Chinese herbal medicine for oesophageal cancer.

Cochrane Database of Systematic Reviews

Chinese herbal medicine for oesophageal cancer (Review) Chen X, Deng L, Jiang X, Wu T

Chen X, Deng L, Jiang X, Wu T. Chinese herbal medicine for oesophageal cancer. Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD004520. DOI: 10.1002/14651858.CD004520.pub7.

www.cochranelibrary.com

Chinese herbal medicine for oesophageal cancer (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 1 Quality of life. . . Analysis 1.2. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 2 Quality of life. . . Analysis 1.3. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 3 Short-term therapeutic effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 4 TCM symptoms. . Analysis 1.5. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 5 Adverse events. . . Analysis 1.6. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 6 Cancer bio-markers. Analysis 1.7. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 7 Weight. . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Chinese herbal medicine for oesophageal cancer Xi Chen1 , Linyu Deng2 , Xuehua Jiang1 , Taixiang Wu3 1 Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu, China. 2 National Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, Chengdu, China. 3 Chinese Clinical Trial Registry, Chinese Ethics Committee of Registering Clinical Trials, West China Hospital, Sichuan University, Chengdu, China

Contact address: Taixiang Wu, Chinese Clinical Trial Registry, Chinese Ethics Committee of Registering Clinical Trials, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. [email protected]. Editorial group: Cochrane Upper GI and Pancreatic Diseases Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 1, 2016. Review content assessed as up-to-date: 8 October 2015. Citation: Chen X, Deng L, Jiang X, Wu T. Chinese herbal medicine for oesophageal cancer. Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD004520. DOI: 10.1002/14651858.CD004520.pub7. Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Oesophageal cancer is the seventh leading cause of cancer death worldwide. Traditional Chinese herbal medicine is sometimes used as an adjunct to radiotherapy or chemotherapy for this type of cancer. This review was first published in 2007 and updated in 2009; this 2016 update is the latest version of the review. Objectives To assess the efficacy and possible adverse effects of the addition of Chinese herbal medicine to treatment with radiotherapy or chemotherapy for oesophageal cancer. Search methods We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Library, MEDLINE, EMBASE, Allied and Complementary Medicine Database (AMED), China National Knowledge Infrastructure (CNKI), VIP database, Wanfang database and the Chinese Cochrane Centre Controlled Trials Register up to 1 October, 2015. We also searched databases of ongoing trials, the Internet and reference lists. Selection criteria Randomised controlled trials (RCTs) comparing the use of radiotherapy or chemotherapy with and without the addition of Chinese herbal medicine. Data collection and analysis At least two review authors independently extracted data and assessed trial quality. Main results We tried to contact the 142 study authors by telephone, and finally included nine studies with 490 participants. All included studies were conducted in China, and allocated advanced oesophageal cancer patients to radiotherapy or chemotherapy groups, with and without additional Chinese herbal medicine. Quality of life, short-term therapeutic effects, TCM symptoms and adverse events caused by radiotherapy or chemotherapy were reported in these studies. Overall, we considered the trials to be at unclear or high risk of bias. Chinese herbal medicine for oesophageal cancer (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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The quality of life measure was conducted before and after the intervention; our analysis showed a beneficial effect, both in number of participants experiencing an improvement (risk ratio (RR) 2.20, 95% confidence interval (CI) 1.42 to 3.39; 5 RCTs, 233 participants, change of performance status score ≥ 10) and number of participants experiencing a deterioration (RR 0.41, 95% CI 0.27 to 0.62; 6 RCTs, 287 participants, change of performance status score ≤ 10). We judged this to have low quality evidence, downgrading quality of evidence for risk of bias and imprecision, and upgrading quality of evidence for the large effect. For short-term therapeutic effects, the results suggest that traditional Chinese medicine (TCM) has a positive impact on improvement (complete response + partial response) (RR 1.17, 95% CI 1.02 to 1.35; 8 RCTs, 450 participants), moderate quality evidence and downgrading for risk of bias. There was no significant difference for progressive disease (RR 0.73, 95% CI 0.52 to 1.01; 8 RCTs, 450 participants), low quality evidence and downgrading for risk of bias and imprecision. Three studies assessed this outcome after four weeks or three months’ follow-up, the remaining studies gave no detailed information for this outcome. TCM symptoms, which was similar to short-term therapeutic effects evaluated with TCM clinical criteria, was diagnosed in two studies of 88 people at the end of the intervention. The results suggest that TCM has a positive impact on both total effectiveness (RR 1.84, 95% CI 1.20 to 2.81) and ineffectiveness (RR 0.22, 95% CI 0.05 to 0.93); we judged the studies to have very low quality evidence, downgrading for risk of bias and imprecision. Nine studies reported a series of adverse events caused by radiotherapy or chemotherapy at the end of the intervention, including mucositis, radiation oesophagitis, arrest of bone marrow, gastrointestinal reactions, renal and hepatic impairment, white blood cell descent, neurotoxicity, cardiac toxicity and anaemia. For those containing multiple studies, we conducted a pooled analysis. As a result, TCM showed a significant effect on radiation oesophagitis (RR 0.66, 95% CI 0.47 to 0.94; 2 RCTs, 90 participants), gastrointestinal reactions (RR 0.54, 95% CI 0.36 to 0.81; 4 RCTs, 268 participants) and white blood cell descent (RR 0.60, 95% CI 0.44 to 0.83; 4 RCTs, 224 participants). The quality of evidence was low or very low, downgrading for risk of bias and imprecision. Authors’ conclusions We currently find no evidence to determine whether TCM is an effective treatment for oesophageal cancer. The effect of TCM on short-term therapeutic effects is uncertain. TCM probably has positive effects on quality of life and on some adverse events caused by radiotherapy or chemotherapy in advanced oesophageal cancer patients undergoing radiotherapy or chemotherapy. The results of the review need to be interpreted cautiously owing to overall low quality evidence. Future trials should be large and correctly designed to detect important clinical effects and minimise risk of bias.

PLAIN LANGUAGE SUMMARY Chinese medicinal herbs for oesophageal cancer Review question Chinese herbal medicine is widely used as adjunct therapy to chemo- or radiotherapy in patients being treated for cancer of the oesophagus. As yet there is no evidence that Chinese herbal medicine is effective or not in this role. Background We performed a systematic review of the potential benefits of Chinese herbal medicine by comparing chemo- or radiotherapy for oesophageal cancer with and without concurrent herbal medicine. We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Library, MEDLINE, EMBASE, Allied and Complementary Medicine Database (AMED), China National Knowledge Infrastructure (CNKI), VIP database, Wanfang database and the Chinese Cochrane Centre Controlled Trials Register up to 1 October, 2015. We also searched databases of ongoing trials, the Internet and reference lists. Study characteristics We identified nine randomised controlled trials (RCTs). All trials were conducted in China. Key results This updated review included nine trials involving 490 participants. When Chinese herbal medicine was used as adjunct therapy to chemo- or radiotherapy for oesophageal cancer, the results showed a positive effect on quality of life, increased tolerance of patients for adverse effects caused by radiotherapy or chemotherapy (e.g. radiation oesophagitis, gastrointestinal reactions and blood cell descent), but no effects on all-cause mortality, median survival times or time to progression. Chinese herbal medicine for oesophageal cancer (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Quality of the evidence We judged the quality of evidence to be low to moderate due to risk of bias; the small number of people enrolled in these studies caused imprecision and inconsistent results. The nine included trials did not allow a subgroup analysis of different kinds of Chinese herbal medicine, the therapeutic purposes of which are different between each other; this might be another reason for imprecise results. High quality trials are required in the future.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Active cancer therapy combined with TCM compared to active cancer therapy for oesophageal cancer Patient or population: patients with oesophageal cancer Settings: inpatient, hospital in china Intervention: active cancer therapy com bined with TCM Comparison: active cancer therapy Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Usual treatment

Usual treatment combined with TCM

Relative effect (95% CI)

No of Participants (studies)

Quality of the evidence Comments (GRADE)

All- cause mortality - See com m ent not reported

See com m ent

Not estim able

-

See com m ent

Not investigated

M edian survival times - See com m ent not reported

See com m ent

Not estim able

-

See com m ent

Not investigated

Time to progression - See com m ent not reported

See com m ent

Not estim able

-

See com m ent

Not investigated

RR 2.2 (1.42 to 3.39)

233 (5 studies)

⊕⊕

low1,2,3

Quality of life - number experiencing improvement M easured with Karnof sky perf orm ance status or the f orm ulation of National Co-operative Oncology Group quality of lif e scale

Study population 190 per 1000

417 per 1000 (269 to 643)

M oderate 177 per 1000

389 per 1000 (251 to 600)

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Quality of life - number experiencing deterioration M easured with Karnof sky perf orm ance status or the f orm ulation of National Co-operative Oncology Group quality of lif e scale


RR 0.41 (0.27 to 0.62)

287 (6 studies)

⊕⊕

low1,2,3

Not estim able

60 (1 study)

⊕⊕

low2

RR 1.17 (1.02 to 1.35)

450 (8 studies)

⊕⊕⊕ moderate 4

RR 0.73 (0.52 to 1.01)

450 (8 studies)

⊕⊕

low2,4

165 per 1000 (108 to 249)


163 per 1000 (107 to 246)

Quality of life - Karnof- See com m ent sky performance status Karnof sky status judged by clinicians. Scale: 0 to 100

See com m ent

Short- term therapeutic Study population effects - improvement (complete response + 538 per 1000 partial response) M easured with the solid tum ours response eval- M oderate uation criteria 5 571 per 1000

Short- term therapeutic Study population effects - progressive 211 per 1000 disease M easured with the solid tum ours response evaluation criteria 5 M oderate 172 per 1000

630 per 1000 (549 to 726)

668 per 1000 (582 to 771)

154 per 1000 (110 to 213)

126 per 1000 (89 to 174)

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TCM symptoms Study population total effectiveness Assessed with TCM 477 per 1000 clinical criteria

RR 1.84 (1.20 to 2.81)

88 (2 studies)

⊕

very low2,6

RR 0.22 (0.05 to 0.93)

88 (2 studies)

⊕

very low3,6,7

878 per 1000 (573 to 1000)


TCM symptoms - inef- Study population fectiveness Assessed with TCM 523 per 1000 clinical criteria

867 per 1000 (565 to 1000)

115 per 1000 (26 to 486)


116 per 1000 (26 to 492)

* The basis f or the assumed risk (e.g. the m edian control group risk across studies) is provided in f ootnotes. The corresponding risk (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI). CI: conf idence interval; RCT: random ised controlled trial; RR: risk ratio; TCM : traditional Chinese m edicine GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our conf idence in the estim ate of ef f ect. M oderate quality: Further research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate. Low quality: Further research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate. Very low quality: We are very uncertain about the estim ate. 1

The studies were parallel-group RCTs, but not blinded. The outcom e m ay be af f ected by the subjective ef f ect of the researcher, thereby resulting in very serious lim itations. 2 Studies include relatively f ew patients and f ew events and have wide conf idence intervals around the estim ate of the ef f ect. 3

RR 2.0 or RR 0.5; the ef f ect was large. The outcom e included parallel-group RCTs, but not blinded; the result m ay have serious lim itations. 5 One study used the WanJun evaluation criteria, f ive studies used the WHO Response Evaluation Criteria in Solid Tum ours and two studies used the New Response Evaluation Criteria in Solid Tum ours (RECIST).

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6


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Non-blinding and did not conceal allocation. TCM clinical criteria was am biguous; the outcom e m ay be m ore af f ected by the researcher, who prepared the TCM , so the risk of bias was very serious. 7 Studies include relatively f ew patients and f ew events and there was very serious im precision.

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BACKGROUND

Description of the condition Oesophageal cancer is a global health problem that has two subtypes: squamous carcinoma and adenocarcinoma. As the seventh leading cause of cancer death worldwide, the occurrence of oesophageal cancer varies by geographic area, ethnic group and gender. The incidence of oesophageal carcinoma can be as high as 30 to 800 cases per 100,000 persons in particular areas of northern Iran, some areas of southern Russia, and in northern China; the incidence in the US is approximately three to six cases per 100,000 persons (Nishihira 1993; Pera 2001). Oesophageal cancer is generally more common in men than in women, with a male-to-female ratio of 7:1, and occurs most commonly during the sixth and seventh decades of life (Blot 1993; Kirby 1994). Oesophageal carcinoma arises in the mucosa. Subsequently it tends to invade the submucosa and the muscular layer of the oesophagus. Eventually contiguous structures such as the tracheobronchial tree, the aorta, or the recurrent laryngeal nerve become involved. Though firstly metastasising to the perioesophageal lymph nodes, oesophageal cancer can also spread to almost any other part of the body, including the liver, lungs, brain and bones (Nishihira 1993). The etiology of oesophageal carcinoma is thought to be related to exposure of the oesophageal mucosa to noxious or toxic stimuli, resulting in a sequence of dysplasia, carcinoma in situ and carcinoma (Lam 2000). Some factors believed to trigger oesophageal carcinoma are: cigarette smoking (Broitman 1983); alcohol consumption (Tuyns 1979); drinking exceptionally hot beverages such as tea (Victora 1987); diets low in beta-carotene, vitamins A, C and B, magnesium and zinc; poor oral hygiene; protease inhibitors (Sammon 1998); high-level exposure to asbestos (O’Byrne 2001); tylosis palmaris et plantaris (Mandard 2000); swallowing lye or other caustic substances (Messmann 2001); and Barrett’s oesophagus (Williamsom 1991). A recent investigation reported that the high incidence of oesophageal carcinoma in Taiwan and India may be associated with betel chewing as a major independent risk factor (Wu 2001a).

Description of the intervention The management of oesophageal cancer presents great challenges in the current practice of gastroenterology; it is highly treatable in its earliest stages but is usually fatal when more advanced (Clark 1994; Steup 1996). Non-operative therapy is usually reserved for patients who are not candidates for surgery. The goal of therapy for these patients is palliation of dysphagia, to allow them to eat. Chemotherapy has limited use as a single modality (Cooper 1999; Entwistle 2002), but radiation therapy is successful in relieving dysphagia in approximately 50% of patients. In patients with advanced oesophageal

cancer, the preoperative combination of chemotherapy and radiotherapy has shown good results (Cooper 1999; Herskovic 1992). Intracavitary radiotherapy, with or without surgery, is safe for many patients (Homs 2003). Laser therapy can destroy cancerous tissue and relieve a blockage in the oesophagus when the cancer cannot be removed by surgery. The relief of a blockage can help to reduce symptoms, especially swallowing problems (Carter 1992). When a tracheoesophageal fistula is present, intubating with expandable metallic stents is particularly useful (Knyrim 1993; Sarper 2003). Oesophageal resection (oesophagectomy) is used in patients who are suitable for surgery. If an oesophagectomy is indicated there are three main procedures that range from minimally invasive to highly invasive (Wu 2003). A transhiatal oesophagectomy without a thoracotomy, a ’standard’ (transthoracic) oesophagectomy, or an en bloc oesophagectomy are current methods used. Many studies have been conducted using the three procedures but a consensus has not been formed as to the preferred technique (Goldminc 1993; Swanstrom 2002; Teng 1999). The application of these treatments is dependent on the stage of the disease at diagnosis. Chinese herbal medicine for oesophageal cancer has commonly been used as adjunct treatment for alleviating the side effects of chemotherapy or radiotherapy, and for improving the quality of life of cancer patients. An investigation conducted in New Zealand found that 49% of cancer patients used complementary and alternative medicine (CAM), including vitamins, antioxidants, alternative diets and herbal therapies. Usage was more common in younger patients. CAM was used by 47% of people to improve quality of life and by 30% in the hope of a cancer cure (Chrystal 2003). In one study, all participants used three or more types of CAM, most commonly herbal or nutritional supplements (Shumay 2001); evidence suggests that at least one cancer patient in three uses some form of CAM (Jacobson 1999). The most commonly-cited reasons for seeking complementary medicine were to reduce side effects of treatment, and because of the lack of effectiveness of standard therapies (Hilsden 1999).

How the intervention might work Possible benefits of herbal medicine includes increasing appetite (Jin 2003), boosting the immune system (Chen 2002a), facilitating the recovery of the body and preventing tumour regeneration or development of metastases (Wang 1999). Some herbs may be effective against cancer (Ye 2002). For example, artemisinin-type compounds inhibit tumour cell growth (Chen 2003), and membranous milkvetch root, Barbary wolfberry fruit, and heterophylly falsestarwort root may enhance immunity (Du 1998). Common yam rhizome and Indian bread could decrease the side effects of radiotherapy and give a better outcome (Jia 2001). The Chinese herbal medicine spreading hedyotis can repress the proliferation of cancer cells and block the progression of oesophageal cancer (Zhou 1996a).


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Traditional Chinese medicine (TCM) is used in the treatment of cancer by following a particular theoretical and methodological pathway that involves assessing the cause, diagnosis and treatment. Drug treatment within TCM typically consists of complex prescriptions of a combination of components.

Why it is important to do this review The evidence to support the use of herbal medicine for anticancer effects, reducing chemotherapy side effects and improving quality of life is mainly theoretical and experiential. Furthermore, there is evidence to indicate that not all CAM is risk-free, with concerns regarding adverse event issues such as allergic reactions and Chinese herbal nephropathy (Lampert 2002; Lord 2001; Nortier 2000). Despite these concerns, herbal medicine is widely used by cancer patients (Dooley 2004; Jacobson 1999).

Types of outcome measures

Primary outcomes

1. 2. 3. 4.

All-cause mortality. Median survival times. Time to progression. Quality of life (using validated measures).

Secondary outcomes

1. Improvement, defined as complete response and partial response as clarified by Miller 1981, or short-term therapeutic effects. 2. Any adverse event that caused: (1) death; (2) lifethreatening illness; or (3) significant toxicity.

OBJECTIVES

Search methods for identification of studies

We aim to update our previous review that was published in 2009 to assess the efficacy and possible adverse effects of combining Chinese herbal medicine with radiotherapy or chemotherapy for the treatment of oesophageal cancer (Wei 2007).

We conducted searches to identify all published and unpublished RCTs of traditional Chinese herbal therapy for oesophageal cancer. The search strategy identified studies in all languages. We translated non-English language papers so that we could fully assess them for inclusion in the review, as necessary.

METHODS

Electronic searches

Types of interventions

We searched the following databases. • CENTRAL (the Cochrane Library, September 2015; Appendix 1). • MEDLINE (1950 to September 2015; Appendix 2). • EMBASE (1980 to September 2015; Appendix 3). • AMED (1985 to September 2015; Appendix 4). • CNKI (1979 to September 2015; Appendix 5). • Chinese journals full-text database (1979 to September 2015; Appendix 5). • Chinese journals full-text database century journals (1979 to September 2015; Appendix 5). • Chinese Doctoral degree thesis full-text database (1979 to September 2015; Appendix 5). • Chinese outstanding master degree thesis full-text database (1979 to September 2015; Appendix 5). • VIP Database (1989 to September 2015; Appendix 6). • Wanfang Database (1993 to September 2015; Appendix 7).

All traditional Chinese medicine (TCM) used in the treatment of oesophageal cancer as an adjunct to active cancer therapy such as radiotherapy or chemotherapy. Water extractions of TCM were administered either orally (in capsules or as powders) or by intravenous infusion.

We constructed the search strategy for Chinese databases by using a combination of MeSH subject headings and text words relating to the use of Chinese medicinal herbs in the treatment of oesophageal cancer (Appendix 8).

Criteria for considering studies for this review

Types of studies We included only randomised controlled trials (RCTs) comparing radiotherapy or chemotherapy with or without additional Chinese herbal medicine.

Types of participants Patients with oesophageal cancer of different subtypes.


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Searching other resources We also handsearched the following Chinese journals. • Acta Medicinae Sinica. • Cancer Research on Prevention and Treatment. • China Journal of Chinese Materia Medica. • China Oncology. • Chinese Journal of Cancer Research. • Chinese Journal of Clinical Oncology and Rehabilitation. • Chinese Journal of Integrated Traditional and Western Medicine on Digestion. • Chinese Journal of Oncology. • Chinese Journal of Radiation Oncology. • Henan Journal of Traditional Chinese Medicine. • Jiangshu Journal of Traditional Chinese Medicine. • Journal of Beijing of Traditional Chinese Medicine. • Journal of Fujian of Traditional Chinese Medicine. • Journal of Jilin of Traditional Chinese Medicine. • Journal of Practical Oncology. • Journal of Nanjing University of Traditional Chinese Medicine. • Journal of Sichuang of Traditional Chinese Medicine. • Journal of Traditional Chinese Medicine. • Traditional Chinese Medicinal Research.

Data collection and analysis Three review authors (XC, LD, TW) undertook data collection and analysis.

Selection of studies To determine the studies to be assessed further we scanned the titles, abstracts and keywords of every record retrieved. We retrieved full articles for further assessment if the information given suggested that the studies: 1. included patients with oesophageal cancer of different subtypes; 2. compared the combination of conventional treatment and Chinese medicinal herbs with conventional therapies without Chinese medicinal herbs; 3. assessed one or more relevant clinical outcome measures; 4. used random allocation to the comparison groups. We then telephoned the authors of potential included studies to determine if the studies were RCTs. There were no recorded disagreements between the review authors. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009), and ’Characteristics of excluded studies’ table.

Data extraction and management

Two review authors (XC, TW) independently extracted data concerning details of study population, intervention used and outcomes by using a data extraction form. We designed the form specifically for this review and it included the following items. 1. General information: published or unpublished, title, authors, reference or source, contact address, country, urban or rural etc., language of publication, year of publication, duplicate publication, sponsor, setting. 2. Trial characteristics: design, duration of follow-up, method of randomisation, allocation concealment, blinding (patients, people administering treatment, outcome assessors). 3. Intervention(s): intervention(s) (dose, route, timing), comparison intervention(s) (dose, route, timing), comedication(s) (dose, route, timing). 4. Patients: exclusion criteria, total number and number in comparison groups, age (adults), baseline characteristics, diagnostic criteria, similarity of groups at baseline (including any comorbidity), assessment of compliance, withdrawals or losses to follow-up (reasons or description), subgroups. 5. Outcomes: outcomes specified in this review, any other outcomes assessed, other events, length of follow-up, quality of reporting of outcomes. 6. Results: for outcomes (including a measure of variation) and times of assessment. If necessary, we converted these to measures of effect as specified below, and using an intention-totreat analysis. 7. Other: the Pinyin, Latin and English names of the TCM preparations of included studies are in Table 1. Original reports of trial results were independently abstracted by XC and TW. Differences in data extraction were resolved by discussion and by referring back to the original article. When necessary, information was sought from the authors of the primary studies. We consulted a third author (LD) to resolve any disagreement. For binary outcomes, we extracted number of events and total number in each group. For continuous outcomes, we extracted the mean, standard deviation and sample size of each group. Assessment of risk of bias in included studies At least two review authors (XC, TW) independently assessed risk of bias by using the following criteria described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Higgins 2011) and (Wu 2007). We assessed the following characteristics. Random sequence generation (selection bias)

We classified a study as a RCT if it was described as randomised (this includes the use of words such as randomly, random, and randomisation, etc.). We judged the study as low risk, high risk, or unclear risk according to the following.


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• Low risk, if the allocation sequence was generated by computer-generated random numbers, published random number table, coin tossing, shuffling cards or envelopes, or throwing dice. • Unclear risk, if the trial was described as randomised but the method used for generation of the allocation sequence was not described. • High risk, if selection was based on patient numbers, birth dates, visit dates, or alternative allocation. • We excluded studies that described selection based on patient or clinical preference, or any selection mechanism that cannot be described as random. We also excluded studies that did not state whether the treatment was randomly allocated. Allocation concealment (selection bias)

• Low risk, if investigators were unaware of the allocation of each participant before they were entered in the trial. Acceptable methods included: central telephone randomisation schemes, pharmacy-based schemes, sequentially numbered, opaque, sealed envelopes, or sequentially numbered drug containers of identical appearance. • Unclear risk, if the authors did not report or provide a description of an allocation concealment approach that allowed for classification as concealed or not concealed. • High risk, when investigators may have been aware of the allocation of each participant before they entered the trial, e.g. when allocation was based on patient data such as date of birth, hospital case note number, or visit dates, sealed envelopes that were not opaque, or a random number table that was not concealed from an investigator. Blinding of participants and personnel (performance bias)

• Low risk, if both participants and physicians were blinded to the treatment allocation, and it was unlikely that the blinding could have been broken. • Unclear risk, if no blinding information was available or there was insufficient information to permit a judgement of low risk or high risk. • High risk, if the authors defined the study as an open study, or no party was blinded. Either participants or some key study personnel were not blinded, and the non-blinding of others was likely to introduce bias. Blinding of outcome assessment (detection bias)

• Low risk, if outcome assessors were blinded to the assigned treatment arm. • Unclear risk, if no information was provided for blinding of outcome assessment. • High risk, if outcome assessors were not blinded to the assigned treatment arm. Lack of blinding is likely to influence adverse events as an outcome.

Incomplete outcome data (attrition bias)

We assessed attrition bias for Helicobacter pylori (H. pylori) eradication and adverse events. • Low risk, if there were no missing outcome data; reasons for missing outcome data were unlikely to be related to true outcome; missing outcome data were balanced in numbers across intervention groups, with similar reasons for missing data across groups; the proportion of missing outcomes compared with the observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; missing data were imputed using appropriate methods. • Unclear risk, if insufficient reporting of attrition or exclusions to permit judgement of low risk or high risk (e.g. no reasons for missing data provided). • High risk, if reasons for missing outcome data were likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; the proportion of missing outcomes compared with observed event risk were enough to induce clinically relevant bias in intervention effect estimate; per protocol analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

Selective reporting (reporting bias)

• Low risk, if the published reports included all expected outcomes, including those that were prespecified. • Unclear risk, if insufficient information to permit judgement of low risk or high risk. • High risk, if not all of the study’s prespecified primary outcomes were reported; the primary outcome was reported using measurements, analysis methods, or subsets of the data that were not prespecified; the primary outcome was not prespecified or was reported incompletely; or the study report failed to include results for a key outcome that would be expected to have been reported for such a study.

Other bias

• Low risk, if the study appears to be free of other sources of bias. • Unclear risk, if there may be a risk of bias but there is either: insufficient information to assess whether an important risk of bias exists (e.g. limited information from a conference proceeding); or insufficient rationale or evidence that an identified problem introduces bias. • High risk, if there is at least one important risk of bias; a potential source of bias related to the specific study design used; stopped early due to a data-dependent process (including a formal stopping rule); extreme baseline imbalance; has been claimed to have been fraudulent; or any other problem.


11

Measures of treatment effect

Data synthesis

If data were sufficiently similar, we carried out meta-analysis using the Review Manager software (RevMan 2014). We expressed results as risk ratios (RRs) for dichotomous outcomes; we used mean difference (MD) or the standardised mean difference (SMD) for continuous outcomes, both with 95% confidence intervals (CIs). We estimated time-to-event (survival) data by O - E (observed value minus expected value) with variance.

We did not intend to combine results of trials with different comparator drugs, and so we only included trials comparing radiotherapy or chemotherapy with or without additional Chinese herbal medicine. We used a random-effects statistical model to conduct pooled analysis throughout. If the number of included studies was too small or heterogeneity was too apparent to conduct a metaanalysis, we performed only a descriptive analysis.

Unit of analysis issues

GRADE and ’Summary of findings’ table

For trials with non-standard designs such as cluster-randomised trials and trials with multiple intervention groups, unit of analysis issues were taken into account. The analysis was based on the individual participant rather than group of individuals. For a study with more than two treatment arms, we extracted only the relevant data.

We created a ’Summary of findings’ table using the following outcomes, all-cause mortality, median survival times, time to progression, quality of life, short-term therapeutic effects or TCM symptoms and adverse events. We used the five GRADE (Atkins 2004) considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta-analyses for the prespecified outcomes. We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEproGDT software (GRADEproGDT 2015). We justified all decisions to down- or up-grade the quality of studies using footnotes, and we made comments to aid the reader’s understanding of the review where necessary.

Dealing with missing data Where required, we requested information about missing data from original trial authors by telephone interview. We conducted an intention-to-treat analysis for missing participants due to dropout. If the missing data were unobtainable, we assumed that the unreported outcomes would provide dissatisfactory results. For example, the missing data from treatment groups would be added to the number experiencing deterioration in quality of life, progressive disease in short-term therapeutic effects and suffering adverse events caused by radiotherapy or chemotherapy. The missing data from control groups would be added to the number experiencing improvement in quality of life and improvement in short-term therapeutic effects. Assessment of heterogeneity We carried out the test for heterogeneity using the Chi2 test with significance set at P < 0.10. We used I2 to estimate the total variation across studies. We considered I2 < 25% as low level heterogeneity, 25% to 50% as a moderate level, and higher than 50% as high level heterogeneity (Higgins 2011). If there was evidence of heterogeneity, we performed subgroup analyses to find possible explanations. Assessment of reporting biases We considered reporting biases, which include publication bias and selective outcome reporting; they are listed in the ’Risk of bias’ table of included studies. We would have assessed the potential publication bias using funnel plots when at least nine trials for one outcome were present. The result of asymmetric funnel plots should be interpreted carefully, because they may not necessarily be caused by publication bias. In this updated review, we could not perform a funnel plots analysis because of the small number of included studies.

Subgroup analysis and investigation of heterogeneity We explored reasons for heterogeneity between studies, and through sensitivity analyses examined the effects of excluding study subgroups, for example, those studies with lower methodological quality. We used a funnel plot to explore publication bias. We intended to explore the following potential sources of heterogeneity using subgroup analyses or meta-regression. 1. Stage of disease. 2. Different TCM formulations. 3. Duration of treatment. Sensitivity analysis We checked if the results were affected by the inclusion of results from certain trials by using a sensitivity analysis, and by comparing a random-effects model to a fixed-effect model.

RESULTS

Description of studies


12

Results of the search In this updated review, the initial search of the electronic databases and handsearching yielded 3813 records after we removed duplicates. After scrutinising these records, we assessed 288 full-text records for eligibility (see Figure 1 for details of the screening process of the search results). We excluded 146 full-text records and retained 142 full-text records which claimed “randomly allocated patients” in their text. Then we telephoned authors of 142 reports

to determine if the trials were authentic RCTs or not (see Figure 2 for details of the telephone interview process and the results). Finally, we judged 92 studies as not true RCTs (see Characteristics of excluded studies). We identified nine studies to be true RCTs which met the inclusion criteria (see Characteristics of included studies). However, up to October 30, 2015, we have been unable to contact 41 authors in this update, and we have provided details of these studies in Studies awaiting classification.

Figure 1. Study flow diagram.


13

Figure 2. Flow diagram of telephone interviews.


14

Included studies In the last version of this review, no study was eligible for inclusion. We included nine studies that met our inclusion criteria in this updated review (Chen 2012; Cheng 2010; He 2010a; Lin 2013; Mu 2012; Ren 2013; Shao 2011; Wang 2010c; Wu 2013a). All included trials were conducted in China, and were single-centre two-arm studies, except Wang 2010c which involved patients from two hospitals. The details are presented in the Characteristics of included studies tables.

Trial characteristics

All studies used a parallel-group design. No details were given about the duration of follow-up, except Wu 2013a, in which the median time of follow-up was 5.3 months. No traditional Chinese medicine (TCM) placebo was used in any of the control groups, and so they could not be blinded.

Interventions

All studies compared radiotherapy or chemotherapy with and without additional Chinese herbal medicine. Chemoradiotherapy was given in Chen 2012, five trials used chemotherapy (Cheng 2010; Lin 2013; Shao 2011; Wang 2010c; Wu 2013a), and the remaining trials used radiotherapy (He 2010a; Mu 2012; Ren 2013). • Chen 2012 compared Fuzheng Guben granules combined with chemoradiotherapy versus chemoradiotherapy. The duration of chemoradiotherapy lasted six weeks; Fuzheng Guben granules lasted six to seven weeks. • Cheng 2010 compared Xihuang Pill combined with chemotherapy versus chemotherapy. The duration of treatment continued for six weeks. • He 2010a compared Brucea javanica oil emulsion plus radiotherapy versus radiotherapy. The duration of radiotherapy treatment continued for six to seven weeks; Brucea javanica oil emulsion was given for 18 to 27 days. • Lin 2013 compared Xiaoaiping injection combined with chemotherapy versus chemotherapy. The duration of treatment continued for eight weeks. • Mu 2012 and Ren 2013 compared Kangai injection plus radiotherapy versus radiotherapy. The duration of treatment continued for six weeks. • Shao 2011 compared Yiqi yang yin Huatan quyu decoction combined with chemotherapy versus chemotherapy. The duration of treatment continued for two months. • Wang 2010c compared Zhisheng capsule combined with chemotherapy versus chemotherapy. The duration of treatment continued for nine weeks.

• In Wu 2013a, all participants received chemotherapy for a maximum of six weeks; an additional Aidi injection was given to participants in the treatment group for 14 days. The Pinyin, Latin and English names of the TCM preparations of the included studies are in Table 1. Patients

A total of 490 participants (355 males, 135 females) were included in these nine studies, with 247 participants in the treatment group and 243 participants in the control group. All participants were recruited from Chinese hospitals and had oesophageal carcinoma confirmed by pathology or imaging (computed tomography (CT), magnetic resonance imaging (MRI), X-ray). All reports described no significant clinically statistical difference between treatment and control groups. • In Chen 2012, patients were diagnosed to be stage

,

b,

. • In Cheng 2010, the trial author diagnosed the patients as having advanced or metastatic oesophageal cancer by CT and Xray. • In He 2010a, the trial author diagnosed the disease to be stage , using the International Union for Cancer Control staging system. • In Lin 2013, the trial author diagnosed the disease to be stage , . • In Mu 2012, the trial author described the cancer as having developed to an advanced stage. • In Ren 2013, the stage of disease was not mentioned. • In Shao 2011, the trial author identified the oesophageal cancer to be stage

,

.

• In Wang 2010c, the cancer was diagnosed to be stage , using the International Union for Cancer Control staging system. • In Wu 2013a, the author diagnosed the cancer to be stage , using the American Joint Committee on Cancer staging system. None of the trials described withdrawals or losses to follow-up. Outcomes

Primary outcomes No study reported all-cause mortality, median survival times or time to progression.


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Eight studies assessed quality of life, however, two studies did not use a validated measure, and could not be adopted (He 2010a; Wu 2013a). The remaining six studies, Lin 2013, Mu 2012, Ren 2013, Wang 2010c, Shao 2011 used the Karnofsky scoring scale for quality of life, while Cheng 2010 used the Revision of Quality of Life Index Scale of Chinese cancer patients. The measurement for quality of life was conducted before and after the intervention. Secondary outcomes The included studies reported two different therapeutic evaluation methods; short-term therapeutic effects and TCM symptoms. Short-term therapeutic effects referred to improvement (complete response + partial response) and progressive disease. There were three evaluation criteria, five studies used the World Health Organization Response Evaluation Criteria in Solid Tumours (He 2010a; Lin 2013; Mu 2012; Ren 2013; Wang 2010c), two studies used the New Response Evaluation Criteria in Solid Tumours (RECIST) (Cheng 2010; Wu 2013a), and one study used the WanJun evaluation criteria (Chen 2012). One study measured this outcome after four weeks’ follow-up (Chen 2012), two studies followed up for three months after the intervention (He 2010a; Ren 2013), and the remaining gave no detailed information. TCM symptoms were diagnosed in two studies (Shao 2011; Wang 2010c) at the end of the intervention. The studies classified participants as to total effectiveness and ineffectiveness according to Zheng 2002. The total effectiveness meant the symptom scores decreased ≥30% after intervention, the ineffectiveness represented the symptom scores decreased ≤30% after intervention. Adverse events We focused on any adverse event that caused death, life-threatening illness or significant toxicity. In this updated review, the nine included studies reported many adverse events, such as, mucositis, radiation oesophagitis, arrest of bone marrow, gastrointestinal reactions (vomiting, dyspepsia, nausea), renal and hepatic impairment, white blood cell descent, neurotoxicity, cardiac toxicity,

anaemia and low fever. All these adverse events were observed at the end of the intervention. In addition, we were also concerned with outcomes which could reflect the adjunct treatment characteristics of Chinese herbal medicine, such as bodyweight (reflecting increased appetite) and T-lymphocyte and cancer bio-markers (reflecting boost the immune system).

Excluded studies In the last version of this review (Wei 2007), we included Chen 2002a and Liu 2005 as real RCTs based on the initial interview with the original trial authors. On 31 May, 2007, TW interviewed Dr. Degui Liu and Prof. Zhijian Chen, the original trial authors, to discuss the design and process of the study in detail. The two trial authors very kindly explained that they had not used any randomisation method to generate an allocation sequence; Liu 2005 was actually a retrospective case report. We therefore identified them as non-RCTs and excluded them from the review. According to this situation, it was necessary to critically identify whether the studies which claimed they had “randomly allocated patients” were true RCTs or not. For this purpose, we telephoned the authors of these studies. In conclusion, 13 trial authors refused an interview, 48 studies were retrospective case reports, two trial authors confessed to using no random method, seven trial authors could not describe the details of the random method, and 22 trial authors misunderstood the random allocation method or used an incorrect random method. We recorded the process of telephone interviews, and two review authors (XC and TW) were responsible for judgements (see Figure 2). Summary details of all the trials are given in the Characteristics of excluded studies.

Risk of bias in included studies The risk of bias is described below and summarised in Figure 3 and Figure 4.


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Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.


17

Figure 4. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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Allocation

Random sequence generation

Four included studies mentioned ”randomly allocated patients” (Chen 2012; He 2010a; Mu 2012; Wang 2010c), and five studies stated using random number tables in the articles (Cheng 2010; Lin 2013; Ren 2013; Shao 2011; Wu 2013a), but all studies were short of details of randomisation. After telephone interviews with the trial authors who kindly gave descriptions of random sequence generation, we graded the included studies at low risk of bias, apart from Cheng 2010, which we judged to be at high risk of bias because the descriptions were inconsistent between the telephone interview and reports. Allocation concealment

None of the studies reported on the use of allocation concealment. However, in a telephone interview, one author explained that ”computer-generated random numbers were sealed in envelopes, which were used to allocate patients” (Wu 2013a). We judged this study at low risk bias for allocation concealment.

two arms (Cheng 2010; Ren 2013; Wu 2013a), especially in Ren 2013 where there were 28 participants in the TCM group and 26 in the control group. The reports did not interpret whether the imbalance of participant numbers in the two arms was produced by withdrawals during follow-up or inadequate randomisation, or other reasons.

Selective reporting The protocols of the included studies were unavailable. Two studies did not report one outcome in the results, which had been presented in the methods section of the study (Lin 2013; Ren 2013). We considered these two studies at high risk of reporting bias.

Other potential sources of bias Other bias refers to factors such as conflict of interest, baseline imbalances, the standard deviation and other obvious potential sources that have a disadvantageous impact on risk. Ultimately, we judged three studies to have conflicts of interest (Chen 2012; Shao 2011; Wang 2010c), and He 2010a contained an incorrect description of significant difference; we judged these four studies to be at high risk of bias for this domain.

Blinding None of the nine studies employed a placebo mimicking TCM in the control group, so it was not possible to mask participants and personnel. We therefore judged the risk of performance bias to be high. In detail, blinding was not performed in three studies, one mentioned “no blinding method” in the text (Cheng 2010), two studies transmitted “no blinding” through interviews (Shao 2011; Wu 2013a), and so we judged the detection bias to be high. The remaining six studies did not provide any information about masking, and so we judged the detection bias to be unclear (Chen 2012; He 2010a; Lin 2013; Mu 2012; Ren 2013; Wang 2010c). Incomplete outcome data No study had a statement on drop-outs or withdrawals. In telephone interviews, one author described “ no drop-outs from the TCM group and control group” (Shao 2011), and so we judged the risk to be low. However, in Wang 2010c, there were only 22 patients represented in the outcome of short-term therapeutic effects and 23 patients represented in the TCM clinical symptoms outcome, which were not matched to the total 24 patients allocated in the control group. No intention-to-treat (ITT) analysis was performed either. We considered this study to be at high risk for attrition bias. In addition, three trials showed unequal participant numbers in the

Effects of interventions See: Summary of findings for the main comparison Active cancer therapy combined with TCM compared to active cancer therapy for oesophageal cancer; Summary of findings 2 Active cancer therapy combined with TCM compared to active cancer therapy for oesophageal cancer See: Summary of findings for the main comparison and Summary of findings 2.

Primary outcomes All-cause mortality, median survival times and time to progression were not reported in any of the included studies.

Quality of life

We reported quality of life in terms of number of participants experiencing an improvement and number experiencing a deterioration in quality of life. More specifically, we assessed quality of life pre- and post-intervention with the Karnofsky performance status scale or other validated scales. Participants experiencing an improvement meant that the participants performance score would improve ≥ 10 after the intervention, while experiencing a deterioration meant a change score ≤ 10.


19

Five studies reported improvements in quality of life with a total of 233 participants undergoing radiotherapy or chemotherapy, with or without additional Chinese herbal medicine (Cheng 2010; Lin 2013; Mu 2012; Shao 2011; Wang 2010c). Six studies reported a deterioration in quality of life with 287 participants (Cheng 2010; Lin 2013; Mu 2012; Ren 2013; Shao 2011; Wang 2010c). TCM in these studies probably had a positive effect on quality of life, both in number experiencing improvement (risk ratio (RR) 2.20, 95% confidence interval (CI) 1.42 to 3.39; I² = 0%) and number experiencing deterioration (RR 0.41, 95% CI 0.27 to 0.62; I² = 0%) (Analysis 1.1). All studies in this outcome were parallel-group RCTs, but not blinded; the evaluation may have been affected by the subjective effect of the researcher, resulting in very serious risk of bias. Further, these studies included relatively few patients and few events and have wide confidence intervals around the estimate of the effect that could lead to serious imprecision. Due to the very serious risk of bias and serious imprecision, we downgraded the quality of evidence by three levels. With a RR of number experiencing improvement

2.0 and RR of number experiencing

deterioration 0.5, the effect was large and so we upgraded the quality of evidence by one level. Overall, we judged this outcome to have low quality evidence. In addition, one study provided the Karnofsky score for quality of life in 60 participants (Lin 2013). Results of this study suggest that Xiaoaiping injection may improve the Karnofsky score (mean difference (MD) 6.80, 95% CI 3.86 to 9.74) (Analysis 1.2). We judged this to have low quality evidence, downgrading for very serious risk of bias (Summary of findings for the main comparison).

Secondary outcomes

Short-term therapeutic effects

For short-term therapeutic effects, participants were divided into four different categories - complete response, partial response, stable disease and progressive disease, which should have clear judgement criteria in individual trials. Improvement was defined as complete response and partial response, and it represented the patients being in a more beneficial state after therapy. In contrast to that, progressive disease represented a disadvantageous state after therapy. In detail, eight studies reported short-term therapeutic effects in 450 participants experiencing radiotherapy or chemotherapy, with or without additional Chinese herbal medicine (Chen 2012; Cheng 2010; He 2010a; Lin 2013; Mu 2012; Ren 2013; Wang 2010c; Wu 2013a). The data suggest that TCM probably leads to little or no difference in improvement (RR 1.17, 95% CI 1.02 to 1.35; I² = 0%, P = 0.03) and progressive disease (RR 0.73, 95% CI 0.52 to 1.01; I² = 0%, P = 0.06) (Analysis 1.3). If Chen 2012 is removed from the analysis, the difference for improvement is no

longer statistically significant (RR 1.12, 95% CI 0.95 to 1.32; 7 studies, 360 participants; I² = 0%, P = 0.17). This may be caused by different TCM formulations. However, the data were not sufficient to conduct a subgroup analysis, and we could not explore the potential diverse effects of TCM on short-term therapeutic effects. All studies were parallel-group RCTs but not blinded, the outcomes were measured by imaging such as CT, MRI or X-ray, and judged using the WanJun, WHO or RECIST Evaluation Criteria in Solid Tumours. Due to the lack of blinding, the observations would have experienced the Hawthorne effect. Therefore, the results might have serious limitations. In addition, the effect of progressive disease had wide confidence intervals, resulting in serious imprecision. Overall, we judged improvement to have moderate quality evidence, downgrading for serious risk of bias; and progressive disease to have low quality evidence due to serious risk of bias and serious imprecision (Summary of findings for the main comparison).

TCM symptoms

Similar to short-term therapeutic effects, TCM symptoms divided participants into total effectiveness and ineffectiveness. The TCM symptoms scores were measured before and after intervention according to Zheng 2002. The participants whose symptom scores decreased ≥30% were assigned to the total effectiveness group, the participants whose symptom scores decreased ≤30% were assigned to the ineffectiveness group. This outcome only included two studies with 88 patients (Shao 2011; Wang 2010c). As a result, TCM showed a positive impact on both total effectiveness (RR 1.84, 95% CI 1.20 to 2.81; I² = 37%) and ineffectiveness (RR 0.22, 95% CI 0.05 to 0.93; I² = 49%) (Analysis 1.4). The two studies were not blinded and did not conceal allocation. TCM clinical criteria was ambiguous, the outcome may be more affected by the researcher, who prepared the TCM, so the risk of bias was very serious. Total effectiveness had serious limitations with only two included studies with few patients and few events, while the result for ineffectiveness had very serious limitations due to few patients, few events and wide confidence intervals. With a RR for ineffectiveness of 0.5, the effect was large and so we upgraded the quality of evidence by one level. Overall, we judged total effectiveness to have very low quality evidence due to very serious risk of bias and serious imprecision; we judged ineffectiveness to also have very low quality evidence, downgrading for very serious risk of bias and very serious imprecision, and upgrading for the large effect.

Adverse events Nine studies reported ten kinds of adverse events, including mucositis, radiation oesophagitis, arrest of bone marrow, gastrointestinal reactions, renal and hepatic impairment, white blood cell


20

descent, neurotoxicity, cardiac toxicity, anaemia and low fever (see Analysis 1.5 and Summary of findings 2). • One study reported mucositis caused by radiotherapy (Mu 2012). Twenty-three out of 25 patients in the TCM group and 25/25 patients in the control group suffered from different degrees of mucositis; there was no significant difference between the two groups (RR 0.92, 95% CI 0.80 to 1.06; P = 0.24). We judged the quality of evidence to be low; downgrading for very serious risk of bias. • Two studies reported radiation oesophagitis (Chen 2012; He 2010a). TCM exhibited a potential ability to reduce radiation oesophagitis (RR 0.66, 95% CI 0.47 to 0.94; I² = 0%). We judged this to have low quality evidence; downgrading for serious risk of bias and serious imprecision. • One study reported arrest of bone marrow (Chen 2012). The result showed that TCM probably had an effect on arrest of bone marrow caused by chemoradiotherapy (RR 0.28, 95% CI 0.14 to 0.58). We judged this to be of moderate quality evidence; downgrading for very serious risk of bias, and upgrading for the large effect. • Four studies reported gastrointestinal reactions (Chen 2012; He 2010a; Lin 2013; Wang 2010c). The data showed that TCM probably had a potential effect on gastrointestinal reactions caused by chemotherapy or radiotherapy (RR 0.54, 95% CI 0.36 to 0.81; I² = 30%). We judged this to be of very low quality evidence; downgrading for very serious risk of bias and serious imprecision. • Two studies reported renal and hepatic impairment (Chen

2012; Lin 2013). However, pooled analysis showed significant heterogeneity with I² = 88%, (50% is regarded as high level heterogeneity). Because only two trials were included in this adverse event, we could not explore potential sources of heterogeneity. • Four studies reported white blood cell descent (He 2010a; Lin 2013; Ren 2013; Shao 2011). The data showed that oesophageal cancer patients may benefit from TCM after chemotherapy or radiotherapy (RR 0.60, 95% CI 0.44 to 0.83; I² = 0%) in blood cell descent. We judged this to be of very low quality evidence; downgrading for very serious risk of bias and serious imprecision. • One study reported neurotoxicity (Lin 2013), there was no significant difference between the groups (RR 0.73, 95% CI 0.34 to 1.55; P = 0.41). We judged this to be of low quality evidence; downgrading for very serious risk of bias. • One study reported cardiac toxicity (Lin 2013), there was no significant difference between the groups (RR 0.80, 95% CI 0.24 to 2.69; P = 0.72). We judged this adverse outcome to be of low quality evidence; downgrading for very serious risk of bias. • One trial reported anaemia (Shao 2011); there was no significant difference between the groups (RR 1.33, 95% CI 0.57 to 3.14; P = 0.51). We judged this adverse outcome to be of low quality evidence; downgrading for very serious risk of bias. • In addition, He 2010a reported two cases of low fever in the treatment group; the symptoms disappeared after two to three days. The trial author suggested that low fever was related to the usage of Brucea javanica oil emulsion.


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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Active cancer therapy combined with TCM compared to active cancer therapy for oesophageal cancer Patient or population: oesophageal cancer Settings: inpatient, hospital in china Intervention: active cancer therapy com bined with TCM Comparison: active cancer therapy Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Usual treatment

Usual treatment combined with TCM

Adverse events - mu- Study population cositis Diagnosed by clinicians 1000 per 1000

Relative effect (95% CI)

No of Participants (studies)

Quality of the evidence Comments (GRADE)

RR 0.92 (0.80 to 1.06)

50 (1 study)

⊕⊕

low1

RR 0.66 (0.47 to 0.94)

160 (2 studies)

⊕⊕

low2,3

920 per 1000 (800 to 1000)


Adverse events - radi- Study population ation oesophagitis Assessed with the 550 per 1000 Com m on Term inology Criteria f or Adverse Events M oderate 546 per 1000

920 per 1000 (800 to 1000)

363 per 1000 (258 to 517)

360 per 1000 (257 to 513)

22


Adverse events - arrest Study population of bone marrow Assessed with the 556 per 1000 World Health Organization drug toxicity evaluation standard M oderate 556 per 1000

Adverse events - gas- Study population trointestinal reactions Diagnosed by clinicians 500 per 1000

RR 0.28 (0.14 to 0.58)

90 (1 study)

⊕⊕⊕ moderate 1,4

RR 0.54 (0.36 to 0.81)

268 (4 studies)

⊕

very low1,3

RR 0.33 (0.13 to 0.84)

90 (1 study)

⊕⊕

low1

RR 0.90 (0.12 to 6.48)

60 (1 study)

⊕⊕

low1

156 per 1000 (78 to 322)

156 per 1000 (78 to 322)

270 per 1000 (180 to 405)


Adverse events - renal and hepatic impairment - Fuzheng Guben granules Assessed with the World Health Organization drug toxicity evaluation standard

301 per 1000 (201 to 452)


110 per 1000 (43 to 280)


Adverse events - re- Study population nal and hepatic impair133 per 1000 ment- Xiaoaiping Diagnosed by clinicians M oderate

110 per 1000 (43 to 280)

120 per 1000 (16 to 864)

23


233 per 1000

Adverse events - white Study population blood cell descent Diagnosed by clinicians 486 per 1000

210 per 1000 (28 to 1000) RR 0.60 (0.44 to 0.83)

224 (4 studies)

⊕

very low1,3

RR 0.73 (0.34 to 1.55)

60 (1 study)

⊕⊕

low1

RR 0.80 (0.24 to 2.69)

60 (1 study)

⊕⊕

low1

292 per 1000 (214 to 404)


Adverse events - neu- Study population rotoxicity Diagnosed by clinicians 367 per 1000

268 per 1000 (196 to 370)

268 per 1000 (125 to 568)


Adverse events - car- Study population diac toxicity Diagnosed by clinicians 167 per 1000

268 per 1000 (125 to 569)

133 per 1000 (40 to 448)


134 per 1000 (40 to 449)

* The basis f or the assumed risk (e.g. the m edian control group risk across studies) is provided in f ootnotes. The corresponding risk (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI). CI: Conf idence interval; RCT: random ised controlled trial; RR: Risk ratio; TCM : traditional Chinese m edicine 24


GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our conf idence in the estim ate of ef f ect. M oderate quality: Further research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate. Low quality: Further research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate. Very low quality: We are very uncertain about the estim ate. 1

The study was a parallel-group RCT, but not blinded. The outcom e m ay be af f ected by the subjective ef f ect of the researcher, thereby resulting in very serious lim itations. 2 The outcom e included parallel-group RCTs, but not blinded; the result m ay have serious lim itations. 3 Studies include relatively f ew patients and f ew events and have wide conf idence intervals around the estim ate of the ef f ect. 4

RR

2.0 or RR

0.5; the ef f ect was large.

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DISCUSSION

Summary of main results In this systematic review, we intended to evaluate the efficacy and possible adverse effects of traditional Chinese medicine (TCM) when used as an adjunct to treatment with radiotherapy or chemotherapy for oesophageal cancer. The overall treatment concept for TCM is different from that used in Western medicine, and we hoped to assess if TCM could be used in the effective treatment of oesophageal cancer. TCM is well established and widely used, and based on the principles that the root cause of illness, not the symptoms, must be treated. TCM can be described as being holistic in its approach; it views every aspect of the balance between mind, body, spirit and emotions. In using TCM to treat oesophageal cancer, physicians hope to strengthen and support the body’s systems, using preparations that are formulated to act specifically on imbalances in the way the body functions. In the last version of this review, we excluded all 43 studies which were self described by trial authors as being RCTs, as we later discovered this not to be the case. This may have been due to some Chinese trial authors in the field having misunderstood what the term means, underestimating the importance of randomly allocating participants with oesophageal cancer and knowing how to minimise risk of bias in a RCT. In this updated review, we tried to contact authors of 142 studies to critically identify whether the studies which claimed to be RCTs, were in fact true RCTs. Ultimately, we included nine of the studies (all conducted in China). It is regrettable that none of the studies reported all-cause mortality, median survival times or time to progression, and so we are uncertain as to whether TCM has an effect on oesophageal cancer for these outcomes or how effective it may be. Most studies reported quality of life and short-term therapeutic effects. Both of these outcomes are measured by clinicians according to certain criteria, however, the process was not blinded, thereby increasing the risk of bias. The results of the meta-analyses show that TCM probably had an effect on quality of life. While, the results are complicated for short-term therapeutic effects, TCM showed a statistically significant effect on improvement (complete response + partial response), but no statistically significant effect on progressive disease. These inconsistent results may be caused by the small number of participants and few studies, which leads the result to be more sensitive and volatile. TCM symptoms, which were similar to short-term therapeutic effects evaluated with TCM clinical criteria, were diagnosed in two studies and showed a positive effect. Nine studies reported a series of adverse events, such as mucositis, radiation oesophagitis, arrest of bone marrow, gastrointestinal reactions, renal and hepatic impairment, white blood cell descent, neurotoxicity, cardiac toxicity, anaemia and low fever. All of these adverse effects were caused by radiotherapy or chemotherapy, except for low fever, which was considered to be associated with

TCM. After analyses, TCM showed a positive impact on radiation oesophagitis, arrest of bone marrow, gastrointestinal reactions and white blood cell descent. The effects of TCM on the other adverse effects are uncertain. In this updated review, we were also concerned with the details of other outcomes not specified in the protocol, such as T-lymphocyte, cancer bio-markers and bodyweight. To some extent, these three outcomes would reflect the TCM effect, and as auxiliary outcomes, they have attracted the attention of researchers. If necessary, we will consider the analysis of these outcomes in a future review update.

Overall completeness and applicability of evidence It is difficult to reach definitive conclusions due to variation between TCM formulations in the included studies. Variation in the components of herbal medical preparations is not unique to Chinese traditional herbal medicine; the variation between formulations and batches of treatments being an inevitable consequence of the nature of TCM. In China, the government specifies the limits of variation that are acceptable. This variation should be considered and may be a factor that contributes to any heterogeneity between different study results. Therefore, much importance should be attached to a high quality study when a study uses a self prepared herbal formulation and this study should provide evidence that is strong enough to encourage further studies in different locations to strengthen its validity. Studies treating oesophageal cancer with the same main components, as contained within an efficacious self prepared herbal formulation, are also encouraged. Chinese patented drugs have priority over the self prepared herbal formulations in order to achieve consistency. In this review, we attempted to contact 142 authors, and completed 101 telephone interviews. Eventually we identified nine true RCTs. These RCTs allocated 490 participants in total to either usual treatment or usual treatment combined with TCM. Interventions, either usual treatment or TCM, were complicated. The usual treatment contained chemotherapy, radiotherapy and chemoradiotherapy, while TCM contained eight different types. The included studies have addressed partial objectives assessing quality of life, short-term therapeutic effects and possible adverse effects. However, the question about other outcomes including all-cause mortality, median survival times and time to progression have not been answered. In terms of applicability of evidence, all trials were conducted in China, this characteristic would limit the usage to a broader population. Further, the majority of trials gave no details about the duration of follow-up; the effects on quality of life and adverse events were measured at the end of the intervention. Thus, it was uncertain how long the effects of the intervention would last.


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Quality of the evidence Overall, we rated the quality of evidence of the included studies between very low and moderate due to methodological limitations and imprecision. Methodological quality From the last published version of the review, we checked 142 studies labelled as “randomised controlled trial” by telephone interviews with authors, and finally obtained nine authentic RCTs. Although identified to be RCTs by telephone, all nine studies had problems with methodological quality. None of these studies provided information about allocation concealment, no TCM placebo was used in the control group (making it impossible to mask participants and physicians), there was no information about blinding of outcome assessors, no study had a statement on dropouts or withdrawals, few studies reported the results of outcomes completely according to the methods section of the study, and self prepared TCM brought about conflicts of interest. All the factors mentioned above could lead to selection bias, performance bias, detection bias, attrition bias, reporting bias or other bias - resulting in false positive findings. Outcomes The cumulative sample size and the total number of events were rather low, and 95% confidence intervals around relative effects were wide. We downgraded the quality of evidence for this imprecision of outcomes. In addition, we did not observe dose-response information in any outcomes of TCM to treatment with radiotherapy or chemotherapy for oesophageal cancer. Other The quality of trial reporting, particularly the descriptions of methodology, study processes and the results, were very poor, and we found it difficult to ascertain from the report how the studies were performed. In the future we would like to include high quality studies to determine the effect of Chinese herbal medicine on oesophageal cancer.

Potential biases in the review process Publication bias was also a possibility but we were not able to assess this using a funnel plot due to having less than ten trials included in the review. Anther common problem was that the assessment of quality of life and TCM symptoms response of treatment were performed by authors who were not blinded in the trial conditions. This may have led to potential risk of detection bias and cause false positive results. Valuable assessment about quality of life and TCM symptoms response of treatment in a RCT should be participant-based, include use of a validated multidimensional

questionnaire completed by the participant and use the internationally evaluated ’minimum standard checklist’ (Efficace 2003; Efficace 2006; Efficace 2007).

Agreements and disagreements with other studies or reviews There is no other known systematic review of Chinese herbal medicine for oesophageal cancer. Well designed RCTs with large sample sizes in the future may allow us to draw reliable conclusions.

AUTHORS’ CONCLUSIONS Implications for practice We currently find no evidence to determine whether Chinese herbal medicine is an effective treatment for oesophageal cancer. There is uncertainty about the effect of TCM as an adjunct to radiotherapy or chemotherapy on short-term therapeutic effects for oesophageal cancer. TCM probably has an effect on quality of life in advanced oesophageal cancer patients undergoing radiotherapy or chemotherapy. There is very low or low quality evidence for TCM having positive effects on some adverse events caused by radiotherapy or chemotherapy, such as radiation oesophagitis, gastrointestinal reactions and white blood cell descent. The overall low quality of evidence may be due to poor trial design and performance, few trials and small number of participants. Considering the severe discomfort caused by chemotherapy, radiotherapy and chemoradiotherapy in oesophageal patients, it is important to understand what role TCM plays as an adjunct to these interventions. Further, it would be important to understand which kind of TCM coupled with usual treatment (chemotherapy, radiotherapy or chemoradiotherapy) is optimal for oesophageal cancer treatment.

Implications for research Large, multicentre, correctly randomised, placebo-controlled, triple-masked, eliminating conflict of interest trials should be conducted to evaluate the effectiveness of Chinese herbal medicine for oesophageal cancer. The following factors should be taken into account in future studies: the sample size should be calculated before research; there should be an eligible randomisation procedure; the allocation concealment and blinding of both the participants or results assessors should be performed and reported in detail; the drop-outs or withdrawals should be recorded with an ITT analysis applied to analyse the outcomes; and the reports should be written following the Consolidated Standards of Reporting Trials (CONSORT) (Schulz 2010).


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ACKNOWLEDGEMENTS The authors would like to thank Karin Dearness, Janet Lilleyman, Iris Gordon, Cathy Bennett and Racquel Simpson of the Cochrane Upper Gastrointestinal and Pancreatic Diseases (UGPD) Group, and peer referees Professors Sheila Greenfield, Liz Gardener, Edzard Ernst, David Kirby, Miguel Sanchez Gonzalez, Weidong Lu, Chun-Tao Che, Sarah Rhodes and Jane Blazeby for advice on writing this review. We also thank authors of the included studies who patiently discussed the trials with XC and provided information of their studies.

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Qiu 2013 {published data only} ∗ Qiu ZH. Influence of Traditional Chinese Medicine on chemotherapy side effects of patients with middle-advanced stage oesophageal carcer

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Zhao 2004 {published data only} Zhao GQ, Lin ZP. Compound Ajiaojiang combined with chemotherapy for oesophageal cancer. Traditional Chinese and Western Medicine 2004;4(8):54.

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[ Shanxi Medical Journal 2014;43(22):2674–6. Chen 2015 {published data only} Chen GY, Chen Y. Clinical research of traditional Chinese medicine Jianpi Xiaoyu combined with concurrent chemoradiotherapy in treating 25 cases of advanced oesophageal cancer

Cui 2015 {published data only} Cui JJ, Jiang XY, Tan C. Fufang Hongdoushan capsule combined with intensity modulated radiation therapy in the treatment of elderly patients with advanced oesophageal cancer [ Journal of Basic and Clinical Oncology 2015;28(4):323–5. Dai 2014 {published data only} Dai XH. Clinical evaluation on Elemi oral emulsion combined with cisplatin and fluorouracil in treating advanced gastric cancer in 64 cases

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Huang 2014 {published data only} Huang ZH. Sijunzitang combined conventional radiotherapy for oesophageal cancer randomised parallel group study [ Journal of Practical Traditional Chinese Internal Medicine 2014;28(9):74–6.

[ 25 Jiangsu Journal of Traditional Chinese Medicine 2015;47(9): 39–40.

Dong 2015 {published data only} Dong PF, Deng XM. The clinical effect of Fuzheng Tongge soup combined with chemotherapy in treatment of advanced oesophageal cancer

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Hu 2015 {published data only} Hu XY, Guan XT, Gao P. Traditional Chinese medicine Yiqiyangyin combined with

[ Modern Diagnosis & Treatment 2013;24(17):3873–4.

[ China Pharmaceuticals 2014;23(20):53–5.

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Jia 2008 {published data only} Jia YS, Wu SQ, Lu SL, Zhang LP, Xu LP. Clinical ]. analysis of Brucea javanica oil emulsion injection plus radiotherapy for advanced oesophageal cancer [ ]. China Journal of Chinese Meteria Medica 2008;33(17): 2174–6. Jia 2015 {published data only} Jia].M. Clinical studies of combined therapy of Chinese and Western medicine for patients with advanced oesophageal ]. cancer [ Chinese And Foreign Medical Research 2015;13(18):46–8.

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]. Chongqing Medicine 2011;40(2):170–1.


41

Li 2014 {published data only} Li MJ, Li XZ, Wang YF, Sheng YX. Efficacy of Aidi injection combined intensity modulated radiation therapy for oesophageal cancer [ Chinese Primary Health Care 2014;28(9):108–9.

[ Medical Innovations 2013;10(17):50–1.

Song 2013b {published data only} Song QY. Analysis of safety and the therapeutic effect of Pingxiao Capsule on advanced oesophageal cancer

].

[ China Foreign Medical Treatment 2013;32(24):129–30.

Li 2015 {published data only} Li HF, Sun ZQ, Li YJ, Zhang XB. Clinical observation of chemotherapy combined with Xiaoaiping injection in the treatment of advanced oesophageal cancer

]. Chinese Archives of CA724 CEAGST–Pi Traditional Chinese Medicine 2008;26(11):2380–1. Wang 2014 {published data only} Wang WH, Chen Q, Jiang DW. Clinical study of Kangai Injection combined with radiotherapy in treatment of advanced oesophageal carcinoma

[ TP ]. Master degree thesis of Shandong University of Traditional Chinese Medicine 2011.

[ Drugs & Clinic 2014;29(9):1032–5.

Liao 2015 {published data only} Liao JY. Clinical observation on the methods of clear heat, harmonize the stomach and nourish Yin to prevention and control of radioactive oesophagitis in patients with oesophageal carcinoma

Lv 2014a {published data only} Lv X, Ning P, Zhao P, Zhang JR. Influence of immune function in advanced oesophageal cancer treated with Kang’ai injection combined with chemoradiotherapy regimens

[ 30 ]. Nei Mongol Journal of Traditional Chinese Medicine 2015;34(2): 27–8. Wang 2015b {published data only} Wang XY, Zhang Y. Clinical study on compound Tianxian capsules combined with radiotherapy in the treatment of advanced oesophageal cancer ].

Xia 2012 {published data only} Xia HL. Observation clinical effect of compound Mylabris capsule combined with chemoradiotherapy in the treatment of advanced oesophageal cancer

Pu 2011a {published data only} Pu ZY. Compound Matrine injection combined with radiotherapy, chemotherapy in treatment of advanced oesophageal cancer

Song 2013a {published data only} Song XR. The effect of Chinese medicine treatment on toxicity reaction reduced by chemotherapy in patients with advanced oesophageal cancer

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[ Guiding Journal of Traditional Chinese Medicine and Pharmacy 2014;20(14):36–8.

[ Henan Medical Research 2015;24(2):60–2.

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[ Master thesis of Hunan University of Traditional Chinese Medicine.

Qi 2015 {published data only} Qi JH, Zhang LZ. Efficacy of Javanica oil emulsion injection combined with conformal radiation therapy for locally advanced oesophageal cancer

CA199

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Liang 2011 {published data only} Liang LY. Clinical study on patients with mid and late stage oesophageal cancer treated by “Hua ye tang” combined with PTX+DDP chemotherapy

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Wang 2008 {published data only} Wang DP. Efficacy of Dougenguan Shitong oral liquid combined with chemotherapy and regulation of serum CA199, CEA, GST-Pi on advanced oesophageal cancer

].

[ Journal of North Pharmacy 2015;12(5):110.

]. Chinese

[ Chinese Journal of Clinical Oncology and Rehabilitation 2012;19(2):167–8.

].

].

Xia 2014 {published data only} Xia YX, Shang PJ, Zhang XD. Effect on life quality and efficacy analysis of Herba Hedyotidis diffusae combined with radiotherapy for patients with oesophageal cancer ].

[ Chinese Journal of Experimental Traditional Medical Formulae 2014;20(17):209–11.

].

Xie 2009b {published data only} Xie G, Ren GG, Guo ZX. Study on treatment of early postoperative period of oesophageal cancer with TCM


42

prevention and treatment of radiation oesophagitis

[ ]. Modern Journal of Integrated Traditional Chinese and Western Medicine 2009;18(12):1338–9. Xu 2010 {published data only} Xu M. Clinical research on Shenqi Fuzheng injection as adjuvant combined with chemotherapy in oesophageal carcinoma postoperative

Zhang 2015a {published data only} Zhang H, Huang LZ, Li Y, Yang J, Dai XJ. Liushen pills combined with concurrent chemoradiotherapy for advanced oesophageal cancer

[ Master degree thesis of Liaoning University of Traditional Chinese Medicine 2010.

].

]. Guangming Journal [ of Chinese Medicine 2015;30(7):1505–6.

].

[ 58 ]. Chinese Journal of Experimental Traditional Medical Formulae 2015;21(10):199–202.

Xu 2015b {published data only} Xu H. Treatment based on Syndrome differentiation combined with radiotherapy in the treatment of senile oesophageal cancer for 60 cases

Zhao 2013a {published data only} Zhao SM, Wang P. Observation clinical effect of ECF combined with Oxymatrine on advanced oesophageal carcinoma

60 ]. Chinese [ Medicine Modern Distance Education of China 2015;13(14): 72–3.

]. [ECF Science and Technology Innovation Herald 2013, issue 6: 1–2.

Yan 2015 {published data only} Yan L, Ba N, Wang LJ, Deng XK, Zhang J, Zhang HQ, Xing X. Study on the application of compound Radix Sophorae Flavescentis in the three dimensional conformal intensity modulated radiotherapy for oesophageal carcinoma

Zhao 2014 {published data only} Zhao SM, Wang P, Wang N. Matrine and irinotecan in treating 60 cases of advanced oesophageal cancer 60 ]. Chinese [ Medicine Modern Distance Education of China 2014;12(13): 34–5.

]. [ Guangming Journal of Chinese Medicine 2015;30(8):1826–8. Yang 2010a {published data only} Yang XC, Zheng YL, Wang X. Effect of Dihuang Guanshitong oral associating with chemotherapy by PD formula on the medium or advanced oesophageal patients PD [ Liaoning Journal of Traditional Chinese Medicine 2010;37 (6):1061–3. Yin 2014 {published data only} Yin XB, Tang XQ. Clinical observation of Lianqi capsule combined with chemotherapy in the treatment of 66 cases of advanced oesophageal cancer

Zheng 2014 {published data only} Zheng K, Deng TT, Liu ZC, Dong BQ. Clinical observation on advanced oesophageal carcinoma treated by combined use of acupuncture plus drug and radiotherapy ]. [ ]. Journal of Liaoning University of Traditional Chinese Medicine 2014;16(10):9–11.

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46

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Chen 2012 Methods

Single-centre ”Randomly allocated the patients” was mentioned, and a random number table was identified to be used to allocate patients by telephone interview with the authors Parallel-group design

Participants

Country: China Number of participants: 90 Average age (range): 38 to 84 Sex: the experimental group 27 male/18 female, the control group 30 male/15 female Others: all participants were confirmed to be in initial treatment with oesophageal squamous cell carcinoma by pathology. The disease was diagnosed to be stage b , ,

Interventions

Intervention: Fuzheng Guben granules combined with chemotherapy and radiotherapy (n = 45) Comparator: chemotherapy and radiotherapy (n = 45) Radiotherapy: at a dose of 60-64Gy, 2 Gy/time, 5 times/week Chemotherapy: Paclitaxel mg/m2 , for first day, repeat every week for 6 cycles Fuzheng Guben granules: orally administrated 15 g/time, 3 times a day, 42-49 days for a course To prevent allergic reaction, all participants received antiemetic such as dexamethasone, diphenhydramine, cimetidine before treatment

Outcomes

1. Short-term therapeutic effects according to WanJun evaluation criteria (1989) 2. Toxic reaction including radiation oesophagitis, the reaction of digestive tract, arrest of bone marrow and the function damage liver and kidney 3. Cellular immune function, consisting of CD4+ , CD8+ , CD4+ /CD8+

Notes

Date study conducted: January 2009 to December 2010

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

It was identified by telephone interview with the author that a random number table was used to allocate patients

Allocation concealment (selection bias)

Allocation concealment not described

Unclear risk

Blinding of participants and personnel High risk (performance bias) All outcomes


No TCM placebo was used in control group, so it could not be blinded

47

Chen 2012

(Continued)

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

Unclear

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Unclear


Unclear risk

Unclear

Other bias

High risk

The prescription was self prepared by the hospital colleagues, so there was high risk of conflict of interest

Cheng 2010 Methods

Single-centre ”Random number table” was mentioned, but the method was not described. No-Blinding Parallel-group design

Participants

Country: China Number of participants: 35 Average age (range): treatment group was 52.1 ± 2.5 years, the control group 53.3 ± 3. 2 years Sex: the experimental group 12 male/6 female, the control group 11 male/6 female The subtypes of oesophageal cancer: 30 squamous cell carcinoma, 5 adenocarcinoma Others: participants had not received radiotherapy or chemotherapy in the past one month. The author diagnosed the patients to be advanced or metastatic oesophageal cancer by computerised tomography (CT) and X-ray

Interventions

Intervention: Xihuang Pill combined with chemotherapy (n = 18) Comparator: chemotherapy (n = 17) Chemotherapy: nedaplatin 40 mg/m2 , day 1-2; 5-Fluorouracil 400 mg/m2 , day 1-5; Calcium folinate 200 mg/m2 , day 1-5 Xihuang Pill: 3 g/time, twice a day

Outcomes

1.The difference of quality of life, according to the Revision of Quality of Life Index Scale of Chinese cancer patients 2. Short-term therapeutic effects, evaluated by the New Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) 3. Evaluation of the traditional Chinese medicine symptoms The quality of life, remission rate of some symptoms in the treatment group were much better than the control group, and the haematological toxicity and efficacy were the same

Notes

Date study conducted: November 2005 to May 2008 There was no declaration of interest in the article

Risk of bias


48

Cheng 2010

(Continued)

Bias



Random sequence generation (selection High risk bias)

”a random number table” was mentioned, but the original author described the sequence as generated by computer software in the telephone interview. The actual process was doubtful because of this contradiction between the two descriptions


Allocation concealment was not mentioned

Unclear risk


Not used

Blinding of outcome assessment (detection High risk bias) All outcomes

Not used


Unclear risk

Unclear


Unclear risk

There was potential selective reporting bias due to the imbalanced numbers of participants in the 2 arms

Other bias

Unclear risk

Unclear

He 2010a Methods

Single-centre ”Randomly allocated patients” mentioned but the randomisation method was not described Parallel-group design

Participants

Country: China Number of participants: 70 Average age (range): 52 to 78 years Sex: the experimental group 31 male/4 female, the control group 32 male/3 female The subtypes of oesophageal cancer: all participants had squamous cell carcinoma Others: all participants were initial treatment, and the author diagnosed the disease to be stage ,

Interventions

Intervention: Brucea javanica oil emulsion combined with radiotherapy (n = 35) Comparator: radiotherapy (n = 35) Radiotherapy: at total dose of 60-70 Gy, 2 Gy/time for 6-7 weeks Brucea javanica oil emulsion: intravenous administered 30 mL/day for 18-27 days


49

He 2010a

(Continued)

Outcomes

Two groups were observed in: 1. short-term therapeutic effects, evaluated by the World Health Organization Response Evaluation Criteria in Solid Tumors (WHO 1981) 2. toxicity, judged by the Common Terminology Criteria for Adverse Events (CTCAE v3.0) 3. quality of life differences, judged by Karnofsky performance status (KPS)

Notes

Date study conducted: January 2005 to January 2009 No information of funding source or declaration of interest

Risk of bias Bias




The original author described in telephone interview that computer-generated number method was used to allocate patients


Not described

Unclear risk


No simulation reagent was used in control group, so it could not be blinded


Unclear


Unclear risk

Not mentioned


Unclear risk

Unclear

Other bias

High risk

There were differences between the results and other reports, and part of judgment of significant difference contained incorrect description

Lin 2013 Methods

Single-centre ”Random number table method” was mentioned, but lack of information in detail Parallel-group design

Participants

Country: China Number of participants: 60 Average age (range): treatment group was 55.6 years (45 to 76), the control group 56.2 years (42 to 75)


50

Lin 2013

(Continued)

Sex: the experimental group 19 male/11 female, the control group 18 male/12 female Others: all participants were proved to have oesophageal cancer by pathology, and the author diagnosed the disease to be stage , . The participants had received cisplatin (DDP) chemotherapy + radiotherapy Interventions

Intervention: Xiaoaiping combined with mFOLFOX6 chemotherapy (n = 30) Comparator: mFOLFOX6 chemotherapy (n = 30) mFOLFOX6 chemotherapy biweekly regimen: Oxaliplatin 85 mg/m2 for 3 hours, Calcium folinate 400 mg/m2 , 5-fluorouracil 400 mg/m2 intravenous injection in 10 min, 5-fluorouracil 2.4 g/m2 , all in the first day Xiaoaiping injection administered by intravenous infusion: 60 mL/day for 7 days

Outcomes

1. Symptoms before and after treatment, including signs, blood routine, liver and kidney function, electrocardiogram, cardiac ultrasound, tumour markers (CEA, CA 19-9) 2. Quality of life, judged by Karnofsky performance status (KPS) 3. The toxic reaction, judged by the antitumour drug toxicity evaluation standard 4. Cardiac toxicity 5. Short-term therapeutic effects, evaluated by the World Health Organization Response Evaluation Criteria in Solid Tumours (WHO)

Notes

Date study conducted: January 2009 to September 2012 No information of funding source and declaration of interest

Risk of bias Bias




A random number table method was identified to be used to allocate patients by telephone interview with the original authors


Unclear

Unclear risk


No placebo mimicking traditional Chinese medicine was used in control group, so it could not be blinded


Unclear


Unclear risk

No information


High risk

The results of symptoms before and after treatment were not described

Other bias

Unclear risk

Unclear


51

Mu 2012 Methods

Single-centre ”Randomly allocated patients” mentioned but there was no information about the randomisation procedure Parallel-group design

Participants

Country: China Number of participants: 50 Average age (range): treatment group was 54.3 ± 4.5 years (47 to 69), the control group 53.8 ± 4.9 years (45 to 67) Sex: the experimental group 15 male/10 female, the control group 17 male/8 female The subtypes of oesophageal cancer: all patients were identified to have squamous cell carcinoma Others: all participants were in initial cancer therapy. The author described the cancer as having developed to advanced stage in the text

Interventions

Intervention: Kangai injection combined with radiotherapy (n=25) Comparator: radiotherapy (n = 25) Radiotherapy: 2 Gy/time, 1 time/day, continued exposure for 5 times a week, total 6070 Gy Kangai injection administered by intravenous infusion: 60 mL Kangai injection + 250 mL 5% glucose injection, 1 time/day, continued for 6 weeks

Outcomes

1. Short-term therapeutic effects, evaluated by the World Health Organization Response Evaluation Criteria in Solid Tumours 2. Quality of life, judged by Karnofsky performance status (KPS) 3. Immune function, consisting of CD3+ ,CD4+ , CD8+ , CD4+ /CD8+ 4. Mucosa reaction, the radiation therapy oncology Group (RTOG) acute radiation injury classification standard

Notes

Date study conducted: March 2010 to June 2012 There was no declaration of interest in the article

Risk of bias Bias




In telephone interview, the author described that random numbers were sealed in envelopes which were randomly selected by patients


Unclear

Unclear risk



Blinding of outcome assessment (detection Unclear risk bias)

Unclear


52

Mu 2012

(Continued)

All outcomes Incomplete outcome data (attrition bias) All outcomes

Unclear risk

The researchers have eliminated patients who did not complete the treatment, but the numbers were not reported


Unclear risk

No information

Other bias

Unclear risk

Unclear

Ren 2013 Methods

Multicentre/single-centre: not reported ”Random number table method” was mentioned, but lack of information in detail Parallel-group design

Participants

Country: China Number of participants: 54 Average age (range): 65 to 80 years Sex: 39 male, 15 female The subtypes of oesophageal cancer: 50 squamous cell carcinoma, 4 adenocarcinoma Others: no participants had received radiotherapy

Interventions

Intervention: Kangai injection combined with three dimensional conformal radiotherapy (n = 28) Comparator: three dimensional conformal radiotherapy (n = 26) Three dimensional conformal radiotherapy: 2 Gy/day, 5 times a week, a total exposure dose 60 Gy for 6 weeks Kangai injection administered by intravenous infusion: 40-60 mL Kangai injection + 250 mL 5% glucose injection, 5 times/week, continued for 6 weeks

Outcomes

1. Short-term therapeutic effects, evaluated by World Health Organization Response Evaluation Criteria in Solid Tumours 2. Quality of life, judged by Karnofsky performance status (KPS) 3. Routine blood test and liver and kidney function tests

Notes

Date study conducted: September 2009 to September 2012 There was no declaration of interest in the article Kangai Injection was extracted from astragalus membranaceus, ginseng and Kushenin

Risk of bias Bias




Support for judgement In telephone interview, the original author described that they had strictly performed a ”randomised, controlled” randomisation procedure 53

Ren 2013

(Continued)


Unclear risk

Unclear




Unclear


Unclear risk

There was potential attrition bias due to the imbalanced numbers of participants in the 2 arms


High risk

The results of routine blood test and liver and kidney function tests were not given

Other bias

Unclear risk

Not clear

Shao 2011 Methods

Single-centre ”Random number table” was mentioned in the text, but no information about randomisation procedure in detail Parallel-group design

Participants

Country: China Number of participants: 40 Average age (range): treatment group was 64.40 ± 7.64 years, the control group 63.05 ± 8.61 years Sex: the experimental group 16 male/4 female, the control group 17 male/3 female The subtypes of oesophageal cancer: 35 squamous cell carcinoma, 5 adenocarcinoma Others: The author identified the oesophageal cancer to be stage ,

Interventions

Intervention: Yiqi Yangyin Huatan Quyu decoction combined with Paclitaxel and Cisplatin (TP) chemotherapy (n = 20) Comparator: TP chemotherapy (n = 20) TP chemotherapy: intravenous infusion, paclitaxel liposome 135-150 mg/(m2 · d) at day 1 and day 8, cisplatin 15 mg/(m2 · d), day 1 to 5. Orally take 10 mg dexamethasone 6 and 12 hours before chemotherapy, intramuscular injection of 20 mg benadryl 30 min before chemotherapy, intravenous administered 600 mg cimetidine to prevent allergic reaction Yiqi Yangyin Huatan Quyu decoction: self prepared, traditional Chinese medicine preparations see Table 1

Outcomes

1. Quality of life, judged by Karnofsky performance status (KPS) and the European Organisation for Research and Treatment of Cancer’s QLQ-C30 and QLQ-OES18 2. Chinese Medicine Symptoms, according to the guiding principle of clinical research


54

Shao 2011

(Continued)

on new drugs of traditional Chinese Medicine 3. Bodyweight 4. Serum tumour markers (CEA) 5. Safety, according to the Antineoplastic agents acute and subacute reaction standard Notes

Date study conducted: February 2010 to December 2010 The decoction was self prepared by the researcher, so there was conflict of interest

Risk of bias Bias




”Computer-generated random numbers” was described to be used to allocate patients in telephone interview with the author


Not mentioned

Unclear risk


”No-blinding” was told in telephone interview


”No-blinding” was told in telephone interview


Low risk

”No withdraw from the study” was identified by telephone interview


Unclear risk

Unclear

Other bias

High risk

The decoction was water extractions self prepared by the related colleagues, so there was high risk of conflict of interest

Wang 2010c Methods

Multicentre (2 centres) ”Randomly allocated patients” was mentioned, but the randomisation method used was not described Parallel-group design

Participants

Country: China Number of participants: 48 Average age (range): not mentioned Sex: the experimental group 17 male/7 female, the control group 16 male/8 female The subtypes of oesophageal cancer: no information Others: The cancer was diagnosed to be stage , , by the International Union for


55

Wang 2010c

(Continued)

Cancer Control staging system (UICC) standard Interventions

Intervention: Zhisheng capsule combined with chemotherapy (n = 24) Comparator: chemotherapy (n = 24) chemotherapy: Paclitaxel 135-175 mg/m2 intravenous infusion 3 hours, once a day. 12 and 6 hours before chemotherapy orally took dexamethasone 20 mg, 0.5 hour before treatment intravenous injection of 600 mg cimetidine, intramuscular injection of 40 mg diphenhydramine hydrochloride. Cisplatin intravenous drip total 80 mg/m2 in 3 ~ 4 days. Every 21 days for one course, continued for three courses Zhisheng capsule: orally administrated 2 capsules twice a day, 30 days for one course, lasted two courses with 7 days interval between the courses

Outcomes

1. Short-term therapeutic effects, evaluated by the World Health Organization Response Evaluation Criteria in Solid Tumours (WHO) 2. Traditional Chinese Medicine clinical symptoms 3. Toxic reactions, evaluated by the drug toxicity evaluation standard by the World Health Organization (WHO) 4. Quality of life, judged by Karnofsky performance status (KPS)

Notes

Date study conducted: July 2007 to October 2009 Science and Technology Department of Henan Province, China, for financial support of the study The decoction was prepared by the hospital, so there was high risk of conflict of interest

Risk of bias Bias




In telephone interview, the author described ”random number table method” was used to allocate patients


Unclear

Unclear risk


No traditional Chinese medicine placebo was used in control group, so it could not be blinded


Unclear


High risk

”Patients with poor compliance were excluded” was identified by telephone interview, and parts of result were incomplete


Unclear risk

Not clear


56

Wang 2010c

Other bias

(Continued)

High risk

The decoction was prepared by the hospital, so there was high risk of conflict of interest

Wu 2013a Methods

Multicentre/single-centre: not reported ”Random number table” was mentioned in the text, but no information about randomisation procedure in detail Parallel-group design

Participants

Country: China Number of participants: 43 Average age (range): 31 to 69 years Sex: the experimental group 20 male/2 female, the control group 18 male/3 female The subtypes of oesophageal cancer: 40 squamous cell carcinoma, 3 adenocarcinoma Others: all participants had no other malignant tumour history and had not received radiotherapy in the past. The author diagnosed the cancer to be stage , by the American Joint Committee on Cancer staging system (AJCC) standard

Interventions

Intervention: Aidi injection combined with chemotherapy (n = 22) Comparator: chemotherapy (n = 21) Chemotherapy: docetaxel 75 mg/m2 , date palm pollen 100 mg/m2 for the first day, repeat every 3 weeks, a maximum of 6 courses Aidi injection: 10 mL was added to 250 mL normal saline intravenously administration for day 1-14

Outcomes

1. Short-term therapeutic effects, evaluated by the New Response Evaluation Criteria in Solid Tumours (RECIST) 2. Toxic reactions, judged by the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE v3.0) 3. Quality of life, evaluated by the European Organisation for Research and Treatment of Cancer’s QLQ-C30

Notes

Date study conducted: November 2010 to May 2012 There was no declaration of interest in the article

Risk of bias Bias




Support for judgement In telephone interview, the author told ”computer-generated random numbers were sealed in envelopes, which were allocated to patients, no blinding, no simulation reagent”

57

Wu 2013a

(Continued)


Low risk

”Computer-generated random numbers” was told in telephone interview


”No blinding” was told in telephone interview


”No blinding” was told in telephone interview


Unclear risk

Unclear


Unclear risk

There was potential selective reporting bias due to the imbalanced numbers of participants in the 2 arms

Other bias

Unclear risk

Unclear

CA 19-9: carbohydrate antigen 19-9, also called sialylated Lewis (a) antigen, is a tumour marker CEA: carcinoembryonic antigen QLQ-C30: Quality of life questionnaire core 30, a quality of life instrument for use in international clinical trials in oncology developed by the European Organisation for Research and Treatment of Cancer (EORTC) Study Group QLQ-OES18: an EORTC questionnaire module with good psychometric and clinical validity to assess quality of life in patients with oesophageal cancer

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Bian 2000

Liguzstrazin combined nifedipine as adjunct compared with control, unable to judge the effect of liguzstrazin separately

Cao 1999

Did not meet outcome inclusion criteria

Chen 2002a

“Envelop method” to allocate the participants was mentioned, and thus was included in the first version of the review. In 31 May 2007, Wu TX discussed with Prof. Chen, the first author, and learned that the numbers of the envelopes were not assigned randomly

Chen 2002b

Non-randomised controlled study

Chen 2009

Non-randomised controlled trial


58

(Continued)

Chen 2010a

Claimed “randomised controlled trial”, but it was identified as actually a retrospective study by telephone interview with the original author

Chen 2011


Chen 2013a

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author, who said that due to the expensive drug, the groups were divided according to the requirement of patients

Chen 2013b


Cheng 2013


Cui 2001

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author

Cui 2011


Dai 2012


Dang 2000


Ding 2000


Du 1998

Did not meet participants inclusion criteria

Du 2009


Du 2013

“Randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author

Duan 2001

No data on outcome measure

Fan 1999


Fan 2012

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author, who said that the groups were divided following auther’s random decision


59

(Continued)

Feng 2009


Gao 2001


Gao 2012a

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author,who said that the groups was divided according to the requirement of patients

Gao 2012b

Claimed “randomised controlled trial”, but it was identified using sealed envelope method by telephone interview with the original author, but the author could not describe detailed operation process

Gong 1999

Did not meet participant inclusion criteria

Gu 2013


Guo 1999


Guo 2007


Guo 2010


Hao 2013


He 2000


He 2010b

It was identified as actually a retrospective study by telephone interview with the original author

Hou 1987


Hou 2004


Hou 2012


Hu 2000


Hua 2009



60

(Continued)

Huang 2009a


Huang 2009b


Huang 2010


Huang 2013


Huo 2003

Claimed “randomised controlled trial”, but it was identified actually a non-randomised controlled study by telephone interview the original author

Jia 2001


Jia 2010


Jiang 2009


Jiang 2012

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview

Jiang 2014


Jin 2003


Lan 2000


Lan 2009


Li 1997a


Li 1997b


Li 1998


Li 1999



61

(Continued)

Li 2000


Li 2001a


Li 2001b


Li 2001c

Non-randomised controlled trial, did not meet outcome inclusion criteria

Li 2004a


Li 2004b


Li 2009


Li 2010


Li 2011a


Li 2012a


Li 2012b

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author, who said that the groups were divided according to the visiting sequence of patients

Li 2013a


Li 2013b

It was identified as actually a retrospective study by telephone interview with the original author

Li 2013c


Liang 2002a


Liang 2002b


Liao 2012



62

(Continued)

Lin 2012


Liu 1993


Liu 1995


Liu 1997


Liu 2000


Liu 2001a


Liu 2001b


Liu 2001c


Liu 2003


Liu 2005

Claimed “randomised controlled trial”. But it actually was not a randomised controlled tria; Dr. Liu, the original author had explained very kindly

Liu 2009a


Liu 2009b


Liu 2009c


Liu 2010


Liu 2011a

Claimed “randomised controlled trial”, but it was identified using sealed envelope method by telephone interview with the original author, but the author couldnot describe detailed operation process

Liu 2011b



63

(Continued)

Liu 2012a


Liu 2012b


Liu 2013a


Liu 2013b

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author, who said the paticipants were divided into groups by the decision of the trialist

Lu 2000


Lu 2010


Lu 2012


Luo 2002


Luo 2014

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author, who said part of patients were divided into groups according to their own will

Lv 2013


Lv 2014b


Ma 2008


Ma 2013


Meng 2001


Miao 2013


Pan 2005



64

(Continued)

Peng 2012


Pu 2011b


Qian 2013

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author, who said that the groups were divided according to the age and condition of patients

Qiu 2010


Qiu 2013


Quan 1999


Shan 2011


Shao 1999


Shao 2009a


Shao 2009b


Shen 1998


Shen 2005


Shen 2010


Shi 2000


Shi 2009


Si 1994


Song 2013c


Su 2010



65

(Continued)

Sun 2000


Sun 2002


Sun 2005


Tang 1990


Tang 1999


Tang 2001


Tian 2010


Wan 1995

No data on outcome measurement

Wang 1990


Wang 1996


Wang 1997a


Wang 1997b


Wang 1999


Wang 2000


Wang 2002


Wang 2003a

Non-randomised controlled trial, different objective

Wang 2003b

Non-randomised controlled study

Wang 2003c


Wang 2004



66

(Continued)

Wang 2005


Wang 2009a


Wang 2009b


Wang 2009c


Wang 2010a


Wang 2010b

Claimed “randomised controlled trial”, but it was identified as actually a retrospective study by interview with the original author

Wang 2010d


Wang 2012a


Wang 2012b

Claimed “randomised controlled trial”, but it was identified as actually a retrospective study by interview with the original author

Wang 2012c

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the author, who said that the groups were divided according to the patient’s own will

Wang 2013a


Wang 2013b


Wei 2002


Wu 1994


Wu 1999


Wu 2001b


Wu 2002

No data on outcome measurement


67

(Continued)

Wu 2011a


Wu 2011b


Wu 2011c


Wu 2013b


Wu 2014


Xia 2001


Xiao 2005


Xie 2009a


Xing 2011


Xu 2002


Xu 2012


Xue 2005


Xue 2011


Yan 2009b


Yan 2009a



68

(Continued)

Yang 1999


Yang 2004


Yang 2010b


Yang 2011a


Yang 2011b


Yang 2012

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author, who said that the groups were divided one by one

Ye 2005


Yin 2001


Yuan 2013


Yue 2010


Zhan 2001


Zhang 1995


Zhang 1996


Zhang 1997


Zhang 1999a

Repeat publication

Zhang 1999b

Different participants

Zhang 2001a


Zhang 2001b



69

(Continued)

Zhang 2001c


Zhang 2003


Zhang 2004


Zhang 2007


Zhang 2009a


Zhang 2009b


Zhang 2010a


Zhang 2011a


Zhang 2011b


Zhang 2012


Zhang 2013a


Zhang 2013b


Zhang 2013c

Claimed “block randomised controlled trial”, but it was identified as actually a retrospective study by telephone interview with the original author

Zhang 2013d

Claimed “randomised controlled trial”, but it was identified as actually a retrospective study by telephone interview with the author

Zhao 2002


Zhao 2003


Zhao 2004


Zhao 2009a



70

(Continued)

Zhao 2009b


Zhao 2010a


Zhao 2010b


Zhao 2011


Zhao 2013b


Zheng 2012


Zhong 2012


Zhou 1996b


Zhou 1998


Zhou 2000


Zhou 2004


Zhou 2009a

Repeat publication

Zhou 2009b


Zhou 2009c


Zhou 2012


Zhu 2010

It was identified that the information was wrong

Zhu 2011

Claimed “randomised controlled trial”, but it was identified as actually a non-randomised controlled study by telephone interview with the original author, who said that the groups were divided according to the requirement of patients


71

(Continued)

Zhuang 1998


Characteristics of studies awaiting assessment [ordered by study ID] Bai 2014 Methods

“Randomly allocated patients” was mentioned, but no detailed information

Participants

49 elderly patients were included, 25 in treatment group and 24 in control group

Interventions

Aidi Injection and radiotherapy versus radiotherapy

Outcomes

Obvious efficacy on all-cause mortality and short-term therapeutic effects

Notes

We are trying to contact the original authors to identify the randomisation process

Cai 2015 Methods

“Random table method” and “Randomly allocated patients” were mentioned but no detailed information about the randomisation process

Participants

Total of 144 participants were included

Interventions

Water extractions of TCM and radiochemotherapy versus radiochemotherapy

Outcomes

Similar efficacy on short-term therapeutic effects

Notes

We are trying to contact the original authors to identify the randomisation method they used

Chen 2008 Methods

“Randomly allocated patients” was mentioned but no information on the randomisation process

Participants

Total of 232 advanced oesophageal cancer participants were included

Interventions

Jinnong capsule and radiotherapy versus radiotherapy

Outcomes

Efficacy

Notes



72

Chen 2010b Methods


Participants


Interventions

TCM medicine and chemotherapy versus chemotherapy

Outcomes

Efficacy

Notes


Chen 2013c Methods

“Randomly allocated patients” was mentioned but no information on the randomisation. No blinding

Participants

46 participants were included, treatment group 25 cases and 21 cases in control group

Interventions

Shenqifuzheng injection and concurrent chemoradiotherapy versus concurrent chemoradiotherapy

Outcomes

Similar efficacy on short-term therapeutic effects, but have obvious efficacy on reducing the toxicity of chemoradiotherapy

Notes


Chen 2014 Methods


Participants

52 participants were included

Interventions

Huisheng oral liquid and concurrent chemoradiotherapy versus concurrent chemoradiotherapy

Outcomes

Efficacy

Notes


Chen 2015 Methods

“Randomly allocated patients” was mentioned but no detailed information about the randomisation process

Participants


Interventions

Traditional Chinese medicine Jianpi Xiaoyu combined with chemoradiotherapy versus chemoradiotherapy

Outcomes

Similar short-term therapeutic effects, and marked efficacy on other outcomes


73

Chen 2015

Notes

(Continued)


Cui 2015 Methods

Parallel-group design. “Randomly allocated patients” was mentioned but no detailed information about the randomisation process

Participants

Total 60 elderly participants were included

Interventions

Fufang Hongdoushan capsule and intensity modulated radiation therapy versus intensity modulated radiation therapy

Outcomes

Efficacy

Notes

We are trying to identify the randomisation process

Dai 2014 Methods

“Random table method” mentioned but lack of description about the randomisation process

Participants


Interventions

Elemi Oral emulsion combined with Cisplatin and Fluorouracil versus Cisplatin and Fluorouracil

Outcomes

Efficacy

Notes


Dong 2015 Methods


Participants

Total of 79 participants were included, 39 in the treatment group and 40 in the control group

Interventions

Fuzheng Tongge soup and chemotherapy versus chemotherapy

Outcomes

Short-term therapeutic effects between two groups were similar, but the Fuzheng Tongge soup and chemotherapy group have better efficacy on quality of life

Notes



74

Guo 2014 Methods


Participants


Interventions


Outcomes

Short-term therapeutic effects between two groups were similar

Notes


Hu 2014 Methods


Participants

46 advanced oesophageal cancer participants were included, 24 in observation group and 22 in control group

Interventions

Aidi Injection combined with cisplatin and 5-fluorouracil versus cisplatin and 5-fluorouracil

Outcomes

Marked efficacy on clinical symptom and Karnofsky performance status (KPS)

Notes


Hu 2015 Methods

“Randomly allocated patients” was mentioned but lack of description about the randomisation process

Participants

40 advanced oesophageal cancer participants were included

Interventions

Yiqiyangyin combined with Tegafur, Gimeracil and Oteracil Potassium capsules versus Tegafur, Gimeracil and Oteracil Potassium capsules

Outcomes

Efficacy

Notes


Huang 2014 Methods

“Randomly allocated, parallel, controlled trial” mentioned but no detailed information about the randomisation process

Participants


Interventions

Sijunzitang combined conventional radiotherapy versus conventional radiotherapy

Outcomes

Efficacy


75

Huang 2014

Notes

(Continued)


Jia 2008 Methods

”Prospective, randomly allocated, controlled trial” was mentioned but no information on the randomisation

Participants

76 participants were included in treatment group and 72 cases in control group

Interventions

Brucea javanica oil emulsion injection and radiotherapy versus radiotherapy

Outcomes

Efficacy

Notes


Jia 2015 Methods

“Randomly allocated patients” was mentioned but no information on the randomisation

Participants


Interventions

Traditional Chinese Medicine and chemotherapy versus chemotherapy

Outcomes

Efficacy

Notes


Li 2011 Methods

Parallel-group design. “Randomly allocated patients” was mentioned but lack of description about the randomisation process

Participants


Interventions

Radiotherapy and Brucea javanica oil emulsion injection versus radiotherapy

Outcomes

Efficcay

Notes



76

Li 2014 Methods

Parallel-group design. “Randomly allocated patients” mentioned but lack of description about the randomisation process

Participants


Interventions


Outcomes

Marked efficacy on radioactive oesophageal mucositis, and similar short-term therapeutic effects

Notes

We are trying to contact the original authors to identify the randomisation method

Li 2015 Methods


Participants


Interventions

Chemotherapy combined with Xiaoaiping injection versus chemotherapy

Outcomes

Similar short-term therapeutic effects, and marked efficacy on quality of life

Notes


Liang 2011 Methods

Parallel-group design. “Randomly allocated patients” was mentioned but no information on the randomisation process

Participants


Interventions

“Hua ye tang” combined with PTX+DDP chemotherapy versus PTX+DDP chemotherapy

Outcomes

Similar efficacy on short-term therapeutic effects, but have marked efficacy on quality of life and reducing toxicity of chemoradiotherapy

Notes


Liao 2015 Methods


Participants

Total of 40 oesophageal carcinoma participants were included

Interventions

Clear heat, harmonise the stomach and nourish Yin and radiotherapy versus radiotherapy

Outcomes

Have efficacy on radioactive oesophagitis


77

Liao 2015

(Continued)

Notes


Lv 2014a Methods


Participants


Interventions

Kang’ai injection combined with chemoradiotherapy versus chemoradiotherapy

Outcomes

Similar efficacy on short-term therapeutic effects, but obvious efficacy on other outcomes

Notes


Pu 2011a Methods


Participants


Interventions

Compound Matrine injection combined with chemoradiotherapy versus chemoradiotherapy

Outcomes

Efficacy

Notes


Qi 2015 Methods

“Randomly allocated patients” mentioned but lack of detailed information

Participants

Total 110 locally advanced oesophageal cancer participants were included, 61 in the treatment group and 49 in the control group

Interventions

Javanica oil emulsion injection combined with conformal radiation therapy versus conformal radiation therapy

Outcomes

Efficacy

Notes



78

Song 2013a Methods


Participants

Total of 65 participants were included, 31 cases were divided into treatment group and 34 cases in control group

Interventions

Chinese medicine and chemotherapy versus chemotherapy

Outcomes


Notes


Song 2013b Methods

Parallel-group design. “Randomly allocated patients” was mentioned but no description about the randomisation process

Participants

Total of 84 advanced oesophageal cancer were included

Interventions

Pingxiao capsule and chemotherapy versus chemotherapy

Outcomes

Efficacy

Notes


Wang 2008 Methods

Parallel-group design. “Randomly allocated patients” mentioned but no description about the randomisation process

Participants

Total of 60 advanced oesophageal cancer were included

Interventions

Dougenguan Shitong oral liquid and chemotherapy versus chemotherapy

Outcomes

Efficacy

Notes


Wang 2014 Methods


Participants

Total of 78 advanced oesophageal carcinoma participants were included

Interventions

Kangai Injection combined with radiotherapy versus radiotherapy

Outcomes

Efficacy


79

Wang 2014

Notes

(Continued)


Wang 2015a Methods


Participants

Total of advanced oesophageal cancer participants were included

Interventions

Xiaxing Soup versus chemotherapy

Outcomes

Xiaxing Soup have better efficacy on advanced oesophageal cancer

Notes


Wang 2015b Methods

“Randomly allocated patients” mentioned but no information on the randomisation

Participants


Interventions

Compound Tianxian capsules combined with radiotherapy versus radiotherapy

Outcomes

Efficacy

Notes


Xia 2012 Methods


Participants


Interventions

Compound Mylabris capsule combined with chemoradiotherapy versus chemoradiotherapy

Outcomes


Notes



80

Xia 2014 Methods

Parallel-group design. “Randomly allocated patients” mentioned but lack of detailed information

Participants


Interventions

Herba Hedyotidis diffusate combined with radiotherapy versus radiotherapy

Outcomes

Efficacy

Notes


Xie 2009b Methods

”Prospective, multi-centre, randomised, controlled trial” was mentioned, and allocation sequence generated from computer random-number generator SAS 8.1

Participants

Total of 100 postoperative oesophageal cancer patients were included

Interventions

TCM and nutritive medium versus nutritive medium

Outcomes

Efficacy

Notes


Xu 2010 Methods

Parallel-group design. “Random table method” mentioned but lack of description about the randomisation process

Participants


Interventions

Shenqi Fuzheng injection and chemotherapy versus chemotherapy

Outcomes

Efficacy

Notes


Xu 2015a Methods

“Randomly allocated patients” mentioned but lack of description about the randomisation process

Participants


Interventions

TCM and radiotherapy versus radiotherapy

Outcomes

Efficacy

Notes



81

Xu 2015b Methods

“Randomly allocated patients” mentioned but lack of description about the randomisation process. Parallel-group design

Participants


Interventions

Syndrome differentiation combined with radiotherapy versus radiotherapy

Outcomes

Similar efficacy on short-term therapeutic effects, but have marked efficacy on KPS

Notes


Yan 2015 Methods

“Stratified random method” mentioned but lack of detailed information

Participants


Interventions

Compound Radix Sophorae Flavescentis and radiotherapy versus radiotherapy

Outcomes

Efficacy

Notes

We are trying to identify the randomisation method

Yang 2010a Methods

Parallel-group design. “Randomly allocated patients” mentioned but lack of description about the randomisation process

Participants


Interventions

Dihuang Guanshitong oral associating with chemotherapy versus chemotherapy

Outcomes

Efficacy

Notes


Yin 2014 Methods

“drawing lots” was mentioned but no detailed information

Participants

Total of 130 advanced oesophageal cancer participants were included, 66 in the treatment group and 64 in the control group

Interventions

Lianqi capsule combined with chemotherapy versus chemotherapy

Outcomes

Similar short-term therapeutic effects, but have obvious efficacy on other outcomes


82

Yin 2014

(Continued)

Notes


Zhang 2010b Methods

Parallel-group design. “Random numbers table method” mentioned but no description about the randomisation process

Participants


Interventions

“Qi Ge Shan Jie Tang” combined with radiotherapy versus radiotherapy

Outcomes

Efficacy

Notes


Zhang 2010c Methods

Parallel-group design. “Random numbers table method” mentioned but no description about the randomisation process

Participants


Interventions

“Yi Qi Huo Xue Hua Tan” Chinese medicine and radiotherapy versus radiotherapy

Outcomes

Efficacy

Notes


Zhang 2015a Methods


Participants

A total of 48 advance oesophageal cancer participants were included

Interventions

Liushen pills combined with concurrent chemoradiotherapy versus concurrent chemoradiotherapy

Outcomes

Efficacy of short-term therapeutic effects was similar, but efficacy of other outcomes were marked

Notes



83

Zhang 2015b Methods


Participants

Total of 115 Middle and terminal oesophageal cancer participants were included, 58 in the observation group and 57 in the control group

Interventions

Modified Geqi powder combined concurrent chemoradiotherapy versus concurrent chemoradiotherapy

Outcomes

Similar efficacy on short-term therapeutic effects, but obvious efficacy on other outcomes

Notes


Zhao 2013a Methods

“Randomly allocated patients” mentioned but no description about the randomisation process. No blinding

Participants

80 advanced oesophageal carcinoma participants were included

Interventions

Oxymatrine combined with ECF chemotherapy versus ECF chemotherapy

Outcomes

Similar efficacy on short-term therapeutic effects, but have obvious efficacy on reducing the toxicity of chemoradiotherapy

Notes


Zhao 2014 Methods


Participants


Interventions

Matrine and chemotherapy versus chemotherapy

Outcomes

Similar efficacy

Notes


Zheng 2014 Methods


Participants

Total of 60 advanced oesophageal carcinoma participants were included

Interventions

TCM plus acupuncture and radiotherapy versus radiotherapy

Outcomes

Efficacy


84

Zheng 2014

Notes

(Continued)


ECF chemotherapy: chemotherapy regimen consists of Epirubicin, Cis-platinum and Fluorouracil


85

DATA AND ANALYSES

Comparison 1. Cancer therapy alone versus cancer therapy plus TCM

Outcome or subgroup title 1 Quality of life 1.1 Number experiencing improvement 1.2 Number experiencing deterioration 2 Quality of life 2.1 Karnofsky performance status 3 Short-term therapeutic effects 3.1 Improvement 3.2 Progressive disease 4 TCM symptoms 4.1 Total effectiveness 4.2 Ineffectiveness 5 Adverse events 5.1 Mucositis 5.2 Radiation oesophagitis 5.3 Arrest of bone marrow 5.4 Gastrointestinal reactions 5.5 Renal and hepatic impairment-Fuzheng Guben granules 5.6 Renal and hepatic impairment-Xiaoaiping 5.7 White blood cell descent 5.8 Neurotoxicity 5.9 Cardiac toxicity 5.10 Anaemia 6 Cancer bio-markers 6.1 Carcinoembryonic antigen 7 Weight 7.1 Increased 7.2 Decreased

No. of studies

No. of participants

6 5

233

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Subtotals only 2.20 [1.42, 3.39]

6

287

Risk Ratio (M-H, Random, 95% CI)

0.41 [0.27, 0.62]

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

Totals not selected 0.0 [0.0, 0.0]

50 160 90 268 90

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Subtotals only 1.17 [1.02, 1.35] 0.73 [0.52, 1.01] Subtotals only 1.84 [1.20, 2.81] 0.22 [0.05, 0.93] Subtotals only 0.92 [0.80, 1.06] 0.66 [0.47, 0.94] 0.28 [0.14, 0.58] 0.54 [0.36, 0.81] 0.33 [0.13, 0.84]

1

60

Risk Ratio (M-H, Random, 95% CI)

2.5 [0.88, 7.10]

4 1 1 1 1 1

224 60 60 40

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

0.60 [0.44, 0.83] 0.73 [0.34, 1.55] 0.8 [0.24, 2.69] 1.33 [0.57, 3.14] Totals not selected 0.0 [0.0, 0.0]

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0]

1 1 8 8 8 2 2 2 7 1 2 1 4 1

1 1 1

450 450 88 88

Statistical method


Effect size

86

Analysis 1.1. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 1 Quality of life. Review:

Chinese herbal medicine for oesophageal cancer

Comparison: 1 Cancer therapy alone versus cancer therapy plus TCM Outcome: 1 Quality of life

Study or subgroup

TCM

usual treatment

n/N

n/N

Risk Ratio MH,Random,95% CI

Weight


1 Number experiencing improvement Cheng 2010 (1)

7/18

3/17

13.6 %

2.20 [ 0.68, 7.16 ]

Lin 2013 (2)

12/30

7/30

30.8 %

1.71 [ 0.78, 3.75 ]

Mu 2012 (3)

9/25

4/25

17.5 %

2.25 [ 0.80, 6.36 ]

Shao 2011 (4)

4/20

3/20

10.2 %

1.33 [ 0.34, 5.21 ]

17/24

5/24

28.0 %

3.40 [ 1.50, 7.73 ]

117

116

100.0 %

2.20 [ 1.42, 3.39 ]

Wang 2010c (5)

Subtotal (95% CI)

Total events: 49 (TCM), 22 (usual treatment) Heterogeneity: Tau2 = 0.0; Chi2 = 1.99, df = 4 (P = 0.74); I2 =0.0% Test for overall effect: Z = 3.55 (P = 0.00039) 2 Number experiencing deterioration Cheng 2010

1/18

6/17

4.5 %

0.16 [ 0.02, 1.18 ]

Lin 2013

10/30

17/30

51.5 %

0.59 [ 0.32, 1.07 ]

Mu 2012

3/25

11/25

13.8 %

0.27 [ 0.09, 0.86 ]

Ren 2013 (6)

2/28

7/26

8.3 %

0.27 [ 0.06, 1.16 ]

Shao 2011

2/20

5/20

7.9 %

0.40 [ 0.09, 1.83 ]

Wang 2010c

3/24

11/24

13.9 %

0.27 [ 0.09, 0.86 ]

145

142

100.0 %

0.41 [ 0.27, 0.62 ]

Subtotal (95% CI)

Total events: 21 (TCM), 57 (usual treatment) Heterogeneity: Tau2 = 0.0; Chi2 = 3.85, df = 5 (P = 0.57); I2 =0.0% Test for overall effect: Z = 4.13 (P = 0.000036)

0.01

0.1

Favours TCM

1

10

100

Favours usual treatment

(1) (2) karnofsky (3) karnofsky (4) karnofsky (5) karnofsky (6) karnofsky


87

Analysis 1.2. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 2 Quality of life. Review:


Comparison: 1 Cancer therapy alone versus cancer therapy plus TCM Outcome: 2 Quality of life

Study or subgroup

TCM

Mean Difference

usual treatment

N

Mean(SD)

N

Mean(SD)

69.3 (6.78)

30

62.5 (4.65)

Mean Difference

IV,Random,95% CI

IV,Random,95% CI

1 Karnofsky performance status Lin 2013

30

6.80 [ 3.86, 9.74 ]

-20

-10

Favours TCM

0

10

20


Analysis 1.3. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 3 Short-term therapeutic effects. Review:


Comparison: 1 Cancer therapy alone versus cancer therapy plus TCM Outcome: 3 Short-term therapeutic effects

Study or subgroup

TCM

usual treatment


Weight


n/N

n/N

Chen 2012 (1)

36/45

27/45

25.8 %

1.33 [ 1.01, 1.76 ]

Cheng 2010 (2)

9/18

8/17

4.3 %

1.06 [ 0.54, 2.11 ]

He 2010a (3)

26/35

25/35

24.7 %

1.04 [ 0.78, 1.38 ]

Lin 2013 (4)

6/30

5/30

1.8 %

1.20 [ 0.41, 3.51 ]

Mu 2012 (5)

17/25

15/25

11.6 %

1.13 [ 0.75, 1.72 ]

Ren 2013 (6)

21/28

17/26

16.3 %

1.15 [ 0.81, 1.63 ]

Wang 2010c (7)

16/24

13/24

9.4 %

1.23 [ 0.77, 1.96 ]

1 Improvement

0.05

0.2

Favours TCM

1

5

20


(Continued . . . )


88

(. . .

Study or subgroup

TCM n/N

n/N

Wu 2013a (8)

13/22

10/21

6.3 %

1.24 [ 0.70, 2.19 ]

227

223

100.0 %

1.17 [ 1.02, 1.35 ]

Subtotal (95% CI)

usual treatment


Weight

Continued)


Total events: 144 (TCM), 120 (usual treatment) Heterogeneity: Tau2 = 0.0; Chi2 = 1.69, df = 7 (P = 0.97); I2 =0.0% Test for overall effect: Z = 2.20 (P = 0.028) 2 Progressive disease Chen 2012 (9)

1/45

2/45

2.0 %

0.50 [ 0.05, 5.32 ]

Cheng 2010 (10)

2/18

3/17

4.0 %

0.63 [ 0.12, 3.32 ]

He 2010a (11)

0/35

0/35

Lin 2013 (12)

17/30

20/30

67.4 %

0.85 [ 0.57, 1.27 ]

Mu 2012 (13)

2/25

5/25

4.6 %

0.40 [ 0.09, 1.87 ]

Ren 2013 (14)

1/28

4/26

2.4 %

0.23 [ 0.03, 1.94 ]

Wang 2010c (15)

2/24

4/24

4.3 %

0.50 [ 0.10, 2.48 ]

Wu 2013a (16)

6/22

9/21

15.4 %

0.64 [ 0.27, 1.48 ]

227

223

100.0 %

0.73 [ 0.52, 1.01 ]

Subtotal (95% CI)

Not estimable

Total events: 31 (TCM), 47 (usual treatment) Heterogeneity: Tau2 = 0.0; Chi2 = 3.16, df = 6 (P = 0.79); I2 =0.0% Test for overall effect: Z = 1.89 (P = 0.059)

0.05

0.2

Favours TCM

1

5

20



89

(1) WanJun (2) RECIST (3) WHO (4) WHO (5) WHO (6) WHO (7) WHO (8) RECIST (9) WanJun (10) RECIST (11) WHO (12) WHO (13) WHO (14) WHO (15) WHO (16) RECIST


90

Analysis 1.4. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 4 TCM symptoms. Review:


Comparison: 1 Cancer therapy alone versus cancer therapy plus TCM Outcome: 4 TCM symptoms

Study or subgroup

TCM

usual treatment


Weight


n/N

n/N

Shao 2011

19/20

8/20

41.2 %

2.38 [ 1.38, 4.10 ]

Wang 2010c

20/24

13/24

58.8 %

1.54 [ 1.02, 2.32 ]

44

44

100.0 %

1.84 [ 1.20, 2.81 ]

1 Total effectiveness

Subtotal (95% CI)

Total events: 39 (TCM), 21 (usual treatment) Heterogeneity: Tau2 = 0.04; Chi2 = 1.59, df = 1 (P = 0.21); I2 =37% Test for overall effect: Z = 2.82 (P = 0.0048) 2 Ineffectiveness Shao 2011

1/20

12/20

35.1 %

0.08 [ 0.01, 0.58 ]

Wang 2010c

4/24

11/24

64.9 %

0.36 [ 0.13, 0.98 ]

44

44

100.0 %

0.22 [ 0.05, 0.93 ]

Subtotal (95% CI)

Total events: 5 (TCM), 23 (usual treatment) Heterogeneity: Tau2 = 0.60; Chi2 = 1.96, df = 1 (P = 0.16); I2 =49% Test for overall effect: Z = 2.05 (P = 0.040)

0.01

0.1

Favours TCM

1

10

100



91

Analysis 1.5. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 5 Adverse events. Review:


Comparison: 1 Cancer therapy alone versus cancer therapy plus TCM Outcome: 5 Adverse events

Study or subgroup

TCM

usual treatment


Weight


n/N

n/N

23/25

25/25

100.0 %

0.92 [ 0.80, 1.06 ]

25

25

100.0 %

0.92 [ 0.80, 1.06 ]

1 Mucositis Mu 2012

Subtotal (95% CI)

Total events: 23 (TCM), 25 (usual treatment) Heterogeneity: not applicable Test for overall effect: Z = 1.17 (P = 0.24) 2 Radiation oesophagitis Chen 2012

15/45

26/45

53.5 %

0.58 [ 0.36, 0.93 ]

He 2010a

14/35

18/35

46.5 %

0.78 [ 0.46, 1.31 ]

80

80

100.0 %

0.66 [ 0.47, 0.94 ]

Subtotal (95% CI)

Total events: 29 (TCM), 44 (usual treatment) Heterogeneity: Tau2 = 0.0; Chi2 = 0.68, df = 1 (P = 0.41); I2 =0.0% Test for overall effect: Z = 2.28 (P = 0.023) 3 Arrest of bone marrow Chen 2012

Subtotal (95% CI)

7/45

25/45

100.0 %

0.28 [ 0.14, 0.58 ]

45

45

100.0 %

0.28 [ 0.14, 0.58 ]

Total events: 7 (TCM), 25 (usual treatment) Heterogeneity: not applicable Test for overall effect: Z = 3.42 (P = 0.00062) 4 Gastrointestinal reactions Chen 2012

10/45

28/45

29.9 %

0.36 [ 0.20, 0.65 ]

He 2010a

8/35

9/35

18.5 %

0.89 [ 0.39, 2.04 ]

Lin 2013

11/30

16/30

30.9 %

0.69 [ 0.39, 1.22 ]

6/24

14/24

20.7 %

0.43 [ 0.20, 0.93 ]

134

134

100.0 %

0.54 [ 0.36, 0.81 ]

Wang 2010c

Subtotal (95% CI)

Total events: 35 (TCM), 67 (usual treatment) Heterogeneity: Tau2 = 0.05; Chi2 = 4.29, df = 3 (P = 0.23); I2 =30% Test for overall effect: Z = 3.01 (P = 0.0026) 5 Renal and hepatic impairment-Fuzheng Guben granules Chen 2012

Subtotal (95% CI)

5/45

15/45

100.0 %

0.33 [ 0.13, 0.84 ]

45

45

100.0 %

0.33 [ 0.13, 0.84 ]

0.5

0.7

Favours TCM

1

1.5

2


(Continued . . . )


92

(. . . Study or subgroup

TCM

usual treatment

n/N

n/N


Weight

Continued) Risk Ratio MH,Random,95% CI

Total events: 5 (TCM), 15 (usual treatment) Heterogeneity: not applicable Test for overall effect: Z = 2.33 (P = 0.020) 6 Renal and hepatic impairment-Xiaoaiping Lin 2013

Subtotal (95% CI)

10/30

4/30

100.0 %

2.50 [ 0.88, 7.10 ]

30

30

100.0 %

2.50 [ 0.88, 7.10 ]

Total events: 10 (TCM), 4 (usual treatment) Heterogeneity: not applicable Test for overall effect: Z = 1.72 (P = 0.085) 7 White blood cell descent He 2010a

7/35

12/35

15.9 %

0.58 [ 0.26, 1.31 ]

Lin 2013

14/30

23/30

55.9 %

0.61 [ 0.40, 0.94 ]

Ren 2013

2/28

8/26

4.9 %

0.23 [ 0.05, 0.99 ]

Shao 2011

8/20

11/20

23.3 %

0.73 [ 0.37, 1.42 ]

113

111

100.0 %

0.60 [ 0.44, 0.83 ]

Subtotal (95% CI)

Total events: 31 (TCM), 54 (usual treatment) Heterogeneity: Tau2 = 0.0; Chi2 = 2.07, df = 3 (P = 0.56); I2 =0.0% Test for overall effect: Z = 3.10 (P = 0.0019) 8 Neurotoxicity Lin 2013

Subtotal (95% CI)

8/30

11/30

100.0 %

0.73 [ 0.34, 1.55 ]

30

30

100.0 %

0.73 [ 0.34, 1.55 ]

4/30

5/30

100.0 %

0.80 [ 0.24, 2.69 ]

30

30

100.0 %

0.80 [ 0.24, 2.69 ]

8/20

6/20

100.0 %

1.33 [ 0.57, 3.14 ]

20

20

100.0 %

1.33 [ 0.57, 3.14 ]

Total events: 8 (TCM), 11 (usual treatment) Heterogeneity: not applicable Test for overall effect: Z = 0.82 (P = 0.41) 9 Cardiac toxicity Lin 2013

Subtotal (95% CI)

Total events: 4 (TCM), 5 (usual treatment) Heterogeneity: not applicable Test for overall effect: Z = 0.36 (P = 0.72) 10 Anaemia Shao 2011

Subtotal (95% CI)

Total events: 8 (TCM), 6 (usual treatment) Heterogeneity: not applicable Test for overall effect: Z = 0.66 (P = 0.51)

0.5

0.7

Favours TCM

1

1.5

2



93

Analysis 1.6. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 6 Cancer biomarkers. Review:


Comparison: 1 Cancer therapy alone versus cancer therapy plus TCM Outcome: 6 Cancer bio-markers

Study or subgroup

TCM

Mean Difference

usual treatment

N

Mean(SD)

N

Mean(SD)

20

8.5 (5.88)

20

9.09 (6.48)

Mean Difference

IV,Random,95% CI

IV,Random,95% CI

1 Carcinoembryonic antigen Shao 2011

-0.59 [ -4.42, 3.24 ]

-10

-5

0

Favours TCM

5

10


Analysis 1.7. Comparison 1 Cancer therapy alone versus cancer therapy plus TCM, Outcome 7 Weight. Review:


Comparison: 1 Cancer therapy alone versus cancer therapy plus TCM Outcome: 7 Weight

Study or subgroup

TCM

usual treatment



n/N

n/N

13/20

4/20

3.25 [ 1.28, 8.27 ]

2/20

6/20

0.33 [ 0.08, 1.46 ]

1 Increased Shao 2011 2 Decreased Shao 2011

0.01

0.1

Favours TCM


1

10

100


94

ADDITIONAL TABLES Table 1. Traditional Chinese Medicine preparations

Study ID

TCM

Pinyin name

Latin name

English name

Preparation

Chen 2012

Fuzheng Guben granules

Huangqi Dangshen Shanzha Chenpi Nuzhenzi Buguzhi Baizhu Gouqizi Fuling Shenqu Maiya Jixueteng Yinchenhao Tusizi

Radix Astragali Radix Codonopsis Fructus Crataegi Pericarpium Citri Reticulatae Fructus Ligustri Lucidi Fructus Psoraleae Rhizoma Atractylodis Macrocephalae Fructus Lycii Poria Massa Medicata Fermentata Fructus Hordei Germinatus Caulis Spatholobi Herba Artemisiae Scopariae Semen Cuscutae

Milkvetch Root Pilose Asiabell Root Hawthorn Fruit Tangerine Peel Glossy Privet Fruit Malaytea Scurfpea Fruit Largehead Atractylodes Rhizome Barbary Wolfberry Fruit Indian Buead Medicated Leaven Malt Suberect Spatholobus Virgate Wormwood Herb South Dodder Seed

Not described in detail Produced by Gansu Prorincial Wuwei Tumour Hospital

Cheng 2010

Xihuang Pill

Niuhuang Ruxiang Moyao Shexiang

Calculus Bovis Olibanum Myrrha Moschus

Bezoar Frankincense Myrrh Musk

Frankincense and Myrrh were treated by vinegarprocessing method Produced by Beijing Tongrentang Pharmaceutical Factory

He 2010a

Brucea Javanica oil emulsion

YadanzI

Fructus Bruceae

Java Brucea Fruit

Not described in detail

Lin 2013

Xiaoaiping injection

Wuguteng

Radix Fissistigmae Root of Glaucescent Xiaoaiping injecGlaucescentis Fissistigma tion was extracted from Glaucescent Fissistigma Produced by Nanjing Shenghe Pharmaceutical Co Ltd


95

Table 1. Traditional Chinese Medicine preparations

(Continued)

Mu 2012 Ren 2013

Kangai injection

Renshen Huangqi Kushen

Radix Ginseng Radix Astragali Radix Sophorae Flavescentis

Ginseng Milkvetch Root Lightyellow Sophora Root

Not described in detail

Shao2011

Yiqiyangyin Huatanquyu decoction

Taizishen Nanshashen Beishashen Maidong Chenpi Banxia Ezhu Banzhilian Baihuasheshecao Zhigancao Jineijin Maiya Guya Baizhu Shanyao Tiandong Wuweizi Fuling Yiyiren Danggui

Radix Pseudostellariae Radix Adenophorae Radix Glehniae Radix Ophiopogonis Pericarpium Citri Reticulatae Rhizoma Pinelliae Rhizoma Curcumae Herba Scutellariae Barbatae Herba Hedyotidis Diffusae Glycyrrhizae Endothelium Corneum Gigeriae Galli Fructus Hordei Germinatus Fructus Oryzae Germinatus Rhizoma Atractylodis Macrocephala Rhizoma Diosscoreae Radix Asparagi Fructus Schisandrae Poria Semen Coicis Radix Angelicae Sinensis

Heterophylly Falsestarwort Root Ladybell Root Coastal Glehnia Root Dwarf Lilyturf Tuber Tangerine Peel Pinellia Tuber Zedoary Barbed Skullcap Herb Spreading Hedyotis Herb Radix glycyrrhizae preparata Chicken’s Gizzardmembrane Malt Rice-grain Sprout Largehead Atractylodes Rhizome Common Yam Rhizome Cochinchinese Asparagus Root Chinese Magnoliavine Fruit Indian Buead Coix Seed Chinese Angelic

Modification according to symptoms: Largehead Atractylodes Rhizome Common Yam Rhizome Cochinchinese Asparagus Root Chinese Magnoliavine Fruit Indian Buead, Coix Seed and Chinese Angelic Yiqiyangyin Huatanquyu decoction was prepared by researchers of hospital

Wang 2010c

Zhisheng capsule

Shexiang Ezhu Bingpian Renshen Niuhuang Dongcongxiacao Xiyangshen

Moschus Rhizoma Curcumae Borneolum Radix Ginseng Calculus Bovis Cordyceps Radix Panacis Quinquefolii

Musk Zedoary Borneol Ginseng Bezoar Chinese Caterpillar Fungus American Ginseng

The composition of Zhisheng capsule contained 16 traditional Chinese medicines, only 7 of them were given Produced by the first affiliated Hospital of Henan University of


96

Table 1. Traditional Chinese Medicine preparations

(Continued)

Traditional Chinese Medicine Wu 2013a

Aidi injection

Renshen, Ciwujia, Bianmao, Huangqi.

Radix Ginseng, Radix Acanthopanacis Senticosi, Mylabris, Radix Astragali.

Ginseng, Not described in deManyprickle tail Acanto-Panax Root, Blister Beetle, Milkvetch Root.

APPENDICES Appendix 1. CENTRAL search strategy 1. esophag$.mp. 2. oesophag$.mp. 3. 1 or 2 4. Neoplasms/ 5. cancer$.mp. 6. exp Adenocarcinoma/ 7. carcino$.mp. 8. exp Carcinoma, Squamous Cell/ 9. or/4-8 10. 3 and 9 11. exp Medicine, Chinese Traditional/ 12. exp Drugs, Chinese Herbal/ or exp Plant Extracts/ 13. exp Herbal Medicine/ or exp Plants, Medicinal/ 14. exp Complementary Therapies/ 15. alternative medicine.ab,ti. 16. artemisinin.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 17. milkvetch root.mp. 18. wolfberry fruit.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 19. yam rhizome.mp. 20. indian bread.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 21. hedyotis.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 22. or/11-21 23. 10 and 22


97

Appendix 2. MEDLINE search strategy 1. randomized controlled trial.pt. 2. controlled clinical trial.pt. 3. randomized.ab. 4. placebo.ab. 5. drug therapy.fs. 6. randomly.ab. 7. trial.ab. 8. groups.ab. 9. or/1-8 10. (animals not (humans and animals)).sh. 11. 9 not 10 12. esophag$.mp. 13. oesophag$.mp. 14. 12 or 13 15. Neoplasms/ 16. cancer$.mp. 17. exp Adenocarcinoma/ 18. carcino$.mp. 19. exp Carcinoma, Squamous Cell/ 20. or/15-19 21. 14 and 20 22. exp Medicine, Chinese Traditional/ 23. exp Drugs, Chinese Herbal/ or exp Plant Extracts/ 24. exp Herbal Medicine/ or exp Plants, Medicinal/ 25. exp Complementary Therapies/ 26. alternative medicine.ab,ti. 27. artemisinin.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 28. milkvetch root.mp. 29. wolfberry fruit.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 30. yam rhizome.mp. 31. indian bread.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 32. hedyotis.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 33. or/22-32 34. 11 and 21 and 33

Appendix 3. EMBASE search strategy 1. (random$ or placebo$).ti,ab. 2. ((single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab. 3. controlled clinical trial$.ti,ab. 4. RETRACTED ARTICLE/ 5. or/1-4 6. (animal$ not human$).sh,hw. 7. 5 not 6 8. esophag$.mp. 9. oesophag$.mp. 10. 8 or 9 11. Neoplasms/ 12. cancer$.mp. 13. exp Adenocarcinoma/ 14. carcino$.mp. Chinese herbal medicine for oesophageal cancer (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

98

15. exp Carcinoma, Squamous Cell/ 16. or/11-15 17. 10 and 16 18. exp Medicine, Chinese Traditional/ 19. exp Drugs, Chinese Herbal/ or exp Plant Extracts/ 20. exp Herbal Medicine/ or exp Plants, Medicinal/ 21. exp Complementary Therapies/ 22. alternative medicine.ab,ti. 23. artemisinin.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 24. milkvetch root.mp. 25. wolfberry fruit.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 26. yam rhizome.mp. 27. indian bread.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 28. hedyotis.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 29. or/18-28 30. 7 and 17 and 29

Appendix 4. AMED search strategy 1. esophag$.mp. 2. oesophag$.mp. 3. 1 or 2 4. Neoplasms/ 5. cancer$.mp. 6. exp Adenocarcinoma/ 7. carcino$.mp. 8. exp Carcinoma, Squamous Cell/ 9. or/4-8 10. 3 and 9 11. exp Medicine, Chinese Traditional/ 12. exp Drugs, Chinese Herbal/ or exp Plant Extracts/ 13. exp Herbal Medicine/ or exp Plants, Medicinal/ 14. exp Complementary Therapies/ 15. alternative medicine.ab,ti. 16. artemisinin.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 17. milkvetch root.mp. 18. wolfberry fruit.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 19. yam rhizome.mp. 20. indian bread.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 21. hedyotis.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 22. or/11-21 23. 10 and 22


99

Appendix 5. CNKI search strategy CNKI, Chinese journals full-text database, Chinese journals full-text database˙century journals, Chinese Doctoral degree thesis fulltext database, Chinese outstanding master degree thesis full-text database 1. ti =

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100

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Appendix 6. VIP search strategy 1. ti =

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101

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Appendix 7. Wanfang search strategy Wanfang Database, Chinese degree thesis database, Chinese meetings articles full-text database 1.

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2.

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3.

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5.

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102

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and tx:

22.

and ti:

23.

and ab:

24.

and tx:

25.

and ti:

26.

and ab:

27.

and tx:

28.

and ti:

29.

and ab:

30.

and tx:

31. 32.

and ti:

33.

and ab:

34.

and tx:

35.

and ti:

36.

and ab:

37.

and tx:

38.

and ti:

39.

and ab:

40.

and tx:

41.

and ti:

42.

and ab:

43.

and tx:

44.

and ti:

45.

and ab:

46.

and tx:


103

Appendix 8. Search strategy for Chinese databases 1. oesophageal cancer ti, ab, tx 2. traditional Chinese medicine ti, ab, tx 3. traditional Chinese herbal medicine ti, ab, tx 4. 1 and (2 or 3) (For detailed information and the search strategies used see Appendix 5; Appendix 6; Appendix 7)

WHAT’S NEW Last assessed as up-to-date: 8 October 2015.

Date

Event

Description

8 October 2015

New search has been performed

We re-ran literature searches and included new studies

1 October 2015

New citation required and conclusions have changed

We included nine new randomised controlled trials (RCTs). We found no evidence of an effect of Chinese herbal medicine in the treatment of oesophageal cancer

HISTORY Protocol first published: Issue 4, 2003 Review first published: Issue 1, 2007

Date

Event

Description

31 August 2011


Authors of all studies identified have been contacted to confirm if study was a RCT. As a result, no studies were eligible for inclusion in the review

20 July 2008

Amended

Converted to new review format

30 December 2007


Substantive amendment

20 May 2004

New search has been performed

Minor update


104

CONTRIBUTIONS OF AUTHORS Xin Wei (XW), Zhiyu Chen (ZC) and Taixiang Wu (TW) were responsible for development of the protocol. Xi Chen (XC), Linyu Deng (LD) and TW were responsible for searching for trials, quality assessment of the trials, data extraction, data analysis and review development. TW interviewed the original trial authors of self described “RCTs” included in the initial version of this review. XC and Xuehua Jiang (XJ) interviewed the trial authors of this version of the review.

DECLARATIONS OF INTEREST XC: none known. LD: none known. XJ: none known. TW: none known.

SOURCES OF SUPPORT Internal sources • Chinese Cochrane Centre, West China Hospital of Sichuan University, China.

External sources • Chinese Medical Board of New York (CMB), USA.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW 1. We changed the title of the review from ’Medicinal herbs for oesophageal cancer’ to ’Chinese herbal medicine for oesophageal cancer.’ 2. Types of studies: we had intended to include cross-over trials and within-patient studies, but limited our review to only RCTs comparing radiotherapy or chemotherapy with or without additional Chinese herbal medicine. 3. Types of interventions: we revised and limited control treatment ’other treatments that are widely used by the doctors for oesophageal cancer’ to ’active cancer therapy such as radiotherapy or chemotherapy’. We changed ’Chinese medicinal herbs are used by oral intake’ to ’Water extractions of TCM were administered either orally (in capsules or as powders) or by intravenous infusion’. These revised inclusion criteria are more common in clinical studies. 4. Types of outcome measures: we added ’Improvement, defined as complete response (CR) and partial response (PR) as clarified by Miller 1981 or short-term therapeutic effects or TCM symptoms’ to the ’Secondary outcomes’. 5. Search strategy: we changed from the Chinese Biomedical Database and CISCOM (the Research Council for Complementary Medicine) to the VIP and Wanfang databases. 6. We added effect of time-to-events data analysis to the ’Measures of treatment effect’ section, and added ’GRADE and Summary of findings’ tables. 7. We revised and rewrote the ’Assessment of risk of bias in included studies’, ’Subgroup analysis and investigation of heterogeneity’, and ’Sensitivity analysis’ sections.


105

INDEX TERMS Medical Subject Headings (MeSH) Combined Modality Therapy [methods]; Drugs, Chinese Herbal [∗ therapeutic use]; Esophageal Neoplasms [∗ drug therapy; radiotherapy]; Phytotherapy [∗ methods]; Quality of Life; Radiation Injuries; Randomized Controlled Trials as Topic

MeSH check words Humans


106

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Antiplatelet effect of active components derived from Chinese herbal medicine.

Letter: Herbal hepatotoxicity--an update on traditional Chinese medicine preparations.

Prescription of Chinese Herbal Medicine in Pattern-Based Traditional Chinese Medicine Treatment for Depression: A Systematic Review.

Current application of chemometrics in traditional Chinese herbal medicine research.

Synergism of Chinese Herbal Medicine: Illustrated by Danshen Compound.

Chinese herbal medicine on dyslipidemia: progress and perspective.

Systematic Review on Chinese Herbal Medicine Induced Liver Injury.

Effects of Chinese herbal medicine Xiangbin prescription on gastrointestinal motility.

Regenerative medicine for oesophageal reconstruction after cancer treatment.

Effects of Chinese herbal medicine in combination with mitomycin C on gastric cancer cells.

Acupuncture and herbal medicine for cancer patients 2014.