed according to priority.

  1. All-cause mortality.

  2. Thyroid cancer.

  3. Health-related quality of life.

  4. Adverse events.

  5. Pressure symptoms, cosmetic complaints or both.

  6. Nodule volume reduction of 50% or more.

  7. Socioeconomic effects.

Potential covariates, effect modifiers and confounders
  • Compliance/tolerability.

  • Disease status.

Search methods for identification of studies

Electronic searches

We used the following sources from inception until the date specified for the identification of trials.

  • The Cochrane Library (April 2014).

  • MEDLINE (April 2014).

  • EMBASE (April 2014).

  • LILACS (April 2014).

We also searched trial registers, including ClinicalTrials.gov (http://ClinicalTrials.gov/), metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/), the EU Clinical Trials register (https://www.clinicaltrialsregister.eu/) and the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal (http://apps.who.int/trialsearch/). For every included study we tried to find its protocol, either in databases of ongoing trials, in publications of study designs, or both.

For detailed search strategies, see Appendix 1. Searches were not older than one month at the moment the final review draft was checked into the Cochrane Information and Management System for editorial approval. We used PubMed's 'My NCBI' (National Center for Biotechnology Information) email alert service to identify newly published studies using a basic search strategy (see Appendix 1).

If additional key words of relevance had been detected during any of the electronic or other searches we had intended to modify electronic search strategies to incorporate these terms. However, it was not necessary to add additional key words. We included studies published in any language.

Searching other resources

We tried to identify other potentially eligible trials or ancillary publications by searching the reference lists of the retrieved included trials, (systematic) reviews, meta-analyses and health-technology assessment reports.

Data collection and analysis

Selection of studies

Two review authors (EBE, BR) independently scanned the title, abstract and keywords of every record retrieved to determine which studies required further assessment. We investigated all potentially relevant articles as full text, and resolved any disagreements by discussion; reference to a third party (KB) was not required. We attach an adapted PRISMA (preferred reporting Items for systematic reviews and meta-analyses) flow-chart of study selection (Liberati 2009).

Data extraction and management

For studies that fulfilled the inclusion criteria, two review authors (EBE, BR) independently abstracted relevant population and intervention characteristics using standard data extraction templates (for details, see Characteristics of included studies, Table 1; Table 2; Table 3; Table 4; Table 5; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 14; Appendix 15; Appendix 16). We resolved any disagreements by discussion; reference to a third party (KB) was not required.

Table 1. Overview of study populations (levothyroxine treatment)
  1. "-" denotes not reported

    an = 41 ("were followed for 24 months and the obtained results prompted us to stop the observation period after 12 months for the remaining subjects")
    bn = 1020 - 7 (did not receive medication) = 1013 (sensitivity analysis); total = 682 (86% from 794 finishing the study; information from authors' letter in JCEM 2011;96:2786-95; post hoc analysis: n = 600)
    cCross-over study without washout period
    dPredetermined total sample size n = 160; study was stopped with the results from 80 participants
    eCalculation of all subtotals was not possible due availability of total numbers finishing study only (LT4 Grussendorf 2011)

    ITT: intention-to-treat; LT4: levothyroxine; N/A: not applicable; TSH: thyrotropin

 Intervention(s) and
comparator(s)
Screened/eligible
[N]
Randomised
[N]
Safety
[N]
ITT
[N]
Finishing study
[N]
Randomised finishing study
[%]
1. LT4 Bayani 2012LT4-2020-20100
No treatment2020-20100
total:  -  
2. LT4 Boguszewski 1998LT4 -2525-25100
Placebo2323-23100
total:4848-48100
3. LT4 Cesareo 2010aLT49536362158.3
No treatment3535-2057.1
total:7171-4157.7
4. LT4 Gharib 1987LT4562828-28100
Placebo2525-25100
total:5353-53100
5. LT4 Grineva 2003LT4 -59 59-59100
Sodium iodide59 59-59100
total:118118-118100
6. LT4 Grussendorf 2011bLT4 + iodide1245250191191 -N/A
LT4260206206 -N/A
Iodide256198198 -N/A
Placebo254199199 -N/A
total:102079479468266.9
7. LT4 Koc 2002cTSH high-level suppression791313-1184.6
TSH low-level suppression1212-1083.3
Placebo1212975.0
Placebo12121083.3
total:4949-4081.6
8. LT4 La Rosa 1995dLT4 -2727-2385.2
Potassium iodide28282589.3
No treatment2525-2288.0
total:8080-7087.5
9. LT4 Larijani 2005LT4623131-31100
Placebo2727-27100
total:5858-58100
10. LT4 Ozkaya 2010LT4 -35 -35100
No treatment27 -27100
total:62 -62100
11. LT4 Papini 1993LT42155451-5194.4
Placebo5650-5089.3
total:110101 10191.8
12. LT4 Papini 1998LT41005142-4282.4
No treatment4941-4183.7
total:10083-8383.0
13. LT4 Reverter 1992LT4 -2020-1470.0
No treatment2020-20100
total:4040-3485.0
14. LT4 Tsai 2006LT4 -3030-30100
Placebo3030-30100
total:6060-60100
15. LT4 Wemeau 2002LT41356464645890.6
Placebo5959594881.4
total:12312312310686.2
16. LT4 Zelmanovitz 1998LT4 -2421-2187.5
Placebo2724-2488.9
total:5145-4588.2
Subtotals for levothyroxine treatmente Levothyroxine groups   789   N/A N/A
Comparator groups 1294 N/A N/A
All participants 2083 1641 78.8
Table 2. Overview of study populations (percutaneous sclerotherapy)
  1. "-" denotes not reported

    an = 160 screened - 42 (operated) - 58 (refused surgery/treatment) = 60 randomised
    bn = 4 in each group were lost to follow-up after treatment

    ITT: intention-to-treat; LT4: levothyroxine; NaCl: isotonic saline; PEI: percutaneous ethanol injection; PEI-1: percutaneous ethanol injection - one session; PEI-3: percutaneous ethanol injection - three sessions; PHI: percutaneous hydrochloric acid injection; RF: radiofrequency

 Intervention(s) and
comparator(s)
Screened/eligible
[N]
Randomised
[N]
Safety
[N]
ITT
[N]
Finishing study
[N]
Randomised finishing study
[%]
1. PEI Bennedbaek 1998PEI12325252525100
LT425252525100
total:50505050100
2. PEI Bennedbaek 1999aPEI-116030303030100
PEI-33030302790.0
total:6060605795.0
3. PEI Bennedbaek 2003PEI683333-33100
NaCl3333-33100
total:6666-66100
4. PEI Chu 2003PEI -1010-10100
PHI88-8100
Aspiration99-9100
total:2727-27100
5. PEI Sung 2013bPEI532525212080
RF2525211976
total:5050423978
6. TETRA Hegedüs 1998Tetracycline602323-23100
NaCl3030-30100
total:5353-53100
7. PEI Valcavi 2004PEI -143 -13594.4
Aspiration138 -13194.9
total:281 -26694.7
8. PEI Verde 1994PEI -1010-10100
Aspiration1010-10100
total:2020-20100
Subtotals for sclerotherapy Sclerotherapy groups   337  321 95.3
Comparator groups 270 257 95.2
All participants 607 578 95.2
Table 3. Overview of study populations (laser photocoagulation)
  1. "-" denotes not reported

    ASP: aspiration; ITT: intention-to-treat; LP: ultrasound-guided laser photocoagulation; LP-1: ultrasound-guided laser photocoagulation - one session; LP-3: ultrasound-guided laser photocoagulation - three sessions; LT4: levothyroxine

 Intervention(s) and
comparator(s)
Screened/eligible
[N]
Randomised
[N]
Safety
[N]
ITT
[N]
Finishing study
[N]
Randomised finishing study
[%]
1. LP Dossing 2005LP -1515-15100
No treatment1515-15100
total:3030-30100
2. LP Dossing 2006LP-1 -15151515100
LP-315151515100
total:30303030100
3. LP Dossing 2013LP + ASP 2222-22100
ASP2222-22100
total:4444-44100
4. LP Gambelunghe 2006LP1313-13100
No treatment1313-13100
total:2626-26100
5. LP Papini 2007LP862121-21100
LT42121-21100
No treatment2020-1995.0
total:6262-6198.4
Subtotals for laser photocoagulation Laser photocoagulation groups   101  101 100
Comparator groups 91 90 98.9
All participants 192 191 99.5
Table 4. Overview of study populations (radiofrequency ablation)
  1. "-" denotes not reported

    ITT: intention-to-treat; RF: radiofrequency ablation; RF-1: radiofrequency ablation - one session; RF-2: radiofrequency ablation - two sessions

 Intervention(s) and
comparator(s)
Screened/eligible
[N]
Randomised
[N]
Safety
[N]
ITT
[N]
Finishing study
[N]
Randomised finishing study
[%]
1. RF Faggiano 2012RF442020-20100
No treatment2020-20100
total:4040-40100
2. RF Huh 2012RF-114215151515100
RF-215151515100
total:30303030100
Subtotals for radiofrequency ablation Radiofrequency ablation groups  50  50 100
Comparator groups 20 20 100
All participants 70 70 100
Table 5. Overview of study populations (all interventions and comparators)
  1. aNumbers do not exactly match for 'all interventions' versus 'all comparators' owing to provision for total numbers only in LT4 Grussendorf 2011

    N/A: not applicable

 Intervention(s) and comparator(s)Randomised
[N]
Finishing
study
[N]
Randomised
finishing study
[%]
Grand totala All interventions 1277 N/A N/A
All comparators 1675 N/A N/A
All interventions and comparators 2952 2480 84
Dealing with duplicate publications

In the case of duplicate publications and companion papers of a primary study, we maximised the yield of information by the simultaneous evaluation of all available data. We used recent publications to complement results from preliminary articles (LT4 Larijani 2005; LT4 Wemeau 2002).

Assessment of risk of bias in included studies

Two authors (EBE, BR) assessed each trial independently. We resolved any disagreements by discussion; reference to a third party (KB) was not required.

We assessed risk of bias using The Cochrane Collaboration tool (Higgins 2011a; Higgins 2011b). We used the following criteria.

  • Random sequence generation (selection bias).

  • Allocation concealment (selection bias).

  • Blinding (performance bias and detection bias), separated for blinding of participants and personnel and blinding of outcome assessment.

  • Incomplete outcome data (attrition bias).

  • Selective reporting (reporting bias).

  • Other bias.

We used the criteria for individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We present a 'Risk of bias' figure and a 'Risk of bias summary' figure.

We assessed the impact of individual bias domains on study results at endpoint and study levels.

For blinding of participants and personnel (performance bias), detection bias (blinding of outcome assessors) and attrition bias (incomplete outcome data), we evaluated risk of bias separately for subjective and objective outcomes (Hrobjartsson 2012; Hrobjartsson 2013). We investigated the impact of missing data on outcome measures.

We defined the following endpoints as subjective outcomes.

  • Pressure symptoms.

  • Cosmetic complaints.

  • Tolerability (indicator pain).

  • Adverse events.

  • Health-related quality of life

We defined the following outcomes as semi-objective outcomes.

  • Compliance (pill count and thyroid hormone measurements).

  • Nodule volume reduction of 50% or more (measured by ultrasonography).

We defined the following outcomes as objective outcomes.

  • All-cause mortality.

  • Thyroid cancer.

  • Laboratory measurements of thyroid function.

  • Socioeconomic effects.

Measures of treatment effect

Dichotomous data

We expressed dichotomous data (e.g. improvement in or disappearance of pressure symptoms: yes or no) as risk ratios (RRs) with 95% CIs.

Continuous data

We expressed continuous data (e.g. nodule volumes measured in mL) as mean differences with 95% CIs.

Unit of analysis issues

We planned to take into account the level at which randomisation occurred, such as cross-over trials, cluster-randomised trials and multiple observations for the same outcome. No study of such design was included in any meta-analysis.

Dealing with missing data

Whenever possible, we obtained relevant missing data from authors. We carefully evaluated important numerical data, such as screened, randomised participants, as well as intention-to-treat (ITT), as-treated and per-protocol populations. We investigated attrition rates (e.g. dropouts, losses to follow-up and withdrawals) and critically appraised issues of missing data and imputation methods (e.g. last observation carried forward).

Assessment of heterogeneity

In the event of substantial clinical, methodological or statistical heterogeneity, we did not report study results as meta-analytically pooled effect estimates.

We identified heterogeneity by visual inspection of the forest plots and by using a standard Chi² test with a significance level of α = 0.1, in view of the low power of this test. We specifically examined heterogeneity using the I² statistic, which quantifies inconsistency across studies, to assess the impact of heterogeneity on the meta-analysis (Higgins 2002; Higgins 2003), where an I² statistic of 75% or more indicates a considerable level of inconsistency (Higgins 2011a).

When we found heterogeneity, we attempted to determine potential reasons for it by examining individual study and subgroup characteristics.

Assessment of reporting biases

We planned to use funnel plots in when 10 studies or more were included for a given outcome, in order to assess small study effects. Owing to several possible explanations for funnel plot asymmetry we intended to interpret the results carefully (Stern 2011).

Data synthesis

We primarily summarised data with a low risk of bias by means of a random-effects model (Wood 2008). We interpreted random-effects meta-analyses with due consideration of the whole distribution of effects (Higgins 2009) and performed statistical analyses according to the guidelines referenced in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses and wanted to investigate interaction.

  • Duration of follow-up.

  • Type of nodule.

  • Type of treatment.

Sensitivity analysis

We planned to perform sensitivity analyses in order to explore the influence of the following factors on effect sizes.

  • Restricting the analysis to published studies.

  • Restricting the analysis taking into account risk of bias, as specified in the section Assessment of risk of bias in included studies.

  • Restricting the analysis to very long or large studies to establish how much they dominate the results.

  • Restricting the analysis to studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.

We also planned to test the robustness of the results by repeating the analysis using different measures of effect size (RR, OR etc.) and different statistical models (fixed-effect and random-effects models).

Results

Description of studies

Results of the search

We identified 4597 records including 46 (systematic) reviews/meta-analyses or guidelines. From these, we recognised 51 potentially relevant publications including six systematic reviews (Castro 2002; Fuller 2014; Richter 2002; Sdano 2005; Yousef 2010; Zelmanovitz 1998) for full-text examination. The other records were excluded on the basis of their abstracts, titles or both because they were not relevant to our question or clearly did not meet inclusion criteria. After screening the full text of the selected papers and excluding 10 studies, six systematic reviews and four potentially relevant ongoing studies, 31 completed RCTs (33 publications) fulfilled the inclusion criteria. We did not identify additional studies after scrutinising the full publications of the six identified systematic reviews. For details, see Figure 1 of the amended PRISMA (preferred reporting Items for systematic reviews and meta-Analyses) flow diagram of study selection (Liberati 2009).

Figure 1.

Study flow diagram

Assessment of interrater agreement

Interrater agreement between the two authors (EBE, BR) who rated studies for selection (i.e. decided whether a study was included or potentially relevant) was 100%. Consultation with a third party (KB) was not required.

Included studies

Of the 31 included trials,16 studies investigated treatment with LT4 (LT4 Bayani 2012; LT4 Boguszewski 1998; LT4 Cesareo 2010; LT4 Gharib 1987; LT4 Grineva 2003; LT4 Grussendorf 2011; LT4 Koc 2002; LT4 Larijani 2005; LT4 La Rosa 1995; LT4 Ozkaya 2010; LT4 Papini 1993; LT4 Papini 1998; LT4 Reverter 1992; LT4 Tsai 2006; LT4 Wemeau 2002; LT4 Zelmanovitz 1998), eight studies analysed PEI sclerotherapy, seven using ethanol (PEI Bennedbaek 1998; PEI Bennedbaek 1999; PEI Bennedbaek 2003; PEI Chu 2003; PEI Sung 2013; PEI Valcavi 2004; PEI Verde 1994) and one using tetracycline hydrochloride (TETRA Hegedüs 1988). Five studies evaluated ultrasound-guided interstitial or percutaneous LP (LP Dossing 2005; LP Dossing 2006; LP Dossing 2013; LP Gambelunghe 2006; LP Papini 2007). Two studies investigated the effects of RF ablation therapy by comparing one with two treatment sessions (RF Huh 2012) or no treatment (RF Faggiano 2012).

We identified no RCTs that investigated HIFU or MW ablation therapy.

We also detected one trial comparing potassium iodide with no treatment (LT4 Grineva 2003) and one trial comparing LT4 plus potassium iodide combination therapy with placebo, potassium iodide or LT4 (LT4 Grussendorf 2011).

We identified trial registrations for four of the included studies (LT4 Bayani 2012; LT4 Grussendorf 2011; PEI Sung 2013; RF Faggiano 2012).

For details about the included studies, see Characteristics of included studies; Table 1; Table 2; Table 3; Table 4; Table 5; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 14; Appendix 15; Appendix 16.

Study design
LT4

We evaluated 16 RCTs with a duration from six months to five years. All trials were parallel RCTs except one cross-over study without a washout period between treatment periods (LT4 Koc 2002). Studies were published in English and in peer-reviewed journals, with the exception of one which was published in Russian (LT4 Grineva 2003). Six studies mentioned commercial or non-commercial funding (LT4 Bayani 2012; LT4 Boguszewski 1998; LT4 La Rosa 1995; LT4 Larijani 2005; LT4 Wemeau 2002; LT4 Zelmanovitz 1998) and two trials were terminated early (LT4 Cesareo 2010; LT4 La Rosa 1995).

PEI

In eight RCTs one up to five PEI treatment sessions were applied. Follow-up varied from 1 (PEI Verde 1994) to 12 months (PEI Bennedbaek 1998; PEI Valcavi 2004; TETRA Hegedüs 1988). All studies were published in English and in peer-reviewed journals. Three trials reported funding (PEI Bennedbaek 1998; PEI Bennedbaek 1999; PEI Bennedbaek 2003); no study was terminated early. One trial directly compared PEI with RF (PEI Sung 2013).

LP

Five RCTs applied one up to three photocoagulation sessions monthly, with follow-up ranging from 6 to 12 months; one trial comparing LP with LT4 lasted 12 months (LP Papini 2007). All trials were published English and in peer-reviewed journals. Two trials reported funding (LP Dossing 2005; LP Dossing 2006) and no trial was terminated early.

RF

One RCT compared one versus two ablation sessions and had a follow-up of six months (RF Huh 2012). One of the authors, who is patent holder for the unidirectional ablation electrode technique investigated in this study mentioned no direct financial activities related to this study. Another study investigated one session of RF versus no treatment and had a follow-up of 12 months. Both studies were published in English in peer-reviewed journals and were not terminated early. A third trial directly compared PEI with RF (PEI Sung 2013).

Participants
LT4

A total of 2083 participants were randomised, 789 to the intervention and 1294 to the comparator groups. Eight studies compared LT4 with placebo (LT4 Boguszewski 1998; LT4 Gharib 1987; LT4 Koc 2002; LT4 Larijani 2005; LT4 Papini 1993; LT4 Tsai 2006; LT4 Wemeau 2002; LT4 Zelmanovitz 1998), six studies compared LT4 with no treatment (LT4 Bayani 2012; LT4 Cesareo 2010; LT4 La Rosa 1995; LT4 Ozkaya 2010; LT4 Papini 1998; LT4 Reverter 1992) and one study compared LT4 with potassium iodide (LT4 Grineva 2003). One trial examined a combination of LT4 plus iodine versus LT4, iodine or placebo alone (LT4 Grussendorf 2011). Participants were euthyroid, mostly female, 18 to 69 years old and had single palpable thyroid nodules without compressive symptoms. In total, 40% of trials were conducted in non-endemic areas and 20% in iodine-deficient regions (Appendix 12). Number of nodules, measurements and characteristics (solid, mixed or cystic nodules) were detected by ultrasound, benignity was confirmed by cytologic diagnosis from FNAB and thyroid nodule function was assessed by thyroid scanning. Participants with suspicious or positive FNAB results, Hashimoto's thyroiditis, osteoporosis, cardiovascular disease or pregnancy were excluded. Three studies reported no comorbidity among participants (LT4 La Rosa 1995; LT4 Ozkaya 2010; LT4 Papini 1993) and two trials mentioned that no participant had previously received any thyroid medication (LT4 Bayani 2012; LT4 Ozkaya 2010). Two studies reported that outcome data were analysed according to the ITT principle (LT4 Grussendorf 2011; LT4 Wemeau 2002).

PEI

Overall 607 participants were randomised, 337 to various interventions and 270 to comparator groups. Trials compared PEI with other doses of PEI (PEI Bennedbaek 1999), NaCl (PEI Bennedbaek 2003), LT4 (PEI Bennedbaek 1998), percutaneous hydrochloric acid injection (PEI Chu 2003), aspiration alone (PEI Chu 2003; PEI Valcavi 2004; PEI Verde 1994) and RF ablation (PEI Sung 2013). One study from Denmark compared tetracycline hydrochloride injection with NaCl (TETRA Hegedüs 1988). Participants were predominantly women complaining of local neck compression due to cystic nodules, who were euthyroid and between 18 to 85 years old. Two trials applied therapy to solid nodules (fluid content less than 10%) (PEI Bennedbaek 1998; PEI Bennedbaek 1999). Trialists identified nodule characteristics by ultrasound, confirmed benignity by cytologic diagnosis from FNAB and assessed thyroid nodule function by thyroid scan. Participants with suspicious or positive FNAB findings were excluded. TETRA Hegedüs 1988 excluded toxic or large multinodular goitres. No publication provided substantial information about comorbidities or comedications.

LP

A total of 192 participants were randomised, 101 to the intervention and 91 to the comparator groups. Three studies compared LP to no treatment (LP Dossing 2005; LP Gambelunghe 2006; LP Papini 2007). One study arm in LP Papini 2007 compared LP with LT4 therapy and another study compared one session of laser ablation with three sessions (LP Dossing 2006). One study compared LP plus cyst aspiration with cyst aspiration only (LP Dossing 2013). Participants were mostly women, euthyroid and between 28 to 58 years old. In one trial, half of the participants had subclinical hyperthyroidism and were between 63 and 92 years old (LP Gambelunghe 2006). Over 80% of women complained of neck compression symptoms, refused thyroidectomy or had a high surgical risk. Diagnostic criteria were based on ultrasound nodule findings, cytologic FNAB confirming benignity and thyroid scintigram for nodule function assessment. In case of MNGs only the dominant nodule was analysed. No publication provided substantial information about comedications or comorbidities.

RF

Overall, 70 participants from two studies were randomised, 50 to the intervention and 20 to the comparator groups. In one trial, comparing one session with two sessions of RF ablation, participants were euthyroid, around 37 years old and mostly women complaining of cosmetic or pressure symptoms (RF Huh 2012). The other trial analysed one session of RF versus no treatment and participants had toxic or non-toxic thyroid nodules with compressive symptoms (RF Faggiano 2012). In both studies, participants refused or were ineligible for surgery or radioiodine therapy. Diagnostic criteria were based on ultrasound evaluation, on two FNABs with cytology confirming benignity and on thyroid scans showing nodule hypofunction. No information about comedications and comorbidities was provided.

Interventions and comparisons

For details, see Appendix 2.

LT4

The vast majority of trials were monocentric but four were multicentric (LT4 Grussendorf 2011; LT4 Papini 1993; LT4 Papini 1998; LT4 Wemeau 2002); they were conducted in outpatients, seven in Europe (one in France, four in Italy, one in Spain and one in Germany), six in Eurasia (two in Iran, one in Russia, two in Turkey and one in Taiwan), two in Brazil and one in the USA. In eight trials, participants were drug-naive and in one, participants underwent previous suppressive therapy longer than one year before the start of the study (LT4 Zelmanovitz 1998). Oral doses varied from 1 μg/kg/day (LT4 La Rosa 1995) to 3 µg/kg/day (LT4 Gharib 1987), being adjusted to TSH suppression levels that ranged from less than 0.01 mIU/L to 0.2 to 0.8 mIU/L (reference value for TSH was mostly between 0.2 to 4.0 mIU/L).

PEI

The eight studies were monocentric and took place in Denmark (PEI Bennedbaek 1998; PEI Bennedbaek 1999; PEI Bennedbaek 2003; TETRA Hegedüs 1988), Italy (PEI Valcavi 2004; PEI Verde 1994) and Asia (South Korea (PEI Sung 2013) and Taiwan (PEI Chu 2003)). All trials were conducted in outpatients of hospitals referred from primary care physicians or from clinics specialising in thyroid diseases. Thyroid cysts were initially aspirated and afterwards filled with ethanol to produce cyst ablation in seven studies. The ethanol volume given varied from 21% (PEI Chu 2003) to 70% of the extracted cyst fluid (PEI Valcavi 2004). For trials with solid or predominantly solid nodules, the median injected volume of ethanol in one session varied from 21% to 25% of pretreatment cyst volume (PEI Bennedbaek 1998; PEI Bennedbaek 1999). Resistance during infusion or pain were reasons for procedure interruption. One study compared the use of tetracycline hydrochloride and NaCl in solitary thyroid cysts of at least 2 mL volume (TETRA Hegedüs 1988). Under ultrasound control the cyst fluid was first aspirated and either 2 mL tetracycline hydrochloride or 2 mL NaCl was injected and then re-aspirated up to five times to achieve complete emptying.

LP

All five studies were monocentric, performed in Europe (three in Denmark and two in Italy) and in outpatients of hospitals. One trial noted that participants were untreated for thyroid disease before intervention (LP Papini 2007). Thyroid nodules were usually solid and photocoagulation was mostly performed in one session. The median energy deposition per mL of pretreatment volume varied from 224 J to 262 J (LP Dossing 2005; LP Dossing 2006). Another study chose a 'step by step' procedure: median energy given was 100 J to 400 J per retracting step (LP Gambelunghe 2006). All procedures were performed with one needle, except in one trial where trialists used four needles for nodule volumes greater than 20 mL (LP Papini 2007).

RF

Both studies were monocentric, performed in Italy and South Korea in outpatients treated in hospital (RF Faggiano 2012; RF Huh 2012). In RF Huh 2012, the mean energy deposited per mL of pretreatment volume was 4377 J compared with 6157 J in one versus two sessions, respectively. The mean total energy deposition was 51,930 J versus 69,160 J, respectively. The method was performed with one needle with an active tip internally cooled electrode. RF Faggiano 2012 utilised one needle with four expandable hooks. The exposure time during the procedure ranged from 5 to 7 minutes and the temperature reached was between 100°C and 105°C.

Outcome measures

Appendix 11 provides an overview on how many studies, comparisons and participants contributed data to the various comparisons.

Primary outcomes
Pressure symptoms, cosmetic complaints, or both

For details on methods of outcome measurements for local symptoms, cosmetic complaints, or both, see, Appendix 13.

LT4

Not investigated.

PEI

Five trials measured participants' cosmetic complaints and local discomfort using.

LP

The effects on participants' pressure symptoms and cosmetic complaints were evaluated using a VAS in four of five interventions (LP Dossing 2005; LP Dossing 2006; LP Dossing 2013; LP Gambelunghe 2006). In one trial, the participants' questionnaire was not validated (LP Papini 2007).

RF

Participants rated pressure symptoms using a VAS and physicians recorded a cosmetic nodule score (from 1 = no palpable mass to 4 = readily observable) at the start of the study and one, three and six months after the procedure (RF Huh 2012). Participants estimated their neck symptoms separately, from 0 (absent), 1 (moderate) and 2 (severe), before, and after 3, 6 and 12 months, creating a final sum score (SYS score) varying from 0 to 6 (RF Faggiano 2012).

Nodule volume reduction of 50% or more

LT4

Nodule volume reduction from baseline of 50% or more was investigated in 12 (75%) studies (LT4 Boguszewski 1998; LT4 Gharib 1987; LT4 Grineva 2003; LT4 Grussendorf 2011; LT4 Koc 2002; LT4 La Rosa 1995; LT4 Larijani 2005; LT4 Papini 1993; LT4 Reverter 1992; LT4 Tsai 2006; LT4 Wemeau 2002; LT4 Zelmanovitz 1998).

PEI and sclerotherapy using other agents

All eight included trials investigated this outcome.

LP

All five included studies reported this endpoint and whether the decrease was related to the mean or median total energy deposition. One study reported that the number of previous aspirations was associated with reduced treatment success if the cyst volume was 1 mL or less (LP Dossing 2013).

RF

RF Huh 2012 defined therapeutic success as a decrease in nodule volume of 50% or more, and investigated whether this decrease was related to the mean total energy deposition.

Adverse events

LT4

In four studies, participants reported signs of hyperthyroidism, such as nervousness, palpitations, sweating or tremor (LT4 Koc 2002; LT4 Papini 1993; LT4 Papini 1998; LT4 Wemeau 2002).

PEI

All studies reported adverse events ranging from mild-to-moderate pain and a burning sensation. Two trials found that major side effects, such as dysphonia, persistent nerve paralysis and paranodular fibrosis (PEI Bennedbaek 1999) and transient laryngeal dysfunction lasting two months (PEI Valcavi 2004), were dependent on the administrated ethanol dose. Two participants experienced extreme pain right after injection of tetracycline that lasted nearly 24 hours (TETRA Hegedüs 1988).

LP

In some studies, participants suffered slight-to-moderate pain lasting three (LP Dossing 2005) up to eight days (LP Dossing 2006), which had to be treated with "mild" analgesics. Generally, the procedure was well tolerated and pain stopped as soon as the energy was turned off. None of the authors described serious complications such as dysphonia, infection, hematoma, vocal cord paralysis or thyrotoxicosis.

RF

All participants experienced some pain or discomfort during the ablation, which ceased once the energy was decreased or turned off (RF Huh 2012). Mild burning sensation was described without the need to interrupt the procedure (RF Faggiano 2012). RF ablation therapy was reported as well tolerated, and no serious complications, such as dysphonia, skin burn, infection, hematoma or oesophageal injury, were observed.

Secondary outcomes
LT4

Compliance was defined and analysed as the suppression of TSH in all studies. Some trialists checked suppression status by applying thyrotropin-releasing hormone (TRH) injection (LT4 Boguszewski 1998; LT4 Gharib 1987) or a combination of TSH suppression measurements with pill counts at follow-up visits (LT4 Grussendorf 2011; LT4 Tsai 2006). All studies measured thyroid hormones at baseline and throughout to demonstrate thyroid function during LT4 therapy. No study reported on thyroid cancer, all-cause mortality, health-related quality of life or socioeconomic effects.

PEI

The degree of pain reported by participants was an indicator of the tolerability of PEI. Use of local anaesthesia was not described in studies treating thyroid cysts (PEI Bennedbaek 2003; PEI Chu 2003; PEI Sung 2013; PEI Verde 1994; TETRA Hegedüs 1988) in contrast to studies in which solid nodules were injected with ethanol, which necessitated the use of local anaesthesia and analgesics(PEI Bennedbaek 1998; PEI Bennedbaek 1999). All studies except three (PEI Chu 2003; PEI Sung 2013; PEI Valcavi 2004) described thyroid hormone measurements periodically during follow-up. PEI Bennedbaek 1999 mentioned cost-effectiveness but did not provide data. Two studies stated the necessity and importance of confirming the absence of malignancy at long-term follow-up (PEI Chu 2003; PEI Valcavi 2004). No trial evaluated all-cause mortality or health-related quality of life.

LP

Investigators measured tolerability as the degree of pain or discomfort experienced by participants after the procedure by means of a VAS (LP Dossing 2005; LP Dossing 2006). In two trials, participants were asked if they would repeat the procedure or not (LP Gambelunghe 2006; LP Papini 2007). In all studies but one (LP Papini 2007), participants received local anaesthesia. In this one trial, participants received an intramuscular injection of betamethasone before LP was applied. In case of persisting cervical pain, participants received ketoprofen for two days. All trials measured thyroid hormones initially and throughout the study. No study reported on all-cause mortality or health-related quality of life. LP Papini 2007 reported the costs of the procedure.

RF

Thyroid hormones were measured at study start and during follow-up. Authors did not evaluate all-cause mortality, health-related quality of life or socioeconomic effects.

Excluded studies

In total we excluded 10 studies after evaluation of the full publication. For more details about reasons for exclusion of studies, see the Characteristics of excluded studies. The main reason for exclusion was a non-randomised study design.

Risk of bias in included studies

For details on study populations. such as numbers randomised, analysed, and the ITT and safety populations, see Table 1; Table 2; Table 3; Table 4; Table 5. For an overview of authors' judgements about each 'Risk of bias' item, see Characteristics of included studies, Figure 2 and Figure 3.

Figure 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)

Figure 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)

Allocation

LT4

All 16 studies were described as randomised trials, but we judged only five as having a low risk of bias for random sequence generation because these trials provided adequate details (LT4 Gharib 1987; LT4 Grussendorf 2011; LT4 Larijani 2005; LT4 Reverter 1992; LT4 Wemeau 2002). Only one study specifically reported how the allocation sequence was generated and concealed (LT4 Grussendorf 2011). We judged the remaining 10 trials as unclear and one study (LT4 Grineva 2003) as having a high risk of selection bias.

PEI

Three of eight studies using PEI sclerotherapy described the randomisation process in adequate detail (PEI Bennedbaek 1998; PEI Bennedbaek 1999; PEI Bennedbaek 2003) and we judged these studies to have a low risk of bias for random sequence generation. Only one study provided details of both generation of allocation sequence and concealment of allocation (PEI Bennedbaek 2003).

LP

Three of four studies described the randomisation process in adequate detail (LP Dossing 2005; LP Dossing 2006; LP Papini 2007), but none reported how allocation was concealed.

RF

One of two studies reported on the randomisation process (RF Huh 2012). No study provided adequate information about concealment of allocation.

Blinding

LT4

With regard to the blinding of participants for both (semi)objective and subjective outcomes, we judged 6 of 16 studies to have a low risk of bias (LT4 Boguszewski 1998; LT4 Gharib 1987; LT4 Papini 1993; LT4 Tsai 2006; LT4 Wemeau 2002; LT4 Zelmanovitz 1998). For the blinding of personnel, we considered seven studies to have a low risk of bias for both (semi)objective and subjective outcomes (LT4 Boguszewski 1998; LT4 Gharib 1987; LT4 Grussendorf 2011; LT4 Larijani 2005; LT4 Tsai 2006; LT4 Wemeau 2002; LT4 Zelmanovitz 1998). Considering both (semi)objective and subjective outcomes, we judged only four studies to have a low risk of bias for outcome assessors (LT4 Boguszewski 1998; LT4 Gharib 1987; LT4 Grussendorf 2011; LT4 Larijani 2005). One study (all outcomes) was triple masked for participants, physicians and outcome assessors (LT4 Gharib 1987).

PEI

Considering the blinding of participants or personnel for both (semi)objective and subjective outcomes, we judged one of eight studies to have a low risk of bias (PEI Bennedbaek 2003). We considered only one study to have a low risk of bias concerning the blinding of outcome assessors for both (semi)objective and subjective outcomes (PEI Sung 2013).

LP

All four studies compared laser treatment with no therapy. For this procedure, participants and personnel were not masked, but in all trials an awareness of treatment allocation could have influenced the endpoints, especially subjective outcomes. We considered all but one study (LP Papini 2007) to have a low risk of bias concerning the blinding of outcome assessors for (semi)objective outcomes.

RF

We judged both studies to have a low risk of bias for the blinding of participants and personnel regarding (semi)objective endpoints and a high risk of bias for subjective outcomes (RF Faggiano 2012; RF Huh 2012). Blinding of outcome assessors was unclear in both trials.

Incomplete outcome data

LT4

We considered eight studies to have a low risk of bias, either because all participants were followed up until the end of the study or the reasons for dropouts or exclusion from the analyses were adequately specified and attrition rates did not differ considerably (LT4 Bayani 2012; LT4 Boguszewski 1998; LT4 Gharib 1987; LT4 Larijani 2005; LT4 La Rosa 1995; LT4 Ozkaya 2010; LT4 Tsai 2006; LT4 Zelmanovitz 1998). Two studies used ITT analyses (LT4 Grussendorf 2011; LT4 Wemeau 2002). In one study approximately 42% of participants in both intervention and comparator groups discontinued the study (LT4 Cesareo 2010) and in another trial 30% versus 0% of participants discontinued the study in the LT4 versus the no-treatment comparator group, respectively (LT4 Reverter 1992).

PEI

We judged six studies to have a low risk of bias, since either all participants were followed up until the end of the study or the reasons for dropouts or exclusion from the analyses were specified and attrition rates did not differ considerably (PEI Bennedbaek 1998; PEI Bennedbaek 1999; PEI Bennedbaek 2003; PEI Sung 2013; PEI Verde 1994; TETRA Hegedüs 1988). In one study, 24% versus 20% of participants discontinued the study in the RF ablation versus the PEI therapy groups, respectively (PEI Sung 2013).

LP

We considered all five studies to have a low risk of bias, since either all participants were followed up until the end of the study or the reasons for dropouts or exclusion from the analyses were specified and attrition rates did not differ considerably. One trial analysed outcomes data according to the ITT principle (LP Dossing 2006)

RF

We judged both trials to have a low risk of bias for attrition bias, as all participants completed the study. One study reported analyses according to the ITT principle (RF Huh 2012).

Selective reporting

LT4

We judged 14 studies to have a low risk of selective outcome reporting, because all expected und prespecified outcomes were reported and analysed. One study had a high risk of reporting bias (LT4 Grussendorf 2011).

PEI

We considered all trials to have a low risk of bias, as all expected outcomes were reported and analysed, or similar endpoints were found in previous publications.

LP

We judged all trials to have a low risk of bias, as all expected outcomes were reported and analysed, or similar endpoints were found in previous publications.

RF

We considered both studies to have a low risk of bias, as all expected outcomes were reported and analysed.

Other potential sources of bias

LT4

We judged one study to have a high risk of bias because this trial was stopped early, probably for benefit (LT4 La Rosa 1995). Four trials mentioned commercial sponsoring (LT4 Boguszewski 1998; LT4 Grussendorf 2011; LT4 La Rosa 1995; LT4 Wemeau 2002), two studies had a combination of commercial and non-commercial funding (LT4 Larijani 2005; LT4 Zelmanovitz 1998), three reported non-commercial funding (LT4 Cesareo 2010; LT4 Gharib 1987; LT4 Koc 2002), and the others did not provide information about funding (LT4 Ozkaya 2010; LT4 Papini 1993; LT4 Papini 1998; LT4 Reverter 1992; LT4 Tsai 2006).

PEI

We considered all studies to have a low or unclear risk of bias.

LP

We judged studies to have either a low (LP Gambelunghe 2006; LP Papini 2007) or unclear risk of bias (LP Dossing 2005; LP Dossing 2006; LP Dossing 2013).

RF

We considered all studies to have either a low (RF Faggiano 2012) or unclear risk of bias (RF Huh 2012).

Effects of interventions

See: Summary of findings for the main comparison Summary of findings (levothyroxine treatment); Summary of findings 2 Summary of findings (percutaneous ethanol injection sclerotherapy); Summary of findings 3 Summary of findings (laser photocoagulation); Summary of findings 4 Summary of findings (radiofrequency ablation)

LT4 versus no treatment or placebo

Two studies are mainly descriptively reported in the appendices: one cross-over study with no wash-out phase in 49 participants investigated LT4 therapy versus placebo over one year in low or high level TSH suppression subgroups (LT4 Koc 2002). Another study evaluated LT4 versus potassium iodide for six months in 108 participants but was at high risk of selection bias (LT4 Grineva 2003).

One study investigated the effects of a combination of LT4 and iodine versus placebo, LT4 only or iodine supplementation only (LT4 Grussendorf 2011). Participants had mild-to-moderate iodine deficiency (Appendix 12). In this review we report the findings of the comparisons of all LT4-containing regimens versus placebo. For the outcome nodule volume reduction of 50% or more, the results for placebo, iodine, LT4 and LT4 plus iodine were 6.5%, 7.1%, 9.7% and 16.2%, respectively (LT4 Grussendorf 2011).

One study (LP Papini 2007) compared LP ablation with LT4 therapy and is described in the section on LP below. Another study investigated LT4 treatment versus PEI sclerotherapy (PEI Bennedbaek 1998) and is described in the section on PEI below.

Primary outcomes
Pressure symptoms/cosmetic complaint

This outcome was not investigated in any LT4 study.

Nodule volume reduction of 50% or more

No study investigated nodule volume reduction of 50% or more as a primary outcome, although all trials evaluated nodule volume changes following LT4 treatment. Considering the 10 of 16 studies investigating this outcome independent of study duration and follow-up, and excluding the cross-over study by LT4 Koc 2002, this endpoint was achieved by 80/489 (16%) participants in the LT4 treatment groups and by 46/469 (10%) participants in the comparator groups after 6 to 24 months of follow-up (Figure 4). The RR was 1.57 (95% CI 1.04 to 2.38); P = 0.03; I² = 17%; 958 participants; 10 studies; Analysis 1.1) in favour of LT4. Overall, we considered this outcome to have a low risk of performance bias across all studies. We judged two studies to have an unclear risk of detection bias (LT4 Bayani 2012; LT4 Reverter 1992). Exclusion of these studies did not substantially change the effect estimate. We judged one study to have a high risk of attrition and reporting bias (LT4 Grussendorf 2011). Excluding this study did not substantially change the effect estimate.

Figure 4.

Forest plot of comparison: 1 Levothyroxine versus control (no treatment, placebo), outcome: 1.1 Nodule volume reduction ≥ 50%.

Adverse events

Study authors described LT4 therapy as generally well tolerated; for more details, see Appendix 14. Some studies observed no adverse events (LT4 Boguszewski 1998; LT4 La Rosa 1995; LT4 Papini 1993) and others did not report untoward effects of the medications (LT4 Gharib 1987; LT4 Grussendorf 2011; LT4 Larijani 2005; LT4 Ozkaya 2010; LT4 Reverter 1992; LT4 Tsai 2006).

Bone loss as measured by bone mineral density

One trial analysed the effect of suppressive doses of LT4 versus placebo on bone mineral density (BMD) in 16 pre- and postmenopausal (intervention group) and 19 pre- and postmenopausal (comparator group) women (LT4 Zelmanovitz 1998 - Appendix 15). After one year, no statistically significant differences in BMD were found. BMD was measured at the lumbar spine and femur before and after one year of treatment.

Hyperthyroidism

In one study, one participant in the LT4 and one in the placebo group developed severe hyperthyroidism requiring withdrawal. Investigators diagnosed underlying Graves' disease in the participant in the placebo group (LT4 Wemeau 2002). Three studies provided quantitative data on signs and symptoms of hyperthyroidism, such as nervousness, tachycardia and tremor (LT4 Papini 1993; LT4 Papini 1998; LT4 Wemeau 2002). Untoward effects were observed in 35/138 (25%) LT4-treated versus 9/131 (7%) placebo-treated participants at 12 to 18 months of follow-up. Random-effects and fixed-effect meta-analyses of numbers of participants without signs of hyperthyroidism indicated either a statistically significant or non-significant effect in favour of placebo. However, heterogeneity was considerable in both cases and we therefore do not report a pooled effect estimate (Analysis 1.2). All three studies had a high risk of detection bias for this outcome.

Nodule volume increase of more than 50%

Three studies reported the numbers of participants showing a thyroid nodule volume increase of more than 50% (LT4 Grussendorf 2011; LT4 Papini 1993; LT4 Zelmanovitz 1998). Analysis 1.3, showing the RR for participants without a nodule volume increase greater than 50% (to conserve forest plot orientation), reveals no statistically significant differences (RR 1.10 (95% CI 0.99 to 1.22); P = 0.09; I² = 0%; 551 participants; 3 trials). Risk of detection bias was low for this outcome.

Secondary outcomes
Compliance

Some studies defined compliance as the number of returned or taken pills throughout follow-up visits, but no details were published (LT4 Grussendorf 2011; LT4 Tsai 2006; LT4 Wemeau 2002). Three trials also considered suppression of TSH after TRH injection (LT4 Boguszewski 1998; LT4 Gharib 1987; LT4 Zelmanovitz 1998), the degree of suppression of TSH measured indicated compliance to treatment.

Tolerability

This outcome was not investigated in any LT4 study.

TSH and T4 serum levels

In most studies, thyroid hormones including thyroid autoantibodies were evaluated at the beginning and throughout the study. Baseline values were always documented. Eight trials (LT4 Bayani 2012; LT4 Boguszewski 1998; LT4 Cesareo 2010; LT4 Gharib 1987; LT4 Ozkaya 2010; LT4 Papini 1993; LT4 Papini 1998; LT4 Zelmanovitz 1998) showed - with the exception of Ozkaya 2010 - lower TSH values following LT4 therapy. However, due to otherwise unexplained considerable heterogeneity we do not report an effect estimate (Analysis 1.4). In five studies comparing LT4 with placebo, total T4 in 296 participants at the end of the trials showed a difference of 48.3 nmol/L (95% CI 35.1 to 61.4; P < 0.00001; 296 participants; 5 trials; I² = 66%; Analysis 1.5) in favour of LT4 (LT4 Boguszewski 1998; LT4 Gharib 1987; LT4 Papini 1993; LT4 Tsai 2006; LT4 Zelmanovitz 1998). We considered the risk of performance and detection bias to be low for these outcomes.

Thyroid cancer

One study confirmed the benignity of some treated nodules through FNAB and cytological re-evaluation at 12 and 24 months in the non-responder group, defined as participants (33/58) with constant or increasing nodule volume (LT4 Larijani 2005).

All-cause mortality

This outcome was not investigated in any LT4 study.

Health-related quality of life

This outcome was not investigated in any LT4 study.

Socioeconomic effects

This outcome was not investigated in any LT4 study.

PEI treatment and sclerotherapy with other agents versus cyst aspiration, isotonic saline, LT4 or RF

Primary outcomes
Pressure symptoms/cosmetic complaints

Signs of improvement of neck compression symptoms at end of study were demonstrated in three trials in 370 participants after 6 to 12 months of follow-up (145/187 (78%) in the treatment groups and 70/183 (38%) in the various comparator groups). Heterogeneity between studies was considerable. Since we could not explain the heterogeneity we do not present an effect estimate (Analysis 2.1). RRs ranged from 1.0 to 3.06 in favour of PEI . Symptom and cosmetic scores did not show statistically significant differences in one trial comparing PEI with RF treatment (PEI Sung 2013). There was a high risk of performance bias for these outcomes across all three studies. All studies showed a high or unclear risk of detection bias.

Nodule volume reduction of 50% or more

Six of eight studies applying PEI provided data on this outcome. PEI versus cyst aspiration showed a statistically significant benefit in favour of PEI after 1 to 24 months of follow-up, with 44 of 53 (83%) participants versus 23/52 (44%) showing a nodule volume reduction of 50% or more (RR 1.83 (95% CI 1.32 to 2.54; P = 0.0003; I² = 0%; 105 participants; 3 trials; Analysis 2.2.1). One study compared PEI with LT4 treatment and showed a nodule volume reduction of 50% or more in 19 of 25 (76%) PEI-treated participants compared with 0 of 25 (0%) LT4-treated participants (Analysis 2.2.2). One study compared PEI with RF ablation therapy and showed a nodule volume reduction of 50% or more in all participants in both the intervention (21/21) and comparator groups (21/21) (Analysis 2.2.3). TETRA Hegedüs 1988 compared tetracycline hydrochloride with isotonic saline injections for the treatment of thyroid cysts of at least 2 mL in volume. In the tetracycline group, the thyroid cyst volume declined more than 50% in 10 of 23 (43%) participants versus 14/30 (47%) in the saline group (difference not statistically significant). This outcome was associated with a low risk of performance bias across all studies. Three studies had an unclear risk of detection bias (PEI Chu 2003; PEI Valcavi 2004; TETRA Hegedüs 1988).

Adverse events

The study authors described the adverse events profile of PEI therapy as acceptable; for details, see Appendix 16.

Cervical pain

In all trials, participants experienced periprocedural cervical tenderness and light-to-moderate pain lasting from minutes to several hours. The duration of pain correlated with the dose of ethanol in one study (PEI Bennedbaek 1999). The injections were applied to predominant solid nodules and were described as painful despite local anaesthesia and analgesics in two studies (PEI Bennedbaek 1998; PEI Bennedbaek 1999). One study comparing PEI with RF treatment reported that PEI was associated with almost no periprocedural pain whereas RF ablation showed a tendency for more pain (PEI Sung 2013). Three studies investigated PEI treatment compared with cyst aspiration: 26% of PEI 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; Analysis 2.3). All studies had a high risk of detection bias (PEI Bennedbaek 2003; PEI Chu 2003; PEI Verde 1994) and two a high risk of performance bias (PEI Chu 2003; PEI Verde 1994) for this outcome.

Major adverse effects

In one study, participants who experienced major adverse effects,such as dysphonia, persistent nerve paralysis and paranodular fibrosis, were given larger ethanol doses (PEI Bennedbaek 1999). Iatrogenic thyrotoxicosis and hyperpyrexia were unrelated to PEI dose in one study (PEI Bennedbaek 1999). One participant suffered from permanent facial dysaesthesia and an increased flow of tears still persisting after one year (PEI Bennedbaek 1999). Two participants reported extreme pain lasting for two days (TETRA Hegedüs 1988).

Secondary outcomes
Compliance

This outcome was not investigated in any PEI study.

Tolerability

Most studies characterised the procedure as well tolerated and did not specify use of local anaesthesia. In one study, investigators reported that local anaesthesia was not necessary and no participant refused further ethanol injections (PEI Valcavi 2004). Local anaesthesia was usually applied for solid nodules (PEI Bennedbaek 1998; PEI Bennedbaek 1999).

TSH and T4 serum levels

In most studies, thyroid hormones including thyroid autoantibodies were evaluated at the beginning and throughout the study. Baseline values were always documented. Some studies described thyroid function as not altered with no significant changes in thyroid hormones levels after PEI treatment (PEI Bennedbaek 1999; PEI Verde 1994; TETRA Hegedüs 1988).

Thyroid cancer

This outcome was not investigated in any PEI study.

All-cause mortality

This outcome was not investigated in any PEI study.

Health-related quality of life

This outcome was not investigated in any PEI study.

Socioeconomic effects

This outcome was not investigated in any PEI study.

LP versus no treatment or comparing different LP sessions

Primary outcomes
Pressure symptoms/cosmetic complaints

Considering the three studies comparing LP with no treatment (LP Dossing 2005; LP Gambelunghe 2006; LP Papini 2007), 36 of 44 (82%) laser-treated participants showed improvement/disappearance of initial pressure symptoms after 6 to 12 months of follow-up. No participant in the no-treatment comparator group showed signs of improvement. The RR for improvement/disappearance of pressure symptoms was 26.65 (95% CI 5.47 to 129.72; P < 0.0001; I² = 0%; 92 participants; 3 trials; Analysis 3.1) in favour of LP. We considered there to be a high risk of performance bias and a high or unclear risk of detection bias for this outcome across all three studies. Comparing one with three PL sessions did not reveal statistically significant differences (LP Dossing 2006).

Nodule volume reduction of 50% or more

Three of five studies reported this outcome at end of study: LP Dossing 2006 compared one with three laser treatment sessions showing an overall mean nodule reduction of 45% versus 58% at six months in favour of three sessions (P = 0.03; Analysis 4.1). LP Papini 2007, investigating laser therapy versus LT4 or no treatment after 12 months of follow-up, found that a mean nodule volume decrease of more than 50% was achieved in 7/21 (33%) treated participants versus no participants (0 of 41) in either comparator groups. LP Dossing 2013, comparing laser plus aspiration versus aspiration for mixed thyroid nodules, showed a median nodule volume reduction of 73% versus 26% (P = 0.001; 44 participants) at six months of follow-up. We associated this outcome with a low risk of performance bias across these three studies. We considered one study to have an unclear risk of detection bias (LP Papini 2007).

A decrease in mean nodule volume was also observed in the two remaining studies. In one study comparing LP with no treatment, the overall mean nodule volume reduction was 44% after LP in contrast to a volume increase after no treatment (LP Dossing 2005). In the second study, the median nodule volume decrease was 44% in the LP group versus no volume change in the no-treatment group (LP Gambelunghe 2006).

Adverse events

The study authors described LP therapy as generally well tolerated; for details, see Appendix 16.

Cervical pain

Three studies reported light-to-moderate cervical pain lasting 48 hours or more (Analysis 3.2), only occurring in the LP treatment group: events ranged between 0% (LP Gambelunghe 2006) and 47% (LP Dossing 2005). We associated this outcome with a high risk of performance bias across both studies. We considered two studies to have a high risk of detection bias for this outcome (LP Dossing 2005; LP Gambelunghe 2006). Altogether, 95% (LP Papini 2007) and 38% of LP treated participants (LP Gambelunghe 2006) experienced intraoperative mild burning cervical pain. Some participants (40% to 50%) reported pain lasting up to three days (LP Dossing 2005; LP Dossing 2006; LP Dossing 2013). In addition, 20% to 27% of participants complained of tenderness for up to one week (LP Dossing 2005; LP Dossing 2006; LP Papini 2007). One participant in one study described the LP procedure as extremely painful, whereas in the LT4-comparator group, 38% of participants reported persistent tachycardia or nervousness (LP Papini 2007).

Major adverse effects

No study reported serious adverse effects such as dysphonia, infection, haematoma, bleeding or vocal cord paralysis.

Secondary outcomes
Compliance

This outcome was not investigated in any LP study.

Tolerability

Tolerability was evaluated by asking the participants if they would repeat the treatment according to the degree of pain suffered. According to this definition, all participants in three studies tolerated the treatment well (LP Dossing 2005; LP Dossing 2006; LP Gambelunghe 2006). One participant refused a second LP session, describing the technique as extremely painful (LP Papini 2007).

TSH and T4 serum levels

In most studies, thyroid hormones including thyroid autoantibodies were evaluated at the beginning and throughout the study. Baseline values were always documented. Two studies including 60 participants and comparing LP with no treatment showed no statistically significant changes in thyroid hormone levels at follow-up (LP Dossing 2005; LP Dossing 2006). Another study found that all participants had normal thyroid function at the end of follow-up (LP Gambelunghe 2006). Finally, in one study two participants treated with LP had an increase in antithyroglobulin autoantibodies of more than 70 U/mL at end of study (LP Papini 2007); the other laboratory parameters were within the normal range and TSH was suppressed in the LT4 group only.

Thyroid cancer

This outcome was not investigated in any LP study.

All-cause mortality

This outcome was not investigated in any LP study.

Health-related quality of life

This outcome was not investigated in any LP study.

Socioeconomic effects

Only one trial reported costs (LP Papini 2007). The cost of LP therapy, including equipment, medical team and disposable kits, was about €450 (approximately US$550, September 2012 conversion).

RF ablation therapy versus no treatment or comparing various RF sessions

One study compared RF ablation with PEI therapy (PEI Sung 2013) and is described in the section on PEI above.

Primary outcomes
Pressure symptoms/cosmetic complaints

The two included studies reported a decrease in pressure symptom scores in both groups at the end of follow-up.

One study, comparing one with two RF sessions after six months, showed a decrease in the symptom score of a 10 cm VAS, from 5.4 (standard deviation (SD) 1.7) at baseline to 2.0 (SD 1.3) after one session, and from 5.3 (SD 1.8) at baseline to 2.2 (SD 0.9) after two sessions (P = 0.25; 30 participants) (RF Huh 2012).

Another study comparing RF with no treatment in 40 participants at 12 months (RF Faggiano 2012) showed a decline in the sum of individual scores (ranging from 0 to 6) from 3.4 (SD 1.3) at baseline to 0.6 (SD 0.5), i.e. a 2.8 decrease, in the intervention group compared with an increase from 3.0 (SD 1.3) to 4.1 (SD 0.9), i.e. a 1.1 increase, in the no-treatment group. The difference between the groups was statistically significant at 12 months (P < 0.0001).

We associated this outcome with a high risk of performance bias and an unclear risk of detection bias for both studies.

Nodule volume reduction of 50% or more

RF Huh 2012 described a mean nodule volume reduction of 70% (range 51% to 94%) for one session and a mean reduction of 78% (range 66% to 93%) after two sessions of RF ablation at six months follow-up (8% difference; P = 0.078; 30 participants; Analysis 5.1).

RF Faggiano 2012 reported a mean nodule volume reduction of 76% for one RF session versus no reduction in the no-treatment group at six months follow-up (P < 0.001; 40 participants; Analysis 5.1); nodule volume reduction was 85% at nine months follow-up.

We associated this outcome with a low risk of performance bias and an unclear risk of detection bias for both studies.

Adverse events

The study authors described RF therapy as generally well tolerated; for details, see Appendix 16. All participants complained of pain and discomfort during RF ablation, which disappeared when the energy was reduced or turned off (RF Huh 2012). All participants experienced a mild sensation of heat in the neck without the need to stop the procedure (RF Faggiano 2012). Neither of the two studies reported any serious adverse event. We associated this outcome with a high risk of performance bias and an unclear risk of detection bias for both studies.

Secondary outcomes
Compliance

This outcome was not investigated in any RF study.

Tolerability

This outcome was not investigated in any RF study.

TSH and T4 serum levels

In most studies, thyroid hormones including thyroid autoantibodies were evaluated at the beginning and throughout the study. Baseline values were always documented. Results of laboratory tests were within reference range at the end of the six month follow-up (RF Huh 2012). All participants who were euthyroid in the treatment group had normal function at each follow-up, whereas in the comparator group, TSH serum levels had fallen in two euthyroid participants (subclinical hyperthyroidism) (RF Faggiano 2012). In a subgroup of 10 participants with toxic nodules treated with RF, hyperthyroidism recovered in 40% (demonstrated after methimazole withdrawal) and improved in a further 40% (demonstrated after methimazole reduction); in a subset of eight participants with toxic nodules in the no-treatment group, hyperthyroidism persisted and methimazole therapy was extended for the entire follow-up period(RF Faggiano 2012).

Thyroid cancer

This outcome was not investigated in any RF study.

All-cause mortality

This outcome was not investigated in any RF study.

Health-related quality of life

This outcome was not investigated in any RF study.

Socioeconomic effects

This outcome was not investigated in any RF study.

Reporting bias

Only one outcome (nodule volume reduction of 50% or more) was investigated in 10 included studies of LT4, and hence provided sufficient data for assessing small study effects. Visual inspection of the funnel plot does not indicate reporting bias (Figure 5).

Figure 5.

Funnel plot of comparison: 1 Levothroxine versus comparator, outcome: 1.1 Nodule volume reduction ≥ 50%

Subgroup analyses

Not performed due to lack of data. Future updates of this review might provide adequate data to perform subgroup analyses.

Sensitivity analyses

We were able to perform only one sensitivity analysis with regard to risk of bias. Ten studies investigated the outcome nodule volume reduction of 50% or more and we judged these studies overall to have a low risk of performance bias. We considered two studies to have an unclear risk of detection bias (LT4 Bayani 2012; LT4 Reverter 1992). Exclusion of these studies did not substantially change the effect estimate. Another study we judged to have a high risk of attrition and reporting bias (LT4 Grussendorf 2011). Excluding this study also did not substantially change the effect estimate. Future updates of this review might provide adequate data to perform additional sensitivity analyses.

Ongoing studies

We identified four ongoing RCTs. LP Dossing 2001, a phase 3 open-label study, is investigating one versus two or three LP sessions for the treatment of benign solitary cold thyroid nodules and also LP versus radioiodine for benign solitary autonomous thyroid nodules. LP Pacella 2008, a multicentre phase 4 open-label study, is evaluating the long-term effects of LP versus no active therapy on benign thyroid nodules, reporting re-occurrence rates during three years of follow-up, reproducibility of results in different environments and under different operators, and the presence of major or minor adverse effects. LT4 Shih 2007, a single-centre cross-over open-label study, is investigating the effect of same dose of LT4 taken before and after breakfast. RF Baek 2013, a single-blind comparison of RF versus ethanol ablation, is investigating the effects of treatments in participants with predominantly cystic thyroid nodules. For more details, see the Characteristics of ongoing studies table.

Discussion

Summary of main results

A total of 31 studies randomised 2952 participants to various treatments for benign thyroid nodules; LT4 trials represented the majority of studies (71%). We identified no RCTs of HIFU or MW ablation therapy for benign thyroid nodules. The duration of treatment varied according to the applied therapies: up to five years for LT4, 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. For an overview of the main findings see Summary of findings for the main comparison, Summary of findings 2, Summary of findings 3 and Summary of findings 4.

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, and reported no abnormal cytological findings. One LP study provided limited information on costs of treatment.

All treatments produced a nodule volume reduction of 50% or more in favour of the active intervention; however, the clinical relevance of this finding is doubtful, mainly because of the unclear relationship between nodule growth alone and malignant transformation of the nodule. Pressure symptoms or cosmetic complaints were not investigated in LT4 studies, but showed improvement following PEI, LP or RF treatments. Signs and symptoms of hyperthyroidism in LT4-treated compared with placebo-treated participants at 12 to 18 months of follow-up were 25% versus 7%, respectively. All minimally invasive procedures induced some light-to-moderate pain and discomfort; serious adverse events were rarely reported.

Overall completeness and applicability of evidence

The overall evidence base for the treatment of benign thyroid nodules is rather incomplete, with the majority of trials evaluating the effects of LT4 suppression therapy. Though LT4 often results in a reduction of the volume of thyroid nodules, the effects on pressure symptoms were not investigated in these included studies. Current clinical practice guidelines do not recommend the use of LT4 for benign thyroid nodules (ATA 2009; Gharib 2010); however, clinical guidelines providing guidance for the management of thyroid nodules and cancer differ in methodological quality (Huang 2013).

In the included studies of this systematic review, minimally invasive therapies reduced pressure symptoms and cosmetic complaints, though risk of bias for these findings was high. With regard to ultrasound-guided PEI, approximately 15% to 30% of thyroid nodules are reported to be cystic or predominantly cystic. Cyst aspiration often results in an improvement of pressure symptoms but the recurrence rate may be high. Ethanol seepage outside the treatment area may result in serious adverse events and hinder later surgery due to local fibrosis. However, depending on the availability of treatment alternatives in a given setting, ultrasound-guided PEI is currently seen as the treatment of choice for recurrent, benign cystic thyroid nodules (Gharib 2013). With regard to LP, experienced operators are needed. The precision of this procedure, especially for small thyroid nodules, is high and tissue ablation is well controlled with minimal or no extranodular tissue damage. Currently, only five trials with 192 participants could be included in this systematic review, so the evidence base is rather low. With regard to RF, experienced operators are needed. The evidence base for this procedure is also very low, currently consisting of two included trials with 70 participants. We found no RCTs on HIFU or MW therapy for benign thyroid nodules. Unfortunately, many of our predefined patient-important outcomes, such as health-related quality of life, adverse events and the development of thyroid cancer, were not (adequately) investigated. Therefore, apart from therapies for thyroid nodules causing symptoms, the question of how to best approach asymptomatic thyroid nodules remains unsolved.

Quality of the evidence

The evidence base for outcomes was of low-to-moderate quality. Key methodological limitations were risk of performance and detection bias for subjective outcomes, indirectness, imprecision of results and few trials with few participants per evaluated intervention. The majority of patient-important outcome measures were not addressed in the included trials.

Potential biases in the review process

Although we undertook a comprehensive literature search, there may be relevant unpublished studies or grey literature that we did not find. Outcome reporting bias could be addressed only partly because we had limited access to study protocols. The strength of our 'Risk of bias' evaluation is the separation between subjective and objective outcome measures, which revealed a high risk of performance and detection bias for subjective outcomes. In future updates of this review we plan to search for observational studies because it is likely that the occurrence of thyroid cancer will not be adequately addressed in RCTs. In addition, we will focus on patient-important outcome measures in future updates of this review.

Agreements and disagreements with other studies or reviews

Several previously published systematic reviews evaluating the treatment of thyroid nodules confirm our findings with regard to the effects of LT4 therapy (Castro 2002; Fuller 2014; Richter 2002; Sdano 2005; Yousef 2010; Zelmanovitz 1998).

Zelmanovitz 1998 reported, by means of a cumulative meta-analysis, a nodule volume decrease of 50% or more following LT4 therapy (risk difference 16.7% (95% CI 5.8 to 27.6%) but did not recommend offering this therapy to all individuals with thyroid nodules. The authors hypothesised that in participants experiencing a reduction in thyroid nodule volume, treatment could be prolonged with lower LT4 doses and TSH levels around the lower reference limit.

Castro 2002 analysed six RCTs investigating the effects of LT4 therapy given for six months or more. The overall treatment response (decreasing volume of solitary nodules by more than 50%) did not achieve statistical significance (RR 1.9 (95% CI 0.95 to 3.81)), depending on the statistical model used.

Richter 2002 reported that TSH suppression therapy inhibits solitary thyroid nodule growth and reduces nodule size. However, the authors noted that "uncertainly about predictors of response or impact on outcomes that are important to participants leaves considerable doubt about the wisdom of applying suppressive therapy."

Sdano 2005 confirmed that LT4 therapy may lead to thyroid nodule volume reduction but did not recommend the routine use of this therapy.

Yousef 2010 noted that significant volume reductions in benign solitary thyroid nodules can be achieved and postulated that, especially in younger participants, LT4 suppression could decrease the chance of malignancy through a reduction in nodule volume size.

Finally, Fuller 2014, in a recently published systematic review, analysed the effects of RF for the treatment of benign thyroid nodules. They included three RCTs and six observational trials. The authors noted a reduction in thyroid nodule size and improvements in symptoms and cosmetic scores. Authors were concerned about a lack of RCTs comparing RF with surgical and non-surgical treatment modalities.

In summary, all systematic reviews showed general agreements with our findings. However, none of these other reviews tried to evaluate all the available RCT evidence for all currently existing interventions for benign thyroid nodules.

Authors' conclusions

Implications for practice

It is unclear whether asymptomatic thyroid nodules should be treated because in most cases they are benign, small and can be managed by active surveillance (Gharib 2007). Thyroid nodules are common in the adult population and from a clinical viewpoint, fewer than 5% of palpable thyroid nodules are malignant. Several therapeutic approaches are available, such as suppressive LT4 therapy and minimally invasive treatments (currently PEI sclerotherapy, LP, and MW, RF and HIFU ablation treatment). Although nodule volume reduction is achievable by all these treatments, the clinical relevance of this outcome measure is doubtful and the evidence base is of moderate-to-low quality. Improvements in pressure symptoms and cosmetic complaints are possible using minimally invasive techniques such as PEI, LP and RF; however, the evidence base for these outcomes is of low quality. These techniques are associated with mild-to-moderate periprocedural pain. RCT evidence is currently not available for HIFU and MW. Included studies provided no information on all-cause mortality, health-related quality of life and the development of thyroid cancer. No firm evidence therefore exists to establish the optimal treatment strategy for thyroid nodules, with the possible exception of minimally invasive techniques utilised for thyroid nodules causing pressure symptoms, cosmetic complaints, or both, especially as an alternative to surgery and depending on the availability of experienced operators.

Implications for research

RCTs with several years of follow-up and good-quality observational studies are needed to provide evidence on all-cause mortality, the development of thyroid cancer and long-term adverse events profiles. One ongoing trial might provide additional insights into the long-term benefits and harms of LP compared with no treatment on benign thyroid nodules (LP Pacella 2008). Patient-important outcome measures, such as health-related quality of life, adverse effects, compliance and tolerance, and socioeconomic effects should be primary endpoints in future trials of thyroid nodule management.

Acknowledgements

None.

Data and analyses

Download statistical data

Comparison 1. Levothyroxine versus control (no treatment, placebo)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Nodule volume reduction ≥ 50%10958Risk Ratio (M-H, Random, 95% CI)1.57 [1.04, 2.38]
2 Adverse events: participants without signs of hyperthyroidism3 Risk Ratio (M-H, Random, 95% CI)Totals not selected
3 Adverse events: participants without a nodule volume increase > 50%3551Risk Ratio (M-H, Random, 95% CI)1.10 [0.99, 1.22]
4 Thyrotropin (TSH) (end of study values)8 Mean Difference (IV, Random, 95% CI)Totals not selected
5 Total thyroxine (T4) (end of study values)5296Mean Difference (IV, Random, 95% CI)48.28 [35.12, 61.43]
Analysis 1.1.

Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 1 Nodule volume reduction ≥ 50%.

Analysis 1.2.

Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 2 Adverse events: participants without signs of hyperthyroidism.

Analysis 1.3.

Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 3 Adverse events: participants without a nodule volume increase > 50%.

Analysis 1.4.

Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 4 Thyrotropin (TSH) (end of study values).

Analysis 1.5.

Comparison 1 Levothyroxine versus control (no treatment, placebo), Outcome 5 Total thyroxine (T4) (end of study values).

Comparison 2. Percutaneous ethanol instillation versus control (cyst aspiration, isotonic saline, levothyroxine, radiofrequency ablation)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement of pressure symptoms (end of study)3 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2 Nodule volume reduction ≥ 50%5197Risk Ratio (M-H, Random, 95% CI)2.58 [0.56, 11.90]
2.1 PEI vs cyst aspiration3105Risk Ratio (M-H, Random, 95% CI)1.83 [1.32, 2.54]
2.2 PEI vs LT4150Risk Ratio (M-H, Random, 95% CI)39.00 [2.48, 612.50]
2.3 PEI vs RF142Risk Ratio (M-H, Random, 95% CI)1.0 [0.91, 1.09]
3 Adverse events: slight to moderate pain3104Risk Ratio (M-H, Random, 95% CI)1.78 [0.62, 5.12]
Analysis 2.1.

Comparison 2 Percutaneous ethanol instillation versus control (cyst aspiration, isotonic saline, levothyroxine, radiofrequency ablation), Outcome 1 Improvement of pressure symptoms (end of study).

Analysis 2.2.

Comparison 2 Percutaneous ethanol instillation versus control (cyst aspiration, isotonic saline, levothyroxine, radiofrequency ablation), Outcome 2 Nodule volume reduction ≥ 50%.

Analysis 2.3.

Comparison 2 Percutaneous ethanol instillation versus control (cyst aspiration, isotonic saline, levothyroxine, radiofrequency ablation), Outcome 3 Adverse events: slight to moderate pain.

Comparison 3. Laser photocoagulation versus no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement/disappearance of pressure symptoms (end of study)392Risk Ratio (M-H, Random, 95% CI)26.65 [5.47, 129.72]
2 Adverse events: light to moderate cervical pain (≥ 48 hours)3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
Analysis 3.1.

Comparison 3 Laser photocoagulation versus no treatment, Outcome 1 Improvement/disappearance of pressure symptoms (end of study).

Analysis 3.2.

Comparison 3 Laser photocoagulation versus no treatment, Outcome 2 Adverse events: light to moderate cervical pain (≥ 48 hours).

Comparison 4. Laser photocoagulation comparing various LP sessions
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Nodule volume reduction (baseline to end of follow-up)  Other dataNo numeric data

Analysis 4.1.

Comparison 4 Laser photocoagulation comparing various LP sessions, Outcome 1 Nodule volume reduction (baseline to end of follow-up).

Nodule volume reduction (baseline to end of follow-up)
StudyComparator groups
[N participants]
Baseline, mean thyroid nodule volume
[ml (SD)]
End of follow-up (6 months)
[ml (SD)]
Mean difference between groups
LP Dossing 2006

Intervention: 1 session (15)

Comparator: 3 sessions (15)

Intervention: 10.1 (4.3)

Comparator: 10.7 (9.0)

Intervention: 5.7 (3.2)

Comparator: 4.6 (3.0)

Intervention: -45%

Comparator: -58%

Difference: 13% (P = 0.03)

Comparison 5. Radiofrequency versus no treatment or comparing various RF sessions
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Nodule volume reduction (baseline to end of follow-up)  Other dataNo numeric data

Analysis 5.1.

Comparison 5 Radiofrequency versus no treatment or comparing various RF sessions, Outcome 1 Nodule volume reduction (baseline to end of follow-up).

Nodule volume reduction (baseline to end of follow-up)
StudyComparator groups
[N participants]
Mean thyroid nodule volume at baseline
[mL, SD]
Mean thyroid nodule volume at 6 month
[mL, SD]
Mean volume reduction
[% (SD)]
Statistical significance
RF Faggiano 2012Intervention: 1 session (20)13.3 (8)3.2 (2.7)76 (12)P < 0.001
RF Faggiano 2012Comparator: no treatment (20)11.2 (6.7)11.4 (6.7)  
RF Huh 2012Intervention: 1 session (15)13.3 (12.9)3.8 (4.4)70 (13.2)P = 0.078
RF Huh 2012Comparator: 2 sessions (15)13.0 (6.8)3.0 (2.2)78 (7.8) 

Appendices

Appendix 1. Search strategies

Search terms and databases

Unless otherwise stated, search terms are free text terms.

Abbreviations:

'$': stands for any character; '?': substitutes one or no character; adj: adjacent (i.e. number of words within range of search term); exp: exploded MeSH; MeSH: medical subject heading (MEDLINE medical index term); pt: publication type; sh: MeSH; tw: text word.

The Cochrane Library

#1      MeSH descriptor Thyroid nodule explode all trees

#2      MeSH descriptor Goiter, nodular explode all trees

#3      (thyroi* in All Text near/6 nod*in All Text)

#4      (thyroi* in All Text near/6 incidentalom*in All Text)

#5      (thyroi* in All Text near/6 goiteri n All Text)

#6      (#1 or #2 or #3 or #4 or #5)

MEDLINE

1     exp Thyroid Nodule/

2     exp Goiter, Nodular/

3     (thyroi* adj6 (nod* or incidentalom* or goiter)).tw,ot.

4     1 or 3 or 2

5     randomized controlled trial.pt.

6     controlled clinical trial.pt.

7     randomi?ed.ab.

8     placebo.ab.

9     drug therapy.fs.

10     randomly.ab.

11     trial.ab.

12     groups.ab.

13     5 or 6 or 7 or 8 or 9 or 10 or 11 or 12

14     exp Technology Assessment, Biomedical/

15     hta.tw,ot.

16     (health technology adj6 assessment$).tw,ot.

17     (search or Cochrane or MEDLINE or EMBASE).tw.

18     (systematic adj3 review).tw.

19     meta-analysis.pt.

20     or/14-19

21     (comment or editorial or historical-article).pt.

22     20 not 21

23     4 and (13 or 22)

24     limit 23 to yr="2009 - 2011"

25     (animals not (animals and humans)).sh.

26     24 not 25

EMBASE

1     exp thyroid nodule/

2     exp nodular goiter/

3     (thyroi* adj6 (nod* or incidentalom* or goiter)).tw,ot.

4     1 or 2 or 3

5     randomized controlled trial/

6     exp controlled clinical trial/

7     randomi?ed.ab.

8     placebo.ab.

9     randomly.ab.

10     trial.ab.

11     groups.ab.

12     5 or 6 or 7 or 8 or 9 or 10 or 11

13     exp biomedical technology assessment/

14     hta.tw,ot.

15     (health technology adj6 assessment*).tw,ot.

16     (search or Cochrane or Medline or Embase).tw,ot.

17     (systematic adj3 review).tw.

18     meta analysis/

19     13 or 14 or 15 or 16 or 17 or 18

20     12 or 19

21     (comment or editorial or historical-article).pt.

22     20 not 21

23     4 and 22

24     limit 23 to yr="2009 - 2011"

25     limit 24 to human

LILACS
Descriptor: thyroid AND nodule$
'My NCBI' alert service
thyroid nodul* AND random (thyroid* AND nodul*) OR (nodul* AND goiter*)
Web of Science
TS=(thyroid nodul*) AND TS=(random*)

Appendix 2. Description of interventions

 Intervention(s)
[route, frequency, total dose/day]
Comparator(s)
[route, frequency, total dose/day]
Levothyroxine treatment
LT4 Bayani 2012LT4: initial dose 50 µg/day (dose adaptation to archive TSH levels < 0.5 mU/L)No treatment
LT4 Boguszewski 1998LT4: participants < 70 kg: 200 μg/day (2 tablets); participants > 70 kg: 250 μg (2 and 3 tablets on alternate days)Placebo
LT4 Cesareo 2010LT4: 2 μg/kg/dayNo treatment
LT4 Gharib 1987  LT4: 3 μg/kg/dayPlacebo
LT4 Grineva 2003LT4: 75 to 150 μg/day, dose adjusted until TSH ≤ 0.5 mU/LPotassium iodide 200 μg/day
LT4 Grussendorf 2011LT4 (75 μg/day; dose adjusted based on TSH between 0.2 to 0.8 mU/L) + potassium iodide (150 μg/day)

Comparator 1: LT4: 75 μg/day (dose adjusted based on TSH between 0.2 to 0.8 mU/L)

Comparator 2: potassium iodide 150 μg/day

Comparator 3: placebo

LT4 Koc 2002Intervention 1: LT4 (group 2; TSH high-level suppression: < 0.01 mU/L; LT4 3 μg/kg/day)
Intervention 2: LT4 (group 4; TSH low-level suppression: 0.4 to 0.6 mU/L; LT4: 1.5 μg/kg/day)

Comparator 1: placebo (group 1)

Comparator 2: placebo (group 3)

LT4 La Rosa 1995

Intervention 1: LT4 1 μg/kg/day oral (1 dose) up 1.8 μg/kg/day oral after 15 days; dose adjusted until TSH < 0.3 mU/L (first 4 months); mean 1.94 (0.16) μg/kg/day

Intervention 2: potassium iodide 1.5 mg every 2 weeks

No treatment
LT4 Larijani 2005LT4: 1.5 to 2 μg/kg/dayPlacebo
LT4 Ozkaya 2010LT4: 50 to 100 mg/dayNo treatment
LT4 Papini 1993LT4: 2 μg/kg/day (initial dose: 50 μg before breakfast and increased by 25 to 50 μg/week to the full dose)Placebo
LT4 Papini 1998LT4: 2 μg/kg/dayNo treatment
LT4 Reverter 1992LT4: 100 μg/day for 2 weeks, then 200 μgNo treatment
LT4 Tsai 2006LT4: 100 μg/dayPlacebo
LT4 Wemeau 2002  LT4: 2.5 μg/kg/day, one dose in the morning, adjusted after the first 4 weeks until TSH < 0.3 mU/LPlacebo
LT4 Zelmanovitz 1998LT4: 2.5 to 3.0 μg/kg/day for 1.5 months; dose adjusted until TSH < 0.3 μU/mL or TSH (after TRH stimulation) < 2 μU/mL; mean dose: 2.73 ± 0.32 μg/kg/dayPlacebo
Percutaneous sclerotherapy
PEI Bennedbaek 1998PEI (98% ethanol): 1 intranodular injection under US control; median ethanol dose given 21% (95% CI 18 to 25) of the pretreatment nodule volumeLT4: 1.5 µg/kg/day until 12 months (dose adjusted monthly until 6 months to lower serum TSH to < 0.40 mU/L) 
PEI Bennedbaek 1999

1 injection

PEI (98% ethanol): 1 intranodular injection (US control); median ethanol dose given: 2.4 ± 1.4 mL; total amount: 2.4 ± 1.4 mL, corresponding to 24.7% ± 7.5% of pretreatment volume

3 injections

PEI (98% ethanol): 3 intranodular injections/week (1 injection/session), under US control; median ethanol dose given (SD):
session 1: 1.8 mL ± 1.1 mL
session 2: 1.5 ± 0.9 mL
session 3: 1.4 ± 0.8 mL; total amount: 4.4 ± 2.5 mL corresponding to 47.9% ± 21.3% of pretreatment volume

PEI Bennedbaek 2003PEI (99% ethanol): 1 session (in case of recurrence, repetition after 1 month to a maximum of 3 treatments) (US control); median ethanol dose given: 3.5 mL (quartiles 2 to 5) corresponding to 36% of the cyst volumeNaCl: 1 session (in case of recurrence, repetition after 1 month to a maximum of 3 treatments) (under US control); median NaCl dose given: 3.0 mL (quartiles 2 to 5), corresponding to 36% of the cyst volume
PEI Chu 2003PEI (95% ethanol): weekly until curea; percutaneous ethanol injected: 10% of the aspirated volume with a maximum of 2 mLComparator 1: percutaneous hydrochloric acid (pH 1.0) weekly until curea ; percutaneous hydrochloric acid injected: 10% of the aspirated volume with a maximum of 2 mL
Comparator 2: cyst aspiration
PEI Sung 2013PEI (99% ethanol): percutaneous ethanol injected: usually 50% of the aspirated volume, 10 minutes of ethanol retentionRF ablation: 18-gauge with 1 cm or 1.5 cm active-tip internally cooled electrode; aspiration of internal fluid ablation; ablation power from 50W/15 W (1 cm /0.5 cm active tip) and increased in 5- to 10-W increments up to 70 W
TETRA Hegedüs 19982 mL of tetracycline hydrochloride (50 mg/mL) + re-aspiration 3 to 4 times (under US control) in one session (if no recurrence)2 mL of NaCl + re-aspiration 3 to 4 times (under US control) in one session (if no recurrence)
PEI Valcavi 2004PEI (95% ethanol): US-guided, 1 session (2 to 3, if fluid content > 2 mL); amount ethanol injected: 50% to 70% of the cystic fluid extractedCyst aspiration only
PEI Verde 1994PEI (95% ethanol): US guided; amount injected: between 1 to 10 mL, based on volume aspirated + alcohol distributionCyst aspiration only (US guided)
Laser photocoagulation
LPDossing 20051 session with median total energy deposition: 2007 J (quartiles 1750 to 2880); median energy given per mL of the pretreatment nodule volume 224 J (quartiles 182 to 331)No treatment
LPDossing 2006

1 session

Mean total energy deposition: 2284 ± 1160 J (duration: mean 744 ± 211 sec); mean total energy/mL of the pretreatment nodule volume given was 262 ± 205 J

3 sessions

3 sessions in one month; mean total energy deposition: 4133 ± 1709 J (duration: mean 1539 ± 599 seconds)

1st session: mean energy deposition 1683 ± 448 J

2nd session: mean energy deposition 1420 ± 720 J

3rd session mean energy deposition 1512 ± 555 J

LPGambelunghe 20061 session with single 21-gauge spinal needle (US guided) placed in the centre of the dominant nodule; laser 300-µm quartz fibre inserted into the lumen of the needle; total median energy given 1900 J (700 to 2200); at each step: energy given (100 to 400 J) based on the hyperechoic area produced by photocoagulationNo treatment
LPPapini 20071 session with two 75 mm, 21-gauge spinal needles inserted into the thyroid lesions (US monitoring; 4 needles and 2 illuminations, if volume > 20 mL); laser 300-µm quartz fibre inserted into the lumen of the needle; laser energy output power 3 W and 10 minutes for illumination; total energy for entire session 3600 to 14400 J; total energy given/fibre/treatment 1800 J; mean energy given/mL was 1221 ± 679 J, median 1054 J/mL

Comparator 1: LT4: 1,5 μg/kg oral (LT4 dose ↑, if TSH > 0.30 μU/mL; LT4 dose ↓, if TSH undetectable with FT3 increase, persistent nervousness, tremor, or tachycardia)

Comparator 2: no treatment

LP Dossing 2013Cyst aspiration session with an 18-gauge needle (US-guided) placed in the cystic part of the nodule; laser fibre inserted in the lumen of this steering needle; total median energy given 1272 J (quartiles 990 to 1500), corresponding to 83 J (quartiles 49; 224)/mL of nodule tissueCyst aspiration only
Radiofrequency ablation
RF Faggiano 20121 session with StarBurst® Talon with 14-gauge and 10-cm long needle with four expandable hooks; these opened to maximal 3.5 cm with exposure time between 5 and 7 minutes and temperature reached between 100°C and 105°CNo treatment
RFHuh 2012

1 session

18-gauge with 1-cm or 1.5-cm active-tip internally cooled electrode; trans-isthmic approach (electrode placed along the short axis of the nodule); TN divided into multiple ablation units: unit-by-unit ablation by moving the electrode (moving shot technique); ablation power from 30 to 50 W up to 120 W in 10-W increases, if transient hyperechoic zone did not form within 5 to 10 seconds; mean total energy deposition: 51,930 ± 47,080 J; energy/mL of pretreatment volume: 4377.3 ± 2199.5 J

2 sessions

1st session: mean energy deposition 38,740 ± 15,454 J

2nd session: mean energy deposition: 30,420 ± 16,057 J

Mean total energy deposition: 69,160 ± 27,808 J; energy/mL of pretreatment volume: 6156.7 ± 2661.3 J

aCure: nodule disappearance or volume reduction < 0.5 mL, maximum 5 sessions

±: single standard deviation; CI: confidence interval; FT3: free tri-iodothyronine; LP: laser photocoagulation; LT4: levothyroxine; NaCl: isotonic saline; PEI: percutaneous ethanol injection; RF: radiofrequency ablation; SD: standard deviation; TN: thyroid nodule; TRH: thyrotropin-releasing hormone; TSH: thyrotropin; US: ultrasound

Appendix 3. Baseline characteristics (levothyroxine treatment I)

  Intervention(s) and comparator(s)

Participating population

 

Sex [female %] Age
[mean years
(SD)/(range)]
Nodule volume at baseline
[mL (SD)/median (95% CI, range)]
US characteristics and/or nodule cytologya
LT4 Bayani 2012

I: LT4

C: no treatment

Euthyroid participants with a single palpable thyroid nodule

I: 85

C: 85

I: 41.6 (9.4)

C: 44.5 (10.9)

I: longitudinal dimension 1.9 cm (1.1); transverse dimension 1.4 cm (0.9)

C: longitudinal dimension 2.2 cm (1.3); transverse dimension 1.6 cm (1)

-
LT4 Boguszewski 1998

I: LT4

C: PLAC

Euthyroid participants with a single palpable thyroid nodule

I: 100

C: 91

I: 41 (9)

C: 40 (9)

I: 14.1 (12.3) 

C:12.7 (12.1)

Solid (> 50%), colloid goitre
LT4 Cesareo 2010

I: LT4

C: no treatment

Euthyroid premenopausal women from Latin America with thyroid multinodular disease (2 to 5 nodules)

I: 100

C: 100

I: 37.2 (10.3)

C: 34.0 (9.1)

 I: 1.8 (2.1)

C: 1.2 (0.9)

Solid (≤ 30% fluid), colloid
LT4 Gharib 1987  

I: LT4

C: PLAC

Participants with a single

palpable thyroid nodule proved to be benign by FNAB

I: 93

C: 88

I: 42.0 (15)

C: 48.2 (17)

 I: 3.0 (2.6)

C: 2.6 (1.7)

Solid, cyst (mixed), colloid
LT4 Grineva 2003

I: LT4

C: PLAC

Participants with benign nodular thyroid lesions (colloid or colloid hypercellular by FNAB; cold or warm by scintigraphy)

I: 97

C: 97

I: 46 (1.4)

C: 45.5 (1.5)

-Colloid
LT4 Grussendorf 2011

I1: LT4 + PI

C1: LT4

C2: PI

C3: PLAC

Euthyroid participants with a nodular goitre, in a region with sufficient iodine supply

I: 68

C1: 71

C2: 72

C3: 74 

I1: 47.4 (46.1 to 48.8)
C1: 47.1 (45.7 to 48.5)
C2: 47 (45.6 to 48.4)
C3: 46.1 (44.6 to 47.5)

I: 2 (1.7 to 2.3)

C1: 1.7 (1.4 to 1.9)

C2: 1.5 (1.3 to 1.7)

C3: 1.7 (1.5 to 2)

Solid (< 20% fluid), mixed
LT4 Koc 2002

I1: LT4: 3 μg/kg/day

I2: LT4: 1.5 μg/kg/day

C1: PLAC high-dose

C2: PLAC low-dose

Euthyroid participants with nodular thyroid disease (solitary TN on palpation)

I1: 91

I2: 90

C1: 100

C2: 90

I1: 40.2 (9.7)

I2: 47.9 (16.6)

C1: 38 (8.3)

C2: 47.7 (19.4)

I1: 3.7 (5.9)

I2: 3.4 (4.4)

C1: 4.2 (3.8)

C2: 3.6 (2.8)

Solid 
LT4 La Rosa 1995

I1: LT4

I2: PI

C: no treatment

Euthyroid participants with a solitary TN

I1: 93

I2: 96

C: 100

I1: 35.7 (11.6)

I2: 38 (10.3)

C: 41 (12.9)

I1: 5.9 (5.7)

I2: 5.0 (6.1)

C: 5.7 (5.8)

Solid (< 10% fluid),

parenchymatous, colloid

LT4 Larijani 2005

I: LT4

C: PLAC

Participants with one palpable benign TN (FNAB, cytology); endemic goitre area)

I: 81

C: 74

I: 34.4 (9.4)

C: 37.1 (11.8)

I: 12.8 (11.9)

C: 13.0 (10.2)

Solid
LT4 Ozkaya 2010

I: LT4

C: no treatment

Euthyroid participants with benign TN (FNAB, cytology)

I: -

C: -

I:b

C:b

I: 0.8

C:  0.4

Solid
LT4 Papini 1993

I: LT4

C: PLAC

Euthyroid participants with a single, palpable TN (non-endemic area)

I: 90

C: 88

I: 43 (10)

C: 42 (11)

I: 6.20 (8.9)

C: 6.25 (7.41)

Solid (< 1 mL fluid), colloid
LT4 Papini 1998

I: LT4

C: no treatment

Participants with one palpable TN (non-endemic area)

I: 88

C: 78

I: 41.4

C: 41.9

I: 1.5

C: 1.5

Solid, colloid 
LT4 Reverter 1992

I: LT4

C: no treatment

Euthyroid women with solitary TN on palpation, cold and single by thyroid scanning and benign by FNAB (colloid goitre)

I: 100

C: 100

I: 40.1 (8.2)

C: 39.5 (12.8)

I: 10.3 (11.9)

C: 9.2 (6.4)

Solid, mixed, colloid goitre
LT4 Tsai 2006

I: LT4

C: PLAC

Euthyroid participants with solitary TN (US), benign (FNAB cytology)

I: 60

C: 67

I: 32 (7.2)

C: 34 (10.1)

I: 7.2 (5.1)

C: 7.3 (4.8)

Solid 
LT4 Wemeau 2002  

I: LT4

C: PLAC

Euthyroid participants (area thought to have a sufficient iodine supply) with a single palpable benign TN

I: 91

C: 90

I: 40.0 (9.0)

C: 38.2 (9.2)

I: 2.8 (2.5)

C: 3.5 (3)

Solid (≤ 20% fluid) 
LT4 Zelmanovitz 1998

I: LT4

C: PLAC

Euthyroid participants with a single TN

I: 90

C1: 96

I: 44.8 (10.3)

C: 41.3 (13.1)

I: 16.4 (18.7)

C: 13.6 (13.9)

Solid (≤ 20% fluid), colloid goitre

"-" denotes not reported

Numbers in italic were calculated by review authors

aAll TN were benign by FNAB cytology
bNo statistical significant differences between I and C for age (P value = 0.11), BMI (P value = 0.17) and time from diagnosis (P value = 0.06)

BMI: body mass index; C: comparator; CI: confidence interval; FNAB: fine needle aspiration biopsy; I: intervention; LT4: levothyroxine; PI: potassium iodine; PLAC: placebo; SD: standard deviation; TN: thyroid nodule(s); US: ultrasonography

Appendix 4. Baseline characteristics (levothyroxine treatment II)

  Intervention(s) and comparator(s) Country Duration of disease/
months from diagnosis [mean/median (SD)]
Duration of intervention Duration of follow up
(n= number of participants)
Comorbidities Comedications
LT4 Bayani 2012

I: LT4

C: no treatment

Iran-6 mo6 moNo serious cardiovascular, hepatic or renal disease-
LT4 Boguszewski 1998

I: LT4

C: PLAC

Brazil

I: 66 (62)

C: 52 (71)

12 mo12 mo--
LT4 Cesareo 2010

I: LT4

C: no treatment

Italy-12 mo

12 mo
(n = 71)

24 mo
(n = 41)

--
LT4 Gharib 1987  

I: LT4

C: PLAC

USA

I: 2

C: 1

6 mo6 mo--
LT4 Grineva 2003

I: LT4

C: PLAC

Russia

I: 6.2 (1.0)

C: 6.9 (1.2)

6 mo6 mo-
LT4 Grussendorf 2011a

I1: LT4 + PI

C1: LT4

C2: PI

C3: PLAC

Germany-12 mo12 mo

 I1: 63%

C1: 62%

C2: 70%

C3: 60%

-
LT4 Koc 2002

I1: LT4: 3 μg/kg/day

I2: LT4: 1.5 μg/kg/day

C1: PLAC high-dose

C2: PLAC low-dose

Turkey-12 mo24 mo--
LT4 La Rosa 1995

I1: LT4

I2: PI

C: no treatment

Italy-12 mo

I: 12 mo + 4 mo

C: 12 + 12 mo
(received LT4 after 1 yr)

No major concomitant disease-
LT4 Larijani 2005

I: LT4

C: PLAC

Iran-24 mo24 mo--
LT4 Ozkaya 2010

I: LT4

C: no treatment

Turkey-12 mo12 moNo cardiovascular-, liver- or renal diseaseNo LT4 suppressive therapy;
no other thyroid medication
LT4 Papini 1993

I: LT4

C: PLAC

Italy

I: 9.8 (7.1)

C: 9.3 (6.2)

12 mo12 mo

Absence of clinically

relevant cardiovascular, hepatic, pulmonary

or renal diseases

-
LT4 Papini 1998

I: LT4

C: no treatment

Italy-5 yr5 yr-
LT4 Reverter 1992

I: LT4

C: no treatment

Spain-11 mo

Ib: 6 to 12 mo

C: 12 mo

-
LT4 Tsai 2006

I: LT4

C: PLAC

Taiwan

I: 6.2 (3.5)

C: 6.4 (4.1)

6 mo6 mo
LT4 Wemeau 2002  

I: LT4

C: PLAC

France< 1218 mo18 moNone
LT4 Zelmanovitz 1998

I: LT4

C: PLAC

Brazil

I: 65 (84)

C: 44 (60)

12 mo12 mo--

"-" denotes not reported

aAllowed and not allowed comedications were described and reviewed periodically; no information available about how many participants received comedications

bn = 6 participants dropped out or abandoned the study at different times of follow up

C: comparator; I: intervention; LT4: levothyroxine; mo: months; PI: potassium iodide; PLAC: placebo; SD: standard deviation; yr: year(s)

Appendix 5. Baseline characteristics (minimally invasive treatments I)

  Intervention(s) and comparator(s) Participants Sex
[female%]
Age
[mean/median years
(SD)/range/quartiles]
Months from diagnosis
[mean (SD) or median (quartiles)]
Nodule volume
[mean/median mL (SD)/95% CI, range)/quartiles]
US characteristics and/or nodule histology
PEI Bennedbaek 1998

I: PEI

C: LT4

Participants who were 20 to 70 yr of age with a benign solitary solid cold palpable thyroid nodule causing local discomfort

I: 88

C: 96

Ia: 46 (41; 52)

Ca: 41 (37; 45)

Ia: 9 (7; 17)

Ca: 8 (6; 12)

I: 9.2 (7.2; 11.6)

C: 7.1 (4.9; 10.8)

Solid, colloid
PEI Bennedbaek 1999

I: PEI (1 dose)

C: PEI (3 doses)

Participants who were 20 to 70 yr of age with a palpable and clinically solitary thyroid nodule
causing local discomfort

I: 97

C: 100

I: 42.6 (10.6)

C: 42.7 (10.0)

I: 21.2 (28.3)

C: 15.2 (15.2)

I: 9.9 (5.7)

C: 9.4 (4.2)

Solid (< 10% fluid), colloid
PEI Bennedbaek 2003

I: PEI

C: NaCl

Participants who were 20 to 70 yr of age with a benign, solitary cold, palpable thyroid nodule causing local discomfort and/or cosmetic complaints

I: 88

C: 79

I: 48
(33 to 57) 

C: 46 (40 to 53)

Ib: 9 (4;12)

Cb: 7 (4;13)

I: 8 (5; 14)

C: 8 (4; 15)

Cystic > 90%, colloid
PEI Chu 2003

I1: PEI

C1: PHI

C2: ASP

Participants aged 24 to 70 yr with thyroid cystic nodules

I1: 60

C1: 50

C2: 44

I1: 50.4 (12.6)

C1: 56.1 (11.9)

C2: 57.2 (11.8)

-

I: 17.3 (11.4)

C1: 13 (9.7)

C2: 19 (13.7)

Cystic ≥ 90%, benign by US-FNAB
PEI Sung 2013

I: PEI

C: RF

Euthyroid participants with thyroid cystic nodules

I: 92

C: 88

I: 45 (10.9)

C: 44.9 (10.6)

-

I: 12.2 (11.0)

C: 9.3 (11.7)

Cystic > 90%, benign by US-FNAB
TETRA Hegedüs 1998

I: TETRA

C: NaCl

Euthyroid participants with a solitary nodule cyst of at least 2 mL and absence of any residual nodule following complete cyst aspiration

I: 83

C: 60

--

I: 10 (2; 45)

C:  8 (2; 50)

Cystic > 2 mL, benign by US-FNAB
PEI Valcavi 2004

I: PEI

C: ASP

Participants with benign thyroid cystic nodulesT: 79Tc: 18 - 85-

I: 19 (19)

C:  20 (13.4)

Cystic ≥ 50%, benign by US-FNAB
PEI Verde 1994

I: PEI (group 2)

C: ASP (group 1)

Euthyroid participants with predominantly
cystic thyroid nodules
T: 65T: 47.3 (9.8)-

 I: 16.6 (10.5; 52.4)

C: 25.8 (12.3; 50.3)

Cystic > 70%, benign by US-FNAB
LPDossing 2005

I: LP

C: no treatment

Euthyroid participants with a solid, solitary, cold, benign thyroid nodule causing discomfort

I: 100

C: 100

Ib: 47 (43; 52)

C1b: 46 (41; 51)

I1b: 6 (3; 12)

C1b: 6 (3; 7.5)

I: 8.2 (6.1; 11.9)

C:  7.4 (5.1; 13.8)

Solid, colloid, benign by US-FNAB
LPDossing 2006

I: LP (1 session)

C: LP (3 sessions)

Euthyroid participants, with a solid, solitary, cold, benign thyroid nodule causing pressure symptoms

I: 93

C: 100

I: 46 (7)

C: 45 (12)

I: 8 (5)

C: 10 (9)

I: 10.1 (4.4)

C: 10.7 (9.0)

Solid, colloid, benign by US-FNAB
LP Dossing 2013

I: ASP + LP

C: ASP

Euthyroid participants with a recurrent solitary predominantly cystic cold thyroid nodule causing discomfort

I: 77

C: 59

Ib: 49 (39; 56)

Cb: 49 (40; 56)

Ib: 12 (6; 18)

Cb: 7.5 (5; 12)

Ib: 11.8 (5.8; 26.8)

Cb: 10 (5.6; 22)

Solid-cystic, colloid, benign by US-FNAB
LPGambelunghe 2006

I: LP

C: no treatment

Participants with compressive symptoms due to multinodular goitre and a high surgical risk T: 81

I: 63
(52; 92)

C: 70 (62; 81)

-

I: 8.2 (2.8; 26.9)

C: 8.1 (7; 12)

Solid, mixed, benign by US-FNAB
LPPapini 2007

I1: LP

C1: LT4

C2: no treatment

Euthyroid participants with a cold thyroid nodule

I1: 86

C1: 90

C2: 90

I1: 44.9 (SD? 5.1)

C1: 46.5 (SD? 8.2)

C2: 47.1 (SD? 7.7)

-

I: 11.7 (5.1)

C1: 13.6 (6.3)

C2: 12.1 (3.9)

Solid (< 20% fluid), benign by US-FNAB
RF Faggiano 2012

I: RF

C: no treatment

Participants with benign, solid or predominantly solid, toxic and nontoxic thyroid nodules causing pressure symptoms

I: 80

C: 75

I: 58.3 (19.2)

C: 62.1 (13.9)

-

I: 13.3 (8.1)

C: 11.2 (6.71)

Solid, cystic < 30%, benign by US-FNAB
RFHuh 2012

I: RF (1 session)

C: RF (2 sessions)

Euthyroid participants refusing or ineligible for surgery with predominant solid, cold, benign thyroid nodules causing compressive symptoms

I: 87

C: 100

I: 37.5 (11.5)

C: 37.7 (9.8)

-

I: 13.3 (12.9)

C: 13 (6.8)

Solid portion > 50%, benign by US-FNAB

"-" denotes not reported

Numbers in italic were calculated by review authors

aValues are medians (95% CI)

bValues are medians (with 25th and 75th centiles/quartiles)
cRange (yr)

ASP: aspiration; C: comparator; CI: confidence intervals; FNAB: fine-needle aspiration biopsy; I: intervention; LP: laser photocoagulation; LT4: levothyroxine; NaCl: isotonic saline; PEI: percutaneous ethanol injection; PHI: percutaneous hydrochloric acid injection; RF: radiofrequency ablation; SD: standard deviation; SD?: unclear whether SD was correctly reported; T: total; TETRA: tetracycline hydrochloride; US: ultrasonography; yr: year(s)

Appendix 6. Baseline characteristics (minimally invasive treatments II)

  Intervention(s) and comparator(s) Country Duration of intervention Duration of follow up Comorbidities Comedications
PEI Bennedbaek 1998

I: PEI

C: LT4

Denmark

I: 1 session

C: until 12 mo

12 moNo major concomitant diseaseNo medication affecting thyroid function
PEI Bennedbaek 1999

I: PEI (1 dose)

C: PEI (3 doses)

Denmark

I: 1 session (1 single injection)

C: 3 sessions/wk (1 single injection/session)

6 moNo major concomitant diseaseNo medication affecting thyroid function
PEI Bennedbaek 2003

I: PEI

C: NaCl

Denmark 1 session (+ 1 session after 4 wk up to max. 3 sessions: 12 wk)6 moNo major concomitant diseaseNo medication affecting thyroid function
PEI Chu 2003

I1: PEI

C1: PHI

C2: ASP

TaiwanI: 1x/wk until cure (maximum 5 wk)12 mo-None
PEI Sung 2013

I: PEI

C: RF

Korea

PEI: 1 session

RF: 1 session

6 mo-No medication or treatment for thyroid nodules
TETRA Hegedüs 1998

I: TETRA

C: NaCl

DenmarkAt least one session

12 mo

after cyst puncture

--
PEI Valcavi 2004

I: PEI

C: ASP

Italy1 session (2 to 3, if fluid content > 2 mL)12 mo
PEI Verde 1994

I: PEI (group 2)

C: ASP (group 1)

Italy1 session1 mo
LPDossing 2005

I: LP

C: no treatment

Denmark1 session6 mo
LPDossing 2006

I: LP (1 session)

C: LP (3 sessions)

Denmark1 session vs 3 sessions (in 1 mo)6 mo
LP Dossing 2013

I: ASP + LP

C: ASP

Denmark1 session6 mo--
LPGambelunghe 2006

I: LP

C: no treatment

Italy

1 session (for wide nodules the procedure

was repeated)

30 wk
LPPapini 2007

I1: LP

C1: LT4

C2: no treatment

Italy

LP: 1 session

LT4 treatment: 12 mo

12 mo-
RF Faggiano 2012

I: RF

C: no treatment

ItalyUS RF: 1 session12 mo--
RFHuh 2012

I: RF (1 session)

C: RF (2 sessions)

Korea

RF: 1 session

RF: 2 sessions

6 mo--

"-" denotes not reported

ASP: aspiration; C: comparator; I: intervention; LT4: levothyroxine; LP: laser photocoagulation; mo: month(s); NaCl: isotonic saline; PEI: percutaneous ethanol injection; PHI: percutaneous hydrochloric acid injection; RF: radiofrequency ablation; TETRA: tetracycline hydrochloride; US: ultrasound; wk: week(s)

Appendix 7. Matrix of study endpoints (levothyroxine treatment)

 Primary endpoint(s)aSecondary endpoint(s)bOtherc endpoint(s)Time of endpoint measurement
LT4 Bayani 2012--
  1. Complete response (> 50% reduction in longitudinal and transverse dimensions of nodules)

  2. Longitudinal and transverse dimensions of thyroid nodules

  3. No response or increased size

  4. Partial response (20% to 50% reduction in the longitudinal and transverse dimensions of nodules)

  5. TSH

  1. 6 mo

  2. 0, 6 mo

  3. 6 mo

  4. 6 mo

  5. 0, 6 mo

LT4 Boguszewski 1998--
  1. Correlation changes in nodule size (palp.) / clinical and laboratory markers

  2. Number of TN decrease (US + palpation)

  3. Nodule volume reduction > 50%

  4. TSH, T4, T3, Tg, TgAb, TPOAb

  5. Compliance (TSH level)

  1. 0, 3, 6, 12 mo

  2. 12 mo

  3. 12 mo

  4. 0, 3, 6, 9, 12 mo

  5. 0, 3, 6, 9, 12 mo

LT4 Cesareo 2010--
  1. Dominant nodule mean volume change (US)

  2. Thyroid volume

  3. Number of nodules > 0.5 mL (reduction, increase)

  4. TSH, FT3, FT4, Tg, TgAb, TPOAb

All: 0, 6,12, 24 mo
LT4 Gharib 1987  --
  1. Nodule volume reduction > 50% (US)

  2. Nodule diameter decrease

  3. Width of opposite lobe (cm)

  4. Compliance (TSH level)

  5. T4, TSH, TRH test

  1. 6 mo

  2. 0, 6 mo

  3. 0, 6 mo

  4. 0, 6 mo

  5. 0, 6 mo

LT4 Grineva 2003--
  1. Nodule volume reduction ≥ 50% (US)

  2. Thyroid size changes

  3. Number of nodules prevented

  4. Nodule growth

  1. 6 mo

  2. 0, 6 mo

  3. 0, 6 mo

  4. 6 mo

LT4 Grussendorf 2011Change in total volume of all nodulesChange in goitre volume; number and echogenicity of nodules
  1. All nodule volume reduction ≥ 50% (US)

  2. TSH ranges according to treatment

  3. Change in iodine excretion

  4. Compliance (at least 80% of the prescribed dose, pill count)

  5. Adverse events

  6. TPOAb

  7. Clinical laboratory

Primary and secondary outcomes:
0, 12 mo

  1. 12 mo

  2. 0, 3, 6, 12 mo

  3. 0, 12 mo

  4. 3, 6, 12 mo

  5. 3, 6, 12 mo

  6. Screening, 12 mo

  7. Screening, 12 mo

LT4 Koc 2002--
  1. Nodule volume reduction (US)

  2. Contralateral lobe volume

  3. Isthmus thickness

  4. New nodules after LT4

  5. TSH, T3, FT3, T4, FT4, Tg

  1. 0, every 6 mo after targeted TSH until 24 mo

  2. 0, every 6 mo after targeted TSH until 24 mo

  3. 0, every 6 mo after targeted TSH until 24 mo

  4. 0, every 6 mo after targeted TSH until 24 mo

  5. every 6 mo after targeted TSH until 24 mo

LT4 La Rosa 1995--
  1. Nodule volume reduction ≥ 50% (US)

  2. Type of nodule volume variation

  3. Nodule maximum diameter

  4. Maximal transversal section of contralateral lobe

  5. FT3, FT4, TSH, Tg

  6. Urinary iodine level

  7. Compliance (TSH level + self report)

  1. 12 mo

  2. 0, 4, 8, 12 mo

  3. 0, 4, 8, 12 mo

  4. 0, 4, 8, 12 mo

  5. 0, 4, 8, 12 mo

  6. 0, 4, 8, 12 mo

  7. 0, 4, 8, 12 mo

LT4 Larijani 2005--
  1. Nodule volume changes

  2. Nodule size reduction (US)

  3. Nodule volume reduction > 50% (complete-, partial-, non-responders)

  4. T3, T4, TSH after TRH test

  1. 0, 6, 12, 24 mo

  2. 0, 6, 12, 24 mo

  3. 24 mo

  4. 0, 6 wk, every 3 mo

LT4 Ozkaya 2010--
  1. Dominant nodule volume changes

  2. Thyroid left/right volume changes

  3. TSH, FT4

All: 0, 12 mo
LT4 Papini 1993--
  1. Nodule volume changes ≥ 50%

  2. Contralateral lobe thickness

  3. Number of nodules (size increase, decrease)

  4. TN size (US)

  5. TSH, T4, FT4, T3, FT3, Tg, TgAb, TPOAb

  1. 12 mo

  2. 0, 6, 12 mo

  3. 0, 6, 12 mo

  4. 0, 6, 12 mo

  5. 0, 2, 6, 12 mo

LT4 Papini 1998--
  1. Nodule volume changes

  2. Thyroid volume changes

  3. New nodules

  4. TSH, FT3, FT4, Tg, TgAb, TPOAb

  1. 0, 36, 60 mo

  2. 0,12, 36, 60 mo

  3. 0, 12, 36, 60 mo

  4. 0, 12, 24, 36, 48, 60 mo

LT4 Reverter 1992--
  1. Nodule volume changes ≥ 50%

  2. Nodule size (US)

  3. TSH, T4, T3, FT4

  1. 6 mo

  2. 0, 6 mo

  3. 0, 3, 6, 9, 12 mo

LT4 Tsai 2006--
  1. Nodule volume changes ≥ 50% (responders, non-responders)

  2. Nodule volume

  3. TSH, T4, T3, FT4, Tg, TgAb, TPOAb

  4. Compliance (pill count)

  1. 6 mo

  2. 0, 6 mo

  3. 0, 6 mo

  4. 6 mo

LT4 Wemeau 2002  Nodule volume changes (US)-
  1. Nodule maximum diameter (US, palpation)

  2. Nodule volume reduction > 50% (responders, partial-, non-responders)

  3. Homolateral lobe size changes

  4. Contralateral lobe size changes

  5. Pretreatment nodule volume/volume reduction relation

  6. TSH, FT4, FT3

  7. Compliance

  8. Need for ß-blockers

  1. 0, 18 mo

  2. 18 mo

  3. 0, 18 mo

  4. 0, 18 mo

  5. 0, 3, 6, 12, 18 mo

  6. 0, 3, 6, 12, 18 mo

  7. 0, 3, 6, 12, 18 mo

  8. -

LT4 Zelmanovitz 1998--
  1. Nodule volume reduction > 50%

  2. Nodule volume increase > 50%

  3. Nodule maximal diameter (US)

  4. Prevention TN growth

  5. TSH, T4, T3, Tg

  6. Effect on BMD (spine, femur)

  7. Compliance (TSH level)

  1. 12 mo

  2. 12 mo

  3. 0, 3, 6, 12 mo

  4. 12 mo

  5. 0, 3, 6, 12 mo

  6. 0, 12 mo

  7. 0, 3, 6, 12 mo

"-" denotes not reported

a,bAs stated in the publication

cNot stated as primary or secondary endpoint(s) in the publication

BMD: bone mineral density; FT3: free tri-iodothyronine; FT4: free thyroxine; LT4: levothyroxine; mo: month(s): palp.: palpatory; T3: plasma (serum) tri-iodothyronine; T4: plasma (serum) thyroxine; Tg: thyroglobulin; TgAb: antithyroglobulin autoantibody; TN: thyroid nodule; TPOAb: antiperoxidase autoantibody; TRH: thyrotropin-releasing hormone; TSH: thyrotropin; US: ultrasound; wk: week(s)

Appendix 8. Matrix of study endpoints (minimally invasive treatments)

 Primary
endpoint(s)a
Secondary endpoint(s)bOtherc endpoint(s)Time of endpoint measurement
PEI Bennedbaek 1998--
  1. Nodule volume

  2. Nodule volume reduction ≥ 50%

  3. Total thyroid volume changes

  4. Ethanol dose/response relationship

  5. Pressure/cosmetic symptoms (questionnaire)

  6. TSH, T4, T3, FT4, FT3, TPOAb

  7. Compliance (TSH suppression)

  1. 0, 1, 2, 3, 6, 12 mo

  2. 12 mo

  3. 1, 2, 3, 6, 12 mo

  4. 12 mo

  5. 0, 12 mo

  6. 0, 1, 2, 3, 6, 12 mo

  7. 0, 1, 2, 3, 6, 12 mo

PEI Bennedbaek 1999--
  1. Nodule volume

  2. Total thyroid volume

  3. Ethanol dose/response relationship

  4. Pressure/cosmetic symptoms (VAS questionnaire)

  5. TSH, T4, T3, FT4, FT3, TPOAb

  6. Cost-benefitd

  7. Compliancee

  1. 0, 1, 2, 3, 6 mo

  2. 0, 1, 2, 3, 6 mo

  3. 6 mo

  4. 0, 6 mo

  5. 0, 1, 2, 3, 6 mo

  6. -

  7. -

PEI Bennedbaek 2003--
  1. Cyst volume changes (US)

  2. Total thyroid volume (US)

  3. Recurrence rate

  4. Cure

  5. Number of previous aspirations/success rate

  6. Number of treatments given/response to treatment

  7. Pretreatment cyst volume/cure rate

  8. Pressure/cosmetic symptoms (yes/no)

  9. TSH, T4, T3, FT4, FT3, calcitonin, TPOAb

  1. 0, 1, 2, 3, 6 mo (from the last treatment in case of recurrence; maximum 3 treatments)

  2. 0, 1, 2, 3, 6 mo

  3. 3, 6 mo

  4. 6 mo

  5. 3, 6 mo

  6. 6 mo

  7. 6 mo

  8. 6 mo

  9. 0, 1, 2, 3, 6 mo

PEI Chu 2003--
  1. Cyst volume

  2. Recurrence

  3. Pretreatment nodule volume/cure rate

  4. Pretreatment nodule volume and number of PEI sessions

  5. Cure rate

  1. 3 mo (end of follow up randomised study)

  2. 3 mo

  3. 3 mo

  4. 3 mo

  5. 3 mo

PEI Sung 2013Volume reduction ratio (%)
  1. Therapeutic success rate (volume reduction > 50%)

  2. Improvement of symptoms and cosmetic problems

  3. Number of major and minor complications

-
  1. 0, 6 mo

  2. 0, 6 mo

  3. 6 mo

TETRA Hegedüs 1998--
  1. Cyst volume

  2. Thyroid volume

  3. Recurrence rate

  4. New nodules

  5. No recurrence/number of treatments

  6. Cure rate

  7. T4, T3, T3 uptake ratio, TSH

  1. 1, 3, 6, 12 mo after cyst puncture

  2. 1, 3, 6, 12 mo

  3. 1, 3, 6, 12 mo

  4. 1, 3, 6, 12 mo

  5. 1, 3, 6, 12 mo

  6. 12 mo

  7. 1, 3, 6, 12 mo

PEI Valcavi 2004--
  1. Cyst volume reduction > 50%

  2. Cure rate (elimination of compressive/cosmetic symptoms)

  3. Risk of malignancyf

  1. 1, 2, 3, 6,12 mo

  2. 12 mo

  3. Annual US neck examination

PEI Verde 1994--
  1. Nodule volume reduction > 50%

  2. Cyst fluid recurrence

  3. TSH, FT3, FT4, Tg, TPOAb, TgAb

  1. 1 mo

  2. 1 mo

  3. 0, 1 mo

LPDossing 2005--
  1. Nodule volume reduction

  2. Thyroid volume changes

  3. T3, T4, FT3, FT4, TSH

  4. TPOAb

  5. Tolerability (pain)

  6. Pressure symptoms/cosmetic complaints (VAS)

  7. Correlation nodule decrease/laser energy

  1. 1, 2, 6 mo

  2. 1, 2, 6 mo

  3. 1, 2, 6 mo

  4. 0, 6 mo

  5. After procedure

  6. 6 mo

  7. 6 mo

LPDossing 2006Nodule volume reduction-
  1. FT3, FT4, TSH

  2. Thyroid volume changes

  3. TPOAb

  4. Tolerability (pain)

  5. Pressure symptoms/cosmetic complaints (VAS)

  6. Correlation nodule decrease/laser energy

  1. 0, 1, 2, 6 mo

  2. 1, 2, 6 mo

  3. 0, 6 mo

  4. After procedure

  5. 6 mo

  6. 6 mo

LP Dossing 2013--
  1. Cure

  2. Recurrence

  3. Pressure symptoms/cosmetic complaints (VAS)

  4. Total thyroid volume reduction

  5. Cyst volume reduction

  6. Reduction of solid part

  7. TSH

  8. TPOAb

  1. 6 mo

  2. 6 mo

  3. 0, 6 mo

  4. 1,3, 6 mo

  5. 1,3, 6 mo

  6. 6 mo

  7. 0, 1, 3, 6 mo

  8. 0, 6 mo

LPGambelunghe 2006--
  1. Nodule volume decrease

  2. TSH, FT4, FT3

  3. TPOAb

  4. Tolerability (pain)

  5. Compressive/cosmetic complaints (VAS)

  6. Correlation nodule decrease/laser energy

  1. 0, 2, 30 wks

  2. 0, 3 days; 6, 30 wks

  3. 0, 30 wks

  4. After procedure

  5. 0, 3 days; 6, 30 wks

  6. 2 wks, 30 wks

LPPapini 2007--
  1. TN volume reduction

  2. TN volume reduction > 50%

  3. Changes in local symptoms (questionnaire)

  4. TSH, FT3, FT4, Tg, TgAb, TPOAb

  5. Tolerability (pain, acceptance of another treatment procedure)

  6. Correlation nodule decrease/laser energy

  7. PLA costs

  1. 0, 1, 6, 12 mo

  2. 12 mo

  3. 0, 1, 6, 12 mo

  4. 0, 1, 6, 12 mo

  5. After procedure

  6. 12 mo

  7. 12 mo

RF Faggiano 2012--
  1. TN volume reduction ≥ 50%

  2. Cosmetic/symptom scores (separately and total: SYS score)

  3. TSH, FT3, FT4, Tg, TgAb, TPOAb, calcitonin

  4. Improvement of hyperthyroidism (by toxic TN)

  1. 0, 1, 3, 6, 12 mo

  2. 0, 12 mo

  3. 0, 1, 3, 6, 12 mo

  4. 0, 1, 3, 6, 12 mo

RFHuh 2012--
  1. Nodule volume changes

  2. Cosmetic/symptom scores (physician record/VAS)

  3. Nodule volume reduction > 50%

  4. Adverse events

  5. TSH, FT3, FT4, TPOAb

  6. Correlation nodule decrease/RF energy

  1. 0, 1, 3, 6 mo

  2. 0, 1, 3, 6 mo

  3. 6 mo

  4. 0, 1, 3, 6 mo

  5. 0, 6 mo

  6. 6 mo

"-" denotes not reported

a,bAs stated in the publication
cNot stated as primary or secondary endpoint(s) in the publication
dMentioned, but not evaluated in the trial
eAssociated with tolerability
fFNAB + cytology = suspicious and positive biopsies were similar between groups

FNAB: fine-needle aspiration biopsy; FT3: free tri-iodothyronine; FT4: free thyroxine; LP: laser photocoagulation; mo: month(s); PEI: percutaneous ethanol injection; PLA: percutaneous laser ablation; RF: radiofrequency; SYS score: the sum of the single scores including pressure symptoms in the neck, difficulty in swallowing, aesthetic complaints; symptoms were scored separately with 0 (absent), 1 (moderate) and 2 (severe); T3: plasma (serum) tri-iodothyronine; T4: plasma (serum) thyroxine; TETRA: tetracycline hydrochloride; T TN: thyroid nodule; TPOAb: antiperoxidase autoantibody; TSH: thyrotropin; US: ultrasonography; VAS: visual analogue scale; wks: weeks

Appendix 9. Definition of endpoint measurement (levothyroxine treatment)

 ComplianceResponderPartial responder/non-responderNew nodules
LT4 Bayani 2012-Complete response (> 50% reduction in longitudinal and transverse dimensions of nodules)Partial response (20% to 50% reduction in the longitudinal and transverse dimensions of nodules)-
LT4 Boguszewsky 1998

TSH suppressiona +

response to TRH

injection

---
LT4 Cesareo 2010---Number of nodules > 0.5 mL at follow up
LT4 Gharib 1987

TSH suppressionb +

TSH response to TRH injection

---
LT4 Grussendorf 2011

At least 80% of

dose taken

--Change in number of nodules
LT4 Larijani 2005-TN volume reduction ≥ 50%

Partial responder: TN volume reduction < 50%

Non-responder: TN volume increase or constant

-
LT4 La Rosa 1995

TSH suppression

+ self-report

---
LT4 Papini 1993TSH suppression---
LT4 Papini 1998---Lesions with diameter > 10 mm at follow up
LT4 TsaiPill countTN volume reduction > 50%Non-responder: TN volume reduction ≤ 50%-
LT4 Wemeau 2002Pill count + self reportTN volume reduction ≥ 50%

Partial responder: TN volume reduction ≥ 20% to 50%

Non-responder: TN volume reduction < 20%

Non palpable TN, additionally detected by US
LT4 Zelmanovitz 1998TSH suppression---

"-" not reported

a,bTSH suppression: from < 0.2 mU/L to 0.5 mU/L

LT4: levothyroxine; TN: thyroid nodule; TRH: thyrotropin-releasing hormone; TSH: thyrotropin; US: ultrasound

Appendix 10. Definition of endpoint measurement (minimally invasive treatments)

 CureSucess rate/therapy successRecurrenceCosmetic/pressure complaintTolerability/compliance
PEI Bennedbaek 1998-TN disappearance or 50% reduction in size-Questionnaire (items none to severe)-
PEI Bennedbaek 1999---VAS (0 to 10 cm)Degree of pain
PEI Bennedbaek 2003Cyst volume ≤ 1 mL-Cyst volume > 1 mLInterview (yes, no)-
PEI Chu 2003TC disappearance or volume reduction < 0.5 mL (maximum 5 sessions)-Cyst volume > 1 mL--
PEI Sung 2013-Percentage of participants who showed a volume reduction > 50%-

VAS (0 to 10 cm) for symptoms by participants

Cosmetic score by physician: 1 = no palpable mass; 2 = no cosmetic problem but a palpable mass; 3 = cosmetic problem on swallowing only; 4 = readily detected cosmetic problem at all times

Degree of procedure-related pain:

Ethanol ablation:

  1. Grade 0: no or mild pain

  2. Grade 1: pain not requiring medication

  3. Grade 2: pain requiring medication

  4. Grade 3: procedure incompletely terminated because of severe pain

RF:

  1. Grade 0: no pain, no RF power turned off

  2. Grade 1: pain, RF power turned of once or twice

  3. Grade 2: pain, RF power turned off more than three times

  4. Grade 3: procedure incompletely terminated because of severe pain

TETRA Hegedüs 1988Absence of any residual nodule and TC < 1 mL (US) 12 months after last treatment-ND--
PEI Valcavi 2004Elimination of discomfort + cosmetic complaints--QuestionnaireLocal burning sensation
PEI Verde 1994--ND--
LPDossing 2005---VAS (0 to 10 cm)Degree of pain (VAS: 0 to 10 cm)
LPDossing 2006---VAS (0 to 10 cm)Degree of pain (VAS: 0 to 10 cm)
LP Dossing 2013Cyst volume ≤ 1 mL (determined by US or aspiration)Cyst volume ≤ 1 mL (determined by US or aspiration)Cystic part of nodule > 1 mL
(US or aspiration)
VAS (0 to 10 cm)-
LP Gambelunghe 2006---VAS (0 to 6 cm)Asked for another ablation
LPPapini 2007---QuestionnaireAsked for a second ablation
RF Faggiano 2012---SYS scorea (range 0 to 6)Mild sensation of heat in the neck
RFHuh 2012-TN volume reduction > 50%-VAS (0 to 10 cm)Acceptance of another therapy session

"-" denotes not reported

aSYS score: the sum of the single scores including pressure symptoms in the neck, difficulty in swallowing, aesthetic complaints; symptoms were scored separately with 0 (absent), 1 (moderate) and 2 (severe)

LP: laser photocoagulation; ND: not defined; PEI: percutaneous ethanol injection; RF: radiofrequency ablation; TC: thyroid cyst; TETRA: tetracycline hydrochloride; TN: thyroid nodule; US: ultrasound; VAS: visual analogue scale

Appendix 11. Study(arms), comparisons and participants contributing data to comparisons

Interventions

Comparators

LP
[studies (participants)]
LT4
[studies (participants)]
PEI
[studies (participants)]
RF
[studies (participants)]
TETRA
[studies (participants)]
Aspiration1 (44)-3 (320)--
LP1 (30)1 (42)---
NaCl--1 (66)-1 (53)
No treatment3 (91)6 (365)-1 (40)-
PEI-1 (50)1 (160)1 (50)-
PHI--1 (18)--
Placebo 9 (806)---
RF---1 (30)-

"-" denotes no comparison available

LP: laser photocoagulation; LT4: levothyroxine; NaCl: isotonic saline; PEI: percutaneous ethanol injection; PHI: percutaneous hydrochloric acid injection; RF: radiofrequency ablation; TETRA: percutaneous tetracycline injection

Appendix 12. Iodine intake status and median urinary iodine concentration

Median urinary iodine concentration
[µg/L]
Corresponding approximate iodine intake
[µg/day]
Iodine nutrition status
< 20< 30Severe deficiency
20 to 4930 to 74Moderate deficiency
50 to 9975 to 149Mild deficiency
100 to 199150 to 299Optimal
200 to 299300 to 449More than adequate
> 299> 449Possible excess

Reference values as used by WHO/ICCIDD/UNICEF to relate iodine nutrition levels to urinary iodine concentration

ICCIDD: International Council for the Control of Iodine Deficiency Disorders; UNICEF: United Nations International Children’s Emergency Fund; WHO: World Health Organization

Appendix 13. Methods of measurement of local symptoms/cosmetic complaints following minimally invasive thyroid nodule therapy

 Symptom scoreCosmetic score
PEI Bennedbaek 1998

Absent

Mild

Moderate

Severe

Absent

Mild

Moderate

Severe

PEI Bennedbaek 199910 cm VAS (0 to 10 cm)10 cm VAS (0 to 10)
PEI Bennedbaek 2003

Absent

Present

Absent

Present

PEI Sung 201310 cm VAS (0 to 10 cm)

1 = no palpable mass

2 = no cosmetic problem but a palpable mass

3 = cosmetic problem on swallowing only

4 = readily detected cosmetic problem at all times

PEI Valcavi 2004Disappearance of compressive or cosmetic symptomsDisappearance of compressive or cosmetic symptoms
LP Dossing 200510 cm VAS (0 to 10 cm)10 cm VAS (0 to 10 cm)
LP Dossing 200610 cm VAS (0 to -10 cm)10 cm VAS (0 to 10 cm)
LP Dossing 201310 cm VAS (0 to 10 cm)10 cm VAS (0 to 10 cm)
LP Gambelunghe 2006VAS (1 to 6 cm)VAS (1 to 6 cm)
LP Papini 2007

0 = absent

1 = presence of local symptoms (cervical constriction, dyspnoea, dysphagia)

0 = absent

1 = cosmetic complaints

RF Faggiano 2012

Pressure symptoms in the neck; difficulty in swallowing

0 = absent

1 = moderate

2 = severe

SYS scorea : 0 to 6 

-
RF Huh 201210 cm VAS (0 to 10 cm)

1 = no palpable mass

2 = palpable mass + no cosmetic problem

3 = cosmetic problem only on swallowing

4 = light observable cosmetic problem

aSYS score: the sum of the single scores including pressure symptoms in the neck, difficulty in swallowing, aesthetic complaints; symptoms were scored separately with 0 (absent), 1 (moderate) and 2 (severe)

LP: laser photocoagulation; PEI: percutaneous ethanol injection; RF: radiofrequency ablation; VAS: visual analogue scale

Appendix 14. Adverse events (levothyroxine treatment)

 Intervention(s) and comparator(s)AEs
[N (%)]
SAEs
[N (%)]
Discontinued study due to an AE
[N (%)]
Nodule regrowth > 50%
[N (%)]
Surgery
[N (%)]
Thyroid cancer
[N (%)]
Deaths
[N]
LT4 Bayani 2012

I: LT4

C: no treatment

-------
LT4 Boguszewski 1998

I: LT4

C: PLAC

-

I: 0

C: -

I: 0

C: -

---

I: 0

C: -

LT4 Cesareo 2010

I: LT4

C: no treatment

Ia: 3/71 (4)

C: -

-

I: 3/71 (4)

C: 0

-

I: 3/71 (4)

C: 5/71 (7)

-

I: 0

C: 0

LT4 Gharib 1987  

I: LT4

C: PLAC

--

I: 0

C: 0

-- 

I: 0

C: 0

LT4 Grussendorf 2011b

I1: LT4 + PI

C1: LT4

C2: PI

C3: PLAC

-C3: 2/199 (1)

38/794 (5)

Serious adverse events (safety population)

----
LT4 Koc 2002

I1: LT4: 3 μg/kg/day

I2: LT4: 1.5 μg/kg/day

C1: PLAC high-dose

C2: PLAC low-dose

I1a: 2/11 (18)

I2: 0

C1a: 2/9 (22)

C2: 0

-----

I1: 0

I2: 0

C1: 0

C2: 0

LT4 La Rosa 1995

I1: LT4

I2: PI

C: no treatment

I1: 0

I2: 0

C: 0

I1: 0

I2: 0

C: 0

I1: 0

I2: 0

C: 0

I1: 0

I2: 0

C: 3 (14)

I1: 1/27 (4)

I2: 0

C: 0

I1c: 0

I2c: 0

Cc: 0

-
LT4 Larijani 2005

I: LT4

C: PLAC

--

I: 0

C: 0

--

I: 0

C: 0

I: 0

C: 0

LT4 Ozkaya 2010

I: LT4

C: no treatment

-------
LT4 Papini 1993

I: LT4

C: PLAC

Ia: 10/51 (20)

Ca: 3/50 (6)

I: 0

C: 0

I: 0

C: 0

I: 7/51 (14)

C: 11/50 (22)

---
LT4 Papini 1998

I: LT4

C: no treatment

Ia: 7/51 (14)

C: -

-

I: 3/51 (6)

C: -

-

I: 1/51 (2)

C: 2/49 (4)

I: 0

C: 0

-
LT4 Reverter 1992

I: LT4

C: no treatment

--

I: -

C: 0

-

I: 3/20 (15)

C: 0

-

I: -

C: 0

LT4 Tsai 2006

I: LT4

C: PLAC

--

I: 0

C: 0

---

I: 0

C: 0

LT4 Wemeau 2002  

I: LT4

C: PLAC

Ie: 2/64 (3)

Ce: 9/59 (15)

-

Ie: 2/64 (3)

Ce: 9/59 (15)

-

If: 1/64 (2)

Cf: 5/59 (8)

I: -

Cd: 1/59 (2)

-
LT4 Zelmanovitz 1998

I: LT4

C: PLAC

--

I: 0

C: 0

I: 2/21 (10)

C: 4/24 (17)

--

I: 0

C: 0

"-" denotes not reported

aAEs: signs of hyperthyroidism (palpitations, sweating, tremor, nervousness, persistent tachycardia)

bAEs: AEs and SAEs were defined and investigated during and at the end of the study, but the results were not presented

cSecond FNAB confirmed benignity for nodules which were not reduced in size and for those which were surgically removed

dPapillary carcinoma

eAEs: I: iatrogenic thyrotoxicosis, nodule growth; C: suspect FNAB at 12 months requiring hemithyroidectomy, nodule pain, benign follicular adenoma, myeloproliferative syndrome, hyperthyroidism and Grave's disease

fI: thyroidectomy; C: hemithyroidectomy

AE: adverse events; C: comparator; FNAB: fine-needle aspiration biopsy; I: intervention; LT4: levothyroxine; PI: potassium iodine; PLAC: placebo; SAE: serious adverse events

Appendix 15. Effects of levothyroxine treatment on bone mineral density

LT4 Zelmanovitz 1998Location of measurementsIntervention (I) and comparator (C)Baseline
[g/cm3 (SD)]
12 months
[g/cm3 (SD)]
Spine L2 to L4I: LT41.133 (0.208)a1.116 (0.213)a
C: PLAC1.093 (0.188)b1.066 (0.164)b
Femoral neckI: LT40.910 (0.205)a0.950 (0.163)a
C: PLAC0.881 (0.110)b0.869 (0.117)b
Femoral wardI: LT40.793 (0.227)a0.848 (0.178)a
C: PLAC0.750 (0.142)b0.744 (0.140)b
Femoral trochanterI: LT40.765 (0.158)a0.793 (0.127)a
C: PLAC0.714 (0.084)b0.708 (0.094)b

aMean BMD of 16 women

bMean BMD of 19 women

BMD: bone mineral density; LT4: levothyroxine therapy; PLAC: placebo; SD: standard deviation

Appendix 16. Adverse events (minimally invasive treatments)

 

Intervention(s)

and comparator(s)

AEs
[N (%)]
SAEs
[N (%)]
Discontinued study due to an AE
[N (%)]
Worsening / no improvement (VAS or other instrument)
[N (%)]
Nodule regrowth > 50%
[N (%)]
Surgery
[N (%)]
Carcinoma development
[N (%)]
Deaths
[N]
PEI Bennedbaek 1998I: PEI
C: LT4

Ia: 24/25 (96)

Cb: 5/25 (20)

Ia: 0

C: 0

I: 0

C: 0

I: 6/25 (24)

C: 12/25 (48)

I: 1/25 (4)

C: -

I: 2/25 (8)

C: -

I: 0

C: -

-
PEI Bennedbaek 1999

I: PEI (1 dose)

C: PEI (3 doses)

Ic: 30/30 (100)

Cc: 30/30 (100)

Id: 14/30 (47)

Cd: 8/30 (28)

Cd: 28/30 (92)

I: 0

C: 0

I: 3/30 (10)

C: 3/30 (10)

-

I: 1/30 (3)

C: -

I: 0

C: -

-
PEI Bennedbaek 2003

I: PEI

C: NaCl

Ic: 7/33 (21)

Cc: 1/33 (3)

I: 0

C: 0

I: 0

C: 0

Ie: 6/33 (18)

Ce: 17/33 (52)

-

I: 6/33 (18)

C: 10/33 (30)

-

I: 0

C: 0

PEI Chu 2003

I1: PEI

C1: PHI

C2: ASP

I1c: 4/10 (40)

C1c: 3/8 (38)

C2: 0

I1: 0

C1: 0

C2: 0

I1: 0

C1: 0

C2: 0

----

I1: 0

C1: 0

C2: 0

PEI Sung 2013

I: PEI

C: RF

I: 0/23 (0)

C: 21/21 (100)

--

I: 1/25 (4)

C: 2/25 (8)

----
TETRA Hegedüs 1998

I: TETRA

C: NaCl

If: 2/23 (9)

C: 0/30 (0)

I: 0

C: 0

I: 0

C: 0

Ig,h: 7/23 (30)

Cg,h: 14/30 (47)

-

I: 3/23 (13)

C: -

I: 0

C: -

I: 0

C: 0

PEI Valcavi 2004

I: PEI

C: ASP

Ic,i: (33)

C: -

Ij: 1/143 (< 1)

C: -

-

I: 34/135 (25)

C: 99/131 (76)

--

Ik

Ck

-
PEI Verde 1994

I: PEI

C: ASP

Ic: 3/10 (30)

Cc: 2/10 (20)

I: 0

C: 0

I: 0

C: 0

----

I: 0

C: 0

LPDossing 2005

I: LP

C: no treatment

Ic: 10/15 (67)

C: -

I: 0

C: 0

I: 0

C: 0

I: 3/15 (20)

C: 15/15 (100)

I: -

C: 0

I: 1/15 (7)

C: -

I: 0

C: -

I: 0

C: 0

LPDossing 2006

I: LP (1 session)

C: LP (3 sessions)

Ic,l: 10/15 (67)

Cc,l: 6/15 (40), 5/13(38), 3/11(27)

I: 0

C: 0

I:

C: 0

I: 8/15 (53) (VAS)

C: 7/13 (54) (VAS)

---

I: 0

C: 0

LP Dossing 2013

I: ASP + LP

C: ASP

Ic: 11/22 (50) l(2)

C: -

I: 0

C: 0

I: 0

C: 0

I: 7/22 (32)

C: 18/22 (82)

-

I: 4/22 (18)

C: 5/22 (23)

I: 0

C: 0

I: 0

C: 0

LPGambelunghe 2006

I: LP

C: no treatment

Im: 8/13 (62)

C: -

I: 0

C: 0

I: 0

C: 0

I: 0/13 (0)

C: 13/13 (100)

I: 0

Cn

--

I: 0

C: 0

LPPapini 2007o

I1: LP

C1: LT4

C2: no treatment

I1p: 20/21 (95)

C1q: 8/21 (38)

C2: 0

I1p: 1/21 (5)

C1: 0

C2: 0

I1: 0

C1: 0

C2: 1/20 (5)

I1: 0/21 (0)

C1: 1/21 (5)

C2: 9/20 (45)

I1: -

C1: -

C2: 1/20 (5)

I1: 0

C1: 0

C2r: 1/20 (5)

--
RF Faggiano 2012

I: RF

C: no treatment

Is: 20 (100)

C: -

I: 0

C: 0

I: 0

C: 0

I: -

Ct: 20 ( 100)

I: 0

C: -

I:

C:

-

I: 0

C: 0

RFHuh 2012

I: RF-1 (1 session)

C: RF-2 (2 sessions)

Iu: 15 (100)

Cu: 15 (100)

I: 0

C: 0

I: 0

C: 0

I: 0

C: 0

I: 0

C: 0

I: 0

C: 0

-

I: 0

C: 0

"-" denotes not reported

Numbers in italic were calculated by review authors

aAEs: slight-to-moderate pain lasting ± tenderness; SAE: fever, haematomas, dysphonia, dysthyroid symptoms

bAEs: symptoms of hyperthyroidism (diarrhoea, palpitations, sweating, tremor)

cAEs: slight-to-moderate pain ± tenderness

d For participants who received larger ethanol doses: I: dysphonia (47%); C: persistent nerve paralysis (28%) and paranodular fibrosis (92%)

eFailure: thyroid cyst volume after intervention > 1 mL

fExtreme pain with injection of TETRA

gRecurrence: cyst volume ≥ 1 mL, 12 months after last puncture for a median of three treatments

hNon-recurrent group, development of cold, solid nodules: I: n = 6/16 (38%); C: n = 2/16 (13%); I: n = 3/16 (19%) were operated on and histological examination revealed pronounced inflammatory changes

iBurning sensation

jTransient laryngeal dysfunction

kFrequency of suspicious/positive biopsy findings (similar between groups)

lParticipants receiving analgesics, duration of AEs: I:) mean 3 ± 3 days; C: 4 ± 4 days, 4 ± 4 days, 2 ± 4 days
l(2)Slight-to-moderate pain with a median (interquartile range) duration of 2 (0; 5) days, necessitating mild analgesics in 8 participants

mMild pain during the procedure + fever (12 hours): n = 5 + 3/13 (62%); transient hyperthyroidism until 6 weeks: n = 8/13 (62%)

nNon-significant increase

oLong-term AEs for LT4 therapy were not assessed (cardiac hypertrophy, atrial arrhythmia and increase in osteoporosis risk)

pAEs: mild cervical pain (20/21), persistent cervical pain (3/21) for 48 hours; SAEs: extremely painful (1/21)

qPersistent tachycardia and nervousness

rBenign follicular adenoma

sMild sensation of heat in the neck

tC: SYS score (sum of the individual scores) worsened in group B from 3.0 (± 1.3) at baseline to 4.1 (± 0.9)

uPain/discomfort during ablation

AE: adverse events; ASP: aspiration; C: comparator; I: intervention; NaCl: isotonic saline; LP: laser photocoagulation; LT4: levothyroxine; PEI: percutaneous ethanol injection; PHI: percutaneous hydrochloric acid injection; RF: radiofrequency ablation; SAE: serious/severe adverse events; TETRA: tetracycline hydrochloride; VAS: visual analogue scale

What's new

DateEventDescription
23 July 2014AmendedContact address corrected.

Contributions of authors

Elizabeth Bandeira-Echtler (EBE): protocol development, first person for trial selection, data extraction, data analysis, data interpretation, review development and future review update.

Bernd Richter (BR): protocol development, second person for trial selection, checked on data extraction, checked on data analysis, checked on data interpretation, review development and future review update.

Karla Bergerhoff (KB): protocol development, acquiring trial reports, third person for trial selection and review development.

Declarations of interest

EBE: none known.

BR: none known.

KB: none known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Heinrich-Heine-University of Duesseldorf, Germany.

Differences between protocol and review

Due to a significant time lag between publication of the protocol and first review draft almost all aspects of the review underwent significant changes due to improvements in methodology, reporting and standardisation. In particular, the contact person and team of authors changed. The scope of the review was enlarged from the evaluation of LT4 therapy only to encompass LT4 and all minimally invasive therapies. Consequently, the title was changed from 'Pharmacotherapy for thyroid nodules' to 'Levothyroxine or minimally invasive therapies for benign thyroid nodules'.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

LP Dossing 2005

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: palpable thyroid nodule; solitary cold (scintigraphically); solid benign (US-guided FNAB) thyroid nodule; cytology (colloid nodule); no suspicion of or a family history of thyroid cancer; no prior neck radiation

Exclusion criteria: see inclusion criteria

Diagnostic criteria: blood tests: TSH, serum T3, T4, FT3, FT4, TPOAb; thyroid scan: cold; US-FNAB: benignity; US (solid); cytology (colloid)

Interventions

Number of study centres: 1

Country/location: Denmark/Odense

Setting: outpatients referred from primary care physicians

Treatment before study: partial thyroidectomy for benign nodular goitre (n = 4/30)

Outcomes Outcomes reported in abstract of publication: nodule volume decrease/increase; thyroid volume changes; pressure and cosmetic complaints evaluated on a 10-cm VAS; correlation between energy deposition and nodule volume reduction; thyroid function (routine assays)
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

Commercial funding from Novo Nordisk Foundation and non-commercial funding from the Agnes and Knut Mørk Foundation, the AP Møller Relief Foundation and the AJ Andersen and Wife Foundation

Stated aim of studyQuote from publication: "To evaluate the efficacy of ultrasound (US)-guided interstitial laser photocoagulation (ILP) on thyroid function, nodule size and patient satisfaction in benign solitary solid cold thyroid nodules by comparing one ILP session with no treatment in a prospective randomised study"
NotesLP: "Under sterile conditions and guided by US, the laser fibre (0.4 mm in diameter) was positioned in the thyroid nodule through the lumen of an 18 gauge (1.2 mm) needle and preceded by local anaesthesia with lidocaine (10 mg/ml). The needle was withdrawn 20 mm leaving the end of the fibre in direct contact with the tissue"; degree of pain/discomfort rated on a VAS as a surrogate marker for tolerability
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Random allocation was achieved using a random number generator on a computer"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "The measurements ... same investigator ... blinded ..."
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessor not blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all randomised participants in the laser photocoagulation group completed the study; probably also in the no-treatment group
Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear riskComment: possible sponsor bias

LP Dossing 2006

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: euthyroid participants, normal serum calcitonin, palpable thyroid nodule causing pressure symptoms; solitary cold (scintigraphically), solid benign (US-guided FNAB) thyroid nodule; cytology (colloid nodule); no suspicion of or a family history of thyroid cancer; no prior neck radiation

Exclusion criteria: see inclusion criteria

Diagnostic criteria: blood tests: TSH, serum T3, T4, FT3, FT4, anti-TPOAb; thyroid scan: cold; US-FNAB: benignity; US (solid); cytology (colloid)

Interventions

Number of study centres: 1

Country/location: Denmark/Odense

Setting: outpatients referred from primary care physicians

Treatment before study: partial thyroidectomy for benign nodular goitre (n = 1/30); 131I years ago for autonomous nodule in the contralateral lobe (n = 1/30)

Outcomes Outcomes reported in abstract of publication: thyroid nodule volume decrease (US); pressure symptoms and cosmetic complaints (VAS); correlation between energy deposition and nodule volume reduction (dose-response relationship); participant satisfaction; side effects
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

Commercial funding from the Novo Nordisk Foundation and non-commercial funding from the Agnes and Knut Mørk Foundation, the AP Møller Relief Foundation and the AJ Andersen and Wife Foundation

Stated aim of studyQuote from publication: "To evaluate the efficacy and dose-response relationship, as well as the safety of US-guided ILP, on the volume of benign solitary solid cold thyroid nodules. Additionally, we evaluated nodule related symptoms in this prospective randomized study comparing one ILP treatment with three treatment sessions"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Random allocation was achieved using a random number generator on a computer"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "The measurements ... performed ... same investigator.. blinded as to previous results"
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessor not blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote from publication: "The treatment was well-tolerated as evidenced by the fact that none of the patients in either group requested termination of the procedure"

Comment: all participants randomised to LP-1 and for LP-3 completed the study

Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear riskComment: possible sponsor bias

LP Dossing 2013

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: euthyroid participants, normal serum calcitonin, palpable thyroid nodule causing pressure symptoms; neither suspicion of thyroid cancer nor a family history of it (clinical); benign cold solitary solid-cystic nodule (US-FNAB, scintigraphy)

Exclusion criteria: not stated

Diagnostic criteria: blood tests: serum TSH, T3, T4; thyroid scan: cold; US-FNAB: benignity; US (solid); cytology (colloid)

Interventions

Number of study centres: 1

Country/location: Denmark/Odense

Setting: outpatients referred from primary care physicians

Treatment before study: cyst aspiration

Outcomes Outcomes reported in abstract of publication: cyst volume decrease ≤ 1 mL ("successful outcome"); reduction of solid (cystic) part of the nodule; decrease of pressure symptoms (VAS); thyroid function; side effects
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

Commercial funding from the Novo Nordisk Foundation

Stated aim of studyQuote from publication: "The aim of this study was to follow up on our pilot study (11) and evaluate the remission rate in patients with a recurrent benign predominantly cystic thyroid nodule randomized to aspiration, with or without subsequent ILP"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "The patients ... and randomized without stratification for nodule size"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "US measurements were performed by the same investigator (H.D.) with blinding toward the previous measurements"
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessor not blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all participants randomised for cyst aspiration only and for cyst aspiration and laser completed the study
Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear riskComment: possible sponsor bias

LP Gambelunghe 2006

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: participants with compressive symptoms due to nodular goitre or single benign (FNA) nodules

Exclusion criteria: not reported

Diagnostic criteria: FNA (nodules > 1 mL): benignity; thyroid scan: cold or mild hyperfunctioning nodules (subclinical hyperthyroidism)

Interventions

Number of study centres: 1

Country/location: Italy

Setting: outpatients

Treatment before study: not reported

Outcomes Outcomes reported in abstract of publication: nodule volume change; compressive symptoms/cosmetic complaints; tolerability; correlation between energy deposition and nodule volume decrease; thyroid function
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: " ... to test the efficacy and safety of percutaneous ultrasound (US)-guided laser photocoagulation (PLP) for treatment of subjects with compressive symptoms due to benign thyroid nodules and/or at high surgical risk"
NotesOnly the dominant nodule was treated in case of multinodular goitres
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "... randomly assigned to one session PLP ... or observation ..."

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "The volume of nodules ... measured ... same investigator, blinded for treatment ..."
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote from publication: "All patients tolerated the treatment well ... answered ... could repeat it"

Comment: all randomised participants were evaluated at study end

Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LP Papini 2007

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: a) presence of a single or dominant palpable nodule, either solid or with a small fluid component (< 20% at US examination), with volume > 5 mL, and with at least one diameter > 30 mm; b) hypoactive appearance at 99mTc thyroid scintiscan; c) benign cytology at two consecutive US-guided FNAB; d) free thyroid hormones, TSH, and antithyroid antibodies within normal range; e) age between 18 and 60 years; f) refusal of or ineligibility for surgery; g) untreated thyroid disease

Exclusion criteria: autoimmune thyroid disease; previous thyroid surgery, radioiodine or LT4 treatment 

Diagnostic criteria: US (solid or small fluid component < 20%); volume > 5 mL, and with at least one diameter > 30 mm); 99mTc thyroid scintiscan (hypoactive appearance); 2 consecutive US-guided FNAB (benignity); blood tests: serum TSH, FT3, FT4, Tg, thyroid antibodies

Interventions

Number of study centres: 1

Country/location: Italy

Setting: outpatients

Treatment before study: none

Outcomes Outcomes reported in abstract of publication: nodule volume changes (decrease/growth); nodule volume reduction > 50%; local symptoms improvement; complications
Study details

Run-in period: LT4 treatment at day 35, scheduled dose based on TSH levels

Study terminated before regular end: no

Publication details

English language of publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: " ... to compare the 12-month changes in nodule volume and local symptoms induced by a single PLA session with those induced by long-term LT4 suppressive therapy in a series of benign large cold thyroid nodules and then to compare the findings in the two groups with the natural history of a series of thyroid nodules followed by means of clinical surveillance with no active treatment"
Notes

"All the patients lived in greater Rome metropolitan area, a borderline iodine-deficient area (median daily urinary excretion: 92 μg)"

Immediately before PLA: betamethasone intramuscularly, if persistent pain: ketoprofen for 2 days (n = 3/21 (14%)); assessment of local symptoms after 12 months treatment or follow up: not validated questionnaires; total thyroid volume was not systematically assessed

Cost of PLA (equipment + medical team + kits): approx. €450 (US$550)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "A computer-based number generator was used to randomly assign each patient to one of the three groups"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the unblinded design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High risk

Quote from publication: "This fact, together with the unblinded design of the trial, makes it impossible to role out ... placebo effect skewing the analysis of the changes in subjective symptoms in the treated ... patients"

Comment: the unblinded design could have introduced bias for subjective outcomes

Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: no detailed information
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote from publication: "One drop-out (5%) was registered in the follow-up group. This patient underwent surgical treatment because of the progressive growth of his nodule and the associated worsening of local symptoms" (Group 3 (C2)); "Eight out of 21 (38.1%) patients complained of persistent tachycardia or nervousness, but no one withdrew from the study" (Group 2 (C1))

Comment: reasons for dropouts explained

Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Bayani 2012

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: participants with single palpable thyroid nodule with confirmed tumour benignity based on FNAB; to ensure existence of single nodule, sonography was performed

Exclusion criteria: thyroid neoplastic lesions in participants or their family, history of neck radiation, hot nodules

Diagnostic criteria: palpation; ultrasonography; FNAB; total T4 and TSH serum tests showed euthyroid status

Interventions

Number of study centres: 1

Country/location: Iran/Babol

Treatment before study: none

Outcomes Outcomes reported in abstract of publication: serum levels of TSH; longitudinal and transverse dimensions of thyroid nodules before and after treatment
Study details

Study terminated before regular end: no

Registered trial: IRCT 201103185692 N3 (WHO Trial Registration Data Set)
Date of registration: 2011-05-26
Primary sponsor: Bobol University of Medical Sciences and Health Services
Date of first enrolment: 2010-04-28
Target sample size: 40
Study design: parallel RCT; single blind
Inclusion criteria: age lower than 60 years old; single thyroid nodule with fine needle aspiration; TSH in normal limits (0.5 to 4.5 mU/L)
Exclusion criteria: age more than 60 years; history of hypo- or hyperthyroidism; neck radiation; history of any cancer; history of thyroid cancer in family; living in another region where the study is performed; history of levothyroxine or other thyroid related drugs; TSH lower than normal; pregnancy; other disease (cardiovascular or hepatic)

Intervention 1: LT4 at an initial dose of 50 µg/day, levothyroxine dose was adapted according to TSH serum levels after 6 weeks of suppressive treatment in order to maintain TSH levels at less than 0.5 mU/L
Intervention 2: comparator group; no intervention
Primary outcome(s): size of benign thyroid nodule; time point: before and 6 months after intervention; method of measurement: sonography
Secondary outcome(s): TSH before, 6 weeks and 6 months after the intervention

Publication details

English language publication in a peer-reviewed journal

Non-commercial funding by the Vice Chancellery For Research of Babol University of Medical Sciences

Stated aim of studyQuote: "... to investigate the effect of suppressive treatment with levothyroxine on the size of thyroid nodules"  
NotesNone of the participants was under suppressive treatment with LT4 or other thyroid-associated drugs prior to the study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "The patients were randomly divided into two groups ..."  

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: no detailed information; study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: no detailed information; study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: no detailed information
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no dropouts
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Boguszewski 1998

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: non-functional ("cold") or isofunctional ("warm" and LT4-suppressible) thyroid nodule on thyroid scanning; cytology negative for malignancy (FNAB); solid or predominantly solid nodule (> 50% of the area) on US; single (palpation) in clinically euthyroid participants

Exclusion criteria: pregnancy; any contraindication for thyroid suppressive therapy; autonomously functioning nodules

Diagnostic criteria: functional diagnosis (thyroid scanning); solid or predominantly solid nodule (> 50% of the area) (US); malignancy or benignity (FNAB and cytology)

Interventions

Number of study centres: 1

Country/location: Brazil

Setting: outpatients

Treatment before study: not reported

Outcomes Outcomes reported in abstract of publication: nodule volume reduction (US); nodule size and number of nodules reduction (palpation); T3, T4, Tg, TgAb, TPOAb measurements; correlation between changes in nodule size and clinical, laboratory markers and scintigraphic characteristics
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

Commercial funding by Sanofi-Winthrop + Laboratorios Aché (LT4 + placebo tablets)

Stated aim of studyQuote from publication: " ... to evaluate the effect of TSH-suppressive therapy with levothyroxine (LT4) on the volume  of clinically solitary thyroid nodules, assessing possible correlations between response to therapy and clinical and laboratory parameters"  
Notes

TRH test: 200 μg i.v. after 30 to 60 minutes, if TSH < 2 mU/L TSH response was considered as suppressed

LT4 and PLAC tablets appeared identical

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "A prospective, randomized and placebo controlled ... hypothesis"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "Both allocation to treatment (LT4 or placebo) and US measurements were double-blind with respect to patients and physicians"; "Both placebo and LT4 tablets were externally identical"
Blinding of participants (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskQuote from publication: "Both allocation to treatment (LT4 or placebo) and US measurements were double-blind with respect to patients and physicians"; "Both placebo and LT4 tablets were externally identical"
Blinding of personnel (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "All US examinations were done by the same radiologist"; "Both allocation to treatment (LT4 or placebo) and US measurements were double-blind with respect to patients and physicians"
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote from publication: "All patients completed the study"; "None of the patients in the LT4 group had side effects requiring withdrawal ... or modification of the initial dose"
Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear risk

Quote from publication: "LT4 and placebo tablets were a generous gift of Sanofi ... Laboratorios Aché"

Comment: possible sponsor bias

LT4 Cesareo 2010

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: ultrasonography characteristics of thyroid multinodular disease (2 to 5 nodules); cytology on dominant or suspicious nodule consistent with a colloid pattern by FNA; 99mTc scan consistent with hypofunctioning or non-visualised nodules; no cystic or mixed nodules with fluid area higher than 30%; normal levels of serum TSH, FT4, FT3 and absence of TgAb and TPOAb antibodies; no previous treatment with thyroid hormones, iodine compounds or antithyroid drugs; no smoking history; no pregnancy in the past 12 months, body mass index between 18.5 and 30 kg/m2, no history of neck irradiation or surgery

Exclusion criteria: see inclusion criteria

Diagnostic criteria: clinical evaluation; laboratory measurements (TSH, FT4, FT3, Tg, TgAb, TPOAb, urinary iodine excretion); US (thyroid multinodular disease); thyroid scan with 99mTc (hypofunctioning)

Interventions

Number of study centres: 1

Country/location: Italy

Setting: outpatients

Treatment before study: none

Outcomes Outcomes reported in abstract of publication: dominant nodule mean volume changes; thyroid volume changes; number of nodules > 0.5 mL; laboratory parameters for thyroid function (TSH, FT4, FT3)
Study details Study terminated before regular end: yes, probably for benefit (see notes)
Publication details

English language publication in a peer-reviewed journal

Non-commercial funding from Italian Ministry of University and Research (Linea D1 “ex-60%” 2008-2009 Università Cattolica Sacro Cuore)

Stated aim of studyQuote from publication: "To evaluate the short term effects of levothyroxine treatment in never treated, pre-menopausal women affected by thyroid multinodular disease"
NotesIt is not clear why only one part of participants continued the study until 24 months: "Forty-one patients were followed for 24 months and the obtained results prompted us to stop the observation period after 12 months for the remaining subjects"
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "The study was a prospective randomized clinical trial"; "Seventy-one consecutive pre-menopausal ... were randomly assigned to a L-T4 (2 μg/kg body weight) treated group or to a non-treated control group"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: no detailed information; study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low risk

Quote from publication: "Clinical and hormonal evaluations were unblinded"

Comment: the study design probably did not introduce bias for (semi)objective outcomes

Blinding of personnel (subjective outcomes)
Subjective outcomes
High risk

Quote from publication: "Clinical and hormonal evaluations were unblinded"

Comment: the study design could have introduced bias for subjective outcomes

Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "... whereas US scans were blinded performed"
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors blinded for US scans only
Incomplete outcome data (attrition bias)
All outcomes
High risk

Quote from publication: "Drop-out patients: 8 subjects underwent surgical treatment (5 in the control and 3 in the L-T4 treated group); 13 patients (5 in the L-T4 treated group and 8 in the control group) abandoned the study and 3 patients of the L-T4 treated group experienced side-effects (nervousness, tachycardia and headache)"; "Forty-one patients were followed for 24 months and the obtained results .... to stop the observation... after 12 months ... remaining subjects"

Comment: 8/36 participants in the intervention group and 13/35 in the comparator group dropped out; only 58% (41/71) of total participants were evaluated at study end

Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Gharib 1987

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: single palpable thyroid nodule < 3 cm; benignity (FNAB); functional, hypofunctional, cold (99mTc scan); volume, size, solid, cystic, mixed, no halo, no calcification (US-characteristics); serologic data (T4, TSH)

Exclusion criteria: more than one palpable nodule; nodule > 3 cm in any dimension; cytologic findings suggesting neoplastic process; pregnancy or CVD

Diagnostic criteria: US (nodule volume, margin, composition; thyroid characteristics); FNAB (benignity); 99mTc thyroid scan (nodule function)

Interventions

Number of study centres: 1

Country/location: USA

Setting: outpatients

Treatment before study: not reported

Outcomes Outcomes reported in abstract of publication: nodule diameter reduction; nodule volume reduction; thyroid function (TSH suppression confirmed by TRH test)
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

Non-commercial funding from the Mayo Foundation (partial grant)

Stated aim of studyQuote from publication: "To compare prospectively ... the effect of thyroxine therapy with that of a placebo on the size of benign thyroid nodules that were solitary on palpation"
NotesInclusion criteria: "single palpable nodule"; US identification: 27 participants had 1 nodule; 12 had 2 nodules; 11 had 3 nodules, 2 had 4 nodules and 1 participant had 6 nodules; only 25 participants had one nodule at follow-up
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Patients were then randomly assigned to levothyroxine or placebo treatment groups with use of a table of random numbers"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: "our study was randomized, included a placebo group ... in a double-blind fashion"

"Both levothyroxine and placebo ... in externally identical capsules"

Blinding of participants (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskQuote from publication: "Neither the ultrasound examiner nor the clinician palpating the gland ... access to previous findings about the nodule or to the treatment code"; "Both levothyroxine and placebo... in externally identical capsules"
Blinding of personnel (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "Neither the ultrasound examiner nor the clinician palpating the gland ... access to previous findings about the nodule or to the treatment code"
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all randomised participants were evaluated at study end
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Grineva 2003

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: benign nodular thyroid lesions (colloid or colloid hypercellular by FNAB; cold or warm by scintigraphy)

Exclusion criteria: hot nodules on scintigraphy, cyst > 1% of nodules, non-euthyroid, pregnancy, ischaemic heart disease, other contraindications for thyroxine

Diagnostic criteria: FNAB (benignity), scintigraphy (nodule function)

Interventions

Number of study centres: 1

Country/location: Russia

Setting: outpatients

Treatment before study: not reported

Outcomes Outcomes reported in abstract of publication: dominant nodule size reduction ≥ 50%; other changes on dominant nodule size and number of nodules; thyroid gland size
Study details Study terminated before regular end: no
Publication details

Russian language publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "To study efficacy of thyroxine (TX) and potassium iodide (PI) in the treatment of benign nodular thyroid lesions (BNTL)"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk

Comment: judgement in relation to translation/translator's remarks

Comment: high risk for selection bias could influence all other domains

Allocation concealment (selection bias)High risk

Comment: judgement in relation to translation/translator's remarks

Comment: high risk for selection bias could influence all other domains

Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: judgement in relation to translation/translator's remarks
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: judgement in relation to translation/translator's remarks
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Unclear riskComment: judgement in relation to translation/translator's remarks
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: judgement in relation to translation/translator's remarks
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: judgement in relation to translation/translator's remarks
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: judgement in relation to translation/translator's remarks
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: judgement in relation to translation/translator's remarks
Selective reporting (reporting bias)Unclear riskComment: judgement in relation to translation/translator's remarks
Other biasUnclear riskComment: judgement in relation to translation/translator's remarks

LT4 Grussendorf 2011

Methods Parallel RCT (superiority design) with randomisation ratio 1:1:1:1
Participants

Inclusion criteria: White; age 18 to 65 years; TSH normal (0.6 to 3.0 mU/L), TN normal size or enlarged thyroid; at least one TN solid (cyst component ≤ 20%), TN ≥ 1 cm, for TN > 1 cm, diagnosis according to guidelines for diagnostic standards of thyroid disorders to exclude malignancy

Exclusion criteria: thyroid therapy within past 3 years; focal or diffuse autonomous thyroid structure; iodine contraindication; concomitant medication containing iodine (amiodarone); use of iodine-containing contrast medium within past 6 weeks; TPO-Ab 2 x above normal value; autoimmune thyropathy; symptomatic coronary disease; former radioiodine therapy or surgery; acute or chronic illness or allergy; pregnancy at screening; dermatitis herpetiformis; pathological laboratory values

Diagnostic criteria: medical history, physical examination, clinical laboratory and TSH, anti-TPO measurements, US nodule examination; nodules > 1 cm diagnosis according to guidelines for diagnostic standards to exclude malignancy

Interventions

Number of study centres: 60

Country/location: Germany

Setting: outpatients

Treatment before study: not reported

Titration period: after 3 months dose adjustment in the LT4 + I and LT4 groups based on TSH values (target range 0.2 to 0.8 mU/L)

Outcomes

Study ID: NCT00277589 (ClinicalTrials.gov); LISA Study

Outcomes reported in abstract of publication: percent volume reduction of all thyroid nodules measured by US; thyroid volume reduction

Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

Commercial funding from Sanofi-Syntelabo GmbH, Henning Berlin

Stated aim of studyQuote from publication: "The measurement of the effect of a treatment with (non suppressive) LT4, iodine, or a combination of both compared with placebo on volume of thyroid nodules and thyroid"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Centerwise randomization sequences with variable block lengths ... by the study statistician and sent to the pharmacy ... blindness"
Allocation concealment (selection bias)Low riskQuote from publication: "Centerwise randomization... and sent to the pharmacy that produced unlabeled coded medication packages for the total follow-up period with sufficient medication for the titration ... guarantee concealment and blindness"
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: "In the I and P arm, the medication was not changed, but an adaptation was simulated to keep investigators and patients blind"; "However, because only licensed drugs ... the patient but not the physician ... found out what group she/he is ... visiting pharmacy and comparing his pills with the available drugs"

Comment: the possibility of unblinding probably did not introduce bias for (semi)objective outcomes

Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: see above, the possibility of unblinding could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low risk

Quote from publication: "In the I and P arm, the medication was not changed, but an adaptation was simulated to keep investigators and patients blind"

Comment: at visit 3, if TSH was outside the target range (0.2 to 0.8 mU/L), the central laboratory sent new medication to the physician, who gave it blindly to the participants

Blinding of personnel (subjective outcomes)
Subjective outcomes
Low riskComment: there was probably no unblinding of personnel potentially introducing bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: "Ultrasonography ... by experienced and proficient examiner, who ... was masked to treatment assignment"

Comment: ultrasonographer was masked to treatment assignment (supplementary appendix)

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Low riskComment: there was probably no unblinding of personnel potentially introducing bias for subjective outcomes
Incomplete outcome data (attrition bias)
All outcomes
High risk

Quote from publication: " ... thus, the primary analysis ... remaining 794 patients. However, a sensitivity analysis in all 1013 patients ... performed ... whether... would change the results"

Comment: the number of participants analysed (post-hoc) after randomisation was similar between groups, but the reasons for incomplete follow up and dropouts were not explained (86% from n = 794 completed the study; 33% dropouts or missing data)

Selective reporting (reporting bias)High risk

Quote from publication: "In 38 patients, who stopped medication because of serious adverse events (e.g. hospitalization ... accidents, gynecological operations, infections, etc.), no ... relationship to medication ... by the investigators"

Comment: serious adverse events (assumed as not related to the medication) were mentioned under 'Methods', but it was not specified in which treatment groups they occurred; other adverse events were not described

Other biasUnclear riskComment: the study was supported by Sanofi-Aventis, Germany; possible sponsor bias

LT4 Koc 2002

Methods Cross-over RCT with randomisation ratio 1:1:1:1
Participants

Inclusion criteria: cold (scan) solitary nodule with palpation (≤ 30 mm); benign (cytology); multiple nodules (US ≤ 10 mm)

Exclusion criteria: Hashimoto's thyroiditis, antithyroid antibodies, previous neck surgery, previous radiation therapy; contraindication to LT4 suppressive therapy (pregnancy, cardiovascular disease), low TSH (< 0.4 mU/L) or high TSH (> 2.5 mU/L); > 45 years old; thyroid nodule diagnosis > 5 years; previously treated with LT4; palpable thyroid nodule > 30 mm or second nodule detected on US > 10 mm; cystic or degenerative nodules

Diagnostic criteria: palpation, thyroid scan, FNAB, cytology, US

Interventions

Number of study centres: 1

Country/location: Turkey/Istanbul

Setting: outpatients

Treatment before study: not reported

Titration period: LT4 was adjusted every 3 weeks until desired TSH level (± 25 μg/day)

Outcomes Outcomes reported in abstract of publication: nodule volume reduction or increase; percentage of participants with 50% or more nodule volume reduction; TSH levels
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

Non-commercial funding from Health Science Research Support Grant no. SA-29, Marmara University, Istanbul, Turkey 

Stated aim of studyQuote from publication: "To determine the response of solitary thyroid nodules to low- or high-level TSH suppression in a placebo-controlled, randomized crossover trial"
NotesIstanbul residents: region with adequate iodine intake; there was no washout period between treatments; urinary iodine excretion was not measured
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "Patients were basically randomized to two main groups according to the level of TSH suppression ... "

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: no detailed information; study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: no detailed information; study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: "Ultrasonography was performed ... same operator ... no access to patients' clinical and laboratorial data"

Comment: outcome assessor probably blinded

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: unblinding of outcome assessors for other outcomes than ultrasound measurements not mentioned
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote from publication: "Nine patients (three patients in group 1...), were excluded from the analysis ... noncompliance or inadequate TSH suppression"
Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear riskComment: there was no washout period between intervention periods

LT4 La Rosa 1995

Methods Parallel RCT with a randomisation ratio of 1:1:1
Participants

Inclusion criteria: solitary nodule ≤ 3.5 cm, solid (< 10% cyst component) (US); other nodules (maximum diameter < 50% of maximum diameter from main nodule; newly diagnosed nodules (< 1 year prior to study start)

Exclusion criteria: nodules > 3.5 cm (US); "hot" nodules (radioiodine scan 25 μCi); malignancy, follicular lesion, cyst haemorrhagic lesion, thyroiditis (FNAB cytology); thyroid hormone, TSH abnormal; serum thyroid antibodies; urinary iodine excretion < 8 μg/dL or > 27 μg/dL; CVD, liver diseases, pregnancy, osteoporosis

Diagnostic criteria: radioiodine scanning (nodule function); US (nodule size and characteristics); FNAB cytology (malignancy, benignity, follicular lesion, cyst haemorrhagic lesion, thyroiditis

Interventions

Number of study centres: 1

Country/location: Italy

Setting: outpatients

Treatment before study: not reported

Titration period: LT4 dose adjusted after the first 4 months until TSH < 0.3 mU/L

Outcomes Outcomes reported in abstract of publication: mean nodule volume decrease or increase, percentage of participants with clinically relevant nodule volume reduction (50% or more)
Study details Study terminated before regular end: yes, probably for benefit
Publication details

English language publication in a peer-reviewed journal

Commercial funding from Cyanamid Italia SpA providing PI tablets

Stated aim of studyQuote from publication: "To determine the effectiveness of levothyroxine and potassium iodide in treating patients with benign solitary cold thyroid nodules"
NotesArea with sufficient iodine supply and goitre prevalence in schoolchildren < 1%; urinary iodine excretion in this area ranged from 80 to 300 µg/day and was measured (all participants at 4-month intervals) to check compliance (participants receiving potassium iodide) and the absence of iodine contamination (participants receiving no treatment and receiving levothyroxine)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "We then randomly assigned patients ... to one of the three treatments (using randomized blocks with a coin slightly biased in favour of treatment groups ..."

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High risk

Quote from publication: "Compliance with therapy was individually controlled in patients receiving levothyroxine by carefully asking the patient ... 4-month intervals"

Comment: the study design could have introduced bias for subjective outcomes

Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: "...with allocation blinded only to the ultrasonography operator"

Comment: outcome assessor blinded to treatment groups (ultrasound measurements only)

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors blinded for ultrasonography measurements only
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote from publication: "Of the 80 patients, 70 (87.5%) completed ... follow-up. Three ... not receiving treatment dropped out (1 ... moved and 2 missed follow-up), as did 4 ... levothyroxine ... and 3 ... iodine (2 ... further treatment and 1 missed follow-up)"
Selective reporting (reporting bias)Low riskComment: none detected
Other biasHigh risk

Quote from publication: "The study was stopped because at the interim analysis, we obtained clinically important results for the first 80 patients who entered the study; we did not include 18 patients who were still being studied at the time of interim analysis"

Comment: study probably stopped for benefit; total sample size including 10% lost to follow up was estimated to be n = 160

Comment: possible sponsor bias

LT4 Larijani 2005

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: one benign palpable TN (FNAB, cytology)

Exclusion criteria: suspicion of or malignancy (FNAB); LT4 consumption at least in the preceding year; abnormal T4, T3, TSH; > 1 palpable TN; pregnancy; CVD; age ≤ 15 years or ≥ 60 years

Diagnostic criteria: serum T3, T4, TSH; US (solid or cystic, single or multiple); FNAB cytology (benign)

Interventions

Number of study centres: 1

Country/location: Iran

Setting: outpatients

Treatment before study: not reported

Titration period: not reported

Outcomes Outcomes reported in abstract of publication: nodule size reduction; mean nodule volume change
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

Commercial funding (?) from Iran Hormone Company and non-commercial funding from Teheran University of Medical Sciences (educational grant)

Stated aim of studyQuote from publication: "This study addresses the problem in an iodine-deficient area, evaluating the efficacy of levothyroxine suppression therapy on a 2-year course"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Patients were randomly assigned to either the levothyroxine ... placebo, with the use of a random number table"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskQuote from publication: "Both clinical and ultrasonographic studies were applied blindly"; "The attending physician and sonographer were blind to the treatment protocol"
Blinding of personnel (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: see above
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote from publication: "A total of 58 patients of the primary enrolled ... completed the second year of study (31 cases and 27 controls). One of the four dropouts ... surgery by choice"
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected (unclear whether commercial funding took place)

LT4 Ozkaya 2010

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: benign TN (FNAB, cytology) 

Exclusion criteria: TN > 2 cm; cystic nodules; pregnancy

Diagnostic criteria: ultrasonography; FNAB (cytology)

Interventions

Number of study centres: 1

Country/location: Turkey/Ankara

Setting: outpatients

Treatment before study: none

Outcomes Outcomes reported in abstract of publication: dominant nodule volume change; thyroid right lobe and thyroid left lobe change
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "We studied the efficacy of thyroxine-suppressive therapy in patients with euthyroid nodular disease"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "The patients were divided randomly into 2 groups, one group ... receiving levothyroxine ... and in the other ... without medication"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear risk

Quote from publication: "The measurements of nodule diameter ... performed by the same person, using high-resolution sonography"

Comment: no detailed information

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: nodule volume analysis after one year remained similar with 2 drop-outs in each group.
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Papini 1993

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: "(a) single thyroid nodule diagnosed by an endocrinologist with expertise in thyroid disease; (b) cytology consistent with a colloid nodule by FNA; (c) ultrasonic characteristics of a solid or prevalently solid nodule; (d) thyroid scan showing a decreased or normal pertechnetate 99mTc uptake of the nodule; (e) normal 131I uptake at 6 and 24 hours; (f) normal titres of TgAb and TPOAb antibodies; (g) normal serum thyroid hormones and TSH concentrations; (h) diagnosis made no more than 2 years before enrolment; no treatment with thyroid hormones, iodine compounds or antithyroid drugs in the same period of time; no history of neck irradiation or surgery; (i) age between 18 and 60 years; (j) absence of clinically relevant cardiovascular, hepatic, pulmonary or renal diseases"

Exclusion criteria: nodules containing a fluid volume ≥1 mL

Diagnostic criteria: palpation (single nodule); cytology FNA with a 22 or 25-gauge needle (colloid nodule); US (solid lesions < 3 mm size and with a theoretical axial resolution < 1 mm); normal values of serum TSH, FT3, FT4, TgAb, TPOAb; decreased or normal values for thyroid scan with 99mTc pertechnetate and 131I uptake at 6 and 24 hours

Interventions

Number of study centres: 3

Country/location: Italy/Rome metropolitan area (non-endemic for goitre)

Setting: outpatients

Treatment before study: none

Titration period: initial dose 50 μg before breakfast and increased by 25 to 50 μg weekly to the full dose, which was thereafter adjusted to induce TSH suppression

Outcomes Outcomes reported in abstract of publication: nodule size (palpation) and nodule volume changes (US); nodule size and thickness of thyroid lobe correlation (palpation and US); contralateral thyroid lobe thickness (US); number of nodules which decreased in size; clinical and laboratory parameters (FT4, FT3, T4, T3, TSH, Tg, TgAb, TPOAb)
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "... to test whether a 12-month suppression of serum TSH below normal range, verified during the whole study duration with a ultra sensitive assay, would modify the clinical evolution of solitary thyroid nodules"
NotesStatistical analysis: repeated, excluding nodules which were "not cold" (LT4: n = 35% (18/51) vs placebo: n = 32% (16/50) - results were unchanged
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "The study was multicentre randomized ..."; "The patient population consisted ... consecutive patients seen ... 1991, randomly allocated to the treatment with standard doses of levothyroxine ... and placebo group"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "Clinical evaluations were single-blinded (patients) while ultrasound measurements were double-blind (patients and examiners)"
Blinding of participants (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: see above (relating to ultrasound measurements)
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors blinded for ultrasonography measurements only
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote from publication: "There were six dropouts in the placebo ... and three ... treatment group"

Comment: reasons for dropouts were not provided

Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Papini 1998

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: single palpable nodule (greatest diameter between 10 to 30 mm; cytology consistent with a colloid nodule (FNAB); single solid nodule (US); thyroid volume within normal limits (< 14.3 mL); 99m Tc thyroid scan consistent with a hypofunctioning or non-visualised nodule; 131I uptake within normal limits; serum TSH, FT3, FT4, Tg, TgAb, TPOAb; no previous treatment with thyroid hormones, iodine compounds, or antithyroid drugs; no history of neck irradiation or surgery.

Exclusion criteria: concomitant nonpalpable nodules > 5 mm

Diagnostic criteria: US (solid), FNAB cytology (benignity); normal levels of serum TSH, FT3, FT4, TgAb, TPOAb ; thyroid scan with 99mTc pertechnetate (hypofunctioning or non-visualised nodule) and 131I uptake with gamma-camera within normal limits

Interventions

Number of study centres: multicentric

Country/location: Italy/Rome

Setting: outpatients

Treatment before study: none

Outcomes Outcomes reported in abstract of publication: nodule or thyroid volume changes; appearance of new nodules; serum TSH, clinical parameters
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "The present study evaluated over a 5-yr period 1) changes in nodule size and thyroid volume in a homogeneous group of patients randomly assigned to L-T4 suppressive therapy or to a control group; 2) enlargement of small concomitant lesions and appearance of new nodules; 3) correlations among baseline size, clinical and laboratory parameters, degree of TSH suppression, and observed thyroid changes; 4) rate of growth (or reduction) of thyroid nodules; and 5) reliability of cytological diagnosis"
Notes

"FNA and scintiscans were performed at enrollment and after 5 yr, after 2 months of L-T4 withdrawal"

This study was a "similar study with a longer follow-up", proposed by Papini 1993 in order to verify whether long-term suppressive therapy prevents growth of new nodules and induces reduction of size in a subgroup of nodules

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "The study was ... randomized clinical trial"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low risk

Quote from publication: "Clinical and hormonal evaluations were unblinded ..."

Comment: the study design probably did not introduce bias for (semi)objective outcomes

Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: see above; the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: " whereas US scans were blindly performed"; "All US evaluations were performed ... same center ... three blinded examiners ..."

Comment: relating to ultrasound measurements

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors were blinded to ultrasound scans only
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote from publication: "There were 14 dropouts ... 6 in the control group). In the L-T4 group, 7 patients experienced side effects ... and 3 of them abandoned the study"

Comment: no reasons stated for comparator group

Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Reverter 1992

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: TN single on palpation; "cold" and single by 99mpertechnetate thyroid scan; benign (colloid goitre) by FNAB

Exclusion criteria: multiples nodules by palpation or by scintigraphy; suggestion of neoplastic process (cytological findings); Hashimoto's thyroiditis; pregnancy and/or any contraindication for LT4 treatment

Diagnostic criteria: palpation (TN single); thyroid scan with 99mpertechnetate (TN "cold" and single); FNAB, cytology (benign, colloid goitre); US

Interventions

Number of study centres: 1

Country/location: Spain

Setting: outpatients

Treatment before study: not reported

Titration period: LT4 dose adjusted until TSH suppression was achieved (TSH < 0.1 mU/L)

Outcomes Outcomes reported in abstract of publication: nodule diameter changes (US); nodule volume changes; number of nodules with significantly volume reduction (> 50%); TSH, T4, FT4, T3
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "To evaluate the effect of treatment with TSH suppressive dose of levothyroxine in patients with benign thyroid nodules"
NotesLT4 dose adjusted until TSH suppression was achieved (TSH < 0.1 mU/L): mean dose to obtain this effective TSH suppression without hyperthyroidism was 2.82 ± 0.6 μg/kg body weight/day; only female participants
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Patients were randomly allocated in two groups... a table of random numbers"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: participants were unblinded; the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: personnel was unblinded; the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: personnel was unblinded; the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: no detailed information
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote from publication: "In this group, six patients dropped out ... (three patients desired the surgical treatment ... and three patients abandoned treatment ...)"; "All the group B patients completed the study"

Comment: first group consisted of thyroxine treated patients, second group (group B) of patients with no treatment. Disparate attrition rates (30%); however, intention-to-treat analysis was performed for nodule volume reduction of more than 50% (n = 4/20 vs n = 3/20)

Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Tsai 2006

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: TN single (US); cold (131I thyroid scan); benign (FNAB cytology); normal levels of T3, T4, FT4, TSH; absence of CVD or renal disease; no LT4 suppressive therapy or other thyroid medication before study

Exclusion criteria: TN > 1 (US and scintiscan); cystic nodules, neoplastic lesion, hot nodules (scintiscan); pregnancy; serious CVD, renal or liver disease

Diagnostic criteria: US, 131I thyroid scan, FNAB and cytology, normal levels of serum TSH, T4, T3, FT4

Interventions

Number of study centres: 1

Country/location: Taiwan

Setting: outpatients

Treatment before study: not reported

Titration period: not reported

Outcomes Outcomes reported in abstract of publication: nodule volume reduction > 50% (responders); nodule size reduction; serum Tg level
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "To study the efficacy of thyroxine-suppressive therapy in patients with solitary non-toxic thyroid nodules and its relation to serum thyroglobulin levels"
NotesTSH suppression: < 0.3 mU/L after LT4 therapy; compliance measurement: pill count
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "All patients ...were randomly divided into two groups ... levothyroxine ... and ... placebo"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "All investigators and patients did not know if the pill was placebo or levothyroxine"
Blinding of participants (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: see above
Blinding of personnel (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear risk

Quote from publication: "The measurements of nodule diameter ... performed ... same person ... linear transducer"

Comment: no detailed information

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: see above
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all randomised participants completed the study
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

LT4 Wemeau 2002

Methods Parallel RCT with randomisation 1:1
Participants

Inclusion criteria: single palpable nodule; benign (FNAB); nodule identified < 1 year before begin of study; age from 18 to 55 years

Exclusion criteria: more than 1 palpable nodule; history of CVD, osteoporosis, previous thyroid surgery, neck irradiation and/or thyroiditis; abnormal serum thyroid hormone or TSH levels, circulating autoantibodies, nodules with cystic component > 20%, hot nodules and suppression of surrounding tissue at thyroid imaging; nodule > 3 cm in any dimension

Diagnostic criteria: serum levels of FT3, FT4, TSH, TgAb, TPOAb, TSH Ab; nodule size, internal contents, peripheral halo or calcifications; additional nodules non palpables (US); benignity (US-FNAB); activity in the nodule region: non-functional, hypofunctional, functional (thyroid scan 99mTc pertechnetate)

Interventions

Number of study centres: 25

Country/location: France

Setting: outpatients

Treatment before study: none

Titration period: until TSH < 0.3 mU/L

Outcomes Outcomes reported in abstract of publication: variations in nodule volume (US); nodule size changes (palpation); clinically relevant TN volume reduction (50% or more); proportion of participants with reduced number of additional nodules (US), serum TSH level
Study details Study terminated before regular end: yes (recruitment problems)
Publication details

English language of publication in a peer-reviewed journal

Commercial funding from Merck-Lipha Santé France (computer, statistical support and LT4 drug supply)

Stated aim of studyQuote from publication: "To assess the efficacy of TSH-suppressing L-T4 therapy in reducing the volume of solitary benign thyroid nodules and in modifying perinodular thyroid tissue"  
NotesArea suggesting a sufficient iodine supply: median urinary iodine excretion: 8 μg/100 mL; ß-Blocker prescription allowed when tachycardia was present (bisoprolol, 5 to 10 mg/day); mean LT4 dose for effective TSH suppression (< 0.3 mU/L) without hyperthyroidism was 2.24 ± 0.45 μg/kg/day
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote from publication: "Patients were then randomly allocated to the LT4 treatment or placebo using a table of random numbers, without stratification according to site"

Comment: no stratification by study centre

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "Both LT4 and placebo were administered ... identical tablets"
Blinding of participants (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment:see above
Blinding of personnel (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: "Ultrasonography was repeated ... examiner had no access to previous findings, about the nodule, TSH ... treatment code"

Comment: relating to ultrasound measurements

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors blinded for ultrasonography only
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote from publication: "Six of the 17 patients who did not complete the protocol spontaneously ... withdrew from the study. Of the remaining 11, 2 ... L-T4 ... dropped-out (one developed iatrogenic thyrotoxicosis ... other ... thyroidectomy ...). The 9 other patients, ... placebo group ... dropped out ... following reasons ... and Graves' disease"

"The characteristics of the patients who dropped out and of their nodules were similar to those ...who completed the study (data not shown)"

Comment: disparate attrition rates; however, analyses were performed on an intention-to-treat basis

Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear risk

Quote from publication: "Despite an expected total sample of 300 patients, patients recruitment was difficult, and it was stopped after 135 informed patients ... 25 centers"

Comment: commercial funding from Merck-Lipha Santé France (computer, statistical support and LT4 drug supply); possible sponsor bias

LT4 Zelmanovitz 1998

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: normal range serum TSH (0.4 to 3.8 μU/mL), T3 (86 to 187 ng/dL), T4 (4.5 to 12.5 μg/dL); antimicrosomal, TgAb (< 1/100); Tg (0 to 52 ng/mL); single thyroid nodule (US); hypofunctioning (131I scintigraphy); benignity (cytology)

Exclusion criteria: cystic or mixed nodules (cystic component > 20%); Hashimoto's thyroiditis (positive antithyroid antibodies or cytopathological findings); previous neck irradiation; cardiovascular disease, pregnancy; contraindication for the use of LT4 suppressive therapy

Diagnostic criteria: US (internal contents); scintiscan (hypofunctional); cytology (benignity); thyroid hormone measurements

Interventions

Number of study centres: 1

Country/location: Brazil

Setting: outpatients

Treatment before study: previous suppressive therapy > 1 year before entering the study: LT4: 19%; placebo: 21%

Titration period: not reported

Outcomes Outcomes reported in abstract of publication: mean nodule volume change (US); nodule volume reduction (> 50%); nodule volume increase (> 50%); BMD
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

Commercial funding from Sanofi (LT4 and placebo tablets) and non-commercial funding from Hospital de Clínicas de Porto Alegre and CAPES scholarship (partial grants)

Stated aim of studyQuote from publication: "To analyze the effect of suppressive doses of T4 on the volume of benign STN and BMD. Furthermore, meta-analyses were performed to examine the quantitative synthesis of data from similar designed controlled trials"
NotesTSH suppression: TSH < 2 μU/mL measured at 20 minutes by TRH test (200 μg intravenous bolus) or TSH < 0.3 μU/mL after LT4 dose-adjustment; female participants were analysed according to their menopausal status (LT4: n = 10 premenopausal and n = 6 postmenopausal women; placebo: n = 12 premenopausal and n = 7 postmenopausal women)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "This study was a randomized ... trial"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: "The patients ... randomly allocated ... T4 or identical placebo pills"

Comment: the study design probably did not introduce bias for (semi)objective outcomes

Blinding of participants (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low risk

Quote from publication: "All examinations were done by the same radiologist, ... no access ... patients' data or ... assignment"

Comment: probably relating to ultrasound measurements

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: low risk of bias for outcomes measured by radiologist only
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: low attrition rate
Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear risk

Quote from publication: "Laboratory Sanofi kindly provided T4 and placebo tablets"

Comment: possible sponsor bias

PEI Bennedbaek 1998

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: 1) 99mTc pertechnetate scintigraphy demonstrating a solitary cold nodule; 2) US demonstrating solitary solid nodule; 3) US-guided FNAB compatible with a colloid nodule; 4) euthyroidism; 5) normal serum ionised calcium and calcitonin; 6) no major concomitant disease; 7) no medication affecting thyroid function; 8) no history of previous head or neck irradiation; and 9) normal indirect laryngoscopy.

Exclusion criteria: not described

Diagnostic criteria: US-guided FNAB compatible with a colloid nodule and benign follicular cells; 99mTc pertechnetate scintigraphy demonstrating a cold nodule; US demonstrating a solitary nodule

Interventions

Number of study centres: 1

Country/location: Denmark/County of Funen

Setting: outpatients (referred by their primary care physicians) 

Treatment before study: none

Titration period: for LT4: up to 6 months dose adjusted to reduce serum TSH to subnormal levels (0.10 to 0.40 mU/L)

Outcomes Outcomes reported in abstract of publication: nodule volume reduction (US); total thyroid volume (US); biochemical thyroid measurements; symptom scores (pressure and cosmetic) evaluated by questionnaire; median TN volume reduction; median perinodular thyroid volume reduction; percent of participants with clinical response (TN volume reduction = 50%); side effects
Study details Study terminated before regular end: no
Publication details English language of publication in a peer-reviewed journal
Non-commercial funding from Agnes and Knut Mørk Foundation and the Clinical Institut of Research, Odense University
Stated aim of studyQuote from publication: "To determine the effectiveness of a single small dose of sterile 98% ethanol injected into the nodule against that of suppressive LT4 (TSH < 0.4 mU/L)"
NotesPEI: n = 2/25 (8%) were operated at 6 months; 6 months follow up; success rate: nodule disappearance or > 50% reduction in size; compliance for LT4: "satisfactory" (two participants had only partial suppression of TSH)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Random allocation was achieved using a random number generator on a computer"; "However, randomization resulted in a comparatively higher frequency of smaller nodules in the LT4 group. Thus, 10 of 25 nodules (40%) were less than 5 mL, compared with 4 of 25 nodules (16%) in the PEIT group ... Nodule volume in both groups showed marked deviations from a normal distribution skewed toward smaller volumes in the LT4 group, thus favoring outcome in the LT4 group, as evidenced by previously published data (9)"; "... some refused ... treatment or control once a benign diagnosis established. Only nodules causing neck discomfort ... combined with a wish for treatment to achieve alleviation were considered for inclusion, ... randomization to no treatment could not be achieved"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: participants were unblinded; the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "For each patient, ultrasound... same operator ... blinding ..."
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors blinded for ultrasound measurements only
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote from publication: "One drop-out in each group was anticipated"; "Six months after ... two patients in the PEIT... operated upon due to unaltered complaints, 6-month evaluation was the end point ..."

Comment: evaluation was based on intention-to-treat analysis

Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear riskComment: baseline imbalance for thyroid nodules < 5 mL, see above

PEI Bennedbaek 1999

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: (1) 99mTc pertechnetate scintigraphy demonstrating a solitary no-uptake or low-uptake lesion; (2) US-demonstrated solitary solid nodule, including those with minimal (< 10%) cystic component; (3) US-guided FNAB compatible with a colloid nodule; (4) euthyroidism; (5) normal serum ionised calcium and calcitonin; (6) no major concomitant disease; (7) no medication affecting thyroid function; (8) no history of previous head or neck irradiation; and (9) normal indirect laryngoscopy.

Exclusion criteria: none described

Diagnostic criteria: US-guided FNAB compatible with a colloid nodule, 99mTc pertechnetate scintigraphy demonstrating a cold nodule; US demonstrating a solitary nodule

Interventions

Number of study centres: 1

Country/location: Denmark/County of Funen

Setting: outpatients (referred by their primary care physicians)

Treatment before study: previous thyroidectomy: PEI-1 = 6 participants; PEI-3 = 3 participants; previous LT4 treatment: PEI-1 = 8 participants; PEI-3 = 7 participants

Outcomes Outcomes reported in abstract of publication: nodule volume reduction; dose ethanol response relationship; pressure/cosmetic symptoms on a VAS; treatment tolerability
Study details

Run-in period: for LT4 participants: 3-month medication stop before randomization and PEI therapy

Study terminated before regular end: no

Publication details

English language of publication in a peer-reviewed journal

Non-commercial funding from Agnes and Knut Mørk Foundation and the Clinical Institut of Research, Odense University

Stated aim of studyQuote from publication: " ... to evaluate the efficacy of percutaneous ethanol injection therapy (PEIT) with special reference to dose response and symptom score and to describe side effects"
Notes"All patients received 1 g of oral paracetamol or 1 g of oral acidum acetyl salicylicum and local anesthesia with 1 mL of subcutaneous lidocaine (10 mg/mL) prior to treatment"
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Random allocation was achieved using a random number generator on a computer"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: participants were unblinded; the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "US measurements ... the same operator ... blinding ..."
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors blinded for ultrasound measurements only
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote from publication: "Statistically analysis is based on intention-to treat and no patients were excluded or changed ..."

Comment: reasons why participants discontinued the predetermined therapy were mentioned

Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

PEI Bennedbaek 2003

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: 1) 99mTc pertechnetate scintigraphy demonstrating a solitary cold nodule; 2) US-demonstrated solitary or prominent (additional nodule(s) < 1 cm detected on US but not on the scintiscan) anechoic cystic lesion with no or < 10% solid component and cyst volume at least 2 mL; 3) recurrence of the cyst fluid more than 1 month after primary aspiration; 4) cytological samples, obtained by FNAB under sonographic guidance, of the cyst fluid, the cyst wall and, if present, a residual solid component, to rule out malignancy; 5) euthyroidism; 6) normal serum calcitonin; 7) no major concomitant disease; 8) no medication affecting thyroid function; 9) no history of previous head or neck irradiation; and 10) normal indirect laryngoscopy.

Exclusion criteria: US-guided FNAB ruled out malignancy

Diagnostic criteria: US to demonstrate solitary nodule; US-guided FNAB for cystic colloid goitre or colloid goitre; 99mTc pertechnetate scintigraphy to demonstrate a cold nodule.

Interventions

Number of study centres: 1

Country/location: Denmark/County of Funen

Setting: outpatients (referred by their primary care physicians)

Treatment before study: previous surgery/131I: PEI = 2 vs NaCl = 4; previous number of aspirations: PEI = 1 (1 to 2) vs NaCl = 1 (1 to 2)

Outcomes Outcomes reported in abstract of publication: recurrence rate for reduction of benign recurrent thyroid cyst (recurrence: volume > 1 mL); cure (cyst volume ≤ 1 mL); thyroid cyst volume; chance of success; adverse events
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

Non-commercial funding from Agnes and Knut Mørk Foundation, A. P. Møller Support Foundation and commercial funding from Novo Nordisk Foundation

Stated aim of studyQuote from publication: "To determine whether US-guided ethanol injection reduces the recurrence rate of benign thyroid cysts"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Random allocation was achieved using a random number generator on a computer"; "The study was carried out with complete blinding of both investigators (F.N.B. and L.H.) and patients"; "Complete blinding was maintained throughout the whole study period until 6-month evaluation of the last patient. Allocation of treatment was thus carried out in a unbiased way"
Allocation concealment (selection bias)Low riskQuote from publication: "The Pharmacy of Odense University Hospital (Centralapoteket OUH) was responsible for the production of absolute ethanol (800 mg/ml) and isotonic saline, for preparation of bottles labeled “project ethanol vs. saline,” and for providing sealed code lists. A pharmacist independent of the investigators provided the investigators with 68 sealed boxes (labeled patient no. 1, 2, etc.). Each box contained three sealed bottles with 10 ml of sterile fluid (34x3 with saline and 34x3 with ethanol), and each was labeled “project medicine." "The corresponding list with codes detailing the content of the bottles was stored in a sealed envelope at the pharmacy"
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "The study was carried out with complete blinding of both investigators (F.N.B. and L.H.) and patients"
Blinding of participants (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: see above
Blinding of personnel (subjective outcomes)
Subjective outcomes
Low riskComment: see above
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "US measurements were performed ... same operator ... blinding toward previous measurements."
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors blinded for ultrasound measurements only
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote from publication: "Two of the 68 patients were excluded due to technical difficulties in one and due to pain during the instillation procedure and therefore discontinuation of the treatment in the other"
Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear riskComment: possible sponsor bias

PEI Chu 2003

Methods Parallel RCT with randomisation ratio 1:1:1
Participants

Inclusion criteria: 1) single palpable thyroid nodule; 2) ultrasonographic picture of a simple thyroid cyst (cystic component over 90% of total nodule volume without intracystic nodules or septa); 3) a thyroid cyst volume over 4 mL; 4) euthyroid on plasma thyroid function test; and 5) an absence of suspicious or malignant cytology

Exclusion criteria: not reported

Diagnostic criteria: US compatible with cystic component over 90% of total nodule volume

Interventions

Number of study centres: 1

Country/location: Taiwan

Setting: outpatients

Treatment before study: not reported

Outcomes Outcomes reported in abstract of publication: cure rate; recurrence rate; treatment failure; cyst volume changes
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: " ... study was designed to determine whether sclerotherapy is a more effective treatment of TCN than aspiration alone"; "We therefore compared PEI with percutaneous hydrochloric acid injection at a pH of 1.0 ... in order to evaluate the role of pH in the efficacy of the sclerosant solution"
Notes

Cure: nodule disappearance or volume reduction < 0.5 mL (maximum 5 sessions); recurrence: cystic volume > 1 mL

PEI therapy: additional 14 participants were enrolled for the long-term results of the treatment; no thyroxine therapy during the intervention and follow-up period

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "TCN patients were randomly assigned to 1 of 3 treatment groups ..."

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear risk

Quote from publication: "Thyroid ultrasonography was carried out ... same observer ..."

Comment: no detailed information

Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote from publication: "Excluding those lost of follow-up, 19 patients received follow-up for 18 months and 8 patients for 24 months"

Comment: no reasons for missing data were provided; 33% (8/24) of participants were followed-up until 24 months

Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: non detected

PEI Sung 2013

Methods

Parallel, non-inferiority RCT with randomisation ratio 1:1

Primary endpoint was the mean difference in volume reduction ratio (%) 6 months after treatment: non-inferiority margin was set as -8% (ethanol injection minus RF ablation) + subsequent superiority comparison after establishment of non-inferiority (two-sided 95% confidence interval of the outcome difference)

Participants

Inclusion criteria: a) presence of a cystic thyroid nodule (cystic portion > 90%); b) reports of pressure symptoms or cosmetic problems; c) cytologic confirmation of benignancy in at least two separate US-guided FNAC examinations (i.e. two biopsies performed with an interval of several months apart) for cystic fluid and/or a mural, solid component; (d) serum levels of thyroid hormone, thyrotropin, and calcitonin within normal limits

Exclusion criteria: a) nodules showing malignant features (i.e. taller than wide, spiculated margin, markedly hypoechoic, micro- or macrocalcifications) at US; b) the participant was prescribed medication or underwent other treatments for thyroid nodules within 6 months before enrolment in this study

Diagnostic criteria: US to demonstrate cystic portion > 90% in the TN, US-guided FNAC (benignity according to the Bethesda classification system), and laboratory and clinical evaluation

Interventions

Number of study centres: 1

Country/location: Korea/Seoul

Setting: outpatients

Treatment before study: no medication for thyroid or other thyroid treatments were allowed six months before study begin

Outcomes Outcomes reported in abstract of publication: volume reduction ratio (percentage) at 6-month follow up, therapeutic success rate, improvement of symptoms and cosmetic problems, and number of major complications
Study details Study terminated before regular end: no
Publication details

English language publication in a peer-reviewed journal

Commercial funding: "JHB is patent holder of unidirectional ablation electrode (but no money paid from the company yet)"; "SHP: Financial activities not related to the present article: institution received a research grant from Dongkook Pharmaceutical and from GE Healthcare".

Stated aim of studyQuote from publication: "The purpose of this study was to compare the volume reduction of single session EA and RF ablation for the treatment of cystic thyroid nodules"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "This study was a single-institution, randomized, non-inferiority trial"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "The outcome assessors (J.Y.S. and K.S.K.) were blinded to the treatment group allocation. US examination was performed in all patients at the time of the 1- and 6-month follow-up examinations"
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Low riskComment: outcome assessors were probably blinded throughout the whole study period
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote from publication: "Therefore, we performed the per-protocol analysis and showed that the results were consistent with the results of the intention-to-treat analysis"

Comment: Three participants (n =1 in the EA group and n = 2 in the RF group) required additional interventions due to incomplete improvement of symptoms. These participants were included in the intention-to-treat analysis, but excluded from the per-protocol analysis.

Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear riskComment: JHB is patent holder of unidirectional ablation electrode; commercial funding: institution received a research grant from Dongkook Pharmaceutical and from GE Healthcare

PEI Valcavi 2004

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: local discomfort or cosmetic damage, volume exceeding 2 mL, 50% or more fluid component as assessed by US examination, benignity as demonstrated by cytologic assessment obtained by US-guided FNAB; euthyroidism

Exclusion criteria: inadequate, suspicious, or positive FNAB cytologic specimens, high serum calcitonin levels, and contralateral  laryngeal cord palsy

Diagnostic criteria: US demonstrating fluid component; US-guided FNAB for benignity 

Interventions

Number of study centres: 1

Country/location: Italy

Setting: outpatients

Treatment before study: not reported

Outcomes Outcomes reported in abstract of publication: cyst volume reduction; cure rate (after 12 months); compressive/cosmetic symptoms; side events
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "To provide am overview of ultrasound (US)-guided percutaneous ethanol injection (PEI) therapy for thyroid cystic nodules and discuss the practical and technical details"
NotesCure rate: elimination of discomfort and cosmetic complaint one year after PEI therapy; no local anaesthesia needed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "Patients were randomly assigned ..."

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: no detailed information
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: no reasons for missing data provided
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

PEI Verde 1994

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: solitary cystic thyroid nodule; no malignancy (FNA); cold areas (scintiscan); no treatment with thyroid hormones, iodine or antithyroid drugs before or after enrolment

Exclusion criteria: not reported

Diagnostic criteria: thyroid cystic nodule: fluid volume > 70% of the total nodule volume (US evaluation); clinically and biochemically (TSH, FT3, FT4, Tg, TPOAb, TgAb)

Interventions

Number of study centres: 1

Country/location: Italy

Setting: outpatient clinics for thyroid diseases

Treatment before study: none

Outcomes Outcomes reported in abstract of publication: nodule volume reduction; percent of participants with nodule volume reduction > 50%; cyst fluid recurrence (US); success rate; serum TSH, FT3, FT4, Tg, TPOAb, TgAb; cost
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "To test whether PEI was more effective than FNA alone in reducing the volume of cystic thyroid nodules"
NotesGroup 3 (prospective study): after evaluation of the study results of group 1 and 2, "a prospective trial was carried out to test long-term efficacy and safety of the procedure on clinical, ultrasonographic and hormonal grounds" with 12 months follow-up.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "20 patients with predominantly cystic thyroid nodules ... randomized in two groups ..."

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Low riskQuote from publication: "After the first visit, nodule volumes ... evaluated ... two consecutive ultrasound scans ... two blinded examiners"
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
High riskComment: outcome assessors blinded for ultrasound scans only
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all randomised participants finished the study
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

RF Faggiano 2012

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: age above 18 years; benign thyroid nodules; solid or predominantly solid ((cystic component 30%), large (4.0 ml) thyroid nodules); and refusal and/or inefficacy of surgery and/or radioiodine therapy; TN with pressure symptoms

Exclusion criteria: pregnancy and malignant or suspicious thyroid nodules

Diagnostic criteria: benignity confirmed by US-guided FNAC in nodules > 1 cm (or less in the presence of US characteristics suspected for malignancy), blood tests for thyroid function (TSH, FT3, FT4, TgAb, TPOAb)

Interventions

Number of study centres: 1

Country/location: Italy

Setting: outpatients (in a hospital)
Treatment before study: unsuccessful surgery (n = 2); unsuccessful radioactive iodine therapy (131I) (n = 2)

Outcomes Outcomes reported in abstract of publication: change in TN volume and thyroid function; pressure symptoms (changes); thyroid function changes; clinically, biochemically evaluation; tolerability
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

Non-commercial funding by the Department of Molecular and Clinical Endocrinology and Oncology, Frederico II University of Naples

Stated aim of studyQuote from publication: "To investigate the long-term effectiveness of RTA in patients with TNs. Both toxic and nontoxic TNs will be evaluated"
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "Patients enrolled ... randomized as follows: 20 patients ... single RTA, ... 20 patients ... followed up (group B)"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: no detailed information
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all randomised participants finished the study
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: none detected

RF Huh 2012

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: 1) predominantly solid nodule (solid portion > 50%); 2) pressure symptoms or cosmetic problems; 3) largest diameter of TN > 2 cm; 4) cold nodule at 99mTc pertechnetate scintigraphy; 5) normal serum levels of thyroid hormone, TSH and calcitonin; 6) cytologic confirmation of benignity (at least two separate US-guided FNAC examinations; 7) nodules showing no malignant features (taller than wide, spiculated margin, markedly hypoechoic, micro- or macrocalcifications) at US; 8) refusal of or ineligibility for surgery

Exclusion criteria: solid portion of the nodule < 50%; TN size < 2 cm; autonomously functioning TN; recurrent thyroid cancers

Diagnostic criteria: laboratory values in normal range (TSH, T3, FT4, TPOAb, serum calcitonin, blood coagulation tests), cytologic examination after at least two FNAB confirming benignity, thyroid scintiscan with 99mTc pertechnetate showing cold thyroid nodule, US investigation

Interventions

Number of study centres: 1

Country/location: Korea/Seoul

Setting: outpatient (in a hospital)

Treatment before study: not reported

Outcomes Outcomes reported in abstract of publication: nodule volume changes; pressure symptoms / cosmetic complaints changes
Study details Study terminated before regular end: no
Publication details English language of publication in a peer-reviewed journal
Commercial funding: "JHB is patent holder of unidirectional ablation electrode (but no money given by the company yet)"
Stated aim of studyQuote from publication: "To prospectively evaluate the efficacy of additional radiofrequency (RF) ablation by comparing the results of one and two sessions"
Notes"The patients were treated with 2% lidocaine at the puncture site for local anesthesia"
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote from publication: "Finally, 30 patients were prospectively randomly ... by using a computer-assisted random number generator"
Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low risk

Quote from publication: "The operator was aware of the group for the patient at the time of thyroid ablation"

Comment: the study design probably did not introduce bias for (semi)objective outcomes

Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: no detailed information
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all participants completed the study
Selective reporting (reporting bias)Low riskComment: none detected
Other biasUnclear risk

Comment: possible sponsor bias

Comment: four cross-over cases throughout the study: group 1: n = 3/15 (20%) received two sessions of RF, due unsatisfactory results after the first ablation and group 2: n = 1/15 (7%) received only one session because of satisfactory results.

TETRA Hegedüs 1988

  1. a

    BMD: bone mineral density; CVD: cardiovascular disease; EA: ethanol ablation; FNA: fine-needle aspiration; FNAB: fine-needle aspiration biopsy; FNAC: fine needle aspiration cytology; FT3: free tri-iodothyronine; FT4: free thyroxine; I: iodine; 131I: iodine 131; ILP: interstitial laser photocoagulation; i.v.: intravenously; LP: laser photocoagulation; LP-1: laser photocoagulation – one session; LP-3: laser photocoagulation - three sessions; LT4/L-T4: levothyroxine; NaCl: sodium chloride; PEI: percutaneous ethanol injection; PEI-1: percutaneous ethanol injection - one session; PEI-3: percutaneous ethanol injection - three sessions; PLA: percutaneous laser ablation; PLAC: placebo; RCT: randomised controlled trial; RF: radiofrequency; RTA: radiofrequency thermal ablation; T3: plasma (serum) tri-iodothyronine; T4: plasma (serum) thyroxine; 99mTc: Technetium 99m; TCN: thyroid cyst nodule; Tg: thyroglobulin; TgAb: antithyroglobulin autoantibody; TN: thyroid nodule; TPOAb: antiperoxidase autoantibody; TRH: thyrotropin-releasing hormone; TSH: thyrotropin; TSH Ab: anti-thyrotropin receptor antibody; US: ultrasonography; VAS: visual analogue scale; WHO: World Health Organization

Methods Parallel RCT with randomisation ratio 1:1
Participants

Inclusion criteria: solitary nodule cyst of at least 2 mL and the absence of any residual following complete cyst aspiration

Exclusion criteria: toxic goitres; large multinodular goitre

Diagnostic criteria: US demonstrating solitary thyroid cyst

Interventions

Number of study centres: 1

Country/location: Denmark

Setting: outpatients

Treatment before study: not reported

Outcomes Outcomes reported in abstract of publication: cure; recurrence/no recurrence; cyst volume changes
Study details Study terminated before regular end: no
Publication details

English language of publication in a peer-reviewed journal

No information on funding

Stated aim of studyQuote from publication: "To investigate, if tetracycline hydrochloride instillation seems promising in further reducing the number of patients who have to undergo surgery in a larger series of patients with solitary thyroid cysts"
NotesCure: absence of any residual nodule and an ultrasonic cyst volume of less than 1 mL 12 months after last treatment; subgroups: hemorrhagic cyst fluid and clear yellow cyst fluid
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote from publication: "Patients were randomized to aspiration followed by flushing ... either ... tetracycline or ... isotonic saline"

Comment: no detailed information

Allocation concealment (selection bias)Unclear riskComment: no detailed information
Blinding of participants ((semi)objective outcomes)
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of participants (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of personnel ((semi)objective outcomes
(Semi)objective outcomes
Low riskComment: the study design probably did not introduce bias for (semi)objective outcomes
Blinding of personnel (subjective outcomes)
Subjective outcomes
High riskComment: the study design could have introduced bias for subjective outcomes
Blinding of outcome assessment ((semi)objective outcomes)
(Semi)objective outcomes
Unclear riskComment: no detailed information
Blinding of outcome assessment (subjective outcomes)
Subjective outcomes
Unclear riskComment: no detailed information
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all randomised participants finished the study
Selective reporting (reporting bias)Low riskComment: none detected
Other biasLow riskComment: gender baseline imbalance

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Baek 2010Not a randomised controlled trial
Cheung 1989Palpation as a method for measurement of nodule size
Diacinti 1992Not a randomised controlled trial
Dossing 2002Not a randomised controlled trial
Erdem 1997Not a randomised controlled trial
Kanotra 2008Not a randomised controlled trial
Kim 2005Not a randomised controlled trial
Knight 2006 Aim of treatment was goitre reduction
Lima 1997Not a randomised controlled trial
Mainini 1995Not a randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

LP Dossing 2001

Trial name or title NCT00150150
Methods

Allocation: randomised

Endpoint classification: safety/efficacy study

Intervention model: parallel assignment

Masking: open label

Primary purpose: treatment

Participants

Condition: benign solitary solid and cystic thyroid nodules

Enrollment: 70

Inclusion criteria

  • Participants with a solitary solid thyroid nodule confirmed by ultrasonography

  • Participants with a solitary cystadenoma (cystic part more than 2 mL) confirmed by ultrasonography

  • Participants with an autonomous functioning thyroid nodule

Exclusion criteria

  • No family history of thyroid cancer

  • Prior neck radiation

  • Fine needle biopsy without valid diagnostic criteria for benign thyroid disease

  • Nodules larger than 4 cm (largest diameter)

  • Suspicion of malignancy

  • Increased serum calcitonin

  • Pregnancy or lactation

  • Alcohol, medicine or drug abuse

  • No safe contraception

  • Physical or psychic condition that hinders corporation

Interventions

Intervention(s): interstitial laser photocoagulation (ILP) (one session)

Comparator(s): ILP (two or three sessions); 131I

Outcomes

Primary outcome(s)

  • "To evaluate the efficacy and feasibility of repeated ILP treatments in a prospective randomised study where the nodule and thyroid volume are measured 1, 3, 6 and 12 months after the ILP"

  • "In the study of patients with a cystadenoma the measures will be done like wise, but also the recurrence of the cystic part will be measured"

  • "In patients with an autonomous functioning nodule measurements of thyroid function are performed 1, 2, 3, 6, 8 and 12 months after ILP or 131I therapy"

Starting date

Study start date: January 2001

Study completion date: March 2006

Contact information Responsible party/principal investigator: Helle Dossing, MD; Odense University Hospital, Denmark
Notes

"The recruitment status of this study is unknown because the information has not been verified recently"

No study results posted on ClinicalTrials.gov

LP Pacella 2008

Trial name or title NCT00858104
Methods

Allocation: randomised, multicentre

Endpoint classification: safety/efficacy study

Intervention model: parallel assignment

Masking: open label

Primary purpose: treatment

Participants

Condition: benign thyroid nodules

Enrollment: 200

Inclusion criteria

  • The presence of a single nodule or dominating nodule

  • A solid or mixed echo-structure with less than 20% fluid volume

  • A lesion volume between 5 and 18 mL (greatest diameter > 3.0 cm and ≤ 4 cm)

  • Thyroid hormone and TSH serum levels within the normal values

  • Two cytologically negative examinations for suspected neoplasia (British Thyroid Association, Second class THY) within the last six months

  • Calcitonin values within the normalcy value

  • Anticoagulant treatment suspension and antiaggregation treatment suspended for at least 72 hours

Exclusion criteria

  • Hyperfunctioning lesion (99mTc scintigraph)

  • Autoimmune thyropathy or elevation of autoantibodies

  • Active anticoagulant treatment or antiaggregation treatment

Interventions

Intervention(s): PLA

Comparator(s): no intervention (only follow up)

Outcomes

Primary outcome(s): "Short- (1-year) and long- (3-year) term evolution of the thyroid nodules volume and symptoms after the treatment vs. simple clinical observation (... endpoint: % nodules with greater than 50% base volume reduction and % patients free of symptoms; time frame 3 years)"

SECONDARY OUTCOME(S): "Assessment of short-term and long-term PLA safety, tolerability and reproducibility ... time frame 3 years)"

Starting date

Study start date: November 2008

Study completion date: December 2012

Contact information Responsible party/principal investigator: Dr Claudio Maurizio Pacella
Notes

This study is ongoing, but not recruiting participants.

No study results posted on ClinicalTrials.gov for this study.

LT4 Shih 2007

Trial name or title NCT00552253
Methods

Allocation: randomised, single centre

Endpoint classification: safety/efficacy study

Intervention model: cross-over

Masking: open label

Primary purpose: treatment

Participants

Condition: benign thyroid nodule

Enrollment: 10

Inclusion criteria

  • Age between 20 to 90 years

  • Benign nodular goitre diagnosed with thyroid echo and fine-needle aspiration cytology

Exclusion criteria

  • Age younger than 20 or older than 90 years

  • Pregnancy

  • Allergy to eltroxin

  • Taking other drugs which will have drug interactions with eltroxin

  • Participants with cardiovascular disease, hypertension, gastrointestinal disease

Interventions

Intervention(s): levothyroxine 100 µg/day (one hour before breakfast) for three months

Comparator(s): levothyroxine (just after breakfast) for three months

Outcomes Primary outcome(s): "The size of thyroid nodules (time frame: 3 months after levothyroxine treatment)"
Starting date

Study start date: October 2007

Study completion date: July 2008

Contact information Responsible party/principal investigator: Shyang-Rong Shih, Internal Medicine, National Taiwan University Hospital
NotesNo study results posted on ClinicalTrials.gov

RF Baek 2013

  1. a

    131I: iodine 131; PLA: percutaneous laser ablation; 99mTc: Technetium 99m; TSH: thyrotropin; US: ultrasound

Trial name or title NCT01778400
Methods

Allocation: randomised

Endpoint classification: efficacy study

Intervention model: parallel assignment

Masking: single blind (outcomes assessor)

Primary purpose: treatment

Participants

Condition: thyroid nodules

Enrollment: 50

Inclusion criteria

  • Individuals with predominantly cystic thyroid nodules (90% > cystic portion > 50%)

  • Reports of pressure symptoms or cosmetic problems

  • Cytologic confirmation of benignity in at least two, separate US-guided, fine-needle aspiration cytology or core needle biopsy for cystic fluid and/or a mural, solid component

  • Serum levels of thyroid hormone, thyrotropin, and calcitonin within normal limits

Exclusion criteria

  • Nodules showing malignant features, i.e. taller than wide, spiculated margin, markedly hypoechoic, micro- or macrocalcifications (on US)

  • Lack of informed consent

  • Less than 20 years old

  • Pregnancy

Interventions

Intervention(s): radiofrequency ablation

Comparator(s): ethanol ablation

Outcomes

Primary outcome(s): "Quantitative volume reduction ratio of a thyroid lesion at six months following compared with before the ablation treatment"

Secondary outcomes(s): "Binary therapeutic success rate which was defined as the proportion of patients who showed volume reduction > 50%, improvement of symptomatic and cosmetic scores, and the number of major complications"

Starting date

Study start date: February 2013

Study completion date: March 2014

Contact information Responsible party/principal investigator: Jung Hwan Baek, Asan Medical Center
NotesThis study is currently recruiting participants