Green tea (Camellia sinensis) for the prevention of cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this systematic review is to critically assess the association between green tea consumption in reducing the risk of cancer morbidity and mortality.
Any association found in this review may be used as a hypothetical establishment to be investigated further in rigorously conducted trials with adequate methodologies.
Background
Cancer patients frequently use some form of complementary and alternative medicine (CAM). CAM has been defined as "all such practices and ideas which are outside the domains of conventional medicine in several countries and defined by its users as preventing or treating illness, or promoting health and well‐being. These practices complement mainstream medicine by 1) contributing to a common whole; 2) satisfying a demand not met by conventional practices; and 3) diversifying the conceptual framework of medicine." (Cochrane 2003).
A recent systematic review including surveys from 13 countries demonstrated that one‐third of all cancer patients use at least one type of CAM (Ernst 2001). The most commonly employed treatments include shark cartilage, mistletoe (Viscum album), thymus therapy (Thymus vulgaris L.), Essiac (Burdock root (Arctium lappa), Sheep sorrel (Rumex acetosella), Slippery Elm bark (Ulmus fulva) and Turkish rhubarb (Rheum palmatum) or Indian rhubarb (Rheum officinale)), hydrazine sulphate (hydra‐zonium sulfate), 714‐X (trimethylbicyclonitramineoheptane chloride), dietary regimens, and Laetrile (laevo‐mandelonitrile‐beta‐glucuronoside)(Ernst 1999). In addition to these, numerous other CAM modalities are used in palliative and supportive care (Ernst 2001; Hodgson 2000; Syrjala 1995; Wilkinson 1999). Presently, only little clinical evidence supports the value of these treatments for cancer care (Ernst 2003). Some CAM modalities are suggested to be active in cancer prevention. For instance, some antioxidants are attracting researchers' attention as possible cancer preventative agent. Some plant‐based remedies are advocated for cancer prevention, e.g. Camellia sinensis.
Camellia sinensis is the most common beverage consumed worldwide (Graham 1992) and is particularly popular in Asian countries. Approximately 20% of the world's Camellia sinensis consumption is in the form of green tea; the other 80% are consumed in black tea (Wu 2003).
Pharmacology of Camellia Sinensis
The active ingredients of green tea include polyphenols i.e. flavanols, which are also known as catechins, which account for 30 to 40% of the extractable solids of dried green tea leaves, alkaloids (such as caffeine and theobromine), carbohydrates, tannins and minerals (such as fluoride and aluminum) (Ahmad 1999). Green tea contains higher amounts of polyphenols than black tea. Epigallocatechin gallate (EGCG) is a polyphenol and powerful antioxidant believed to be an important determinant in the therapeutic qualities of green tea. EGCG has been suggested to work by suppressing the formation of blood vessels (angiogenesis) and regulating their permeability, thereby cutting off the blood supply to cancerous cells (Demeule 2002; Maiti 2003). Other polyphenols include flavanols and their glycosides and depsides, such as cholorogenic acid, coumaroylquinic acid and theogallin (Graham 1992).
After oral intake concentrations of tea polyphenols can be detected in blood, urine and faeces and are thus absorbed and spread through the human or animal body (He 1994). Polyphenols may exert their actions directly at the tissue and cellular level (He 1994).
Possible anti‐cancer effects of Camellia Sinensis
Green tea polyphenols inhibit cell proliferation and exert a strong antioxidant activity (Yang 1993, Yang 1997). Polyphenols, specifically EGCG, have been shown to increase the activity of antioxidation in a variety of mouse organs and thus, enhancing the overall chemo‐preventative effect of antioxidants in those organs (Khan 1992). Polyphenols, particularly catechins, may enhance gap junctional communication between cells and thus protect cells from tumour development (Sigler 1993). The experimental studies suggest an effect on compounds of green tea extract, which may block the promotion of tumour growth by sealing receptors in the affected cells (Komori 1993). A third possible mechanism indicates that EGCG may facilitate direct binding to certain carcinogens (Hayatsu 1992). It has also been suggested that polyphenols assist the inhibition of tumorigenesis in a variety of organs including skin, lung, oral cavity, oesophagus, forestomach, stomach, small intestine, colon, liver, pancreas, ovary and mammary gland (Ahmad 1999; Jankun 1997; Su 2002; Yang 2002; Zhang 2002). Green tea polyphenols have been shown to induce apoptosis in human lymphoid leukaemia cells (Hibasami 1996).
Despite the growing body of research demonstrating the important role of polyphenols as antioxidants with anticarcinogenic properties, a full understanding of the effects of green tea is far from complete. This justifies the need for a systematic review on this topic.
Data from epidemiological studies
Numerous epidemiological studies and very few clinical trials have been performed to test whether Camellia sinensis possesses chemo‐preventive or curative activity on cancer development. Results have been contradictory, as some epidemiological studies comparing tea‐drinkers to non tea‐drinkers claim that drinking tea protects against the development of cancer, whereas other do not support this claim. This may be due to numerous confounding variables, such as diet and population differences that limit the ability of epidemiological studies to detect an effect (Yang 2002).
Two studies from China reported positive findings. One of these studies involved a total of 18,000 men and reported that people who were drinking tea were half as likely to develop stomach or oesophageal cancer compared to men who drank no or only little tea, even after demographics were adjusted according to smoking and other dietary factors (Sun 2002). Another Chinese study involving 250 skin cancer patients showed that patients consuming 3g of green tea (about 2 cups) per day reduced the size and proliferation of leukoplakia (Hakima 2001). However, a study from the Netherlands could not support these findings. After taking into account variables such as smoking and overall diet the researchers could still not find an association between consumption of black tea and the subsequent risk of stomach, colorectal, lung, and breast cancers among 58,279 men and 62,573 women aged 55 to 69 (Goldbohm 1996).
Recently a study assessing the effect of increased black and green tea consumption on oxidative DNA damage was carried out including 143 heavy smokers (Hakim 2003). Results showed that in the green tea group plasma and urinary catechins levels rose significantly and it has been suggested that regular green tea drinking might protect smokers from oxidative damages and could thus reduce cancer risks.
Objectives
The aim of this systematic review is to critically assess the association between green tea consumption in reducing the risk of cancer morbidity and mortality.
Any association found in this review may be used as a hypothetical establishment to be investigated further in rigorously conducted trials with adequate methodologies.
Methods
Criteria for considering studies for this review
Types of studies
Studies in which green tea was orally consumed in the past and which were carried out with one of the following designs will be included.
(1) Prospective controlled studies ‐ Randomised controlled trials (RCTs), non‐randomised and controlled trials (CTs) comparing oral green tea consumption versus no green tea consumption or placebo treatment.
(2) Epidemiological studies ‐ Cohort studies (CS) and case‐control studies (CCS).
Case‐series, case reports and other studies without a comparator, editorials, reviews, animal studies and in‐vitro studies will be excluded from this review.
Types of participants
All healthy participants with any given risk of any malignant neoplastic diseases will be included.
Types of interventions
The consumption of green tea ‐ whether as part of an intervention study or measured in an epidemiological study. The assessment variable is the consumption of green tea or green tea extract (only mono preparations for oral consumption in liquid, powder or tablet form). Green tea is defined as non‐fermented tea leaves and studies must mention that green tea, non‐fermented tea or 'matsu‐cha', as it is called in Asia, has been consumed. Any method of quantifying this variable (e.g. direct measurement, questionnaire) will be considered. Studies that do not distinguish the type of tea or do not report quantitative data of the amount or frequency of green tea consumption will be excluded. Pharmokinetic‐type studies will also be excluded because they are unlikely to contribute useful data on long‐term effects of green tea consumption. The duration of green tea consumption will be extracted for each trial and only studies which explicitly or implicitly state the duration in their research summary will be included. Should, in the future, any RCTs of green tea for cancer prevention be published, the Cochrane Gynaecological Cancer Collaborative Review Group will be contacted and the protocol amended accordingly.
Types of outcome measures
Primary outcomes
The primary outcome measure is the relative risk of cancer morbidity.
Secondary outcomes
Secondary outcome measures are quality of life, risk of gastritis, polyps and Helicobacter pylori infection.
Different types of cancer will be analysed in a combined fashion according to the following categories:
(1) gastro‐intestinal cancer (colorectal cancer, digestive tract cancer, ulcerative gastritis, stomach cancer, gastric cancer, oesophageal cancer, pancreatic cancer);
(2) uro‐general tract cancer (bladder cancer, prostate cancer, ovarian cancer);
(3) breast cancer; and
(4) lung cancer.
Search methods for identification of studies
Electronic searches
The following electronic databases will be searched to retrieve studies for potential inclusion: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via PubMed), EMBASE, Amed, CancerLit, PsychInfo and Phytobase. Manufacturers of green tea will be contacted and asked to contribute published and unpublished studies. The literature search and contacting authors and manufacturers is aimed to last three months.
Search strategy
MeSH terms used to search MEDLINE will include the following:
Search strategy to locate epidemiological studies reporting green tea consumption
1. green tea. ti, ab, rw, sh.
2. camellia sinensis. ti, ab, rw, sh.
3. tea. ti, ab, rw, sh.
4. thea. ti, ab, rw, sh.
5. Gruner Tee. ti, ab, rw, sh.
6. matsu‐cha. ti, ab, rw, sh.
7. mattsu‐cha. ti, ab, rw, sh.
8. antiox$.mp.
9. anti‐oxid$.mp
10. or/1‐9
Search strategy to locate studies measuring cancer incidence
11. tumour. ti, ab, rw, sh.
12. cancer$. ti, ab, rw, sh.
13. oncol$. ti, ab, rw, sh.
14. malignant. ti, ab, rw, sh.
15. survival$.mp.
16. mortality$.mp.
17. or/11‐16
Search strategy to locate studies with various designs
18. trial$. ti, ab, rw, sh.
19. study. ti, ab, rw, sh.
20. cohort$.mp.
21. exp Cohort studies/
22. exp Clinical trials/
23. ((prospectiv$ or observation$) adj5 (research$ or data$ or stud$)).mp.
24. longitud$.mp.
25. or/18‐24
Strategy to locate studies of green tea for cancer
16. 10 and 17 and 25
Searching other resources
References from published studies
References from published studies will be checked for further studies. We assume many articles from Asian countries will not be obtainable via Western medical databases. Thus, all relevant non‐English articles will be obtained and a Japanese/Chinese Cochrane collaborator will act as a filter for study selection. Publications in languages other than English will be translated in‐house or by using relevant services.
Unpublished literature
The Cochrane Complementary Medicine Field will be contacted and asked to search their register. Manufacturers of green tea (in form of green tea dried extract, green tea powder or green tea supplement) and internet resources will be consulted. Original authors of studies and manufacturers of green tea products will be contacted to inquire whether they are aware of unpublished and ongoing trials. Websites, such as www.clinicaltrials.com and www.scirus.com will be searched for ongoing trials.
Adverse events
We will write to green tea manufacturers for long‐term surveillance data on green tea products. The literature included in this review will also be used for data on adverse events, as described in the Methods of the review (item 3, Safety).
Data collection and analysis
Selection of studies
Studies identified by the searchers will be checked by two reviewers (KB, MH). Articles will only be included on initial screen if the reviewers can determine from the abstract that the article is a report of either an intervention or epidemiological study. When a title/abstract cannot be rejected with certainty, the full text article will be obtained for further evaluation. The full text of all studies of possible relevance will be obtained and analysed for independent assessment by two reviewers (KB, MH). The reviewers will assess the trials for methodological quality (see below). The reasons for excluding any trials will be stated. The reviewers will know the author's name, institution and the source of publication. Any disagreement will be resolved by discussion between the two reviewers, involving a third party if necessary, until consensus is reached, as described in Section 7.8 of the Cochrane Reviewers' Handbook (Alderson 2003). If any data are missing from the trial reports attempts will be made to obtain that data by contacting the authors.
Data extraction and management
Data extraction will be performed independently by two reviewers (KB, MH) and discrepancies will be resolved by third and fourth (EE, FB). Data will be categorised according to study design and cancer type.
Articles published in languages other than English will be translated in‐house by native speakers of , for instance, Japanese or Chinese, as many of the articles will be written in an Asian language.
Data will be entered into Review Manager by one reviewer (KB).
Authors of studies that might be included may be contacted for clarification of study methodology and results. A consumer will be involved whilst carrying out the systematic review to ensure readability and understanding of the terminology of the final review.
Safety
Safety data will be extracted as reported from all studies (number and nature of adverse events). We will write to manufacturers for long term surveillance data on green tea safety. The World Health Organisation (WHO) (Uppsalla Monitoring Centre for International Drug Monitoring) will be contacted regarding the yellow card reporting scheme of adverse events and the WHO database will be searched for adverse events of green tea. The German database 'medcertain.org' has a collection of published and unpublished cases of adverse events and this database will also be searched.
Assessment of risk of bias in included studies
Studies will be categorised into controlled trials (CT), uncontrolled trials (UCT) and case‐control studies (CCS). Data extraction will be performed by the contact reviewer (KB), double checked for discrepancies (MH, EE) and processed as described below (Alderson 2003).
The trials will be assessed independently by two investigators (KB, MH) using specific quality criteria adapted from Chalmers (Chalmers 1990). The quality criteria related to the following aspects of study methodology:
(1) randomisation and concealment of allocation;
(2) blinding of caregivers, participants and, in particular, outcome assessors;
(3) follow‐up and intention‐to‐treat analysis.
Trials will be categorised based on the extent to which they meet the quality criteria:
A = all criteria met
B = one or more criteria only partially met
C = one or more criteria not met
We are planning to investigate the influence of quality in a sensitivity analysis.
The Newcastle‐Ottawa assessment tool will be used for assessing the methodological quality of epidemiological studies (Wells 2001). The tool contains eight items categorised into the following three groups: selection, comparability and outcome.
Possible confounding variables will be identified for all included studies and each study will receive a series of stars, indicating which components of quality were addressed rigorously. If most of the confounding variables were identified and results have been adjusted accordingly the study will get two stars. If some of the confounding variables have been identified and been accounted for the study will get one star. If none of the confounding variables have been identified no stars will be given.
Assessment of reporting biases
Where possible, we will do a funnel plot to assess the chance of publication bias.
Data synthesis
Meta‐analysis will be performed if possible using standard meta‐analysis software (RevMan 4.2.3). The Chi‐square test for heterogeneity will be performed to test whether the distribution of the results is compatible with the assumption that inter‐trial differences are attributable to chance variation alone. Sensitivity analyses will be performed post‐hoc to test the robustness of the main analysis.
The analysis of results from observational studies will provide more insights into the cancer‐preventative potential of green tea although no statistical combination of such studies will be carried out, due to the anticipated high heterogeneity of the data.
