Is the traditional Chinese medicine helpful for patients with hematologic malignant diseases? A meta-analysis of randomized controlled trials

Table 1 The Preferred Reporting Items for Systematic Review and Meta-Analysis checklist

Section/topic	n	Checklist item	Reported on page
Title
Title	1	Identify the report as a systematic review, meta-analysis, or both	1
Abstract
Structured summary	2	Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number	2
Introduction
Rationale	3	Describe the rationale for the review in the context of what is already known	3
Objectives	4	Provide an explicit statement of questions being addressed with reference to PICOS	3-4
Methods
Protocol and registration	5	Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number
Eligibility criteria	6	Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale	5
Information sources	7	Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched	5
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated	5-6, Table 2
Study selection	9	State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis)	6-7
Data collection process	10	Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators	7
Data items	11	List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made	7
Risk of bias in individual studies	12	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis	6-7
Summary measures	13	State the principal summary measures (e.g., risk ratio, difference in means)	7
Synthesis of results	14	Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis	7

PICOS: Participants, interventions, comparisons, outcomes, and study design.

Table 2 The PubMed searching strategy

(1) "Complementary therapies" (Mesh)

(2) Tradition or tradition* OR china or chinese OR herb or herbal OR complement* or tcm or "zhong yi" or chm or ethno* or folk or home or indigenous or primitive or materia* or nosod* or east or eastern or orient or oriental or asian or Korea* or Tibet* or herbaceous or plant or plants or botan* or kampo or mongol* or phytogenic or phytotherapy or alternative

(3) Medicine or medicinal or medical or remed* or therapy or therapies or therapeutic or therapeutics or therapist or treat or treatment or drug or drugs

(4) (2) and (3)

(5) (1) or (4)

(6) Leukemia or lymphoma or "multiple myeloma" (mesh)

(7) Hemotolog* or anemia or thrombocytopen* or pancytope* or "bone marrow" or transplant or "stem cell"

(8) Leukemia OR lymphoma OR cancer OR dysplas* OR malignant OR hyperplas* OR hypoplas* or myelom* or Hodgkin or non-hodgkin or blast or blasts or "progression free survival" or "disease free survival" or "overall survival" or OS or PFS or DFS or chemotherapy or (chemical treatment) or radiotherapy or irradia* or oncolog* or monoclon*

(9) (7) and (8)

(10) (6) or (9)

(11) (((((Randomized controlled trial [Publication type]) OR controlled clinical trial [Publication type]) OR (randomized or placebo[Title/Abstract])) OR drug therapy [MeSH Subheading]) OR (randomly or groups or trial [Title/Abstract])) OR rct

(12) Animals [mh] NOT humans [mh]

(13) (11) not (12)

(14) (5) and (10) and (13)

(15) (Cancer or carcinoma or sarcoma)[ti]

(16) Carcinoma[mesh] or sarcoma[mesh]

(17) (14) not (15) or (16)

Table 3 Characteristics of Dian Rong 2009 study

Methods	A randomized double blind placebo controlled I multicenter study
Participants	Refractory acute leukemia patients
Interventions	TCM group: Combine Chinese interventions with standard chemotherapy of western medicine
	Control group: Standard chemotherapy with western medicine
Outcomes	The primary outcome: the response rate

TCM: Traditional Chinese medicine.

Table 4 Risk assessment of Dian Rong 2009 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Central randomized
		Comment: Probably done. Several studies published by this research group reported reliable randomization method
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Low risk	Quote: A double-blind and placebo controlled
All outcomes		Comment: Probably done. Several studies published by this research group reported reliable method to warrant the double blindness
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: Mortality and survival time are objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 5 Characteristics of Xiu Mei 1997 study

Methods	A randomized controlled study
Participants	Non-Hodgkin lymphoma patients
Interventions	TCM group: Standard chemotherapy + traditional Chinese medicine
	Control group: Standard chemotherapy
Outcomes	The primary outcome: The overall response rate

TCM: Traditional Chinese medicine.

Table 6 Risk assessment of Xiu Mei 1997 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: The random sequence produced by rolling the dice
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: Mortality and survival is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 7 Characteristics of Ji Hong 2011 study

Methods	A randomized controlled study
Participants	Initial treat old AML patients
Interventions	TCM group: HAG + TCM
	Control group: HAG
Outcomes	The primary outcome: The overall response rate

TCM: Traditional Chinese medicine; AML: Acute myeloid leukemia; HAG: Homoharringtonine + cytoarabine + granulocye colony stimulating factor.

Table 8 Risk assessment of Ji Hong 2011 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Use the random number table to get the allocation sequence
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: The response rate is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Low risk	Quote: 7 participants in 53 randomized lost to follow-up
All outcomes		Comment
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 9 Characteristics of Ying Fei 2005 study

Methods	A multicenter double-blinded randomized controlled study
Participants	Initial treat leukemia patients
Interventions	TCM group: standard chemotherapy + Shen Qi Fu Zheng Ye
	Control group: Standard chemotherapy
Outcomes	The primary outcome: The overall response rate

TCM: Traditional Chinese medicine.

Table 10 Risk assessment of Ying Fei 2005 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Generate randomization sequence by drawing lots
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: The response rate is an objective parameter subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 11 Characteristics of Wen Jiang 2010 study

Methods	A randomized placebo controlled study
Participants	Initial treat acute leukemia patients
Interventions	TCM group: Standard chemotherapy + Shen Qi Qing Re Ke Li
	Control group: Standard chemotherapy
Outcomes	The primary outcome: The overall response rate

TCM: Traditional Chinese medicine.

Table 12 Risk assessment of Wen Jiang 2010 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Use the random number table to get the allocation sequence
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: The response rate is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 13 Characteristics of Su Juan 2005 study

Methods	A multicenter randomized controlled study
Participants	Acute leukemia
Interventions	TCM group: Standard chemotherapy + TCM Qing Re Jie Du Kang Bai Fang
	Control group: Standard chemotherapy
Outcomes	The primary outcome: The overall response rate

TCM: Traditional Chinese medicine.

Table 14 Risk assessment of Su Juan 2005 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Use the random number table to get the allocation sequence
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: The response rate is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 15 Characteristics of Mao Sheng 2007 study

Methods	A multicenter double-blinded randomized placebo controlled study
Participants	Acute myeloid leukemia patients with micro residual disease
Interventions	TCM group: Standard chemotherapy + Yi Qi Jie Du Huo Xue Fang
	Control group: Standard chemotherapy
Outcomes	The primary outcome: The overall response rate

TCM: Traditional Chinese medicine.

Table 16 Risk assessment of Mao Sheng 2007 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Use the random number table to get the allocation sequence
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: The response rate is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 17 Characteristics of Rui Rong 2004 study

Methods	A multicenter double-blinded randomized placebo controlled study
Participants	Acute myeloid leukemia
Interventions	TCM group: Standard chemotherapy + Yi Qi Yang Yin Qing Re Fa
	Control group: Standard chemotherapy
Outcomes	The primary outcome: The overall response rate

TCM: Traditional Chinese medicine.

Table 18 Risk assessment of Rui Rong 2004 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Use the random number table to get the allocation sequence
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: The response rate is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 19 Characteristics of Chuan Xin 2013 study

Methods	A randomized controlled study
Participants	Child acute myeloid leukemia patients
Interventions	TCM group: Standard chemotherapy + traditional Chinese medicine
	Control group: Standard chemotherapy
Outcomes	The primary outcome: The overall response rate

TCM: Traditional Chinese medicine.

Table 20 Risk assessment of Chuan Xin 2013 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Use the random number table to get the allocation sequence
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: The response rate is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 21 Characteristics of sWei Hong 2013 study

Methods	A randomized controlled study
Participants	Chronic myeloid leukemia patients
Interventions	TCM group: A-interferon or hydroxyurea + TCM
	Control group: A-interferon or hydroxyurea
Outcomes	The primary outcome: The response rate

TCM: Traditional Chinese medicine.

Table 22 Risk assessment of sWei Hong 2013 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: The random number table was used to generate the allocation sequence
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: Mortality and survival is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 23 Characteristics of sHai Yan 2007 study

Methods	A randomized controlled study
Participants	Chronic myeloid leukemia patients
Interventions	Traditional Chinese medicine group: Hydroxyurea + traditional Chinese medicine
	Control group: Hydroxyurea
Outcomes	The primary outcome: The response rate

Table 24 Risk assessment of sHai Yan 2007 study

Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: The random number table was used to generate the allocation sequence
		Comment: Probably done
Allocation concealment (selection bias)	Unclear	Quote: Not mentioned
		Comment: Unclear
Blinding of participants and personnel (performance bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Blinding of outcome assessment (detection bias)	Low risk	Quote: Not mentioned
All outcomes		Comment: Mortality and survival is an objective parameter. Subjective judgement can not influent the result
Incomplete outcome data (attrition bias)	Unclear	Quote: Not mentioned
All outcomes		Comment: Unclear
Selective reporting (reporting bias)	Low risk	The primary outcome listed in the method section are all reported
		Comment: Probably done
Other bias	Unclear	The study did not use the intention to treat strategy to analyze the result

Table 25 Characteristics of included studies

Studies	Age	Sex (male:female)	Race	Disease	No. of participants	Intervention		Published
					(TCM:control)	TCM	Control	language
Dian Rong 2009[15,21,25,31,33]	TCM 39.52 ± 18.87	TCM 50:21	Chinese	Acute leukemia	71:66	Compound Zhe Bei granule +	Placebo + standard	English
	Control 37.94 ± 18.55	Control 39:27				standard chemotherapy	chemotherapy
Mao Sheng 2007[26,27]	TCM 35.63 ± 6.46	TCM 33:27	Chinese	Acute myeloid leukemia	60:60	Yi Qi Jie Du Huo Xue decoction	Standard western	Chinese
	Control 36.57 ± 7.38	Control 31:29				+ standard western mechicine	mechicine
sHai Yan 2007[22]	TCM 18-65	TCM 5:3	Chinese	Chronic myelogenous leukemia	8:10	Qu Du Hua Yu decoction	Hydroxyurea	Chinese
	Control 19-63	Control 7:3				+ hydroxyurea
sWei Hong 2013[23]	TCM 25-60	TCM 22:14	Chinese	Chronic myelogenous leukemia	22:17	TCM + interferon-α	Interferon-α	Chinese
	Control 25-65	Control 17:7
Chuan Xin 2013[32]	TCM 4.30 ± 1.81	TCM 12:8	Chinese	Pediatric acute myeloid leukemia	20:20	TCM + standard chemotherapy	Standard chemotherapy	Chinese
	Control 4.95 ± 2.04	Control 10:10
Ji Hong 2011[34]	TCM 60-71	TCM 16:16	Chinese	Elderly acute myeloid leukemia	32:28	TCM + HAG chemotherapy	HAG chemotherapy	Chinese
	Control 61-72	Control 15:13
Rui Rong 2004[29]	TCM 12-78	TCM 40:28	Chinese	Acute myeloid leukemia	68:46	TCM + standard chemotherapy	Standard chemotherapy	Chinese
	Control 11-76	Control 27:19
Su Juan 2005[24]	TCM 32.5 ± 12.45	TCM 16:14	Chinese	Acute leukemia	30:30	Qing Re Jie Du kang Bai decoction	Standard chemotherapy	Chinese
	Control 31.53 ± 12.41	Control 17:13				+ standard chemotherapy
Wen Jiang 2010[30]	TCM 47-78	TCM 17:12	Chinese	Acute myeloid leukemia	29:28	Shen Qi Qing Re Ke Li	HAG chemotherapy	Chinese
	Control 46-79	Control 15:13				+ HAG chemotherapy
Xiu Mei 1997[35]	TCM 6-73	TCM 72:40	Chinese	Non-Hodgkin lymphoma	112:55	TCM + standard chemotherapy	Standard chemotherapy	Chinese
	Control 6-71	Control 36:19
Ying Fei 2005[28]	TCM 13-72	TCM 22:10	Chinese	Acute leukemia	32:33	Shen Qi Fu Zheng	Standard chemotherapy	Chinese
	Control 15-71	Control 25:8				injection + standard chemotherapy

TCM: Traditional Chinese medicine; HAG: Homoharringtonine + cytoarabine + granulocye colony stimulating factor.

Table 26 Quality assessment of included studies

Studies	Random sequence generation	Allocation concealment	Blinding of participants and	Blinding of outcome	Incomplete outcome	Selective reporting	Other bias
	(selection bias)	(selection bias)	personnel (performance bias)	assessment (detection bias)	data (attrition bias)	(reporting bias)
			All outcomes	All outcomes	All outcomes
Dian Rong 2009[15,21,25,31,33]	Low risk	Unclear	Low risk	Low risk	Unclear	Low risk	Unclear
Mao Sheng 2007[26,27]	Low risk	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear
sHai Yan 2007[22]	Low risk	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear
sWei Hong 2013[23]	Low risk	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear
Chuan Xin 2013[32]	Low risk	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear
Ji Hong 2011[34]	Low risk	Unclear	Unclear	Low risk	Low risk	Low risk	Unclear
Rui Rong 2004[29]	Low risk	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear
Su Juan 2005[24]	Low risk	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear
Wen Jiang 2010[30]	Low risk	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear
Xiu Mei 1997[35]	Low risk	Unclear	Unclear	Unclear	Unclear	Low risk	Unclear
Ying Fei 2005[28]	Low risk	Unclear	Unclear	Low risk	Unclear	Low risk	Unclear

Table 27 Summary of findings of the overall response and complete response outcomes

Outcomes	Illustrative comparative risks1 (95%CI)		Relative effect	No. of participants	Quality of the evidence	Comments
	Assumed risk	Corresponding risk	(95%CI)	(studies)	(GRADE)
	Control	Overall response rate
Overall response rate	Study population		RR = 1.14	974	++--
	761 per 1000	867 per 1000 (784-959)	(1.03-1.26)	(12 studies)	Low
	Moderate
	775 per 1000	883 per 1000 (798-976)
Complete response rate	Study population		RR = 1.21	974	++--
	579 per 1000	701 per 1000 (579-846)	(1-1.46)	(12 studies)	Low23
	Moderate
	579 per 1000	701 per 1000 (579-845)
Overall response rate for malignant hematologic disease
Patient or population: Patients with malignant hematologic disease
Settings:
Intervention: Overall response rate

¹The basis for the assumed risk (e.g., the median control 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);

²Not all studies included were high quality randomized controlled trial;

³Most studies showed better effect when traditional Chinese medicine was added while some studies did not show statistically significant better effect. 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.