Chinese medical herbs for chemotherapy side effects and improving quality of life in colorectal cancer patients
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effect of herbal medicine for chemotherapy side effects and improving quality of life in colorectal cancer patients compared with placebo and other anti‐chemotherapy side effects drugs, and adverse events.
Background
Colorectal cancer is a predominantly disease of elderly people. It is ranks second behind carcinoma of the lung in men and the breast in women, and is a major cause of morbidity and mortality in United States and northern European countries (Beart 1992, Black 1997, Giovannucci 1999). Each year, 155,000 new cases of colorectal cancer in United States and 50,000 die (CDC 2003), and of 33,000 people in United Kingdom (NHS 2003). The rate is lowest in Asia and Africa (Giovannucci 1999). Incidence of colorectal cancer sharply with age, it is rarely diagnosed in those under age 40 and is most common in those aged 50 years and older and the risk increases with age, with 93% of cases diagnosed in people over age 50 (Giovannucci 1999, CDC 2003).
Environmental factors, particularly lifestyle including diet, obesity, physical inactivity, smoking and alcohol consumption is now widely believed that risk of colorectal cancer is largely determined (Shike 1999, Giovannucci 1999). Up to 90% of colon cancers may have a dietary contribution (Doll 1981). High fibre, fruit and vegetable, folate and methionine intake, are protective, whereas high animal fat, red meat, and alcohol consumption increase risk (Chen 1978, Fleiszer 1978, Giovannucci 1999). Investigations showed, Chinese and Japanese migrants living in the United States, the incidence of colorectal cancer approaches or exceeds the level of the American white population that is much higher than Chinese and Japanese living in China and Japan (Haenszel 1968, King 1980; Locke 1980).
TREATMENT
A high percentage of patients with colorectal cancer are curable if the disease is diagnosed and treated in early stages (Diaz‐Canton 1996, Winawer 1997, Winawer 2003). Surgery (colectomy) is the primary treatment for colorectal cancer (Labianca 1997). The effectiveness of surgery for colorectal cancer depends on it being carried out safely, and to select rational adjuvant therapy (CCCG 2000, Marvin 2002).
Adjuvant chemotherapy after surgery aims to destroy cancer cells, it usually started at the end of the first month after surgery and continue six months (Labianca 1997). 6 months of treatment with 5‐FU plus leucovorin plus levamisole was suggested for postoperative surgical adjuvant therapy for patients with high‐risk colon cancer (O'Connell 1998). Standard therapy for colon cancer was represented by fluorouracil plus levamisole and/or calcium folinate (folinic acid) (Moertel 1994). Other strategies are represented by monoclonal antibodies (mAb), which improve survival, (with a decrease in mortality by 32%), and by portal vein fluorouracil, alone or in combination with systemic therapy (Labianca 1997). In rectal cancer, the best results have been obtained with a combination of radiotherapy and chemotherapy (Labianca 1997).
Standard treatment for metastatic colorectal cancer is chemotherapy, usually is in the form of a combination of the drugs 5‐fluorouracil and leucovorin (5FU/LV), or 5FU/LV plus irinotecan (Labianca 1997). Advanced colorectal cancer is usually considered as poorly chemosensitive, and fluorouracil has been the standard drug with a median survival about 1 year (Labianca 1997). Radiation therapy uses X‐rays to kill any possible remained cancer cells after surgery to prevent cancer from reappearing in the same place, or to shrink large tumours before an operation so they can be removed more easily. Radiation is usually reserved for treatment of rectal cancer. The goal of therapy is to damage the tumour without harming the surrounding tissue. For spread cancer through the wall of the rectum, radiation treatments in combination with chemotherapy following surgery always been used (Marvin 2002).
Possible side effects of Chemotherapy and radiation therapy include nausea and vomiting, mouth sores, diarrhea (Martenson 1997), hepatotoxicity (Moertel 1993), suppression of the bone marrow, and obvious decline of human immunity. A lot of drugs are used for these side effects, for example, 5‐HT3‐receptor antagonists Tropisetron is a newer drug for anti‐nausea and vomiting after chemotherapy and radiation therapy (Blower 2002, Madenoglu 2003), Levamisole is used for promoting immunity, survival of those patient who was used levamisole was longer than those who without using (Windle 1987).
APPLICATIONS OF HERBAL MEDICINE IN THE TREATMENT OF NEOPLASTIC DISEASE
Herbal medicine commonly been used as accessory treatment for alleviating chemotherapeutic or radiotherapeutic side effects and for improving quality of life of cancer patient. A population‐based questionnaire investigation found that 42% colorectal cancer patients used herbs (Tough 2002). An investigation conducted in New Zealand found a similar result: 49% of cancer patients used complementary and alternative medicine (CAM), with vitamins, antioxidants, alternative diets, and herbal therapies the most commonly used agents and 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 herbs 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 the patients appetite, boosting the immune system, facilitating the recovery of the body, and prevention of tumour regeneration or metastases. It is effective for anti‐cancer (Ye 2002), inducing cell apoptosis in rectal cancer patients (Xin 2001), preventing cancer metastasis (Ohnishi 1998), and alleviation of symptoms is possible, such as bleeding, diarrhea, and pain (Lin 1996, Jin 2001). Improve median survival time, Karnovsky scoring and immune function (Ohnishi 1998, Zhou 1999, Liu 2000a, Li 2000). Herbal medicine therapy may be used before or after surgery, or combine with the patient regimens of chemotherapy or radiotherapy. For example, ShenMai Injection reduced TNF‐alpha mRNA obviously (P < 0.01) and increased liveability of scald mice markedly (P < 0.05) (Wang 2002), promoted the recovery of hemoglobin, and elevated activity of the natural killer (NK) cell and T lymphocyte ( CD4, CD4/CD8 ratio) (Wang 1999, Liu 2000b), composite Xiansu Capsule has immuno‐regulating effect on T‐cells (Hua 1999). Oren‐gedoku‐to (OGT) be considered may be useful for colon cancer chemoprevention in terms of efficacy and toxicity. Oren (Coptidis rhizoma) and Ogon (Scutellariae radix), OGT and Sanshishi inhibit azoxymethane (AOM)‐induced aberrant crypt foci (ACF) formation. The mechanism is that both OGT and Sanshishi inhibited cyclooxygenase‐2 (COX‐2) (Fukutake 2000).
The rule of using herbal medicine in the treatment of colorectal cancer is according to its syndromes, promoting blood circulation to remove toxic materials and blood stasis, and anti‐cancer. For example, for diarrhea and "ribbon" or pencil‐shaped stools, Semen Coicis (Yi Yi Ren) and Fruetus Sehisandrae (Wu Wei Zi) be added to the preparation, or in the case of those with rectal bleeding, Red sage root (dan shen) and Radix Paeoniae Rubra (Chi Shao) be added, Pericarpium Citri Reticulatae (Chen Pi) and Radix Vladimiriae (Guang Mu Xiang), etc. be used for abdomenal fullness, cramping and rectal pressure (Jin 2001).
RATIONALE FOR UNDERTAKING THIS REVIEW
The evidence for use of herbal medicine for chemotherapy side effects and improving quality of life is mainly theoretical and experiential, and the cancer patients often use multiple therapies not only during conventional treatment, but also without consultation with their oncologist (Chrystal 2002). Whilst it is plausible, existing evidence to support clinical benefit of herbal medicine for chemotherapy side effects and improving quality of life is limited and conflicting. 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 effect of herbal medicine for chemotherapy side effects and improving quality of life in colorectal cancer patients compared with placebo and other anti‐chemotherapy side effects drugs, and adverse events.
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
Anyone who has been diagnosed with colorectal cancer and those who are treated with chemotherapy. Diagnostic criteria such as the Winawer definition (Winawer 1997, Winawer 2003) be acceptable. The chemotherapy will be graded according to its emetogenic potential, e.g. oral TS inhibitors (capecitabline etc), IV 5FU +/‐ folinic acid, IV irinotecan, oxaliplatin, etc (alone or in combination).
Types of interventions
Known to be active against chemotherapy side effects e.g. Shen Mai Injection.
The comparators will be either no treatment, vehicle only, or another active anti‐ against nausea and vomiting drugs e.g. tropisetron, sulpiride, etc.
Types of outcome measures
PRIMARY OUTCOME
CTC >Grade 2 emesis.
SECONDARY OUTCOME
1. The proportion of people with nausea and/or vomiting, it will be documented as a dichotomous variable with a 'yes'/'no' response
2. White blood cell (WBC) count
3. Immunity with the activity of NK cells and T lymphocyte (CTL)
4. Quality of life
ADVERSE EVENTS
Any adverse events as a result of treatment that are (1) fatal, (2) life threatening, (3) toxic response.
Search methods for identification of studies
1. ELECTRONIC SEARCH:
This review will draw on the search strategy developed for the Cochrane Colorectal Cancer Group as a whole. Relevant trials will be identified from the Colorectal Group Specialised Register. We shall also search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1966) and EMBASE (from 1980).
a) Search Strategy for MEDLINE (OVID):
A. Search strategy to locate RCTs
search terms 1‐29, as given in the Cochrane Handbook (Clarke 2002), appendix 5c.2
B. Search strategy to locate colorectal cancer:
#30 colorectal neoplasm*
#31 colorect* neoplasm*
#32 colorect* cancer
#33 colorectal Canc*
#34 colorect* canc*
#35 colorect* carcinoma
#36 colorectal carcinom*
#37 colorect* carcinom*
#38 rect* neoplasms
#38 rectal neoplasm*
#39 rect* neoplasm*
#40 rectal cancer
#41 rect* cancer
#42 rectal canc*
#43 rect* canc*
#44 rect* carcinoma
#45 rectal carcinom*
#46 rect* carcinom*)
C. Search Strategy to locate quality of life:
#47 quality of life
#48 qualit* of life
#49 quality adjusted life years
#50 qualit* adjusted life years
#51 quality adjusted life year*
#52 qualit* adjusted life year*
#53 health status
#54 mental health
#55 well‐being
#56 quality adjusted survival
#57 qualit* adjusted survival
D. Search strategy to locate herbal medicine:
#58 herbal medicine
#59 herb* medic*
#60 medic* herb*
#61 Chinese herbal medicine
#62 Chinese herb* medic*
#63 Chinese medic* herb*
#64 herbal
#65 herb*
#66 complementary
#67 alternative medicine
#68 comp*
#69 alter* medic*
The above search are restricted by combining with 'and' and 'near': (#30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46) and (#47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57) near (#58 or #59 or #60 or #61 or #62 or #63 or #64 or #65 or #66 or #67 or #68 or #69)
b) A similar strategy will be used for EMBASE.
#1 colorectal
#2 neoplasms
#3 colorectal neoplasms
#4 colorect*
#5 neoplasms
#6colorect* neoplasms
#7 colorectal
#8 neoplasm*
#9 colorectal neoplasm*
#10 colorect*
#11 neoplasm*
#12 colorect* neoplasm*
#13 colorectal
#14 cancer
#15 colorectal cancer
#16 colorect*
#17 cancer
#18 colorect* cancer
#19 colorectal
#20 canc*
#21 colorectal canc*
#22 colorect*
#23 canc*
#24 colorect* canc*
#25 colorectal
#26 tumor
#27 colorectal tumour
#28 colorect*
#29 tumour
#30 colorect* tumour
#31 rectal
#32 neoplasms
#33 rectal neoplasms
#34 rect*
#35 neoplasms
#36 rect* neoplasms
#37 rectal
#38 neoplasm*
#39 rectal neoplasm*
#40 rect*
#41 neoplasm*
#42 rect* neoplasm*
#43 rectal
#44 cancer
#45 rectal cancer
#46 rect*
#47 cancer
#48 rect* cancer
#49 rectal
#50 canc*
#51 rectal canc*
#52 rect*
#53canc*
#54 rect* canc*
#55 rectal
#56 tumor
#57 rectal tumour
#58 rect*
#59 tumour
#60 rect* tumour
#61 quality
#62 of
#63 life
#64 quality of life
#65 qualit*
#66 of
#67 life
#68 qualit* of life
#69 quality
#70 adjusted
#71 life
#72 years
#73 quality adjusted life years
#74 qualit*
#75 adjusted
#76 life
#77 years
#78 qualit* adjusted life years
#79 quality
#80 adjusted
#81 life
#82 year*
#83 quality adjusted life year*
#84 health
#85 status
#86 health status
#87 mental
#88 health
#89 mental health
#90 wellbeing
#91 quality
#92 adjusted
#93 survival
#94 quality adjusted survival
(#3 or #6 or #9 or #12 or #15 or #18 or #21 or #24 or #27 or #30 or #33 or #36 or #39 or #42 or #45 or #48 or #51 or #54 or #57 or #60) and (#64 or #68 or #73 or #78 or #83 or #86 or #89 or #90 or #94)
The above EMBASE search is following restricted to study design as below (combine with 'AND'):
#1 explode 'clinical‐trial' / all subheadings
#2 explode 'controlled‐study' / all subheadings
#3 'randomization‐' / all subheadings
#4 'case‐control‐study' / all subheadings
#5 #2 NOT #4
#6 random* or clin*
#7 #1 OR #3 OR #5 OR #6
c) A search strategy in the Cochrane Library:
#1 COLONIC‐NEOPLASMS*:ME
#2 RECTAL‐NEOPLASMS*:ME
#3 (#1 or #2)
#4 ((((COLORECT* near CANCER) or NEOPLASM*) OR CARCINOM*) OR ADENOM*)
#5 ((((COLO* near CANCER) or NEOPLASM*) OR CARCINOM*) OR ADENOM*)
#6 ((((RECT* near CANCER) or NEOPLASM*) OR CARCINOM*) OR ADENOM*)
#7 ((#4 or #5) or #6)
#8 (#3 or #7)
#9 QUALITY‐OF‐LIFE*:ME
#10 (HEALTH and STATUS)
#11 (MENTAL and HEALTH)
#12 WELL‐BEING
#13 ((QUALITY and ADJUSTED) and SURVIVAL)
#14 (((QUALITY and ADJUSTED) and LIFE) and YEARS)
#15 (((((#9 or #10) or #11) or #12) or #13) or #14)
#16 (#8 and #15)
d) A search strategy in the Chinese Biomedical Base (CBM Base)
#1 colorectal cancer
#2 colon cancer
#3 rectal cancer
#4 bowel cancer
#5 Chinese traditional medicine
#6 Chinese herbal medicine
#7 herb* medicine
#8 medic* herbs
#9 medic* herb*
#10 traditional medicine
#11 (#1 or #2 or #3 or #4) and (#5 or #6 or #7 or #8 or #9 or #10)
e) We also intend to search for ongoing trials in:
-
National Research Register
-
Meta‐register of Controlled Trials
-
Medical Research Council Clinical Trials Directory.
2. HANDSEARCHS:
We will hand search the following Chinese Journals: Chinese Journal of Integrated Traditional and Western Medicine, Journal of Traditional Chinese Medicine, Modern Traditional Chinese Medicine, New Journal of Traditional Chinese Medicine, etc.
3. REFERENCES FROM PUBLISHED STUDIES
These will be checked for further trials.
4. UNPUBLISHED LITERATURE
Unpublished and on‐going trials will be identified by correspondence with authors, and by contacting pharmaceutical companies who produce relevant products.
5. CONFERENCE PROCEEDINGS
Major colorectal cancer conference proceedings and poster abstracts over the last 5 years will be handsearched for further RCTs.
6. ADVERSE EFFECTS
A search for side effects studies will be carried out and contact will be made with those who reported adverse reaction.
7. LANGUAGE RESTRICTIONS
There will be no language restrictions when searching for publications.
Data collection and analysis
STUDY SELECTION
Wu Taixiang (WT) will scan the results of the search strategy for potentially relevant trials, and retrieve the full articles for all potentially relevant trials. We will scrutinise each trial report for multiple publications from the same data set. WT and Liu Guanjian (LG) will independently assess each of these trials for inclusion in the review using an eligibility form based on the contents of the section 'Criteria for Inclusion'. We will resolve any disagreements through discussion or by a consulting the Co‐ordinating Editor of the Cochrane Colorectal Cancer Group (CCG). We will exclude studies that do not meet the inclusion criteria and state the reason in 'Characteristics of excluded studies'.
ASSESSMENT OF METHODOLOGICAL QUALITY
WT and LG will assess methodological quality of each trial in terms of generation of allocation sequence, allocation concealment, blinding, and loss to follow up. For each trial, we will class each quality components as 'adequate', 'inadequate', or 'unclear' according to Juni (Juni 2001). We will display this information in an additional table and describe it in the section 'Methodological quality of included studies'. After including all eligible studies in the primary analysis, we aim to conduct sensitivity analyses for each of the quality factors using the subgroups adequate, inadequate, or unclear.
DATA EXTRACTION
WT and LG will independently extract data using a piloted data extraction form. We will extract data on study characteristics including methods, participants, interventions, and outcomes. We will resolve any disagreements by referring to the trial report and through discussion, or by consulting CCG. If data from the trial reports are insufficient or missing, we will contact the authors for additional information.
Where possible we will extract data to allow an intention‐to‐treat analysis (the analysis should include all the participants in the groups to which they were originally randomly assigned). If the number randomised and the numbers analysed are inconsistent, we will calculate the percentage loss‐to‐follow‐up and report this information in an additional table. For binary outcomes, we will record the number of participants experiencing the event in each group of the trial. For continuous outcomes, for each group we will extract the arithmetic means and standard deviations. If the data are reported using geometric means we will extract standard deviations on the log scale. Medians and ranges will be extracted and reported in tables.
DATA ANALYSIS
We will analyse the data using Review Manager (Version 4.2). We will compare outcome measures for binary data using relative risks. For continuous data, we will use the weighted mean difference. If continuous data has been reported using geometric means, we will combine the findings on a log scale and report on the original scale. We will report medians and ranges in tables only. We will assess heterogeneity amongst trials by inspecting the forest plots and using the Chi‐square test for heterogeneity with a 10% level of statistical significance.
Where it is appropriate to pool data and heterogeneity is detected, we will use the random effect model. We do not intend to combine results of trials with different comparator drugs.
We intend to explore the following potential sources of heterogeneity using subgroup analyses or meta‐regression:
(1) intervention ‐ different preparations of herbal medicine compared to placebo or other current treatment regimen;
(2) dose (low, medium, high ‐ based on data).
Reasons for heterogeneity in studies will be explored and, if necessary, sensitivity analyses will examine the effects of excluding study subgroups, e.g. those studies with lower methodological quality.
Non‐randomised controlled studies will be listed but not discussed further. Studies relating to adverse effects will be described qualitatively.
