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Intervention Protocol

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Chinese herbal medicines for benign thyroid nodules in adults

  1. Wenxun Wu1,*,
  2. Detao Yin2,
  3. Weimin Yang3,
  4. Quancheng Kan4,
  5. Zhangsuo Liu5,
  6. Xiaoyan Ren1,
  7. Chenguang Zhai1,
  8. Shengjun Zhang6

Editorial Group: Cochrane Metabolic and Endocrine Disorders Group

Published Online: 30 APR 2013

DOI: 10.1002/14651858.CD010492


How to Cite

Wu W, Yin D, Yang W, Kan Q, Liu Z, Ren X, Zhai C, Zhang S. Chinese herbal medicines for benign thyroid nodules in adults (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD010492. DOI: 10.1002/14651858.CD010492.

Author Information

  1. 1

    First Affiliated Hospital of Zhengzhou University, Department of Metabolic and Endocrine Disorders, Zhengzhou, Henan Province, China

  2. 2

    First Affiliated Hospital of Zhengzhou University, Department of Thyroid Surgery, Zhengzhou, Henan, China

  3. 3

    First Affiliated Hospital of Zhengzhou University, Department of Neurology, Zhengzhou, Henan Province, China

  4. 4

    First Affiliated Hospital of Zhengzhou University, Department of Pharmacology, Zhengzhou, Henan, China

  5. 5

    First Affiliated Hospital of Zhengzhou University, Department of Nephrology, Zhengzhou, Henan, China

  6. 6

    Johns Hopkins University School of Medicine, Pathology Department, Baltimore, USA

*Wenxun Wu, Department of Metabolic and Endocrine Disorders, First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road East, Zhengzhou, Henan Province, 450052, China. wuwenxun@126.com. wwuwenxunn@hotmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 30 APR 2013

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This is not the most recent version of the article. View current version (04 MAR 2014)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
 

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.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest

To assess the effects of Chinese herbal medicines for benign thyroid nodules in adults.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
 

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

 

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.

 

Comparators

  • No treatment.
  • Placebo.
  • L-thyroxine.

 

Types of outcome measures

 

Primary outcomes

  • Nodule volume reduction equal to or greater than 50% (evaluated by ultrasonography measurements)
  • Pressure symptoms, cosmetic complaints or both
  • Adverse events

 

Secondary outcomes

  • 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.

  1. All-cause mortality.
  2. Cancer occurrence.
  3. Health-related quality of life.
  4. Adverse effects.
  5. Pressure symptoms/cosmetic complaints.
  6. Nodule volume reduction of 50% or more.
  7. Socio-economic effects.

 

Search methods for identification of studies

 

Electronic searches

We will search the following sources from inception to the present.

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).

 FigureFigure 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 Chi2 test with a significance level of α = 0.1, in view of the low power of this test. We will examine heterogeneity employing 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% and more indicates a considerable level of inconsistency (Higgins 2011).

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).

 

Data synthesis

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).

 

Sensitivity analysis

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).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest

We thank Gudrun Paletta, Assistant Managing Editor of Cochrane Metabolic and Endocrine Disorders Group, for her expertise and editing.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
 

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 Goiter, nodular explode all trees
#2 (thyroid in All Text near/6 adenom* in All Text) or (thyroid in All Text near/6 nodul* in All Text) or (thyroid in All Text near/6 cyst* in All Text))
#3 ((nodul* in All Text near/6 inflammatory in All Text) or (nodul* in All Text near/6 benign tumo?r in All Text) or (nodul* in All Text near/6 goiter* in All Text))
#4 (#1 or #2 or #3)
#5 MeSH descriptor Medicine, chinese traditional explode all trees
#6 MeSH descriptor Medicine, Traditional explode all trees
#7 MeSH descriptor Herbal medicine explode all trees
#8 MeSH descriptor Phytotherapy explode all trees
#9 MeSH descriptor Plant extracts explode all trees
#10 MeSH descriptor Plants, medicinal explode all trees
#11 MeSH descriptor Plant preparations explode all trees
#12 MeSH descriptor Drugs, chinese herbal explode all trees
#13 MeSH descriptor Plant oils explode all trees
#14 MeSH descriptor Medicine, Kampo explode all trees
#15 (TCM in All Text or TCMs in All Text)
#16 ((herb* in All Text near/6 remed* in All Text) or (herb* in All Text near/6 extract* in All Text) or (herb* in All Text near/6 preparation* in All Text) or (herb* in All Text near/6 mixture* in All Text) or (herb* in All Text near/6 medi* in All Text) or (herb* in All Text near/6 therap* in All Text) or (herb* in All Text near/6 treatment* in All Text))
#17 ((plant* in All Text near/6 extract* in All Text) or (plant* in All Text near/6 remed* in All Text) or (plant* in All Text near/6 preparation* in All Text) or (plant* in All Text near/6 mixture* in All Text))
#18 ((botanical in All Text near/6 extract* in All Text) or (botanical in All Text near/6 remed* in All Text) or (botanical in All Text near/6 preparation* in All Text) or (botanical in All Text near/6 mixture* in All Text))
#19 ((phyto in All Text near/6 therap* in All Text) or (phyto in All Text near/6 medic* in All Text) or (phyto in All Text near/6 pharmaceutical* in All Text) or (phyto in All Text near/6 therap* in All Text) or (phyto in All Text near/6 treatment* in All Text))
#20 ((chinese in All Text near/6 herb* in All Text) or (chinese in All Text near/6 plant* in All Text) or (chinese in All Text near/6 medic* in All Text) or (chinese in All Text near/6 drug* in All Text) or (chinese in All Text near/6 formul* in All Text) or (chinese in All Text near/6 prescri* in All Text) or (chinese in All Text near/6 therap* in All Text) or (chinese in All Text near/6 treatment* in All Text))
#21 ((medic* in All Text near/6 traditional in All Text) or (medic* in All Text near/6 chinese in All Text) or (medic in All Text near/6 kampo in All Text) or (chinese in All Text near/6 plant* in All Text))
#22 (#5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21)
#23 (#5 and #22)

MEDLINE

1 exp Goiter, Nodular/
2 (thyroid adj6 (adenoma* or nodul* or cyst*)).tw,ot.
3 (nodul* adj6 (benign tumo?r* or inflammatory or goiter*)).tw,ot.
4 or/1-3
5 exp Medicine, Chinese Traditional/
6 exp Medicine, traditional/
7 exp Herbal medicine/
8 exp Phytotherapy/
9 exp Plant Extracts/
10 exp Plants, Medicinal/
11 exp Plant preparations/
12 exp Drugs, Chinese Herbal/
13 exp Plant oils/
14 exp Medicine, Kampo/
15 (TCM or TCMs).tw,ot.
16 (herb* adj6 (remed* or extract* or preparation* or mixture* or medic* or therap* or treatment*)).tw,ot.
17 ((plant* or botanical) adj6 (extract* or remed* or preparation* or mixture*)).tw,ot.
18 (phyto adj6 (drug* or medic* or pharmaceutical* or therap* or treatment*)).tw,ot.
19 (chinese adj6 (herb* or plant* or medic* or drug* or formul* or prescri* or therap* or treatment*)).tw,ot.
20 (medic* adj3 (traditional or chinese or kampo or plant*)).tw,ot.
21 or/5-20
22 5 and 21
23 limit 22 to humans

EMBASE

1 exp thyroid tumor/
2 exp nodular goiter/
3 (nodular adj6 (cyst* or inflammatory or benign tumo?r or goiter*)).tw,ot.
4 (thyroid adj6 (adenoma* or nodul* or cyst*)).tw,ot.
5 or/1-4
6 exp chinese medicine/ or exp traditional medicine/
7 exp phytotherapy/
8 exp plant extract/
9 medicinal plant/
10 exp vegetable oil/
11 exp Chinese drug/
12 *plant medicinal product/
13 (TCM or TCMs).tw,ot.
14 (herb* adj6 (remed* or extract* or preparation* or mixture* or medic* or therap* or treatment*)).tw,ot.
15 ((plant* or botanical) adj6 (extract* or remed* or preparation* or mixture*)).tw,ot.
16 (chinese adj6 (herb* or plant* or medic* or drug* or formul* or prescri* or therap* or treatment*)).tw,ot.
17 (medic* adj6 (traditional or chinese or kampo or plant*)).tw,ot.
18 (phyto adj6 (drug* or medic* or pharmaceutical* or therap* or treatment*)).tw,ot.
19 or/6-18
20 (cancer or carcinom*).tw,ot.
21 5 not 20
22 19 and 21
23 limit 22 to human

CBM

#1 nodular goiter
#2 thyroid tumour
#3 thyroid nodule

#4 thyroid neoplasia
#5#1?#4/or
#6 traditional Chinese herbal medicine
#7 Chinese herbal medicine
#8 herbal medicine
#9 traditional Chinese medicine
#10 traditional medicine
#11 Chinese medicine
#12 #6?#11/or
#13 random
#14 #5and #12and #13
#15 exp animals/ not humans.sh.
#16#14not #15

All of the search terms will be translated to Chinese terms when we conduct the searches in CBM database.

CNKI

1. exp Randomized Controlled trials / all subheadings
2. Random*
3. 1 or 2
4. exp traditional Chinese medicine/ all subheadings
5. exp integrated Chinese and western medicine/ all subheadings

6. exp herbal medicine / all subheadings
7. or/ 4-6
8. thyroid nodule
9. thyroid tumour

10.thyroid nodule

11. or/8-10
12. Human
13. 3 and 7 and 11 and 12

All of the search terms will be translated to Chinese terms when we conduct the searches in CNKI database.

VIP

Title/Topic/Keyword=( "nodular goiter" or "thyroid tumour" or "thyroid nodule ") AND Title/Topic/Keyword=("Chinese medicine" or "Chinese traditional medicine" or "Chinese herb*" or "oriental medicine" or "oriental traditional medicine" or "medicinal plant*" or herb*)

All of the search terms will be translated to Chinese terms when we conduct the searches in VIP database.

Chinese Conference Papers Database

Title/Topic/Keyword=( ""nodular goiter" or "thyroid tumour" or "thyroid nodule "") AND Title/Topic/Keyword=("Chinese medicine" or "Chinese traditional medicine" or "Chinese herb*" or "oriental medicine" or "oriental traditional medicine" or "medicinal plant*" or herb*)

All of the search terms will be translated to Chinese terms.

Chinese Dissertation Database

Title/Topic/Keyword=( "thyroid nodule " or "thyroid tumour" or "thyroid nodule ") AND Title/Topic/Keyword=("Chinese medicine" or "Chinese traditional medicine" or "Chinese herb*" or "oriental medicine" or "oriental traditional medicine" or "medicinal plant*" or herb*)

All of the search terms will be translated to Chinese terms.

'My NCBI' alert service

("asian continental ancestry group"[MeSH Terms] OR ("asian"[All Fields] AND "continental"[All Fields] AND "ancestry"[All Fields] AND "group"[All Fields]) OR "asian continental ancestry group"[All Fields] OR "chinese"[All Fields]) AND ("herbal medicine"[MeSH Terms] OR ("herbal"[All Fields] AND "medicine"[All Fields]) OR "herbal medicine"[All Fields]) AND ("thyroid gland"[MeSH Terms] OR ("thyroid"[All Fields] AND "gland"[All Fields]) OR "thyroid gland"[All Fields] OR "thyroid"[All Fields] OR "thyroid (usp)"[MeSH Terms] OR ("thyroid"[All Fields] AND "(usp)"[All Fields]) OR "thyroid (usp)"[All Fields])



 

Appendix 2. Characteristics of included studies table: template


MethodsDelete as appropriate

Parallel/cross-over/cluster/factorial randomised controlled clinical trial (RCT)

Randomisation ratio:

Superiority design

Non-inferiority design (specify 1- or 2-sided confidence interval)

Equivalence design (specify 1- or 2-sided confidence interval)

Controlled clinical trial (CCT)

ParticipantsInclusion criteria: participants regardless of ethnic group but age > 18 with imaging-confirmed thyroid nodules

Exclusion criteria: participants with the malignant nodules on cytology will be excluded

Diagnostic criteria: participants regardless of ethnic group but age > 18 with imaging-confirmed thyroid nodules

InterventionsNumber of study centres:

Treatment before study:

Titration period: treatment duration will be at least four weeks
(Complex interventions: detailed description of all interventions!)

OutcomesOutcomes reported in abstract of publication:

Study detailsRun-in period:

Study terminated before regular end (for benefit/because of adverse events): yes/no

Publication detailsDelete as appropriate

Language of publication: Chinese or English

Commercial/non-commercial/other funding

Publication status (peer reviewed journal/journal supplement/full article/conference paper/other (specify))

Stated aim of studyQuote from publication: "..."

NotesAbbreviations:



 

Appendix 3. Description of interventions


CharacteristicIntervention(s) [route, frequency, total dose/day]Comparator(s) [route, frequency, total dose/day]

Study 1Intervention 1Comparator 1

Intervention 2Comparator 2

Study 2Intervention 1Comparator 1

Intervention 2Comparator 2

Study 3Intervention 1Comparator 1

Intervention 2Comparator 2

Study 4Intervention 1Comparator 1

Intervention 2Comparator 2

Footnotes

"-" denotes not reported



 

Appendix 4. Baseline characteristics (I)


CharacteristicIntervention(s) and comparator(s)Duration of intervention (duration of follow-up)Participating populationStudy period [year to year]CountrySettingEthnic groups [%]Duration of disease [mean/range years (SD), or as reported]

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 2Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 3Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 4Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported

SD: standard deviation



 

Appendix 5. Baseline characteristics (II)


CharacteristicIntervention(s) and comparator(s)Sex [female %]Age [mean/range years (SD), or as reported]Number of thyroid nodules [n]Size of thyroid nodule(s) [ml]Thyroid size [ml]Co-medications/Co-interventionsCo-morbidities

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 2Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 3Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 4Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported

SD: standard deviation



 

Appendix 6. Matrix of study endpoints (publications)


CharacteristicEndpoint reported in publicationEndpoint not reported in publicationTime of measurementa

ExampleReview's primary outcomes

Nodule volume reduction equal to or greater than 50%x0, 6, 12 mo

Pressure symptoms, cosmetic complaintsxN/A

Adverse eventsx0, 12 mo

Review's secondary outcomes

Health-related quality of lifex0, 12 mo

All-cause mortalityx0, 6, 12 mo

Cancer occurrencexN/A

Changes in number and size of the thyroid nodulesx0, 12, 24 mo

Changes in thyroid volumex12 mo

Thyrotropin (TSH), thyroxine (T4) and tri-iodothyronine (T3) serum levelsx0, 6, 12 mo

Socio-economic effectsx

Other than review's primary/secondary outcomes reported in publication (classification: P/S/O)b

HDL-cholesterol (O), LDL-cholesterol (O), patient satisfaction (S), safety parameters (O), total cholesterol (O), triglycerides (O)

Subgroups reported in publication

Age < 65 years vs ≥ 65 years, cardiovascular risk factors vs no cardiovascular risk factors



Study 1Review's primary outcomes

Nodule volume reduction equal to or greater than 50%

Pressure symptoms, cosmetic complaints

Adverse events

Review's secondary outcomes

Health-related quality of life

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

Other than review's primary/secondary outcomes reported in publication (classification: P/S/O)b


Subgroups reported in publication


Study 2Review's primary outcomes

Nodule volume reduction equal to or greater than 50%

Pressure symptoms, cosmetic complaints

Adverse events

Review's secondary outcomes

Health-related quality of life

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

Other than review's primary/secondary outcomes reported in publication (classification: P/S/O)b


Subgroups reported in publication


Study 3Review's primary outcomes

Nodule volume reduction equal to or greater than 50%

Pressure symptoms, cosmetic complaints

Adverse events

Review's secondary outcomes

Health-related quality of life

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

Other than review's primary/secondary outcomes reported in publication (classification: P/S/O)b


Subgroups reported in publication


Study 4Review's primary outcomes

Nodule volume reduction equal to or greater than 50%

Pressure symptoms, cosmetic complaints

Adverse events

Review's secondary outcomes

Health-related quality of life

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

Other than review's primary/secondary outcomes reported in publication (classification: P/S/O)b


Subgroups reported in publication


Footnotes

aUnderlined data denote times of measurement for primary and secondary review outcomes, if measured and reported in the results section of the publication (other times represent planned but not reported points in time).

b(P) Primary or (S) secondary endpoint(s) refer to verbatim statements in the publication, (O) other endpoints relate to outcomes which were not specified as 'primary' or 'secondary' outcomes in the publication.

HDL: high-density lipoprotein; LDL: low-density lipoprotein; mo: months; N/A: not applicable



 

Appendix 7. Matrix of study endpoints (protocol/trial documents)


Characteristic / Study ID (trial identifier)EndpointTime of measurement

ExampleNodule volume reduction equal to or greater than 50%a (P)b0, 16, 2 mo

Health-related quality of life (O)0, 6, 12 mo

Cancer occurrence (O)N/AA

Changes in thyroid volume (S)0, 12 mo


Study 1EndpointTime of measurement








Study 2








Study 3








Study 4








Footnotes

"-" denotes not reported

aEndpoint in bold/italic = review's primary/secondary outcome.

b(P) Primary or (S) secondary endpoint(s) refer to verbatim statements in the publication, (O) other endpoints relate to outcomes which were not specified as 'primary' or 'secondary' outcomes in the report.

mo: months; N/A: not acknowledged



 

Appendix 8. Examination of outcome reporting bias


CharacteristicClear that outcome was measured and analyseda [trial report states that outcome was analysed but only reports that result was not significant]Clear that outcome was measured and analysedb [trial report states that outcome was analysed but no results reported]Clear that outcome was measuredc [clear that outcome was measured but not necessarily analysed (judgement says likely to have been analysed but not reported because of non-significant results)]Unclear whether the outcome was measuredd [not mentioned but clinical judgement says likely to have been measured and analysed but not reported on the basis of non-significant results]

Study 1

Study 2

Study 3

Study 4

Footnotes

'High risk of bias' categories for outcome reporting bias according to the Outcome Reporting Bias In Trials (ORBIT) study classification system for missing or incomplete outcome reporting in reports of randomised trials (Kirkham 2010).

aClassification 'A' (table 2, Kirkham 2010)

bClassification 'D' (table 2, Kirkham 2010)

cClassification 'E' (table 2, Kirkham 2010)

dClassification 'G' (table 2, Kirkham 2010)



 

Appendix 9. Definition of endpoint measurement (I)


CharacteristicNodule volume reduction ≥ 50%Health-related quality of lifeCancer occurrenceChanges in number and size of the thyroid nodulesChanges in thyroid volumeSocio-economic effectsSevere/serious adverse events

Study 1

Study 2

Study 3

Study 4

Footnotes

ND: not defined



 

Appendix 10. Definition of endpoint measurement (II)


CharacteristicComplianceResponderPartial responder / non-responderNew nodulesCureSuccess rate/therapy successRecurrenceCosmetic/pressure complaint

Study 1

Study 2

Study 3

Study 4

Footnotes

ND: not defined



 

Appendix 11. Adverse events (I)


CharacteristicIntervention(s) and comparator(s)Randomised / Safety [N]Deaths [N]Deaths [%]All adverse events [N]All adverse events [%]Severe/serious adverse events [N]Severe/serious adverse events [%]

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 2Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 3Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 4Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported



 

Appendix 12. Adverse events (II)


CharacteristicIntervention(s) and comparator(s)Randomised / Safety [N]Left study due to adverse events [N]Left study due to adverse events [%]Hospitalisation [N]Hospitalisation [%]Out-patient treatment [N]Out-patient treatment [%]

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 2Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 3Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 4Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported



 

Appendix 13. Adverse events (III)


CharacteristicIntervention(s) and comparator(s)Randomised /Safety [N]Specific adverse events [description]Specific adverse events [N]Specific adverse events [%]

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 2Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 3Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Study 4Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported



 

Appendix 14. Survey of authors providing information on trials


CharacteristicStudy author contactedStudy author repliedStudy author asked for additional informationStudy author provided data

Study 1

Study 2

Study 3

Study 4

Footnotes

n: no; y: yes



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest

None known

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Additional references
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