Clinical Trials

By Dr. Byeongsang Oh , Dr. Guorang Hu , Dr. Steven Kao , Dr. Val Gebski , Prof. Ronald Walls , Ms. Lili Truong , Prof. Philip Beale , Prof. Stephen Clarke
Corresponding Author Dr. Byeongsang Oh
Sydney Medical School, University of Sydney, - Australia
Submitting Author Dr. Byeongsang Oh
Other Authors Dr. Guorang Hu
Department of Immunology, Concord Hospital, - Australia

Dr. Steven Kao
Department of Medical Oncology, Sydney Cancer Centre, Concord Hospital, - Australia

Dr. Val Gebski
Statistical Methodology Group, NHMRC Clinical Trials Centre, University of Sydney, - Australia

Prof. Ronald Walls
Department of Immunology, Concord Hospital,, - Australia

Ms. Lili Truong
2Department of Medical Oncology, Sydney Cancer Centre, Concord Hospital, - Australia

Prof. Philip Beale
Medical Oncology Dept, Sydney Cancer Centre, Concord Hospital, - Australia

Prof. Stephen Clarke
Department of Medical Oncology, Royal North Shore Hospital, - Australia


Chinese Herbal Medicine, Cancer, Chemotherapy, Safety, Tolerability

Oh B, Hu G, Kao S, Gebski V, Walls R, Truong L, et al. The Safety and Tolerability of Chinese Herbal Medicine in Cancer Patients Receiving Chemotherapy: Pilot Study. WebmedCentral CHINESE MEDICINE 2011;2(3):WMC001671
doi: 10.9754/journal.wmc.2011.001671
Submitted on: 03 Mar 2011 05:38:51 AM GMT
Published on: 03 Mar 2011 06:51:30 PM GMT


Background: Use of Chinese herbal medicines (CHM) by cancer patients is growing although scientific evidence on their safety and efficacy is limited.
Method: A pilot study of CHM06, comprising 12 herbs, was conducted to assess the associated safety, tolerability and toxicity in cancer patients receiving chemotherapy. Patients with metastatic cancer who were about to receive a new line of chemotherapy started CHM06 a week prior to chemotherapy. Patients were assessed full blood counts and liver function were recorded at the commencement of CHM06, before each cycle, and at the end of cycle 3 chemotherapy for their toxicity, tolerability, and adverse events.
Results: Of the 16 participants, 11 completed all 3 cycles of treatment and used 80% of the prescribed CHM. In the patients that completed the study, there was no significant difference in white blood cell (WBC), haemoglobin (Hb) and platelet counts after the use of CHM06 alone prior to commencement of chemotherapy. Fourteen patients tolerated the CHM06 well while tolerance was poor in 2 patients.
Conclusion: This study suggests that CHM06 was well tolerated and accepted by patients undergoing chemotherapy. To further evaluate the safety and efficacy of CHM06 in conjunction with chemotherapy, randomised trials will be required.


Cancer patients commonly using complementary and alternative medicine (CAM) including Chinese herbal medicine (CHM). [1]  The use of CHM by cancer patients during chemotherapy is increasing. [2]  A recent Australian study [3] reported that approximately 40% of cancer patients are using CHM similar to the results of a recent United States (US) study. [4]  Not surprisingly, CHM use is much higher in China.  A recent population-based analysis of 1065 breast cancer patients in Shanghai reported that 98% of women had used at least one form of CAM after diagnosis, and CHM was used by 87% of patients. [5]
CHM has been widely practiced in China, Japan and Korea and has a history of over 4000 years. The CHM often use a combination of multiple herbs to increase the efficacy and reduce the toxicities of single herbs based on the traditional Chinese medical theory of synergistic interaction of multiple ingredients. [6]  Studies have suggested a positive role of CHM for treatment of symptoms of arthritis,[7] asthma, [8] allergies,[9, 10]   irritable bowel syndrome[11] and cancer pain. [12] However, others have reported possible adverse effects of CHM including nephropathy,[13] acute hepatitis, [14] cardiovascular [15]  and gastrointestinal problems.[16]   These issues highlight the need for further in-depth research into CHM and other herbal medicines.
In the US, there is increasing interest in conducting clinical trials with CHM in cancer patients.  This involves a wide range of interventions including the use of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting, shark cartilage in treating patients with advanced colorectal or breast cancer, and an evaluation of Scutellaria barbatae – a Chinese herbal extract, in treating women who have metastatic breast cancer .[17]  Latest systemic reviews and meta-analysis suggest that astragalus-based CHM may increase effectiveness of standard platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC) patients by improving patient survival, performance status and tumour response as well as reducing chemotherapy-related toxicity.[18]
Cancer patients want more information about CHM and want to be sure that the herbs will not diminish the efficacy of the chemotherapy.[19]  However, one study found that cancer patients often take CHM without telling the treating physician due to a fear of disapproval or the fact that the health professionals did not enquire about such use.[20]  There are reasonable grounds for  oncologists to be concerned about systemically administered CAM such as CHM, as it might interact with conventional anti-cancer drugs resulting in either excess toxicity or reduced efficacy.[21]
Despite this widespread use of CHM by cancer patients, oncologists’ concern of possible drug-herbal interaction and increasing interest in clinical trials, there is a current lack of high quality clinical data.  Therefore, an understanding of the safety, toxicity and side effects of CHM may assist patients and clinicians in advising patients about the use CHM in conjunction with cancer treatments.
In this pilot study, an investigation of an encapsulated Chinese herbal formulation – CHM06 – comprising 12 herbs was carried out to assess the safety and tolerability of these herbal capsules in patients with advanced cancer receiving chemotherapy.


Patients were recruited between March 2006 and March 2007 at the Sydney Cancer Centre, Concord Repatriation General Hospital. Patients were screened for eligibility to enter the trial, and were treated and assessed by one of 2 medical oncologists. Inclusion criteria were: patients with metastatic cancer about to commence a new regimen of palliative chemotherapy; ages ≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; life expectancy ≥ 3 months; ability to swallow capsules; ability to comply with the study protocol; provision of written evidence of informed consent. Laboratory analyses required for study entry were: white blood cell (WBC) count ≥ 3x109/L, neutrophil count ≥ 1.5x109/L, platelet count ≥ 100x109/L, haemogloblin (Hb) ≥ 10g/dL; adequate renal, hepatic and cardiac function. It was required that plasma levels of creatinine and bilirubin be ≤ 1.5x upper limit normal (ULN). In addition, plasma concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) were required to be ≤ 2.5xULN. In the presence of hepatic metastases, ALT/AST/ALP were allowed to be up to 5x ULN.
Exclusion criteria were: any concurrent serious medical illness or post-surgical complication; major psychiatric illness; pregnant or lactating women; cerebral or leptomeningeal disease; current or impending bowel obstruction; surgery within 2 weeks prior to study treatment; concurrent radiotherapy; current use of Chinese herbal medicine, homeopathic or naturopathic medicine or use < 1 week prior to trial commencement.
Participants underwent initial screening 1 week prior to commencement of herbal capsules. Subsequently, they were assessed prior to each cycle of chemotherapy for 3 cycles and at the end of cycle 3. If patients withdrew from study, an early discontinuation assessment was made.
Pre-treatment evaluations included history, physical examination, assessment of performance status using ECOG scale, and routine blood tests including full blood count (FBC), and liver and kidney function tests. Evaluation pre-chemotherapy included: physician’s assessment, assessment of performance status, collection of daily symptom diary, and routine blood tests. At conclusion of the study, assessments included physician’s assessment, performance status, and routine blood tests. Herbal capsules were dispensed by an oncology pharmacist prior to each cycle of chemotherapy. Participant compliance was assessed by counting capsules in the trial medication container at each visit.
Ethics approval was obtained from the Human Research Ethics Committee of Concord Hospital. The clinical trial notification was filed with the Drug Safety and Evaluation Branch of the Therapeutic Goods Administration (TGA), Canberra, Australia.
Participants commenced taking three CHM06 capsules after meals three times daily one week prior to start of chemotherapy. Treatment continued until completion of three cycles of chemotherapy.
CHM06 capsules were manufactured in a Good Manufacturing Practice (GMP) licensed pharmaceutical company (Guangdong Yifang Pharmaceutical Co. Ltd, China) certified by the TGA, Australia. CHM06 contains 12 herbal extracts. The individual herbs are listed with the TGA in the Australian Approved Names for Therapeutic Substances (AAN List), acknowledged to be suitable for human consumption and are available over-the-counter in Australia. The exact herbal composition is as follows: Ren Sheng (Radix Panax ginseng 6 %), Huang Qi (Radix Astragalus membranaceus 12 %), Gou Qi Zi (Fructus Lycium barbarum 9%), Huang Qin (Radix Scutellaria baicalensis 9%), Dang Gui (Radix Angelica sinensis 9%), Bai Zhu (Rhizome Atractylodes macrocephala 9%), Di Huang (Radix Rehmannia glutinosa 9%), Yin Yang Huo (Herba Epimedium brevicornu 9%), Chi Shao (Radix Paeonia lactiflora 9%), Fu Ling (Poria cocos 9 %), Sheng Jiang (Rhizome Zingiber officinale 5 %), Gan Cao (Radix Glycyrrhiza uralensis 5%). Each capsule contains 460mg of dried herbal extracts, equivalent to 4.6g of dry herbs.
Statistical Analysis
As a single arm pilot study, a convenient sample size (n=16) was used to assess the safety and tolerability of the CHM06. Categorical variables were summarized as frequencies and percentages. Independent sample t-test was conducted to examine the safety of pre and post CHM06 treatment and compared CHM06 and CHM plus chemotherapy on full blood counts (WBC, Hb and platelets ) and liver function tests (ALT, AST and ALP). A two sided p value


Seventeen patients were recruited to this study, however only 16 patients were included in the current analysis as 1 patient decided to have chemotherapy at another institution prior to commencement of the study. Seven patients had newly diagnosed advanced cancer, 2 patients had been diagnosed more than 4 years ago and 7 patients had also received prior chemotherapy in the preceding 2 years. Participants’ median age was 60 years with a range from 40 to 79. There were equal numbers of male and female patients. Fifty four percent were Caucasians while 35% were Asians. A variety of tumour types were represented including 6 patients with colorectal cancer, 4 with NSCLC, 2 with stomach cancer, 2 with ovarian cancer, 1 with breast cancer and 1 with small cell lung cancer (SCLC). A variety of chemotherapy agents were used.
Of the 16 participants, 11 completed all 3 planned cycles of treatment. Five patients withdrew from the study prior to completion of the trial due to a number of reasons: death (n=2); abnormal liver function tests (n=1); non-compliance (n=1) and diarrhoea (n=1). Among the patients who completed the trial 20% of prescribed CHM capsules were unused.
Physician’s assessment
Of the 11 patients who completed 3 cycles of chemotherapy with herbal medicine, 1 patient had minimal toxicity from herbal medicine, while 10 patients were assessed as having no toxicity attributable to the herbal medicine (Table 1). Three patients had less than expected toxicity from chemotherapy while 8 patients had expected toxicity from chemotherapy.


This pilot study demonstrated that cancer patients with a variety of tumour histologies who were receiving palliative chemotherapy of varying types tolerated concomitant administration of CHM06.  The serial measures of the liver function tests (ALT, AST, ALP) suggested that CHM06 does not cause any hepatic damage in advanced cancer patients who are treated with standard chemotherapy, except in one patient who had biliary obstruction.  In contrast to this study, most literature reports possible toxicity of herbal medicine. [22, 23]  This is one of the reasons that most oncologists recommend to their cancer patients not to use biological CAM including herbal medicine at least during chemotherapy. Although this result showed that the liver function did not deteriorate in patients who took CHM06, a further pharmacokinetic study is needed to confirm the drug-herbal interaction.
The only toxicities that could be attributed to the herbal mixture were diarrhoea and abnormal liver function tests that each occurred in two patients and necessitated cessation of the herbs.  The liver function test abnormalities could in part have been attributed to biliary tract obstruction, however there was a temporal relationship between herb administration and exacerbation of liver function tests.  Otherwise the herbs were well tolerated.
There appeared to be relatively few serious adverse events including myelosuppresion, with only one patient with grade IV anaemia requiring transfusion.  This would suggest either the CHM06 works in reducing the side effects of chemotherapy, or more concerning, interact with chemotherapy in ways that reduce the efficacy of anti-cancer drugs by reducing the drug levels.  There is at least some evidence from pre-clinical studies that a range of Chinese herbal remedies may interact with hepatic drug metabolising enzymes which may then impact on tolerability and efficacy of chemotherapy.[21]  However, there have been few prospective clinical studies of Chinese herbal medicines in conjunction with chemotherapy. [6, 17] These issues need to be assessed in a prospective, placebo controlled study in which the pharmacokinetics of the cancer agents are evaluated.
The major limitation of this pilot study was its single arm study design. This study was designed to assess the feasibility of administration of CHM06 in cancer patients undergoing chemotherapy in terms of patient acceptance and the safety and tolerability of CHM06, prior to planning a phase II clinical trial. Therefore, the results of this study precludes the determination of the efficacy of CHM06 in patients receiving chemotherapy. However, through commencing CHM06 a week prior to the chemotherapy with follow up liver function tests, an assessment could be made regarding the possible adverse effects of CHM06, ensuring the safety of patients participating in this study.  Liver function tests and full blood counts after treatment with CHM06 and prior to the chemotherapy suggested that it is most unlikely CHM06 causes hepatic damage or adverse effects. Of sixteen patients, two experienced adverse effects (diarrohea and biliary obstruction) and ceased taking CHM06 before chemotherapy
Another limitation is that this study did not investigate the dosage of CHM06. This study followed conservative dose as recommended by the manufacturer, in order to avoid possible drug-herb interaction that might occur with high doses.  Future studies should consider examining higher dosages of CHM06 as the current dosage produced no major adverse effects.  Lastly, the follow up assessment in this study ware not continued beyond 10 weeks which limits our knowledge of the long term potential benefits and toxicities of CHM06 for cancer patients. Previous studies reported that long term use of some types of CHM may be associated with nephropathy, [13] hepatotoxicity [14] and hemostatic impairment.[24]  This means that a longer term follow up may be required to confirm the safety of CHM06.
Further, this study was not designed to investigate the interaction of CHM06 and anticancer drugs. A number of studies have reported the interaction of individual herb and anticancer drugs. For example, St. John’s wort induces cytochrome P450 mixed function oxidase as well as modulates P-glycoprotein in intestine and reduces plasma concentration of cyclosporine, tacrolimus, amitriptyline, digoxin and warfarine. Important interactions of various drugs with ginseng, ginko bioba, Kava and garlic also have been reported.[22]  However, there are limited studies with drug-multi herbal interaction.[6]  This suggests that future studies require comparisons of toxicity level and herbal–drug interaction between Chinese herbal medicine formula (combination of several herbs) and individual herbs.
In conclusion, CHM06 appears to be well tolerated and does not worsen the expected side effects of chemotherapy in the setting off metastatic cancer. This pilot study has shown that the study of CHM 06 is feasible and may be safe in cancer patients undergoing palliative chemotherapy.  This serves as the basis for designing a phase II randomised trial for the use of this combination herbal preparation concurrently with chemotherapy.


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Source(s) of Funding

This study was supported by the Area Health Services of NSW and Sydney Cancer Centre.

Competing Interests

No conflict of interest


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