Description of the condition
A thyroid nodule is a discrete lesion within the thyroid gland that is palpable and ultrasonographically distinct from the surrounding thyroid parenchyma (ATA 2006). The thyroid nodules are divided into cysts, inflammatory nodules, tumoral nodules (benign, malignant) and may present as proliferatives nodular goiter (CSE 2007). Thyroid nodules are a common clinical problem. The incidence of nodular thyroid disease varies among different populations around the world. In iodine sufficient areas, for instance, palpable thyroid nodules are found in about 4% to 7% of the population, while they are even more prevalent in individuals living in areas of iodine deficiency (Hegedüs 2004). The use of newer high-sensitivity neck ultrasonography has increased the number of detectable thyroid nodules (Massoll 2002), resulting in a very high prevalence (70%) of nodules within the general population (Shimura 2005). Thyroid nodules are more common as age increases and as iodine intake decreases, and they occur more frequently in women (Lansford 2006). There are 3% to 7% of the population with palpable thyroid nodules found in China, however high-resolution ultrasound can detect thyroid nodules in 20% to 70% of the population (CSE 2007). Therefore, we are now facing an 'epidemic' of thyroid nodules.
Most thyroid nodules are asymptomatic and people often find them incidentally on physical examination or self-palpation or incidentally on imaging studies performed for unrelated reasons. A minority of patients with thyroid nodules have thyroid dysfunction, while some patients with thyroid nodules show obstructive symptoms. Although the incidence of malignancy is only about 5% of all nodules (Hegedüs 2004), the clinical importance of newly diagnosed thyroid nodules is primarily the exclusion of thyroid malignant lesion (Belfiore 1989; Hegedüs 2004; Tan 1997). Thyroid malignancy may be associated with the following: clinical features (1) historical features: young (less than 20 years) or old (greater than 60 years) age, male sex, neck irradiation during childhood or adolescence, rapid growth, recent changes in speaking, breathing or swallowing, family history of thyroid malignancy or multiple endocrine neoplasia type 2; (2) physical examination: firm and irregular consistency of nodule, fixation to underlying or overlying tissues, vocal cord paralysis, regional lymphadenopathy; ultrasound findings: (1) hypoechoic lesions, irregular margins, presence of calcifications, absence of halo, internal or central blood flow; (2) low suspicion: echo-free (cystic) lesion, homogeneously hyperechoic lesions (Henry 2008).
Thyroid-stimulating hormone (TSH), thyroid ultrasound and fine-needle aspiration biopsy (FNAB) are key tests to help differentiate malignant from benign lesions. The diagnosis of thyroid nodule malignancy is established through history and physical examination, followed by ultrasonography, FNAB and evaluation of the sample by an experienced cytologist (Hegedüs 2003). With the discovery of a thyroid nodule larger than 1 cm to 1.5 cm in any diameter, one may use serum TSH and free thyroid hormone concentrations as a first-line screening test (Henry 2008). With an elevated TSH level, measurement of serum anti-thyroid peroxidase (anti-TPO) antibody and anti-thyroglobulin (anti-Tg) antibody levels may be helpful for diagnosis of chronic autoimmune thyroiditis (Tan 1997). If the serum TSH is subnormal, one should obtain a radionuclide thyroid scan to document whether the nodule is functioning, shows dysfunction ('warm'), or is non-functioning ('cold'). Functioning nodules rarely harbour malignancy (ATA 2006). Calcitonin may be a useful serum marker of medullary thyroid carcinoma (Cohen 2000). A baseline serum calcitonin value of 10 to 100 pg/mL is abnormal (normal baseline less than 10 pg/mL) and should result in further investigations; values that exceed 100 pg/mL are highly suggestive of medullary thyroid carcinoma (AACE/AME 2006). Computerised tomography (CT) scanning and magnetic resonance imaging (MRI) in the initial diagnosis of thyroid malignancy do not provide higher quality images of the thyroid and cervical nodes than ultrasonography. CT examination of the lower central neck is preferable when tracheal or mediastinal invasion is suspected (Hegedüs 2003). FNAB of thyroid nodules has eclipsed all other techniques for diagnosing thyroid cancer, with reported overall rates of sensitivity and specificity exceeding 90% in iodine-sufficient geographical areas (Henry 2008).
Description of the intervention
All current therapies are effective, but all have their problems. In China and many other countries, doctors use Chinese herbal medicines (CHM) to treat many diseases including thyroid nodules. The contents of traditional Chinese herbal preparations are variable depending on traditional Chinese medicine syndromes of patients. CHM for treating thyroid nodules include Milkvetch, Codonopsis Pilosula, Figwort root, Pangolin Scales, Selfheal, Chinese Thorowax root, Nutgrass Galingale Rhizome, Seaweed, Laminaria Tents, Musk and others. They are made into a Chinese proprietary medicine or a compound of several herbs irrespective of preparation. Besides the traditional herbal decoction (remaining liquid prepared by boiling a mixture of different herbal medicine), there are various forms of herbal medicines such as patent medicine (fixed formula of Chinese medicines in different forms, such as granules, tablets, capsules, or liquids) (Sun 2007), and extracts of herbal medicine (Song 2006), for example Selfheal oral liquid (liquid prepared by boiling Selfheal).
How the intervention might work
Clinical studies from the Chinese literature show that Chinese herbal preparations might shrink the thyroid nodules without significant adverse effects (Tan 2011; Wu 2010; Zhang 2006a). According to the theory of Chinese medicine, practitioners recognise that thyroid nodules are due to blood stasis, Qi stagnation and phlegm coagulation. There are several explanations for CHMs' effects inhibiting the proliferation of thyroid nodule cells: 1. decreased sensitivity of thyroid nodule cells to TSH; 2. decreased activity of TSH; 3. induced apoptosis of thyroid nodule cells; and 4. direct injury of thyroid nodule cells (Zhang 2006b). Herbal preparations are prescribed by practitioners based on the patients' symptoms and observation of the tongue and pulse, so there is a great deal of variation in the use of herbal preparations (Liu 2009).
Why it is important to do this review
Up to now, there are many published studies about the effects of CHM for thyroid nodules (Tan 2011; Wu 2010; Zhang 2006a). However the quality and results of these studies have not been systematically reviewed. There is no systematic review on CHM for benign thyroid nodules in adults so far. Therefore, we aim to assess the existing evidence of CHM for the treatment of benign thyroid nodules.
To assess the effects of Chinese herbal medicines for benign thyroid nodules in adults.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
Participants (aged 18 years and above) with imaging-confirmed thyroid nodules.
We will exclude participants with malignant thyroid nodules on cytology.
Types of interventions
- Chinese herbal medicines (CHM).
- CHM plus L-thyroxine.
This will include Chinese patent herbal medicines, other patent herbal products pertaining to different traditional medicines, extracts of a single herb or compound of herbs, or other individualised herbal remedies being made from decoction and granulate. We will also include trials of CHM plus L-thyroxine compared with L-thyroxine.
The treatment duration will be at least four weeks.
- No treatment.
Types of outcome measures
- Nodule volume reduction equal to or greater than 50% (evaluated by ultrasonography measurements)
- Pressure symptoms, cosmetic complaints or both
- Adverse events
- Health-related quality of life (measured by a validated instrument)
- All-cause mortality
- Cancer occurrence
- Changes in number and size of the thyroid nodules
- Changes in thyroid volume
- Thyrotropin (TSH), thyroxine (T4) and tri-iodothyronine (T3) serum levels
- Socio-economic effects (for example hospital stay, sick leave days, avoidance of surgery, costs)
Timing of outcome measurements
We define short-term measurements as up to four weeks, middle-term as four to eight weeks and long-term as greater than eight weeks.
'Summary of findings' table
We will present a 'Summary of findings' table reporting the following outcomes listed according to priority.
- All-cause mortality.
- Cancer occurrence.
- Health-related quality of life.
- Adverse effects.
- Pressure symptoms/cosmetic complaints.
- Nodule volume reduction of 50% or more.
- Socio-economic effects.
Search methods for identification of studies
We will search the following sources from inception to the present.
- The Cochrane Library.
- Chinese Conference Papers Database.
- Chinese Dissertation Database.
We will also search databases of ongoing trials (www.clinicaltrials.gov/, www.controlled-trials.com/) with links to several databases and (www.clinicaltrialsregister.eu/). We will provide information (including trial identifier) about potentially-relevant ongoing studies in the table 'Characteristics of ongoing studies' and in the appendix 'Matrix of study endpoints (protocol/trial documents)'. We will try to find the protocol of each included study, either in databases of ongoing trials, in publications of study designs, or both, and specify data in the appendix 'Matrix of study endpoints (protocol/trial documents)'.
For detailed search strategies see Appendix 1. We will continuously apply 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). Four weeks before we submit the final review draft to the Cochrane Metabolic and Endocrine Disorders Group (CMED) for editorial approval we will perform a complete updated search on all specified databases. Should we detect new studies for inclusion we will evaluate these and incorporate findings in our review before submission of the final review draft. If the peer review process takes longer than six months after submission of our final review draft due to the necessity to revise our draft, we will perform another full updated search.
If we detect additional relevant key words during any of the electronic or other searches we will modify the electronic search strategies to incorporate these terms, and document the changes. We will include studies published in any language.
We will send results of electronic searches to the Cochrane Metabolic and Endocrine Disorders Review Group for databases which are not available at the editorial office.
Searching other resources
We will try to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, (systematic) reviews, meta-analyses and health technology assessment reports.
We will also check 'grey' literature including unpublished conference proceedings or abstract books, and contact pharmaceutical companies which produce herbal medicines for thyroid nodules to identify unpublished trials.
Data collection and analysis
Selection of studies
To determine the studies to be assessed further, two authors (WW, WY) will independently scan the abstracts, titles or both sections of every record retrieved. We will investigate all potentially-relevant articles as full text. Where differences in opinion exist, they will be resolved by a third party. If resolving disagreement is not possible, the article will be added to those 'awaiting assessment' and we will contact study authors for clarification. We will present an adapted PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow-chart of study selection (Figure 1) (Liberati 2009).
|Figure 1. Study flow diagram.|
Data extraction and management
For studies that fulfil inclusion criteria, two authors (WW, XR) will independently abstract relevant population and intervention characteristics using standard data extraction templates (for details see Table 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13) with any disagreements to be resolved by discussion, or if required by a third party.
We will send an email to authors of included studies to enquire whether they are willing to answer questions regarding their trials. We will present the results of this survey in Appendix 14. Furthermore, we will seek relevant missing information on the trial from the primary author(s) of the article, if required.
Dealing with duplicate publications and companion papers
In the case of duplicate publications and companion papers of a primary study, we will try to maximise yield of information by simultaneous evaluation of all available data.
Assessment of risk of bias in included studies
Two review authors (WWu, WYang) will assess the risk of bias of each included study independently. We will resolve disagreements by consensus, or by consultation with a third party.
We will assess risk of bias using The Cochrane Collaboration’s tool (Higgins 2011). We will use 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 will assess outcome reporting bias (Kirkham 2010) by integrating the results of 'Examination of outcome reporting bias' (Appendix 8), 'Matrix of study endpoints (protocol/trial documents)' (Appendix 7) and section 'Outcomes (outcomes reported in abstract of publication)' of the 'Characteristics of included studies' table. This analysis will form the basis for the judgement of selective reporting (reporting bias).
We will judge risk of bias criteria as 'low risk', 'high risk' or 'unclear risk' and evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will present a 'Risk of bias' figure and a 'Risk of bias summary' figure.
We will assess 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 intend to evaluate risk of bias separately for subjective and objective outcomes (Hróbjartsson 2013).
We will define the following endpoints as subjective outcomes.
- Adverse events.
- Health-related quality of life (using a validated instrument).
- Pressure symptoms, cosmetic complaints or both.
- Socio-economic effects (for example hospital stay, sick leave days, avoidance of surgery, costs).
We will define the following outcomes as (semi)objective outcomes.
- All-cause mortality.
- Cancer occurrence.
- Changes in number and size of the thyroid nodules.
- Changes in thyroid volume.
- Nodule volume reduction equal to or greater than 50% (evaluated by ultrasonography measurements).
- Thyrotropin (TSH), thyroxine (T4) and tri-iodothyronine (T3) serum levels.
Measures of treatment effect
We will express dichotomous data as odds ratio (OR) or risk ratio (RR) with 95% confidence intervals (CI). We will express continuous data as differences in means (MD) with 95% CI.
Unit of analysis issues
We will take into account the level at which randomisation occurred, such as cross-over trials, cluster-randomised trials and multiple observations for the same outcome.
Dealing with missing data
We will obtain relevant missing data from authors, if feasible, and carefully evaluate important numerical data such as screened, randomised patients as well as intention-to-treat (ITT), as-treated, and per-protocol (PP) populations. We will investigate attrition rates, for example dropouts, losses to follow-up and withdrawals, and critically appraise issues of missing data and imputation methods (for example last-observation-carried-forward (LOCF)).
Assessment of heterogeneity
In the event of substantial clinical, methodological or statistical heterogeneity, we will not report study results as meta-analytically pooled effect estimates.
We will identify heterogeneity by visual inspection of the forest plots and by using a standard Chi
When we find heterogeneity, we will attempt to determine potential reasons for it by examining individual study and subgroup characteristics.
We expect the following characteristics to introduce clinical heterogeneity.
- Incidental diagnosis or diagnosis because of clinical symptoms or physical signs.
- Difference in participating populations.
- Different drug manufacturers or drug doses.
- Duration of intervention.
Assessment of reporting biases
If we include 10 studies or more for a given outcome, we will use funnel plots to assess small study bias. There are a number of explanations for the asymmetry of a funnel plot (Sterne 2001). Therefore, we will interpret results carefully (Lau 2006).
We will primarily summarise low risk of bias data by means of a random-effects model. We will perform statistical analyses according to the statistical guidelines referenced in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Subgroup analysis and investigation of heterogeneity
We will carry out the following subgroup analyses and plan to investigate interaction.
- Age (less than 18 years, 18 to 70 years, more than 70 years).
- Duration of intervention (depending on data).
We will perform sensitivity analyses in order to explore the influence of the following factors on effect size.
- Restricting the analysis to published studies.
- Restricting the analysis taking into account risk of bias, as specified at '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 will also 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).
We thank Gudrun Paletta, Assistant Managing Editor of Cochrane Metabolic and Endocrine Disorders Group, for her expertise and editing.
Appendix 1. Search strategies
Appendix 2. Characteristics of included studies table: template
Appendix 3. Description of interventions
Appendix 4. Baseline characteristics (I)
Appendix 5. Baseline characteristics (II)
Appendix 6. Matrix of study endpoints (publications)
Appendix 7. Matrix of study endpoints (protocol/trial documents)
Appendix 8. Examination of outcome reporting bias
Appendix 9. Definition of endpoint measurement (I)
Appendix 10. Definition of endpoint measurement (II)
Appendix 11. Adverse events (I)
Appendix 12. Adverse events (II)
Appendix 13. Adverse events (III)
Appendix 14. Survey of authors providing information on trials
Contributions of authors
Wenxun Wu (WW): protocol draft, search strategy development, acquiring trial reports, trial selection, data extraction, data analysis, data interpretation, review draft and update draft.
Detao Yin (DY): protocol draft, search strategy development, acquiring trial reports, trial selection, data extraction, data analysis and review draft and language editing.
Weimin Yang (WY): protocol draft, search strategy development, data extraction, data analysis and data interpretation.
Quancheng Kan (QK): search strategy development, trial selection, data extraction and data interpretation.
Zhangsuo Liu (ZL): protocol draft, search strategy development and data analysis.
Xiaoyan Ren (XR): acquiring trial reports, trial selection and data extraction.
Chenguang Zhai (CZ): trial selection and data extraction.
Shengjun Zhang (SZ): language editing.
Declarations of interest