Annals of Oncology Advance Access originally published online on January 17, 2007
Annals of Oncology 2007 18(4):768-774; doi:10.1093/annonc/mdl465
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© 2007 European Society for Medical Oncology
quality of life and supportive care |
A double-blind placebo-controlled randomized study of Chinese herbal medicine as complementary therapy for reduction of chemotherapy-induced toxicity
1 Department of Clinical Oncology, Prince of Wales Hospital, Institute of Chinese Medicine, Hong Kong Cancer Institute, Chinese University of Hong Kong, Hong Kong Special Administrative Region (HKSAR), China
2 Department of Oncology, University of Birmingham, Birmingham, UK
3 School of Chinese Medicine, Baptist Hospital, Hong Kong Special Administrative Region (HKSAR), China
4 Centre for Clinical Trials, School of Public Health, Chinese University of Hong Kong, China
* Correspondence to: Dr T. S. K. Mok, Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, HKSAR, China. Tel: +852-2632-1032; Fax: +852-2632-5816; E-mail: tony{at}clo.cuhk.edu.hk
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Abstract |
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Background: Chinese herbal medicine (CHM) is a common complementary therapy used by patients with cancer for reduction of chemotherapy-induced toxic effects. This study applied the highest standard of clinical trial methodology to examine the role of CHM in reducing chemotherapy-induced toxicity, while maintaining a tailored approach to therapy.
Patients and methods: Patients with early-stage breast or colon cancer who required postoperative adjuvant chemotherapy were eligible for the study. Enrolled patients were randomly assigned to one of three Chinese herbalists who evaluated and prescribed a combination of single-item packaged herbal extract granules. Patients received either CHM or placebo packages with a corresponding serial number. The placebo package contained nontherapeutic herbs with an artificial smell and taste similar to a typical herbal tea. The primary end points were hematologic and non-hematologic toxicity according to the National Cancer Institute Common Toxicity Criteria Version 2.
Results: One hundred and twenty patients were accrued at the time of premature study termination. Patient characteristics of the two groups were similar. The incidence of grade 3/4 anemia, leukopenia, neutropenia, and thrombocytopenia for the CHM and placebo groups were 5.4%, 47.3%, 52.7%, and 1.8% and 1.8%, 32.2%, 44.7%, and 3.6%, respectively (P = 0.27, 0.37, 0.63, and 0.13, respectively). Incidence of grade 2 nausea was the only non-hematologic toxicity that was significantly reduced in the CHM group (14.6% versus 35.7%, P = 0.04).
Conclusions: Traditional CHM does not reduce the hematologic toxicity associated with chemotherapy. CHM, however, does have a significant impact on control of nausea.
Key words: alternative and complementary medicine, chemotherapy, Chinese herbal medicine, colonic neoplasms, emesis, toxicity
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendix. list of stocked...AcknowledgementsReferences |
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Complementary and alternative medicine (CAM) is used by an increasing number of cancer patients [1–4]. A study from the M.D. Anderson Cancer Center showed that 83.3% of outpatients had used at least one CAM approach and 62.6% had used herbs [5]. The reasons cited for using CAM included immunomodulation, survival prolongation, quality of life (QoL), and reduction of treatment-related toxic effects [3, 5]. Chinese herbal medicine (CHM) is a popular form of CAM in China [6, 7] and its popularity outside China is also undeniable [8].
The practice of CHM involves selecting a combination of herbal or botanical items for treatment of varying body conditions [9]. The belief that CHM may reduce cancer therapy-induced toxicity is prevalent in China and throughout Asia [7], but only limited scientific information is available. Two small comparative studies from Japan indicated CHM to be effective in reduction of chemotherapy-induced muscle pain and diarrhea [10, 11]. Both studies focused on a fixed combination of herbal extracts but failed to address the essence of CHM on the dynamic interaction between changing body conditions.
Conventional Western medicine is founded on a structured concept with fixed quantification, thus all scientific facts should be evidence based. CHM is fundamentally different. Randomized controlled study is the most rigorous methodology for clinical research and usually involves a standardized therapeutic agent for a homogenous population with clearly defined outcome variables. In contrast, CHM is a nonstandardized entity that can vary over time and between patients. The clinical trial methodology for CHM borrows from the pragmatic trial design rationale, but must be able to capture the essence of CHM and comply with the high ethical and scientific standards of traditional Western medicine. In this study, we aimed to examine the role of CHM as complementary therapy for patients receiving adjuvant chemotherapy. The basic principles of the study design, data management, monitoring, and analysis were conducted according to the Good Clinical Practice Guideline [12]. The study end points were also quantified according to standardized international scales. The intervention was, however, designed in accordance with a true CHM practice that provides variable combinations of herbs according to the condition of individual patients.
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patients and methods |
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The aim of this double-blind placebo-controlled randomized trial was to compare the efficacy of toxicity reduction of CHM with placebo in patients receiving adjuvant chemotherapy. The primary end points were hematologic and non-hematologic toxic effects. Secondary end points included QoL during therapy, treatment compliance, dose intensity, and tumor recurrence rate. The study was approved by the Clinical Research Ethics Committee of The Chinese University of Hong Kong, and written informed consent was obtained from all patients before trial entry. Patients who declined consent to the trial received adjuvant systemic chemotherapy according to standard practice.
entry and exclusion criteria
Consecutive postoperative patients with histologically confirmed breast or colon cancer requiring adjuvant chemotherapy were assessed for eligibility from March 2000 to February 2004. The inclusion criteria were age at least 18 years, Eastern Cooperative Oncology Group (ECOG) performance status of two or less, no prior chemotherapy, and normal hematological function with a total neutrophil count >1.5 x 109/l and platelets >100 x 109/l. The criteria for liver and renal function included total bilirubin less than or equal to twice the upper limits of normal (ULN), alanine transaminase less than or equal to three times ULN, and serum creatinine 
1.5 times ULN. Patients who required concurrent radiotherapy or were unable to comply with daily oral medication were excluded. Other exclusion criteria included evidence of distant metastasis, substantial concurrent medical illness, prior chemotherapy, and, for female patients, being pregnant or breast-feeding.
adjuvant chemotherapy
The standard adjuvant chemotherapy for patients with breast cancer was a combination of adriamycin (Ebewe Pharma, Unterach, Austria) 60 mg/m2 and cyclophosphamide (Baxter Healthcare, Eindhoven, The Netherlands) 600 mg/m2 (AC) given three-weekly for four cycles. All patients received intravenous granisetron 3 mg and dexamethasone 10 mg as prophylactic antiemetic therapy. Locoregional radiotherapy was deferred until completion of chemotherapy. Standard adjuvant chemotherapy for patients with colon cancer was a combination of 5-fluorouracil (Ebewe Pharma, Unterach, Austria) 425 mg/m2 and folinic acid (Mayne Pharma, Melbourne, Australia)20 mg/m2 (FUFA) given once daily on days 1–5 of a 28-days cycle for six cycles. Patients receiving FUFA did not routinely receive prophylactic antiemetic therapy, but if they experienced nausea or vomiting, prophylactic metoclopramide and dexamethasone was given as required. Patients in both groups were prescribed oral metoclopramide 10 mg every 4 h, as required.
Dose intensity was defined as the total dose of cytotoxic drugs administered during the four cycles of AC or six cycles of FUFA [13]. The time interval was defined as the interval in weeks from day 1 of the first cycle of chemotherapy to day 21 and day 28 of the last cycle of AC and FUFA, respectively. For patients who received fewer than the intended number of cycles of chemotherapy, the treatment duration was calculated on the basis of the projected interval.
treatment groups
Patients who were eligible for adjuvant chemotherapy were routinely screened. Consented patients were randomly assigned to one of three qualified Chinese herbalists. All the herbalists had completed university training and were licenced to practice CHM in China and Hong Kong. Their experience in CHM practice ranged from 15 to 18 years. Each herbalist practiced CHM according to his own training and experience and there was no direct contact or discussion between the herbalists.
For the purpose of this study, we setup a CHM clinic in our cancer center so that the patients' records could be available for the herbalists. The colocation within a cancer center is quite unusual for Hong Kong although the integrative approach is commonplace in Mainland China. On days 1 and 14 of each cycle of chemotherapy, the herbalist evaluated the patients according to the principles of CHM and documented the findings on a case report form. According to the patient's condition, the herbalist prescribed a combination of single-itemized herbs from the stock of commonly used herbs. The patients took the prescription form to a separate room staffed by a technician who randomized each patient to receive either the prescribed herbal combination or placebo packages with corresponding serial number and dispensed accordingly. A 14-day supply of the prescribed combination was dispensed at each clinic visit. Each patient was responsible to completing logbook for each day's consumption.
Two hundred and twenty-five types of the commonly used herbs were stocked in packaged form (Appendix). Each package contained 3–10 g of water-soluble herbal granules that were manufactured at a Good Manufacture Practice standard facility (E-Fong Ltd, Guangzhou, China). Individual herb was boiled in water according to the traditional method of herbal tea preparation. The liquid extract was dehydrated by the nebulization dehydration method, quantified in dry weight, and stored in air-free foil packages (Figure 1). Each package was labeled with a serial number. The prescription form comprised the stock list with both the name and serial number. Random samples of the herbal granule packages were submitted to the Laboratory Testing and Development Services at the Institute of Chinese Medicine, The Chinese University of Hong Kong, for heavy metals analyses, organochlorine pesticide determination, organophosphorus pesticide determination, and microbial evaluation. All packages were within the normal limits set by the local regulatory authority. The raw materials for the placebo included Chinese Puer tea (Camellia amellia sinensis var assamica), black bean paste (Semen Sojae Praeparatum), malt sugar (Fructus Hordei Germinatus), food color, and artificial flavor. It is difficult to define a pure placebo in CHM where all natural substances are potentially therapeutic. We have chosen these substances for their similarity in smell, taste, and appearance to a typical herbal tea. Camellia sinensis is known to have anticarcinogenic and chemopreventive effect [14, 15], while Semen Sojae Praeparatum and Fructus Herdei Germinatus are used in CHM for reduction of food stagnation in stomach. To improve the authenticity, seven varieties of flavors and colors were created. The placebo packages were randomly filled with one of the seven varieties of nontherapeutic granules and were labeled with a serial number matching the therapeutic packages. The placebo and therapeutic packages were stored in different cabinets and only the dispensing technician knew the contents of the packages.
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randomization
Patients were stratified according to the chemotherapy regimens. The statistician generated the randomization list by the stratified permuted block method and programmed the list in a designated computer inside the dispensing room. The dispensing technician and the data monitoring committee were the only people with access to the randomization list and the contents of each prescription.
end point evaluation
Clinical evaluation at enrollment included a full medical history, physical examination, and assessment for ECOG performance status. Laboratory investigation included complete blood count, serum electrolytes, serum creatinine, liver function test, hepatitis B serology, prothrombin time, International Normalized Ratio (INR), and urinalysis. All patients had full staging radiological work-up according to the institutional protocol before enrollment; only chest X-ray was repeated before randomization. The primary end point of the study was chemotherapy-induced toxicity graded according to the National Cancer Institute Common Toxicity Criteria Version 2 (CTC-V2). Complete blood count, renal, and liver function tests were repeated at baseline and on day 1 of each cycle of chemotherapy. The nadir blood count was done on day 10 of the chemotherapy cycle for patients with breast cancer and on day 15 of the chemotherapy cycle for patients with colon cancer. Subjective assessment of non-hematologic toxicity was carried out on day 1 of each chemotherapy cycle. QoL was measured by the European Organization for Research and Treatment of Cancer (EORTC) core questions on the Quality of Life Questionnaire version 2 (QLQ-C30) [16]. The validated official Chinese translation was adopted [17]. This self-administered questionnaire was completed by the patients at baseline, on day 1 of each cycle of chemotherapy, and at follow-up 4 months after treatment. Compliance with CHM was evaluated using the record on the patients' logbooks.
statistical design and analysis
Sample size was calculated on the basis that 
40% of patients would develop severe toxicity (CTC-V2 grade 3 or more) from adjuvant chemotherapy. Using the two-sided 5% level test to have 80% power of detecting a 20% decrease in a single toxicity 164 patients were required for the study. Considering that patients may experience one or more toxicity during chemotherapy, five common toxic effects were arbitrarily selected for the purpose of sample size estimation. To have 80% power of detecting a 20% difference in at least one of the five toxic effects, the sample size was calculated to be 234 after accounting for multiple comparisons.
Outcomes of toxicity, treatment compliance, and QoL were analyzed using Chi-square and Fisher's exact tests. All P values were two-tailed and the 
level of significance was set at 0.05. Logistic regression analysis was used to assess and control for potential prognostic factors. Data are presented according to an intention-to-treat principle, in which patients who withdrew from the trial were recorded as having worsened (if appropriate) for categorical items only.
interim analysis
A formal interim analysis was undertaken by the Data Safety Monitoring Committee on 18 February 2004 when data from 50% of the target accrual became available. The committee found the rate of accrual to be slower than expected. The main reasons for the slow accrual were patients' lack of interest in participating in a placebo-controlled study and their preference of receiving true CHM. At the interim analysis, there was no significant difference in severe toxicity (CTC-V2 grade 3 or above) between the two groups. Despite the small difference in less severe (CTC-V2 grade 2) non-hematological toxicity, the committee concluded that the study would be difficult to continue and recommended early termination.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendix. list of stocked...AcknowledgementsReferences |
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study population
One hundred and twenty patients with resected breast or colon cancer were enrolled in the study, and 60 patients were randomly assigned to each group (Figure 2). Eight patients refused to use the study herbal packages and one patient was diagnosed with metastatic disease after randomization. The characteristics of the 111 assessable patients are summarized in Table 1. Age, gender, education level, performance status, tumor type, and chemotherapy regimen were similar in the two groups. The number of patients with stage Ib breast cancer was higher in the group receiving CHM, but the difference was not statistically significant.
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adjuvant chemotherapy
Two hundred and ninety cycles of AC were given to the 84 patients with breast cancer (CHM group, 154 cycles; placebo arm, 136 cycles). Treatment compliance rates for the two groups were similar (Table 2). The mean dose intensity for adriamycin in the CHM and placebo groups were 31.0 mg/week [95% confidence interval (CI) 29.3–32.8 mg/week] and 30.7 mg/week (95% CI 29.8–31.5 mg/week), respectively (P = 0.71), and for cyclophosphamide was 311.2 mg/week (95% CI 294.0–328.4 mg/week) and 306.9 mg/week (95% CI 298.3–315.6 mg/week), respectively (P = 0.66). Twenty-seven patients with colon cancer received 138 cycles of FUFA. More treatment cycles were administered to patients in the placebo group (80 cycles) than to those in the CHM group (58 cycles) (P = 0.48). Mean dose intensity for FUFA for patients in the CHM group was 726.4 mg/week (95% CI 687.6–765.3 mg/week) and 34.3 mg/week (95% CI 32.5–36.1 mg/week), respectively, and for patients in the placebo group was 763.7 mg/week (95% CI 721.5–806.0 mg/week) and 36.3 mg/week (95% CI 33.6–39.1 mg/week), respectively (P = 0.21).
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efficacy of CHM for reducing chemotherapy-induced toxicity
Patients were prescribed individualized combination of herbal extract, and the mean number of packages consumed daily was 25.3 (standard deviation 9.8). Hematologic toxic effects experienced by patients in the CHM and placebo groups are listed in Table 3. Both groups were associated with a moderate incidence of severe (CTC-V2 grades 3 and 4) neutropenia (52.7% versus 44.7%, P = 0.63) and leukopenia (47.3% versus 32.2%, P = 0.37). Seven patients (CHM four, placebo three; P = 0.68) had febrile neutropenia requiring admission to hospital but all patients had an uneventful recovery. Severe anemia and thrombocytopenia were infrequent and the incidence in the two groups was similar.
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Common non-hematologic toxic effects are summarized in Table 4. Fewer patients in the CHM group experienced moderate (grade 2 or more) nausea than in the placebo group, and the difference was statistically significant (CHM 16.4% versus placebo 37.6%, P = 0.04). The incidence of moderate vomiting was also less frequent in the CHM group, but this was not statistically significant (CHM 34.6% versus placebo 51.7%, P = 0.22). Anorexia, however, was similar between the two groups (CHM 12.7% versus placebo 10.7%, P = 0.60). There were no significant differences in other non-hematologic toxic effects between the CHM and placebo groups.
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quality of life
The change in the score for each domain in the EORTC QLQ-C30 between each cycle of chemotherapy and baseline was compared and there was no significant difference between the CHM and placebo groups. Specifically, the changes in mean score for nausea from AC for cycles one to four from baseline in CHM versus placebo group were 19.9 versus 20.6 (P = 0.84); 21.1 versus 27.8 (P = 0.39); 22.9 versus 20.4 (P = 0.65); and 8.7 and 13.7 (P = 0.19). The magnitude of change of the nausea score was less for patients receiving FUFA than for those receiving AC. The change in scores for cycle one to six of FUFA from baseline was also not statistically significant.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendix. list of stocked...AcknowledgementsReferences |
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To the authors' knowledge, this is the first double-blind placebo-controlled randomized trial of the role of CHM in reducing chemotherapy-induced toxicity. CHM was not found to be efficacious for reducing hematologic toxicity associated with adjuvant chemotherapy for breast and colon cancer. The only non-hematologic toxicity that was reduced by CHM was nausea. These results refute the claim made by many patients and herbalists who use CHM as complementary therapy during chemotherapy. Similar to a study by Bensoussan et al. [18] who carried out a double-blind placebo-controlled randomized study of CHM for patients with irritable bowel syndrome, this study adhered to the traditional practice of Chinese medicine that individualized the therapy. Our objective of applying a rigorous clinical trial methodology to traditional practice of CHM, both in terms of individualization and variation over time, is achieved.
Our Chinese herbalists, with university qualification and clinical experience, were at the level that a patient would expect from a Chinese herbal practitioner in the community. One may argue that the lack of improvement in outcomes could merely be a reflection of the herbalists' ability to make a difference. The key feature of traditional Chinese herbal therapy, however, is the high degree of variability between patients, doctors, and the patient's condition at the consultation. The execution of the practice of CHM within this trial was a reasonable representation of the real-life situation.
We found a significant reduction of grade 2 nausea in the CHM group compared with the placebo group. The difference in this toxicity, however, was not reflected by the EORTC QoL questionnaire. The changes in scores from baseline for nausea were similar between the CHM and placebo groups. This may be explained by the sensitivity of the QoL questionnaire to capture subjective differences between grade 1 and grade 2 nausea. The overall incidence of patients experiencing any nausea (grades 1–3) was similar between the two groups (87.3% in the CHM group and 84.0% in the placebo group). The change in QoL score reflected only the mean experiences of patients who had nausea during treatment. The questionnaire was not designed to distinguish the difference in severity in each subgroup of patients. Other gastrointestinal toxicity such as grade 2 constipation was more common in the placebo group but the difference was not statistically significant.
The majority of our enrolled patients were female because of the diagnosis of breast cancer. We recognize the survival outcomes of breast and colon cancer to be different, so we have only compared the short-term toxicity related to adjuvant chemotherapy. We chose patients on adjuvant chemotherapy as our primary study objects in order to minimize any cancer-related symptom. Therefore, specific cancer type is not crucial to our study as long as the patient was clinically cancer-free after surgical resection and their general health was fit for chemotherapy.
Our patient population would have little incentive to participate in a placebo-controlled trial on CHM. Many patients have also assumed CHM to be effective and resort to it regularly, so found the placebo-controlled design to be unacceptable. We screened and offered consent to 322 patients but only 120 agreed to participate. Seventy-nine patients (39.2%) could not accept the placebo-controlled design, 45 patients (22.3%) had already been taking CHM before starting chemotherapy, and the rest either refused without a reason or were not interested. A multicenter study would have improved the accrual rate, but the cost of stocking 225 different types of herbal or natural product granules and placebo in multiple centers was prohibitive. Future study on CHM should consider these factors in their design.
The practice of CHM on the basis of the described methodology does not reduce the hematologic toxicity associated with chemotherapy. It does, however, have a significant impact on the control of nausea. The traditional individualized herbal therapy is better than the placebo herbs that are associated with some antinausea effect. Application of a double-blind placebo-controlled randomized study design of CHM is limited by cost and patient accrual.
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appendix. list of stocked herbs |
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TopAbstractintroductionpatients and methodsresultsdiscussionappendix. list of stocked...AcknowledgementsReferences |
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Radix Scrophulariae; Polyporus; Coix Lacrymajobi; Semen Plantaginis; Herba Lysimachiae; Spora Lygodii; Herba Artemisiae Scopariae; Fructus Kochiae; Herba Dianthi; Herba Plantaginis; Pericarpium Arecae; Rhizoma Smilacis Glabrae; processed Radix Aconiti; Rhizoma Zingiberis; Cinnamomun cassia; Herba Asari; Fructus Evodiae; Radix Aconiti Kusnezoffii; Citrus Reticulata; Fructus Auranti Immaturus; Citrus medica; Cyperus Rotundus; Wuyao; Fructus Toosendan; Caulis Perillae; Massa Medicata Fermentata; Fructus Hordei Germinatus; Fructus Crataegi; Semen Raphani; Herba seu Radix Cirsii Japonici; Herba Cephalanoploris; Radix Sanguisorbae; Sophora Japonica; Thuja orientalis; Herba Agrimoniae; Radizoma Bletillae; Pollen Typhae; Radix Notoginseng; Radix Sangyisorbae; Rhizoma Chuanxiong; Olibanum; Myrrha; Rhizoma Corydelis; Radix Curcumae; Rhizoma Curcumae; Rhizoma Sparganii; Radix Salviae Miltiorrhizae; Herba Leonuri; Semen Persicae; Flos CArthami; Faeces Trogopterori; Achyranthes Bidentata Blume; Cyathula Officinalis Kuan; Squama Manitia; Lignum Dalbergiae Odoriferae; Fructus Liquidambaris; processed Rhizoma Pinelliae; Rhizoma Pinelliae; Rhizoma Arisaematis; Rhizoma Typhonii; Radix Aconiti Coreani; Radix Platycodi; Flos Inulae; Bulbus Fritillariae Thunbergii; Rhizoma Cynanchi Stauntonii; Fructus Trichosanthis; Bulbus Fritillariae Cirrhosae; Caulis Bambusae in Taeniam; Bitter Apricot Kernel; Sargassum Fusiforme; Radix Stemonae; Radix Stemonae; Loquat leaf; Radix Scutellariae; Sangbaipi; Semen Lepidii; Stir-baked Flos Farfarae; Radix Peucedani; Ferrosoferric Oxide; Os Draconis Fossilia; Semen Ziziphi Spinosae; Semen Biotae; Radix Polygalae; Cortex Albiziae; Radix Codonopsis; Radix Pseudostellariae; Radix Astragali; Rhizoma Atractylodis Macrocephalae; Rhizoma Dioscoreae; Glycyrrhiza Uralensis; Radix Panacis Quinquefolii; Ziziphus Jujuba; Radix Morindae Officinalis; Herba Cistanches; Rhizoma Curculiginis; Herba Epimedii; Cortex Eucommiae; Radix Dipsaci; Rhizoma Cibotii; Rhizoma Drynariae; Fructus Psoraleae; Frucyus Alpiniae Oxyphyllae; Cuscuia Japonica; Herba Cynomorii; Radix Angelicae Sinensis; Rehmannia glutinosa; Radix Polygoni Multiflori; Radix Paeoniae Alba; Radix Ophiopogonis; Herba Dendrobii; Bulbus lilii; Fructus Lycii; Herba Ecliptae; Ligustrum Lucidum; Radix Glehniae; Rhizoma Atractylodis Macrocephalae; Fructus Schisandrae; Fructus Tritici Levis; Radix Oryzae Glutinosae; Radix Ephedrae; Fructus Corni; Fructus Rosae Laevigatae; Fructus Rubi; Concha Arcae; Folium Ginseng; Radix Adenophorae.
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We would like to thank all of the research nurses and assistants of the Department of Clinical Oncology, The Chinese University of Hong Kong, for supporting this study. This study was supported by a research grant from the Hong Kong Research Grant Council (Grant number CUHK 4109/00M). This study was presented (poster) at the 27th European Society of Medical Oncology Annual Meeting, Nice, France, 18–22 October 2002.
Received for publication August 20, 2006. Revision received November 14, 2006. Accepted for publication November 14, 2006.
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