Herbal medicines for advanced colorectal cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Our primary objective of this review is to assess efficacy of herbal medicines as a treatment for advanced colorectal cancer compared with placebo, no intervention or chemotherapy (including herbal medicines combined with chemotherapy). The secondary objective is to assess the safety of the use of herbal medicines and effects on quality of life.
Background
Colorectal cancer is one of the most common cancers worldwide, with estimated 944,720 new cases diagnosed and 492,411 deaths in 2000 (WHO 2000). The incidence is higher in industrialized countries compared to developing countries (WHO 2000). Of all cancer incidents reported, the distribution of colorectal cancer in industrialised countries is 12.6% for men and 14.1% for women. Elsewhere colorectal cancer represents 7.7% in men and 7.9% in women of all reported cases (Boyle 2000). In the recent 5 to 10 years in China, the incidence of colorectal cancer has increased, and is now the fourth to fifth most common cancer in urban areas and counties, with rising tendency of both incidence and mortality (CTPTRO 2002).
As symptoms often are spare, early diagnosis is difficult. At the time of initial diagnosis, approximately 30% of the patients will have developed an advanced colorectal cancer. In addition, 25% of cases will relapse after the first operation (Cohen 1993). Five year survival of advanced colorectal cancer is less than 5% and the median survival time is about 4‐5 months (Moertel 1994).
There is an overall survival benefit for intensifying the follow‐up of patients after curative surgery for colorectal cancer (Jeffery 2002). But as colorectal cancer often appears resistant to radiotherapy and chemotherapy, a majority of scholars think that chemotherapy had no significant influence on overall or disease‐free survival (Lindel 2001). Further, the outcomes of treatment for advanced colorectal cancer still remain poor (Zalcberg 1996). Meta‐analysis of a subset of trials using individual patient data demonstrated that palliative chemotherapy was associated with a 35% (95% confidence interval (CI), 24% to 44%) reduction in the risk of death. This translates into an absolute improvement in survival of 16% at both 6 months and 12 months and an improvement in median survival of 3.7 months. The overall qualities of evidence relating to treatment toxicity, symptom control, and quality of life were poor (Best 2000).
There is an abundance of theories concerning tumors in Traditional Chinese Medicine (TCM). From the early editions of the medical classical book of China, comprehensive descriptions of tumor established a good basis for the current Traditional Chinese Medical Oncology (Wang 2000). During Jin Sui and Tang dynasties, there are deep recognition and great improvement in the treatment of tumors (Wang 1995). During Song, Yuan, Ming and Qing dynasties, the theory and treatment of the Traditional Chinese Medical Oncology had been substatially improved (Hu 1999). After the establishment of the People Republic of China special tumor research institutions have been established, and clinicians have been working on the integration of TCM with western medicine for the treatment of tumors, and during the past 40 years a great deal of this clinical experience has been accumulated and compiled in several books and magazines (Li 1994).
TCM has its unique theories for concepts of etiology, systems of diagnosis and treatment, which are vital to its practice. TCM drug treatment consists typically of complex prescriptions of a combination of several herbs. The combination based on the chinese diagnostic patterns (i.e., inspection, listening, smelling, inquiry, and palpation) follows a completely different rationale than many western drug treatments. Herbal medicines are also widely used in Indian, Japan, and Southeast Asia.
From clinical research in China during the last decades, it has been documented that herbal medicines are able to relieve symptoms of patients with colorectal cancer. For example an effect on the recovery from surgery, on the adverse effects of the adjuvant chemotherapy, improvement of the quality of life, an increase in the cure rate, and on the immunological response in patients with advanced colorectal cancer (Li 1994; Liu 2001; Zhang 1997; Rao 2000).
Clinical controlled trials have been designed to evaluate the efficacy of treatment with chinese herbal medicines (Zhang 1997). These trials suggest that the use of herbal medicines may have potential advantages in the treatment of advanced colorectal cancer. However, the effectiveness of such treatment needs to be reviewed systematically, and the studies needs to be appraised critically to inform current practice and direct the continued search for new treatment approach.
Objectives
Our primary objective of this review is to assess efficacy of herbal medicines as a treatment for advanced colorectal cancer compared with placebo, no intervention or chemotherapy (including herbal medicines combined with chemotherapy). The secondary objective is to assess the safety of the use of herbal medicines and effects on quality of life.
Methods
Criteria for considering studies for this review
Types of studies
Randomized or quasi‐randomized controlled trials regardless of blinding. Only trials with a minimum follow‐up of six month will be included. Trials that include patients undergoing curative resection will be excluded from this review.
Types of participants
Male or female patients of any age, with advanced colorectal cancer, diagnosed according to the American Joint Committee on Cancer Staging System for Colorectal Cancer stage IV (Martin 2001) and UICC (Union Internationale Contre le Cancer) stage C, when curative resection is generally not possible. The diagnosis of colorectal cancer needs to be confirmed by pathological findings.
Types of interventions
Herbal medicines regardless of their compositions or formulations are compared with no intervention, placebo, or western medical interventions (chemotherapy or radiotherapy). Herbal medicines plus chemotherapy or radiotherapy versus chemotherapy or radiotherapy alone will also be included.
Types of outcome measures
The following outcome measures will be sought after six months and maximal follow‐up after completion of the treatment:
1. Mortality (primary outcome)
2. Survival‐time.
Relative response rates (complete response, partial response, stable disease, progression disease) Response Criteria : Complete response implies disappearance of all measurable or evaluable disease, signs, symptoms, and biochemical changes related to the tumor for at least 4 weeks, during which time no new lesions may appear. Partial response implies a reduction of greater than 50 percent in the sum of the products of the perpendicular diameters of all measurements, lasting at least 4 weeks, during which no new lesions may enlarge. For hepatic lesions, a reduction of greater than 30percent in the sum of the measured distances from the costal margin at the sure distances from the costal margin at the midclavicularline and at the xiphoid process to the edge of the liver is required. Stable disease is a less than 50 percent reduction or less than 25 percent increase in the sum of the products of the two perpendicular diameters of all measured lesions, and the appearance of no new lesions for 8 week. Progrssion or relapse is defined as an increase in the product of two perpendicular diameters of any measurable lesion by gueater than 25 percent over the size present at entry into the study or, for patients who respond, the size at time of maximum regression, or the appearance of new areas of malignant disease (usually excluding central nervous system metastases), A two‐step deterioration in performance status, greater than 10 percent loss of pretreatment weight, or increasing symptoms, in and of themselves, do not constitute progression. Their appearance, however, should initiate a new evaluation for disease extent (Cohen 1993).
3. Quality of life (parametres such as body weight, pain, functional status: Using Karnofsky (KPS), Performance Status: Zubrod‐ECOG‐WHO (ZPS), FLIC:EORTC QLQ‐C30 scales)
4. Adverse effects
Search methods for identification of studies
See: Collaborative Review Group search strategy
ELECTRONIC SEARCHES
The specialised trials register of the Cochrane Colorectal Cancer Group, the Cochrane Central Register of Controlled Trials (CENTRAL) and the register of complementary and alternative medical treatments maintained by the Cochrane Complementary Medicine Field will be searched.
Further MEDLINE, EMBASE, BIOSIS, and Chinese Biomedical database CD‐ROM (CBM) will be searched from their date of inception onwards. MeSH terms will include colorectal neoplasm, medicine‐Chinese‐traditional, plants‐medicinal, drugs‐Chinese‐herbal, plants extracts, and herbs.
No languages restrictions will be applied.
HANDSEARCHING
We will search the following sources from date (in brackets) and onward to date:
Chinese Journal of Clinical Gastroenterology (October 1994), Chinese Journal of Digestion (February 1981), Chinese Journal of Clinical Oncology and Rehabilitation (October 1994), Chinese Journal of Oncology (March 1979), Chinese Journal of Cancer (February 1982), Chinese Journal of Cancer Research and Bulletin of Chinese Cancer (January 1992), Tumor (January 1981), Chinese Clinical Oncology (October 1995), China Cancer (January 1992), Chinese Journal of Clinical Oncology (March 1963), Cancer Research on Prevention and Treatment (January 1973), Chinese Journal of Cancer Palliative Medicine (July 1981) , and the Chinese Journal of Integrated Traditional and Western Medicine (July 1981).
Unpublished abstracts from meetings and graduate thesis in Chinese will also be handsearched (including abstracts from meetings not published in public journals, and unpublished articles).
We also seek help from the Cochrane Colorectal Cancer Group on translation of non‐English and Chinese papers.
Data collection and analysis
Selection of trials for inclusion
Two reviewers (YF Yang and ZX Chen) will independently select the trials to be included in the review according to the prespecified selection criteria. Any disagreement will be resolved by discussion.
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 (Schulz 1995).
The quality components are:
‐ 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),
‐ double blinding: adequate (identical placebo or similar) or inadequate (not performed or tablets versus injections or similar),
‐ follow‐up: adequate (number and reasons for dropouts and withdrawals described) or inadequate (number or reasons for dropouts and withdrawals not described). Data extraction
Data will be extracted independently by two reviewers (Y Liu, ZX Chen) and validated by a third party (YF Yang) using a self‐developed data extraction form. Disagreement will be resolved by discussion. Papers not in Chinese, English, and Japanese will be translated with the help of the Cochrane Colorectal Cancer Group.
The following characteristics and data will be extracted from each included trial: primary author, funding source, quality assessment, mean age, and proportion of male patients, number of randomized patients, reason and number dropped out or lost during follow‐up, patient inclusion and exclusion criteria, stage of colorectal cancer, the diagnostic criteria, type of herbal medicines, method of administration, dosage and duration of intervention, details of the comparison regime, outcome measures, and number and type of adverse events.
Data on the number of patients with each outcome, by allocated treatment group, irrespective of compliance or follow‐up, are sought to allow an intention‐to‐treat analysis. If the above data are not available in the trial reports, further information will be sought by correspondence with the principal investigator.
Data synthesis
Any regimen of herbal medicines will be compared with each control individually regardless of route of administration, dose, or preparation. Meta‐analysis is performed within comparisons where individual trial compares same herb versus same control intervention. Dichotomous data will be presented as relative risk (RR) and continuous outcomes as weighted mean difference (WMD), both with 95% CI. Analyses are performed by intention‐to‐treat whenever 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 the Z score and Chi square with significance being set at p < 0.10. Whenever there is significant heterogeneity, the random effects model will be used. The analyses will be carried out using MetaView 4.2 within Review Manager 4.2.2.
The following comparisons will be tabulated where data is available:
‐herbal medicines versus no intervention or placebo;
‐herbal medicines versus western medicine (chemotherapy or radiotherapy);
Trials of herbal medicines plus chemotherapy or radiotherapy versus chemotherapy or radiotherapy will be presented as a separate comparison.
Data from non‐randomized studies for assessment of safety will be tabulated, analyzed and presented in additional tables.
If a sufficient number of randomized trials are identified, we will perform subgroup analyses on mean‐survival‐time, pathology diagnosis (yes or no), formulation of herbs (extract, single herb, or mixture of herbs), and treatment duration (short and long term).
Sensitivity analysis
Furthermore, if a sufficient number of randomized trials are identified, we plan to perform sensitivity analyses to explore the influence of trial quality on effect estimates. The quality components of methodology include adequacy of generation of allocation sequence, concealment of allocation, double blinding, the use of intention‐to‐treat (yes or no). Potential biases (Vickers 1998) will be investigated using the funnel plot or other corrective analytical methods according to Egger et al. (Egger 1997).
