The Safety and Tolerability of Chinese Herbal Medicine in Cancer Patients Receiving Chemotherapy: Pilot Study

Article ID: WMC001671 2046-1690

Corresponding Author: Dr. Byeongsang Oh, Clinical Senior Lecturer, Sydney Medical School, University of Sydney - Australia

Submitting Author: Dr. Byeongsang Oh, Clinical Senior Lecturer, Sydney Medical School, University of Sydney - Australia

Article ID: WMC001671 Article Type: Clinical Trials Submitted on:03-Mar-2011, 05:38:51 AM GMT Published on: 03-Mar-2011, 06:51:30 PM GMT Article URL: http://www.webmedcentral.com/article_view/1671 Subject Categories:CHINESE MEDICINE Keywords:Chinese Herbal Medicine, Cancer, Chemotherapy, Safety, Tolerability How to cite the article:Oh B , Hu G , Kao S , Gebski V , Walls R , Truong L , Beale P , Clarke S . The Safety and Tolerability of Chinese Herbal Medicine in Cancer Patients Receiving Chemotherapy: Pilot Study . WebmedCentral CHINESE MEDICINE 2011;2(3):WMC001671 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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The Safety and Tolerability of Chinese Herbal Medicine in Cancer Patients Receiving Chemotherapy: Pilot Study

Author(s): Oh B , Hu G , Kao S , Gebski V , Walls R , Truong L , Beale P , Clarke S

Abstract 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 Background: Use of Chinese herbal medicines (CHM) often use a combination of multiple herbs to increase by cancer patients is growing although scientific the efficacy and reduce the toxicities of single herbs evidence on their safety and efficacy is limited. based on the traditional Chinese medical theory of Method: A pilot study of CHM06, comprising 12 herbs, synergistic interaction of multiple ingredients. [6] was conducted to assess the associated safety, Studies have suggested a positive role of CHM for tolerability and toxicity in cancer patients receiving treatment of symptoms of arthritis,[7] asthma, [8] chemotherapy. Patients with metastatic cancer who allergies,[9, 10] irritable bowel syndrome[11] and were about to receive a new line of chemotherapy cancer pain. [12] However, others have reported started CHM06 a week prior to chemotherapy. possible adverse effects of CHM including Patients were assessed full blood counts and liver nephropathy,[13] acute hepatitis, [14] cardiovascular function were recorded at the commencement of [15] and gastrointestinal problems.[16] These issues CHM06, before each cycle, and at the end of cycle 3 highlight the need for further in-depth research into chemotherapy for their toxicity, tolerability, and CHM and other herbal medicines. adverse events. In the US, there is increasing interest in conducting Results: Of the 16 participants, 11 completed all 3 clinical trials with CHM in cancer patients. This cycles of treatment and used 80% of the prescribed involves a wide range of interventions including the CHM. In the patients that completed the study, there use of encapsulated ginger as a treatment for was no significant difference in white blood cell chemotherapy-induced nausea and vomiting, shark (WBC), haemoglobin (Hb) and platelet counts after the cartilage in treating patients with advanced colorectal use of CHM06 alone prior to commencement of or breast cancer, and an evaluation of Scutellaria chemotherapy. Fourteen patients tolerated the CHM06 barbatae – a Chinese herbal extract, in treating well while tolerance was poor in 2 patients. women who have metastatic breast cancer .[17] Conclusion: This study suggests that CHM06 was well Latest systemic reviews and meta-analysis suggest tolerated and accepted by patients undergoing that astragalus-based CHM may increase chemotherapy. To further evaluate the safety and effectiveness of standard platinum-based efficacy of CHM06 in conjunction with chemotherapy, chemotherapy for advanced non-small-cell lung randomised trials will be required. cancer (NSCLC) patients by improving patient survival, performance status and tumour response as well as reducing chemotherapy-related toxicity.[18] Introduction 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 Cancer patients commonly using complementary and found that cancer patients often take CHM without alternative medicine (CAM) including Chinese herbal telling the treating physician due to a fear of medicine (CHM). [1] The use of CHM by cancer disapproval or the fact that the health professionals did patients during chemotherapy is increasing. [2] A not enquire about such use.[20] There are reasonable recent Australian study [3] reported that approximately grounds for oncologists to be concerned about 40% of cancer patients are using CHM similar to the systemically administered CAM such as CHM, as it results of a recent United States (US) study. [4] Not might interact with conventional anti-cancer drugs surprisingly, CHM use is much higher in China. A resulting in either excess toxicity or reduced recent population-based analysis of 1065 breast efficacy.[21] cancer patients in Shanghai reported that 98% of Despite this widespread use of CHM by cancer

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

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CHM plus chemotherapy on full blood counts (WBC, with standard chemotherapy, except in one patient Hb and platelets ) and liver function tests (ALT, AST who had biliary obstruction. In contrast to this study, and ALP). A two sided p value most literature reports possible toxicity of herbal medicine. [22, 23] This is one of the reasons that Results most oncologists recommend to their cancer patients not to use biological CAM including herbal medicine at least during chemotherapy. Although this result Participants showed that the liver function did not deteriorate in Seventeen patients were recruited to this study, patients who took CHM06, a further pharmacokinetic however only 16 patients were included in the current study is needed to confirm the drug-herbal interaction. analysis as 1 patient decided to have chemotherapy at The only toxicities that could be attributed to the herbal another institution prior to commencement of the study. mixture were diarrhoea and abnormal liver function Seven patients had newly diagnosed advanced cancer, tests that each occurred in two patients and 2 patients had been diagnosed more than 4 years ago necessitated cessation of the herbs. The liver function and 7 patients had also received prior chemotherapy test abnormalities could in part have been attributed to in the preceding 2 years. Participants’ median age was biliary tract obstruction, however there was a temporal 60 years with a range from 40 to 79. There were equal relationship between herb administration and numbers of male and female patients. Fifty four exacerbation of liver function tests. Otherwise the percent were Caucasians while 35% were Asians. A herbs were well tolerated. variety of tumour types were represented including 6 There appeared to be relatively few serious adverse patients with colorectal cancer, 4 with NSCLC, 2 with events including myelosuppresion, with only one stomach cancer, 2 with ovarian cancer, 1 with breast patient with grade IV anaemia requiring transfusion. cancer and 1 with small cell lung cancer (SCLC). A This would suggest either the CHM06 works in variety of chemotherapy agents were used. reducing the side effects of chemotherapy, or more Compliance concerning, interact with chemotherapy in ways that Of the 16 participants, 11 completed all 3 planned reduce the efficacy of anti-cancer drugs by reducing cycles of treatment. Five patients withdrew from the the drug levels. There is at least some evidence from study prior to completion of the trial due to a number of pre-clinical studies that a range of Chinese herbal reasons: death (n=2); abnormal liver function tests remedies may interact with hepatic drug metabolising (n=1); non-compliance (n=1) and diarrhoea (n=1). enzymes which may then impact on tolerability and Among the patients who completed the trial 20% of efficacy of chemotherapy.[21] However, there have prescribed CHM capsules were unused. been few prospective clinical studies of Chinese Toxicity herbal medicines in conjunction with chemotherapy. [6, Physician’s assessment 17] These issues need to be assessed in a Of the 11 patients who completed 3 cycles of prospective, placebo controlled study in which the chemotherapy with herbal medicine, 1 patient had pharmacokinetics of the cancer agents are evaluated. minimal toxicity from herbal medicine, while 10 The major limitation of this pilot study was its single patients were assessed as having no toxicity arm study design. This study was designed to assess attributable to the herbal medicine (Table 1). Three the feasibility of administration of CHM06 in cancer patients had less than expected toxicity from patients undergoing chemotherapy in terms of patient chemotherapy while 8 patients had expected toxicity acceptance and the safety and tolerability of CHM06, from chemotherapy. 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. Discussion However, through commencing CHM06 a week prior to the chemotherapy with follow up liver function tests, an assessment could be made regarding the possible This pilot study demonstrated that cancer patients with adverse effects of CHM06, ensuring the safety of a variety of tumour histologies who were receiving patients participating in this study. Liver function tests palliative chemotherapy of varying types tolerated and full blood counts after treatment with CHM06 and concomitant administration of CHM06. The serial prior to the chemotherapy suggested that it is most measures of the liver function tests (ALT, AST, ALP) unlikely CHM06 causes hepatic damage or adverse suggested that CHM06 does not cause any hepatic effects. Of sixteen patients, two experienced adverse damage in advanced cancer patients who are treated effects (diarrohea and biliary obstruction) and ceased

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taking CHM06 before chemotherapy 3. Oh B, Butow P, Mullan B, et al. Patient-doctor Another limitation is that this study did not investigate communication: The use of complementary and the dosage of CHM06. This study followed alternative medicine by adult patients with cancer. conservative dose as recommended by the Journal of the Society for Integrative Oncology. manufacturer, in order to avoid possible drug-herb 2010;8(2):56-64. interaction that might occur with high doses. Future 4. Richardson MA, Sanders T, Palmer JL, et al. studies should consider examining higher dosages of Complementary/Alternative Medicine Use in a CHM06 as the current dosage produced no major Comprehensive Cancer Center and the Implications adverse effects. Lastly, the follow up assessment in for Oncology. Journal of Clinical Oncology. 2000 July this study ware not continued beyond 10 weeks which 1;18(13):2505-14. limits our knowledge of the long term potential benefits 5. Cui Y, Shu X-O, Gao Y, et al. Use of and toxicities of CHM06 for cancer patients. Previous complementary and alternative medicine by Chinese studies reported that long term use of some types of women with breast cancer. Breast Cancer Research CHM may be associated with nephropathy, [13] and Treatment. hepatotoxicity [14] and hemostatic impairment.[24] [10.1023/B:BREA.0000025422.26148.8d]. This means that a longer term follow up may be 2004;85(3):263-70. required to confirm the safety of CHM06. 6. Mok T, Yeo W, Johnson P, et al. A double-blind Further, this study was not designed to investigate the placebo-controlled randomized study of Chinese interaction of CHM06 and anticancer drugs. A number herbal medicine as complementary therapy for of studies have reported the interaction of individual reduction of chemotherapy-induced toxicity. Annals of herb and anticancer drugs. For example, St. John’s Oncology. 2007 April 1, 2007;18(4):768-74. wort induces cytochrome P450 mixed function oxidase 7. Soeken KL, Miller SA, Ernst E. Herbal medicines for as well as modulates P-glycoprotein in intestine and the treatment of rheumatoid arthritis: a systematic reduces plasma concentration of cyclosporine, review. Rheumatology. 2003 May 1, 2003;42(5):652-9. tacrolimus, amitriptyline, digoxin and warfarine. 8. Xiu-Min L. Traditional Chinese herbal remedies for Important interactions of various drugs with ginseng, asthma and food allergy. The Journal of allergy and ginko bioba, Kava and garlic also have been clinical immunology. 2007;120(1):25-31. reported.[22] However, there are limited studies with 9. Hu G, Walls RS, Bass D, et al. The Chinese herbal drug-multi herbal interaction.[6] This suggests that formulation Biminne in management of perennial future studies require comparisons of toxicity level and allergic rhinitis: a randomized, double-blind, herbal–drug interaction between Chinese herbal placebo-controlled, 12-week clinical trial. Annals of medicine formula (combination of several herbs) and Allergy, Asthma & Immunology. 2002;88(5):478-87. individual herbs. 10. Yang S-H, Yu C-L. Antiinflammatory effects of In conclusion, CHM06 appears to be well tolerated Bu-zhong-yi-qi-tang in patients with perennial allergic and does not worsen the expected side effects of rhinitis. Journal of Ethnopharmacology. chemotherapy in the setting off metastatic cancer. This 2008;115(1):104-9. pilot study has shown that the study of CHM 06 is 11. Bensoussan A, Talley NJ, Hing M, et al. Treatment feasible and may be safe in cancer patients of Irritable Bowel Syndrome With Chinese Herbal undergoing palliative chemotherapy. This serves as Medicine: A Randomized Controlled Trial. JAMA. 1998 the basis for designing a phase II randomised trial for November 11, 1998;280(18):1585-9. the use of this combination herbal preparation 12. Ling Xu, Li Xing Lao, Ge A, et al. Chinese Herbal concurrently with chemotherapy. Medicine for Cancer Pain. Integrative Cancer Therapies. 2007 September 1, 2007;6(3):208-34. References 13. Graham ML, Terry C, Volker MA, et al. Urothelial malignant disease and Chinese herbal nephropathy. Lancet. 2001;358(9292):1515-6. 1. Bielory L. Replacing myth and prejudice with 14. Seeff LB. Herbal Hepatotoxicity. Clinics in Liver scientific facts about complementary and alternative Disease. 2007;11(3):577-96. medicine. Annals of Allergy, Asthma & Immunology. 15. Buettner C, Yeh GY, Phillips RS, et al. Systematic 2002;88(3):249-50. Review of the Effects of Ginseng on Cardiovascular 2. Bhowmik S, Lu W, Rosenthal DS. Effects of Risk Factors. Ann Pharmacother. 2006 January 1, Chinese herbal medicine on cytochrome P450, a 2006;40(1):83-95. systematic review. J Clin Oncol (Meeting Abstracts). 16. Sharma RA, McLelland HR, Hill KA, et al. 2010 May 20, 2010;28(15_suppl):e13150-. Pharmacodynamic and Pharmacokinetic Study of Oral

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Curcuma Extract in Patients with Colorectal Cancer. Clinical Cancer Research. 2001 July 2001;7(7):1894-900. 17. Rugo H, Shtivelman E, Perez A, et al. Phase I trial and antitumor effects of BZL101 for patients with advanced breast cancer. Breast Cancer Research and Treatment. 2007;105(1):17-28. 18. McCulloch M, See C, Shu X, et al. Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials. J Clin Oncol. 2006;24(3):419 - 30. 19. Powell C, Dibble S, Dall'Era J, et al. Use of herbs in women diagnosed with ovarian tcancer. International Journal of Gynecological Cancer. 2002;12(2):214-7. 20. Roberts CS, Baker F, Hann D, et al. Patient-physician communication regarding use of complementary therapies during cancer treatment. Journal of Psychosocial Oncology. 2005;23(4):35-60. 21. Sparreboom A, Cox MC, Acharya MR, et al. Herbal Remedies in the United States: Potential Adverse Interactions With Anticancer Agents. J Clin Oncol. 2004 June 15, 2004;22(12):2489-503. 22. Dasgupta A. Drug–Herb and Drug–Food Interactions. In: Dasgupta A, editor. Handbook of Drug Monitoring Methods: Humana Press; 2008. p. 235-61. 23. Zhou S-F. Toxicology, Safety and Herb–drug Interactions in Cancer Therapy. In: Cho WCS, editor. Supportive Cancer Care with Chinese Medicine: Springer Netherlands; 2010. p. 293-340. 24. Page. RL, Lawrence. JD. Potentiation of warfarin by dong quai. Pharmacotherapy. 1999;19(7):870-6.

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Illustrations Illustration 1

Tables

Table 1 Physician’s overall assessment of toxicities for patients

Toxicity of chemotherapy Perception of toxicity of Tolerability of CHM CHM

Groups As Less than Worse None Minima SignificantWell Poor expectedexpected than l expected

*Completed intervention 8 3 0 10 1 11 0 (n=11)

**Not complete 1 2 2 2 0 3 3 2 intervention (n=5)

*summary of data

**Reasons for withdraw (2 deceased, 1 biliary obstruction, 1 not taken CHM06)

Of the 5 patients who did not complete the trial, two experienced significant toxicities that could possibly be attributed to CHM06. One stopped taking CHM06 after only 4 doses prior to commencing chemotherapy due to the development of diarrhoea while another developed grade III liver dysfunction while taking CHM06 prior to commencing chemotherapy due to biliary obstruction. Webmedcentral > Clinical Trials Page 7 of 14 Adverse event assessment

Out of the 38 assessable cycles in 16 patients, there were five grade III adverse events (Table 2). These included two grade III vomiting, constipation (n=1), dehydration (n=1) and abnormal liver function test (n=1). A Grade IV adverse event occurred in one patient with anaemia (n=1). WMC001671 Downloaded from http://www.webmedcentral.com on 23-Dec-2011, 06:45:15 AM

Table 2: Worst Adverse Events during treatment course per patient

Grade (Number of patients/%) n=16

Common Terminology Criteria For Adverse Events (CTCAE) Version 3.0 Toxicity 0 1 2 3 4

Anaemia 10 (63%) 1 (6%) 4 (25%) 0 1 (6%)

Haemato-lo Neutropaenia 12 (75%) 2 (13%) 2 (13%) 0 0 gical Thrombocytopaenia 15 (94%) 0 1 (6%) 0 0

Nausea 7 (44%) 4 (25%) 5 (31%) 0 0

Vomiting 9 (56%) 2 (13%) 3 (19%) 2 (13%) 0

Diarrhoea 10 (63%) 2 (13%) 4 (25%) 0 0

Mucositis 10 (63%) 5 (31%) 1 (6%) 0 0

Non-haema Fatigue 4 (25%) 6 (38%) 6 (38%) 0 0 to-logical Anorexia 5 (31%) 5 (31%) 6 (38%) 0 0

Constipation 10 (63%) 3 (19%) 2 (13%) 1 (6%) 0

Dehydration 14 (88%) 0 1 (6%) 1 (6%) 0

Abnormal LFT 15 (94%) 0 0 1 (6%) 0

Peripheral 13 (81%) 3 (19%) 0 0 0 Neuropathy Webmedcentral > Clinical Trials Page 8 of 14 Pain 7 (44%) 2 (13%) 7 (44%) 0 0

Non-neutropenic 12 (75%) 1 (6%) 3 (19%) 0 0 Infection

Skin/Nail 10 (63%) 3 (19%) 3 (19%) 0 0

Others 4 (25%) 6 (38%) 6 (38%) 0 0 WMC001671 Downloaded from http://www.webmedcentral.com on 23-Dec-2011, 06:45:15 AM

Full blood counts and liver function test

Out of the 11 patients who completed all 3 cycles of chemotherapy, the mean baseline WBC count was 7.1 (normal range 4.0 – 10.0 x109/L). There was no significant difference in the mean WBC with the use of CHM06 between the baseline and prior to chemotherapy but there was a significant reduction of WBC count after chemotherapy treatment.

The baseline mean Hb level was 133 (normal range 120-170 g/L). There was no significant difference in the mean Hb with the use of CHM06 between the baseline and prior to chemotherapy but there was a significant reduction in Hb level after the chemotherapy treatment.

The baseline mean platelets count was 269 (normal range 150-400x109/L). There was no significant difference in the mean platelets level with the use of CHM06 between the baseline and prior to chemotherapy, nor after the chemotherapy treatment (Table 3).

Table 3 Full blood count in patients who completed the study

WBCMean P Hb Mean P PlateletMean P difference value difference value difference value

Baseline 7.1 0.0 1.000 1330.0 1.000 269 0.0 1.000

Pre cycle 7.0 -0.1 0.851 1330.1 0.979 272 2.6 0.913 1

Pre cycle 5.5 -1.6 0.021 123-9.8 0.082 300 31.2 0.346 2 Webmedcentral > Clinical Trials Page 9 of 14 Pre cycle 5.4 -1.7 0.002 119-14.0 0.024 249 -19.9 0.573 3

Pre cycle 5.2 -1.9 0.006 112-20.3 0.003 249 -20.2 0.482 4

Overall LFTs improved after commencement of CHM06 before chemotherapy (Table 4). The LFT was improved further with chemotherapy and concurrent herbal medication. The mean ALT (normal range 5-55 U/L) decreased from 59.8 to 26.1 after three cycles of chemotherapy, while mean AST (normal range 5-55 U/L) decreased from 42.8 to 25.3. The cholestatic enzyme ALP (normal range 30-130 U/L) also decreased from 181.6 to 143.7. WMC001671 Downloaded from http://www.webmedcentral.com on 23-Dec-2011, 06:45:15 AM

Table 4 Liver function tests in patients who completed the study

ALTMean P ASTMean P ALP Mean P difference value difference value difference value

Baseline 59.8 0 1.000 42.8 0 1.000 181.60 1.000

Pre cycle 30.4 -29.5 0.000 30.6 -12.3 .030 177.6-4. 0.922 1

Pre cycle 32.4 -27.5 0.001 31.8 -11.0 .013 184.63.0 0.956 2

Pre cycle 28.3 -31.5 0.000 26.2 -16.6 .000 148.8-32.8 0.300 3

Pre cycle 26.1 -33.7 0.000 25.3 -17.5 .000 143.7-37.9 0.248 4

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Reviews Review 1

Review Title: CHM06 and Chemotherapy

Posted by Dr. Miguel Lopez-Lazaro on 07 Mar 2011 05:44:48 PM GMT

1 Is the subject of the article within the scope of the subject category? Yes 2 Are the interpretations / conclusions sound and justified by the data? Yes 3 Is this a new and original contribution? Yes 4 Does this paper exemplify an awareness of other research on the topic? Yes 5 Are structure and length satisfactory? Yes 6 Can you suggest brief additions or amendments or an introductory statement that will increase No the value of this paper for an international audience? 7 Can you suggest any reductions in the paper, or deletions of parts? Yes 8 Is the quality of the diction satisfactory? Yes 9 Are the illustrations and tables necessary and acceptable? Yes 10 Are the references adequate and are they all necessary? Yes 11 Are the keywords and abstract or summary informative? Yes

Rating: 8 Comment:

Despite limited scientific evidence, many cancer patients seek complementary and alternative medicine to palliate chemotherapy toxicity and/or to increase its activity. Additional studies are needed to evaluate the efficacy and safety of these therapies. In this work, the authors have evaluated the safety and tolerability of a Chinese herbal medicine containing 12 herbal extracts (CHM06) in cancer patients receiving chemotherapy.

I believe that the results are presented clearly and that the merits and limitations of the study are discussed properly. They also achieve their objective, which is the assessment of 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. They conclude that the study of CHM 06 in cancer patients undergoing palliative chemotherapy is feasible and may be safe, which could serve as the basis for designing a phase II randomised trial for the use of this combination herbal preparation concurrently with chemotherapy.

In my opinion, the main limitation of this study is that it does not provide data regarding the effects of CHM06 on chemotherapy efficacy. Although the authors mention that this was not the aim of their study, I believe that this information would be valuable before designing a phase II clinical trial. The authors observed that, of sixteen patients, two experienced adverse effects (diarrhea and biliary obstruction) and ceased taking CHM06 before chemotherapy. On the positive side, they observed that three patients had less than expected toxicity from chemotherapy. Because the positive effects of CHM06 on tolerability seem to be limited, it is important to evaluate if CHM06 has a positive or negative effect on chemotherapy efficacy. If the effect is positive (or at least not negative) CHM06 could be evaluated further in a phase II clinical trial. If the effect is negative, however, I do not think that a future phase II clinical trial would be a good idea. Perhaps the authors could evaluate and report if the survival of the patients receiving chemotherapy plus CHM06 (if or when available) is higher, similar or lower than the expected in patients with the same types of cancer receiving similar chemotherapy regimens. I believe that this information would be important to decide whether CHM06 deserves further study in Phase II clinical trials.

Competing interests: No

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Invited by the author to make a review on this article? : No Experience and credentials in the specific area of science: Cancer research, Pharmacognosy

Publications in the same or a related area of science: Yes How to cite: Lopez-Lazaro M.CHM06 and Chemotherapy[Review of the article 'The Safety and Tolerability of Chinese Herbal Medicine in Cancer Patients Receiving Chemotherapy: Pilot Study ' by ].WebmedCentral 1970;2(3):REVIEW_REF_NUM554

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