Herbal medicine for relapse and metastasis in patients operated for colorectal cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review is to assess the effect of herbal medicine on preventing relapse and metastasis of postoperative colorectal cancer with no‐intervention or chemotherapy or radiotherapy, including herbal medicine combined with chemotherapy or radiotherapy compared with chemotherapy or radiotherapy alone.
Background
Colorectal cancer refers to malignant tumor in the cecum, the entire colon and the rectum, and is the third most common malignant tumor and the second most frequent cause of cancer‐related death in the United States, with 145,290 new cases and 56,290 deaths anticipated in 2005 (Jemal 2005). Worldwide, colorectal cancer is the fourth most commonly diagnosed malignant disease, with an estimated 1,023,000 new cases and 529,000 deaths each year (Ferlay 2004).The incidence of colorectal cancer is normally higher in developed and industrialized countries than in developing countries. However, during the past five to ten years, the incidence of colorectal cancer in China has increased, now ranked as the fourth for men and third for women among the most common cancers (Report 2002).
The conventional treatment of colorectal cancer include surgery, chemotherapy (including palliative chemotherapy in progressive stage), and radiotherapy. The surgical resection rate has been reported up to 50 percent to 70 percent (Abulafi 1994). The postoperative relapse and metastasis of patients diagnosed as either Dukes' stage A or B is 15 percent, whereas Dukes' stage C is as high as 50 percent (Abulafi 1994). Colorectal cancer patients usually receives chemotherapy or radiotherapy to reduce the rate of relapse and metastasis after radical operation. In a pooled analysis of seven clinical trials of patients with stage III colorectal cancer, Gill and co‐workers demonstrated that adjuvant chemotherapy increased the probability of remaining free of tumor relapse after five years, from 42 to 58 percent. In addition, overall five‐year survival increased from 51 to 64 percent, and an analysis of data from above studies showed five‐year survival probability in the range of 80 percent, with or without chemotherapy treatment (Gill 2004). The value of postoperative fluorouracil‐based therapy with stage II disease of colon cancer has remained controversial (Mamounas 1999), and the American Society of Clinical Oncology (ASCO) concluded that adjuvant chemotherapy should not be routinely recommended for all patients with stage II disease (Meyerhardt 2005). Post‐surgical five‐year survival rate varies with diagnosis. After the TNM classification, five‐year survival is 90 percent for stage I in colorectal cancer, 65 to 85 percent for stage II, 25 to 65 percent for stage III, and only 5 to 7percent for stage IV (Greene 2002). The predominant cause of death is relapse of and metastasis from colorectal cancer. Majority of relapse can be observed within two years after operation, and is often accompanied with remote metastasis (in 80 percent of the cases), resulting in a poor overall survival rate. Nearly half of the patients would die from the metastases. Therefore, the rational choice of postoperative adjuvant therapy is essential for preventing relapse and metastasis.
Traditional Chinese Medicine (TCM) has a long history in recognition of tumors. Around more than one thousand years ago, the word "tumor" was found in historical record in Shang Dynasty (Li 2002). Much later, the etiology and pathogenesis regarding intestinal tumors has been established and described in 'the Canon of TCM' (Huang Di Nei Jing) (Nanjing 1996). Based upon the symptoms, such as hematochezia (blood in the stool), abdominal pain, and abdominal mass, and the syndrome differentiation, prescription of herb treatment was performed by Chinese practitioners. Principal treatment approaches include strengthening the essence of the whole body and eliminating pathogenic factors, combined with other therapies such as acupuncture, moxibustion (heat therapy, often in combination with accupuncture), and excision of external tumors. During the past 30 years, integrative approach of both conventional and TCM has been advocated, and the effect of Chinese Herbal medicines have been tested in clinical trials on patients undergoing radical surgery for colorectal cancer. Promising effects have been shown from a number of studies, including decreasing relapse and metastasis, prolonged survival, improved quality of life, and alleviated adverse effects of radio/chemotherapy (Bao 1992; Guo 1999; Pan 2003; Shen 2003), but not evaluated systematically.
Therefore, we will perform a systematic review on herbal medicines for preventing relapse and metastasis of postoperative colorectal cancer, to inform the current status of clinical practice and to guide further clinical studies in this area.
Objectives
The objective of this review is to assess the effect of herbal medicine on preventing relapse and metastasis of postoperative colorectal cancer with no‐intervention or chemotherapy or radiotherapy, including herbal medicine combined with chemotherapy or radiotherapy compared with chemotherapy or radiotherapy alone.
Methods
Criteria for considering studies for this review
Types of studies
Randomized or quasi‐randomized trial will be considered regardless of blinding. Non‐randomized controlled studies will be included in exploratory analysis.
Types of participants
Patients diagnosed with colorectal cancer (pathologically diagnosis of any tumor stage except for stage D/stage IV) and undergoing radical surgery, regardless gender, age or race.
Types of interventions
Herbal medicine (single herb or compound recipe), regardless administration route (orally, intravenously, or local administration such as clysis), compared with:
‐ herbal medicine versus no‐intervention
‐ herbal medicine versus chemotherapy or radiotherapy
‐ herbal medicine combined with radio‐chemotherapy versus chemotherapy or radiotherapy alone
Types of outcome measures
Evaluation of the principal criteria would be made one to five year after the termination of treatment; while secondary criteria would be evaluated during the therapeutic process.
Primary outcomes:
1. Incidence of relapse and/or metastasis
2. Incidence of survival
Secondary outcomes:
3. Time of relapse and/or metastasis
4. Time of survival
5. Quality of life
6. Serum CEA level (ng/ml)
7. Immune function such as CD4+,CD8+, CD4+/ CD8+, NK,IgA,IgE,IgG.
8. Relief of adverse events caused chemotherapy/radiotherapy
9. Adverse event of herbal medicine
Search methods for identification of studies
1. Electronic searching:
Using Cochrane Colorectal Cancer Group search strategy to retrieve primary trials from the Cochrane Library, MEDLINE, EMBASE, CBM (Chinese Biological Medicine Database), CMCC (Chinese Medical Current Contents) and BIOSIS database since their start publication.
The search key words for searching for databases above are as follows:
1) colorectal cancer, colonic cancer, rectal cancer.
2) traditional Chinese medicine, Chinese herbal medicine plant extract, herbal medicine.
The search strategy is listed in additional table 1 (Table 1).
| Database | Searched period | Search strategy |
| The Cochrane Library | 1800‐2006 | #1 (colorectal tumor) or (colorectal cancer) or (colorectal carcinoma) or (colorectal neoplasm) or (colorectal adenocarcinoma) or (colorectal adenoma) or (colonic cancer) in All Fields in all products 3483 edit delete |
| Medline | ||
| Embase |
2. Hand searching:
We will handsearch relevant Chinese journals: Journal of Gastroentologic Diseases(20002006), Journal of Chinese Digestion (1981‐2006), Journal of Chinese Oncology (1979‐2006), Journal of Chinese Cancer (1991‐2006), Tumor (1981‐2006), Cancer (1982‐2006), Chinese Tumor Clinic (1986‐2006), Chinese Tumor (1992.‐2006), Journal of Clinical Oncology (1995‐2006), Tumor Research on Prevention‐Treatment (1973‐2006), Chinese Journal of Integrative Medicine on Traditional and Western Medicine (1981‐2006), Journal of Integrative Medicine on Spleen and Stomach (now changed to Journal of Integrative Medicine on Digestion, 1993‐2006).
Furthermore, unpublished trial reports from academic conferences, and theses of postgraduates are included in the range of manual searching.
Data collection and analysis
1. Selection of trials for inclusion
Identified trials will be evaluated by two authors (LL, ZXC) independently. Inclusion of a trial will be solved in consensus with a third part.
As the majority of identified trials is supposed to be in chinese, extraction of data from the trials will be translated into english.
2.Assessment of methodological quality
The methodological quality will be assessed by separated components i.e. adequacy of generation of the allocation sequence, allocation concealment, double blinding, and follow up. The quality components will be:
‐ generation of the allocation sequence: adequate (computer generated random numbers or similar) or inadequate (other methods or not described),
‐ allocation concealment: adequate (central independent unit, serially numbered, opaque, sealed envelopes, or similar) or inadequate (not described or open table of random numbers or similar),
‐ follow‐up: adequate (number and reasons for dropouts and withdrawals described) or inadequate (number or reasons for dropouts and withdrawals not described).
3. Data extraction
Two authors (LL, ZXC) will independently extract data. For trials in other languages than chinese, we will seek help from Cochrane Colorectal Cancer Group for translation.
Every included trial should extract following data and characteristics: The author, mean age, gender, race, inclusion and exclusion criteria, methodology, stage of colorectal cancer, diagnostic approaches, type of herbal medicine, mode of administering, dosage and treatment duration, detail of controls, outcome measurement and number and type of adverse events.If the above data are not available in the trial reports, further information will be sought by correspondence with the principal investigator.
4. Data Synthesis
No matter the administration modes, dosage and treatment duration, each herbal medicine would be independently compared to a control. Same herbal medicine compared with the same control, meta‐analysis would be used to present their comparison. The dichotomous data will be presented as relatively risk (RR), continuous variance adopts weighted mean difference, both expressed by the 95 percent confidence interval (CI). Analyses are performed by intention‐to‐treat where possible. For dichotomous outcomes, patients with incomplete or missing data will be included in a sensitivity analysis by counting them as treatment failures to explore the possible effect of loss to follow‐up on the findings ('worst‐case' scenario).
Heterogeneity will be tested for using Chi square with significance being set at p < 0.10. Whenever there is significant heterogeneity, the random effects model will be used. Meta‐analysis will be performed using the Cochrane software, RevMan Analysis, in Review Manager 4.2.
If necessary we will contact a statistician for data analyses (for example determining hazard ratios)
Non‐randomized studies will be analysed in exploratory. If a sufficient number of randomized trials is identified and included, the following subgroup analysis will be performed: clinical staging (stage A,B,C or stage I , II, III); pathological classification.
Data from non‐randomised studies for assessment of safety will be presented without summary statistics as an additional table, and discussed.
| Database | Searched period | Search strategy |
| The Cochrane Library | 1800‐2006 | #1 (colorectal tumor) or (colorectal cancer) or (colorectal carcinoma) or (colorectal neoplasm) or (colorectal adenocarcinoma) or (colorectal adenoma) or (colonic cancer) in All Fields in all products 3483 edit delete |
| Medline | ||
| Embase |
