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Traditional Chinese herbal medicine and its effects on the quality of life of lung cancer patients: a meta-analysis

Traditional Chinese herbal medicine and its effects on the quality of life of lung cancer... BioscienceHorizons Volume 10 2017 10.1093/biohorizons/hzx018 ............................................................................................ ..................................................................... Research article Traditional Chinese herbal medicine and its effects on the quality of life of lung cancer patients: a meta-analysis Amy Stewart The School of Society, Enterprise and Environment, Bath Spa University, Newton St Loe, Bath, BA2 9BN, United Kingdom *Corresponding author: The School of Society, Enterprise and Environment, Bath Spa University, Newton St Loe, Bath BA2 9BN, United Kingdom.Tel: +44 1761435335. Email: amy.stewart13@bathspa.ac.uk Supervisor: Dr Nigel Chaffey, The School of Society, Enterprise and Environment, Bath Spa University, Newton St Loe, Bath BA2 9BN, United Kingdom. n.chaffey@bathspa.ac.uk ............................................................................................ ..................................................................... Cases of lung cancer are increasing every year globally, with little improvement in survival rates. Therefore, the quality of life (QOL) of these patients is of increasing interest. This could mean that whilst undergoing treatment the impact on them both physically and mentally can be reduced from the stress of invasive and strong treatments. By looking at plants used medicin- ally in Traditional Chinese herbal Medicine (TCM), it is hoped that a source of QOL improvement can be found for patients. To investigate whether TCM could provide a source of new medicines that could improve QOL, a systematic literature search and meta-analysis was undertaken for randomized control trials published in this area. The quality and reliability of papers was also assessed to determine why further research has not yet been completed. This used a random effects model to take into account methodological differences when completing quantitative analysis. Heterogeneity analysis and publication bias of the included papers was also completed. A total of 1270 papers were initially screened with 10 being used in final analysis after applying exclusion and inclusion criteria. It was found that there was a small to medium summary Cohens D value of 0.33 (95% CI, −0.12, 0.78). However, the quality of these papers was found to be very poor leading to questions about their reliability and accuracy. There was also found to be a publication bias with only studies with statistically significant effects being published. In conclusion papers were poor quality and heterogeneity was high (I = 90.38%). Thus, making it difficult to determine if traditional Chinese herbal medicine has a beneficial effect on the quality of life of lung cancer patients and showing why research in this area has not been taken up more rapidly despite initial beneficial effects being found and dis- cussed in research papers. Key words: Chinese, medicine, cancer, quality of life Submitted on 25 November 2016; editorial decision on 6 October 2017 ............................................................................................ ..................................................................... been passed down through generations and civilizations (Kong Introduction et al., 2009), with derivatives obtained from this knowledge still in common use today (Jeannette, 2012; Veeresham, 2012). Humans have long sought medications to reduce pain and cure illness (Petrovska, 2012), with a focus on nature as the source, Traditional Chinese medicine (TCM) developed and evolved and with ‘trial and error’ being the way to determine the effect- through this same process over a period of over 2 500 years iveness of a treatment (Petrovska, 2012). This information has (NCCIH, 2013). This includes herbal remedies that are used as ............................................................................................... .................................................................. © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. alternative treatments in current western medicine (NCCIH, Another example of a targeted treatment used in the treat- 2013), however, it is most widely used in China to support ment of lung cancer is immunotherapy, where the patient’s treatments in a range of medical conditions (Liu et al., 2015). own immune system is used to attack cancer cells (Brett et al., 2017). This is usually initiated using a medication that allows The herbal remedies used are of growing interest and it is the patient’s immune system to be able to recognize the cells hoped that by investigating plants that have a history of med- as abnormal, and therefore triggering the immune response ical use, their positive effects and compounds can be used to (Brett et al., 2017). However, all these treatments can have form a complementary or new therapy (Liu et al., 2015). some severe side effects, which would impact the QOL of A particular interest for the application of plants used in patients whilst undergoing treatment and could potentially TCM is their role in cancer prevention therapy. For example, have long-term effects to the individual. Therefore, there is a some TCM herbs are potent sources of natural antioxidants need to undertake research and trials into less toxic treatment (Guo et al., 2011). Such plants act as chemo-preventive agents with fewer side effects to maintain patient QOL. by targeting and reducing the number of free radicals in the body (Guo et al., 2011), therefore, reducing the chance of cel- lular mutations and the development of cancerous tissues Literature review (Guo et al., 2011). This characteristic means TCM shows great potential in Research on the use of TCM in cancer therapy was found to cancer drug development. As the plants or compounds could focus on three areas; the use of TCM during radio- and work alongside conventional treatments or as a standalone chemotherapy; the therapeutic function of TCM; and the treatment that could offer the same level of efficacy as cur- mechanism of action of TCM (Liu et al., 2015). As a result of rently used therapies in reducing tumours (Efferth et al., this research two products with activity against cancer have 2007). Whilst tumour reducing qualities have been found in been isolated from TCM herbal remedies. These are camp- Chinese herbs, experiments are still being conducted to find tothecin (from Camptotheca acuminata) and homoharringto- the molecular mechanisms of these compounds and how they nine (from Cephalotaxus harringtonia)(Konkimalla and trigger apoptosis in cancerous cells, whilst showing little tox- Efferth, 2008). These discoveries indicate the presence of icity to normally functioning cells (Li-Weber, 2013). plants in TCM that contain active compounds which are effective in cancer therapy and this justifies further research. This is relevant, as globally cancerisamajorissue,withthe number of cases increasing year on year due to the aging of Shu et al. (2005) conducted a meta-analysis on TCM and populations and an increase in the uptake of behaviours that the improvement of responses to chemotherapy and found can increase the risk of developing cancer (especially in develop- Chinese herbal medicine had a beneficial effect. Furthermore ing nations) (Jemal et al., 2011). Within cancer treatments there McCulloch, See, Shu (2006) found that TCM reduced the is aneed formoreefficient and more specific therapies, as well toxicity associated with chemotherapy by stimulating the as treatments with fewer side effects that can offer a greater immune system and increasing macrophage and killer cell quality of life (QOL) for patients (Jemal et al.,2011). activity. Both of these papers also stated that the use of TCM led to a reduction in negative side effects (McCulloch, See, QOL is particularly important to lung cancer patients, Shu, 2006) and also improved survival rate (Shu et al., 2005). with 69% undergoing surgery as part of their treatment and with 25% of these also receiving chemo- or radiotherapies Despite this, there is some resistance to further research (Miller et al., 2016). These are known to have potentially into the development of new cancer drugs from TCM herbal severe side effects. Overall, it is estimated that 13% of new remedies. This is due to potential unwanted interactions cases of cancer are lung cancer (Cancer Research UK, 2014) between the plants and current cancer therapies (Liu et al., and within cancer mortality rates, lung cancer is estimated to 2015). For this reason, more research and evaluation of cur- account for 22% of cancer deaths, which is the highest death rent clinical studies needs to be conducted to determine rate for a single cancer type in both genders (Cancer Research whether the interactions will be beneficial. UK, 2014). Another reason for a lack of research is due to the absence The most common treatments used for lung cancer are of consensus on the treatment regimens used, as well as ques- chemo- and radiotherapies (NICE, 2011). However, more tions about the validity and quality of currently published targeted treatments include epidermal growth factor receptor papers (Tan et al., 2008). In addition to this the majority of (EGFR) inhibitors and anaplastic lymphoma kinase receptor controlled clinical studies in this area are only available in (ALK) inhibitors (Bartholomew et al., 2017 and Liao et al., Chinese (Li et al., 2013a), making some difficult to under- 2015). Both of which target different growth receptors that stand or translate accurately. Also, when observing the meth- can cause the rapid growth of cancerous cells (Bethune et al., odology used in these papers there appears to be no standard, 2010; Kayaniyil et al., 2016). These can be used either in con- with methods and analysis varying widely, making it difficult junction with chemo- and radiotherapies, or when these ther- to reliably compare the results. Therefore, by conducting a apies have had little or no effect on the growth of cancerous meta-analysis these differences should be minimized, to allow cells (Bethune et al., 2010; Kayaniyil et al., 2016). an overall conclusion based on the results and effects sizes of ............................................................................................... .................................................................. 2 Bioscience Horizons � Volume 10 2017 Research article ............................................................................................... .................................................................. papers that provide relevant and appropriate data to allow Additional methods of obtaining data included contacting analysis. authors who had undertaken a lot of work in this field. This was to find studies that may not have yet been published, or It is clear that studies indicate certain herbs used in TCM to obtain data on a specific study so that it could be included have beneficial effects in cancer treatment (Li et al., 2013b), in analysis. whether used individually; or in conjunction with chemo- or radiotherapy treatments. However, there is a reluctance to Before inclusion and exclusion criteria were applied to the develop and continue this research especially in western medi- papers, all the results were searched for duplicate papers and cine and drug/treatment development (Li et al., 2013a). This those were removed using RevMan (2014). is due to concerns about the reliability and validity of reports and their methodology, which could be caused by a lack of Inclusion and exclusion criteria for the access to more reliable papers that have been primarily pub- study lished in the Chinese domain (Li et al., 2013a). Criteria for inclusion of a paper in analysis were: sufficiency of provided for analysis – or gained on request to author, it being a randomized controlled clinical trial (RCT), it being published Aims and objectives within the time frame of 2005 to 2016; having QOL as an out- come measured and it being research into the effect of a TCM The aim of this investigation was to determine whether plants herbal remedy on lung cancer. Studies were included where used in TCM can have effects on the QOL of lung cancer TCM was used as a treatment in conjunction with a conven- patients. By doing so it should be clearer as to whether TCM tional treatment and where it was compared to a control group could hold the potential for future lung cancer therapies that being treated with only conventional treatments. Papers were provide a better QOL during treatment. also included where TCM was used as a standalone treatment This was achieved by the following objectives: and compared to a conventional treatment as a control. � Completion of a comprehensive systematic review, with a Criteria for exclusion of a paper were: the data not being focus on the effect of Traditional Chinese herbal medicine possible to extract, or not received on request from the on the quality of life of lung cancer patients. authors; the paper being a review or meta-analysis, an animal � Determination of the quality and heterogeneity of the stud- study, a case study or a retrospective study. ies selected, to see if assumptions on the poor quality of these reports are correct. Study selection, data extraction and quality � Determination of any publication bias of papers on this assessment topic. After conducting the literature search, abstracts of the selected papers were read to assess eligibility. Those that were suitable were Methodology obtained as full-text versions so that all criteria could be examined. If the study was found to have insufficient data the authors were Literature searches and search strategy contacted where possible, to try to obtain sufficient data. The studies used in this investigation were found by undertak- A data extraction form (shown in Table 1), was designed so ing systematic searches between 1 December 2015 and the 10 that once a paper was selected for inclusion in the meta- January 2016. This search was limited to articles that were analysis, appropriate information and characteristics could be published between 2005 and 2016. Due to a lack of research extracted. The information was categorized into several infor- in this area published before 2005. mation areas, including; general information; study characteris- These searches were undertaken using the online databases tics; intervention; outcomes measured and quality assessment. Sciencedirect, and PubMed, due to their high level of accessib- To assess the quality of the selected papers, a quality assess- ility. Supplementary searches were undertaken using Google ment tool created by the National Institute of Health (NIH) Scholar. The reference lists of relevant studies were examined (2014) for assessing controlled intervention studies was used. to identify papers that had not been found during database Responses to the questions employed were used to create the searches. quality assessment information section (Table 1). When the Search terms used keywords and phrases including: information in a given category was described to an adequate ‘Traditional Chinese medicine’, ‘cancer’, ‘lung cancer’, ‘treat- standard a score of 1 was given; if the information was not pro- ment’, ‘quality of life’ and ‘chemotherapy’, in a variety of vided at an adequate standard a score of 0 was given. Where combinations and were searched across all fields (i.e. title, the information was not reported it was recorded as NR. No abstract, keywords). The same phrases, were used in each of score was also given when the information could not be deter- the databases searched. For each search, the filters were mined from the analysis given and was reported as CD. When applied and the outcomes were recorded, with the results summing the score of all categories, the maximum a study could being stored and organized using RevMan (2014). achieve was 11. ............................................................................................... .................................................................. 3 Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. Table 1. Data, information and general characteristics to be extracted from included studies Information General information First author Year of publication Language published in Characteristics Sample size Gender ratio of sample Age range of sample specified Intervention Conventional treatment used Outcomes measured Quality of life (How was it measured? e.g. Karnofsky performance score) Quality Assessment Was the study described as randomized? Was the method of randomization adequate? Was the treatment allocation blinded? Were the study participants and providers blinded to the treatment group? Was the overall drop-out rate at the endpoint 20% or lower than at the beginning? Was there high adherence to intervention protocols for each of the groups? Were the outcomes assessed using valid and reliable measures, implemented consistently? Criteria specified for participant selection Side-effects/adverse effects reported and appropriate intervention described for treatment Methods used for statistical analysis appropriate and reported calculated as a chi-squared result that assessed whether the Statistical analysis observed differences in results of the included studies are com- In order to undertake a meta-analysis on the studies selected, patible with chance alone, and to ensure the right model was theeffect size foreachstudy hadtobecalculated. This was used in analysis (Higgins and Green, 2011). To quantify the undertaken using the compute.es (Compute effect sizes) package inconsistency that could be present across the studies and their (Del Re, 2013a)in R (R core team, 2015). Continuous data impact on the meta-analysis result an I value was calculated were presented as mean difference (MD) in the form of Cohens also using R (R core team, 2015) and the package RcmdrPlugin. d value, so that the sample size of each group in the studies was MA (Del Re, 2013b). This value describes the percentage vari- taken into consideration. 95% confidence intervals (CI) were ability in effect estimates that is caused by heterogeneity rather also calculated as well as the variance in the Cohens d value. than sampling error or chance (Higgins and Green, 2011). A single effect-size summary was calculated using a random- To assess the distribution of the results of the studies in effects model proposed by DerSimonian and Laird (1986),which the meta-analysis a funnel plot was constructed using takes into account the variability in the methodology of the R(R core team, 2015), so that any asymmetry in the studies papers in the quantitative analysis and considers this in the final used can be seen and determined. This was undertaken as it outcome. This was undertaken using the metafor package demonstrates whether all studies, including those which are (Viechtbauer, 2010)installedonR andused aspart ofthe Rcmdr uninteresting in their outcomes or unfavourable in results, (Fox, 2005) interface using the package RcmdrPlugin.MA (Del have been published on the topic in question and shows Re, 2013b) and employing the methodology proposed by Del Re whether there is any skew in the available data. (2015) for conducting a meta-analysis using these packages. To obtain a quantitative value for the asymmetry of the After calculating a single effect-size summary the heterogen- funnel plot a Rank Corr test and a Regression test were con- eity of the studies was calculated using R (R core team, 2015) ducted using R (R core team, 2015). and the package RcmdrPlugin.MA (Del Re, 2013b). This was ............................................................................................... .................................................................. 4 Bioscience Horizons � Volume 10 2017 Research article ............................................................................................... .................................................................. report this information (Table 2). It is unclear whether this Results gender imbalance is due to a higher prevalence of the disease in males, or males were more likely to be invited to trials. Literature search Most papers did report the age range of participants with One thousand two hundred and seventy four papers were only one paper not providing this information. The minimum identified from the search terms used (Fig. 1). After applying age required was often 18 years old for most of the papers, exclusion and inclusion criteria, 10 papers were used in the but of the selected participants the youngest was 30 years old final analysis, two of which resulted from direct contact with in the papers analysed. authors for further information. Chemotherapy was the most used conventional treatment with 4 out of 10 papers using it as a control against TCM Characteristics of included studies treatment. Furthermore, the most commonly used method of Many of the papers selected, did not provide adequate infor- measuring QOL in 6 out of the 10 studies was the Karnofsky mation with the characteristics being reported as NP (not pro- performance status scale (Table 2). The functional assessment vided) (Table 2). The information provided varied between of cancer therapy (Table 2) (a version specified for use with studies, with information published in one paper not always lung cancer sufferers) was used in 2 of the 10 papers. being provided in another. Seven of the included papers reported the gender ratio in both the intervention groups; Quality assessment of included trials however, three did not provide this information. The highest score achieved was 9, of which only one study Six papers were published in Chinese and four in English attained and the overall scores of the papers ranged from 5 to (Table 2) and the oldest study was published in 2009, with 9 (Table 3), i.e. many of the papers were of a poor standard. the most recent in 2014 (Table 2). Sample sizes ranged from 40 to 133 participants and the gender ratio reported showed All of the papers included were randomized with partici- there were more male participants than female participants in pants being randomly allocated to a control or intervention both treatment and control groups, but three papers did not group, however, only five papers specified the method of the Figure 1. The number of studies and flow of information in the literature search and paper selection process. Showing the number of papers included and excluded at each stage of the literature search with ’n’ being the number of papers. From a total of 1270 papers 10 were selected for quantitative analysis. ............................................................................................... .................................................................. 5 Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. ............................................................................................... .................................................................. Table 2. Information extracted from the selected studies and their characteristics Studies Year of Language of Sample Gender ratio Age range Treatment used in control group How was quality of life measured? publication publication size Dai et al. 2013 Chinese 46 TG 14:9 males to TG 47–72 Gefitinib (Cancer growth inhibitor) Functional assessment of cancer therapy – Lung females CG 18:8 males to CG 41–74 females Lin et al. 2013 English 98 NP NP Chemotherapy, supportive treatment Karnofsky Score and symptomatic treatment Liu and Liu 2013 English 60 TG 10:20 males to TG 58-79 Kushen Injection for pain Karnofsky Score females CG management 59–77 CG 12:18 males to females Liu et al. 2009 Chinese 60 TG 19: 11 males to 35–77 No intervention Karnofsky Score females CG 20:10 males to females Long et al. 2011 Chinese 133 NP 30–70 Chemotherapy The Quality of life Questionnaire –Core 30 and the Functional living index- Cancer Ma, Liu, Wang 2014 English 96 TG 31:17 males to TG 33–66 Dendritic cells Functional assessment of cancer therapy – Lung females CG 32:16 males to CG 32–65 females Wang et al. 2013 English 40 TG 16:4 males to 18–80 Normal pain treatment – tramadol Karnofsky Score females CG 15:5 males to females Xiao et al. 2010 Chinese 88 TG 39:7 males to TG mean: Radiotherapy Karnofsky Score females 59.32 CG 36:6 males to CG mean: females 55.66 Yan et al. 2011 Chinese 74 TG 21:16 males to 18–78 Chemotherapy Karnofsky Score females CG 21:16 males to females Yao et al. 2012 Chinese 118 NP 18–75 Chemotherapy Anxiety Severity Index Key: With NP indicating where the information was not provided in the report; TG = Treatment group; CG = Control group. ............................................................................................... .................................................................. Table 3. Quality assessment of studies included in the meta-analysis Study Was the Was the Was the Were the Were the Was the Was there Where Criteria Side effects Method of Total study method of treatment participant similar overall high outcomes for reported statistical score randomized? randomization allocation and bassline drop-out adherence assessed selection and analysis adequate? blinded? providers characteristics rate at to the using valid reported appropriate reported blind to between end-point intervention and reliable intervention and treatment groups? 20% or protocols? measures, plans appropriate group? lower than implemented at the consistently? beginning? Dai et al. 1CD NP NP 1 NP 11 1 1 1 7 (2013) Lin et al. 1CD NP NP CD NP 1 1 1 1 1 6 (2013) Liu and Liu 1CD NP NP 1 NP 11 1 NP 1 6 (2013) Liu et al. 1 1 NP NP 1 1 CD 1 1 1 1 8 (2009) Long et al. 1 CD NP NP 1 NP CD 1 1 NP 1 5 (2011) Ma, Liu, 1 1 NP NP 1 NP 1 1 1 NP 1 7 Wang (2014) Wang 1 1 1 CD 1 NP 1 1 1 NP 1 8 et al. (2013) Xiao et al. 1 1 NP NP 1 1 1 1 1 1 1 9 (2010) Yan et al. 1CD NP NP 1 NP 11 1 NP 1 6 (2011) Yao et al. 11 1 CD 1 1 CD 1 1 NP 1 8 (2012) Key: A score of 1 indicates the information being available in the study and of an acceptable standard, and a score of 0 indicates the information being supplied but criteria not met. With NP indicating the information was not provided and CD indicating the information cannot be determined. Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. allocation; the adequacy of the randomization of the other papers could not be determined. Furthermore, only two of the papers specified that the investigation was blinded, with the participant being unaware which treatment they were receiv- ing; however, neither paper reported how this blinding was conducted. Nine of the 10 papers reported similar baseline characteris- tics of participants included in the investigations. The other paper reported general characteristics of the treatment and control groups, but did not provide information to determine if the characteristics were similar between groups. Continually, the occurrence of participant withdrawals was only reported in three papers. In these the final sample size remained at 80% or higher of the original sample size. The other papers did not report such data or withdrawal occurrences. The majority of the papers adhered to intervention proto- cols that had been described, but in three studies this could Figure 2. Forest plot showing the effect size of Traditional Chinese not be determined. But, all of the papers assessed whether the Herbal Medicine on the quality of life of cancer patients, calculated for outcomes were measured reliably, validly and consistently each study used in quantitative analysis and the 95% confidence between groups. Furthermore, the potential side-effects and intervals for each of these. With effect sizes ranging from −0.77 to 2.15 and the overall effect size calculated using a random effects model for method of dealing with side-effects was reported in 4 of the all of the studies being 0.33 (95% CI −0.12, 0.78). 10 studies. Finally, all the included studies specified the inclu- sion and exclusion criteria of participants and the method of statistical analysis used. account the differing precisions between studies). However, Liu and Liu (2013) falls outside of this confidence interval, Statistical analysis (meta-analysis) which indicates that this study differed in its observed out- comes when taking into account the variation in method- Upon calcualtion of the effect-sizes (Cohens D), three papers ology between studies. (Dai et al. 2013; Wang et al. 2013; Ma, Liu, Wang, 2014) showed a negative Cohens D value and therfore a greater Publication bias effect was found in the control group in these studies. The other papers showed a postive Cohens D value and therefore Fig. 4 shows publication bias in the studies selected as the plot a greater effect was found in the group with TCM interven- is asymmetrical with Z = 0.5739, P = 0.5661 and Tau = tion. Of the papers with postive Cohens D values the range −0.0967 and P = 0.7095. This indicates there may be an over was from 0.00 (95% CI –0.39, 0.39) (Lin et al. 2013) to 2.15 emphasis on positive effects sizes within the studies selected. (95% CI 1.53, 2.77) (Liu and Liu, 2013) (Fig. 2). The summary effect-size calculated for the papers’ meta- Discussion analysis was 0.33 (95% CI −0.12, 0.78) with Z = 1.451 and P = 0.147, indicating the results were not statitically signif- Data extraction and study characteristics cant and meaning it could not be determined whether chinese A total of 10 randomized control studies were identified and herbal medicine can imporve the quality of life for lung cancer included in the meta-analysis of this investigation. All were patients. published from 2009 onwards, giving the analysis a greater relevance to current practices and overall, 813 participants Heterogeneity analysis were included in analysis. However, only two studies had a The heterogeneity of the papers used in quantitative analysis sample size greater than 100, so the majority of the papers (Fig. 4) and the fit of the random effects model, displayed a had small sample sizes. This means there is more uncertainty heterogeneity and fitof I = 90.38%. This indicates that and less reliability surrounding the results from these studies 90.38% of the variability in the individual effect sizes calcu- (Button et al. 2013). Consequently, there is a chance that sig- lated is due to heterogeneity (i.e. differences between studies) nificant results are often exaggerated (Button et al. 2013). rather than a sampling error. Another feature of the studies analysed is the method of Nine of the studies (indicated by the dots in Fig. 3)fall assessing QOL. It is important to consider these assessments between the intervals presented, which means that they and their benefits and accuracy in assessing QOL correctly. were consistent with their observed outcomes (taking into Although the Karnovsky performance score, (which is a score ............................................................................................... .................................................................. 8 Bioscience Horizons � Volume 10 2017 Research article ............................................................................................... .................................................................. It is also important to consider who was conducting the QOL assessment and whether it was conducted on a single day. If QOL was assessed by the patients themselves, they could over or under emphasize their results to try to get placed into the treatment group they think will be more effect- ive for them (Peus, Newcomb, Hofer, 2013). If the assessment was only compared to the QOL on an individual day, this may not be a reliable view of the overall QOL of the individ- ual (Peus, Newcomb, Hofer, 2013) since people have days where they feel they have a greater QOL than others, due to variations in side-effects and symptoms. Meta-analysis After analysis, it was unclear whether TCM herbal remedies had a beneficial effect on the QOL of lung cancer patients des- Figure 3. Galbraith radial plot of heterogeneity between studies pite the summary effect size calculated (Fig. 2) indicating a included in analysis, with two dotted lines indicating 90% CI of the value that was between small and medium effect with a population effect and the centre line indicating the pooled effect with Cohens D value of 0.33 (Cohen, 1988). This therefore shows the slop equal to the pooled effect. A heterogeneity score of l = 90.38% was calculated indicating a high level of variability between TCM does have an effect on the QOL of lung cancer patients, the studies and with 9 of the 10 studies (indicated by the dots) falling with a higher Cohens D value indicating a stronger effect. between the confidence intervals, it shows consistency in observed However, because the 95% confidence intervals were –0.12, outcomes between studies. 0.78 (Fig. 2), this shows the value was just as likely to be 0 or negative as it was to be 0.33 and so no confident conclusion can be determined. When observing the P-value obtained for this result (Fig. 2) it was found to be 0.147. This indicates that the over- all effect-size was not statistically significant. This was poten- tially influenced by the wide range of results and the variability between the studies used in analysis with the stud- ies having a high heterogeneity score of 90.38%. However, this means there is also no evidence to suggest that TCM does not have a beneficial impact on the QOL of lung cancer patients. With other meta-analyses in a similar topic area showing the benefits of TCM on QOL of all cancer patients (Oh et al., 2010; Jian-cheng et al., 2015), this indicates that with studies of a lower heterogeneity, greater quality and less vari- ability between the methods used and information published, evidence could be eventually found to support the beneficial effects of TCM on the QOL of lung cancer patients. Quality assessment Figure 4. Funnel plot showing the publication bias within the selected studies used in the investigation. Each study is indicated by Table 3 shows that many of the papers were a poor standard the dots, which have formed an asymmetrical graph indicating with only one paper achieving a high score of 9 (out of a max- publication bias is present. Z was found to be 0.5739, P = 0.5661 and imum score of 11). This finding is supported by Tan et al. Tau = −0.0967 and P = 0.7095. (2008) and Li et al. (2013a, 2013b) and could be a reason why there has not been an uptake into research on TCM as an aid in cancer treatment. If the quality and by extension reli- out of 100 based on an individual’s ability to carry out daily ability, of published results is not considered to be of suffi- tasks) was the method used most commonly by the included ciently high enough standard this may stifle further research papers (Table 2) it is not without criticisms. For instance, in this important area. Karnofsky does not consider mental health, instead it just focuses on physical function (Peus, Newcomb, Hofer, 2013) Many of the papers provided little information on the and whether this is hindered by their symptoms. As a result of methods they used (Table 2, Table 3). This makes it difficult this the results are narrow and a broader assessment is needed to determine if they met the protocol required and is a con- (Peus, Newcomb, Hofer, 2013). tributing factor into the poor quality of the papers. ............................................................................................... .................................................................. 9 Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. Furthermore, this makes it difficult to use the results of these application of this investigation should be to promote further studies to replicate investigations. research that is of a greater quality to allow more confident conclusions on whether TCM has effects on the QOL of lung cancer patients. Heterogeneity and fit Also after finding that the most commonly used method The heterogeneity (I = 90.38%) of the papers, shows that the for accessing QOL has criticisms and the possibility of correct mathematical model was used in the analysis. This is inconsistency between studies. It is important to create a because a random-effects model does not assume that the effects method of assessment that fully assesses QOL and includes measured are identical between papers and calculates the aver- both mental and physical function over a longer period of age effect of a treatment or intervention. Therefore, a high het- time and then use this method in further studies that moni- erogeneity level of 90.38% indicates that the differences tor QOL. between the effects sizes calculated was determined by variabil- ity (heterogeneity) between the studies and their methodology. However, a heterogeneity above 90% is relatively rare Conclusions (Higgins and Thompson, 2002), indicating that there was a very high amount of variability between studies. When there It can be concluded that it is unclear whether TCM herbal is too much variation between the methodologies or outcomes remedies can have a beneficial impact on the QOL of lung measured the results are difficult to equate to each other. This cancer patients. This was as a result of several limitations in makes it difficult to combine the results accurately to calculate the previously published papers on the topic including, the a single effect size. This could therefore be a contributing fac- wide range of methods used as well as the amount of informa- tor into why a confident conclusion cannot be determined. tion provided. Therefore, it is difficult to draw definitive con- clusions on the use of TCM and its effect on QOL. Publication bias However, this lack of evidence to indicate TCM does not have an effect on QOL demonstrates that further high-quality The asymmetry of the funnel plot (Fig. 4) indicates there is data is needed before a conclusion on its effectiveness can be publication bias in the papers used in analysis (Rothstein, determined and action could then be taken, with potential Sutton, Bornstein, 2006), i.e. there may be papers with statis- future benefits to QOL of cancer patients during and after tically significant or not significant results that remain unpub- treatments and even the development of new cancer lished. If so this could lead to an overestimation of the treatments. effectiveness of the treatment, due to a bias in the publication of papers reporting large positive or negative effect sizes (Guyatt et al. 2011). Author biography Five of the papers in this investigation were outside the 95% CI demonstrated by the lines presented on the funnel Amy completed her undergraduate degree at Bath Spa plot (Fig. 4). This is evidence of the ‘closed draw effect’,in University and graduated in 2016 with a first-class BSc which only large investigations that have statistically signifi- (Hons) in Biology. She has a particular interest in health, cant results are published (Guyatt et al., 2011). This leads to a human biology and microbiology. In the near future, she sample for analysis that is less representative of research hopes to complete a MSc in Biotechnology at the University undertaken. of York with an emphasis on biotechnology use in clinical settings. Furthermore, the results of the rank correlation coefficient (Tau = −0.0967) indicate that whilst publication was found to be biased, such bias was probably due to papers largely Acknowledgements being published based on P-values rather than the effect sizes calculated (Berg, 1994). This is indicated by the results being I would like to thank the following individuals who have a negative value. given assistance, guidance and support during this investiga- tion. First of all, I must thank Nigel Chaffey, Project It is also important to consider the reliability of the meth- Supervisor, who has guided and assisted throughout the ods used on meta-analyses with fewer than 25 papers. The investigation by providing his insight and has been a great reliability of this assessment decreases as the number of help throughout the submission process. Secondly, thanks papers included also decreases (Guyatt et al. 2011). should be given to Graham Smith who provided advice on the Therefore, the accuracy of these results may be limited due to statistical element of this project. Finally, I would like to the low number of papers included. thank Dr Chun Xiao of the Department of Traditional Chinese Medicine at the Chinese PLA General Hospital, Implications and applications of findings Beijing, for providing extra information on their published The overall meta-analysis, demonstrates that the effect of paper, as well as another study that was not found during the TCM on QOL cannot be determined, it is clear that an literature search. ............................................................................................... .................................................................. 10 Bioscience Horizons � Volume 10 2017 Research article ............................................................................................... .................................................................. Higgins, J. P. T. and Green, S. eds. (2011) Cochrane Handbook for References Systematic Reviews of Interventions, Version 5.1.0. 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Traditional Chinese herbal medicine and its effects on the quality of life of lung cancer patients: a meta-analysis

Bioscience Horizons , Volume 10 – Nov 14, 2017

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Abstract

BioscienceHorizons Volume 10 2017 10.1093/biohorizons/hzx018 ............................................................................................ ..................................................................... Research article Traditional Chinese herbal medicine and its effects on the quality of life of lung cancer patients: a meta-analysis Amy Stewart The School of Society, Enterprise and Environment, Bath Spa University, Newton St Loe, Bath, BA2 9BN, United Kingdom *Corresponding author: The School of Society, Enterprise and Environment, Bath Spa University, Newton St Loe, Bath BA2 9BN, United Kingdom.Tel: +44 1761435335. Email: amy.stewart13@bathspa.ac.uk Supervisor: Dr Nigel Chaffey, The School of Society, Enterprise and Environment, Bath Spa University, Newton St Loe, Bath BA2 9BN, United Kingdom. n.chaffey@bathspa.ac.uk ............................................................................................ ..................................................................... Cases of lung cancer are increasing every year globally, with little improvement in survival rates. Therefore, the quality of life (QOL) of these patients is of increasing interest. This could mean that whilst undergoing treatment the impact on them both physically and mentally can be reduced from the stress of invasive and strong treatments. By looking at plants used medicin- ally in Traditional Chinese herbal Medicine (TCM), it is hoped that a source of QOL improvement can be found for patients. To investigate whether TCM could provide a source of new medicines that could improve QOL, a systematic literature search and meta-analysis was undertaken for randomized control trials published in this area. The quality and reliability of papers was also assessed to determine why further research has not yet been completed. This used a random effects model to take into account methodological differences when completing quantitative analysis. Heterogeneity analysis and publication bias of the included papers was also completed. A total of 1270 papers were initially screened with 10 being used in final analysis after applying exclusion and inclusion criteria. It was found that there was a small to medium summary Cohens D value of 0.33 (95% CI, −0.12, 0.78). However, the quality of these papers was found to be very poor leading to questions about their reliability and accuracy. There was also found to be a publication bias with only studies with statistically significant effects being published. In conclusion papers were poor quality and heterogeneity was high (I = 90.38%). Thus, making it difficult to determine if traditional Chinese herbal medicine has a beneficial effect on the quality of life of lung cancer patients and showing why research in this area has not been taken up more rapidly despite initial beneficial effects being found and dis- cussed in research papers. Key words: Chinese, medicine, cancer, quality of life Submitted on 25 November 2016; editorial decision on 6 October 2017 ............................................................................................ ..................................................................... been passed down through generations and civilizations (Kong Introduction et al., 2009), with derivatives obtained from this knowledge still in common use today (Jeannette, 2012; Veeresham, 2012). Humans have long sought medications to reduce pain and cure illness (Petrovska, 2012), with a focus on nature as the source, Traditional Chinese medicine (TCM) developed and evolved and with ‘trial and error’ being the way to determine the effect- through this same process over a period of over 2 500 years iveness of a treatment (Petrovska, 2012). This information has (NCCIH, 2013). This includes herbal remedies that are used as ............................................................................................... .................................................................. © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. alternative treatments in current western medicine (NCCIH, Another example of a targeted treatment used in the treat- 2013), however, it is most widely used in China to support ment of lung cancer is immunotherapy, where the patient’s treatments in a range of medical conditions (Liu et al., 2015). own immune system is used to attack cancer cells (Brett et al., 2017). This is usually initiated using a medication that allows The herbal remedies used are of growing interest and it is the patient’s immune system to be able to recognize the cells hoped that by investigating plants that have a history of med- as abnormal, and therefore triggering the immune response ical use, their positive effects and compounds can be used to (Brett et al., 2017). However, all these treatments can have form a complementary or new therapy (Liu et al., 2015). some severe side effects, which would impact the QOL of A particular interest for the application of plants used in patients whilst undergoing treatment and could potentially TCM is their role in cancer prevention therapy. For example, have long-term effects to the individual. Therefore, there is a some TCM herbs are potent sources of natural antioxidants need to undertake research and trials into less toxic treatment (Guo et al., 2011). Such plants act as chemo-preventive agents with fewer side effects to maintain patient QOL. by targeting and reducing the number of free radicals in the body (Guo et al., 2011), therefore, reducing the chance of cel- lular mutations and the development of cancerous tissues Literature review (Guo et al., 2011). This characteristic means TCM shows great potential in Research on the use of TCM in cancer therapy was found to cancer drug development. As the plants or compounds could focus on three areas; the use of TCM during radio- and work alongside conventional treatments or as a standalone chemotherapy; the therapeutic function of TCM; and the treatment that could offer the same level of efficacy as cur- mechanism of action of TCM (Liu et al., 2015). As a result of rently used therapies in reducing tumours (Efferth et al., this research two products with activity against cancer have 2007). Whilst tumour reducing qualities have been found in been isolated from TCM herbal remedies. These are camp- Chinese herbs, experiments are still being conducted to find tothecin (from Camptotheca acuminata) and homoharringto- the molecular mechanisms of these compounds and how they nine (from Cephalotaxus harringtonia)(Konkimalla and trigger apoptosis in cancerous cells, whilst showing little tox- Efferth, 2008). These discoveries indicate the presence of icity to normally functioning cells (Li-Weber, 2013). plants in TCM that contain active compounds which are effective in cancer therapy and this justifies further research. This is relevant, as globally cancerisamajorissue,withthe number of cases increasing year on year due to the aging of Shu et al. (2005) conducted a meta-analysis on TCM and populations and an increase in the uptake of behaviours that the improvement of responses to chemotherapy and found can increase the risk of developing cancer (especially in develop- Chinese herbal medicine had a beneficial effect. Furthermore ing nations) (Jemal et al., 2011). Within cancer treatments there McCulloch, See, Shu (2006) found that TCM reduced the is aneed formoreefficient and more specific therapies, as well toxicity associated with chemotherapy by stimulating the as treatments with fewer side effects that can offer a greater immune system and increasing macrophage and killer cell quality of life (QOL) for patients (Jemal et al.,2011). activity. Both of these papers also stated that the use of TCM led to a reduction in negative side effects (McCulloch, See, QOL is particularly important to lung cancer patients, Shu, 2006) and also improved survival rate (Shu et al., 2005). with 69% undergoing surgery as part of their treatment and with 25% of these also receiving chemo- or radiotherapies Despite this, there is some resistance to further research (Miller et al., 2016). These are known to have potentially into the development of new cancer drugs from TCM herbal severe side effects. Overall, it is estimated that 13% of new remedies. This is due to potential unwanted interactions cases of cancer are lung cancer (Cancer Research UK, 2014) between the plants and current cancer therapies (Liu et al., and within cancer mortality rates, lung cancer is estimated to 2015). For this reason, more research and evaluation of cur- account for 22% of cancer deaths, which is the highest death rent clinical studies needs to be conducted to determine rate for a single cancer type in both genders (Cancer Research whether the interactions will be beneficial. UK, 2014). Another reason for a lack of research is due to the absence The most common treatments used for lung cancer are of consensus on the treatment regimens used, as well as ques- chemo- and radiotherapies (NICE, 2011). However, more tions about the validity and quality of currently published targeted treatments include epidermal growth factor receptor papers (Tan et al., 2008). In addition to this the majority of (EGFR) inhibitors and anaplastic lymphoma kinase receptor controlled clinical studies in this area are only available in (ALK) inhibitors (Bartholomew et al., 2017 and Liao et al., Chinese (Li et al., 2013a), making some difficult to under- 2015). Both of which target different growth receptors that stand or translate accurately. Also, when observing the meth- can cause the rapid growth of cancerous cells (Bethune et al., odology used in these papers there appears to be no standard, 2010; Kayaniyil et al., 2016). These can be used either in con- with methods and analysis varying widely, making it difficult junction with chemo- and radiotherapies, or when these ther- to reliably compare the results. Therefore, by conducting a apies have had little or no effect on the growth of cancerous meta-analysis these differences should be minimized, to allow cells (Bethune et al., 2010; Kayaniyil et al., 2016). an overall conclusion based on the results and effects sizes of ............................................................................................... .................................................................. 2 Bioscience Horizons � Volume 10 2017 Research article ............................................................................................... .................................................................. papers that provide relevant and appropriate data to allow Additional methods of obtaining data included contacting analysis. authors who had undertaken a lot of work in this field. This was to find studies that may not have yet been published, or It is clear that studies indicate certain herbs used in TCM to obtain data on a specific study so that it could be included have beneficial effects in cancer treatment (Li et al., 2013b), in analysis. whether used individually; or in conjunction with chemo- or radiotherapy treatments. However, there is a reluctance to Before inclusion and exclusion criteria were applied to the develop and continue this research especially in western medi- papers, all the results were searched for duplicate papers and cine and drug/treatment development (Li et al., 2013a). This those were removed using RevMan (2014). is due to concerns about the reliability and validity of reports and their methodology, which could be caused by a lack of Inclusion and exclusion criteria for the access to more reliable papers that have been primarily pub- study lished in the Chinese domain (Li et al., 2013a). Criteria for inclusion of a paper in analysis were: sufficiency of provided for analysis – or gained on request to author, it being a randomized controlled clinical trial (RCT), it being published Aims and objectives within the time frame of 2005 to 2016; having QOL as an out- come measured and it being research into the effect of a TCM The aim of this investigation was to determine whether plants herbal remedy on lung cancer. Studies were included where used in TCM can have effects on the QOL of lung cancer TCM was used as a treatment in conjunction with a conven- patients. By doing so it should be clearer as to whether TCM tional treatment and where it was compared to a control group could hold the potential for future lung cancer therapies that being treated with only conventional treatments. Papers were provide a better QOL during treatment. also included where TCM was used as a standalone treatment This was achieved by the following objectives: and compared to a conventional treatment as a control. � Completion of a comprehensive systematic review, with a Criteria for exclusion of a paper were: the data not being focus on the effect of Traditional Chinese herbal medicine possible to extract, or not received on request from the on the quality of life of lung cancer patients. authors; the paper being a review or meta-analysis, an animal � Determination of the quality and heterogeneity of the stud- study, a case study or a retrospective study. ies selected, to see if assumptions on the poor quality of these reports are correct. Study selection, data extraction and quality � Determination of any publication bias of papers on this assessment topic. After conducting the literature search, abstracts of the selected papers were read to assess eligibility. Those that were suitable were Methodology obtained as full-text versions so that all criteria could be examined. If the study was found to have insufficient data the authors were Literature searches and search strategy contacted where possible, to try to obtain sufficient data. The studies used in this investigation were found by undertak- A data extraction form (shown in Table 1), was designed so ing systematic searches between 1 December 2015 and the 10 that once a paper was selected for inclusion in the meta- January 2016. This search was limited to articles that were analysis, appropriate information and characteristics could be published between 2005 and 2016. Due to a lack of research extracted. The information was categorized into several infor- in this area published before 2005. mation areas, including; general information; study characteris- These searches were undertaken using the online databases tics; intervention; outcomes measured and quality assessment. Sciencedirect, and PubMed, due to their high level of accessib- To assess the quality of the selected papers, a quality assess- ility. Supplementary searches were undertaken using Google ment tool created by the National Institute of Health (NIH) Scholar. The reference lists of relevant studies were examined (2014) for assessing controlled intervention studies was used. to identify papers that had not been found during database Responses to the questions employed were used to create the searches. quality assessment information section (Table 1). When the Search terms used keywords and phrases including: information in a given category was described to an adequate ‘Traditional Chinese medicine’, ‘cancer’, ‘lung cancer’, ‘treat- standard a score of 1 was given; if the information was not pro- ment’, ‘quality of life’ and ‘chemotherapy’, in a variety of vided at an adequate standard a score of 0 was given. Where combinations and were searched across all fields (i.e. title, the information was not reported it was recorded as NR. No abstract, keywords). The same phrases, were used in each of score was also given when the information could not be deter- the databases searched. For each search, the filters were mined from the analysis given and was reported as CD. When applied and the outcomes were recorded, with the results summing the score of all categories, the maximum a study could being stored and organized using RevMan (2014). achieve was 11. ............................................................................................... .................................................................. 3 Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. Table 1. Data, information and general characteristics to be extracted from included studies Information General information First author Year of publication Language published in Characteristics Sample size Gender ratio of sample Age range of sample specified Intervention Conventional treatment used Outcomes measured Quality of life (How was it measured? e.g. Karnofsky performance score) Quality Assessment Was the study described as randomized? Was the method of randomization adequate? Was the treatment allocation blinded? Were the study participants and providers blinded to the treatment group? Was the overall drop-out rate at the endpoint 20% or lower than at the beginning? Was there high adherence to intervention protocols for each of the groups? Were the outcomes assessed using valid and reliable measures, implemented consistently? Criteria specified for participant selection Side-effects/adverse effects reported and appropriate intervention described for treatment Methods used for statistical analysis appropriate and reported calculated as a chi-squared result that assessed whether the Statistical analysis observed differences in results of the included studies are com- In order to undertake a meta-analysis on the studies selected, patible with chance alone, and to ensure the right model was theeffect size foreachstudy hadtobecalculated. This was used in analysis (Higgins and Green, 2011). To quantify the undertaken using the compute.es (Compute effect sizes) package inconsistency that could be present across the studies and their (Del Re, 2013a)in R (R core team, 2015). Continuous data impact on the meta-analysis result an I value was calculated were presented as mean difference (MD) in the form of Cohens also using R (R core team, 2015) and the package RcmdrPlugin. d value, so that the sample size of each group in the studies was MA (Del Re, 2013b). This value describes the percentage vari- taken into consideration. 95% confidence intervals (CI) were ability in effect estimates that is caused by heterogeneity rather also calculated as well as the variance in the Cohens d value. than sampling error or chance (Higgins and Green, 2011). A single effect-size summary was calculated using a random- To assess the distribution of the results of the studies in effects model proposed by DerSimonian and Laird (1986),which the meta-analysis a funnel plot was constructed using takes into account the variability in the methodology of the R(R core team, 2015), so that any asymmetry in the studies papers in the quantitative analysis and considers this in the final used can be seen and determined. This was undertaken as it outcome. This was undertaken using the metafor package demonstrates whether all studies, including those which are (Viechtbauer, 2010)installedonR andused aspart ofthe Rcmdr uninteresting in their outcomes or unfavourable in results, (Fox, 2005) interface using the package RcmdrPlugin.MA (Del have been published on the topic in question and shows Re, 2013b) and employing the methodology proposed by Del Re whether there is any skew in the available data. (2015) for conducting a meta-analysis using these packages. To obtain a quantitative value for the asymmetry of the After calculating a single effect-size summary the heterogen- funnel plot a Rank Corr test and a Regression test were con- eity of the studies was calculated using R (R core team, 2015) ducted using R (R core team, 2015). and the package RcmdrPlugin.MA (Del Re, 2013b). This was ............................................................................................... .................................................................. 4 Bioscience Horizons � Volume 10 2017 Research article ............................................................................................... .................................................................. report this information (Table 2). It is unclear whether this Results gender imbalance is due to a higher prevalence of the disease in males, or males were more likely to be invited to trials. Literature search Most papers did report the age range of participants with One thousand two hundred and seventy four papers were only one paper not providing this information. The minimum identified from the search terms used (Fig. 1). After applying age required was often 18 years old for most of the papers, exclusion and inclusion criteria, 10 papers were used in the but of the selected participants the youngest was 30 years old final analysis, two of which resulted from direct contact with in the papers analysed. authors for further information. Chemotherapy was the most used conventional treatment with 4 out of 10 papers using it as a control against TCM Characteristics of included studies treatment. Furthermore, the most commonly used method of Many of the papers selected, did not provide adequate infor- measuring QOL in 6 out of the 10 studies was the Karnofsky mation with the characteristics being reported as NP (not pro- performance status scale (Table 2). The functional assessment vided) (Table 2). The information provided varied between of cancer therapy (Table 2) (a version specified for use with studies, with information published in one paper not always lung cancer sufferers) was used in 2 of the 10 papers. being provided in another. Seven of the included papers reported the gender ratio in both the intervention groups; Quality assessment of included trials however, three did not provide this information. The highest score achieved was 9, of which only one study Six papers were published in Chinese and four in English attained and the overall scores of the papers ranged from 5 to (Table 2) and the oldest study was published in 2009, with 9 (Table 3), i.e. many of the papers were of a poor standard. the most recent in 2014 (Table 2). Sample sizes ranged from 40 to 133 participants and the gender ratio reported showed All of the papers included were randomized with partici- there were more male participants than female participants in pants being randomly allocated to a control or intervention both treatment and control groups, but three papers did not group, however, only five papers specified the method of the Figure 1. The number of studies and flow of information in the literature search and paper selection process. Showing the number of papers included and excluded at each stage of the literature search with ’n’ being the number of papers. From a total of 1270 papers 10 were selected for quantitative analysis. ............................................................................................... .................................................................. 5 Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. ............................................................................................... .................................................................. Table 2. Information extracted from the selected studies and their characteristics Studies Year of Language of Sample Gender ratio Age range Treatment used in control group How was quality of life measured? publication publication size Dai et al. 2013 Chinese 46 TG 14:9 males to TG 47–72 Gefitinib (Cancer growth inhibitor) Functional assessment of cancer therapy – Lung females CG 18:8 males to CG 41–74 females Lin et al. 2013 English 98 NP NP Chemotherapy, supportive treatment Karnofsky Score and symptomatic treatment Liu and Liu 2013 English 60 TG 10:20 males to TG 58-79 Kushen Injection for pain Karnofsky Score females CG management 59–77 CG 12:18 males to females Liu et al. 2009 Chinese 60 TG 19: 11 males to 35–77 No intervention Karnofsky Score females CG 20:10 males to females Long et al. 2011 Chinese 133 NP 30–70 Chemotherapy The Quality of life Questionnaire –Core 30 and the Functional living index- Cancer Ma, Liu, Wang 2014 English 96 TG 31:17 males to TG 33–66 Dendritic cells Functional assessment of cancer therapy – Lung females CG 32:16 males to CG 32–65 females Wang et al. 2013 English 40 TG 16:4 males to 18–80 Normal pain treatment – tramadol Karnofsky Score females CG 15:5 males to females Xiao et al. 2010 Chinese 88 TG 39:7 males to TG mean: Radiotherapy Karnofsky Score females 59.32 CG 36:6 males to CG mean: females 55.66 Yan et al. 2011 Chinese 74 TG 21:16 males to 18–78 Chemotherapy Karnofsky Score females CG 21:16 males to females Yao et al. 2012 Chinese 118 NP 18–75 Chemotherapy Anxiety Severity Index Key: With NP indicating where the information was not provided in the report; TG = Treatment group; CG = Control group. ............................................................................................... .................................................................. Table 3. Quality assessment of studies included in the meta-analysis Study Was the Was the Was the Were the Were the Was the Was there Where Criteria Side effects Method of Total study method of treatment participant similar overall high outcomes for reported statistical score randomized? randomization allocation and bassline drop-out adherence assessed selection and analysis adequate? blinded? providers characteristics rate at to the using valid reported appropriate reported blind to between end-point intervention and reliable intervention and treatment groups? 20% or protocols? measures, plans appropriate group? lower than implemented at the consistently? beginning? Dai et al. 1CD NP NP 1 NP 11 1 1 1 7 (2013) Lin et al. 1CD NP NP CD NP 1 1 1 1 1 6 (2013) Liu and Liu 1CD NP NP 1 NP 11 1 NP 1 6 (2013) Liu et al. 1 1 NP NP 1 1 CD 1 1 1 1 8 (2009) Long et al. 1 CD NP NP 1 NP CD 1 1 NP 1 5 (2011) Ma, Liu, 1 1 NP NP 1 NP 1 1 1 NP 1 7 Wang (2014) Wang 1 1 1 CD 1 NP 1 1 1 NP 1 8 et al. (2013) Xiao et al. 1 1 NP NP 1 1 1 1 1 1 1 9 (2010) Yan et al. 1CD NP NP 1 NP 11 1 NP 1 6 (2011) Yao et al. 11 1 CD 1 1 CD 1 1 NP 1 8 (2012) Key: A score of 1 indicates the information being available in the study and of an acceptable standard, and a score of 0 indicates the information being supplied but criteria not met. With NP indicating the information was not provided and CD indicating the information cannot be determined. Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. allocation; the adequacy of the randomization of the other papers could not be determined. Furthermore, only two of the papers specified that the investigation was blinded, with the participant being unaware which treatment they were receiv- ing; however, neither paper reported how this blinding was conducted. Nine of the 10 papers reported similar baseline characteris- tics of participants included in the investigations. The other paper reported general characteristics of the treatment and control groups, but did not provide information to determine if the characteristics were similar between groups. Continually, the occurrence of participant withdrawals was only reported in three papers. In these the final sample size remained at 80% or higher of the original sample size. The other papers did not report such data or withdrawal occurrences. The majority of the papers adhered to intervention proto- cols that had been described, but in three studies this could Figure 2. Forest plot showing the effect size of Traditional Chinese not be determined. But, all of the papers assessed whether the Herbal Medicine on the quality of life of cancer patients, calculated for outcomes were measured reliably, validly and consistently each study used in quantitative analysis and the 95% confidence between groups. Furthermore, the potential side-effects and intervals for each of these. With effect sizes ranging from −0.77 to 2.15 and the overall effect size calculated using a random effects model for method of dealing with side-effects was reported in 4 of the all of the studies being 0.33 (95% CI −0.12, 0.78). 10 studies. Finally, all the included studies specified the inclu- sion and exclusion criteria of participants and the method of statistical analysis used. account the differing precisions between studies). However, Liu and Liu (2013) falls outside of this confidence interval, Statistical analysis (meta-analysis) which indicates that this study differed in its observed out- comes when taking into account the variation in method- Upon calcualtion of the effect-sizes (Cohens D), three papers ology between studies. (Dai et al. 2013; Wang et al. 2013; Ma, Liu, Wang, 2014) showed a negative Cohens D value and therfore a greater Publication bias effect was found in the control group in these studies. The other papers showed a postive Cohens D value and therefore Fig. 4 shows publication bias in the studies selected as the plot a greater effect was found in the group with TCM interven- is asymmetrical with Z = 0.5739, P = 0.5661 and Tau = tion. Of the papers with postive Cohens D values the range −0.0967 and P = 0.7095. This indicates there may be an over was from 0.00 (95% CI –0.39, 0.39) (Lin et al. 2013) to 2.15 emphasis on positive effects sizes within the studies selected. (95% CI 1.53, 2.77) (Liu and Liu, 2013) (Fig. 2). The summary effect-size calculated for the papers’ meta- Discussion analysis was 0.33 (95% CI −0.12, 0.78) with Z = 1.451 and P = 0.147, indicating the results were not statitically signif- Data extraction and study characteristics cant and meaning it could not be determined whether chinese A total of 10 randomized control studies were identified and herbal medicine can imporve the quality of life for lung cancer included in the meta-analysis of this investigation. All were patients. published from 2009 onwards, giving the analysis a greater relevance to current practices and overall, 813 participants Heterogeneity analysis were included in analysis. However, only two studies had a The heterogeneity of the papers used in quantitative analysis sample size greater than 100, so the majority of the papers (Fig. 4) and the fit of the random effects model, displayed a had small sample sizes. This means there is more uncertainty heterogeneity and fitof I = 90.38%. This indicates that and less reliability surrounding the results from these studies 90.38% of the variability in the individual effect sizes calcu- (Button et al. 2013). Consequently, there is a chance that sig- lated is due to heterogeneity (i.e. differences between studies) nificant results are often exaggerated (Button et al. 2013). rather than a sampling error. Another feature of the studies analysed is the method of Nine of the studies (indicated by the dots in Fig. 3)fall assessing QOL. It is important to consider these assessments between the intervals presented, which means that they and their benefits and accuracy in assessing QOL correctly. were consistent with their observed outcomes (taking into Although the Karnovsky performance score, (which is a score ............................................................................................... .................................................................. 8 Bioscience Horizons � Volume 10 2017 Research article ............................................................................................... .................................................................. It is also important to consider who was conducting the QOL assessment and whether it was conducted on a single day. If QOL was assessed by the patients themselves, they could over or under emphasize their results to try to get placed into the treatment group they think will be more effect- ive for them (Peus, Newcomb, Hofer, 2013). If the assessment was only compared to the QOL on an individual day, this may not be a reliable view of the overall QOL of the individ- ual (Peus, Newcomb, Hofer, 2013) since people have days where they feel they have a greater QOL than others, due to variations in side-effects and symptoms. Meta-analysis After analysis, it was unclear whether TCM herbal remedies had a beneficial effect on the QOL of lung cancer patients des- Figure 3. Galbraith radial plot of heterogeneity between studies pite the summary effect size calculated (Fig. 2) indicating a included in analysis, with two dotted lines indicating 90% CI of the value that was between small and medium effect with a population effect and the centre line indicating the pooled effect with Cohens D value of 0.33 (Cohen, 1988). This therefore shows the slop equal to the pooled effect. A heterogeneity score of l = 90.38% was calculated indicating a high level of variability between TCM does have an effect on the QOL of lung cancer patients, the studies and with 9 of the 10 studies (indicated by the dots) falling with a higher Cohens D value indicating a stronger effect. between the confidence intervals, it shows consistency in observed However, because the 95% confidence intervals were –0.12, outcomes between studies. 0.78 (Fig. 2), this shows the value was just as likely to be 0 or negative as it was to be 0.33 and so no confident conclusion can be determined. When observing the P-value obtained for this result (Fig. 2) it was found to be 0.147. This indicates that the over- all effect-size was not statistically significant. This was poten- tially influenced by the wide range of results and the variability between the studies used in analysis with the stud- ies having a high heterogeneity score of 90.38%. However, this means there is also no evidence to suggest that TCM does not have a beneficial impact on the QOL of lung cancer patients. With other meta-analyses in a similar topic area showing the benefits of TCM on QOL of all cancer patients (Oh et al., 2010; Jian-cheng et al., 2015), this indicates that with studies of a lower heterogeneity, greater quality and less vari- ability between the methods used and information published, evidence could be eventually found to support the beneficial effects of TCM on the QOL of lung cancer patients. Quality assessment Figure 4. Funnel plot showing the publication bias within the selected studies used in the investigation. Each study is indicated by Table 3 shows that many of the papers were a poor standard the dots, which have formed an asymmetrical graph indicating with only one paper achieving a high score of 9 (out of a max- publication bias is present. Z was found to be 0.5739, P = 0.5661 and imum score of 11). This finding is supported by Tan et al. Tau = −0.0967 and P = 0.7095. (2008) and Li et al. (2013a, 2013b) and could be a reason why there has not been an uptake into research on TCM as an aid in cancer treatment. If the quality and by extension reli- out of 100 based on an individual’s ability to carry out daily ability, of published results is not considered to be of suffi- tasks) was the method used most commonly by the included ciently high enough standard this may stifle further research papers (Table 2) it is not without criticisms. For instance, in this important area. Karnofsky does not consider mental health, instead it just focuses on physical function (Peus, Newcomb, Hofer, 2013) Many of the papers provided little information on the and whether this is hindered by their symptoms. As a result of methods they used (Table 2, Table 3). This makes it difficult this the results are narrow and a broader assessment is needed to determine if they met the protocol required and is a con- (Peus, Newcomb, Hofer, 2013). tributing factor into the poor quality of the papers. ............................................................................................... .................................................................. 9 Research article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. Furthermore, this makes it difficult to use the results of these application of this investigation should be to promote further studies to replicate investigations. research that is of a greater quality to allow more confident conclusions on whether TCM has effects on the QOL of lung cancer patients. Heterogeneity and fit Also after finding that the most commonly used method The heterogeneity (I = 90.38%) of the papers, shows that the for accessing QOL has criticisms and the possibility of correct mathematical model was used in the analysis. This is inconsistency between studies. It is important to create a because a random-effects model does not assume that the effects method of assessment that fully assesses QOL and includes measured are identical between papers and calculates the aver- both mental and physical function over a longer period of age effect of a treatment or intervention. Therefore, a high het- time and then use this method in further studies that moni- erogeneity level of 90.38% indicates that the differences tor QOL. between the effects sizes calculated was determined by variabil- ity (heterogeneity) between the studies and their methodology. However, a heterogeneity above 90% is relatively rare Conclusions (Higgins and Thompson, 2002), indicating that there was a very high amount of variability between studies. When there It can be concluded that it is unclear whether TCM herbal is too much variation between the methodologies or outcomes remedies can have a beneficial impact on the QOL of lung measured the results are difficult to equate to each other. This cancer patients. This was as a result of several limitations in makes it difficult to combine the results accurately to calculate the previously published papers on the topic including, the a single effect size. This could therefore be a contributing fac- wide range of methods used as well as the amount of informa- tor into why a confident conclusion cannot be determined. tion provided. Therefore, it is difficult to draw definitive con- clusions on the use of TCM and its effect on QOL. Publication bias However, this lack of evidence to indicate TCM does not have an effect on QOL demonstrates that further high-quality The asymmetry of the funnel plot (Fig. 4) indicates there is data is needed before a conclusion on its effectiveness can be publication bias in the papers used in analysis (Rothstein, determined and action could then be taken, with potential Sutton, Bornstein, 2006), i.e. there may be papers with statis- future benefits to QOL of cancer patients during and after tically significant or not significant results that remain unpub- treatments and even the development of new cancer lished. If so this could lead to an overestimation of the treatments. effectiveness of the treatment, due to a bias in the publication of papers reporting large positive or negative effect sizes (Guyatt et al. 2011). Author biography Five of the papers in this investigation were outside the 95% CI demonstrated by the lines presented on the funnel Amy completed her undergraduate degree at Bath Spa plot (Fig. 4). This is evidence of the ‘closed draw effect’,in University and graduated in 2016 with a first-class BSc which only large investigations that have statistically signifi- (Hons) in Biology. She has a particular interest in health, cant results are published (Guyatt et al., 2011). This leads to a human biology and microbiology. In the near future, she sample for analysis that is less representative of research hopes to complete a MSc in Biotechnology at the University undertaken. of York with an emphasis on biotechnology use in clinical settings. Furthermore, the results of the rank correlation coefficient (Tau = −0.0967) indicate that whilst publication was found to be biased, such bias was probably due to papers largely Acknowledgements being published based on P-values rather than the effect sizes calculated (Berg, 1994). This is indicated by the results being I would like to thank the following individuals who have a negative value. given assistance, guidance and support during this investiga- tion. First of all, I must thank Nigel Chaffey, Project It is also important to consider the reliability of the meth- Supervisor, who has guided and assisted throughout the ods used on meta-analyses with fewer than 25 papers. The investigation by providing his insight and has been a great reliability of this assessment decreases as the number of help throughout the submission process. Secondly, thanks papers included also decreases (Guyatt et al. 2011). should be given to Graham Smith who provided advice on the Therefore, the accuracy of these results may be limited due to statistical element of this project. Finally, I would like to the low number of papers included. thank Dr Chun Xiao of the Department of Traditional Chinese Medicine at the Chinese PLA General Hospital, Implications and applications of findings Beijing, for providing extra information on their published The overall meta-analysis, demonstrates that the effect of paper, as well as another study that was not found during the TCM on QOL cannot be determined, it is clear that an literature search. ............................................................................................... .................................................................. 10 Bioscience Horizons � Volume 10 2017 Research article ............................................................................................... .................................................................. Higgins, J. P. T. and Green, S. eds. (2011) Cochrane Handbook for References Systematic Reviews of Interventions, Version 5.1.0. 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