Medicinal herbs for esophageal cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and possible adverse effects of combination of ordinary treatment and Chinese medicinal herbs for esophageal cancer, compared to ordinary treatment without Chinese medicinal herbs.
Background
EPIDEMIOLOGY
Esophageal cancer is a global health problem with two subtypes: squamous carcinoma and adenocarcinoma. As the seventh leading cause of cancer death worldwide, esophageal cancer vary by geographic area, ethnic group, and sex. Incidence of esophageal carcinoma can be as high as 30‐800 cases per 100,000 persons in particular areas of northern Iran, some areas of southern Russia, and northern China, while the incidence of esophageal carcinoma in US is approximately 3‐6 cases per 100,000 persons(Nishihira 1993, Pera 2001). Esophageal cancer generally is more common in men than in women, with a male‐to‐female ratio of 7:1. It occurs most commonly during the sixth and seventh decades of life (Kirby 1994, Blot 1993).
PATHOPHYSIOLOGY AND ETIOLOGY
Esophageal carcinoma arises in the mucosa. Subsequently, it tends to invade the submucosa and the muscular layer and, eventually, contiguous structures such as the tracheobronchial tree, the aorta, or the recurrent laryngeal nerve. Though firstly metastasising to the periesophageal lymph nodes, esophageal cancer can also spread to almost any other part of the body, including the liver, lungs, brain, and bones (Nishihira 1993).
The etiology of esophageal carcinoma is thought to be related to exposure of the esophageal mucosa to noxious or toxic stimuli, resulting in a sequence of dysplasia to carcinoma in situ to carcinoma(Lam 2000).
Some factors are believed to trigger esophageal carcinoma: cigarette smoking (Broitman 1983); alcohol drinking (Tuyns 1979); drinking exceptionally hot beverages (tea)(Victora 1987); diets low in beta‐carotene, vitamins A, C, B, magnesium, and zinc; poor oral hygiene; Protease inhibitors(Sammon 1998); high level exposure to asbestos(O'Byrne 2001); tylosis palmaris at plantaris (Mandard 2000); swallowing lye or other caustic substances (Messmann 2001); barrett's esophagus (Williamsom 1991). The recent investigation reported that the high incidence of esophageal carcinoma in Taiwan and India may be associated with betel chewing, which is one of the major independent risk factors in the development of this tumor (Wu 2001).
CURRENT TREATMENT
The management of esophageal cancer presents great challenges in the current practice of gastroenterology. Highly curable in its earliest stages, esophageal cancer is treatable but is usually fatal when more advanced (Clark 1994, Steup 1996).
Nonoperative therapy is usually reserved for patients who have esophageal carcinoma and are not candidates for surgery. The goal of therapy for these patients is palliation of dysphagia, allowing them to eat. Chemotherapy as a single modality has limited use (Entwistle 2002, Cooper 1999). Radiation therapy is successful in relieving dysphagia in approximately 50% of patients. In patients with advanced esophageal cancer, the preoperative combination of chemotherapy and radiotherapy has shown good results (Herskovic 1992, Cooper 1999). Intracavitary radiotherapy with or without surgery is safe for normal patients (Homs 2003).
Laser therapy can destroy cancerous tissue and relieve a blockage in the esophagus when the cancer cannot be removed by surgery. The relief of a blockage can help to reduce symptoms, especially swallowing problems (Carter 1992). When a tracheoesophageal fistula is present, intubating with expandable metallic stents is particularly useful (Knyrim 1993, Sarper 2003).
Esophageal resection (esophagectomy) is used in patients who are considered candidates for surgery. If an esophagectomy is indicated, there are three main avenues ranging from minimally invasive to highly invasive(Wu 2003), a transhiatal esophagectomy without a thoracotomy, a "standard" (transthoracic) esophagectomy, or a en bloc esophagectomy are current methods. Many studies have been conducted using all three procedures and a consensus has not been formed as to the preference of one technique (Teng 1999, Swanstrom 2002, Goldminc 1993).
The application of these treatments is dependent on the stage of the disease at diagnosis.
CHINESE MEDICINAL HERBS FOR ESOPHAGEAL CANCER
Herbal medicine has commonly been used as accessory treatment for alleviating chemotherapeutic or radiotherapeutic side effects and for improving quality of life for cancer patients. An investigation conducted in New Zealand found that 49% of cancer patients used complementary and alternative medicine (CAM), with vitamins, antioxidants, alternative diets, and herbal therapies. Usage was more common in younger patients. CAM was used by 47% to improve quality of life and by 30% in the hope of a cure of their cancer (Chrystal 2002). In Shumay's study, all participants used 3 or more types of CAM, most commonly herbal or nutritional supplements (Shumay 2001). These findings suggest that herbal medicine is widely used among cancer patients. The most commonly cited reasons for seeking complementary medicine were side effects and lack of effectiveness of standard therapies (Hilsden 1999).
The herbal medicine have their own benefits including increasing appetite, boosting the immune system, facilitating the recovery of the body, and preventing tumour regeneration or metastases. It is effective for anti‐cancer (Ye 2002), for example, artemisinin‐type compounds inhibite tumor cell growth (Chen 2003), membranous milkvetch root, barbary wolfberry fruit and heterophylly falsestarwort root can enhance patients' immunity (Du 1998). Common yam rhizome and india bread can decrease the side effects of radiotherapy , so radiotherapy combined with them may have a better outcome (Jia 2001). Chinese medicinal herbs of spreading hedyotis herb can repress the proliferation of cancer cells and block the progression of esophageal cancer (Zhou 1996). Liquorice root is used to harmonize the herbs above (Shi 2000).
RATIONALE FOR UNDERTAKING THIS REVIEW
The evidence for use of herbal medicine for anti‐cancer, chemotherapy side effects and improving quality of life is mainly theoretical and experiential. However there is evidence to indicate that not all CAM is risk‐free. There are concerns regarding adverse event issues, e.g. allergic reaction, Chinese herbal nephropathy (CHN) (Nortier 2000, Lord 2001, Lampert 2002). Despite these concerns, herbal medicines are widely used.
Objectives
To assess the efficacy and possible adverse effects of combination of ordinary treatment and Chinese medicinal herbs for esophageal cancer, compared to ordinary treatment without Chinese medicinal herbs.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials. This will include cross‐over trials and within patient studies.
Types of participants
Patients with esophageal cancer of different subtypes will be included.
Types of interventions
The combination of ordinary treatment and Chinese medicinal herbs will be compared with other treatments that are widely used by the doctors for esophageal cancer. While the ordinary therapy is applied, Chinese medicinal herbs are used by oral intake. The duration should last for one month or more.
Types of outcome measures
We will consider the following outcome measures:
PRIMARY OUTCOME MEASURES:
1. Mortality
2. Median Survival Times (MST)
3. Time to Progression (TTP)
4. Quality of Life (QOL)
ADVERSE EVENTS:
1. Life threatening
2. Toxic response
3. Result in the discontinuation of treatment
The side effect will be brought to minor patients by Chinese medicinal herbs or/and ordinary treatment.
Search methods for identification of studies
A search will be conducted to identify all published and unpublished randomised controlled trials. The search strategy will identify studies in all languages and when necessary non English language papers will be translated so that they could be fully assessed for potential inclusion in the review.
Trials will be identified by searching the following electronic databases ‐ The Cochrane Library, Medline, Embase, AHMED (Allied and Complementary Medicine Database), CBM (Chinese Biomedical Database), Chinese Cochrane Centre Controlled Trials Register and CISCOM (The Research Council for Complementary Medicine).
The search strategy for the review will be constructed by using a combination of MESH subject headings and textwords relating to the use of medicinal herbs in the treatment of esophageal cancer.
Reference lists from trials selected by electronic searching will handsearched to identify further relevant trials. Published abstracts from the following conference proceedings will also be handsearched:
Acta Medicinae Sinica
Cancer Research on Prevention and Treatment
China Journal of Chinese Materia Medica
China Oncology
Chinese Journal of Cancer Research
Chinese Journal of Clinical Oncology and Rehabilitation
Chinese Journal of Integrated Traditional and Western Medicine on Digestion
Chinese Journal of Oncology
Chinese Journal of Radiation Oncology
Henan Journal of Traditional Chinese Medicine
Jiangshu Journal of Traditional Chinese Medicine
Journal of Beijing of Traditional Chinese Medicine
Journal of Fujian of Traditional Chinese Medicine
Journal of Jilin of Traditional Chinese Medicine
Journal of Practical Oncology
Journal of Nanjing University of Traditional Chinese Medicine
Journal of Sichuang of Traditional Chinese Medicine
JTCM(Journal of Traditional Chinese Medicine)
Traditional Chinese Medicinal Research
In addition members of the Cochrane UGPD Group, experts in the field and medicinal herb manufactuers will be contacted and asked to provide details of outstanding clinical trials and any relevant unpublished materials.
Data collection and analysis
1. TRIALS SELECTION:
To determine the studies to be assessed further, we will scan the titles, abstract sections and keywords of every record retrieved. Full articles will be retrieved for further assessment if the information given suggests that the study:
1. Includes patients with esophaseal cancer of different subtypes.
2. Compares the combination of ordinary treatment and Chinese medicinal herbs with ordinary therapies without Chinese medicinal herbs.
3. Assesses one or more relevant clinical outcome measure.
4. Uses random allocation to the comparison groups.
If there is any doubt regarding these criteria from the information given in the title and abstract, the full article will be retrieved for clarification. Interrater agreement for study selection will be measured using the kappa statistic (Cohen 1960). Where differences in opinion exist, they will by resolved by discussion. If resolving disagreement is not possible, the article will be added to those 'awaiting assessment' and the authors will be contacted for clarification. If no clarification is provided, the review group editorial base will be consulted.
2. QUALITY ASSESSMENT OF TRIALS:
The quality of reporting each trial will be assessed based largely on the quality criteria specified by Juni (Juni 2001). In particular, the following factors will be studied:
1. Minimisation of selection bias ‐ a) was the randomisation procedure adequate? b) Was the allocation concealment adequate?
2. Minimisation of performance bias ‐ a)were the patients administering the treatment blind to the intervention? Were the people administering the treatment blind to the intervention?
3. Minimisation of attrition bias ‐ a) were withdrawals and dropouts completely described? b) Was analysis by intention‐to‐treat?
4. Minimisation of detection bias ‐ were outcome assessors blind to the intervention?
Based on these criteria, studies will be broadly subdivided into the following three categories:
A ‐ all quality criteria met: low risk of bias.
B ‐ one or more of the quality criteria only partly met: moderate risk of bias.
C ‐ one or more criteria not met: high risk of bias.
This classification will be used as the basis of a sensitivity analysis. Additionally, we will explore the influence of individual quality criteria in a sensitivity analysis.
Each trial will be assessed by two reviewers independently (Chen, Wu). Interrater agreement will be calculated using the kappa statistic, and disagreements will be resolved, where necessary, by recourse to a third reviewer (Yang). In cases of disagreement, the rest of the group will be consulted and a judgment will be made based on consensus, and we will keep a record of this using reference management software such as ProCite.
3. DATA EXTRACTION
Data concerning details of study population, intervention and outcomes will be extracted independently by two reviewers (Chen,Wu) using a data extraction form. This form will be specifically designed for this review. Data on participants, interventions, and outcomes, as described above, will be extracted. The form will include the following items:
1. General information: published/unpublished, title, authors, reference/source, contact address, country, urban/rural etc., language of publication, year of publication, duplicate publications, sponsor, setting.
2. Trial characteristics: design, duration of follow up, method of randomisation, allocation concealment, blinding (patients, people administering treatment, outcome assessors).
3. Intervention(s): intervention(s) (dose, route, timing), comparison intervention(s) (dose, route, timing), co‐medication(s) (dose, route, timing).
4. Patients: exclusion criteria, total number and number in comparison groups, age (adults), baseline characteristics, diagnostic criteria, similarity of groups at baseline (including any co‐morbidity), assessment of compliance, withdrawals/losses to follow‐up (reasons/description), subgroups.
5. Outcomes: outcomes specified above, any other outcomes assessed, other events, length of follow‐up, quality of reporting of outcomes.
6. Results: for outcomes and times of assessment (including a measure of variation), if necessary converted to measures of effect specified below, intention‐to‐treat analysis. Differences in data extraction will be resolved by consensus, referring back to the original article. When necessary, information will be sought from the authors of the primary studies.
Original reports of trial results will be independently abstracted by Chen and Wu. Disagreement will be resolved by discussion and, where necessary, in consultation with a third reviewer (Yang). For binary outcomes, number of events and total number in each group will be extracted. For continuous outcomes, mean, standard deviation and sample size of each group will be extracted.
4. DATA ANALYSIS
Data will be included in a meta‐analysis if they are available, of sufficient quality and sufficiently similar. Only randomised controlled trials will be included in a meta‐analysis. We expect both event (dichotomous) data and continuous data. Dichotomous data will be expressed as relative risks (RR). They may be converted to absolute measures like the number needed to treat if doses and follow‐up times are similar. Continuous data will be expressed as weighted mean differences (WMD). Overall results will be calculated based on the random effects model. Heterogeneity will be tested for using the Z score and the Chi square statistic with significance being set at p < 0.1. Possible sources of heterogeneity will be assessed by sensitivity and subgroup analyses as described below. Small study bias will be tested for using the funnel plot or other corrective analytical methods depending on the number of clinical trials included in the systematic review.
5. SUBGROUP ANALYSES
We will aim to perform subgroup analyses in order to explore effect size differences as follows:
1. Duration of treatment (one course, two courses versus even more courses ‐ based on data)
2. Dose of Chinese medicinal herbs (low, medium, high ‐ based on data)
6. SENSITIVITY ANALYSES
We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:
1. Repeating the analysis excluding unpublished studies (if there were any).
2. Repeating the analysis taking account of study quality, as specified above.
3. Repeat the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.
The robustness of the results will also be tested by repeating the analysis using different measures of effects size (risk difference, odds ratio etc.) and different statistic models (fixed and random effects models).
